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THIRD EDITION
Manual of
Hypertension
of the European Society of Hypertension
THIRD EDITION
Manual of
Hypertension
of the European Society of Hypertension
EDITED BY
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Contents
Editors xi
Contributors xiii
Introduction xxiii
5. Socioeconomic Determinants 31
Theodora Psaltopoulou and Theodoros N. Sergentanis
Index 629
Editors
Empar Lurbe
Stefano Masi
Pediatric Department
Department of Clinical and Experimental
Consorcio Hospital General
Medicine
University of Valencia
University of Pisa
Valencia, Spain
Pisa, Italy
and
CIBER Fisiopatología Obesidad y Nutrición
Instituto de Salud Carlos III Richard McManus
Madrid, Spain Nuffield Department of Primary Care Health Sciences
University of Oxford
Thomas F. Luscher Oxford, United Kingdom
Royal Brompton and Harefield Hospital Trust and Imperial
College Franz H. Messerli
London, United Kingdom University of Bern
Bern, Switzerland
Anne-Marie Madjalian
and
Hypertension Unit
Mount Sinai Icahn School of Medicine
Hôpital Européen Georges Pompidou and Paris – Descartes
New York, New York
University
and
Paris, France
Jagiellonian University
Felix Mahfoud Krakow, Poland
Internal Medicine III Clinic
Cardiology, Angiology and Internal Intensive Care Medicine Augusto C. Montezano
Saarland University Hospital Institute of Cardiovascular and Medical Sciences
Homburg, Germany BHF Glasgow Cardiovascular Research Centre
University of Glasgow
Giuseppe Mancia Glasgow, Scotland, United Kingdom
University of Milano-Bicocca
Milan and Policlinico di Monza
Monza, Italy Alberto Morganti
Centro Fisiologia e Ipertensione
Efstathios Manios Ospedale Policlinico
National and Kapodistrian University of Athens University of Milan
Medical School Milan, Italy
Department of Clinical Therapeutics
Alexandra Hospital Maria Lorenza Muiesan
Athens, Greece Department of Clinical and Experimental Sciences
University of Brescia
A.J. Manolis
Brescia, Italy
Cardiology Department
Asklepieion General Hospital
Voula, Hellas M. Mulvany
Department of Pharmacology
Julian E. Mariampillai University of Aarhus
Department of Cardiology Aarhus, Denmark
Oslo University Hospital
Oslo, Norway
Krzysztof Narkiewicz
Fernando Martinez Department of Hypertension and Diabetology
Hypertension Clinic, Internal Medicine Medical University of Gdansk
Hospital Clinico and INCLIVA Research Institute Gdansk, Poland
University of Valencia
Valencia, Spain Peter M. Nilsson
and Department of Clinical Sciences
CIBERObn Health Institute Carlos III Lund University
University of Valencia Skåne University Hospital
Madrid, Spain Malmö, Sweden
xviii Contributors
Athanase D. Protogerou
Sandosh Padmanabhan Cardiovascular Prevention and Research Unit
Institute of Cardiovascular and Medical Clinic and Laboratory of Pathophysiology
Sciences Department of Medicine
Glasgow, Scotland, United Kingdom National and Kapodistrian University of Athens
Athens, Greece
Anna Paini
Department of Medicine Theodora Psaltopoulou
ASST Spedali Civili
Medical School
University Hospital
National and Kapodistrian University of Athens
Brescia, Italy
Athens, Greece
Paolo Palatini
Karl Heinz Rahn
Department of Medicine
Department of Medicine D
University of Padova
University of Muenster
Padua, Italy
Muenster, Germany
Vassilios Papademetriou
Interventional Hypertension and Vascular Medicine Gianpaolo Reboldi
Program Department of Medicine
VA Medical Center University of Perugia
Georgetown University Perugia, Italy
Washington, DC
Josep Redon
Gianfranco Parati Hypertension Clinic, Internal Medicine
Istituto Auxologico Italiano Hospital Clinico and INCLIVA Research Institute
Department of Cardiovascular Neural and Metabolic University of Valencia
Sciences Valencia, Spain
and and
Department of Medicine and Surgery CIBERObn Health Institute Carlos III
University of Milano-Bicocca University of Valencia
Milan, Italy Madrid, Spain
We are delighted to present to doctors and students of the beneficial effects of antihypertensive treatment in vir-
hypertension and related cardiovascular diseases the third tually all hypertension phenotypes well ahead of a simi-
edition of the Manual of Hypertension of the European Society lar achievement in diabetes or dyslipidemias. Yet, several
of Hypertension. As in the previous editions, the epidemi- important problems remain unresolved, above all the fact
ological, pathophysiological, diagnostic and treatment that, despite the availability of a large number of effective
aspects of hypertension are addressed in detail by recog- antihypertensive drugs and drug combinations, blood
nized experts in this important area of medicine. This pressure control by treatment remains disappointingly
edition of the Manual, however, also includes chapters on low, which keeps hypertension still the most important
the emerging aspects of hypertension which are of great cause of mortality worldwide. This depends on the barri-
current interest, either because of the mechanistic, diag- ers to effectiveness of treatment that characterize clinical
nostic and treatment openings provided by basic and clini- practice, such as low adherence to the prescribed treatment
cal research, or because results are somewhat inconsistent regimen and therapeutic inertia. As the readers will see,
or even controversial, leading to differences in opinion this is the object of great attention in the Manual, which
within the medical community. devotes much more space than in the past to the problems
The recent hypertension guidelines of the European posed by real-life hypertension management as well as by
Society of Cardiology and the European Society of the optimization of the follow-up of treated hypertensive
Hypertension are also included to provide the reader less individuals.
interested in research details and more in the daily manage- We express our deep gratitude to the authors of the
ment of the high blood pressure condition with informa- chapters for the time and effort they have devoted to this
tion on how to deal with hypertension in clinical practice. book, as well as for the scientific excellence of their contri-
Hypertension represents a success story for modern butions. We are sure that this will make the Manual useful
medicine. Although the causes of the blood pressure and pleasant reading.
elevation remain in most individual patients almost as
obscure in the third millennium as they were a century Giuseppe Mancia
ago, mechanistic research has allowed us to discover most Guido Grassi
of the systems involved in cardiovascular control known Konstantinos P. Tsioufis
today, while clinical hypertension research has pioneered Anna F. Dominiczak
the era of randomized outcome-based trials, documenting Enrico Agabiti Rosei
Section I
Background and Epidemiology
HISTORY OF THE EUROPEAN
SOCIETY OF HYPERTENSION: 1
PAST, PRESENT AND FUTURE
Table 1.2 Working Groups of the ESH The ESH Hypertension Specialist Programme was started in
2000 aimed towards hypertension specialists in Europe, to
On blood pressure in children and adolescents further enhance their expertise and eventually to improve
hypertension management in European countries. The
On blood pressure monitoring and cardiovascular variability
ESH specialists should be members of the ESH, having
On Endocrine hypertension clinical experience in difficult hypertension, documented
recognized scientific activity and continuous interest in
On endothelins and endothelial factors hypertension. More than 1000 ESH Specialists have been
approved following nominations by national societies.
On hypertension and the brain
Republic of China and Venezuela). These centres contribute has always been the careful collection and evaluation of
to the continuous effort of the ESH to stimulate scientific data as well as the extensive review process. The latest
exchange in hypertension, and support and build organiza- joint European Hypertension Guidelines were presented
tions committed to enhance hypertension control worldwide. at the annual ESH meeting in Barcelona, June 2018, with
Collaboration attempts among excellence centres have been simultaneous publication in the two official journals of
possible by sharing protocols in clinical work and research, ESH and ESC, Journal of Hypertension and European Heart
by organizing specific sessions during the annual meetings Journal, respectively (6).
and by centre participation in multicentre studies.
SCIENTIFIC DOCUMENTS
AFFILIATED SOCIETIES
The ESH has published a series of acclaimed guidelines,
The close relationship of the ESH with national societies of position statements and consensus documents covering all
hypertension has been a main priority. Therefore, the ESH subjects in hypertension management: blood pressure mea-
has developed an affiliation and association programme to surement, hypertension in children and adolescents (7) and
provide a formal link with national societies from European hypertension management in specific patient groups such
countries. The relationship between ESH and the national as sleep apnea and dialysis patients, to name a few (8–11).
hypertension societies has been growing stronger over The ESH issues a scientific newsletters at a regular basis:
the years, and members of the ESH-affiliated societies are Update on Hypertension Management has the latest news and
encouraged to participate in ESH activities. In close coop- research in many clinical topics. Sixty-three newsletters
eration with them, the ESH has been expanding in activi- have been published between 2000 and 2016. Over the
ties including organization or endorsement of meetings years, the ESH newsletters have been distributed as single-
and educational activities such as summer schools and page documents at the ESH annual meetings and are avail-
advanced courses. There are 35 ESH-affiliated societies in able in PDF format on the ESH website.
Europe, and there are also five associated hypertension soci-
eties and organizations from non-European countries that
have established professional relationships with the ESH. JOURNALS
Two scientific journals are endorsed by the ESH. The Journal
of Hypertension, the official journal of the ISH and the ESH,
ESH RESEARCH PROJECTS is published monthly and spans over 200 pages. With a team
of international associate editors, the journal publishes peer-
The Society has always focused on promoting research in reviewed, original basic and clinical research with an about
the field of hypertension. As of now, a number of research one-to-three ratio, as well as review articles, guidelines,
programmes have been initiated and there is a call for col- intriguing commentaries and meeting abstracts. With an
laboration to all centres. Current ESH research activities impact factor of 4.085 (2016) and ranking 12th out of 63
include the atrial fibrillation survey, the fibromuscular dys- peripheral vascular disease journals, it is a leading journal
plasia registry, the multicentre study on the management in hypertension with submissions from research centres all
of acute hypertensive events, the MASked-unconTrolled over the world. Blood Pressure is a journal dedicated to clini-
hypERtension Management Based on Office BP or on Out- cal hypertension research, with an editorial board that also
of-office (Ambulatory) BP Measurement (MASTER) study features leading experts from Europe and the United States.
and the BP control study across Europe. This journal was introduced in 1992 and has gained increas-
ing popularity, reaching an impact factor of 2.163 in 2016.
PUBLICATIONS
BOOKS
2. European Society of Hypertension–European Society of Practice guidelines of the European Society of Hypertension
Cardiology Guidelines Committee. 2003 European Society of for clinic, ambulatory and self blood pressure measurement.
Hypertension–European Society of Cardiology guidelines for J Hypertens 2005; 23(4): 697–701.
the management of arterial hypertension. J Hypertens 2003; 21: 9. Lurbe E, Cifkova R, Cruickshank JK et al. European Society of
1011–1153. Hypertension. management of high blood pressure in children
3. Mancia G, De Backer G, Dominiczak A et al. ESH-ESC Task Force and adolescents: Recommendations of the European Society of
on the Management of Arterial Hypertension. 2007 ESH-ESC Hypertension. J Hypertens 2009; 27(9): 1719–1742.
practice guidelines for the management of arterial hyperten- 10. Parati G, Lombardi C, Hedner J et al. European respiratory
sion: ESH-ESC Task Force on the Management of Arterial society; EU COST ACTION B26 members. Position paper on
Hypertension. J Hypertens 2007; 25: 1751–1762. the management of patients with obstructive sleep apnea and
4. Mancia G, Laurent S, Agabiti-Rosei E et al. European Society of hypertension: Joint recommendations by the European Society
Hypertension. Reappraisal of European guidelines on hyperten- of Hypertension, by the European Respiratory Society and by
sion management: A European Society of Hypertension Task the members of European COST (COoperation in scientific and
Force document. J Hypertens 2009; 27(11): 2121–2158. technological research) ACTION B26 on obstructive sleep apnea.
5. Mancia G, Fagard R, Narkiewicz K et al. Task force members. 2013 J Hypertens 2012; 30(4): 633–646.
ESH/ESC guidelines for the management of arterial hypertension: 11. Sarafidis PA, Persu A, Agarwal R et al. Hypertension in dialysis
The task force for the management of arterial hypertension of the patients: A consensus document by the European renal and
European Society of Hypertension (ESH) and of the European cardiovascular medicine (EURECA-m) working group of the
Society of Cardiology (ESC). J Hypertens 2013; 31(7): 1281–1357. European Renal Association - European Dialysis and Transplant
6. Williams B, Mancia G, Spiering W et al. Task Force Members. Association (ERA-EDTA) and the hypertension and the kidney
2018 ESC/ESH Guidelines for the management of arterial hyper- working group of the European Society of Hypertension (ESH).
tension. J Hypertension 2018, 36; 1953–2041. J Hypertens 2017; 35(4): 657–676.
7. Lurbe E, Agabiti Rosei E, Cruickshank et al. Task Force 12. Agabiti Rosei E, Mancia G. Assessment of Preclinical Organ Damage
members. European Society of Hypertension g uidelines in Hypertension. Springer International Publishing, Switzerland;
of high blood pressure in children and adolescents. 2015.
J Hypertension 2016; 34: 1887–1920. 13. Tsioufis C, Schmieder R, Mancia G. Interventional Therapies for
8. O’Brien E, Asmar R, Beilin L et al. European Society of Secondary and Essential Hypertension. Springer, Switzerland; 2016.
Hypertensionworking group on blood pressure monitoring. 14. Coca A. Hypertension and Brain Damage. Springer,Switzerland; 2016.
HYPERTENSION AS A
CARDIOVASCULAR RISK FACTOR 2
Stroke mortality
16 16
8 8
4 4
2 2
1 1
Figure 2.1 Stroke mortality rate in each decade of age plotted for the usual systolic (a) and diastolic (b) blood pressure at
the start of that decade. Data from 1 million adults in 61 prospective studies. (Adapted from Lewington S et al. Lancet 2002;
360(10): 1903–1913.)
The latest US hypertension guidelines (16) recommend subjects whose potential lifespan, despite intervention, is
use of the ACC/AHA Pooled Cohort Equation (http://tools. relatively limited, while young subjects at high relative risk
acc.org/ASCVD-Risk-Estimator/) to estimate the 10-year remain untreated despite, in the absence of intervention,
risk of atherosclerotic CVD (ASCVD) to establish the BP a predicted significant shortening of their otherwise much
threshold for treatment (35). longer potential lifespan (37,38).
Given the need for a European model based on a large Use of the SCORE chart for estimating total CV risk in
database, the SCORE (Systemic Coronary Risk Evaluation) hypertension should be considered a minimal require-
project (36) was used to develop SCORE charts for high- ment taking into account the fact that total CV risk can be
and low-risk countries in Europe estimating the risk of underestimated (39).
dying from CV (not just coronary) disease over 10 years, On the basis of these considerations, the 2013 ESH-ESC
and allowing calibration of the charts for individual guidelines (15) suggest total CV risk be stratified as shown
countries provided that national mortality statistics and in Table 2.1. The terms low (<1%), moderate (≥1 and <5%),
estimates of the prevalence of major CV risk factors are high (≥5 and <10%) and very high (≥10%) risk refer to the
available. The SCORE model has also been used in the 10-year risk of CV mortality as defined by the 2012 ESC
HeartScore, the official European Society of Cardiology prevention guidelines (40). The factors on which this strat-
management tool for implementation of CVD prevention ification is based are listed in Table 2.2. They include risk
in clinical practice (http://www.escardio.org). factors, asymptomatic organ damage, diabetes mellitus
The main disadvantage associated with an interven- and established CV or renal disease.
tion threshold based on relatively short-term absolute risk
is that younger adults (particularly women), while hav-
ing more than one risk factor, are unlikely to reach treat-
ment thresholds despite being at high risk relative to their SEARCHING FOR SUBCLINICAL
peers. By contrast, most elderly men (e.g., those aged 65) (ASYMPTOMATIC) ORGAN DAMAGE
will often reach treatment thresholds whilst being at very
little increased risk relative to their peers. This situation Given the importance of subclinical organ damage as an
results in most resources being concentrated on the oldest intermediate stage in the continuum of vascular disease
Hypertension as a Cardiovascular Risk Factor 9
IHD mortality
16 16
40–49
years 40–49
8 8 years
4 4
2 2
1 1
Figure 2.2 Ischaemic heart disease (IHD) mortality rate in each decade of age plotted for the usual systolic (a) and dia-
stolic (b) blood pressure at the start of that decade. Data from one million adults in 61 prospective studies. (Adapted from
Lewington S et al. Lancet 2002; 360(10): 1903–1913.)
and as a determinant of overall CV risk, signs of organ hypertrophy (LVH), and carotid plaques, predicts
involvement in hypertensive individuals should be sought CV mortality independently of SCORE stratification
for carefully, using appropriate techniques. (41–43). This is an argument favouring routine use of
The presence of any of the four following markers, organ damage assessment, particularly in specialized
that is, increased urinary albumin excretion (UAE), centres or clinics. The risk increases with the number of
increased pulse wave velocity (PW V), left ventricular damaged organs (41).
Moderate to
1–2 RF Low risk Moderate risk High risk
high risk
Low to Moderate to
≥3 RF High risk High risk
moderate risk high risk
Moderate to High to
OD, CKD stage 3 or diabetes High risk High risk
high risk very high risk
Symptomatic CVD, CKD stage ≥4 or
Very high risk Very high risk Very high risk Very high risk
diabetes with OD/RFs
BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovscular disease; DBP = diastolic blood pressure;
HT = hypertension; OD = organ damage; RF = risk factor; SBP = systolic blood pressure.
10 Manual of Hypertension of the European Society of Hypertension
A1 A2 A3
Prognosis of CKD by GFR
Normal to
and albuminuria categories: Moderately Severely
mildly
KDIGO 2012 increased
increased increased
Midly to moderately
G3a 45–59
decreased
Moderately to
G3b 30–44
severely decreased
Green: low risk (if no other markers of kidney disease, no CKD); yellow: moderately increased risk; orange: high risk;
red, very high risk.
increase in urinary albumin or protein excretion reflects is associated with cognitive, psychiatric and physical disabil-
derangement in the glomerular filtration barrier. UAE has ities contributing to the risk of stroke, cognitive dysfunction
been shown to predict the development of overt diabetic and dementia (126–128). The following signs of VBI can be
nephropathy in both type 1 and 2 diabetics (109), while recognized on brain imaging: white matter hyperintensity,
the presence of overt proteinuria generally indicates the cerebral microbleeds, recent small subcortical infarcts, lacu-
presence of established renal parenchymal damage (110). nes, dilated perivascular space and atrophy (129).
Urinary albumin excretion, even below the current thresh- Several studies have shown that VBI detected using
old values, has been shown to predict CV events in both magnetic resonance imaging (MRI) is quite common in
diabetic and nondiabetic hypertensive patients (111,112). the general population (126,130), with prevalence increas-
There is a continuous relationship between CV and non- ing with age and hypertension. The availability and cost
CV mortality and urinary protein excretion (113,114). considerations do not allow widespread use of MRI in
Albuminuria can be measured from spot urine samples, the evaluation of elderly patients, but silent brain infarcts
preferably early morning urine (24-hour or night urine should be sought in all hypertensives with neural dis-
samples are discouraged due to the inaccuracy of urine col- turbance, and particularly memory loss. Cognitive tests
lection) by indexing the urinary albumin concentration to should be used in the clinical assessment of elderly hyper-
the urinary creatinine concentration (107). tensives (131).
Progressive reduction in eGFR and increased albumin-
uria indicate progressive loss of renal function towards
end-stage renal disease and are both independent pre- PROGNOSTIC VALUE OF TREATMENT-INDUCED
dictors of increased CV risk in diabetic and nondiabetic
kidney disease (115). The presence of both increased albu- AND MULTIORGAN SUBCLINICAL ORGAN
minuria and reduced eGFR is associated with a greater risk DAMAGE
of renal and CV complications (Table 2.4).
Hyperuricemia is frequently seen in untreated hyper- Treatment-induced changes in organ damage affect the
tensives (particularly in pre-eclampsia) and has also been incidence of CV events, hence organ damage should be
shown to correlate with reduced renal blood flow and in assessed also during treatment (132) because LVH regres-
the presence of nephrosclerosis (116). sion and reduction of urinary protein excretion indicate
Serum creatinine, eGFR and urinalysis, including mea- treatment-induced CV protection (132,133). There is also
surement of albumin-to-creatinine ratio, are considered some evidence that treatment-induced changes in eGFR
routine laboratory tests to be performed in all hyperten- predict CV events (134–140).
sive patients and to be repeated at least annually. On the other hand, two meta-analyses did not show
any predictive value of treatment-induced reduction in
carotid IMT for CV events (141,142). There is no or limited
evidence for the predictive power of treatment-induced
RETINAL VESSELS changes in PWV and ABI.
Whenever possible, a search for subclinical organ dam-
Most hypertensive patients usually present early in the age should be made simultaneously in various organs,
process of their disease, and haemorrhages and exudates because multiorgan subclinical organ damage is associ-
(grade 3) and papilledema (grade 4) are observed very ated with a worse prognosis.
rarely but are highly reproducible and always associated A population-based study from Denmark showed that
with an increased risk of CV events (117,118). On the other subclinical organ damage predicted CV death indepen-
hand, grade 1 (focal or general arteriolar narrowing) and 2 dently of SCORE and use of the combination of SCORE
(arteriovenous nipping) retinal changes are reported much and subclinical organ damage may improve risk predic-
more frequently than other subclinical organ damage with tion, particularly in subjects with moderate CV risk, by
documented clinical significance (LVH, carotid plaques assessing UAE and PWV (41).
and albuminuria), but the prognostic significance of these Regression of target-organ damage may not be achieved
mild retinal changes has been questioned (119–122) and even under satisfactory BP control. Some changes may
their reproducibility is limited. These changes appear to be irreversible because they are too advanced. Blood
be largely nonspecific except for young patients, in whom pressure-lowering treatment can also prevent develop-
a deviation from an entirely normal retina should raise ment of target-organ damage (143). If target-organ dam-
concern. More selective methods for objective assessment age develops during antihypertensive treatment, it may be
of the eye fundus have been developed; for example digi- associated with an increased risk (53).
talized retinal photographs, which showed that retinal In conclusion, it is important to assess target-organ
arteriolar and venular narrowing may precede the devel- damage on treatment; if there is target-organ damage at
opment of hypertension (123,124). baseline, its evaluation should be repeated at least once
during the first year of effective BP control. If there is no
target-organ damage at baseline, the reassessment may be
postponed.
BRAIN
Hypertension is associated with an increased risk of
ischaemic and haemorrhagic stroke and vascular brain
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HYPERTENSION
AND THE KIDNEY 3
Hypertension and kidney share a bidirectional relation- and a significant heterogeneity among regions, from 3.3%
ship. The kidneys participate in the development and in Norway to 17.3% in northeast Germany. Even when
maintenance of primary hypertension and chronic kid- restricting the analysis to more severe stages, and account-
ney disease (CKD) is one of the most common causes of ing for stratification by risk factors such as diabetes, hyper-
secondary hypertension. On the other hand, increased tension and obesity in the general population, differences
blood pressure of any etiology can lead to renal dam- among regions remain substantial: prevalence of CKD
age and, especially if accompanied by proteinuria, is an stages 3–5 varies from 1.0% in Italy to 5.9% in northeast
important factor for CKD progression. Germany (5).
CKD is frequently observed in patients with arterial
hypertension, as the same factors that promote the develop-
ment and progression of atherosclerosis can also promote
HYPERTENSION, CHRONIC KIDNEY CKD. Assessment of hypertension-related kidney damage
DISEASE AND CARDIOVASCULAR RISK requires the evaluation of glomerular filtration rate (GFR)
as well as quantification of albuminuria. Knowledge of
Primary hypertension was present in only 5–10% of the both these markers allows renal and cardiovascular risk
adult population in the early 1900s, but over the last sev- assessment at the same time (6). The coexistence of CKD
eral decades its prevalence has steadily increased to the in hypertension is accompanied by a further significant
remarkable figure of 30–40% currently reported in most enhancement in CV risk that reinforces the need for simul-
developed countries. It is projected that there will be more taneous protection of both the renal and the CV systems.
than 1.5 billion people affected by hypertension world- While hypertension is a well-known and strong risk factor
wide by the year 2025 (1). Based on surveys conducted in for development of CKD, the latter, even in its early phases,
the 1990s, Europe should be considered as a region with can cause an increase in blood pressure, thereby contribut-
high hypertension prevalence as compared to the United ing to increase cardiovascular risk in affected patients (7).
States and Canada (2). Furthermore, most recent epide- An inverse relationship between renal functional impair-
miological studies (3) indicate the highest prevalence of ment and prevalence of hypertension has been reported in
hypertension in Central and Eastern European countries the Chronic Renal Insufficiency Cohort (CRIC) study in
and the lowest in northern and southern countries, rang- which about 92% of patients with an estimated glomerular
ing between 32% (Estonia) and 15% (UK). filtration rate (eGFR) <30 mL/min/1.73 m2 were hyperten-
Approximately 10% of the population worldwide is sive, while 67% of those with eGFR >60 mL/min/1.73 m2
affected by chronic kidney disease (CKD) with signifi- had elevated blood pressure (BP) (8). The prevalence of
cant differences among regions. While increasing life hypertension in CKD seems also to depend on the type of
expectancy has an impact on CKD, as ageing is tradition- nephropathy, being highest in renal vascular disease (93%),
ally associated with a loss of renal function, nonetheless in established diabetic nephropathy (87%) and in polycys-
recent demographic trends alone cannot explain the steep tic kidney disease (74%) compared to a lower prevalence
increase in the prevalence and incidence of CKD recently in glomerulonephritis and tubular interstitial disease (9).
recorded. The rising prevalence of several well-known risk Furthermore, clinic blood pressure measurements might
factors for renal damage such as diabetes mellitus, hyper- be misleading, since masked hypertension may occur in up
tension, smoking and obesity as well as public health to 30% and apparent treatment-resistant hypertension in
policies may affect CKD prevalence. Data from the 2013 up to 40% of patients with CKD (10).
ERA-EDTA Registry Annual Report (4) indicate that the Unsurprisingly, it has recently been emphasized that renal
number of patients starting renal replacement therapy impairment is also the most common cause of treatment-
(RRT) varies considerably from less than 30 to over 200 resistant hypertension, defined as the failure to achieve rec-
people per million population across European coun- ommended BP values despite an optimal combination of at
tries, with higher prevalence in high income countries least three different drugs, including a diuretic (11).
20 Manual of Hypertension of the European Society of Hypertension
(a)
11
10
9
Plasma renin activity, ng/ml/h
3
(b)
2
0
0 100 200 300
Urinary sodium excretion, mEq/24 h
sympathetic nervous systems. Further attenuating hypo- damage, such as the individual susceptibility to hyperten-
tensive effect of nitric oxide is the generation of reactive sive renal damage and the different renoprotective effect
oxygen species by catecholamines, vascular distention of various antihypertensive drug classes, are still incom-
and RAAS activation. These free radicals are both proin- pletely understood (43). The renal pathology typically
flammatory and decrease nitric oxide bioavailability, ulti- observed in the vast majority of individuals with primary
mately promoting increases in BP (36). hypertension is benign nephrosclerosis, a condition char-
Arterial stiffness, long considered a consequence of acterized by accelerated ageing of the renal vasculature
hypertension, may indeed antecede its onset. For exam- with a slow progressive thickening and sclerosis of the
ple, owing to the pulsatile load associated with ventricu- renal resistance vessels, with a substantial sparing of glo-
lar contraction, arteriolar elastin fibres are fractured and merular capillaries (Figure 3.3a). Therefore, it is not sur-
ultimately replaced by the less distensible collagen, further prising that primary hypertension rarely leads to advanced
decreasing vascular compliance (37). stages of renal damage. In fact, except for genetically sus-
Serum uric acid (SUA) is both a product of purine degrada- ceptible groups, such as blacks, the only individuals with
tion and a result of renal handling, therefore largely depen- primary hypertension who develop severe hypertension-
dent on renal function. A great deal of experimental and induced renal damage to reach ESRD are those with very
clinical evidence supports the possibility that an elevated high levels of BP that result in the development of malig-
SUA level may independently lead to or worsen hyperten- nant nephrosclerosis, characterized by acute disruptive
sion. The mechanisms linking hyperuricemia to hyperten- injury and fibrinoid necrosis of small arteries, arterioles
sion remain uncertain at present, and include endothelial and glomerular capillaries, with a prevalent glomerular
dysfunction and arterial stiffening through increased oxi- ischemia. In these cases, acute renal failure develops over
dative stress, RAAS activity and inflammation (38,39). days, and despite treatment is often followed by progres-
sive renal damage leading to CKD or even ESRD.
On the other hand, individuals with CKD and diabe-
tes seem to have greater susceptibility to the adverse renal
THE KIDNEY AS A VICTIM OF effects of even moderate hypertension. At variance with the
HYPERTENSION largely vascular pathology of benign and malignant neph-
rosclerosis, the site of hypertension-related renal damage
The kidney is a major target for hypertensive organ dam- in CKD is predominantly glomerular, with a pattern of
age. Data from several renal databases identifies systemic accelerated segmental or global glomerulosclerosis often
hypertension as the second most common cause of end- superimposed on the intrinsic phenotype peculiar of the
stage renal disease (ESRD), with diabetic nephropathy underlying renal disease (Figure 3.3b). Recent studies have
being the first. In the United States, hypertension is the hypothesized that the severity of such damage depends
leading cause of ESRD in African American patients. on the degree to which renal autoregulatory mechanisms
In Europe, according to 2015 ERA-EDTA registry (40), fail to prevent the transmission of BP elevation to renal
hypertensive nephrosclerosis is a less common cause of microvasculature. In fact, under normal physiologic condi-
ESRD, accounting for 14% of new patients starting RRT. tions, autoregulatory vasoconstriction of the preglomeru-
However, the incidence varies among countries − hyper- lar resistance vessels, mainly the afferent arteriole, prevents
tensive nephrosclerosis is reported as responsible for ESRD transmission of systemic hypertension to glomerular
in 25% and 29% in patients starting RRT in France and in microvasculature, thus maintaining constant renal blood
Norway, while in the UK this figure is approximately 6%. flow, intraglomerular hydrostatic pressure and ultimately
Most hypertensive patients develop mild to moderate preserving GFR and avoiding hypertensive renal damage.
hypertensive nephrosclerosis that progresses to ESRD in only In patients with chronic hypertension, both upper and
a relatively small percentage of patients. In particular, eleva- lower thresholds of autoregulation are usually shifted to the
tions in serum creatinine have not been frequently observed right as a means of protective adaptation. However, intrare-
in clinical trials involving patients of European ancestry with nal resistance arteries and arterioles exposed to long-term
mild-to-moderate hypertension. Defining CKD as a rise in hemodynamic stress progressively develop atherosclerotic
baseline serum creatinine concentration by 50% or to levels changes leading to benign nephrosclerosis. Furthermore,
>2 mg/dL, the disease was detected in 0.1% (approximately an acute and severe increase in BP is probably able to exceed
1 per 1000) of participants with mild-to-moderate hyperten- the autoregulatory limits and may cause more disruptive
sion in the Multiple Risk Factor Intervention Trial (MRFIT) vascular damage particular to malignant nephrosclerosis.
(41). On the contrary, in the Hypertension Detection and An impairment of these protective mechanisms associated
Follow-up Program (HDFP) which enrolled a relatively large with a significant reduction in renal mass in patients with
percentage of African American subjects, 1% of participants diabetic and nondiabetic CKD is likely to account for their
developed an elevated serum creatinine concentration, increased susceptibility to progressive glomerulosclerosis
which probably reflects the role of increased genetic suscep- even with a moderate increase in systemic BP. In addition,
tibility to nondiabetic nephropathy in this ethnicity (42). the consequent renal damage results in additional neph-
The lack of specific criteria to define a histological diag- ron loss and further strengthens transmission of systemic
nosis often limits a clear demonstration that hyperten- hemodynamic load to the glomerulus.
sion causes the development of renal damage and makes
it difficult to correctly estimate the impact of hypertension
in renal dysfunction. In fact, regardless of the underly-
ing etiology of CKD, the increase in systemic blood pres- CONCLUSIONS
sure accelerates per se the rate of glomerular filtration rate
deterioration, especially in the presence of proteinuria. The kidney presides over long-term extracellular fluid and
However, many aspects of hypertension-related renal BP homeostasis by balancing dietary sodium intake and
Hypertension and the Kidney 23
excretion in the urine. This is the result of a complex physi- 16. Guyton AC. Blood pressure control–special role of the kidneys
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17. Dahl LK, Heine M, Thompson K. Genetic influence of the kidneys on
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19. Bianchi G, Fox U, Di Francesco GF et al. Blood pressure changes
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of hypertension in patients with CKD, wherein effective sion after renal transplantation. N Engl J Med 1983; 309: 1009–1015.
22. Matchar DB, McCrory DC, Orlando LA et al. Systematic review:
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tial hypertension. Ann Intern Med 2008; 148: 16–29.
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BLOOD PRESSURE
CONTROL IN EUROPE 4
AND ELSEWHERE
Table 4.1 Summary of the methodology and BP control results from the literature in European patients with hypertension (published
between 2008–2017)
Agyemang et al. The Netherlands Secondary analyses of 13,999 White-Dutch: 9.1% White-Dutch: 40.9%
(14) and United population-based studies White-English: 11.1% White-English: 45.3%
Kingdom between 2006 Dutch-African: 10.5% Dutch-African: 30.9%
English-African: 26.2% English-African: 56.7%
English-Caribbean: 23.8% English-Caribbean: 50.3%
Dutch South-Asian: 16.1% Dutch South-Asian: 34.4%
English-Indian: 17.9% English-Indian: 44.5%
English-Pakistani: 29.5% English-Pakistani: 65.8%
English-Bangladeshi: English-Bangladeshi:
31.7% 57.9%
Serumaga et al. United Kingdom Interrupted time series analysis 470,725 – 70%b
(16) in primary care using THIN
database (2000 to 2007)
Cifková et al. (17) Czech Republic Cross-sectional population 13,972 24.6% 42.1%
survey 2007–2008
(Continued)
Blood Pressure Control in Europe and Elsewhere 27
Table 4.1 (Continued) Summary of the methodology and BP control results from the literature in European patients with hypertension
(published between 2008–2017)
Ferrari et al. (23) Western, Central 5-year observational Western/ – Western/Central Europe:
and Eastern longitudinal cohort study Central ∼55%
Europe (CLARIFY) in outpatients with Europe: Eastern Europe: 47%
stable CAD recruited in 15,388
2009/2010 Eastern Europe:
3026
Kotseva et al. (32) Europe EUROASPIRE IV (2012–2013) 8456 with CHD 55.3%
a Defined as ≥140/90 mmHg (<130/80 mmHg in patients with comorbid conditions) or being treated for high blood pressure, unless specified.
b BP <150/90 mmHg.
Abbreviations: CAD, coronary artery disease; CRISTOPH, Cardiovascular Risk Intervention Study to Optimise Treatment in Patients with Hypertension; CLARIFY, the
prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease; HSE, Health Survey for England; PRESCAP, PRESión arterial en la
población Española en los Centros de Atención Primaria; DETECT, Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment;
THIN, The Health Improvement Netw.
28 Manual of Hypertension of the European Society of Hypertension
Table 4.2 Summary of the methodology and BP control results from the literature in European patients with hypertension (published
between 2008–2015)
Cifková R et al. (17) Czech Six independent cross-sectional 13,972 1985: 3.9% 1985: 13.2%
Republic population surveys from 1985 2007/2008: 24.6% 2007/2008: 42.1%
to 2007/2008
Falaschetti E et al. England Two cross-sectional, nationally 2003: 8834 2003: 22% 2003: 46%
(13) representative, random samples 2006: 7478 2006: 28% 2006: 52%
(HSE) of non-institutionalised
adults in 2003 and 2006
Falaschetti E et al. England Five cross-sectional, nationally 1994: 12,117 1994: 11% 1994: 33%
(29) representative, random samples 2011: 4466 2011: 37% 2011: 63%
(HSE) of non-institutionalised
adults between 1994 and 2011
Kotseva et al. (32) Europe EUROASPIRE 8456 with CHD EA II (99-00): 45.7%
EA III (06–07): 47.8%
EA IV (12–13): 55.3%
Dregan A. et al. (33) England English Longitudinal Study of 24,699 More or less than 80 yr
Ageing 2002–2003: 37–32%
2004–2005: 31–40%
2008–2009: 37–44%
2012–2013: 47–50%
Ruckert et al. (36) Germany CARLA (baseline 2002–2006 4683 diabetics Nondiabetics 10 to 26%
and follow-up 2007–2010), and nondiabetics Diabetics 20 to 40%
KORA (baseline 1999–2001
and follow-up 2006–2008) and
SHIP (baseline 1997–2001 and
follow-up 2002–2006)
Banegas et al. (18) Spain Field survey of total population 4623 2000–2001: 16.3%
>60 year old 2008–2010: 25.4%
Escobar C et al. (21) Spain Three cross-section surveys 2002: 12,754 – 2002: 31.1
(PRESCAP) in primary care 2006: 10,520 2006: 41.4
setting in 2002, 2006 and 2010: 12,961 2010: 46.3
2010
Management in Usual Daily Practice (EURIKA) (25), a Health Organization (39) and a fact sheet issued by the
cross-sectional study of the status of primary cardiovas- World Hypertension League and the International Society
cular disease (CVD) prevention, identified that 38.8% of Hypertension (40).
of patients achieved a target BP. The rates of control, In 2008, a white paper was published by a group of
however, have improved to around 50% or even higher. researchers in hypertension with a call for action to
Likewise, the rate of control reported by the EUROASPIRE improve the rates of control. The manuscript identified
IV was 55.6% in subjects with a previous coronary event the key challenges in the treatment of hypertension and
(32). The observed improvement is the result of different suggested recommendations for improving control (41).
interventions in many of the European countries. Despite some improvements in 2016, a new publication (5)
It is worth noting the different rate of control in minori- points to the fact that six challenges are still present: inad-
ties living in European countries, mainly in the UK and equate primary prevention, faulty awareness of risk, lack
the Netherlands. The control rates in the general popula- of simplicity in the treatments, therapeutic inertia, insuf-
tion of minorities are low, around 20%, while the control ficient patient empowerment and unsupportive healthcare
in the treated subjects is twice that (20). systems. In the last few years a new challenge has emerged
Considering control rates trends over time, 13 publica- − the discrepancies and changes in the BP goals provided
tions reported surveys on hypertension control rates over by guidelines, which contribute to physician uncertainties.
time with the same or similar methodology (Table 4.2). For continuing advances in control, supplementary
As in the prevalence studies, Western European countries effort is necessary, as what has been achieved in the past
predominated. In both general population studies or in reflects a slow improvement, with the exception of suc-
hypertensive treated subjects, the rate of control improved cessful program such is the Canadian Hypertension
between 10−20% in a 10-year time period. Educational Program (CHEP), a professional education
program which provides annually updated simple recom-
mendations and clinical practice guidelines for the detec-
tion, treatment and control of hypertension with control
INDIRECT ASSESSMENT OF CONTROL rates around 68% in the general population and greater
than 75% among the treated subjects (20). Recently, some
Recognizing the difficulties in obtaining timely and com- programs have been launched in some European countries
parable population surveys, alternative methods to assess (France and Italy) with the objective of achieving 70%
the BP status across populations could be an important control rates.
quality indicator for health systems. Assessing the inci- In order to progress in hypertension control, a few actions
dence and trends of hypertension-induced clinical condi- can produce success. Among them, simplify the BP treatment
tions could prove useful in this regard. Among the options target to <140/90 mmHg for the majority of patients and the
for a surveillance measure, stroke incidence and/or mor- treatment options with a single pill combination of drugs.
tality presents an attractive option (37). In parallel, encourage patient empowerment and involve
In a study by our group, a positive relationship exists healthcare systems, shifting the focus away from cost. These
between stroke mortality and the average of SBP at the simple key actions should form the basis of hypertension
country level in the 25 in which BP values were available management in Europe going forward, ensuring that more
(38). The relationship was quantitatively larger in women patients are achieving BP control in the future, and thereby
that it was in men. Likewise, the relationship varied with reducing cardiovascular morbidity and mortality.
age, being more apparent in the younger age strata. We
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342:d108. hypertension management and mortality among octogenarians:
17. Cifkova R, Skodova Z, Bruthans J et al. Longitudinal trends in Prospective Cohort Study. Hypertension 2016; 68: 97–105.
cardiovascular mortality and blood pressure levels, prevalence, 34. Tocci G, Muiesan ML, Parati G et al. Trends in prevalence, aware-
awareness, treatment, and control of hypertension in the Czech ness, treatment, and control of Blood Pressure recorded from
population from 1985 to 2007/2008. J Hypertens 2010; 28: 2004 to 2014 during World Hypertension Day in Italy. J Clin
2196–2203. Hypertens (Greenwich) 2016; 18: 551–556.
18. Banegas JR, Navarro-Vidal B, Ruilope LM et al. Trends in hyper- 35. Dorobantu M, Tautu OF, Dimulescu D et al. Perspectives on
tension control among the older population of Spain from 2000 hypertension’s prevalence, treatment and control in a high cardio-
to 2001 to 2008 to 2010: Role of frequency and intensity of drug vascular risk East European country: Data from the SEPHAR III
treatment. Circ Cardiovasc Qual Outcomes 2015; 8: 67–76. survey. J Hypertens 2018 Mar; 36(3): 690−700.
19. Paulsen MS, Andersen M, Thomsen JL et al. Multimorbidity and 36. Rückert IM, Baumert J, Schunk M et al. Blood pressure control has
blood pressure control in 37 651 hypertensive patients from improved in people with and without type 2 diabetes but remains
Danish general practice. J Am Heart Assoc 2013; 2:e004531. suboptimal: A longitudinal study based on the German DIAB-
20. Leung AA, Daskalopoulou SS, Dasgupta K et al. Hypertension CORE consortium. PLOS ONE 2015; 10:e0133493.
Canada. Hypertension Canada’s 2017 Guidelines for Diagnosis, 37. Cooper RS. Using public health indicators to measure the success
Risk Assessment, Prevention, and Treatment of Hypertension in of hypertension control. Hypertension 2007; 49: 773–774.
Adults. Can J Cardiol 2017; 33: 557–576. 38. Redón J, Cea-Calvo L, Lozano JV et al. Differences in blood pres-
21. Escobar C, Barrios V, Alonso-Moreno FJ et al. Evolution of therapy sure control and stroke mortality across Spain: The Prevención
inertia in primary care setting in Spain during 2002–2010. J de Riesgo de Ictus (PREV-ICTUS) study. Hypertension 2007; 49:
Hypertens 2014; 32: 1138–1145. 799–805.
22. Rodriguez-Roca GC, Llisterri JL, Prieto-Diaz MA et al. Blood 39. WHO. A global brief on hypertension. Silent killer, global public
pressure control and management of very elderly patients with health crisis. 2013 [cited July 2015]; Available from: http://apps.who.
hypertension in primary care settings in Spain. Hypertens Res int/iris/bitstream/10665/79059/1/WHO_DCO_WHD_2013.2_eng.
2014; 37: 166–171. pdf?ua=1.
23. Ferrari R, Ford I, Greenlaw N et al. Geographical variations in 40. WHO I. High blood pressure: Why prevention and con-
the prevalence and management of cardiovascular risk factors in trol are urgent and important. A 2014 fact sheet from the
outpatients with CAD: Data from the contemporary CLARIFY World Hypertension League and the International Society of
registry. Eur J Prev Cardiol 2015; 22: 1056–1065. Hypertension. 2014 [cited July 2015]; Available from: http://ish-
24. Catala-Lopez F, Sanfelix-Gimeno G, Garcia-Torres C et al. Control world.com/news/a/WHL-and-ISH-Hypertension-Fact-Sheet/.
of arterial hypertension in Spain: A systematic review and meta- 41. Redon J, Brunner HR, Ferri C et al. Practical solutions to the chal-
analysis of 76 epidemiological studies on 341 632 participants. lenges of uncontrolled hypertension: A white paper. J Hypertens
J Hypertens 2012; 30: 168–176. Suppl 2008; 26:S1–14.
SOCIOECONOMIC
DETERMINANTS 5
African countries present with the highest cerebrovascu- income, education, and occupation. This study, published
lar disease mortality rates. These alarming figures have in 2017, highlighted that adverse social environment was a
prompted the Pan-African Society of Cardiology (PASCAR) crucial factor associated with higher prevalence of hyperten-
to issue a roadmap to achieve 25% hypertension control sion, diabetes, depressive symptoms, elevated inflammatory
in Africa by 2025, underlining that the majority of the biomarkers and less access to health insurance (28). From
sub-Saharan countries do not have a clear hypertension a methodological viewpoint, the reproducibility of asso-
policy (18). ciations at the level of composite indices that may describe
Given that two-thirds of the 1 billion people with socioeconomic status globally further supports the role of
hypertension globally live in low- and middle-income socioeconomic status as a factor affecting the occurrence
countries, another meta-analysis focused especially on of hypertension. The association between neighbourhood
the latter and aimed to examine whether socioeconomic disadvantage and hypertension has also been supported
determinants were associated with hypertension, espe- by other studies, such as the University of Alabama at
cially in rural areas. Although educational status corre- Birmingham Study of Ageing, which showed that neigh-
lated inversely with hypertension in East Asia, variable bourhood deprivation was associated with higher preva-
associations were reported by the meta-analysis across the lence of hypertension and poor BP control (29).
examined regions, whereas regions such as Latin America Apart from the efforts to objectively express and quantify
were underrepresented in terms of studies addressing this socioeconomic status and its components, a level of subjec-
research question (19). tive self-perception of socioeconomic status in relation to
On the other hand, studies associating higher socio- society as a whole may also be relevant in this debate. A
economic status with hypertension in low-income coun- recent meta-analysis published in 2016 evaluated the asso-
tries have appeared, underlining local particularities ciation between subjective social status, namely the individ-
in the African context. For instance, a relatively large ual’s perception of his/her position in the social hierarchy,
cross-sectional survey of 9254 participants in the urban and the presence of risk factors for coronary artery disease,
capital region of Tanzania demonstrated a positive asso- synthesizing nine studies. Comparing the bottom versus
ciation between hypertension and socioeconomic status, the top of the subjective social status ladder measures such
reflecting that the ongoing urbanization and affluence of as income, education or occupation, the OR (odds ratio)
African regions may account for the further increase in for hypertension was 1.88 (95% CI: 1.27–2.79); this pattern
hypertension rates (20). It seems therefore that country- was reproducible also in coronary artery disease as well as
specific factors and variable degrees of urbanization may other risk factors, such as diabetes and dyslipidemia. Hence
modify the associations between socioeconomic determi- it seems that apart from the actual socioeconomic status,
nants and hypertension, with variable patterns in rural the self-perception of one’s own status on the social hierar-
and urban areas. chy might exert health effects beyond those exerted by the
actual socioeconomic determinants (30).
Taking an additional step, a meta-analysis evaluated an
interesting aspect; that is, whether socioeconomic status
may also act through fostering nonadherence to antihy-
SOCIOECONOMIC STATUS AND pertensive drugs. The meta-analysis synthesized 30 stud-
HYPERTENSION: META-ANALYSES AND ies that reported on 40 cohorts, and uncovered a pooled
CURRENT CONCEPTS adjusted risk estimate for nonadherence according to
socioeconomic status (high vs. low) equal to 0.89 (95%
Summarizing the accumulating evidence, a seminal meta- CI: 0.87–0.92); nevertheless, the authors emphasized that
analysis published in 2015 synthesized 51 studies and these cohorts as a rule did not adopt comprehensive, mul-
demonstrated the increased risk of hypertension in the tidimensional measures (31). Accordingly, subsequent
lowest socioeconomic strata in terms of all three relevant studies also highlighted the association between higher
indicators, namely income (pooled OR = 1.19, 95% CI: education and hypertension control (32).
0.96–1.48), occupation (pooled OR = 1.31, 95% CI: 1.04–
1.64) and education (pooled OR = 2.02, 95% CI: 1.55–
2.63). Significant associations emerged in high-income
countries and were especially evident in women (21); the POSSIBLE MECHANISMS
meta-analysis, however, confirmed the distinct correlation
between higher socioeconomic status and hypertension Multiple mechanisms may link socioeconomic status and
in Africa that was detailed in the previous section of this hypertension. Lower socioeconomic status may signal
chapter. Studies published after the seminal meta-analysis suboptimal awareness of hypertension prevention and
have consistently supported the link between hypertension BP control, restricted accessibility to preventive health
and lower socioeconomic status, from diverse non-A frican services and lack of adherence to medical treatment (33).
populations (22–24). Recent evidence has confirmed that Lower socioeconomic status may also be accompanied by
the association between lower socioeconomic status and health-related lifestyles and behaviours that contribute to
hypertension is present as early as in childhood and ado- the existence of hypertension. Subjects of lower education
lescence, according to studies from various countries, or income may also consume larger amounts of alcohol
including China (25), Canada (26) and Europe (27). (34) and smoke to a greater extent (35,36), and unhealthy
The Multi-Ethnic Study of Atherosclerosis (MESA), a pro- choices of nutrition and obesity prevail in this group (37).
spective cohort study of subclinical CVD in 6814 adults aged Interestingly, a meta-analysis published in 2017 showed
45–84 years from six sites and states in the US adopted a that people of low socioeconomic status also consume
multidimensional assessment of neighbourhood socioeco- greater amounts of sodium, a fact that may also contrib-
nomic status through a scale that integrated level of wealth, ute to the socioeconomic disparities in hypertension
Socioeconomic Determinants 33
Blacks in the Health and Retirement Study. AAAS Annual Meeting alcohol consumption in this relationship: A systematic review and
and Science Innovation Exposition. 2016; 62(1): 19–35. meta-analysis. BMC Public Health 2015 April 1; 1: 00–1.
25. Ip P, Ho FK, So HK et al. Socioeconomic gradient in childhood 35. Casetta B, Videla AJ, Bardach A et al. Association between ciga-
obesity and hypertension: A multilevel population-based study in rette smoking prevalence and income level: A systematic review
a Chinese Community. PLOS ONE 2016; 11(6):e0156945. and meta-analysis. Nicotine Tob Res 2017 November; 19(12):
26. Shi Y, de Groh M, Bancej C. Socioeconomic gradients in cardio- 1401–1407.
vascular risk in Canadian children and adolescents. Health Promot 36. Centers for Disease Control and Prevention. Cigarette Smoking
Chronic Dis Prev Can 2016 February; 36(2): 21–31. and Tobacco Use Among People of Low Socioeconomic Status.
27. Kaczmarek M, Stawinska-Witoszynska B, Krzyzaniak A et al. Who 2017. Available from: https://www.cdc.gov/tobacco/disparities/
is at higher risk of hypertension? Socioeconomic status differ- low-ses/index.htm.
ences in blood pressure among Polish adolescents: A population- 37. Newton S, Braithwaite D, Akinyemiju TF. Socio-economic status
based ADOPOLNOR study. Eur J Pediatr 2015 November; 174(11): over the life course and obesity: Systematic review and meta-
1461–1473. analysis. PLOS ONE 2017; 12(5): e0177151.
28. Hussein M, Diez Roux AV, Mujahid MS et al. Unequal exposure or 38. de Mestral C, Mayen AL, Petrovic D et al. Socioeconomic deter-
unequal vulnerability? Contributions of neighborhood condi- minants of sodium intake in adult populations of high-income
tions and cardiovascular risk factors to socioeconomic inequality countries: A systematic review and meta-analysis. Am J Public
in incident cardiovascular disease in the multi-ethnic study of Health 2017 April; 107(4): 563.
atherosclerosis. Am J Epidemiol 2018 Jul 1; 187(7): 1424−1437. 39. Kershaw KN, Droomers M, Robinson WR et al. Quantifying the
29. Buys DR, Howard VJ, McClure LA et al. Association between contributions of behavioral and biological risk factors to socio-
neighborhood disadvantage and hypertension prevalence, aware- economic disparities in coronary heart disease incidence: The
ness, treatment, and control in older adults: Results from the MORGEN study. Eur J Epidemiol 2013 October; 28(10): 807–814.
University of Alabama at Birmingham Study of Aging. Am J Public 40. Cois A, Ehrlich R. Analysing the socioeconomic determinants of
Health 2015 June; 105(6): 1181–1188. hypertension in South Africa: A structural equation modelling
30. Tang KL, Rashid R, Godley J, Ghali WA. Association between sub- approach. BMC Public Health 2014 May; 1: 14.
jective social status and cardiovascular disease and cardiovascular 41. Liu MY, Li N, Li WA, Khan H. Association between psychosocial
risk factors: A systematic review and meta-analysis. BMJ Open stress and hypertension: A systematic review and meta-analysis.
2016 March 1; 6(3): e010137. Neurol Res 2017 June; 39(6): 573–580.
31. Alsabbagh MH, Lemstra M, Eurich D et al. Socioeconomic status 42. Chiu M, Rezai MR, Maclagan LC et al. Moving to a highly walkable
and nonadherence to antihypertensive drugs: A systematic review neighborhood and incidence of hypertension: A propensity-score
and meta-analysis. Value Health 2014 March; 17(2): 288–296. matched cohort study. Environ Health Perspect 2016 June; 124(6):
32. Chor D, Pinho Ribeiro AL, Sa Carvalho M et al. Prevalence, 754–760.
awareness, treatment and influence of socioeconomic variables on 43. Kaiser P, Diez Roux AV, Mujahid M et al. Neighborhood
control of high blood pressure: Results of the ELSA-Brasil Study. e nvironments and incident hypertension in the multi-ethnic
PLOS ONE 2014; 10(6):e0127382. study of atherosclerosis. Am J Epidemiol 2016 June; 183(11):
33. Grotto I, Huerta M, Sharabi Y. Hypertension and socioeconomic 988–997.
status. Curr Opin Cardiol 2008 July; 23(4): 335–339. 44. Mulatu MS, Schooler C. Causal connections between socio-
34. Jones L, Bates G, McCoy E, Bellis MA. Relationship between alco- economic status and health: Reciprocal effects and mediating
hol-attributable disease and socioeconomic status, and the role of mechanisms. J Health Soc Behav 2002 March; 43(1): 22–41.
Section II
Etiological and
Pathophysiological Aspects
HEMODYNAMIC PATTERNS IN
HYPERTENSION 6
METHODS OF CENTRAL HEMODYNAMIC TPR cannot be measured directly, but is derived by cal-
culation as the ratio between the mean arterial pressure
MEASUREMENTS (MAP) and CO:
It is essential for clinical hemodynamic assessment to
acquire accurate BP and CO measurements. TPR ≈ MAP/CO (6.5)
The most precise measurement of BP is obtained by
intra-arterial recording using a pressure transducer, which The TPR in Equation 6.5 is usually transformed by a
permits detection of immediate beat-by-beat pressure constant (1332) to be expressed by the unit dyn s cm−5.
changes, for example, during variations in physical activ- Indexed values for TPR, as well as for CO and SV, are
ity or by other interventions (1). Intra-arterial recordings obtained by relating data to body surface area (BSA). The
may also be carried out at different sites within the arterial corresponding variables are designated cardiac index (CI),
38 Manual of Hypertension of the European Society of Hypertension
AGE
60 4
50 3.5
Cardiac index
Stroke index
40 3
30 2.5
20 2
17–29 30–39 40–49 50–56 17–29 30–39 40–49 50–56
90 4500
70 3000
60 2250
50 1500
17–29 30–39 40–49 50–56 17–29 30–39 40–49 50–56
140
Mean arterial pressure
120
100
80
60
17–29 30–39 40–49 50–56
Figure 6.1 Cross-sectional study of central hemodynamics in normotensive subjects (light bars) and patients with hyper-
tension (dark bars). The figure shows data in the rest (sitting) position from four different age groups. Units of Measurement:
Cardiac index = L/min/m 2; Heart rate = beats/min; Mean arterial pressure = mmHg; Stroke index = mL/min/m 2; Total
peripheral resistance index = dyn s cm−5 m 2. (Adapted from Lund-Johansen P. Acta Med Scand 1967; 18 (Suppl 482): 1–101.)
who were normotensive both at the screening and at the in cardiac pump function with age in hypertensives as sug-
time of the current study (Table 6.2) (27). Similar findings gested from the cross-sectional studies is also seen by longi-
have been made in other studies, suggesting increased left tudinal follow-up in individual patients.
ventricular stiffness and reduced ventricular filling rate even In our laboratory a second restudy after a total of 20
before development of left ventricular hypertrophy (28–31). years from the first hemodynamic study was performed
in a limited group of patients (32,33,38). During the sec-
LONGITUDINAL STUDIES ond decade, most patients developed diastolic BP above
Available follow-up studies on spontaneous changes in cen- 100 mmHg, and active antihypertensive treatment was
tral hemodynamics in hypertensives are of short duration − initiated in all but two patients. After consent from the
typically 2–5 years (3,15,32–38). Generally, BP remained patients, and under close scrutiny, the drug therapy was
unchanged, while the CO decreased, and TPR showed an temporarily discontinued for 1 month in order to evaluate
increase. In our laboratory similar results were found after a the hemodynamic status without drug effects after 20 years
10-year follow-up period (32,38). The reduction in CO was of follow-up. The principal results were further increases
associated with a reduction in SV in the order of 15%, while in systolic and diastolic BPs associated with increase in
HR was almost unchanged. Thus, the progressive decrease TPR and further reductions in CO and SV (Figure 6.2) (33).
40 Manual of Hypertension of the European Society of Hypertension
CI TPRI
12
4000
8 3000
MAP 2000
4
140
60 130
NT
40 HT 80
HT-20
Figure 6.2 Central hemodynamics in young hypertensive (HT) men and in the same subjects 20 years later (HT-20) in
comparison with age-matched normotensive (NT) controls. Data shown at the lowest oxygen consumption (VO2) values
represent measurements at rest sitting, while the remaining data show measurements during steady state dynamic exercise
at 50, 100 and 150 W, respectively. Abbreviations: CI, cardiac index(L/min/m 2); HR, heart rate (beats/min); MAP, mean arte-
rial pressure (mmHg); SI, stroke index (mL/beat/m 2); TPRI, total peripheral resistance index (dyn sec cm−5 m 2); VO2, oxy-
gen consumption (mL/min/m 2), measured by the Douglas bag technique.). (From Lund-Johansen P. Acta Med Scand 1967;
18(Suppl 482): 1–101; Lund-Johansen P. In: Birkenhäger WH, Reid JL (eds). Handbook of Hypertension, vol 22. Birkenhäger
WH, Robertson JIS, Zanchetti A (eds). Hypertension in the Twentieth Century: Concepts and Achievements. Elsevier, Amsterdam;
2004:151–72; Lund-Johansen P. Hypertension 1991; 18(Suppl): III-54–III-61.)
Figure 6.3 Central hemodynamic variables in young 24-hour ambulatory BP 112/65 122/74***
subjects with mild essential hypertension. Data are shown (mmHg)
as percent compared with normotensive (NT) subjects
Office HR (beats/min) 69 76**
(dashed line = 100%) and are the weighted mean values for
the supine position at rest from seven studies in a total of 24-hour ambulatory HR 70 76*
189 NT subjects and 222 patients with essential hyperten- (beats/min)
sion. Abbreviations: CI, cardiac index; HR, heart rate; MAP,
mean arterial pressure; SI, stroke index; TPRI, total periph- Posterior wall thickness 9.3 10.1*
(mm)
eral resistance index. (From Lund-Johansen P. Acta Med
Scand 1967; 181(Suppl 482): 1–101; Bello CT et al. Am J Relative wall thickness 0.36 0.41***
Med Sci 1967; 253: 194–208; Frohlich ED et al. Am J Med
Sci 1969; 257: 9-23; Safar M et al. La Presse Medicale 1970; Peak late flow (m/s) 0.42 0.52***
78: 111-4; Julius S et al. Circulation 1971; 43: 382–90; Jern S.
Early/late flow (ratio) 1.72 1.41***
Acta Med Scand Suppl 1982; 662: 1–55; Andersson OK et al.
J Hypertens 1983; 1(Suppl 2): 91–93. (10,19–24)) Source: Mo R et al. Blood Pressure 1995; 4: 16–22.
Note: The Bergen Blood Pressure Study; Statistical difference between off-
spring of normotensive and hypertensive families: * = p < 0.05;
that the filling of the left ventricle is slightly reduced and ** = p < 0.01; *** = p < 0.001.
more dependent on the atrial contraction in hypertension
than in normal subjects.
Muscular exercise increases the workload on the heart of similar age, it is seen that during rest in the hyperten-
and the myocardial oxygen need. The product of HR × SAP sive groups, the RPP is similar to what normotensives are
(the rate – pressure product [RPP]) is a clinically useful exposed to during 50 W exercise (Figure 6.4) (48). This
index of myocardial oxygen demand (47). When the RPP illustrates the chronic increased burden on the hyperten-
is compared in hypertensives and normotensive subjects sive heart – also at rest.
25,000
50 W
20,000
SAP (mmHg) × HR (beats/min)
15,000 Rest
50 W
10,000 Rest
5,000
I II III I II III I II III I II III
0
NORMOTENSION HYPERTENSION
Figure 6.4 The systolic arterial pressure-heart rate product (SAP × HR) at rest (solid bars) and during steady state 50 W bicy-
cle exercise (open bars) in normotensive subjects and hypertensive patients in three age groups: I = 18–29 years; II = 30–39
years; III = 40–49 years. (From Lund-Johansen P. Eur Heart J 1999; 1(Suppl B): B10–B17.)
42 Manual of Hypertension of the European Society of Hypertension
PP/SI (mmHg/mL/ 2.17 2.40 2.13 2.48* CCBs have the common property of interacting with L-type
beat/m2) voltage-gated plasma membrane calcium channels. There
are several subtypes of CCBs which from both a pharma-
VO2 (mL/min/m2) 168 169 852 972*** cological and hemodynamic point of view may broadly
be divided into dihydropyridines and non-dihydropyridines
a MAP = DAP + 1/3(SAP — DAP). Mean arterial pressure (MAP) was (91,92). Generally, all CCBs are vasodilators, reducing BP
obtained by electrical damping of the intra-arterial pressure curve (28).
by a reduction of TPR.
Abbreviations: SAP, systolic arterial pressure; DAP, diastolic arterial pres-
sure; HR, heart rate; SI, stroke index; CI, cardiac index; TPRI, total peripheral
However, the mechanisms by which CCBs reduce vas-
resistance index; HR*SAP, rate-pressure product; PP/SI, pulse pressure/
cular resistance is complex, including both vasoconstrictor
stroke volume index; VO2, oxygen consumption (measured by the Douglas and vasodilator components. One mechanism is stimu-
bag technique). Statistical significance of difference between males and lation of renin release due to reduction in intracellular
females: * p < 0.05; ** p < 0.01; *** p < 0.001. Ca 2+ (92). Another is inhibition of endothelin-I−induced
Hemodynamic Patterns in Hypertension 43
Systolic arterial pressure (mmHg) Cardiac index (L/min/m2) Total peripheral resistance index
(dyn s cm–5 m2)
220 8
4000
6
200 3000
4
2000
180
Female
Male
Diastolic arterial pressure (mmHg) Stroke index (mL/beat/m2) Heart rate (beats/min)
125 55 170
115 45 130
105 35 90
Figure 6.5 Central hemodynamics at rest and during exercise in 57 women (triangles) with essential hypertension and 57
men (circles) with matching age, and systolic, diastolic and mean arterial pressure (at rest sitting). Abbreviations: CI, cardiac
index; SI, stroke index; HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; TPRI, total peripheral
resistance index.
vasoconstriction as shown by forearm venous occlusion antihypertensive treatment because of increased morbid-
plethysmography (93,94). ity and mortality related to heart failure compared with
Acute administration of dihydropyridine CCBs is other antihypertensive drugs in randomized clinical tri-
accompanied by a reflex increase in HR, and thereby an als (96,97). Alpha receptor blockers are still included here
increase in CO which, in spite of a marked reduction in because of interesting hemodynamic properties in patients
TPR, blunts the immediate hypotensive effect (74,95). with hypertension. As may be seen from Tables 6.4 and 6.5,
After the initial rise, HR gradually levels off towards its compounds from this group (and ARBs) were the only ‘true’
usual level. The long-term antihypertensive response to vasodilators, in other words, compounds that at the same
CCBs is partly dependent on sympathetic reflex activa- time led to significant reduction in TPR and increases in
tion (95). SV and CO without affecting HR at rest or during exercise.
The central hemodynamic difference between dihydro- However, it should be noted that even though the hemody-
pyridine and non-dihydropyridine CCBs is related to dif- namic profile approached normal after 1-year alpha recep-
ferent HR response. As shown in Tables 6.4 and 6.5, the tor blockade, there was still a wide gap to fully normalizing
main long-term hemodynamic difference between the central hemodynamics by alpha receptor blocker treatment.
two groups of CCBs is a small reduction in HR (about
5 beats/min; 6%) by non-dihydropyridines (Figure 6.7) as
opposed to unaltered HR during dihydropyridine t herapy.
The negative chronotropic effect of non-dihydropyridines ANGIOTENSIN-CONVERTING ENZYME
is compensated for by an increase in SV (at rest sitting INHIBITORS
9,3%, Figure 6.7), leaving CO almost unchanged at rest
and during exercise with both CCB groups. Angiotensin-converting enzyme inhibitors (ACEIs) slow
down the conversion of angiotensin-1 to angiotensin-2
which, among other effects, is a strong stimulus for arte-
riolar vasoconstriction (Chapter 13). Modulation of the
ALPHA RECEPTOR BLOCKERS hemodynamic pattern by ACE inhibitors was studied in
five trials: Captopril, enalapril, lisinopril + hydrochlo-
Postsynaptic alpha receptor blockers have in general rothiazide, lisinopril + low salt diet, and perindoprilat
been omitted from international recommendations on (acute, not long-term response) (43,78–80). The general
44 Manual of Hypertension of the European Society of Hypertension
Table 6.4 One-year central hemodynamic changes (%) induced by different classes of antihypertensive drugs or low sodium diet
Number
Antihypertensive N = studies TPRI (4040 dyn MAP CI (2,65 SI (36,5 HR (73,6
treatment group n = patients s cm−5 m2)a (128,2 mmHg) L/min/m2) mL/min/m2) beats/min)
Low sodium diet N = 3; n = 58 10.6 −1.6 −8.1 −5.1 −3.8
(Tables 6.4 and 6.5). The dual-action drugs reduce CO by hemodynamic profiles seen after 1-year treatment with
reducing HR, but not to the same extent as beta-blockers two compounds, labetalol and carvedilol, were maintained
without additional vasodilating effect. In the same man- almost unchanged also after a 6-year treatment period (103).
ner as with beta-blockers, the reduction in HR during exer- One of the compounds in this class, prizidilol, has been
cise is partly compensated for by an increase in SV. The withdrawn because of serious side effects.
Table 6.5 One-year central hemodynamic changes (%) induced by different classes of antihypertensive drugs or low sodium diet
Number
Antihypertensive N = studies TPRI (1743 dyn MAP CI (6,87 SI (53,0 HR (132,1
treatment group n = patients s cm−5 m2)a (145,4 mmHg) L/min/m2) mL/min/m2) beats/min)
130 130
100 100
140 140
HT
100 100
HT-Rx
NT
65 65
50 50
8 8
4 4
0 0
2800 2800
1400 1400
0 0
Rest sitting 50 W 100 W 150 W Rest sitting 50 W 100 W 150 W
Figure 6.7 Effects of one-year treatment with non-dihydropyridine CCBs (left hand panels) (69–71) or β-receptor block-
ers (right hand panels) (61–68) on central hemodynamics at rest and during exercise in patients with essential hyperten-
sion. Abbreviation: CCB = calcium channel blocker. Symbols: Open circles = before treatment; filled circles = same patients
after one-year antihypertensive treatment; open squares = normotensive subjects. (Adapted from Lund-Johansen P. Acta Med
Scand 1967; 18(Suppl 482): 1–101.)
Hemodynamic Patterns in Hypertension 47
34. Eich RH, Cuddy RP, Smulyan H, Lyons RH. Hemodynamics 59. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic
in labile hypertension. A follow-up study. Circulation 1966; 34: haemodynamic effects of doxazosin in hypertension at rest and
299–307. during exercise. Br J Clin Pharmacol 1986; 21(Suppl 1): 45S–54S.
35. Birkenhäger WH, Schalekamp MA, Krauss XH et al. Consecutive 60. Omvik P, Lund-Johansen P. Long-term haemodynamic effects of
hemodynamic patterns in essential hypertension. Lancet 1972; sustained-release trimazosin at rest and during exercise in essen-
1(7750): 560–564. tial hypertension. Eur J Clin Pharmacol 1991; 40: 131–134.
36. Birkenhäger WH, de Leeuw PW. Cardiac aspects of essential 61. Lund-Johansen P. Haemodynamic long-term effects of a new
hypertension. J Hypertens 1984; 2: 121–125. beta-adrenoceptor blocking drug, atenolol (ICI 66082), in essen-
37. Weiss YA, Safar ME, London GM et al. Repeat hemodynamic tial hypertension. Br J Clin Pharmacol 1976; 3: 445–451.
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GENETIC BASIS OF BLOOD
PRESSURE AND HYPERTENSION 7
such that it will be prepared for survival in an environ- on reproductive fitness. Two contrasting models have been
ment in which resources are likely to be short, resulting proposed to explain the genetic basis for common diseases:
in a thrifty phenotype. The mismatch between early- and
late-life nutritional status renders those born in poverty ■■ The common disease/common variant hypothesis: It holds
and growing into plenty especially vulnerable (7). It is also that complex traits are caused by common genetic
hypothesized that the renin-angiotensin-aldosterone sys- variants which have undergone little or no selection
tem (RAAS) was initially adapted for sodium conservation in earlier populations and are likely to date back
and may be maladaptive in modern societies with ready >100,000 years (23,24). The individual effects of
access to dietary sodium (11). these variants on the disease phenotype are small,
and numerous variants in multiple genes are needed
to express the trait. Moreover, as the human popula-
tion rapidly expanded from a small founder pool over
HERITABILITY OF BLOOD PRESSURE AND a short period, there was not enough time for new
HYPERTENSION alleles generated during population growth to dilute
out the disease-risk alleles that were common in the
Family studies have consistently demonstrated a genetic founder population (24,25).
component influencing blood pressure (BP) and HTN. The ■■ The common disease rare variant hypothesis: It posits an
Montreal Adoption Study (12) demonstrated correlation inverse relationship between the magnitude of genetic
coefficients of 0.38 and 0.16 between biological and adop- effect and allele frequency. This indicates that the high
tive sibs respectively, while the Victorian Family Heart Study frequency of common diseases is not due to the cumu-
(13) estimated correlation coefficients of 0.44 for non-twin lative effect of numerous common variants but to rare
siblings, 0.78 for monozygous twins, 0.50 for dizygous twins variants on a background of highly prevalent environ-
and 0.12 for spouse-spouse pairs. All these data indicate mental influences. There is evidence that the recent
presence of a genetic component if the environmental influ- explosive human population growth has resulted in
ence is assumed to be similar between comparison groups. an excess of rare genetic variants, with almost 86% of
Hunt et al. (14) showed familial aggregation of HTN from the deleterious mutations arising in the past 5000–
an analysis of life table data for 94,292 persons and found 10,000 years (26). This would indicate that rare vari-
the relative risks of developing HTN were 4.1 in men and 5 ants have a role in determining common phenotypes
in women aged 20–39 who had at least two first-degree rela- supported by data showing rare nonsynonymous vari-
tives affected by HTN. Two additional measures commonly ants in salt-handling genes have comparatively larger
used to assess the genetic component of a trait are: effects on BP in the general population (27).
■■ Heritability (h2): The fraction of variation in disease This is reminiscent of the Platt-Pickering debate in the
susceptibility due to genetic factors. 1950s (5,28), when Platt argued that HTN was a dichoto-
■■ Sibling recurrent risk (λs): The degree of elevated risk of mous trait and a simple Mendelian disease while Pickering
disease for a sibling of an affected individual com- thought BP was inherited as a ‘graded character’, and
pared with a member of the general population. hence a complex non-Mendelian trait (28,29). The normal
unimodal distribution of BP in the general population
The heritability of clinic systolic BP and diastolic BP is supports the complex multifactorial basis of BP regula-
around 15–40% and 15–30% respectively, whereas for tion (30–32). This is further put forth by the discovery
ambulatory nighttime systolic and diastolic BP the heri- of numerous SNPs from genome-wide association stud-
tabilities are 32–70% and 32–50% (15–21). It is pertinent ies (GWAS) associated with BP and HTN (33–38). Platt’s
to point out that though the heritability estimates are con- hypothesis would require a bimodal distribution of BP in
siderable, this does not equate to magnitude of genetic the general population which is not evident, but Platt’s
effect. This is because the denominator in the estimate of view is not entirely discounted as there exist highly pen-
heritability comprises measurement error and variances etrant rare genetic variants with large effects in families
attributable to genes, shared environment, non-shared with Mendelian forms of HTN and hypotension (39).
environment and unmeasured determinants. Heritability
is also a property of the population studied, and low herita-
bility estimates would suggest that genetic mapping would
be difficult for that phenotype. The sibling recurrent risk
(λs) of HTN is around 1.2–1.5 (22), and taking this along
BLOOD PRESSURE REGULATORY
with heritability and correlation estimates, HTN and BP PATHWAYS AND THEIR GENETIC BASIS
can be considered a trait with relatively modest genetic
effect (λs – CAD = 2.0–3.9; type 2 diabetes = 4.3; type 1 The identification of rare mutations in genes causing mono-
diabetes = 15; Huntington disease = 2000). genic forms of HTN come from linkage analysis of pedi-
grees exhibiting a Mendelian pattern of inheritance of the
BP phenotype. In contrast, the standard method for genetic
dissection of a complex trait is a GWAS which is based on
COMMON VARIANT OR RARE VARIANT the common disease/common variant hypothesis. GWAS
analyses have identified nearly 200 SNPs associated with BP
Single-nucleotide polymorphisms (SNPs) defined based on and continue to discover more associations with studies of
a minor allele frequency (MAF) >1% are known as com- increasing sample sizes (top GWAS signals are summarised
mon variants. These account for more than 90% of the in Table 7.1). However, the percentage of the BP trait variance
genetic differences between individuals and have no effect explained by all the SNPs is less than 5% (40–44).
Table 7.1 Summary of genome-wide association study results for blood pressure and hypertension
(Continued )
Table 7.1 (Continued ) Summary of genome-wide association study results for blood pressure and hypertension
(Continued )
Table 7.1 (Continued ) Summary of genome-wide association study results for blood pressure and hypertension
(Continued )
Table 7.1 (Continued ) Summary of genome-wide association study results for blood pressure and hypertension
(Continued )
Table 7.1 (Continued ) Summary of genome-wide association study results for blood pressure and hypertension
are involved include, but are not limited to, WNK (with
SODIUM AND INTRAVASCULAR VOLUME no lysine) kinases − a family of large serine/threonine
Vascular volume is a primary determinant of arterial pressure protein kinases (WNK1 and WNK4) (52). While WNK1
over the long term, and sodium acts as the principal determi- is widely expressed, WNK4 is expressed primarily in the
nant of extracellular fluid volume. Epidemiologic studies have kidney, localized to tight junctions. WNK4 is responsible
linked dietary NaCl intake with HTN (45,46), with non-chlo- for tonic inhibition of the thiazide-sensitive Na+ channel
ride salts of sodium having little or no effect on BP (47,48). (SLC12A3), while WNK1 is a negative regulator of WNK4.
Sodium homeostasis is maintained primarily by the kidneys. WNK1 also activates NCC (SLC12A3), ENaC (SCNN1A,
The renal glomeruli of a 70-kg man filter ∼25,000 mEq of SCNN1B, SCNN1G, SCNN1D), and inhibits the renal K+
Na+ and 180 L of water per day, and 99–100% of this amount channel ROMK (KCNJ1) (52,53). Under hyperosmotic or
is reabsorbed in different segments of the nephron – proxi- hypotonic low-Cl− conditions, WNK isoforms are acti-
mal convoluted tubule (60%), the thick ascending limb of vated, and subsequently phosphorylate and activate the
the Henle loop (30%), the distal convoluted tubule (7%) and related protein kinases SPAK (STK39) and OSR1 (OXSR1)
the connecting and the collecting duct (0–3%, controlled by (54). SPAK and OSR1 phosphorylate and activate ion
aldosterone and angiotensin-2) (49), pointing to the critical cotransporters that include NCC, NKCC1 (SLC12A2) and
role of the kidneys in sodium balance. NKCC2 (SLC12A1), which are targets for the commonly
There are multiple lines of evidence supporting the link thiazide-diuretic and loop-diuretic drugs, the former
between the kidney, sodium and HTN. Guyton’s ‘pressure- being an excellent antihypertensive drug (55).
natriuresis’ model posits that arterial pressure increases in ENaC is an important molecular target of aldosterone,
response to a high NaCl intake, in turn leading to increases which plays a central role in Na+ homeostasis by control-
in urinary sodium excretion to maintain sodium balance ling Na+ reabsorption in the aldosterone-sensitive distal
(30–32). Renal transplant studies in rats and in humans nephron. Under basal conditions, ENaC-alpha (SCNN1A)
have shown that the HTN status of the donor has a major gene transcription is constrained, but can be induced by
impact on long-term BP in the recipients (50,51). Finally, aldosterone and other stimuli such as serum- and gluco-
Mendelian forms of syndromic hypotension and HTN (39) corticoid-induced kinase-1 (SGK1) even in the absence of
have all been linked to mutations in genes whose encoded steroids (56,57). SGK1 can rapidly promote increased api-
proteins regulate salt−water balance in the kidney, sup- cal density of ENaC channels by disinhibiting Nedd4-2
porting the primacy of the kidneys in BP regulation. The (NEDD4L)-triggered internalization and degradation of
RAAS contributes to the regulation of BP not only through ENaC subunits (58). The mechanisms underlying this
the salt-retaining properties of the mineralocorticoid hor- basal repression of SCNN1A and its release during gene
mone aldosterone (CYP11B2) but also through the vaso- induction have not yet been established, but there are indi-
constrictor properties of angiotensin II. RAAS involves the cations of epigenetic regulation involving combinatorial
renin (REN) acting on angiotensinogen (AGT), to form an interactions of Dot1a, the DNA-binding protein Af9, and
inactive decapeptide, angiotensin I, which is converted by SGK1 (59), which regulate histone H3 Lys-79 methylation
an angiotensin-converting enzyme (ACE) to angiotensin of chromatin associated with the SCNN1A promoter and
II which binds to angiotensin II receptors (AGTR1). ACE suppress its transcriptional activity. Aldosterone can dis-
also cleaves and inactivates a number of other peptides rupt this nuclear complex and result in histone H3 Lys-79
including the vasodilator bradykinin, which is cleaved hypomethylation at specific subregions and de-repression
from kininogen (KNG1) by kallikrein (KLK1) (Figure 7.1). of the SCNN1A promoter. Histone modification has been
shown to play an important role in epigenetic modulation
of WNK4 transcription, contributing to the development of
salt-sensitive HTN. Isoproterenol-induced transcriptional
NA+ HOMEOSTASIS suppression of the WNK4 gene was shown to be mediated
via inhibition of histone deacetylase-8 activity (HDAC8)
Na+ reabsorption is controlled by mineralocorticoid active in the promoter region of the WNK4 gene (60) which in
steroid hormones in both the distal convoluted tubule turn can stimulate NCC, implying that sympathetic nerve
and the collecting duct (Figure 7.1). The amiloride-sen- activity can increase BP partly by activating NCC.
sitive epithelial Na+ channel (ENaC; SCNN1A, SCNN1B,
SCNN1G, SCNN1D) is found predominantly in princi-
pal cells of the collecting duct and the thiazide-sensitive
sodium chloride cotransporter (NCC; SLC12A3) in the GENETIC BASIS OF MONOGENIC HTN
distal convoluted tubule. In addition, basolateral sodium-
potassium adenosine triphosphate (ATP1A1-3, ATP1B1-4) The monogenic forms of HTN are usually associated with
and the luminal renal outer medulla K+ channel (ROMK; volume expansion and low plasma renin activity second-
KCNJ1) are responsible for Na+ and K+ homeostasis. ary to salt retention (39) (Figure 7.1).
Aldosterone binds to the cytosolic mineralocorticoid
receptor (MR; NR3C2) and leads to increased activity of ■■ Glucocorticoid-remediable aldosteronism, or famil-
the apical Na+ transporter, ENaC. Deoxycorticosterone ial hyperaldosteronism type 1 (OMIM #103,900) is
and deoxycortisol and their metabolites are alternative an autosomal dominant syndrome in which HTN is
agonists of the MR, with cortisol being the most impor- caused by increased aldosterone secretion driven by
tant one. The 11β-hydroxysteroid dehydrogenase type 2 adrenocorticotropic hormone (ACTH). The fusion
enzyme (HSD11B2), which converts active cortisol to the of the 5′ regulatory sequences of 11β-hydroxylase
inactive cortisone, protects the MR from cortisol, an alter- (CYP11B1) (which confers ACTH responsiveness) with
native agonist of the MR, thus establishing the aldosterone the distal coding sequences of aldosterone synthase
specificity of the MR. Additional regulatory elements that (CYP11B2) leads to a chimeric gene which results in
Genetic Basis of Blood Pressure and Hypertension 59
Figure 7.1 Mutations altering blood pressure in humans and GWAS loci linked to plausible genes. The figure shows the
circulatory system and pathways that modulate blood pressure containing genes with known mutations that cause mono-
genic high or low blood pressure syndromes. In addition, plausible genes linked GWAS loci are shown based on multiple
lines of evidence (eQTL or nonsynonymous SNPs or genome-wide 3D proximity maps). (Reprinted with permission from
Padmanabhan S, Joe B. Physiol Rev 2017; 97(4): 1469–1528.)
60 Manual of Hypertension of the European Society of Hypertension
ACTH becoming the main controller for aldosterone cholesterol desmolase (OMIM #118,485; CYP11A1).
secretion instead of angiotensin II or potassium (61). Furthermore, a common SNP near CYP17A1 has
It is characterised by early-onset HTN, hyperaldo- emerged in multiple large BP GWAS meta-analyses
steronism, variable hypokalaemia, low plasma renin (34–37).
activity (PRA), and abnormal production of 18-oxo- ■■ Aldosterone-producing adenomas (APAs): It is estimated
cortisol and 18-hydroxycortisol. Low-dose glucocor- that ≤40% of APAs harbour a gain-of-function
ticoids to suppress ACTH secretion, or amiloride to somatic mutation in a K+ channel, KCNJ5, which
directly block the epithelial sodium channel (ENaC), results in membrane depolarization and enhanced
or spironolactone to block binding of aldosterone to aldosterone production. Mutations in three other
the mineralocorticoid receptor (MR) are the specific genes have been discovered in a further 7% of APAs −
treatment options for HTN in these individuals. ATP1A1, encoding the α1 subunit of Na+/K+-ATPase
■■ Familial hyperaldosteronism type 2 (FH II) (OMIM itself; ATP2B3, encoding a plasma membrane Ca2+-
#605,635) is an autosomal dominant syndrome ATPase 3 homologous to the sarcoplasmic endo-
due to hyperplasia or adenoma of the aldosterone- plasmic reticulum Ca2+-ATPases (ATP2A2); and
producing adrenal cortex (APA). The genetic CACNA1D, encoding an L-type Ca2+ channel, CaV1.3
abnormality causing FH-II has been localized to (67). The distinction between APA and bilateral
chromosome 7p22 (62), though the causative gene hyperplasia is clinically important because removal
has not yet been identified. FH II is not suppressible of the affected adrenal gland in APAs cures or ame-
by dexamethasone. Adrenalectomy is performed in liorates HTN in the majority of patients, whereas
cases of APA, and medical therapy with aldosterone bilateral adrenal hyperplasia requires lifelong treat-
antagonists in cases of bilateral adrenal hyperplasia. ment with an aldosterone antagonist and bilateral
In cases of severe and/or resistant HTN, additional adrenalectomy is not indicated.
antihypertensive medication is required.
■■ Apparent mineralocorticoid excess (AME) (OMIM Monogenic low renin HTN syndromes can also be
#218,030) is another low-renin HTN syndrome caused by mutations in the renal ion transporters.
accompanied by hypokalaemia and metabolic
alkalosis. The main defect in AME is absence or ■■ Pseudohypoaldosteronism type II (Gordon syn-
reduced activity of 11β-hydroxysteroid dehydrogenase drome; familial hyperkalaemia; OMIM #145,260) is
(HSD11B2), resulting in HTN in which cortisol acts as an autosomal dominant form of HTN characterised
if it were a potent mineralocorticoid (63). Normally, by hyperkalaemia, hyperchloremic metabolic acido-
both cortisol and aldosterone have MR agonist sis, normal or elevated aldosterone, low renin and
activity and HSD11B2 is protective by metabolising normal renal function. Patients under the age of 20
cortisol to prevent its binding to the MR. A serine to generally have normal BP but then develop HTN in
leucine mutation in the MR (S810L) results in gain adulthood. Gordon syndrome thus results from either
of function leading to severe early-onset HTN, and gain-of-function mutations in WNK1, or loss-of-func-
HTN during pregnancy. One possible mechanism tion mutations in WNK4, and mutations in Kelch-like
is that cortisone, the main metabolite of cortisol in 3 (KLHL3) and Cullin 3 (CUL3) genes. Mutations in
the kidney, can activate the mutation, conferring a WNK1/4 genes lead to increased NaCl reabsorption
potential permanent increase in renal sodium reab- and decreased potassium secretion. CUL3 and KLHL3
sorption (64,65). AME is usually diagnosed within mutations putatively inhibit the ubiquitylation of
the first years of life and is characterized by polyuria WNK4, and probably other WNK isoforms, resulting
and polydipsia, failure to thrive, severe HTN with low in the overactivation of NCC/NKCC2 ion cotrans-
renin and aldosterone levels, profound hypokalaemia porters, and consequently, increased salt retention
with metabolic alkalosis and most often nephrocalci- and HTN. Treatment is based on low-dose thiazide
nosis. Detection of a marked increase (10- to 100- diuretics that are very effective in the correction of
fold) in the ratio of cortisol/cortisone (F/E) or of the HTN, hyperkalaemia and hypercalciuria. Patients
tetrahydroxylated metabolites (THF+alloTHF/THE) with WNK4 mutations show a better response to
in plasma and urine is a strong indication for diagno- thiazide diuretics than those with WNK1 muta-
sis. Treatment is usually through blockade of the MR tions. They generally do not respond to exogenous
combined with thiazides to normalize BP and reduce mineralocorticoids.
hypercalciuria and nephrocalcinosis. Exogenous ■■ Liddle syndrome (OMIM # 177,200) is an autosomal
corticosteroids to block ACTH and suppression of dominant condition with a clinical picture of HTN
the endogenous secretion of cortisol is also used as a and aldosterone excess, but with very low aldoste-
complementary strategy. rone and renin levels. Severe HTN is found in young
■■ Congenital adrenal hyperplasia (CAH) is a group patients, from infancy to young adulthood (<35 years
of autosomal recessive disorders caused by defects of age). This is caused by gain-of-function mutations
in enzymes of cortisol biosynthesis (66). In some of in the genes coding the beta or gamma subunits of
these syndromes, plasma ACTH will increase in an ENaC (SCNN1B, SCNN1G) resulting in deletions of
attempt to produce cortisol leading to the accumu- proline-rich regions (68,69). These regions facilitate
lation of aberrant products, some of which lead to binding of Nedd4-2 (NEDD4L), a regulatory repressor
HTN. Enzyme mutations that are associated with that promotes channel degradation. The inability of
HTN include (in order of frequency): 11β-hydroxylase beta and gamma subunits to bind Nedd4 results in
(OMIM #202,010; CYP11B1), 3β-hydroxysteroid constitutive expression of sodium channels and pro-
dehydrogenase (OMIM #613,890; HSD3B2), longs the half-life of ENaCs at the renal distal tubule
17α-hydroxylase (OMIM #609,300; CYP17A1) and apical cell surface, inducing sodium reabsorption,
Genetic Basis of Blood Pressure and Hypertension 61
secondary potassium secretion and ultimately, HTN. 40 and by 9.0 mmHg at age 60, and in aggregate reduce the
The clinical picture resembles that of primary hyper- risk of HTN by 60% at age 60 (27). This is the first indica-
aldosteronism but the hormonal profile resembles tion that rare variants can produce clinically significant BP
that of hyporeninism-hypoaldosteronism. Treatment reduction in the general population and support the rare-
is based on administration of potassium-sparing variant-common-disease hypothesis (70,71).
diuretics, such as amiloride or triamterene, which act In addition to the kidney, the heart secretes a family
by blocking ENaC activity. This results in reduction of vasodilatory and natriuretic hormones in response to
of BP and correction of hypokalaemia and metabolic increased wall stress − atrial natriuretic peptide (NPPA)
alkalosis. Conventional antihypertensive therapies and B-type natriuretic peptide (NPPB). Knockout of one
are not effective. copy of NPPA in mice increases BP while overexpression of
■■ Bartter (SLC12A1, KCNJ1, CLCNKB, BSND, CaSR, NPPA lowers BP (72,73). There is now convincing evidence
ClCK-A) and Gitelman (SLC12A3) syndromes are for common variations in the NPPA-NPPB locus influenc-
associated with mutations that reduce salt retention, ing both levels of natriuretic peptides and BP in opposite
lower BP and protect against the development of HTN directions (35–37,74). Furthermore, a SNP near the natri-
(27,39). Bartter syndrome (OMIM #607,364) patients uretic peptide clearance receptor (NPR3) also showed
usually present after the neonatal period with failure genome-wide significant association in European, African
to thrive, fatigue, muscle weakness, cramps and and Japanese BP GWAS studies (35,36,75). Interestingly,
carpopedal spasms. Hypokalaemia and alkalosis are there is evidence of convergence between studies in ani-
common. Mutation in CLCNKB gene (1p36), encod- mal models of HTN and their emerging signals from BP
ing a basolateral chloride channel ClCKb, has been GWAS analyses (76–78).
identified as the most frequent cause of classic Bartter A GWAS for HTN using an extreme case-control design
syndrome. Both the chloride channels, ClCKa and identified a SNP in the 5′ region of Uromodulin gene
ClCKb, are expressed in the thick ascending limb (UMOD) which is almost exclusively expressed in the
(TAL) of the loop of Henle. ClCKa is exclusively thick ascending limb of the loop of Henle in the kidney,
expressed in the ascending limb, while ClCKb is identifying a potentially novel pathway of BP regulation
also expressed in distal convoluted tubule (DCT). through an effect on sodium homeostasis (33). Moreover,
Mutations in SLC12A1 and KCNJ1 cause the clas- independent studies have identified SNPs highly corre-
sic, less severe phenotype. The differential diagnosis lated with the HTN SNP near UMOD to be associated
includes pseudo-Bartter syndrome (diuretic abuse, with chronic kidney disease (79). In UMOD knockout
surreptitious vomiting), cystic fibrosis, Gitelman mice, there is increased localization of the salt-retaining
syndrome and celiac disease. Treatment includes NKCC2 (sodium-potassium-chloride cotransporter-2) in
oral potassium supplements, nonsteroidal anti- subapical vesicles of TAL cells with reduced phosphory-
inflammatory drugs (e.g. indomethacin) and possibly lation, resulting in reduced cotransporter activity with
potassium-sparing diuretics. resulting greater sodium excretion and a 20 mmHg lower
■■ Gitelman syndrome (GS) (OMIM #263,800), also BP compared with wild-type mice. Notably, this differ-
referred to as familial hypokalaemia-hypomagne- ence in BP was exacerbated with salt, whereby the knock-
semia, is characterized by hypokalaemic metabolic out mice were resistant to the hypertensive effects of salt
alkalosis in combination with significant hypomag- (80). Conversely, UMOD overexpression was associated
nesemia and low urinary calcium excretion. The with an increase in BP. The main sodium transporter in
prevalence of heterozygotes is approximately 1% in TAL is NKCC2, which is blocked by the commonly used
Caucasian populations, making it one of the most loop-diuretic furosemide. Trudu et al. (81). showed furo-
frequent inherited renal tubular disorders. Mutations semide treatment significantly enhanced natriuresis and
in the solute carrier family12, member 3 gene, reduced BP levels both in the transgenic mice and in the
SLC12A3, which encodes the thiazide-sensitive NaCl hypertensive individuals homozygous for the UMOD
cotransporter (NCC), are found in the majority of GS increasing allele.
patients. At present, more than 140 different NCC
mutations throughout the whole protein have been
identified. In a small minority of GS patients, muta-
tions in the CLCNKB gene, encoding the chloride AUTONOMIC NERVOUS SYSTEM
channel ClC-Kb, have been identified. Symptoms do
not appear before the age of 6 years, and the disease is The autonomic nervous system maintains cardiovascular
usually diagnosed during adolescence or adulthood. homeostasis via pressure, volume, and chemoreceptor sig-
BP is lower than that in the general population. Most nals through three endogenous catecholamines: norepi-
asymptomatic patients with GS remain untreated. nephrine, epinephrine, and dopamine synthesised in the
Lifelong supplementation of magnesium (magnesium adrenal medulla (epinephrine) and cytosol of adrenergic
oxide and magnesium sulphate) is recommended. neurons. Adrenergic reflexes modulate BP over the short
All GS patients are encouraged to maintain a high term, and adrenergic function, in concert with hormonal
sodium and high potassium diet. and volume-related factors, contributes to the long-term
regulation of arterial pressure. Increased sympathetic ner-
Resequencing three candidate genes (SLC12A3, vous system activity has a role in causing HTN (82) which
SLC12A1, KCNJ1) involved in Bartter and Gitelman syn- may be the result of background genetic susceptibility
drome in the Framingham Heart Study population iden- interacting with chronic psychogenic stress, obesity or
tified 30 distinct potentially deleterious rare mutations high sodium intake. HTN could also arise or be sustained
present in 49 subjects. In the heterozygous state, these by defects in baroreceptor function (83). Adrenergic recep-
variants were associated with 5.7 mmHg lower BP at age tors are classified into two types:
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OXIDATIVE STRESS,
INFLAMMATION, IMMUNE 8
SYSTEM AND HYPERTENSION
Pro-hypertensive factors
Immune system RAAS, ET-1, SNS
Genes, environment
Oxidative stress
ROS ROS
Oxidative stress
Hypertension
Figure 8.1 Interactions between reactive oxygen species (ROS), the immune system, kidneys and the cardiovascular sys-
tem in the pathogenesis of hypertension. Prohypertensive factors induce activation of immune cells, which produce ROS
that influence proinflammatory responses. Activation of Noxs in the kidney, heart and vascular wall, in response to prohy-
pertensive factors, induces excessive ROS generation and oxidative stress, leading to inflammation, fibrosis, vascular and
renal injury, and consequent hypertension. Abbreviations: RAAS, renin-angiotensin-aldosterone system; ET-1, endothelin-1;
SNS, sympathetic nervous system.
are associated with decreased risk for heart failure (46,47). participation of macrophages and immune-competent
Clinical studies in Japanese women showed a positive cells (particularly different subsets of lymphocytes) in
association between serum DJ-1 levels and improvements the mechanisms associated with the pathophysiology of
in metabolic syndrome (48). hypertension (58,59) (Figure 8.1).
Causes of perturbed redox status in hypertension Participation of the innate and the adaptive immune
are unclear but may relate in part to genetic factors. response in mechanisms that contribute to inflammation in
Polymorphisms in glutathione-S-transferase (intracellular cardiovascular disease has been reported in atherosclerosis
antioxidant enzyme) and the risk of essential hyperten- (58) and hypertension (59,60). Circulating and tissue leuko-
sion has been demonstrated (49). Polymorphisms have cytes/macrophages are important players in the inflamma-
also been shown in NADPH oxidase subunits in hyperten- tory response. However, it seems that some T-lymphocyte
sive patients. Individuals with p22phox polymorphisms subpopulations are involved in the development of high
exhibit altered Nox activity and increased ROS production blood pressure, endothelial dysfunction and vascular
in human cardiovascular disease. More recently, GWAS remodelling (61,62). Subsets of T lymphocytes, either effec-
data from over 450,000 individuals identified Nox4 and tor T cells, such as Th-1 (interferon-γ -producing), Th2 lym-
Nox5 as novel blood pressure-related genes (50). phocytes (producing interleukin-4, and Th17 (producing
interleukin-17), as well as T suppressor lymphocytes, such
as Tregs, which express the transcription factor Forkhead
box P3 (Foxp3), may play critical roles in the development
ROS − THE LINK BETWEEN of hypertension induced by Ang II infusion or in deoxy-
INFLAMMATION, IMMUNITY AND corticosterone/salt-sensitive or Dahl salt-sensitive hyper-
tensive rats. In addition, they have been demonstrated to
HYPERTENSION be involved in the progression of vascular remodelling
ROS play a pivotal role in linking the immune system, in these models of genetic or experimental hypertension
inflammation and hypertension. Immune cells produce (60,63) (Figure 8.2).
O2− and H2O2, which promote inflammation. Almost every T lymphocyte activation and inflammation are triggered
cell type involved in innate and adaptive immunity has by oxidative stress in hypertension (64,65). Enhanced
been suggested to be involved in the pathophysiology of adaptive immunity arising from a genetic predisposition
hypertension. Chronic subclinical, low-grade inflamma- may underlie vascular inflammation. This may be a conse-
tion involves ROS production by innate immune cells, quence of reduced immunosuppressant function of Tregs
leading to oxidative stress, causing vascular and renal dys- (60). Infiltrating T cells in the kidney exacerbate renal
function in hypertension. The importance of the innate damage in Ang II-induced hypertension in salt-sensitive
immune system in hypertension was demonstrated in rats (56).
mice deficient in macrophage colony stimulating factor Clinical studies demonstrated that T lymphocytes may
(M-CSF), an important hematopoietic growth involved also be important in the onset of microvascular damage
in maturation of myeloid cell populations (51). In these (66). A significant inverse correlation was demonstrated
mice, which have a reduced number of macrophages, Ang between indices of microvascular structure (media-to-
II-induced hypertension is attenuated, and vascular dys- lumen ratio of subcutaneous small arteries and wall-
function is ameliorated. These cardiovascular protective to-lumen ratio of retinal arterioles) and circulating Treg
effects are associated with reduced oxidative stress and lymphocytes (66). Positive correlations were also observed
decreased inflammation. Effector T cells, especially Th-1 between the media-to-lumen ratio of subcutaneous small
and Th-17, and regulatory lymphocytes, which are part of arteries and circulating Th17 lymphocytes (66). A rela-
the adaptive immune system, have been identified in the tionship between different subpopulations of circulating
kidneys and vascular wall in experimental and clinical CD4+ T lymphocytes and microvascular or systemic oxi-
hypertension (52). Recent studies indicate that subsets of T dative stress in humans was also observed. Hence some
cells express the mineralocorticoid receptor, important in circulating lymphocyte subpopulations may be related to
hypertension pathophysiology (53,54). Regulatory T cells microvascular remodelling through processes involving
(Tregs) suppress immune response activation and inflam- inflammation, oxidative stress and redox-sensitive prolif-
mation through immunosuppressive cytokines, including eration of vascular smooth muscle cells, important in vas-
TGF-β,IL-10, IL-35 and modulation of cAMP levels in tar- cular remodelling (67).
get cells (52). Activated B cells produce antibodies that also Infiltration of immune cells in various organs such as
have been implicated in hypertension. In Ang II-induced blood vessels, kidney and perivascular adipose tissue is
hypertension, the number of activated B cells and plasma an important component of the inflammatory response
cells is increased. When B cells are depleted with a CD20 leading to cardiovascular damage and hypertension (58–
antibody, Ang II-induced hypertension is blunted (55,56). 60). How activation of immunity is triggered remains
In pulmonary hypertension, lung vascular remodelling is unknown, but neoantigens could be generated by elevated
associated with B-cell activation induced by IL-6 produced blood pressure through damage-associated molecular pat-
by mast cells (57). tern receptors (DAMPs) or other unknown mechanisms
(60). Once activated, Th1 cells may contribute to blood
pressure elevation by affecting the kidney, vascular remod-
elling of blood vessels via direct effects of the cytokines or
THE IMMUNE SYSTEM IN HYPERTENSION through activation of the perivascular adipose tissue (62).
On the other hand, Treg cells might protect from blood
An increasing number of studies have addressed the role pressure elevation through immunoprotective mediators.
of innate and adaptive immunity in cardiovascular dis- It has been suggested that adaptive immunity is
ease, revealing a new paradigm that includes the active enhanced due to a genetic predisposition with loci on
Oxidative Stress, Inflammation, Immune System and Hypertension 71
Naïve T B
lymphocyte lymphocyte
Antigen
presentation
Granulocyte Dendritic cell CD4+ CD8+ Plasma Memory
T cell T cell cell cell
Th Tc
Treg
Th3 Th2 Th17 Th1 (CD4+ or CD8+ and CD25+)
Hypertension
IL-10 IL-4 IL-17 IFNγ
TGFβ IL-22
IL-21
Figure 8.2 Cells of the immune system that have been implicated in the pathogenesis of hypertension. Adaptive and
immune cells produce interleukins (IL) and various mediators that influence processes involved in hypertension.
Abbreviations: AP: antigen presentation, NK: natural killer, Tc: T cytotoxic, Th: T helper, Treg: T regulatory.
chromosome 2, which bears many proinflammatory oxidative stress and vascular injury, further supporting
genes, in hypertensive models such as the Dahl salt-sen- the idea that immune mechanisms are important in Ang
sitive rat, which exhibits an activated endothelin system II-dependent hypertension (66–69).
(63). The presence of the Brown Norway chromosome 2 While there is extensive experimental evidence suggest-
on the Dahl salt-sensitive background in the consomic rat ing a role for effector T lymphocytes in the pathophysiology
(SSBN2) was associated with upregulation of Treg mark- of hypertension, there is a paucity of information in humans
ers and activity, Foxp3 transcription factor expression (70,71). However, in human hypertension, with ageing,
and production of IL-10 and transforming growth factor effector lymphocytes may become senescent and lose some
(TGF)-β (63). Increased populations of T-lymphocytes and of their CD28, leading to blunting of the CD28:CD80/86 co-
Treg cells in the blood and the spleen were associated with stimulation axis, increased surface adhesion molecules and
increased blood pressure and vascular inflammation (63). enhanced cytotoxicity (72). In hypertensive patients, cir-
The vasculature of hypertensive rats revealed dysfunc- culating levels of interleukin-17A−producing CD4+ T cells
tional Treg cells that express low levels of Foxp3b and did and CD4+ and CD8+ T cells that produce interferon-γ were
not produce immunosuppressive mediators (TGF-β and found to be increased compared with normotensive controls
interleukin-10), thus leading to upregulation of inflamma- (73). In another clinical study, an increase of CD4+CD28-
tory responses (63,64). This also influenced vascular struc- IFN-γ+ Th1 circulating lymphocytes was observed in hyper-
ture, since in the aortas of Dahl salt-sensitive rats, wall tensive patients, compared with normotensive subjects. This
thickness was increased and preproendothelin-1 levels population corresponds to senescent lymphocytes and was
were increased. These alterations were partially attenuated previously demonstrated to be increased in some pathologi-
in consomic rats (63), supporting the notion that Tregs are cal conditions, including atherosclerotic vascular damage
involved in the development of cardiovascular disease and (74,75). Therefore, T cells might contribute to human hyper-
that T lymphocytes may influence blood pressure (63,64), tension as suggested by animal studies and may also regu-
at least in the models studied. late microvascular function (76).
In Ang II-infused mice lacking T and B cells (RAG-1−/− Th2 lymphocyte subpopulations have been shown
mice), development of hypertension is blunted and vas- to be important in microvascular function and struc-
cular remodelling is prevented compared with control ture, which might influence blood pressure by changes
C57BL/6 mice. Adoptive transfer of T, but not B, cells in capillary density. However, the role of Th2 lympho-
restored these abnormalities (65). Moreover, in Ang cytes is unclear because these cells have been shown to
II-infused mice, adoptive transfer of Tregs, but not of T have both vasoprotective and vasoinjurious effects (77).
effector cells, prevented development of hypertension, Some data suggest that Th1 and Th2 lymphocytes have
72 Manual of Hypertension of the European Society of Hypertension
counterregulatory effects and that the ratio of subtypes of disease, vascular remodelling and hypertension (84,85).
T lymphocytes may be important (78). The Th1/Th2 bal- Fundamental to these processes is increased generation of
ance may be crucial for chronic inflammation involved in ROS, decreased NO levels, oxidative damage and inflam-
the initiation and development of hypertensive vascular mation (86,87). However, exactly how immune cells are
disease and atherosclerosis (78). Th1 lymphocytes may activated, exactly what their functions are and where they
exert a detrimental role in terms of excessive ROS genera- are localized in hypertension still await clarification,
tion, production of vasoactive cytokines and promotion especially in the clinical setting. Nevertheless, strategies
of inflammation (70,71), which together with blunting of to normalize immune activation, reduce oxidative stress
vasoprotective Th2 lymphocytes might contribute to vas- and manipulate the inflammasome may have therapeu-
cular inflammation and damage. tic potential (87), especially in the prevention of vascular
Th17 cells produce IL-17A, which seems to be important injury and target-organ damage associated with hyperten-
in vascular dysfunction and inflammation associated with sion and other cardiovascular diseases.
hypertension (52). Mice deficient in IL-17A have blunted
Ang II-induced hypertension and reduced cardiovascular
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SODIUM AND
POTASSIUM 9
arterial structure and function even without an increase in BP response to changes in salt intake exquisitely behaves
BP, by inducing the endothelial production of transform- as a continuous variable with a simil-Gaussian distribution
ing growth factor-beta 1 (TGF-β1) and by decreasing the (17), not allowing detection of any distinct subpopulation.
expression of endothelial nitric oxide synthase. Moreover, Moreover, there is evidence that salt sensitivity of BP is asso-
sodium overload was found to decrease the endothelial ciated with a higher incidence of hypertension and with
glycocalyx sodium barrier and to increase endothelial stiff- other cardiometabolic risk factors. In addition to the genetic
ness. Other studies pointed to the local renin−angiotensin− and demographic factors, several metabolic and neurohor-
aldosterone system (RAAS) (heart, vessels and kidney) as monal conditions affect BP salt sensitivity, including excess
one of the mediators of organ damage. Indeed, in animal body weight and its related alterations (such as insulin resis-
experimental studies, a high-sodium regimen was shown tance, overactivity of the RAAS and of the SNS). Most of
to increase the expression of angiotensin II type 1 receptors these conditions are in turn associated with altered renal
(AT1-R) in the cardiovascular system and to increase the sodium handling. These observations provide a plausible
AT1-R density in the renal cortex while increasing the activ- support for the strong unfavorable interaction observed in
ity of the local RAAS. In keeping with these findings, the some studies between sodium intake and cardiovascular
administration of an AT1-R blocker during sodium load- risk in individuals with excess body weight (18).
ing decreased aortic collagen accumulation and improved
the cardiac, vascular and renal function. In addition, high
sodium intake was reported to increase the levels of vascu- SODIUM INTAKE AND CARDIOVASCULAR
lar and renal angiotensin-converting enzyme. DISEASE
Dietary sodium intake may also affect the sympathetic
nervous system (SNS) activity by increasing plasma osmo- In consideration of the proven relationship between
lality, which is in turn associated with significant incre- sodium intake and BP and of the additional BP-independent
ments in plasma norepinephrine and muscle sympathetic cardiovascular effects of high sodium intake, several lon-
nerve activity, additionally to the rise in BP. gitudinal studies have investigated the impact of habitual
Further to the experimental data, recent clinical stud- sodium intake on the incidence of cardiovascular events.
ies also support a contribution of excess sodium intake to The Scottish Heart Health Study, including 11,629 partici-
target-organ damage, even independently of increases in pants, found a significant association between sodium intake
BP. Assessment of the effect of sodium intake on AS, an and risk of coronary heart disease in women and a positive
independent cardiovascular risk factor and a predictor of but not significant trend in men (19). Another study per-
all-cause mortality (13), was the object of a recent meta- formed in Finland showed that a 100 mmol higher urinary
analysis, including 11 randomized controlled trials and 431 sodium excretion at baseline was associated with significantly
participants (3). The main results of this study indicated a higher coronary heart disease incidence, higher coronary
statistically significant effect of reduction in sodium intake heart disease death rate and higher mortality from all causes
on AS (expressed as carotid-femoral pulse wave velocity). (20). In the Trials of Hypertension Prevention (TOHP) I (21)
In particular, an average weighed difference of 89.3 mmol and TOHP II (22) intervention trials, including patients with
of sodium per day (5.2 g of salt) led to a 2.8% decrease in pre-hypertension at baseline, a significant decrease in BP was
AS, at least in part independent of the changes in BP. The achieved in the sodium-restricted group in comparison with
results were strengthened by the absence of significant het- the control group. Moreover, after 10–15 years of follow-up,
erogeneity among the studies, the lack of detectable publi- a significantly lower risk of CVD was observed in the partici-
cation bias, and the observation of a trend to AS decrease pants randomized to the sodium reduction group compared
with salt restriction in the majority of the cohorts included. to controls, without further active intervention (23). A recent
In addition, urinary albumin excretion, an expression analysis of these cohorts confirmed the beneficial effect of
of subclinical organ damage and risk factor for the devel- low sodium intake and detected a significant linear associa-
opment and progression of renal disease (13), is associ- tion between sodium intake and mortality (24).
ated with sodium intake. A meta-analysis of 23 studies A strong direct association between sodium intake and
(of which 11 were randomized controlled trials), includ- stroke has also been detected in several longitudinal studies.
ing 516 male and female participants overall, indicated The first meta-analysis of the available prospective studies
that sodium intake reduction markedly reduces albumin carried out in samples of general population unequivo-
excretion (2). An average reduction in sodium intake of cally showed a direct and significant association between
92 mmol per day (5.4 g of salt) was significantly associ- higher sodium intake and risk of stroke (25). The analysis
ated with a 32% reduction in urinary albumin excretion. included the results of 13 studies published between 1998
The effect of sodium restriction was higher in the cohorts and 2008, 170,000 participants and more than 11,000 vas-
including patients on concomitant RAAS-blocking therapy cular events. Based on a follow-up period of between 3.5
in the studies with intervention lasting at least 2 weeks, and 19 years, there was a 23% greater risk of stroke (and a
and among participants with evidence of kidney damage. 17% greater risk of total cardiovascular events) for an aver-
Left ventricular hypertrophy, another expression of organ age difference in salt intake of 5 g of salt per day.
damage and independent predictor of cardiovascular mor- Further meta-analyses were later published. In one meta-
bidity and mortality (13), was positively associated with analysis, the risk of stroke was calculated in 10 studies for a
sodium intake in two studies apparently through the increase total of 72,878 individuals, again from general population
in BP (14,15). However, an intervention study showed that samples (26). Higher compared with lower sodium intake
sodium restriction was associated with reduction in left ven- was associated with a 24% higher rate of stroke, while a 32%
tricular mass, in part independently of BP decrease (16). greater risk of coronary heart disease mortality was achieved
The so-called ‘BP salt-sensitivity’ may play a role in these in a sample of 30,000 participants. A further meta-analysis
results. The majority of individuals experience a decrease by Graudal et al. pooled both studies on general popula-
in BP when reducing dietary sodium intake. Actually, the tion and studies in high cardiovascular risk individuals or
Sodium and Potassium 77
patients with clinical cardiovascular disorders (27). The Several randomized controlled trials of the effect of
comparison of high (more than 215 mmol/day) versus usual potassium supplementation on BP were carried out and
sodium intake (115–215 mmol/day) with seven studies and their results have been examined in aggregate in several
186,091 individuals yielded a 21% higher rate of stroke in meta-analyses. The first such meta-analysis detected a sig-
the first group, whereas the comparison of low (less than nificant reduction of 4.4 mmHg systolic and 2.5 mmHg
115 mmol/day) sodium versus usual sodium, again with diastolic BP in hypertensive patients upon increasing
seven studies and 56,582 subjects, did not show a significant potassium intake by at least 0.78 grams per day (33).
difference. This study, however, has been criticized because A smaller effect was observed in trials with normoten-
of inadequate assessment of sodium intake and of high risk sive individuals (systolic BP: –1.8 mmHg and diastolic
of reverse causality due to the inclusion of cohorts of seri- BP: –1.0 mmHg), The antihypertensive effect of potas-
ously ill patients under intensive medical treatment. sium supplementation was more pronounced in the pres-
ence of elevated sodium intake and in black participants
compared with white. Similar results were provided by
SUMMARY AND RECOMMENDATIONS two more recent meta-analyses: one, including 22 tri-
als with assessment of potassium intake by 24-h urinary
A large amount of animal experimental investigation, epi- potassium excretion, showed an overall BP reduction of
demiological studies and controlled clinical trials support 3.5/2.0 mmHg, with a greater effect in hypertensive sub-
the causal relationship existing between excess sodium jects, in those who achieved a higher potassium intake and
intake and cardiovascular health (26). In most countries in those with a higher sodium intake (30). A third meta-
worldwide the habitual average sodium intake largely analysis, including 25 trials of hypertensive participants,
exceeds the physiological needs and the recommended found that long-term supplementation with potassium
adequate intake determined on the basis of scientific evi- salts reduced BP (systolic BP: 4.5 mmHg and diastolic BP:
dence (28). Mainly on the basis that the majority of indi- 3.0 mmHg), and that the effect was greater in individu-
viduals experience a decrease in BP when reducing salt als on antihypertensive treatment, having a high sodium
intake for a sufficiently prolonged period of time and that intake and with baseline potassium intake less than 3.5 g
the decrease is linear upon reduction of salt intake to val- per day (34).
ues below 5 g/day, a reduction of sodium chloride intake As there might be a difference in the response to potas-
to 5 g (2 g of sodium) based on WHO recommendation sium supplementation provided (usually as potassium
(28,29) is recommended. chloride) as a pharmacological preparation and one fol-
lowing a high potassium intake through natural foods in
which potassium occurs as a combination of organic and
inorganic compounds, it is important that some studies
POTASSIUM analyzed the effect of potassium-rich food consumption
as an alternative to oral potassium supplements. A long-
The main sources of dietary potassium are vegetables, fruits term randomized controlled trial evaluated the effects of
and dairy products. In foods, potassium occurs as a mixture increased potassium intake by an increase in fruit, vegeta-
of organic and inorganic compounds, whereas potassium ble and pulses consumption. After a 1-year follow-up, the
supplementation is most often provided as potassium- participants assigned to the potassium-rich diet achieved
chloride (1 mmol of potassium = 39 mg). Several stud- and maintained a satisfactory BP control with less than
ies have detected an inverse relationship between dietary half the amount of drugs needed by the control group (35).
potassium intake and BP both within and across popula- The protective role of dietary potassium toward CVD may,
tions (30). In consideration of this association and because however, include both the effects on BP regulation and other
hypertension is the leading cause of CVD, it is conceivable BP-independent effects. Indeed, many studies in animal
to expect that potassium intake may affect cardiovascular models suggested that a high potassium intake may reduce
morbidity and mortality. cardiovascular organ damage and counteract the increase in
cardiovascular event rates caused by a high sodium intake,
even independently from its effect on BP (36).
POTASSIUM INTAKE, BLOOD PRESSURE A study on stroke-prone spontaneously hypertensive
AND ORGAN DAMAGE rats (SHR-SP) kept on a high sodium diet showed that
a high versus low potassium intake was associated with
A relationship between dietary potassium intake and BP a significant reduction in death rate. This antagonistic
has long been known (4). A few studies evaluated the effect of potassium in relation to sodium was also shown
protective effect of a potassium-rich diet on the develop- in Dahl salt-sensitive rats, in which increased potassium
ment of hypertension. The main findings of the Health intake neutralized sodium-induced renal damage and the
Professionals Study were that the participants at potassium release of endothelium- and macrophage-derived growth
intake greater than 3.6 g/day had a reduced risk of hyper- factors. Moreover, after exposure to a high potassium
tension of 35% than those on a lower intake (less than intake, significant decreases of lipid peroxide accumula-
2.4 g/day) (31). Likewise, in the Nurses’ Health Study, base- tion, endothelial permeability and macrophage adherence
line potassium intake greater than 3.2 g/day was related to to the vascular wall were seen in the aortic wall and in the
a 23% lower risk of hypertension development in 4 years plasma of SHR-SP. In addition, in vitro investigations sup-
compared with an intake lower than 2 g/day (32). A more port a cardiovascular protective effect of high potassium
recent evaluation of the NHANES-2014 cohort, based on diet toward organ damage caused by a salt load, at least
24-h urine collections, again showed a strong and inverse in part through suppression of the production of reactive
relationship between urinary potassium excretion, BP and oxygen species (ROS) and through inhibition of vascu-
risk of hypertension (5). lar smooth muscle cell proliferation. Finally, potassium
78 Manual of Hypertension of the European Society of Hypertension
supplementation in SHR-SP was shown to provide neu- events. A beneficial effect was suggested both for men
roprotection by reducing the ischaemic cerebral infarct (45) and women (43), but the effect was significant only
size, whereas in DOCA-salt rats a potassium-rich diet led for men (45).
to a reduction of cardiac and renal hypertrophy, indepen- A small number of studies are available on the effect of
dently of reduction in BP. potassium consumption on occurrence of total cardiovas-
Unfortunately, only few data are available about the cular events and coronary heart disease.
effect of potassium supplementation on cardiovascular A meta-analysis of prospective studies in samples of
organ damage in humans. A randomized controlled trial general population showed an inverse and significant
on 42 mild hypertensive patients found that both potas- association between higher habitual potassium intake and
sium chloride and potassium bicarbonate supplementa- risk of CVD (40). In particular, the analysis based on the
tion improved AS (assessed as carotid-femoral pulse wave results of six cohorts, including 82,000 people and more
velocity) and endothelial function (expressed as brachial than 3000 coronary heart disease events, detected a 7%
artery flow−mediated dilatation), decreased left ventricu- lower risk of coronary heart disease for 1.4 g per day dif-
lar mass and ameliorated left ventricular diastolic function ference in potassium intake. In addition, the analysis of
when compared with placebo (37). No difference between total cardiovascular events based on four cohorts, 62,000
the two potassium salts was detected. On the other hand, participants and 2500 events found a 26% lower risk of
only potassium chloride supplementation also reduced total cardiovascular events for an average difference of
24-h urinary albumin excretion. 1.3 g per day. The trend was substantially confirmed by a
The data on the effects of potassium supplementation more recent meta-analysis that included only trials with
on AS were pooled in a recent meta-analysis including a assessment of potassium intake by 24-h urinary potassium
small number of randomized controlled trials (38). The excretion (30).
main results confirmed the favourable trend; however,
potassium supplementation significantly improved only
pulse pressure, while a not significant reduction in pulse SUMMARY AND RECOMMENDATIONS
wave velocity and augmentation index was detected.
In conclusion, experimental, clinical and epidemiological
studies consistently support a favourable effect of dietary
POTASSIUM INTAKE AND CARDIOVASCULAR potassium intake on stroke risk and stroke mortality, at
DISEASE least in part independently of its well-recognized ben-
eficial effect on BP. More data are needed to reach a firm
Given the clear-cut relationship between potassium conclusion about the relationship between potassium sup-
intake and BP, and considering the additional and in part plementation and cardiovascular events rate.
BP-independent cardiovascular effects of potassium sup- Based on the large body of evidence available, most
plementation, a number of studies over three decades have national authorities recommend as adequate a potassium
also explored the possible association between habitual intake of 90 mmol or more per day (3.5 g per day) for the
dietary potassium intake and the incidence of cardiovas- adult population, with the exception of individuals with
cular events. renal disease compromising potassium handling (46).
A particularly strong inverse association has been demon-
strated between potassium intake and risk of stroke. A pioneer
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346: f1326.
STRUCTURAL CARDIOVASCULAR
CHANGES IN HYPERTENSION 10
ventricle (LV) volume and relative wall thickness (RWT) more evident in patients with concentric LVH (16). Several
or LVM/volume ratio. Using this approach, different pat- mechanisms may be involved in the pathophysiology
terns of geometric adaptation can be identified, i.e. non- of coronary angiopathy (1,17,18). The first is endothelial
dilated ventricles, concentric remodelling or concentric dysfunction causing an impaired vasodilator potential of
LVH, eccentric remodelling or eccentric LVH. Concentric coronary microvessels. In addition, hypertension favours
hypertrophy is the condition associated with the high- an increased atherosclerotic process leading to accelerated
est cardiovascular risk. The assessment of LVH is per- development of plaques in coronary epicardial arteries. A
formed using the classical electrocardiogram, the more further mechanism is a structural inward remodelling of
sensitive echocardiographic technique (both two- and the coronary arterial wall, causing an increased wall/lumen
three-dimensional), and with cardiac magnetic resonance ratio of small coronary arteries and arterioles. This remod-
imaging, which is the gold standard, but often of limited elling can occur in combination with perivascular fibrosis
availability, relatively costly and time consuming (5,6). and subsequent compression of the outer surface of these
In early, mild hypertension, even before the detection of small vessels (19). Finally, reduction of the number of small
LVH, the first manifestation of cardiac organ damage may arteries, arterioles and capillaries (rarefaction) is a fur-
be LV diastolic dysfunction, usually clinically assessed by ther mechanism that induces reduced coronary perfusion
echo Doppler examination. This abnormality is even more (19–21).
evident with the development of LVH and increased colla- Coronary reserve, a measure of the capacity of the cor-
gen content in the LV, being often associated with enlarge- onary vasculature to respond maximally to vasodilator
ment of the left atrium, as a consequence of increased agents, is significantly decreased in hypertensive patients
LV filling pressure. In addition, systolic function may be (18). Presumably, under conditions of increased myocar-
reduced, but usually a depressed LV pump function may dial oxygen demand, decreased ability to dilate the coro-
be detected in an advanced stage of cardiac organ damage. nary microvasculature translates into diffuse ischemia
Most patients with longstanding hypertension, particu- and infarction. Such a propensity to ischemia may explain
larly those with LVH, ultimately develop HF, and therefore some of the increased risk for coronary events and sudden
in about 70–75% of patients with HF a history of hyperten- cardiac death, particularly in patients with LVH. In addi-
sion may be present (7,8). In fact, with sustained pressure tion, impaired subendocardial blood flow may contribute
overload, the development of LVH and the impairment of to diastolic dysfunction and increase the risk and sever-
diastolic function lead to the clinical signs and symptoms ity of HF. The microcirculation is more often abnormal in
of HF with preserved ejection fraction (HFpEF), which is HFpEF (8). The role of the microcirculation is dealt with
above 50%. In this transition, fibrosis of the interstitium more fully in the section below concerned with the struc-
of the myocardium plays a central role. Fibrosis can be ture and function of resistance vessels.
triggered by humoral factors. The RAAS is again a key fac-
tor in initiating fibrotic changes in the heart, in particular
via the action of aldosterone (9). Other important media-
tors include matrix metalloproteinases (10), integrins such STRUCTURAL CHANGES IN BLOOD
as osteopontin (11), and inflammatory cytokines, includ- VESSELS
ing transforming growth factor beta. Recent research
has focused on the role of reactive oxygen species in the Hypertension is associated with a range of structural
fibrotic changes of the heart and in cardiac remodelling changes in the vasculature. The nature of the changes and
(12,13). All these mediators are now important targets for their functional consequences differ per segment of the
novel drugs in the regression of LV structural changes. vascular tree (Table 10.1). The most significant alterations
Patients with HFpEF are usually older women with a occur on the arterial side and in the microcirculation. With
long history of hypertension, frequently obese, with diabe- respect to arterial structural changes, a distinction can be
tes, hyperlipidaemia and atrial fibrillation. Hypertension made in large arteries (the aorta and its side branches), and
may also favour the development of coronary artery dis- resistance vessels. The large arteries primarily serve a con-
ease and of an enlarged LV (eccentric LVH), with reduction duit and compliance function, whereas the small arteries
of systolic function, as assessed by EF, leading to HF with and arterioles control vascular resistance. The difference
reduced EF (HFrEF). Further studies are needed in order to
clarify whether there is usually a transition from concen-
tric LVH to HF with normal LV dimension to dilated HF, Table 10.1 Segments of the vascular tree and their structural
or whether HFpEF and HFrEF should be considered two change in hypertension
separate entities, related to differences in hemodynamics,
neurohumoral activation and/or genetic factors (1,8). Segment of the Functional
vascular tree Structural change consequence
between large and resistance arteries is also reflected in are also involved in the control of VSMC function, such as
the heterogeneity of the way in which they remodel in migration, proliferation, adhesion and cytoskeletal rear-
response to a rise in BP. Large arteries adapt to increased rangement (25,27) and may thus influence large artery
pressure by expressing early response genes that lead to properties in different ways.
vascular smooth muscle cell (VSMC) hypertrophy and The molecular basis of arterial stiffness has been the
an increased wall thickness. Small arteries, on the other topic of recent intensive research with a particular focus
hand, rapidly constrict without changing wall material on vascular calcification (30) and histone metabolism
(eutrophic inward remodelling) and thereby normalizing (31). A recent study provides the transcriptomic land-
wall stress. Only in severe hypertension, small vessels may scape of human aortic VSMCs in response to extracellu-
also undergo hypertrophic remodelling (22). lar matrix stiffness and identifies novel stiffness-sensitive
The basic architecture of arteries is usually described in human long noncoding RNAs (32). Nongenomic influ-
terms of cross-sectional arrangement of cells and extracel- ences also contribute importantly to the increased large
lular matrix. Cells include the endothelial cell layer and artery stiffness in hypertension. One factor is the ele-
VSMCs. The extracellular matrix consists of lamellae of vated blood pressure as such. An elevated pressure shifts
elastic material with intervening layers of VSMCs, colla- the pressure-distensibility relationship toward a lower
gen fibres and ground substance (23). However, the dis- distensibility value (33,34). This observation led to the
tribution of elastin and collagen varies markedly along conclusion that hypertension-induced large artery hyper-
the longitudinal axis. In the proximal aorta, elastin is the trophy is not necessarily associated with increased arte-
dominant component, whereas in the distal aorta and its rial stiffness (33). Despite increased wall thickness due
side branches, as well as in the smaller arteries, collagen to VSMC hypertrophy, the stiffness of the artery wall
predominates. The smaller the arteries become, the more material as assessed by the modules of elasticity is not
VSMCs predominate. These differences find their origin in increased in hypertensive patients or in the spontane-
the early development of the vascular system. The reader is ously hypertensive rat (33).
referred to the specialized literature for further details on Another source of nongenomic influence on large
this aspect of vascular development (23). artery structure and function is a range of humoral and
metabolic products. It is beyond the scope of this contri-
bution to discuss all these products in detail. The RAAS
has received the most attention in this respect (35,36). Its
LARGE ARTERY STRUCTURE AND major mediators − angiotensin II and aldosterone − affect
FUNCTION IN HYPERTENSION arterial structure considerably and beyond their effects on
BP. They activate signal transduction pathways that pro-
In hypertensive patients, the stiffness of large arteries is mote VSMC growth, inflammation and fibrosis. Studies in
usually increased. Arterial stiffening is part of the ageing both experimental animals and humans with hyperten-
process, but it is accelerated in humans prone to develop sion suggest that drugs blocking the RAAS have an impact
hypertension (24). A complex interplay of molecular, cel- on early mechanisms of vascular disease, such as endothe-
lular and functional modifications of the arterial wall lial dysfunction and arterial remodelling (36).
contributes to the increased stiffness. The French school The clinical significance of arterial stiffness is consider-
of vascular investigators who have made important contri- able. Clinical studies have demonstrated that large artery
butions to this field of research have recently reviewed this stiffness is a strong risk factor and contributor to heart fail-
complex interplay in detail (24,25). Epidemiological stud- ure, coronary heart disease, stroke, cognitive impairment,
ies have shown that up to 40% of the variance in indices chronic kidney disease and aneurysms (24,37). The patho-
for arterial stiffness may be genetically determined (26). physiological basis of this enhanced risk for target-organ
The major genetic factors that determine arterial stiffness damage−related diseases is the abnormal pulsatile hemo-
have been reviewed (27,28). Furthermore, the relation- dynamics due to arterial stiffening that causes microvas-
ship between polymorphisms of several candidate genes cular dysfunction (38). In particular, large artery stiffening
and arterial stiffness has been investigated. Various candi- produces impedance matching that reduces wave reflec-
date genes of the RAAS play a key role in arterial stiffness. tion and exposes the microcirculation to excessive pulsa-
However, the contribution of a given polymorphism to tile stress, resulting in microvascular target-organ damage
the variance of a specific phenotype is limited (27,28). In and dysfunction. The reader is referred to recent detailed
subjects of the Flemish Study on Environment, Genes and reviews on this topic (38,39).
Heat Outcomes (FLEMINGHO) we found a much stron-
ger contribution in individuals showing specific combina-
tions of gene variants (29). For instance, the combination
of angiotensin-converting enzyme DD subjects homozy-
gous for alpha-adducin gly 460 was a powerful predictor
STRUCTURE AND FUNCTION
of increased large artery stiffness (29). OF RESISTANCE ARTERIES IN
Another genetic approach, particularly followed by HYPERTENSION
Lacolley, Laurent and their co-workers, is the study of
large artery properties in subjects with monogenic disease The precapillary vessels distal to the large (conduit) arter-
or in knockout mice with phenotype changes in arterial ies are collectively known as resistance vessels. These ves-
wall properties (25,27). The data obtained following this sels consist of the arterioles (vessels with only one layer of
approach highlight the role of vascular smooth muscle smooth muscle cells) and the more proximal small arter-
cells and extracellular matrix components. Furthermore, ies. The division between large and small arteries is arbi-
the data show that collagen and elastin are not simply pas- trarily set to vessels with diameter ca. 200 µm (40), keeping
sive compounds that can be elastic or rigid, but that they in mind that there is considerable cross-talk between the
84 Manual of Hypertension of the European Society of Hypertension
large arteries and the resistance vessels (41,42). The resis- In renovascular hypertension, patients exhibit hypertro-
tance vessels contribute to the major part of the peripheral phic remodelling of small arteries due to smooth muscle
resistance and to its control. Furthermore, the resistance cell hypertrophy, without evidence of hyperplasia (59).
vessels are responsible for the increased peripheral resis- The prognostic value of abnormal small artery structure
tance seen in established essential hypertension, and the has been investigated in a number of studies. These stud-
resistance vessels thus play a key role in the pathogenesis ies have shown that an increased media-to-lumen ratio of
of this disease. gluteal small arteries is associated with increased cardio-
In principle, the increased resistance of the resistance vascular risk (60,61). There is also evidence that a hyper-
vessels can be due either to a narrowing of the lumen or trophic response of the more proximal small arteries to
to a rarefaction (with fewer parallel-connected vessels). essential hypertension is predictive of additional cardio-
Evidence concerning narrowing of the vessels has been vascular risk (62).
obtained primarily from gluteal biopsies of small arter- Izzard et al. (62) have reviewed the mechanisms of
ies (43), findings that have been widely confirmed (44). inward eutrophic remodelling of small arteries from
Evidence for rarefaction in essential hypertension is older essential hypertensive individuals. Their conclusion was
(45) but again has been widely confirmed (21,46). The that chronic vasoconstriction is the stimulus for a struc-
clinical relevance of microvascular structure as a prognos- tural reduction in lumen diameter, a conclusion supported
tically relevant endpoint has been recently reviewed (47). by more recent experimental studies (63). The nature of
the contractile stimulus is still not fully resolved. Neural
or humoral factors may be involved, although Izzard et al.
(62) favour the myogenic properties of the small arteries
HEMODYNAMIC STUDIES as the underlying mechanism. The myogenic vasoconstric-
tion could serve to maintain wall stress at constant value.
Measurements of peripheral resistance using forearm
Patients with type 2 diabetes show a severely impaired
plethysmography as pioneered by Folkow (48) have
myogenic constriction to increases in intraluminal pres-
repeatedly indicated a structural basis for increased resis-
sure. In these patients, impaired myogenic tone would
tance of the resistance vasculature in essential hyperten-
increase wall stress and thereby promote small artery
sion. Such hemodynamic studies have been extended to
hypertrophy (62). The molecular pathways may include
other vascular beds, including the coronary circulation
tissue transglutaminase (64,65) and ROS-activated MMP9
where essential hypertension has been shown to be asso-
(66). Schiffrin and co-workers (67) have recently obtained
ciated with a reduced coronary reserve (49). Such studies
evidence that low-grade inflammation plays an important
have also shown that in essential hypertension, compared
role in small artery remodelling. In particular, activated
to controls, excessive microvascular structural abnormali-
T cells may contribute to vascular remodelling directly on
ties in the coronary and peripheral circulations are raised
blood vessels via effects of the cytokines produced or indi-
proportionally more than the blood pressure, suggesting
rectly by actions on the kidney (67). Similar evidence for
that structural changes might precede the rise in blood
a role of angiotensin II type-1 receptor−mediated immune
pressure (50). An alternative approach is based on analysis
responses in the development of vascular changes in
of the pulse wave, where reflection of the pulse from the
hypertension has been found (68).
resistance vasculature causes an increase in the augmenta-
tion index (AIx) (51). To some extent the AIx is a measure
of the resistance vessel structure (52), and recent evidence
has indicated that AIx is increased in offspring of essential DIRECT OBSERVATION
hypertensive parents independent of blood pressure (53).
The possibility that the increased peripheral resistance in
essential hypertension is associated with rarefaction of
the arterioles was supported by numerous animal studies
EX VIVO EVIDENCE where selected vascular beds could be examined either in
vivo or histologically (69,70). Microvascular rarefaction
The reason for the narrowing of resistance vessels in hyper- has two major consequences. Firstly, reduction of arte-
tension appears to be primarily due to changes in struc- riolar density increases vascular resistance. Secondly, it
ture, and few functional changes have been observed (54). disturbs the tissue delivery of oxygen and nutrients, thus
The structural change is an inward eutrophic remodelling: contributing to target-organ damage in hypertension.
a reorganization of the VSMC around a narrower lumen Microvascular rarefaction can be functional or structural.
(55,56). Indeed, Schiffrin and co-workers (57) concluded Functional rarefaction refers to an abnormally low preva-
from their observations that small artery structure is one of lence of anatomically existing but nonperfused microves-
the first manifestations of target-organ damage, occurring sels. Structural rarefaction represents a situation in which
before proteinuria or cardiac hypertrophy. In addition to the microvessels are anatomically absent. This can be due
these changes in VSMC structure and function, the extra- either to active elimination of microvessels or to a lack of
cellular matrix is critically important in the altered proper- growth during the development of microvascular networks
ties of small arteries in hypertensive subjects. With chronic (71). In humans, Ruedemann in 1933 reported that hyper-
vasoconstriction, some degree of cell migration, secretion tensive patients had an abnormally low number of small
of fibrillar and nonfibrillar components, and rearrange- conjunctival vessels (45). The relevance of rarefaction for
ment of extracellular matrix-cell interactions may occur human essential hypertension has been demonstrated in
(44). Data from gluteal subcutaneous small arteries have the skin vasculature (46,72). There is also evidence that
indicated an age-dependent increase in reactive oxygen rarefaction precedes the onset of hypertension (73) sug-
species (ROS) and in collagen in both essential hyperten- gesting that the primary defect in angiogenic mechanisms
sion (EH) and normotension (NT), greatest in EH (56–58). could be responsible for the development of hypertension.
Structural Cardiovascular Changes in Hypertension 85
The cause-and-effect relationships between microvascu- hypertensive disease. Furthermore, structural changes
lar rarefaction and hypertension are still under discussion. in the heart and blood vessels play an important role in
Various authors have shown that mechanical forces due to hypertension-induced target-organ damage. In the treat-
increased pressure and/or flow may cause structural arteri- ment of hypertension, prevention of target-organ dam-
olar and capillary rarefaction (70). Conversely, antiangio- age is an increasingly important goal. We may expect
genic treatment of cancer can cause hypertension (74,75). that future therapies will specifically target the structural
Rarefaction has been proposed linked to a lack of bone changes reviewed in this chapter.
marrow−derived endothelial progenitor cells (EPC) (76).
However, the role of EPCs is complex (77) and a clear rela-
tionship of EPCs to hypertension has not been established.
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EARLY VASCULAR
AGEING 11
100% damaged
Arterial wall
100% normal
Childhood Early adulthood Middle-age Advanced age Elderly (> 80)
Figure 11.1 Healthy vascular ageing (HVA), early vascular ageing (EVA) and supernormal vascular ageing (SUPERNOVA),
determined as a function of arterial wall damage according to age. EVA can be defined as an aortic pulse wave velocity
(aPWV) more than 2 standard deviations above the predicted value for a certain age and sex within a defined population (i.e.
higher than the 97.5th percentile of aPWV). SUPERNOVA can be defined as aPWV more than 2 standard deviations below
the predicted value for a certain age and sex within a defined population (i.e. lower than the 2.5th percentile of aPWV).
Nonmodifiable Modifiable
to bridge more than a century to revive the importance resistance arteries, and thus increase arterial stiffness and
of large arteries and their properties in cardiovascular induce arteriolar remodelling, respectively. In response
medicine. to this large/small artery cross-talk (20), central blood
pressure and tensile pulsatile circumferential stress are
increased. Thus, a feedback mechanism (21) is developed,
since central pressure and tensile pulsatile circumferen-
THE EMERGENCE OF THE EVA CONCEPT tial stress act as key mechanical determinants of arterial
AND ATTEMPTS MADE TO DEFINE IT wall remodelling and cell-ECM interactions. Lacolley
et al. (19) have speculated on the contribution of cellular
Arterial stiffness has been accumulating evidence as an stiffness along the arterial tree to vascular wall stiffness
intermediate cardiovascular endpoint. It has been estab- (18). Now that important hemodynamic and molecular
lished as an independent risk marker for cardiovascular mechanisms of arterial stiffness have been elucidated and
disease and reflects the dissociation between chronologic the complex interplay between ECM, cells, and sensors
and biologic age of large arteries, causing the earlier devel- identified, further research should study their potential to
opment of cardiovascular risk that normal vascular ageing halt or reverse the development of arterial stiffness.
could induce several years later (10). The EVA concept is
developed to establish primordial prevention, identifying
individuals whose ageing path has been accelerated either
by inherent features, interaction with the environment, or GENETICS OF ARTERIAL STIFFNESS AND
arterial exposure to several types of insults that evolve to
medial layer morphological changes. Understanding the THE ROLE OF GLYCAEMIA
pathophysiology of vascular ageing, its consequences and In the review by Lacolley et al., a summary of the evidence
therapeutic opportunities, is therefore an advantage that linking genetic factors to arterial stiffness has been pro-
could be translated in time of prevention and survival free vided (19). This is an expanding area of research and could
of cardiovascular disease. As the EVA construct is advanc- contribute to finding causal pathways influencing arterial
ing, new features appear as interesting to better translate stiffness based on Mendelian randomization methodol-
it into clinical practice (10), particularly through gold ogy. New and very recent data indicate that a genetic risk
standard measurements (15) and reference values (16). score (GRS) for a hyperglycaemic trait, separate from GRSs
Attempts have been made to define EVA. The most use- linked to type 2 diabetes, hypertension or hyperlipidae-
ful is perhaps to define it as aPWV more than 2 standard mia, is significantly associated with aPWV in an elderly
deviations above the predicted value (i.e. higher than the Swedish population (22), thereby strengthening the link
97.5th percentile of aPWV) for a certain age and sex within between impaired glucose metabolism and increased arte-
a defined population (10) or based on a large European rial stiffness that a number of observational, epidemio-
database of healthy, normotensive individuals (16). Even logical studies have also been reported (23,24). Increased
the out-of-proportion remodelling of the aorta, as vis- aPWV is even a risk marker for future incidence of type 2
ible from magnetic resonance imaging (MRI), has been diabetes in the same population (25).
regarded as a marker of vascular ageing (17), a phenom-
enon most pronounced in the thoracic part of the aorta
and in, for example, female patients with Turner (45, X0)
syndrome (18). CHRONIC INFLAMMATION
Another important aspect of vascular ageing is the influ-
ence of chronic low-grade inflammation. Large artery stiff-
MOLECULAR MECHANISMS BEHIND ening has been reported during various diseases associated
ARTERIAL STIFFNESS AND with chronic low-grade inflammation, such as rheumatoid
arthritis, systemic lupus erythematosus, systemic vascu-
MECHANOTRANSDUCTION litis, human immunodeficiency virus and inflammatory
It is important to develop a deeper understanding of the bowel disease (26,27). In a population-based study, it was
molecular basis of arterial stiffness in order to find new shown that inflammatory markers at baseline predicted
treatment targets beyond conventional risk factor control. the development of arterial stiffness during follow-up (28).
A recent review has summarized the state-of-the art knowl- Various mechanisms have been suggested, including endo-
edge in this area (19). Although it is generally accepted thelial dysfunction, activation of VSMC-mineralocorticoid
that the major components that contribute to arterial receptor related to ANG II, cell release of a number of
stiffening are extracellular matrix (ECM) proteins, such inducible matrix metalloproteinases, elastocalcinosis and
as elastin and collagens, a second important component is accumulation of proteoglycans in the media, and finally
vascular smooth muscle cells (VSMCs), the role of which adventitial immune cells and cytokines released from the
has been highlighted more recently. VSMCs not only vasa vasorum in response to vessel ischemia (29).
regulate actomyosin interactions for contraction but also
mediate mechanotransduction in cell-ECM homeostasis.
Both VSMC contraction and changes in cell-ECM interac- COGNITION – BRAIN AGEING
tion, for instance through the architecture of cytoskeletal
proteins and focal adhesions, can transfer the mechanical The process of vascular ageing is also reflected by brain age-
load from elastic components to stiff components, and ing and cognitive decline. Subjects with increased arterial
thus increase the stiffness of the wall material. VSMCs stiffness are more prone to deteriorate according to cognitive
plasticity and signalling can affect both c onductance and function over time (30), and to show more abnormalities by
92 Manual of Hypertension of the European Society of Hypertension
complications. In particular, calorie restriction and moder- other risk factors to influence risk in a life course perspec-
ate physical activity are recommended in primordial pre- tive (43). Finally, new ways to understand biological ageing
vention, even if it is often difficult for individuals to accept. in general, and vascular ageing in particular, could con-
Calorie restriction is one of the most effective among tribute to a better understanding and identification of new
the potential interventions that retard vascular ageing treatment targets. For example, studies on telomere length
(39). Calorie restriction has been reproducibly shown to and impaired glucose metabolism in relation to PWV could
improve endothelial function, prevent atherosclerosis and bring new knowledge. In the end we should, however, focus
arterial stiffening, reduce myocardial interstitial fibrosis not only on risk associated with PWV and EVA in various
and cardiac apoptosis, improve cardiac function and pro- populations, and corresponding treatment, but also on HVA
long lifespan in various experimental model animals (39). and SUPERNOVA to learn more about vascular protection.
Calorie restriction also confers significant microvascular
protection by improving endothelial angiogenic capacity,
increasing cortical microvascular density, and restoring
microvascular nitric oxide synthesis, all of which enhance ACKNOWLEDGEMENTS
the metabolism of parenchymal tissues.
Niiranen et al. (34) assessed the prevalence, correlates This work was supported by the Research Council of
and prognosis of HVA in 3196 Framingham Study partici- Sweden (PMN) and by INSERM, Assistance-Publique
pants aged ≥50 years during a follow-up of 9.6 years. In Hopitaux de Paris, and Paris Descartes University (SL).
Cox regression models adjusted for traditional cardiovas-
cular risk factors, including blood pressure, they showed
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Diet and Cancer study. J Hypertens 2015; 33(5): 957–965. gatherer subsistence mode on arterial distensibility in
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cence and pentosidine are associated with aortic stiffening: The 37. Hollenberg NK, Fisher ND, McCullough ML. Flavanols, the Kuna,
Maastricht study. Hypertension 2016; 68(4): 956–963. cocoa consumption, and nitric oxide. JASH 2009; 3: 105–112.
25. Muhammad IF, Borné Y, Östling G et al. Arterial stiffness and 38. Grimes KM, Reddy AK, Lindsey ML, Buffenstein R. And the beat
incidence of diabetes: A population-based cohort study. Diabetes goes on: Maintained cardiovascular function during aging in the
Care 29 September 2017. pii: dc171071. doi: 10.2337/dc17-1071. longest-lived rodent, the naked mole-rat. Am J Physiol Heart Circ
26. Roman MJ, Devereux RB, Schwartz JE et al. Arterial stiffness in Physiol 2014; 307: H284–H291.
chronic inflammatory diseases. Hypertension 2005; 46: 194–199. 39. Alfaras I, Di Germanio C, Bernier M et al. Pharmacological strate-
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with inflammatory bowel disease. J Am Heart Assoc 2017; 6(10). devices for hypertension. Lancet 2012; 380(9841): 591–600.
28. Muhammad IF, Borné Y, Östling G et al. Acute phase proteins as 41. Paulis L, Becker ST, Lucht K et al. Direct angiotensin II type 2
prospective risk markers for arterial stiffness: The Malmö Diet receptor stimulation in Nω-nitro-l-arginine-methyl ester-induced
and Cancer cohort. PLOS ONE 2017; 12(7): e0181718. hypertension: The effect on pulse wave velocity and aortic remod-
29. Laurent S, Boutouyrie P. The structural factor in hypertension: eling. Hypertension 2012; 59(2): 485–492.
Large and small artery alterations. Circ Res 2015; 116: 1007–1021. 42. Williams B, Mancia G, Spiering W et al. Authors/Task Force
30. Scuteri A, Tesauro M, Appolloni S et al. Arterial stiffness as an Members: 2018 ESC/ESH Guidelines for the management of
independent predictor of longitudinal changes in cognitive func- arterial hypertension: The Task Force for the management of
tion in the older individual. J Hypertens 2007; 25(5): 1035–1040. arterial hypertension of the European Society of Cardiology and
31. Mitchell GF, van Buchem MA, Sigurdsson S et al. Arterial the European Society of Hypertension: The Task Force for the
stiffness, pressure and flow pulsatility and brain structure and management of arterial hypertension of the European Society of
function: The Age, Gene/Environment Susceptibility—Reykjavik Cardiology and the European Society of Hypertension. J Hypertens
study. Brain 2011; 134(Pt 11): 3398–3407. 2018; 36(10): 1953–2041.
32. Nilsson ED, Elmståhl S, Minthon L et al. Nonlinear association 43. Olsen MH, Angell SY, Asma S et al. A call to action and a life-
between pulse wave velocity and cognitive function: A popula- course strategy to address the global burden of raised blood pres-
tion-based study. J Hypertens 2014; 32(11): 2152–2157, discussion sure on current and future generations: The Lancet Commission
2157. on Hypertension. Lancet 2016; 388(10060): 2665–2712.
AUTONOMIC
DYSFUNCTION 12
Gino Seravalle and Guido Grassi
MSNA (bs/min)
Pre-hypertension (7,8,10) ↑ ↑
*
Systo-diastolic HT (15) ↑ ↑ 40 **
HT mild (9,13) ↑ ↑
20
HT severe (9,13) ↑ ↑
Baroreflex dysfunction
Chemoreflex dysfunction
Cardiopulmonary reflex dysfunction
Central factors
Insulin
SNS
Leptin
RAA system
Oxidative stress
Hypertension
Inflammation
Organ damage
Antifibrinolysis
Hypercoagulability
CV risk
Figure 12.2 Schematic drawing of the mechanisms potentially responsible for sympathetic activation in hypertension.
SNS, sympathetic nervous system; RAA, renin-angiotensin-aldosterone; CV, cardiovascular.
98 Manual of Hypertension of the European Society of Hypertension
Intervention MSNA
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THE RENIN−ANGIOTENSIN−
ALDOSTERONE SYSTEM 13
INTRODUCTION RENIN
The renin−angiotensin−aldosterone system (RAAS) is one The gene encoding the renin precursor preprorenin is
of the oldest hormonal systems—regardless of whether localized on chromosome 1q32. Mature renin contains
‘old’ is defined as phylogenetically old, or in the sense 340 amino acids and has a mass of 37 kD (6). Renin is pri-
of being discovered a long time ago (1). The first descrip- marily released by the juxtaglomerular apparatus of the
tion of a RAAS component came from Robert Tigerstedt kidney. Renin secretion is under tight control of several
and his student Per Bergman as early as 1897, when they parameters, such as BP and blood volume, plasma sodium
injected a kidney homogenate derived from a healthy rab- content, and sympathetic activation (7). A tight control
bit into another healthy rabbit, resulting in a marked eleva- of renin release is absolutely necessary, because cleavage
tion in blood pressure (BP) in the recipient (2). Tigerstedt of angiotensinogen by renin is the rate-limiting step in
and Bergman termed the BP-elevating substance ‘renin’. the enzymatic cascade leading to Ang II synthesis, i.e. the
It took decades until, in 1934, the groups by Eduardo rate of angiotensinogen cleavage is set by the amount and
Braun-Menendez in Buenos Aires and by Irvine Page in activity of renin, not by the amount of angiotensinogen,
Indianapolis coincidentally, but independently, found that which is always available in abundance in the plasma.
the actual BP-elevating substance was not renin itself, but
a molecule that was cleaved and activated by renin, and
which is nowadays termed angiotensin II (Ang II) (3,4).
Today, we know that the RAAS represents a cascade of ANGIOTENSIN-CONVERTING ENZYME
enzymatic reactions. The huge precursor molecule of Ang II,
angiotensinogen, is cleaved by renin, resulting in the still The gene for ACE has been mapped to chromosome 17q23
inactive decapeptide angiotensin I (Ang I), which is then and translates into a 150 kDa protein, which belongs to
further cleaved by the membrane-bound metalloenzyme the family of zinc metallopeptidases (8). ACE cleaves the
angiotensin-converting enzyme (ACE) to give the main C-terminal dipeptide His-Leu from Ang I, thus generat-
effector hormone of the RAAS, Ang II (Figure 13.1) (1). ing Ang II. However, Ang I is by far not the only substrate
of ACE. ACE also metabolizes bradykinin, substance P,
luteinizing hormone (LH)-releasing hormone, enkepha-
lins, or the insulin β-chain. In all these latter cases, cleavage
COMPONENTS OF THE RENIN– by ACE does not elicit an activation of the molecule (as
ANGIOTENSIN–ALDOSTERONE SYSTEM with Ang I), but degradation and inactivation. Thus, inhi-
bition of ACE activity, which is one of the most common
pharmacological principles in cardiovascular medicine,
ANGIOTENSINOGEN not only leads to a decrease in Ang II synthesis, but also
to the accumulation of those molecules, which are physi-
Angiotensinogen is a glycosylated α 2-plasmaprotein with ologically degraded by ACE.
a molecular weight of 55–65 kDa (5). In situ hybridization A variation in the ACE gene structure was recognized in
studies indicate that the human angiotensinogen gene is 1990, consisting of the insertion (I) or deletion (D) of a 250
located on chromosome 1q42-3. It codes for the angioten- BP DNA fragment located in intron 16 (9). This so-called
sinogen protein, which, in its mature form, is built from ‘ACE I/D polymorphism’ has been suspected to be associ-
452 amino acids. Renin cleaves the first 10 amino acids, ated with a variety of cardiovascular and noncardiovascu-
which correspond to Ang I. lar diseases but currently, conclusive data pointing to an
There is evidence that a variant of the angiotensinogen association with the I/D polymorphism only exist for dia-
gene is associated with increased angiotensinogen plasma betic nephropathy and Alzheimer’s disease, while reports
levels and hypertension (5). on most cardiovascular phenotypes are still controversial
102 Manual of Hypertension of the European Society of Hypertension
a kind of ‘mobile’ RAAS, accumulating at places of injury a natriuretic effect of the AT2R through internalisation/
and inflammation (42). inactivation of the Na+/H+ exchanger-3 and Na+/K+
Other organs displaying AT1R and AT2R comprise the ATPase within the proximal tubule (50). The natriuretic
lung, retina, spleen, thymus and liver (1). effect is of such strength that the AT2R may be regarded
as potential target for novel diuretics.
The central actions of Ang II affecting blood pressure
control are also subject to the ying-yang relationship
PHYSIOLOGICAL ACTIONS between AT1R and AT2R: while the AT1R promotes vaso-
OF ANGIOTENSIN II pressin release and sympathetic tone, the AT2R inhibits
vasopressin release and sympathetic outflow by interfer-
Since angiotensin receptors mediate a wide variety of ence with GABAergic signalling (51,52).
actions depending on receptor subtype, tissue or species, we
concentrate in this chapter on their cardiovascular actions
in health and disease, with an emphasis on hypertension.
One of the major physiological functions of Ang II con-
sists in the control and maintenance of adequate BP. This
PATHOPHYSIOLOGICAL ACTIONS OF
is achieved by a row of independent mechanisms, one of ANGIOTENSIN II IN HYPERTENSION
them the control of vascular tone. AND RELATED END-ORGAN DAMAGE
Vascular tone is determined by a well-orchestrated
action of endothelial cells and vascular smooth muscle While the above-stated actions of Ang II on blood vessels,
cells (VSMCs). In this context, stimulation of the AT1R kidneys and the brain serve to maintain adequate BP and
on VSMCs is responsible for the contractile response via extracellular fluid volume in times of sodium depletion
activation of phospholipase C and an increase in intracel- (a problem our early ancestors were confronted with more
lular Ca-concentrations (43). Endothelial cells are capable than present-day populations) or fluid (blood) loss, an
of promoting vasodilation by synthesis of NO, which can excess of circulating or local Ang II or an overactivity of
penetrate into VSMC, where it initiates cGMP generation, the RAAS have deleterious effects and contribute to hyper-
thus stimulating protein kinase G, which again leads to tension and related end-organ damage.
a decrease in cytoplasmic calcium. Apart from its direct For some forms of secondary hypertension, the activa-
effect on vascular tone, Ang II also promotes vasocon- tion of the RAAS is an obvious and well-examined patho-
striction by facilitating noradrenalin release from vascu- physiological mechanism (53). For instance, in the case
lar nerve endings and by improving the responsiveness of of reduced renal perfusion pressure as a result of renal
VSMC to noradrenalin (44). artery stenosis or parenchymal disease (e.g. chronic glo-
Ang II, via the AT2R, has been shown to induce NO merulonephritis or pyelonephritis, polycystic renal dis-
synthesis by activation of eNOS through phosphoryla- ease, connective tissue disorders), renin secretion from
tion of the serine1177 residue and dephosphorylation the juxtaglomerular apparatus is increased, resulting in
of tyrosine657 (45,46). There is strong evidence that the elevated plasma Ang II levels (7). The pathophysiological
AT2R-induced synthesis and release of NO translates into role of the RAAS in essential hypertension is less obvi-
vasodilation in isolated vessels ex vivo (47). However, with ous. The most prominent hint towards a dysregulation of
the exception of specific conditions such as intracerebro- the RAAS in essential hypertension comes from the
ventricular or intrarenal application of AT2R agonists or observation that in the majority of hypertensive patients,
obese animals, AT2R stimulation does not lead to a lower- renin levels are either normal or upregulated, although
ing of systemic blood pressure in animals. reduced renin levels would be expected as a reaction to
Apart from the above-described effect of Ang II on BP increased renal perfusion pressure. Only about one-third
by modification of the diameter of resistance arteries, of patients display low renin levels (54). Several sug-
control and maintenance of adequate BP by Ang II fur- gestions have been made to explain what causes these
thermore involves the modulation of extracellular fluid ‘inappropriately’ high levels of renin: (a) increased sym-
volume. Ang II plays a major role in volume and elec- pathetic drive, (b) nephron heterogeneity with a subpop-
trolyte homeostasis by its numerous actions on kidney ulation of ischaemic nephrons responsible for increased
function. For example, Ang II can directly modify the glo- tonic renin release and (c) defective feedback regulation
merular filtration rate by constricting efferent and affer- of RAAS activity in kidneys and adrenals in response to
ent arterioles (48). In addition, Ang II is able to facilitate varying levels of sodium intake.
sodium retention by direct effects in the proximal tubule Hypertension is one of the most relevant risk factors
or by indirect effects such as decreased medullary blood for cardiovascular morbidity and mortality due to its
flow or an enhanced filtration fraction. Ang II−induced deleterious effects on end-organ structure and function
aldosterone release from the adrenals represents another (55). It is well established for most affected tissues that
mechanism contributing to the control of sodium and an activated RAAS contributes to hypertension-related
water retention. All these renal effects resulting in sodium end-organ damage (56). The vasculature reacts to chroni-
and water reabsorption are mediated via the AT1R cally elevated BP levels with remodelling of the vascular
(1,26,48). In recent years, much progress has been made wall, leading to an increased media-to-lumen ratio. This
in the understanding of the role of the AT2R in water and growth-promoting effect of Ang II can be largely attributed
sodium homeostasis. There is evidence that AT2R stimu- to the activation of growth factors such as PDGF, VEGF or
lation may inhibit renin release from the juxtaglomerular bFGF via the AT1R (55). However, there is more to vascu-
apparatus, thus acting in concert with the AT1R, which is lar end-organ damage than just hypertrophy. Ang II via
a very rare exception of the rule that the AT2R counter- the AT1-receptor stimulates NAD(P)H oxidases, resulting
acts AT1R actions (49). Furthermore, recent data point to in the production of reactive oxygen species (ROS) and
The Renin−Angiotensin−Aldosterone System 105
increased oxidative stress (57). NO, a major vasodilator ischaemic cerebral damage by promoting oxidative stress
and vasoprotective agent, reacts strongly with the super- and inflammation, by further deteriorating brain perfu-
oxide anion O2− , thus losing bioactivity (58). Furthermore, sion and by pro-apoptotic mechanisms (79).
the powerful oxidant ONOO− emanates from this reac- Again, the AT2R has effects opposing those of the AT1R
tion. Oxidative stress and ROS production are nowadays and acts neuroprotective in stroke by various mechanisms
considered to be stimuli for local inflammation and including anti-inflammation and BDNF synthesis (80).
fibrosis via activation of key transcription factors, such as
NF-kappaB and AP-1, followed by an enhanced transcrip-
tional rate of various cytokines, chemokines, adhesion
factors and, again, growth factors (59). Direct stimulation THERAPEUTIC INTERVENTION WITH
of NF-kappaB and AP-1 by Ang II itself may further add to THE RAAS
this effect (60). While the arising inflammatory response
contributes to the higher susceptibility of hypertensive Therapeutic intervention with the RAAS is discussed in
patients for developing atherosclerosis and cardiovascu- detail in the following chapters of this book. In brief,
lar disease, vascular fibrosis is the major determinant of there are two main mechanisms by which the RAAS can
arterial stiffness. be inhibited: either by inactivation of the enzymes respon-
In contrast to the role of the AT1R in hypertensive sible for Ang II generation or by blockade of the angioten-
vascular remodelling, inflammation and atherogenesis, sin AT1-receptor (Figure 13.2) (81). ACE inhibitors have
the AT2R has been described to attenuate hypertension- been the first development in this row of RAAS-interfering
induced vascular remodelling, inflammation and to delay drugs (82). Originally, they were thought of as therapeu-
the development of atherosclerosis (61–63). tics for hypertensive patients with an activated RAAS and
Regarding Ang II actions in the heart, it is well docu- high renin plasma levels. However, it soon turned out
mented that Ang II via the AT1R promotes cardiac hyper- that they were also effective in patients with normal renin
trophy, which is mainly due to cardiomyocyte hypertrophy plasma activity, which constitute the majority of patients
(64). Cardiac hypertrophy develops as a reaction to chron- with essential hypertension. Moreover, in parallel with
ically elevated intracardiac pressure (due to hypertension growing scientific knowledge about Ang II actions beyond
or as a result of stenosis of the cardiac valves or the big, BP regulation, in particular its role in the promotion of
afferent blood vessels). Cardiac hypertrophy is a compen- end-organ damage, clinical data revealed that ACE inhibi-
satory mechanism, which in earlier stages preserves car- tors have the potential to prevent end-organ damage by
diac function. However, an excess of hypertrophy leads to mechanisms exceeding the reduction of BP, for example,
decompensation, resulting in cardiac failure and increased by inhibition of inflammation, fibrosis or hypertrophy
mortality (65). Several mechanisms lead to a deterioration (83). The same additional effectiveness was found to be a
of cardiac function due to enhanced Ang II production, feature of AT1R-blockers (ARBs) (83). Both drugs − ACE
among them impaired diastolic calcium handling (66), inhibitors and ARBs − act by diminishing Ang II actions
cardiac fibrosis (67), impaired diastolic relaxation due to mediated by the AT1 receptor − ACE inhibitors by reduc-
disturbed sarcoplasmic reticulum calcium pump activity ing the amount of stimulating Ang II, ARBs by direct recep-
(68) and also arrhythmias (69). tor blockade. Furthermore, both drugs display additional
The role of the AT2R in cardiac hypertrophy − whether it mechanisms of action: ACE inhibitors by accumulation of
is pro- or antihypertrophic − is a current matter of debate. bradykinin, thus stimulating bradykinin actions such as
Controversial data arose from studies in AT2R-knockout increased NO synthesis, and also by enhancing the forma-
mice with different locations of the deletion and with dif- tion of the protective RAAS mediator, angiotensin-(1-7),
ferent genetic backgrounds. However, more recent studies and ARBs by facilitating the activation of unblocked AT2-
using AT2R-agonists for direct AT2R-stimulation rather receptors by Ang II.
pointed to an antihypertrophic or neutral role of the AT2R
regarding cardiac hypertrophy (70,71).
Renal damage is a frequent long-term consequence of Angiotensinogen
hypertension (72). It is characterized by renal arteriolar
thickening, fibrinoid deposition into the glomeruli, and Renin-inhibition Renin
is accompanied by an inflammatory response and protein-
uria (73). Ang II by acting on the A1TR is involved in these Angiotensin I
pathogenetic mechanisms by its growth-promoting, pro-
inflammatory and profibrotic features as discussed above. ACE-inhibition ACE
Furthermore, fibrinoid deposition is facilitated by leakage
of renal microvessels (74). Ang II seems to promote leak-
age of microvessels in the kidney and other organs (e.g. in Angiotensin II
retina or heart) via increased VEGF expression (75).
In contrast, the protective effect of AT2R stimulation
on hypertensive kidney damage has been demonstrated
in spontaneously hypertensive rats and in Ang II induced
hypertension (50,76,77). AT1R-blockade
AT1 AT2
Hypertension is the most important risk factor for stroke.
Stroke is caused by either intracranial haemorrhage or cere-
bral infarction, the latter being a consequence of athero- Figure 13.2 Therapeutic interventions with the renin−
sclerotic plaque formation in arteries nourishing the brain angiotensin−aldosterone system.
or of embolism of cardiac origin (78). Ang II contributes to
106 Manual of Hypertension of the European Society of Hypertension
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STRESS, STRESS REDUCTION
AND HYPERTENSION: 14
AN UPDATED REVIEW
PSYCHOSOCIAL STRESS
RAAS
Central AT-1R
Oxidative
stress
Brain RAAS
↑ ROS, ↑ ET-1
SNS Endothelial Activation of
Inflammation Immune system
↑ Catecholamines
Endothelial Endothelial
dysfunction dysfunction
↑ ET-1, ↓NO
Vasoconstriction
↑ BLOOD PRESSURE
HYPERTENSION
Figure 14.1 Pathways linking psychological stress to hypertension. Abbreviations: RAAS, renin–angiotensin–aldosterone
system; ANG-II, angiotensin -II; AT-1R, angiotensin type-1 receptors; SNS, sympathetic nervous system; ROS, reactive oxy-
gen species; ET-1, endothelin-1; NO, nitric oxide; ↑, increase; ↓, decrease.
Stress also decreases the baroreceptor reflex response, potentiate the hypertensive effect of norepinephrine (NE)
‘adjusting’ BP to a higher level (27,35). by increasing its expression and inhibiting its uptake from
the nerve endings (37,38). Increased Ang II levels also
increase the production of endothelin-1 (ET-1) and reac-
ROLE OF RENIN–ANGIOTENSIN–ALDOSTERONE tive oxygen species (ROS), which leads to vasoconstriction,
SYSTEM endothelium dysfunction and up-regulation of transcrip-
tion factors such as nuclear factor-κB, consequently pro-
Stress-induced increased SNS activity and catecholamine moting vascular inflammation and causing hypertension.
levels activate the RAAS, which increases angiotensin- Increased circulating Ang II by stimulating the physiologi-
II (Ang II) and aldosterone levels. Increased aldosterone cally active angiotensin-1 receptors (AT-1R) in the brain
results in sodium retention, and increased Ang II causes may also contribute to the formation and release of glu-
vasoconstriction (36). Both aldosterone and Ang II cocorticoids, aldosterone and catecholamine (39,40), all
Stress, Stress Reduction and Hypertension 111
of which play role in the pathogenesis of hypertension Guidelines for Diagnosis, Risk Assessment, Prevention,
(27,32). and Treatment of Hypertension in Adults recommended
stress management in individuals in whom stress might
be contributing to high BP (56). Below, we review the
ROLE OF THE HYPOTHALAMIC−PITUITARY− existing evidence on efficacy of the most common stress
reduction approaches for elevated BP, with critical updates
ADRENAL AXIS on the data.
Stress-induced activation of the HPA axis results in increase
of glucocorticoid and aldosterone levels (30,41–43).
Though the exact role of glucocorticoids in stress-induced
hypertension is not yet fully understood, it is thought TRANSCENDENTAL MEDITATION TECHNIQUE
that the glucocorticoids show their BP-increasing effects
by supporting the peripheral effects of catecholamines A September 2017 scientific statement from the AHA
(27,44). Like catecholamines, glucocorticoids may alter the reported that meditation practices are a widely acces-
endothelial and vascular smooth muscle cell functions by sible group of methods for stress reduction that may be
triggering the secretion of ET-1, cytokines and the produc- considered as an attractive cost-effective adjunct to more
tion of ROS in vitro (45,46). Aldosterone increases sodium traditional medical therapies for BP reduction and car-
and water retention, decreases NE uptake at nerve endings diovascular disease (CVD) prevention (57). In this scien-
and has a negative effect on endothelial function (38). tific statement, the AHA committee did not distinguish
between different types of meditation despite their het-
erogeneous effects on BP reduction and CVD prevention.
However, the 2013 AHA scientific statement on alterna-
ROLE OF THE IMMUNE SYSTEM AND tive methods to lower BP did consider the evidence for dif-
ENDOTHELIAL DYSFUNCTION ferent stress-reduction behavioural methods on BP (55).
This included various approaches to meditation as well.
Endothelial dysfunction due to repeated episodes of The authors found that the only meditation practice that
BP elevation under stress contributes to development of had sufficient evidence to warrant a recommendation for
hypertension. It is suggested that repeated episodes of consideration in clinical practice was the Transcendental
acute sympathetic stimulation result in sharp increases Meditation (TM) technique (55).
in BP which may damage the vascular endothelium and The AHA committee recommendation for TM in clinical
impair the release of NO, which under normal condi- hypertension was based on the series of systematic reviews,
tions causes vasodilatation and resists the effects of vaso- meta-analyses, and clinical trials that corroborated the
constrictors such as Ang II and ET-1 (47,48). In addition, efficacy of TM in reducing BP and cardiovascular risk (55).
ROS generated after stress reduce the production and/ Among the studies considered by the scientific committee
or bioavailability of NO (49). Acute elevations in BP are was a meta-analysis comprising nine randomized con-
also associated with increased activation of circulating T trolled trials (RCTs) of TM with 711 subjects. The inves-
cells that infiltrate blood vessels. These cells release proin- tigators found significant reduction in SBP (−4.7 mmHg)
flammatory cytokines that promote vasoconstriction and and diastolic blood pressure (DBP) (−3.2 mmHg) with TM
sodium retention, leading to hypertension (50–52). compared to control arms (58). The reduction in BP for
the hypertensive subgroup was −5.1/−2.1 mmHg and for
high quality studies was −6.4/−3.4 mmHg (58). A second
SUMMARY systematic review and meta-analysis of high quality RCTs
on stress reduction treatment for BP reported the average
Though details of pathophysiological mechanisms under- change of −5.0/−2.8 mmHg with TM (59).
lying stress-induced hypertension are not completely Meta-analyses published after the 2013 AHA state-
known, substantial evidence suggests complex interaction ment have confirmed the efficacy of TM in reducing BP
between the nervous, endocrine (SNS, RAAS, HPA axis) (60,61). Bai et al. in 2015 conducted a systematic review
and immune systems. and meta-analysis of 12 studies including 996 partici-
pants and found −4.26 mmHg reduction in SBP and
−2.33 mmHg reduction in DBP with TM practice com-
pared with control groups (60). Most recently, Ooi et al.
STRESS REDUCTION IN HYPERTENSION conducted an overview of eight systematic reviews and
meta-analyses that included a report by the Agency for
Considering the findings that psychosocial stress contrib- Healthcare Research and Quality, a Cochrane systematic
utes to development of hypertension (53,54), it is relevant review, four independent reviews, and two other reviews
to consider stress reduction interventions for treatment (61). The authors found a clear trend of increasing evi-
and prevention of hypertension. dence over the years supporting the efficacy of TM in low-
A variety of stress reduction methods have been pro- ering BP (61).
posed to be useful in hypertension. A recent American In clinical practice, TM is described as a simple, easy and
Heart Association (AHA) scientific statement reviewed natural technique for reducing stress and gaining deep rest
and recommended behavioural methods to lower BP. and relaxation. It is practiced twice daily for 20 minutes
Based on evidence from the literature published through while sitting in a comfortable position (62,63). Related
2013, AHA reviewed a range of mind−body approaches to research on the TM technique has shown significant reduc-
provide a class of recommendation for their implementa- tions in psychological distress (64) including anxiety (65),
tion in clinical practice (55). In addition, Canada’s 2017 posttraumatic stress (66) and depression (67,68).
112 Manual of Hypertension of the European Society of Hypertension
EFFECTS ON CARDIOVASCULAR MORBIDITY DBP with MBSR compared to the control group (87,88).
AND MORTALITY Because of the negative or mixed results of studies, AHA
RCTs on the TM technique have reported reduction in did not recommend the use of MBSR in clinical practice to
cardiovascular clinical events. In an RCT of 201 patients reduce BP (55).
with coronary heart disease, after an average follow-up of Since the AHA 2013 scientific statement, more RCTs have
5.4 years there was a 48% reduction (hazard ratio 0.52; been published that assessed the BP-lowering efficacy of
95% CI, 0.29–0.92) in the composite of all-cause mortal- MBSR. Some found MBSR effective in reducing BP (85,89),
ity, myocardial infarction or stroke in the TM practitioners while others did not (90,91). In 2014, Abbott et al. con-
compared to health education controls (69). In 202 older ducted a systematic review and meta-analysis to determine
hypertensive patients randomly assigned to TM or controls the effectiveness of MBSR in patients with vascular disease
with a mean follow-up of 7.6 ± 3.5 years, TM practice was (92). For assessing the efficacy of MBSR on BP reduction,
associated with a decrease in cardiovascular mortality by they pooled the results of 4 RCTs and found moderate
30%, and 23% decrease in all-cause mortality compared effect sizes of MBSR for SBP, standardized mean difference
with other behavioural interventions and usual care con- (SMD) −0.78 (95% CI −1.46 to −0.09, p = 0.03), and DBP,
trols (70). SMD −0.67 (95% CI −1.26 to −0.08, p = 0.03) compared
to the control group (92). However, the authors did not
report the change of BP in units/mmHg. In order to deter-
MECHANISMS OF BP LOWERING mine BP reduction in mmHg with MBSR, we calculated the
Results from a series of laboratory studies suggest that weighted mean difference in BP by including all the RCTs
TM counteracts pathophysiologic mechanisms associated published in the English language, including those in the
with stress. A meta-analysis of 31 studies showed signifi- Abbott et al. review, plus RCTs published subsequently that
cant reductions in several indicators of autonomic activity had assessed the effects of MBSR on BP. Seven RCTs were
during practice of the TM compared to resting quietly with published through 2017 (84–86,88–91). The calculated
eyes closed (71). In adolescents at risk for hypertension, weighted means of these trials showed −2.99 mmHg in
TM has been found to reduce cardiovascular reactivity SBP and −1.03 mmHg in DBP with MBSR compared to the
(72) and enhance autonomic recovery to laboratory stress- control group (Table 14.1). Of the seven RCTs, the small
ors (73). Studies have reported decrease in sympathetic study by Palta et al. (86) reported markedly different effects
activity (74,75), decreased plasma catecholamine levels from the other six studies and had the smallest sample size
(76), decreased adrenergic receptor sensitivity (77) and (n = 20). Therefore, in a sensitivity analysis, the weighted
decreased cortisol (78) with TM practice. mean difference was recalculated without this study. The
results showed a weighted mean difference of −2.36 mmHg
in SBP and −0.52 mmHg in DBP with MBSR compared to
the control groups (Table 14.2).
CONCLUSION
The concordance in BP reduction reported by several inde-
pendently conducted systematic reviews, meta-analyses
EFFECTS ON CARDIOVASCULAR MORBIDITY
and scientific statements emphasize the effectiveness of the
TM technique in BP reduction. The mean decreases in SBP AND MORTALITY
and DBP of approximately 5 and 3 mmHg, respectively, No RCTs have reported the effect of MBSR on cardiovascu-
are comparable to lifestyle modification therapies recom- lar clinical events as of this writing.
mended by AHA and European Society of Hypertension
guidelines (e.g. sodium restriction, weight loss, aerobic
exercise) (79–81). In long-term RCTs, TM practice was MECHANISM OF BP LOWERING
found to decrease rates of mortality, myocardial infarc- The mechanisms of possible BP lowering by MBSR have
tion and stroke, which has not been documented for other not been fully elucidated, but it is proposed that MBSR
stress-reducing approaches for hypertension to date. reduces psychological stress and its psychological cor-
relates. There are few studies that have assessed changes
in catecholamines and cortisol, though results are het-
erogeneous. One study found decrease in catecholamine
MINDFULNESS-BASED STRESS REDUCTION
levels with MBSR compared to the control group (94). A
Mindfulness-based stress reduction (MBSR) is another few other studies reported significant decrease in cortisol
extensively practiced stress reduction program that levels (83,95–97) while several did not find any change in
employs an 8-week structured mindfulness meditation catecholamine or cortisol levels with MBSR compared to
program to ease mental and physical suffering associ- the control group (91,98–103).
ated with physical, psychosomatic and psychiatric disor-
ders (82). The individual learns the capacity to live with
open and non-judgemental awareness towards all expe- CONCLUSION
riences within the present moment (82). In the 2013 sci- Systemic reviews and meta-analysis have suggested the
entific statement, the AHA committee ascribed Class III, efficacy of MBSR in reducing psychological stress, but the
no benefit, Level of Evidence C to MBSR (55). There was effect on physiological correlates of stress have been het-
no meta-analysis available before 2013, and the avail- erogeneous. The weighted mean BP change derived from
able randomized and nonrandomized studies reported all the randomized controlled trials published through
varied results of BP-lowering efficacy of MBSR, rang- 2017 on MBSR found modest decrease in SBP ∼−2 mmHg
ing from decrease in SBP only (83) or DBP only (84), or and DBP ∼−1 mmHg. No long-term effects on CVD clini-
both (85,86), or no significant reduction in either SBP or cal events have been documented.
Stress, Stress Reduction and Hypertension 113
Abbreviations: RCT, randomized controlled trial; ΔSBP, change in systolic blood pressure; ΔDBP, change in diastolic blood pressure.
Table 14.2 Weighted mean of BP reduction with MBSR excluding study by Palta et al.
Abbreviations: RCT, randomized controlled trial; ΔSBP, change in systolic blood pressure; ΔDBP, change in diastolic blood pressure.
(−2.4/−2.1 mmHg) in BP in the relaxation-assisted bio- Whether additional pathways are involved requires future
feedback group compared to control (108). investigation.
Since the AHA 2013 scientific statement, no new meta-
analysis or systemic review has been published, but a
recent RCT published in 2016 on 59 prehypertensive or CONCLUSION
stage I hypertensive patients did not find significant differ- The evidence for the effectiveness of yoga as a treatment
ence in BP change between the active BP feedback group for hypertension shows average reductions of ∼−5 mmHg
and the pseudo-feedback control group (109). Overall, we SBP and ∼−3 mmHg DBP. There is no current evidence
find no consistent reduction in BP with biofeedback-based for efficacy in reducing cardiovascular morbidity and
reviews of meta-analyses and recent RCTs. mortality.
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Section III
Associated Risk Factors: Pathogenetic Role
and Risk Modification
HEART RATE AS A
CARDIOVASCULAR RISK 15
FACTOR IN HYPERTENSION
Paolo Palatini
18
0.04
16
14
0.03
Relative frequency (%)
12
10
Frequency
0.02
8
4 0.01
0 0.00
45 52 58 65 72 78 85 92 98 105 112 40 60 80 100 120
Heart rate (bpm) Heart rate (bpm)
Figure 15.1 Heart rate distribution of resting heart rate in the HARVEST study. Left panel shows a skewed distribu-
tion. The Kolmogorov-Smirnov test for normal distribution rejects normality (P = 0.0027). Coefficient of skewness, 0.58
(P < 0.0001). The right panel shows heart rate distribution after application of mixture analysis. Two different subpopula-
tions have been identified, a larger one with normal heart rate and a smaller one with high heart rate. (Adapted from Palatini
P et al. Hypertension 1997; 30: 1267–1273.)
were taken into account (18). The same group of investiga- Several other pioneer studies confirmed that association.
tors later documented that tachycardia was also a potent The correlation was particularly strong for sudden death
predictor of the metabolic syndrome (19). Similar associa- in the Framingham Study with a sixfold increase in risk for
tions were found in Japanese populations (20,21). The rela- the men in the top heart rate quintile compared to those
tionship between heart rate and the metabolic syndrome of the bottom quintile (27). In the last 15 years, numer-
was addressed by a recent meta-analysis which included ous new analyses that used refined statistical methods
17 cross-sectional and longitudinal prospective studies adjusting for a large number of confounders and risk fac-
encompassing 170,000 subjects (22). This study showed tors confirmed the findings of the above-cited pioneering
that high heart rate is a potent predictor of metabolic studies. In the Copenhagen Male Study, Jensen and col-
abnormalities, with a 28% increase in risk of the metabolic leagues (28) assessed whether a raised resting heart rate
syndrome for a 10-bpm increment in heart rate. The risk was a robust predictor of cardiovascular mortality inde-
was more than doubled for the highest versus the lowest pendent of inflammation. In that study, a 10-bpm increase
heart rate category. in heart rate was still associated with a 14% increased
In conclusion, the above data indicate that tachycar- risk of cardiovascular mortality. A significant association
dia primarily reflects a heightened sympathetic tone and between heart rate and death from cardiovascular disease
that the sympathetic predominance is a causative factor was also found in a large Norwegian cohort of 180,353
for the development of obesity and insulin resistance in men and 199,490 women aged 40–45 years (29), though
hypertension. This contention is supported by a number the relationship was reduced when adjustments for main
of longitudinal studies in which the baseline heart rate risk factors were made. Recent results from the MESA
predicted future metabolic abnormalities. Particularly rel- (Multi-Ethnic Study of Atherosclerosis) study (30) in 6766
evant to this issue are the results obtained in studies of asymptomatic participants showed that elevated resting
heart rate variability which allows a thorough assessment heart rate was also associated with increased risk for inci-
of the sympatho/vagal balance (23–25). dent heart failure. For 10-bpm increase in resting heart
rate, there was a 40% greater adjusted relative risk of heart
failure. Studies performed in Asian populations confirmed
the results obtained in Western societies (31,32). In the
PROGNOSTIC VALUE OF HIGH HEART National Survey on Circulatory Disorders, resting heart
RATE IN GENERAL POPULATIONS rate showed a significant association with cardiovascular
and all-cause death in middle-aged men (33). Heart rate
A relationship between tachycardia and adverse cardio- also showed a significant association with cardiac events
vascular outcome was shown for the first time by Levy but not with stroke. A relationship between heart rate
et al. (26), who found that cardiovascular mortality was and cardiovascular or total mortality was also found in
higher among subjects with sustained tachycardia at base- the setting of general practises. In a prospective study of a
line evaluation than among those with normal heart rate. cohort of men from 24 British towns (the British Regional
Heart Rate as a Cardiovascular Risk Factor in Hypertension 123
Heart Study) (34), there was a strong positive association trandolapril STudy (INVEST) study, a 5-bpm increment
between resting heart rate and rates of all major ischaemic in resting heart rate was associated with a 6% excess risk
heart disease events (fatal and nonfatal), ischaemic heart in all-cause death, nonfatal myocardial infarction, or
disease deaths and sudden cardiac death. The risk of sud- nonfatal stroke (44). Of particular interest are the results
den cardiac death in men with tachycardia was five times obtained in the VALUE study (45), in a large number of
higher than in those with heart rate <60 bpm. The avail- patients with high-risk hypertension. Both baseline and
able evidence from general populations has been recently in-trial heart rates were powerful predictors of the com-
summarized by Zhang et al. in a meta-analysis of 46 stud- posite cardiovascular outcome. The highest risk was
ies, which showed that people with heart rate >80 bpm found in the patients with tachycardia and blood pressure
had a 45% increased risk of total mortality compared with uncontrolled by treatment. However, the risk was elevated
those with heart rate <60 bpm (35). More recently, the also in the patients with blood pressure well controlled by
same group of investigators found a significant association treatment if their heart rate was >80 bpm. This indicates
between heart rate and cardiovascular events in a meta- that in hypertension the risk can be lowered only margin-
analysis of 45 studies (36). ally by antihypertensive treatment if heart rate remains
elevated. In the ASCOT-BPLA study (46), baseline heart
rate predicted all-cause, noncardiovascular, and cardio-
vascular mortality that occurred during the follow-up,
PROGNOSTIC VALUE OF HIGH HEART but not nonfatal cardiovascular events. Among the hyper-
RATE IN HYPERTENSION tensive patients from the ONTARGET and TRANSCEND
studies, the risk of cardiovascular mortality increased by
Tachycardia is a common feature in patients with hyper- 77% in those with heart rate >78 bpm (47). In a prospec-
tension. According to an Italian study performed in gen- tive study of 528 patients with resistant hypertension (48)
eral practises, over 30% of hypertensive patients exhibit a U-shaped relationship was found between heart rate
a heart rate >80 bpm, a cutoff frequently used to separate and prognosis, particularly for heart rate measured with
out tachycardia from normal heart rate (37). Using this ambulatory monitoring.
threshold level, 27% of 1200 young grade 1 hypertensive In conclusion, the data from the literature consistently
subjects from the HARVEST study exhibited tachycardia demonstrate that heart rate is a potent risk factor for mor-
(10). Due to the large number of people with fast heart tality and/or cardiovascular disease in hypertension. In
rate, establishing whether tachycardia is a risk factor for all of the studies in which patients who died within the
cardiovascular disease is of great relevance in patients with initial years of follow-up were excluded from analysis, the
hypertension. association between elevated heart rate and risk of car-
A positive association with adverse outcome has been diovascular events or mortality remained significant and
found in all analyses performed in hypertensive cohorts did not change substantially from the risk observed in the
or in clinical trials of hypertensive patients. In the full group thereby excluding that the relationship between
Framingham Study, Gillman et al. found that the relative heart rate and adverse outcome was due to an underlying
risk of cardiovascular death adjusted for age and blood chronic illness (5).
pressure was 1.68 among hypertensive men and 1.70
among hypertensive women for an increase in heart rate
of 40 bpm (27). In a study by Benetos et al. in a French
male population, all-cause and cardiovascular mortality PROGNOSTIC VALUE OF AMBULATORY
steadily increased with increasing heart rates (38). In the HEART RATE
Glasgow Blood Pressure Clinic Study (39), hypertensive
patients with a heart rate persistently >80 bpm had an A number of experimental studies have shown that a fast
increased risk of all-cause and cardiovascular mortality. heart rate has adverse effects on the circulation. The risk
The highest risk of all-cause mortality was found for a of pulsatile damage to vascular structure increases with
final heart rate of 81–90 bpm. In the Cooper Clinic study higher frequency of heart beats because high heart rate
(40), hypertensive individuals with high resting heart exposes the arteries to increased magnitude and frequency
rate ≥80 bpm were found to be at greater risk for cardio- of mechanical load, which eventually increases the stiff-
vascular and all-cause mortality compared with those ness of the vascular wall (49). It is thus conceivable that
with heart rate <60 bpm. An association between heart the overall mechanical stress exerted by heart rate on the
rate and mortality was found also among the prehyper- cardiovascular system during the lifespan can be better
tensive participants from the ARIC study (41). Subjects assessed by measuring heart rate with ambulatory moni-
with heart rate ≥80 bpm had 50% higher risk of all-cause toring for 24 hours.
mortality than people with lower resting heart rate. The relationship between ambulatory heart rate and
Results obtained in six clinical trials are consistent with cardiovascular events in hypertension was evaluated
those from the cohort studies. Elderly patients with heart within the frame of the ABP-International study (50)
rate >79 bpm from the Syst-Eur study had a 1.89 greater (Figure 15.2). In age- and sex-adjusted models, both office
risk of all-cause mortality and a 1.60 greater risk of car- and ambulatory heart rates were significant predictors of
diovascular mortality than subjects with heart rate below outcome. However, in a multivariable model that included
that level (42). In the LIFE study, a 10-bpm increment in all major cardiovascular risk factors, only ambulatory
heart rate was associated with a 25% increased risk of car- heart rate remained independently associated with car-
diovascular mortality and a 27% greater risk of all-cause diovascular events. Among the ambulatory heart rates,
death (43). In the patients with hypertension and coro- nighttime heart rate showed the strongest association with
nary artery disease from the INternational VErapamil-SR/ these outcomes. The superiority of ambulatory over office
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OBESITY AND OBSTRUCTIVE
SLEEP APNOEA 16
AHI ≥15 and ≤30 events per hour; and severe, AHI >30
Hypertension
Type 2 diabetes events per hour (13).
Notably, current clinical and research studies used
Depression Stroke inconsistent definition of a hypopnea event (flow reduc-
tion ≥30% for >10 seconds associated with a ≥3% oxygen
OSA desaturation or a cortical arousal, or a ≥4% oxygen desatu-
Chronic kidney
Dementia disease ration without consideration of cortical arousals). This has
therefore impacted on the AHI levels in a given individual
Obesity
Coronary and disease severity, resulting in diverse prevalence values
Dyslipidemia
heart disease for sleep-disordered breathing (8,13,14).
Metabolic
Atrial
Heart failure abnormalities
fibrillation
PREVALENCE OF OSA
Figure 16.1 Adverse consequences of obstructive sleep
Despite growing evidence linking OSA to increased CV
apnoea and obesity.
risk, improvements in diagnosis and treatment, OSA still
remains highly prevalent, often underdiagnosed and
undertreated, in both the general population and in a large
(7). Overall, the quality of available evidence derived from proportion of patients receiving regular CV treatment.
numerous studies comparing the use of ESS against poly- A recent study which included a sample of the general
somnography (PSG) across apnoea-hypopnea index (AHI) population (n = 415) aged 40–65 years found that 24.1%
cutoffs is low (8). had mild OSA, 15.4% moderate-to-severe disease and
Other recognised screening tools of note include the 3.6% had already received OSA-treatment (15). Moreover,
STOP questionnaire (snoring, tiredness, observed apnoea, although one in five individuals demonstrated moderate-
high BP) and the STOP-Bang Questionnaire which in addi- to-severe OSA, the majority of these subjects were asymp-
tion to the STOP test evaluates body mass index (BMI), age, tomatic or had minimal symptoms (15).
neck circumference and gender. The STOP questionnaire Further, evidence for the need to improve awareness of
demonstrates moderate to high sensitivity, low specificity sleep-disordered breathing comes from a prospective study
and moderate accuracy. The STOP-Bang questionnaire has of a total of 500 consecutive outpatients equally included
a high sensitivity and low specificity for detecting OSA; from five clinical subspecialties in which patients were
however, this substantially improves with the higher lev- treated for hypertension, coronary disease, arrhythmia,
els of AHI cutoffs (8). Indeed, a high STOP-Bang score has heart failure and valvular heart disease (16). The risk of OSA
demonstrated high sensitivity and probability in detecting was primarily assessed by the use of the BQ, previous diag-
moderate-to-severe OSA and was found to be comparable nosis and treatment for OSA. This study found that 51.6%
to home or laboratory PSG (9). In addition, the sensitiv- (n = 258) of patients had a high risk for OSA, of whom only
ity of the STOP-Bang questionnaire in predicting OSA can 3.1% (n = 13) had been previously diagnosed and only six
be further improved following the measurement of serum patients were treated for OSA. A high prevalence of OSA
bicarbonate (10). A recent meta-analysis of 17 studies with (66%), varying from 50 (hypertension group) to 80% (HF
a total of 9206 patients confirmed the high performance group) indicates that OSA is also underdiagnosed in several
of the STOP-Bang questionnaire for screening OSA in the cardiology subspecialties (16), highlighting an unmet need
sleep clinic and surgical population (11). A higher STOP- to raise awareness of sleep-disordered breathing.
Bang score has been linked to the greater probability of It is noteworthy that the prevalence of OSA varies con-
moderate-to-severe OSA (11). siderably and depends on testing methodology and scoring
While these questionnaires are helpful in screening criteria used for the respiratory events. Utilizing an AHI
OSA, available evidence indicates the potential risk for cutoff of ≥5 events per hour (hypopnea event defined as a
bias including false-positive and false-negative results. ≥4% reduction in oxyhaemoglobin saturation), the preva-
Therefore, self-reported tests cannot be used for OSA diag- lence of OSA has been estimated at 14% in men and 5% in
nosis in the absence of PSG – the gold standard technique, women (17). Within the same selected urban population,
or home sleep apnoea testing with a technically adequate 13% of men and 6% of women demonstrated moderate-
device in uncomplicated patients with a high OSA pre-test to-severe OSA (AHI ≥15 events per hour) (17). However,
probability (8). the estimated prevalence of sleep-disordered breathing
Patients presenting with typical OSA symptoms can range from approximately 14% up to 55% depending
(e.g. hypersomnolence, sleep-time choking, snoring, on age group, gender and severity of the disease (17).
observed apnoeas) are diagnosed if five or more score- A large discrepancy in OSA prevalence has been con-
able respiratory events (predominantly obstructive or firmed in a recent systematic review of 24 cross-sectional
mixed apnoeas, hyponoeas or respiratory effort-related studies and the cross-sectional components of longitudi-
arousals [RERAs]) per hour of sleep are reported on PSG. nal studies conducted in all world regions (18). The het-
Alternatively, 15 respiratory events per hour of sleep on erogeneity amongst the included studies (i.e. sampling
reporting PSG justifies diagnosis, irrespective of patient’s methods, diagnostic criteria, methods used to measure
complaints (12). Based on the index denoting average airflow, etc.) had an impact on the reported prevalence of
number of apnoeic and hypopnoeic episodes per hour of OSA which considerably varies depending on the diagnos-
sleep (AHI) or obstructive respiratory disturbance index tic criteria used, age, gender and study population (18).
(RDI) if RERAs are considered, OSA is classified as fol- Nevertheless, the overall prevalence of OSA using the AHI
lows: mild, AHI ≥5 and <15 events per hour; moderate, of ≥5 events per hour, in the general adult population
Obesity and Obstructive Sleep Apnoea 129
ranged from 9 to 38% and increased with the degree of fat promotes metabolic abnormalities including insulin
obesity. Obese men and women had a higher incidence of resistance and dyslipidemia leading to hypertension, type
OSA compared to their overweight counterparts. It also 2 diabetes and adverse CV sequelae (27). The predictive
increased with ageing, with the highest peak at 90% for value of regional (abdominal) body fat distribution (but
men and 78% for women aged 60–85 years (18). However, not fat accumulation in the neck or pharyngeal region) for
despite an observed increase with age, OSA at AHI of ≥15 the presence and severity of OSA has been confirmed by
events per hour was less prevalent in the elderly, account- the findings from yet another study (26).
ing for 6–17%, reaching 49% in the advanced age group.
While these findings confirm that a higher BMI, advanced
age and male gender increases the risk of OSA, the exact
prevalence of OSA still needs to be determined by a uni- OBESITY ATTRIBUTABLE TO OSA
form methodology (e.g. type 1 PSG vs. polygraphic record-
ings), and diagnostic threshold in future studies. It is not only obesity that triggers the development of OSA,
but surprisingly there is growing evidence that the converse
is also possible. Sleep-disordered breathing with resultant
sleep deprivation, daytime sleepiness, tiredness and lack
INTERACTION BETWEEN OSA AND of physical activity are important adverse contributors to
accelerated body weight. Patients with sleep apnoea have
OBESITY the propensity for a rapid increase in weight gain a year
Obesity is the most important contributor to the develop- preceding the onset of disease (28). In contrast, no signifi-
ment and progression of OSA. The relationship between cant weight changes have been observed in obese subjects
weight change and the change in OSA severity comes without sleep apnoea (28). Amongst numerous contribut-
from the longitudinal prospective Wisconsin Sleep Cohort ing factors, a lack of regular exercise and depression have
Study in which 690 randomly selected representatives also been demonstrated as significant independent predic-
underwent PSG twice within a 4-year interval (19). In this tors of excessive daytime sleepiness independent of age,
study, a 10% weight gain predicted an approximate 32% BMI, gender, diabetes and central nervous system medica-
increase in the AHI and a sixfold increase in the likelihood tion use in patients with sleep apnoea (29).
of developing moderate-to-severe sleep-disordered breath- Previous experimental, epidemiological and prospective
ing. On the contrary, a 10% weight loss was associated studies have demonstrated that sleep deprivation and poor
with a 26% decrease in the AHI (19), indicating that weight quality of nighttime sleep adversely affects metabolic and
management is an effective approach for the prevention neuroendocrine regulation, resulting in increased calorie
and remission of OSA. These findings have been supported intake, thereby playing a critical role in the development
by the results from the Sleep Heart Health Study in which of obesity (30–32). In fact, a sleep duration of less than
a total of 2968 men and women were followed over with a 5 hours has been linked to central body fat distribution and
5-year duration (20). With a given increase in weight gain, increased percentage of body fat compared to sleep time of
men were more likely to have an increase in RDI compared an average of 7–8 hours, and these associations persisted
to women, and this was independent of differences in ini- following the adjustment for sleep apnoea, insomnia or day-
tial weight, waist circumference, age or ethnicity (20). time sleepiness (30). Moreover, despite unchanged plasma
A strong and independent association of overweight and glucose levels, even an acute total sleep loss has been found
obesity with the development of severe-to-moderate OSA to enhance centrally mediated responses to hedonistic food
confirmed by PSG has been indicated in a cohort of 1042 stimuli and hunger compared to normal sleep (32).
volunteers (21). The risk of OSA was 10.5-fold higher among The association between OSA and clinical outcomes
obese subjects compared to individuals with normal BMI. including the incident of hypertension, type 2 diabetes,
In fact, the prevalence of moderate-to-severe OSA in obese metabolic abnormalities, coronary heart disease, heart fail-
patients with BMI ≥30 kg/m2 has been found to exceed 50% ure, ischaemic stroke, chronic kidney disease, depression,
(22), reaching as high as 71.4% in the severely obese group dementia and higher risk of mortality is well established
(BMI 35.0–39.9 kg/m2), 74% in the morbidly obese group (Figure 16.1) and has been discussed elsewhere (33,34).
(BMI 40.0–40.9 kg/m2), and even higher percentage of OSA
with greater degrees of obesity in patients undergoing bariatric
surgery for weigh loss (23). Notably, severe OSA with an aver- MECHANISMS UNDERLYING OSA
age of total RDI 88.9 ± 42 (standard deviation [SD]) has been
noted in more than 75% of morbidly obese patients under-
going bariatric surgery (24). Amongst numerous variables, ROLE OF THE SYMPATHETIC NERVOUS SYSTEM
snoring, the STOP-Bang score ≥3, fatty liver and BMI were
significantly associated with OSA when compared to subjects OSA and obesity share multiple pathophysiological mech-
without OSA (24). BMI and dyslipidemia were directly linked anisms resulting in adverse consequences on various
to the severity of OSA in this morbidly obese cohort (24). organs, with sympathetic nervous system activation play-
Importantly, among obese patients, abdominal (vis- ing a pivotal role in this scenario (33). Microneurography
ceral) fat rather than subcutaneous or generalized (total) studies have documented high levels of muscle sympa-
body fat seems to be a critical contributor to the devel- thetic nerve activity (MSNA) in OSA patients during wake-
opment of OSA (25,26). In fact, despite comparable BMI fulness, with further increase during sleep (35). Repetitive
levels or subcutaneous or total body fat distribution, a episodes of apnoea and hypopnea events and the resul-
significantly higher amount of visceral fat has been found tant intermittent hypoxemia during sleep alter sympa-
in OSA patients when compared to obese control subjects thetic CV regulation, leading to augmented sympathetic
(25). Central obesity accompanied by increased abdominal drive. Recurrent incidents of hypoxemia in OSA patients
130 Manual of Hypertension of the European Society of Hypertension
stimulates arterial peripheral chemoreceptors, leading displayed by the overweight state has also been con-
to increased minute ventilation (fast and deep breath- firmed by other findings (40).
ing), subsequent episodes of acute lowering of heart rate Moreover, altered sympathetic CV variability evident
(HR) and attenuation of adrenergic activity followed by a in OSA patients, even in the absence of other comorbidi-
marked increase in HR and MSNA at the end of the period ties (41), is likely to increase with the severity of OSA,
of hypoxia during apnoeic episodes (36) (Figure 16.2). thereby triggering OSA-related acute CV events (i.e. car-
Chronic potentiated activation of arterial chemoreflexes as diac arrhythmia, sudden cardiac death, ischaemic heart
a result of recurrent evets of oxygen desaturation appears disease, stroke, heart failure). Impaired CV reactivity dur-
to be the leading contributor for persistently elevated sym- ing exercise and resultant reduced physical working capac-
pathetic nerve activity to the skeletal muscle (36,37). ity is a further important mechanism through which OSA
Studies using microneurography consistently con- leads to obesity (42).
firmed that human obesity is associated with increased
sympathetic activation (38). However, obese subjects
with sleep apnoea were found to demonstrate extremely METABOLIC DISTURBANCES
elevated levels of MSNA (61 ± 8 bursts per 100 heart-
beats) when compared to obese subjects without sleep Patients with sleep apnoea commonly display higher
apnoea (42 ± 3 bursts per 100 heartbeats) or normal- levels of the adipose tissue-derived hormone, leptin,
weight subjects (41 ± 3 bursts per 100 heartbeats) (39), inflammatory markers, fasting plasma glucose, insulin
as indicated in Figure 16.3. These findings indicate that and insulin resistance-producing cytokines (i.e. tumour
obesity alone, in the absence of OSA, is not accompanied necrosis factor-alpha, interleukin-6 etc.) when compared
by increased sympathetic outflow to the skeletal muscle to BMI-matched controls without sleep apnoea who dem-
vascular bed. Accordingly, unrecognized OSA in obese onstrate intermediate values, or lean subjects with the low-
patients may play a critical role in triggering metabolic est values (25).
derangements and potentiating further associated CV Although excess adiposity is the major indicator of
risk. Augmented sympathetic activation in OSA patients insulin resistance, not all overweight or obese individuals
that is independent of body weight but additive to that are insulin resistant (43). Studies in sleep apnoea patients
Neurogram
Neurogram
Figure 16.2 Representative recordings of heart rate (HR) and muscle sympathetic nerve activity (MSNA) at baseline, dur-
ing a 3-minute hypoxia and during a 10-second apnoea at the end of a 3-minute hypoxia, in a normal control subject (top)
and in a patient with OSA (bottom). Despite a similar reduction in oxygen saturation, hypoxia produced greater increases
in HR, minute ventilation (V E), and mean arterial pressure (MAP) in patient with OSA. Hypoxia increased MSNA both
in control subject and in OSA patient, even though changes in blood pressure and V E (both of which inhibit MSNA) were
greater in OSA patient. When autonomic inhibitory influence of breathing was eliminated by apnoea, increase in MSNA in
patient with OSA was greater than that in control subject and was accompanied by prolongation of R-R interval. (Adapted
with permission from Narkiewicz K et al. Circulation 1999; 99(9): 1183–1189.)
Obesity and Obstructive Sleep Apnoea 131
38 yrs., BMI = 23, AHI = 0 38 yrs., BMI = 36, AHI = 0 37 yrs., BMI = 33, AHI = 18
38 yrs., BMI = 25, AHI = 0 41 yrs., BMI = 34, AHI = 4 45 yrs., BMI = 33, AHI = 13
34 yrs., BMI = 23, AHI = 0 34 yrs., BMI = 30, AHI = 0 45 yrs., BMI = 30, AHI = 19
10 seconds
Figure 16.3 Representative recordings of muscle sympathetic nerve activity (MSNA) in a subject with normal weight
without obstructive sleep apnoea (OSA), an obese subject without OSA, and a subject initially thought to be normal obese
but found on polysomnography to have occult OSA, matched for age and gender. Increased MSNA was evident in subjects
with occult OSA but not in an obese individual without OSA. (Adapted with permission from Narkiewicz K et al. Circulation
1998; 98(8): 772–776.)
have documented that sleep-disordered breathing param- cells to increase appetite, and influences energy homeosta-
eters including AHI and minimum oxygen saturation sis. The circulating level of leptin directly correlates with
are independent determinants of insulin resistance (44). BMI and has been found to be paradoxically increased in
Consequently, the association between OSA and insulin obese subjects causing the phenomena known as leptin
resistance remained significant in both obese and non- resistance (similar to insulin resistance) through various
obese subjects (44). The independent relationship between mechanisms including modulation of the leptin recep-
sleep-disordered breathing and metabolic dysfunction tor−signalling pathway (47). Plasma ghrelin is inversely
has been also confirmed by the results of the Sleep Heart related to body weight, with decreased levels in obesity
Health Study (45). Sleep-disordered breathing has been and increased concentration following weight loss (46).
associated with glucose intolerance and insulin resistance A large variation in serum leptin levels has been doc-
independently of BMI, waist circumference, age, gender, umented in OSA patients including higher, unchanged
smoking and sleep duration. The severity of OSA, as deter- or lower leptin concentrations (48). Most studies have
mined by the RDI, has been associated with the degree reported higher leptin values in OSA subjects independent
of insulin resistance, whereas sleep-related hypoxemia of BMI. Compared to subjects with a similar BMI but with-
has been linked to both glucose intolerance and insulin out sleep-disordered breathing, OSA subjects had higher
resistance (45). While the mechanistic pathways were not circulating leptin levels which positively correlated with
directly indicated in this study, it is likely that sympathetic BMI, skinfold thickness, serum cholesterol, low-density
activation underlying OSA-related hypoxemia impor- lipoprotein cholesterol, insulin, insulin/glucose ratio, AHI
tantly contributes to metabolic abnormalities and subse- and oxygen desaturation time (49). Another study which
quent risk of type 2 diabetes. included male subjects confirmed higher leptin values
in both moderate-to-severe and severe OSA compared to
matched BMI controls (50). Interestingly, in this study
the percentage of total sleep time spent with hypoxemia
ROLE OF LEPTIN AND GHRELIN IN OSA (saturation <90%) was found to be a significant predic-
tor for leptin levels independent of obesity (50). While the
Leptin and ghrelin are the two important hormones mechanisms underlying the association between noctur-
involved in the regulation of energy balance and body nal hypoxemia and hyperleptinemia were not addressed
weight in humans (46). Leptin, predominantly produced in this study, the sympathetic activation seems to play a
by adipose tissue, acts through the receptors located in critical underlying role in this scenario. Interestingly, ele-
the hypothalamus and inhibits feeding, increases sympa- vated plasma leptin and MSNA levels have been demon-
thetic activation and promotes inflammation. The action strated in newly diagnosed healthy patients with untreated
of leptin is opposed by the hormone ghrelin produced by sleep apnoea compared to similarly obese control subjects
the gastrointestinal tract acting on the hypothalamic brain without sleep apnoea (51). Higher leptin levels in OSA
132 Manual of Hypertension of the European Society of Hypertension
independent of body fat content suggest that OSA is asso- compared to healthy controls (61). Treatment of the OSA
ciated with greater resistance to the action of leptin and cohort with CPAP for at least 1 year also resulted in lower
predisposition to weight as compared to similarly obese values of orexin-A compared to healthy controls (61). A
individuals without sleep apnoea (51). reduced orexin-A level appeared to be independent of the
Further, findings from experimental studies have demon- number of apnoeas during sleep, the presence of daytime
strated that chronic intermittent hypoxia induces changes sleepiness or obesity (61).
in leptin and leptin-signalling protein within the carotid Conversely, there is also evidence documenting higher
bodies, thereby possibly altering chemoreflex sensitivity orexin-A levels which correlated with the clinical severity
(52). Hyperleptinemia alone potentiates sympathoexcit- of OSA and arousal index (63). In this study, 3 months’
atory responses during the reflex activation of arterial che- therapy with CPAP decreased orexin-A levels and the
moreceptors (53) and exaggerates the hypoxic CV responses ESS score (63). Whether elevated plasma orexin levels
through the activation of the chemoreflexes (54). reflect central manifestations of apnoea-hypopnea-related
Another study in a male patient cohort with OSA doc- arousal is yet to be determined.
umented a higher fasting leptin and ghrelin levels com-
pared to BMI-matched controls without OSA (55). This
study found that a 2-day treatment with continuous posi-
tive airway pressure (CPAP) decreased plasma ghrelin in THERAPEUTIC INTERVENTIONS
almost all OSA patients to the levels that were only slightly
higher compared to that in controls (n = 9). While a 2-day Treatment of OSA should be initiated with CPAP therapy
therapy resulted in no changes in leptin levels, an 8-week based on technically adequate PSG or home sleep apnoea
CPAP treatment produced a significant reduction in leptin testing (8). Recently, a meta-analysis of seven randomized
levels without an effect on BMI (55). These findings indi- controlled trials (n = 4268) of the use of CPAP therapy in the
cate that elevated leptin and ghrelin levels evident in OSA prevention of CV events in patients with OSA has demon-
subjects are not determined by obesity alone (55). strated non-significant 26% relative risk reduction in major
It should be noted that not all studies found increased adverse CV events (MACE) (64). However, CPAP adherence
leptin and ghrelin levels in OSA patients. Significantly time ≥4 hours per night reduced the risk of MACE by 57%
higher serum leptin levels were found in OSA patients with no beneficial effects on myocardial infarction, all-
compared to controls but without significant differences cause mortality, atrial fibrillation/flutter or heart failure.
in serum ghrelin levels between OSA patients and con- CPAP had a positive effect on mood and reduced the day-
trols. Serum leptin levels were significantly correlated time sleepiness assessed by the ESS questionnaire (64).
with BMI in both OSA patients and controls, but only in The effect of CPAP therapy on body weight remains
OSA patients was leptin associated with AHI (56). Another unclear, with studies reporting no change or increases in
study found significantly higher serum ghrelin levels in an BMI. A recent meta-analysis of 25 RCTs (n = 3181) has indi-
OSAS group compared to the control group. Ghrelin levels cated that OSA treatment with CPAP promotes significant
were associated with AHI and the ESS score in OSA only increase in BMI and weight and that baseline weight was a
but there were no significant differences noted in the levels predictor of increased BMI after CPAP (65). The increasing
of leptin, adiponectin and resistin between groups (57). weight associated with OSA treatment was not influenced
Despite these controversial results, leptin has been pro- by age, gender, baseline BMI, baseline weight, OSA sever-
posed to be a prognostic marker of OSA. This is supported ity, differences in study design, and duration of follow-up,
by the findings from studies documenting reversibility CPAP compliance, dieting or physical activity (65).
of hyperleptinemia following therapy with nasal CPAP The bidirectional link between obesity and sleep-
(nCPAP). A significant decrease in circulating leptin levels disordered breathing emphasizes that CPAP initiation to
was achieved with 6 months of therapy with nCPAP, indi- treat overweight and obese patients with OSA should be
cating that hyperleptinemia in OSA cannot be explained complemented by therapies for body weight reduction (i.e.
entirely by increased adiposity (49). lifestyle interventions). This is corroborated by the find-
ings from the randomized controlled trial in which obese
patients with moderate-to-severe OSA were assigned to
receive CPAP therapy, a weight-loss intervention (dietary
ROLE OF HYPOCRETIN IN OSA program) only, or both CPAP plus a weight-loss program
for 24 weeks (66). Weight loss only and the combined
Amongst numerous neurohormones, the hypocretin sys- interventions (CPAP plus weight loss) produced reduc-
tem (orexin-A) has been found to play an important role tions in CRP levels, insulin resistance, and serum tri-
in the regulation of sleep and arousal states, feeding and glyceride levels. None of these changes were observed in
energy balance, centrally mediated CV regulatory actions patients receiving CPAP alone. No significant incremental
and other peripheral functions (58). The vast majority of effect on CRP levels was found for the combined interven-
studies documenting orexin deficiency come from patients tions as compared with either weight loss or CPAP alone.
demonstrating narcolepsy or primary hypersomnia (59). The decline in body weight was comparable in the weight-
Given the presence of sleep disturbances (i.e. daytime loss and combined-intervention groups (6.8 and 7.0 kg,
sleepiness, wakefulness) in OSA patients, it has been respectively), but no significant weight changes were
suggested that orexin may be implicated in the patho- noted in the CPAP group. In addition to improved met-
genesis of disease. Previous studies documented low lev- abolic parameters, this study found that the combined
els of orexin-A in OSA patients (60–62), which decrease interventions resulted in a greater systolic BP reduction
in parallel with the severity of disease (60). Abnormally (14.1 mmHg) when compared to weight loss (6.8 mmHg)
low orexin-A levels have been found in untreated patients or CPAP (3.0 mmHg) alone at 24 weeks’ follow-up among
with severe OSA (mean AHI 54 ± 4 events per hour) when adherent subjects (66). While outcomes on OSA severity
Obesity and Obstructive Sleep Apnoea 133
were not reported in this study, the combined CPAP and 13. Penzel T, Schobel C, Fietze I. Revise respiratory event criteria or
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THE METABOLIC SYNDROME IN
HYPERTENSION 17
Table 17.1 Criteria for diagnosing the metabolic syndrome according the Adult Treatment Panel (ATP) III; the International Diabetes
Federation (IDF) and the American Heart Association (AHA)
Note: Diagnosis of metabolic syndrome is based on: (a) principal criteria plus at least two other; (b) in those without principal criteria, at least three.
a or in treatment for.
uric acid is an active participant in a complex network of of MS in developed countries (44). A further increase in
pathological processes. MS prevalence can be expected in the future due to the
MS is a common condition globally, and can be found in demographic trend of increasing age. MS is much more
approximately one-third of patients with essential hyper- common in subjects with diabetes than in the general
tension. Importantly, MS considerably increases the risk of population, with reported rates that approximate 80–90%
CV and renal events even in absence of overt diabetes. In (45,46). In populations with low socioeconomic status,
this chapter, the prevalence, mechanisms, prognostic sig- MS is further becoming an emerging epidemic due to sev-
nificance and treatment of MS in hypertensive patients are eral factors, including urbanization, lifestyle alterations
reviewed. (diet and exercise), economic influences, and increased life
expectancy (47).
Among individuals with essential hypertension, the
prevalence of MS is higher than in the general population
PREVALENCE OF MS (48–54). Hypertensives have an increased risk of develop-
ing MS and vice versa: MS components have been found
Over the past several decades, the global prevalence of MS to predict the incidence of hypertension (55,56). In addi-
has increased dramatically. In the US, data from the National tion, BP control is closely related to MS criteria: A higher
Health and Nutrition Examination Survey (NHANES) prevalence of MS has been reported among uncontrolled
showed that the prevalence of MS in adults increased from hypertensives as compared to hypertensives with BP levels
25.3% in 1988–1994 to 34.2% in 2007–2012 (31). A similar below target levels (48). Moreover, the risk of uncontrolled
trend can be observed in all population subgroups inde- hypertension increases with the number of MS compo-
pendent of gender and ethnic background, as well as in nents (57). These findings suggest a reduced efficacy of
children and adolescents (32–35). In the past 5–10 years, antihypertensive treatment in subjects characterized by an
the prevalence of MS remained stable and followed demo- adverse cardiometabolic profile that might be attributed
graphic trends of obesity. A greater awareness of MS-related to a more pronounced subclinical target-organ damage in
health consequences and a stricter control of MS compo- these patients.
nents including hypertension and diabetes may contribute
to the stabilizing prevalence of MS in recent years.
In Europe, a considerable variation in the prevalence of
obesity and MS has been observed. The age-standardized ELEVATED BP AS A KEY COMPONENT
percentage of men and women with MS ranges from 42.7% OF MS
to 24%, respectively, in Southern European cohorts up to
78.2%, and 64.8% in Northern European cohorts (36). Hypertension is frequent in MS, and overall elevated BP,
The variation in MS prevalence observed in different study which represents one of the five components that lead
populations can largely be explained by differences in to the identification of this condition. The prevalence of
characteristics of the study populations and the use of dif- hypertension in MS can increase if the new threshold of
ferent criteria for the definition of MS (37–39). It is known 130/80 mmHg, proposed by the AHA guidelines, is used
that gender has a large impact on the estimation of MS (58). In the PAMELA population study, for example, a
prevalence, and an equal, higher or lower prevalence of MS blood pressure in the high normal or frankly hypertension
in men compared to women has been reported (39–43). In range was found in more than 80% of the individuals with
addition, MS is strongly related to age. Approximately half MS, followed in decreasing order of prevalence by visceral
of individuals aged 60 years or older fulfils current criteria obesity, lipid abnormalities and impaired fasting glucose.
The Metabolic Syndrome in Hypertension 137
The high prevalence of BP abnormalities in MS explains dietary emulsifiers, can alter the microbiota and lead to an
the frequent occurrence of subclinical organ damage of inflammatory state (68). The final individual phenotype
the type that is frequently associated with and dependent probably results from complex interactions among all of
on a BP elevation, such as left ventricular hypertrophy, the above-mentioned factors (2,69–71).
arterial stiffening and increased urinary protein excretion Altered function of adipose tissue, mainly in visceral
(59). Some of these types of organ damage, however, also fat, has been identified as a key driver, which precludes
show an increased prevalence in individuals who have an the development of the other features of MS, including
MS without BP elevation to the hypertensive levels, sug- impaired glucose homeostasis (72–74). The first structural
gesting that other components of this condition play a role event which follows from fat tissue increase is the infil-
independently on BP. tration of adipose tissue by bone marrow−derived macro-
In a pooled analysis of prospective atherosclerosis progres- phages in response to as-yet unknown signals (5,6,75,76).
sion/regression intra vascular ultra sound (IVUS) trials that This is both a paracrine regulator of adipocyte function
included 3459 patients with established coronary artery dis- influencing free fatty acid (FFA) liberation and hormone
ease, MS and its component risk factors were associated with secretion of leptin and adiponectin, as well as a source
plaque progression (60). MS was highly prevalent (57.8%) in of the inflammatory mediators interleukin (IL)-6 and
this cohort and was associated with higher rates of disease tumour-necrosis factor (TNF)-α released by adipose tissue.
progression. However, multivariable analysis showed that In addition to the structural changes, various functional
the excess plaque progression appeared to be driven more by abnormalities of adipose tissue−derived products have
its individual risk factors. Although each of the components been described. These include an increase in FFA, leptin
predicted greater disease progression, hypertriglyceridemia and cytokine release, and a reduction in adiponectin secre-
and elevated body mass index (BMI) had the highest haz- tion. Age can also have a role in adipocyte dysfunction,
ard ratios for atheroma progression. There were no signifi- and several genes associated with longevity such as IGF-1
cant differences for the risk of atherosclerosis progression in and mTOR could influence the adipocyte function (73,77).
those patients with MS with or without high blood pressure A second key issue in the development of MS is insu-
or hypertension. Moreover, to have BP ≥130/85 mmHg or lin resistance. It is established in the skeletal muscle and
the use of medication was not significantly associated with the liver as a result of the inhibition of insulin-stimulated
disease progression in a multivariable model adjusting for glucose transport activity mainly by accumulation of acyl
age, sex, race, baseline LDL-C level and baseline statin use, CoA and diacylglycerol in the cytoplasm easy by a reduc-
with or without considering MS (51). tion in the mitochondrial oxidative capacity (78,79).
This increases serine kinase activity, which leads to the
suppression of insulin signalling by reducing IRS-2 and
Glut-4 transport (80). There are several factors related to
MECHANISMS OF MS IR. Adipocytokines which are released from the adipose
tissue seem to alter insulin sensitivity in the liver and
MS is probably the result of multiple interactions among a muscle (81). The visceral adipose tissue could be consid-
large number of interconnected mechanisms. The precise ered as a surrogate marker for the accumulation of lipids
sequence of events in MS is largely unknown but they even- at ectopic sites and of lipotoxicity, which would occur in
tually lead to an increase in cardiovascular and renal risk, parallel in the liver and muscle, causing IR in these tissues
and to the development of diabetes. The close relation- (81). Also, the excess of visceral fat may have direct diabe-
ships among the different components of the syndrome togenic properties. This theory would be supported by the
and their associated disturbances make it difficult to dif- increase of macrophages in this tissue that would release
ferentiate causes and consequences. Insulin resistance (IR) proinflammatory cytokines leading to IR. It is also pos-
has been classically situated central in the origin of MS but sible that both the lipotoxicity in peripheral tissues and
it is probably the excess of caloric intake that leads to the the production of cytokines by visceral fat could contrib-
various manifestations of the syndrome (61,62). ute to the systemic IR (81). IR and the consequent hyper-
Mechanisms involved in MS are over-nutrition, excess insulinemia have always been considered key elements in
of adipose tissue, IR and a constellation of independent the development of MS, although IR is strongly associated
factors, which include molecules of hepatic, vascular and with atherogenic dyslipidemia and inflammation, whereas
immunologic origin with proinflammatory and procoag- its mechanistic link with other MS components, such as
ulant properties (61–63). Although IR is associated with hypertension and a prothrombotic state (63,82), is less
obesity and central adipose tissue, not all obese subjects well established.
have IR. Those mechanisms controlling the expansion of There is increasing evidence that aldosterone through
the subcutaneous adipose tissue could be responsible for genomic and nongenomic effects on the mineralocorticoid
this observation (64,65). Skeletal muscle and the liver, not receptor (MR) may be related to insulin resistance, endo-
adipose tissue, are the two key insulin-response tissues thelial dysfunction and with other components of MS
involved in maintaining glucose balance, although abnor- (83,84). The adipose tissue produces a lipid soluble factor
mal insulin action in the adipocytes also plays a role in that stimulates glucocorticoids and aldosterone secretion,
development of the syndrome (66). and these hormones can promote the adipogenesis and
At each of these key points, IR and obesity/proinflam- inflammation in fat tissue. This unidentified lipid soluble
matory molecules are probably modulated by demo- factor could be leptin, which has recently been described
graphics, lifestyle, and genetic, environmental and fetal as a direct regulator of the aldosterone synthase expression
factors (67). Superimposed upon these are infections and/ through calcium-dependent mechanisms (85–87). Several
or chronic exposure to certain drugs which can also con- clinical studies support the potential benefit of MR antag-
tribute. The role of gut microbiota in MS is now receiv- onism in hypertensive patients with MS (88–90). This
ing more attention, and certain food components, such as can be partly due to a reduction in the proinflammatory
138 Manual of Hypertension of the European Society of Hypertension
adipokine levels, which are usually elevated in MS, such as systemic vasoconstriction and/or remodelling of the arte-
TNF-α, MCP-1, and IL-6, together with an improvement in rioles leading to an increase in their wall-to-lumen ratio
the expression of adiponectin (91,92). and a consequent structural increment in vascular resis-
tance (108). A short review focused on new information
about the role of sympathetic nervous system in the MS
has recently been published by Seravalle (102).
MECHANISMS OF ELEVATED BLOOD Together with the SNS, the activity of the RAS is increased
PRESSURE IN MS in most obese individuals (109) despite the fact that obe-
sity is accompanied by sodium retention and increased
Obesity and IR, two of the main components of MS, prob- extracellular fluid volume, which should inactivate renin
ably play an important role on the increment of BP and the release from the kidney and angiotensin II formation. The
development of hypertension (93). Although the precise cause of RAS activation may be due to enhanced renin pro-
mechanisms involved remain partially unresolved, factors duction caused by diminished sodium delivery to the mac-
such as overactivity of the sympathetic (94), stimulation ula densa because of its greater reabsorption in the loop of
of the renin-angiotensin systems (RAS) (7,95), abnormal Henle. This can be mediated by insulin, which can also
renal sodium handling (96), and endothelial dysfunction activate the different enzymes of the system in vascular
(97,98) need to be considered (Figure 17.1). endothelial cells and therefore contribute to an increase
Abnormal sodium handling has been postulated to be one in the levels of angiotensin II (110). A stimulation of renin
of the main suspects for the development of hyperten- release by the increased sympathetic nerve activity to the
sion in MS. It is known that not all obese or MS patients kidneys may also be involved (96,111). Finally, an increase
develop hypertension as it happens in the rodent model of of angiotensinogen formation in adipose tissue may con-
MS or obesity (99,100). One potential explanation is the tribute to RAS activation. Serum uric acid has long been
increase in salt sensitivity, which could be related to acti- associated with obesity, MS and hypertension, although
vation of the epithelial Na+ channel (ENaC) by insulin or its role as an independent cardiovascular risk factor has
other factors (101). However, the chronic block of ENaC not yet been proved (112). Uric acid may induce hyper-
does not affect the BP, which means that other retentive tension (HTN) by different mechanisms, including kidney
Na pathways are probably involved (99). sodium retention by ENa+C and activation of the RAAS
Overactivity of the sympathetic nervous system (SNS) is system by increasing the angiotensinogen levels (113–117).
mainly mediated by five physiopathological mechanisms: Moreover, the inhibitors of the enzyme xanthine oxidase
(1) hormones such as cortisol or aldosterone; (2) metabolic have demonstrated significant reduction in BP, at least in
factors such as leptin, insulin or FFA; (3) reflex activation the early stages (118). Angiotensin II enhances tubular
by baro- or chemoreceptors; (4) inflammation; and (5) sodium reabsorption (119), increases peripheral arterial
endothelial or haematological factors may play an impor- resistance (111) and stimulates the SNS (120).
tant role in the frequent association of MS with hyperten- The increase in aldosterone levels which has been
sion (93,102). A great deal of evidence supports the finding seen in hypertensives with visceral obesity (121) is one
that obese individuals have increased levels of plasma of the potential links to obesity-associated hypertension.
norepinephrine, faster urine turnover of norepinephrine Moreover, aldosterone has been proposed as a biomarker
in peripheral tissues and increased muscle sympathetic for several components of MS and related organ damage
activity, as measured directly by microneurographic meth- even in general populations (122). Overproduction of
ods (103–107). Long-term sympathetic activation in MS aldosterone has been directed to the production of potent
may raise BP through multiple mechanisms, including mineralocorticoid-releasing factors in fat tissue (85) as well
an increase in renal tubular sodium reabsorption (105), as to the ability of oxidized derivatives of linoleic acid to
induce aldosterone synthesis (123). Aldosterone may raise
blood pressure in obesity also through an action on MRs
located not only in the kidney but also in the vasculature
and the brain. The sensitivity of MR not only to aldosterone
but also to glucocorticoids seems to be increased, as well as
Sympathetic overdrive
the ability of the enzyme 11β- hydroxysteroid dehydroge-
High FFAs Insulin resistance and nase type 2 (11β-HSD2) to convert cortisol into cortisone,
levels hyperinsulinemia Hyper- which does not have mineralocorticoid activity (124).
Hypo- aldosteronism Weight gain is associated with hypertension by several
RAS overactivity
adiponectinemia mechanisms, but mainly through abnormal kidney func-
Leptin resistance and
tion. Obese patients usually show an increase in sodium
hyperleptinemia reabsorption and an impaired renal-pressure natriuresis that
lead to an increase in extracellular volume (124). As pre-
Endothelial Abnormal viously discussed, sympathetic activity, RAS activation,
dysfunction sodium handling hyperaldosteronism and disturbances in hemodynamic
and intrarenal physical forces are all involved (94,124).
Although initially the sodium balance is maintained
through an elevated BP and GFR, the result of long-term
hyperfiltration finally leads to glomerulosclerosis, and
High blood pressure contributes to the sodium dependency of the elevated BP
values in more advanced stages (125). Another mecha-
Figure 17.1 Mechanisms of hypertension in the MS. nism of obesity-related hypertension is related to the
physical compression of the kidneys by the accumulation
The Metabolic Syndrome in Hypertension 139
of visceral fat. This has shown to increase the interstitial intron region of the T-cadherin (CDH13) gene and has been
hydrostatic pressure which can impair tubular flow and further associated with an increased risk of MS (OR 1.42,
increase sodium reabsorption (124). p = 0.027) (135). This gene encodes the cadherin-related
Various components of MS and also uric acid have an superfamily of transmembrane proteins that mediate
adverse impact on the endothelium, leading initially to oxi- calcium-dependent intercellular adhesion. Both LDL and
dative stress, reduced nitric oxide (NO) bioavailability, adiponectin can be specific ligands for T-cadherin, and
endothelial dysfunction and vascular damage (116,126). its activation can further activate the nuclear factor-k B
Endothelial dysfunction is reflected by the presence of (NF-k B)-signalling pathway, which plays a central role in
impaired endothelium-dependent vasodilatation as well as inflammation. The exact mechanisms by which this gene
by the activation of inflammatory, proliferative and coagu- could be related to the appearance of MS in hypertension
lation markers that are responsible for the proinflamma- are not clearly understood. Other variants of this CDH13
tory and procoagulant states frequently seen in MS. gene also seem to play a role in the development of MS, at
In this sense, one study, using a primate model of MS, least in women in northern Europe (136). Recently, certain
supports the contribution of endothelial dysfunction for genotypes of polymorphisms of the adiponectin gene have
MS and its components (127). The animals selected for been associated with MS and low levels of adiponectin in
this study developed MS during the follow-up, so the adolescents from China (137). Although this study (137)
authors were able to study this complex syndrome from has certain limitations, such as the cross-sectional design,
its origin. Brachial flow-mediated dilatation (FMD) was the limited sample size and the fact that it probably can-
clearly impaired in MS monkeys, which supports the idea not be applied to other ethnicities, it is clear that variants
that loss of endothelial reactivity is an early event in the of this gene could modulate adiponectin levels, modifying
progression of MS (127). Moreover, visceral obesity and the risk of developing hypertension and MS. It is hoped
hypertension could be key initial factors for the later that these genetic results can help to identify genetic sus-
development of the whole syndrome (127). This research ceptibility to MS and associated traits.
was also able to demonstrate that the divergence between Finally, plasma FFA elevation and also impaired endo-
MS animals and controls was not only due to a difference thelial-dependent vasodilatation FFA reduce the circu-
in food or calorie intake, but that other factors such as lating levels of most amino acids, including l-arginine
genetics or metabolic predisposition could interact with (i.e. the substrate for NO production) (133), and an inhi-
environmental factors for the final phenotype (127). bition of NO production by these compounds has been
The initial trigger for the development of endothelial described. Acute short-lasting increases in FFA plasma
dysfunction in MS is unknown, although several factors level which follows a high lipid content meal induced
have been described. Insulin-resistant states are char- transitory endothelial-dependent vasodilatation (138). It
acterized by blunted insulin-mediated vasodilatation is not clear whether the association of FFA with hyperten-
because of impairment of the phosphatidylinositol path- sion is dependent on the presence of IR. For example, in
way (PI-3), which may lead to a decrease in the eNOS the Japanese population-based Nagahama study (139), the
activity and the consequently lower NO production. authors found a favourable association of FFA levels with
The adverse consequences of these phenomena may be central BP, but it was not clear if these findings were related
enhanced by the fact that since the MAP-kinase pathway with the insulin-signalling pathways. In this sense, one
is unaffected by insulin, there may be an unimpaired syn- small study comparing FFA levels among different groups
thesis of endothelin 1 (ET-1), which favours vasoconstric- with or without HTN and with or without IR did not find
tion (128), vascular smooth muscle cell growth and cell significant interaction between the presence of HTN and
migration from the vessel medial to the internal layer. IR, therefore supporting an independent association of
This may promote an increase in vascular stiffness and FFA with HTN (140).
thickness, favouring the cascade of events responsible
for formation and progression of atherosclerotic plaque.
Taken together, these phenomena may explain at least in
part the increased BP and cardiovascular risk associated MS AND HYPERTENSION-INDUCED
with hyperinsulinemia (129,130). ORGAN DAMAGE
Low adiponectin levels also seem to induce endothelial
dysfunction by the same pathway, through a PI-3 kinase− The prevalence of target-organ damage at different levels,
dependent mechanism (126). By this mechanism, adipo- including left ventricular hypertrophy (LVH), diastolic
nectin is able to increase the activity of eNOS, although dysfunction, carotid atherosclerosis, arterial stiffness, reti-
other enzymes, such as 5′ adenosine monophosphate-acti- nopathy and microalbuminuria, is increased in hyperten-
vated protein kinase (AMPK) or cyclooxygenase-2 (COX-2) sive patients with MS when compared to those without it
have also been involved (126). Low plasma adiponectin (52,59,141–148). Most of these types of organ damage are
levels have been shown to be associated with impaired well-recognized surrogate endpoints, which may explain
endothelium-dependent vasodilatation (131–133), gener- the association of MS with a higher risk of CV and renal
ating the hypothesis that hypoadiponectinemia contrib- events (142,147,149–153).
utes to the development of obesity-related hypertension Several studies have demonstrated that MS is associated
via direct effect on the vasculature. Whether or not adipo- with a high prevalence of LVH in hypertensives, and that
nectin supplementation may represent a potentially useful this is the case throughout a wide age spectrum. Moreover,
therapeutic modality in MS individuals with or without MS by itself without hypertension has also been associated
hypertension requires further study (132,134). with greater left ventricular mass (LVM) and LVH (154).
Some genetic variants that could be related to low adi- The number of MS components has been directly related
ponectin levels have been discovered in Asian hyperten- to the risk of having electrocardiographic (EKG) (146) and
sive patients (135). One of these variants is located in an echocardiographic LVH (51,52,155), although this has not
140 Manual of Hypertension of the European Society of Hypertension
been confirmed in other studies (156,157). The effect of the risk of extremely high IMT (defined as an IMT greater
MS on LV structure seems to be more pronounced and less than percentile 95th). The risk to high IMT is greater when
dependent on hemodynamic factors in women than in men hypertension and abdominal obesity are present (176).
(59,156,158). However, the potential gender influence of Pulse wave velocity (PWV) is greater in hypertensives
MS for the development of LVH was not confirmed in other with MS and has also been associated with a faster pro-
series (159). Atrial enlargement, a prognostic factor for the gression of aortic stiffness with age, independently of
development of atrial fibrillation and stroke, has also been major individual CV risk factors, suggesting that it may
associated with MS and its components independently of promote premature vascular senescence (174,177). In the
LVM and geometry (156,160,161). Large prospective studies same way as for IMT, the MARE Consortium also showed
demonstrate an increased risk of new-onset atrial fibrillation that BP and abdominal obesity are the main contribu-
(AF) in MS being the hazard ratio (HR) for hypertension tors to an increase in PWV, the gold standard noninvasive
greater than for the other components [HR = 1.69 (1.66– method to determine arterial stiffness (178). Again, there
2.27)] (162). More recently, the REasons for Geographic and seems to exist a relationship between the number of MS
Racial Differences in Stroke [REGARDS] study (163) showed components and arterial stiffness, and when serum uric
a significant association among the number of components acid is elevated could also play an additional role (179).
of MS, each individual component including hyperten-
sion and MS itself with AF. Again, the largest adjusted HR
[HR = 1.30 (1.19–1.41)] was for those individuals who had
BP values ≥ 130/85 mmHg (163). This has been further PROGNOSTIC VALUE OF MS
observed in a more recent Swedish longitudinal study (164). IN HYPERTENSION
An increase in the prevalence of abnormal urinary albu-
min excretion has been observed among hypertensives Whether MS increases CVD risk beyond its individual com-
with MS as compared to those without MS (51,52,160,165), ponents is still a matter of controversy (6,10,145,153,180–
and indeed microalbuminuria was considered a diagnos- 182). Among the components of MS, central obesity,
tic element for MS in early definitions of this condition. elevated BP and hyperglycaemia had the greatest risk for
The prevalence of microalbuminuria has been shown to CVD [HR 2.36 (1.54–3.61)] and mortality [HR 3.09 (1.93–
increase with the number of MS components, a finding 4.94)] in the Framingham Offspring Study (183). Only a
seen also in nondiabetic subjects and being fasting glucose limited number of studies seem to support that the pres-
and systolic blood pressure (SBP) the two components with ence of MS or its individual components worsens the prog-
major impact (51,166,167). nosis in essential hypertension subjects.
The relationship between MS and glomerular filtra- In the Copenhagen Male Study (184), 2906 male par-
tion rate (GFR) was studied in several population studies ticipants were divided into three groups according to their
(165,168,169), although only few in hypertensives (148). fasting plasma triglyceride and HDL cholesterol levels,
In a cross-sectional survey of hypertensives seen in pri- two lipid parameters highly related to IR and hyperinsu-
mary care, MS was associated with lower GFR, estimated linemia. The CV risk was not increased in patients with
by the Modification of Diet in Renal Disease formula (170). hypertension in the absence of the above-defined dyslipi-
Furthermore, the number of MS components was linearly daemia. However, the group with high BP and dyslipidae-
related to the prevalence of GFR <60 mL/min/1.73 m2 (171). mia was the one displaying the highest risk.
Meta-analysis of published studies seems to confirm the The prognostic significance of MS in hypertension was
association of MS and its components with both microal- also analysed in the PIUMA cohort, which consisted of
buminuria and a decrease in GFR being the risk associated 1742 hypertensive patients without CV disease at entry.
with higher BP than for other components of MS [OR 1.61 Over a 10.5-year follow-up, MS patients, as defined by the
(1.29–2.01)] (172,173). Interestingly, a large cross-sectional ATP III criteria, had a CV event rate that was almost double
study, including more than 19,000 hypertensives, pointed that of the patients without MS. In patients with MS, the
out that serum uric acid could add synergically with MS to CV risk remained greater after adjusting for age, gender,
increase the risk of renal damage, but further studies are total plasma cholesterol serum, creatinine, smoking, LVH
needed to confirm this observation (17). and 24-h systolic BP. The presence of MS was an indepen-
MS and its components are also closely related to dent predictor of both cardiac and cerebrovascular events,
carotid atherosclerosis and intima-media thickness (IMT). and the risk remained higher after removal of diabetic sub-
The association between MS and carotid IMT has been jects (147).
observed in several studies (51,141,174), although to a In a Turkish study, 2225 men and women, free of CV
weaker degree than that observed for markers of organ disease at baseline and with a BP in the high-normal
damage such as LVH and microalbuminuria. In a large or hypertension range, were followed up for a mean of
survey of Japanese subjects, it was found that the preva- 4.1 years (185). Subjects defined as dyslipidemic hyper-
lence of carotid atherosclerosis increased progressively tensives, based on BP, plasma triglycerides and HDL-
with the number of MS components in hypertensives but cholesterol criteria for MS identification used by the
not in normotensives (174). National Cholesterol Education Program guidelines, had
Cuspidi et al., in a recent meta-analysis for the associa- a higher CV risk as compared to hypertensives who did
tion of MS with subclinical carotid damage in the general not have dyslipidaemia after adjustment for sex, age, LDL-
population, further confirms the results from previous cholesterol and smoking status. The dyslipidemic pheno-
observations (175). The Metabolic syndrome and Artery type was associated with half of the attributable CV risk
Research (MARE) Consortium (11) was established to of the MS (185).
identify different clusters of MS components as well as In the Hoorn study (186), 615 men and 749 women aged
sociocultural differences. Results for this collaboration 50–75 years and without diabetes or a history of CV dis-
demonstrate that not all the clusters seem to increase the ease at baseline were followed over a 10-year period. With
The Metabolic Syndrome in Hypertension 141
prevalence of MS at baseline ranging from 17−32%, MS Growing evidence shows that regular physical exercise
was associated with a higher CV risk, and the risk increased has beneficial effects on the cardiometabolic profile of
with the number of MS components. When the various MS both healthy individuals and patients with MS. In a cohort
definitions were compared, the ATPIII definition was asso- of 3148 healthy adults followed over 6 years, improving
ciated with about a twofold increase in the age-adjusted the fitness status and reducing fat was associated with a
risk of fatal CV disease in men and nonfatal CV disease in reduction in the risk of developing HTN and MS (189).
women. For the World Health Organization (WHO), the Cardiorespiratory fitness (CRF) further reduced the risk for
European Group for the Study of Insulin (EGIR) and the systemic hypertension in a cohort including 3800 Korean
American College of Endrocrinology (ACE) definitions of men (189,190). Another large study including 53,772
MS, the hazard ratios per CV events were slightly lower. men and 18,852 women found a significant association
The PAMELA study has provided further data on the between CRF and both cardiovascular mortality and coro-
association of MS with cardiac organ damage and increased nary heart d isease (191).
cardiovascular risk (59). MS, as diagnosed using the 2003 In addition to an improvement in the cardiometabolic
ATP III criteria, was identified in 16.2% of 2051 individu- profile of patients with MS, physical exercise seems to be
als living in an urban population from northern Italy, with a key strategy for the prevention of MS. Large prospective
the prevalence increasing to about 25% in middle-aged cohort studies have shown that even modest exercise (less
and elderly subjects. The most and the least frequent MS than 1 hour per week) was associated with a 30% lower
components were high normal BP and impaired fasting risk of development of MS (192).
glucose, respectively. Echocardiographically documented In general, a total of 150 minutes of exercise per week
LV hypertrophy was seen more frequently in subjects with including a regimen of physical activity with moderate-
than in those without MS (20.6% vs. 10.6%), the differ- to high-intensity exercise of 30-minute bouts on several
ence occurring in males and females at all ages and after days is recommended for BP and glycaemic management
exclusion from either group of individuals with hyperten- (193). The pathophysiological mechanisms underlying
sion, as well as after adjustment of data for the 24-h mean the potential benefit of exercise in MS are currently under
systolic BP values. Over 148 months of follow-up, the risk investigation; however, changes in adipokine metabolism
of CV and all-cause death was significantly higher in MS and reduction of the proinflammatory state seem to be key
individuals as compared with controls without MS even players (194,195).
when adjusted by age, gender, and other cardiovascular In addition to physical exercise, the regular consump-
risk factors (59). tion of certain nutrients has been found to have an impact
A more recent Spanish study (187), performed in the on BP and the metabolic profile of healthy individuals
general population aged more than 50 years and with a and patients with MS. The consumption of dark chocolate
limited sample size, has tried to answer the question of has been related to a reduction in BP and total cholesterol
whether diagnosis of MS helps to improve the prediction levels in several studies (196–198). Although the exact
of CV events over its individual components or over the mechanisms are unknown, dark chocolate is rich in poly-
Framingham Risk Score (FRS). According to the results, phenols, especially flavonoids, which produce vasodila-
the addition of MS as a dichotomic variable to FRS or to tion and decrease BP through the liberation of endothelial
its individual components did not improve or worsen the NO (199). Meta-analyses on the impact of flavanol-rich
prediction using a new index to evaluate a prediction tool cocoa products on BP suggest beneficial effects, at least
such as the net reclassification improvement (NRI) (187). in hypertension and pre-hypertension (197,199–202).
Moreover, some investigators have tried to model statis-
tically the long-term effects and associated cost-effective-
ness of dark chocolate intervention in a population with
MANAGEMENT OF MS MS and hypertension (198). Ideally, dark chocolate con-
sumption could potentially prevent 70 nonfatal and 15
The main objective of treatment of individuals with MS fatal cardiovascular events per 10,000 population treated
is to reduce the risk of cardiovascular or renal events over 10 years. The estimated incremental cost effectiveness
and to prevent the development of type 2 diabetes or ratio was $50,000 per years of life saved assuming that $40
hypertension. In addition, treatment should prevent the per person/year has been spent on a prevention strategy
progression (and favour the regression) of target-organ using dark chocolate.
damage, which is commonly present in patients with Several trials have found that a diet enriched with nuts
MS. The ideal treatment strategy consists of the oppo- could be beneficial for MS management. Available evidence
sition of underlying pathophysiological mechanisms has shown that nut consumption is related to a reduction
of MS. An effective reduction of visceral obesity, a hall- in the postprandial glycaemic response, a decrease in the
mark of MS, is a desirable goal in the management of risk of diabetes incidence in women, a cholesterol-lowering
MS. Non-pharmacological strategies are based mainly on effect and a beneficial effect on BP and endothelial func-
lifestyle interventions, including physical exercise and tion (203). The protective effects of nut consumption on BP
diet strategies. Despite the favourable cost-effectiveness and metabolism can largely be explained by the modula-
of non-pharmacological MS management strategies, the tion of inflammation and oxidation.
implementation of these strategies rarely results in a It has also been suggested that hypertensive patients
long-lasting reduction in visceral fat and central obesity. with MS might be more susceptible to the adverse effects
However, every single MS component can successfully be of salt intake as compared to hypertensives without MS
improved with lifestyle and diet modifications, and cur- (204). However, the potential role of reduced salt intake
rent technologies such as mobile and Internet-based com- in the treatment of MS has not yet been clearly elucidated.
munication seem to increase the effectiveness of lifestyle Regarding pharmacological strategies, the development
change in MS patients (188). of drugs that oppose IR or the metabolic hyperactivity that
142 Manual of Hypertension of the European Society of Hypertension
Table 17.2 Management recommendations for hypertension and metabolic syndrome (position statement of the ESH)
High blood pressure 130/85 mmHg <130/80 mmHg Non-pharmacologic treatment Thiazide-like diuretics should be avoided
Antihypertensive treatment: in monotherapy or in high-dose
First choice: ACEi or ARB β-blockers should be avoided if not
Second choice: CCB or compelling indication exists
β-blockers with vasodilatory Combination of thiazide diuretics plus
activity β-blockers should be avoided
Source: Grundy SM et al. Arterioscler Thromb Vasc Biol 2004 February; 24(2): e19–e24.
may help body weight gain is promising, but the actual antihypertensive drug class as compared to the others
involvement of these drugs in MS is still unclear. The in terms of BP and cardiovascular risk reduction in MS
administration of pioglitazone, a peroxisome proliferator – patients. However, it is known that each antihypertensive
activated receptor γ agonist, led to normalization of meta- drug class has a different impact on the metabolic profile
bolic parameters and complete restoration of endothelial of hypertensive patients. Given the fact that the devel-
function in primate models with MS (127). Another prom- opment of diabetes or atherogenic dyslipidemia in MS
ising candidate for the causal treatment of MS is molecules patients confers a considerable increase in cardiovascular
that interfere with the metabolism of epoxyeicosatrienoic risk, certain drug classes should be avoided in MS patients
acids (EETs). EETs have several beneficial properties includ- due to their adverse cardiometabolic effect.
ing anti-inflammatory, antihypertensive and pro-prolifer- Angiotensin-converting enzyme inhibitors (ACEi),
ative effects. Cytochrome P450 (CYP2J3) epoxygenases angiotensin II-AT1 receptor blockers (ARAII) and cal-
metabolize arachidonic acid into EETs. A study conducted cium channel blockers may induce a reduction of insu-
in rodents aimed to assess the effects of CYP2J3 gene deliv- lin resistance and beneficial changes in lipid profile
ery on insulin resistance and diabetes in fructose-induced (208). Therefore, these drug classes are preferable over
insulin-resistant rats and db/db diabetic mice (205). The diuretics and β-blockers in monotherapy if no compel-
gene therapy was able to reduce BP and reverse insulin ling indications are present for their use. If a combina-
resistance mediated by an increase in EET. This therapy fur- tion of drugs is required, low-range doses of diuretics can
ther led to an improvement in insulin sensitivity through be introduced. In contrast, a combination of thiazidic
the AMP-activated protein kinases in tissues including diuretics and β-blockers should be avoided due to their
liver, muscle, heart, kidney and aorta. Although the results potentially adverse cardiometabolic effects (Table 17.2).
of gene therapy are promising in animal models, further Despite the current recommendation against the use of
investigation is needed in order to explore whether CYP2J3 β-blockers in MS patients, the potential benefits of vasodi-
gene delivery is feasible and beneficial in humans. lating β-blockers are currently under investigation (209).
In addition to lifestyle and diet modifications, hyper- The majority of studies indicating a reduced protective
tensive patients with MS should receive pharmacologi- activity of β-blockers were carried out with atenolol, a
cal treatment, according to the recommendations of the β1-adrenergic selective antagonist. However, the β-blocker
ESH (206). The threshold for initiation of antihyperten- family has grown in the past years, and molecules with dif-
sive treatment is similar for both healthy individuals and ferent selectivity, partial intrinsic sympathetic activity, and
subjects with MS: BP-lowering drugs should be given vasodilatory capacity have been developed. Vasodilating
when peripheral BP is persistently equal to or greater than β-blockers including nebivolol may have a neutral or even
140/90 mmHg. In the presence of diabetes, the threshold favourable cardiometabolic profile as compared to non-
for drug intervention is lower, and antihypertensive treat- vasodilating β-blockers (210,211). Whether or not these
ment should be started at BP values greater than or equal molecules improve outcomes in MS patients under antihy-
to 130/85 mmHg. However, the target BP level in both pertensive treatment needs to be addressed in future trials.
patients with MS and in diabetics should be lower than
130/80 mmHg, in line with current recommendations for
individuals with a high cardiovascular risk. Similar goals
and an even lower threshold for drug intervention (below CONCLUSIONS
130/80 mmHg) should be considered when MS is present
in subjects with a very high CV risk, such as in the pres- MS is a highly prevalent condition characterized by a
ence of a history of CV or advanced renal disease. cluster of clinical and metabolic cardiovascular risk fac-
The ideal BP threshold for antihypertensive drug inter- tors including high BP. BP levels are related to MS compo-
vention in MS patients without diabetes or overt CVD is nents: Individuals with elevated BP have a higher risk of
difficult to establish due to the lack of adequately designed the development and progression of MS, and vice versa.
randomized trials targeting this subject. Although no In the hypertensive population, the presence of MS con-
available study has tested the long-term benefit of anti- fers an increase in cardiovascular risk on top of the risk
hypertensive drug initiation at different BP levels in this induced by BP elevation alone. Consequently, the assess-
specific population stratum, it seems reasonable to sup- ment of MS components and BP management based on
port early BP-lowering treatment in order to prevent the individual risk is relevant from a clinical point of view in
appearance or progression of target-organ damage (207). order to reduce morbidity and mortality. The development
Concerning BP-lowering drug classes, no avail- of hypertension is commonly associated with both obe-
able trial has investigated the superiority of a specific sity and insulin resistance. The main pathophysiological
The Metabolic Syndrome in Hypertension 143
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the renin−angiotensin−aldosterone system, abnormal of risk factors: Is the whole greater than the sum of its parts?:
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PSYCHOSOCIAL RISK
FACTORS, AIRBORNE 18
POLLUTION, HYPERTENSION
AND CARDIOVASCULAR
DISEASES
Philippe van de Borne
ANXIETY
STRESS IN DAILY LIFE Whether anxiety has an adverse effect on cardiovascular
disease is not entirely clear. While panic attacks may have
Recurrent expositions to stressful conditions at work may raised cardiovascular events to some extent (21,29,30),
lead to an enhanced cardiovascular risk, although the other forms of anxiety such as phobic anxiety did not
150 Manual of Hypertension of the European Society of Hypertension
(22–24). Conversely, total mortality was even lower in activity, alcohol consumption and financial barriers to
patients with documented cardiovascular disease and healthcare. Psychological interventions for coronary heart
anxiety unless systolic ventricular function was impaired. disease modestly reduce cardiovascular mortality and
These bidirectional effects of anxiety on health in patients improve mental health in meta-analysis.
at risk suggest that other factors may be involved. An alter-
native interpretation could be that in some circumstances,
anxiety may improve adherence to therapy and thereby
prognosis, while in other circumstances, anxiety accompa- OTHER CARDIOVASCULAR RISK
nies a severe disabling disease such as heart failure, where FACTORS: AIRBORNE POLLUTION
the prognosis is poor. Interestingly, after correction for
several confounding factors, anxiety appeared neverthe- AND HYPERTENSION
less an independent risk factor for ischaemic heart disease
Air pollution is a ubiquitous and highly heterogeneous
and subsequent poor outcome when studies were pooled
mixture of particulate matter (PM), various gaseous com-
into meta-analyses (25,26).
pounds and molecules in vapor phase (33). The gaseous
part of polluted air encompasses nitrogen oxides, sulphur
oxides, and ozone, while PM includes different elements
PERSONALITY TRAITS such as nitrates, sulphates, transition metals and organic
and elemental carbon. Fine PM (<2.5 µm in diameter;
Patients, colleagues or family members who express PM 2.5) is linked to cardiovascular morbidity and mortal-
extensive mistrust and demonstrate repeatedly aggressive ity excess (33). Epidemiological studies have shown that
behaviours where anger and rage tend to preclude normal short-term rises in PM 2.5 are accompanied within a few
social relationships often present the well-known person- days by additional myocardial infarcts, heart failure exac-
ality trait called hostility (27,28). This has been shown to erbations, cardiac arrhythmias and strokes.
increase the incidence of new and recurrent cardiovascular
events (27). Suppressing anger expression predicts excess
risk in patients with cardiovascular disease (28), while the
reverse condition could contribute to increasing the daily POSSIBLE MECHANISMS OF DISEASE
life stress of colleagues and family members (8–11).
Several mechanisms may explain these observations:
(i) an acute autonomic nervous system imbalance, due
to PM 2.5 accumulation within the pulmonary tree and
RECENT INSIGHTS activation of nerve endings and receptors (34), and (ii)
an inflammatory response to air pollution in the lungs,
Several studies have further pooled individual and pub- with extended effects outside the pulmonary vasculature
lished data from cohorts into large databases in order to (35). Subsequent cytokine release and immune cell activa-
better understand the association between stress and tion then result in further oxidative stress and endothelial
cardiovascular disease. While marriage remains accom- dysfunction. Tumour necrosis factor, interleukin 6, endo-
panied by a lower cardiovascular disease rate, and after a thelin and activated leukocytes can also induce systemic
cardiovascular event, marital status is associated with an upregulation of reactive oxygen species pathways through
improved prognosis (29). The reverse occurs in the pres- nicotinamide adenine dinucleotide phosphate (NADPH)
ence of depression or lack social support (29). In a gen- oxidase and promote endothelial nitric oxide synthase
eral population at work, job strain should be removed (eNOS) uncoupling. PM 2.5 exposure reduces tetrahydrop-
from 550 employees for 5 years to prevent one myocardial terin level in various organs, and these effects may per-
infarction (30). In comparison, antihypertensive therapy sist for weeks after the inhalation (35). Enhanced vascular
in intermediate cardiovascular risk individuals is 6–7 responsiveness to a variety of vasoactive substances fur-
times more efficacious to prevent one major cardiovascu- ther reveals that airborne pollution shifts vasomotor tone
lar event (31). Recent evidence indicates that in the general towards vasoconstriction (35). Endothelium-dependent
population, work and private-life stress increases the risk vasodilation impairment is related to PM exposition not
of incident coronary heart disease and stroke by 1.1- to 1.6- only in higher-risk individuals (e.g. those with diabe-
fold (32). Accordingly, a Cochrane systematic review and tes) but also in healthy adults (36,37). Moreover, among
meta-analysis of psychological interventions for coronary elderly subjects, a reduction in 48-hour PM 2.5 levels due
heart disease reported a reduction in cardiovascular mor- to filtering of air in subjects’ homes resulted in improved
tality (relative risk 0.79%, 95% confidence interval [CI] microvascular function (38). These abnormalities are
0.63–0.98) and favourable effects on depressive symp- more likely to be due to a decreased nitric oxide bioavail-
toms, anxiety and stress (32). ability as a consequence of systemic inflammation or oxi-
dative stress. This may explain why PM10 air pollution
levels are associated with heightened amplitude of the
SUMMARY reflection wave leading to significant alterations in central
pulse pressure (39). Last, inhalation of some metallic com-
Low socioeconomic status, lack of social support, stress ponents, as well as very small particles, may impair vaso-
at work and in family life, depression, anxiety, hostility, motor regulation after reaching the circulation directly. As
and the type D personality not only contribute to the risk such, passive smoking not only increases plasma nicotine
of developing cardiovascular disease but also worsen its levels and wave reflection when compared to nontobacco
clinical course. These risk factors are often associated with smoke (40) but also results in higher blood pressure lev-
other risk factors such as unhealthy diet, lack of physical els in children of smoking parents (41). In the latter study,
Psychosocial Risk Factors, Airborne Pollution, Hypertension and Cardiovascular Diseases 151
parental smoking independently affected systolic blood systemic arterial blood pressure, a common cause of left
pressure even after correction for other risk factors such as ventricular hypertrophy. Elevated ambient PM 2.5 levels are
body mass index, parental hypertension or birth weight. associated, within 3–5 days, with systolic and diastolic
Interestingly, the quantitative relationship was established blood pressure elevations (49), unless heart rate was lower
for maternal, but not parental, cigarette consumption. This than 70 bpm in these cardiac rehabilitation patients, sug-
is likely because mothers are more likely to smoke pre- gesting that cardiovascular medication may protect against
dominantly at home, whereas fathers may consume their the hypertensive effects of air pollution. A study in South
cigarettes at work or outside of the home, and thus in the Korea (50) and a study in six US cities (51) also observed
absence of the children. these associations. In the latter study, adjusted blood pres-
sure rose within 1–2 days by 3 mmHg, and this association
was stronger in patients with hypertension as well as under
BLOOD PRESSURE AND AIRBORNE POLLUTION other conditions such as warm weather and traffic proxim-
ity. A study in Detroit (52) reported a 3-mmHg increase
Does acute exposure to airborne pollution increase blood in systolic blood pressure per 10 µg/m3 rise in PM 2.5 with
pressure, and are hypertensive patients at risk or protected a lag of 2 days. However, similar rises in PM 2.5 did not
against these effects? result in comparable blood pressure effects in the different
districts of Detroit, and this was attributed to differences
in PM composition. The composition, concentration and
dimension of the particles give a specific toxicity profile
EXPERIMENTAL STUDIES to the particles and may explain the seasonal variation
in the strength of the association between PM exposure
Controlled animal studies have been performed under and blood pressure (50). In the warm weather season, the
different conditions, using different recording systems effect of PM10 on blood pressure increase is more consis-
(mainly tail-cuff and radio telemetry) and not surpris- tent than in the cold weather season. Finally, changes in
ingly, have reported variable results where blood pressure systolic blood pressure were not significant in patients tak-
remained unchanged, decreased (when very large amounts ing antihypertensive medications (+0.7 mmHg), as com-
of PM are administered intrabronchially or intravenously) pared to those who were untreated (+6 mmHg).
or increased. In controlled human studies (middle-aged or On the other hand, a large meta-analysis suggested
elderly healthy adults and patients with coronary artery that air pollution is an important trigger for myocardial
disease), blood pressure remained either unchanged or infarction, even more than a classic cardiovascular risk
increased in most of the publications (42). However, using factor (53). Trigger studies in this case typically assessed
a controlled experimental design in healthy humans spe- risk exposure in the period ranging from a few minutes
cifically dedicated to study the impact of PM exposure on to 24 hours before the onset of myocardial infarction. Air
blood pressure, it has been shown that exposure to PM pollution exposure induced a small individual odds ratio
increases diastolic blood pressure rapidly (42,43). for cardiovascular events but had a large and significant
impact on the whole population. These effects may be
more pronounced in patients with markedly elevated car-
EVIDENCE FROM EPIDEMIOLOGICAL STUDIES diovascular risk factors.
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SERUM URIC ACID, BLOOD
PRESSURE AND HYPERTENSION 19
Claudio Borghi
O OH
O
Guanine Xanthine
deaminase N oxidase N
N HN N
HN
O N N
H2N N N H N
N H H H
Guanine Xanthine
Guanine 5′ Adenosine 5′
OH
monophosphate monophosphate
H
N
N
O
HO N
N H
Uric acid
Figure 19.1 Biochemical pathway involved in SUA production. (Adapted from Dawson J et al. Curr Med Chem 2007; 14(17):
1879–1886.)
* *
60 60
50 50
Metabolic syndrome (%)
Hypertension (%)
40 40
30 30
20 20
10 10
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Quartiles of serum uric acid Quartiles of serum uric acid
* *p = 0.005
1.05 9.50 *
1.00 9.00
0.95 8.50
PWV (m/s)
IMT (mm)
0.90 8.00
0.85 7.50
0.80 7.00
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Quartiles of serum uric acid Quartiles of serum uric acid
Figure 19.2 Schematic summary of the main pathways involved in SUA production, plasma levels and cardiovascular
disease.
Serum Uric Acid, Blood Pressure and Hypertension 157
Purine load
Oxidative
Genes XOR stress
Gout
i.c. and mitochondrial oxidative stress
Reduced No bioavailability
i.c. RAAS stimulation
Enhanced lipogeneisis and FA oxidation
Insulin-resistance
Endothelial dysfunction
LDL-oxidation
Figure 19.3 Quartiles of SUA and prevalence of CV risk factors and TOD in the cohort of the Brisighella Heart Study.
(From Cicero AF et al. J Hypertens 2014; 32: 57–64.)
in the normotensive or pre-hypertensive population (54). potential confounders (62). In particular increased SUA
Most of the studies has considered as a risk factor circu- concentrations were found to be a risk factor for sever-
lating uric acid levels above 7 mg/dL currently adopted ity of coronary artery disease (63), atrial fibrillation (64),
in the management of gout. Conversely, some degree of myocardial infarction, stroke (65) and heart failure (66).
cardiovascular involvement can be already demonstrated
for SUA levels significantly lower and considered in the
normal range (from 4.5 to 6.0 mg/dL). In exposed popula-
tions, the risk of primary hypertension increased signifi- TREATMENT OF HYPERURICEMIA AND
cantly starting from SUA levels of 5.5 mg/dL (40,45) and
supports the option that the cardiovascular effects of SUA
HYPERTENSION
do not necessarily involve urate deposition. The considerable amount of evidence supporting a close
correlation between elevated levels of SUA and hyperten-
sion can have important therapeutic implications particu-
HYPERURICAEMIA IN PATIENTS WITH larly for xanthine-oxidase inhibitors (67). At present, only
HYPERTENSION a limited number of studies have investigated the effects of
urate lowering drugs in patients with hyperuricemia and
The connection between hyperuricaemia and hypertension elevated blood pressure reporting variable results depend-
has been known for over a century (30). Hyperuricaemia ing on the characteristics of the patient populations and
is found in 25% of individuals with untreated hyperten- the designs of the studies. The complexity of the mecha-
sion and three-quarters of patients with malignant hyper- nisms involved in the increase in SUA (overproduction vs.
tension (55). The prevalence of hyperuricaemia has been under-excretion) and the lack of control of concomitant
found to be higher in people with more severe hyperten- risk factors affecting blood pressure (e.g. use of diuretics)
sion (56). In patients treated for hypertension, hyperuri- are probably responsible for the differences in the results
caemia is associated with an increased risk of uncontrolled of the interventional studies and conclusive results are
hypertension (57). In addition, hyperuricaemia has also awaited from the clinical trials currently ongoing in this
been reported to be associated with resistance to antihy- area (Table 19.1).
pertensive treatment (58).
PRE-HYPERTENSION OR STAGE 1
HYPERURICAEMIA, HYPERTENSION AND HYPERTENSION
CARDIOVASCULAR DISEASE
Pilot studies suggest that lowering uric acid can result in an
Despite the earlier studies tended to conclude that elevated improvement in blood pressure in obese adolescents with
uric acid levels were only a marker of cardiovascular risk hyperuricemia and pre-hypertension (68), in adolescents
without any predictive role (59–61), more recent evidence with newly diagnosed hypertension (69), and in adults
have supported a causative relationship in hypertensive with asymptomatic hyperuricemia (70,71). Soletsky et al.
patients that remained robust and after adjustment for (70), have investigated a group of obese pre-hypertensive
Serum Uric Acid, Blood Pressure and Hypertension 159
Table 19.1 Summary of randomized clinical trials in the field of urate-lowering treatment and cardiovascular disease
Coronary endothelial dysfunction Febuxostat vs. placebo Coronary flow NCT01763996a; completed
Vascular structure and function Febuxostat vs. allopurinol Carotid-femoral PWV EudraCT 2014-5567-33;
(FORWARD) enrollment closed
New on set metabolic syndrome Febuxostat vs. placebo Insulin resistance and features of NCT01654276a; ongoing
(FAST) metabolic syndrome
Cerebrovascular protection Allopurinol vs. placebo White matter protection NCT02122718a; starting
(XILO-FIST) recruitment
Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CHD, coronary heart disease; CV, cardiovascular; ETT, exercise tolerance testing;
MACE, major adverse cardiovascular events; PWV, pulse wave velocity.
aClinicaltrials.gov.
adolescents showing that both a xanthine-oxidase inhibi- pressure compared with the control group with a substan-
tor (allopurinol) or an uricosuric agent (probenecid) had tial homogeneity across the studies despite a remarkable
a significant effect on ambulatory systolic and diastolic difference in the characteristics of the study populations.
blood pressure. In another study, Feig et al. (69) investi-
gated the effects of urate-lowering treatment in 30 adoles-
cents with newly diagnosed stage 1 essential hypertension PREVENTION OF CARDIOVASCULAR EVENTS
reporting a significant reduction in blood pressure only in
response to allopurinol. A comprehensive population study has demonstrated
that the treatment with allopurinol is associated with an
improved survival in the general population including
ESTABLISHED HYPERTENSIVE PATIENTS patients with hypertension (75). In hypertensive patients a
retrospective study reported decreased incidence of stroke
Uric acid-lowering treatment has been shown to reduce
and cardiovascular in response to allopurinol (76). The
blood pressure also in patients with established hyperten-
favourable effect was greater in patients treated with the
sion. The UK Clinical Practice Research Datalink involv-
higher dose of allopurinol, confirming the importance of
ing 365 elderly patients with hypertension and 6678
XO inhibition in patients with hypertension. These results
controls, found that the treatment with allopurinol was
are in agreement with those of a systematic review and
associated with significant reductions in both systolic
meta-analysis reporting that treatment with XO inhibi-
and diastolic blood pressure (72). The efficacy of another
tors improved endothelial function, circulating oxidative
X inhibitor, febuxostat, was evaluated by Gunawardhana
stress markers and cardiovascular prognosis in patients
et al. (74), in a phase II, randomised, double-blind, pla-
with or at risk of cardiovascular disease (77,78).
cebo-controlled study of 121 patients with hypertension
and hyperuricaemia. At week 6, there were no significant
differences between the febuxostat and the placebo group
in the 24-hour mean ambulatory systolic blood pres- CONCLUSIONS
sure. However, a pre-specified subgroup analysis systolic
blood pressure was significantly reduced after 6 weeks of A large number of experimental and clinical studies sug-
treatment in patients with normal renal function (73). A gest that uric acid may be actively involved in the com-
comprehensive meta-analysis of both prospective and plex pathophysiological pathway leading to hypertension.
retrospective studies carried out by Agrawal et al. (75), Hyperuricaemia is the consequence of several dietary and
evaluated the effects of allopurinol treatment on blood genetic factors leading to stimulation of XO activity and
pressure in 10 studies involving 738 patients. In this analy- oxidative stress. A causality role for uric acid in hyperten-
sis allopurinol significantly reduced systolic and diastolic sion is supported by experimental and clinical studies as
160 Manual of Hypertension of the European Society of Hypertension
well as by some preliminary therapeutic evidence involv- growth factor A-chain expression. J Biol Chem 1991; 266:
ing XO inhibitors. Whether or not this evidence will be 8604–8608.
24. Mustard JF, Murphy EA, Ogryzlo MA, Smythe HA. Blood coagula-
confirmed by other ongoing studies, the increase in the tion and platelet economy in subjects with primary gout. CMAJ
amount of research focused on the role of uric acid in 1963; 89: 1207–1211.
hypertension has provided new insights into the manage- 25. Kanellis J, Watanabe S, Li JH et al. Uric acid stimulates monocyte
ment of hypertension and related cardiovascular diseases. chemoattractant protein-1 production in vascular smooth muscle
cells via mitogen-activated protein kinase and cyclooxygenase-2.
Hypertension 2003; 41: 1287–1293.
26. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative
stress with an activation of the renin-angiotensin system in human
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DYSLIPIDAEMIA IN
HYPERTENSION 20
increased by 23% and 39%, in patients with total choles- For these reasons, ESC guidelines (14) do not recom-
terol and non-HDL cholesterol levels in the highest quin- mend treatment decisions based on long-term risk stratifi-
tile, respectively. On the other hand, the risk of becoming cation, although this issue will probably need to be revised
hypertensive was decreased by 32% in patients with HDL in the future.
cholesterol in the highest quintile compared with those in As an example, young people at estimated low 10-year
the lowest quintile (8). risk (due to their age) but with high levels of other con-
In the San Antonio Heart Study, the relative risk of new- comitant risk factors are expected to have a high long-term
onset hypertension was 1.42 in patients with triglyceride risk of CV morbidity and mortality. In addition, the rel-
levels >110 mg/dL after a 7-year follow up (9). atively low levels of risk to which each subject might be
In a study including 16,130 adult normotensive women, exposed are more responsible for the increased absolute
after a 10-year follow up the incidence of hypertension risk of major CV events than that derived from high-risk
was increased by 14% and 25% in patients with high con- levels involving only limited proportions of patients.
centrations of total cholesterol and non-HDL cholesterol, This evidence is confirmed by the fact that the vast major-
respectively, and decreased by 19% in subjects with high ity of CV events occur in low- or intermediate-risk catego-
HDL-cholesterol (10). Another study demonstrated that ries, whereas only a minor proportion of events occurs
high concentrations of apolipoprotein-B were associated in individuals at high or very high risk (14,15). For these
with a 1.4-fold higher risk of hypertension. reasons, prevention strategies should ideally be applied to
In this latter regard, it should be highlighted that other the entire population, including young adults, through-
features of dyslipidaemia, including apolipoproteins, out all risk categories, and the intensity of the therapeutic
should be always considered. As an example, if all the approach should take into account not only the absolute
lipid variables were simultaneously analysed in a mul- level of single CV risk factors but also the potential impact
tiple logistic regression analysis, the risk of hypertension of the size of the abnormality of concomitant risk factors,
was increased by 2.3-fold in those individuals with high particularly BP and LDL-c levels.
compared with those with low cholesterol levels (11). On With regard to dyslipidaemias, specific recommenda-
the basis of these results, abnormal lipid profile seems to tions about when to start pharmacological therapies and
anticipate and predict the future development of hyper- how many times the assessment of lipid profile should
tension, and particularly its consequences and outcomes. be repeated are currently lacking. According to European
guidelines, screening should be carried out in men aged
>40 years and women aged >50 years or in post meno-
pause, whereas it is not indicated in younger people with-
out other additional risk factors. In addition, patients with
TOTAL CARDIOVASCULAR RISK PROFILE diabetes, peripheral artery disease, hypertension or with
IDENTIFICATION, PROGNOSTIC family history of premature CV events should undergo
RELEVANCE AND MANAGEMENT lipid evaluation at the time of the diagnosis, indepen-
dently from age (16). Indications for starting and/or main-
Several observational studies and randomized clinical taining lipid-lowering therapies are discussed below.
trials have demonstrated that the net clinical benefit of
lipid-lowering therapy depends on baseline individual
risk profile, with a more intensive therapeutic approach
required in patients with a high- or very-high−risk profile. LIPID-LOWERING THERAPIES AND
As mentioned earlier, according to the current guide- HYPERTENSION
lines from European Society of Cardiology (ESC) (12), the
assessment of individual risk is a cornerstone of all clini- Since there is clear evidence that dyslipidaemia and hyper-
cal decisions in terms of diagnosis and treatment strate- tension have a synergistic impact on the genesis and pro-
gies. These guidelines suggest the use of the SCORE system gression of atherosclerotic disease, with relevant clinical
(13), which estimates the 10-year risk of CV mortality on consequences on the risk of developing major CV events,
the basis of total cholesterol levels, blood pressure, age, sex such as coronary artery disease, stroke, heart failure and
and smoking habit. CV mortality, it is necessary to focus on both primary
Four categories of risk have been established and related and secondary prevention of these conditions by adopt-
to different therapeutic recommendations: (1) low risk ing early pharmacological interventions and long-term
(SCORE ≤1% of 10-year CV mortality): lifestyle education clinical management in order to the recommended target
aimed at avoiding the progression of atherosclerotic dis- LDL-c and BP levels.
ease and maintaining a low level of CV risk; (2) moder- Recent guidelines have recommended therapeutic
ate risk (SCORE ≥1% − <5%): pharmacological therapy thresholds of LDL-c lower than those previously set, mostly
may be evaluated in addition to lifestyle interventions; (3) when multiple CV and metabolic risk factors coexist, and
high risk (SCORE ≥5% − <10%): the beginning of phar- even in the low- to intermediate-risk patients. In this view,
macological therapy is suggested in the absence of contra- the NCEP ATP guidelines support the benefits of reducing
indications; (4) very high risk (≥10%): pharmacological cholesterol in the presence of concomitant risk factors, even
therapy is necessary. It should be also noted, however, that when plasma levels of LDL-c are not elevated, and suggest
although reproducible, simple, largely applicable and not considering the start of lipid-lowering therapy in all hyper-
expensive, this risk score evaluation is limited to individ- tensive patients, independently from their lipid profile (17).
uals aged from 40−65 years and estimates only the risk Among different components of the lipid profile, the
of mortality, and within the relatively short period of 10 reduction of LDL-c plasma concentrations represents the
years, not taking into account the long-term probability of most important therapeutic target due to its pathologi-
death. cal role in increasing risk of coronary and cerebrovascular
Dyslipidaemia in Hypertension 165
events. Indeed, therapeutic strategies aimed at reducing consideration of not only hard endpoints of coronary artery
levels of triglycerides or increasing levels of HDL-c have disease, including fatal and nonfatal myocardial infarction,
displayed less consistent proofs of providing benefits in but also stable and unstable angina and cerebrovascular dis-
reducing the incidence rate of major CV events (18,19). ease in the assessment of the 10-year risk.
The suggested therapeutic targets of LDL-c derive from Several studies have demonstrated a continuous posi-
the results of several randomized clinical trials, and tive association between LDL-c concentrations and the
depend mostly on individual CV risk profile. It should be incidence of vascular disease, but a threshold below which
noted that the absolute benefit of lowering LDL-c depends the risk of CV events is almost eliminated has not been
on the absolute individual risk rather than the baseline yet identified, and the former thresholds have been chal-
plasma LDL-c levels. Thus, guidelines currently focus not lenged by recent studies (23).
only on LDL-c plasma concentrations, but also on baseline
estimated CV risk profile.
In patients at very high CV risk, a reduction of LDL-c
levels below 70 mg/dL or at least 50% from baseline value CLINICAL SURVEYS ON STATIN THERAPY
should be obtained. In those individuals at high CV risk,
There are also many observational studies and clinical sur-
the therapeutic target is LDL-c <100 mg/dL, whereas in
veys reporting favourable effects of statin therapy on BP
those with moderate CV risk the goal of <115 mg/dL can
reduction and control. For example, the Brisighella Heart
be achieved (13).
Study evaluated the effects of different strategies of lipid
These recommendations are supported by the recent
lowering on BP, comparing diet, cholestyramine, gemfi-
results of the Heart Outcomes Prevention Evaluation
brozil and simvastatin, demonstrating the greatest results
(HOPE-3) trial, that demonstrated significantly benefi-
in the group treated with simvastatin (24).
cial effects of rosuvastatin 10 mg compared to placebo in
Similar results have been obtained by Borghi and co-
reducing major CV events (24%), also in individuals at
workers, who demonstrated that the use of statins, beyond
moderate risk with at least one risk factor in the setting of
antihypertensive drugs, may improve BP control. In this
primary prevention (20).
study, the administration of statins in combination with
The United States Preventive Services Task Force
a calcium channel blocker significantly reduced BP more
(USPSTF) recommend starting lipid-lowering therapies,
than the calcium channel blocker alone (25).
especially with low- to moderate-intensity statins, in adults
Tocci et al. have recently investigated the potential effects
aged between 40–75 years with the following additional CV
of statins on nighttime ambulatory systolic and diastolic
risk factors: smoking, hypertension, dyslipidaemia, diabe-
BP and on home, clinic, ambulatory daytime and 24-hour
tes or at least a 10% 10-year CV risk. If the estimated 10-year
systolic and diastolic BP in a cohort of 5634 patients.
risk is between 7.5% and 10%, starting pharmacological
Among individuals who did or did not receive statin treat-
therapy is not mandatory and physicians should take into
ment, there were significant differences in terms of 24-hour
account the patient’s preferences and attitudes, and may
(129.7 vs. 130.9 mmHg, respectively) and daytime systolic
give high priority to lifestyle recommendations (21).
BP (133.0 vs. 134.5 mmHg), and in terms of home (80.7 vs.
The ACC/AHA Guidelines on the Treatment of Blood
84.5 mmHg), clinic (86.5 vs. 91.7 mmHg), 24-hour (75.0
Cholesterol, published in 2013, emphasize that high LDL-c
vs. 79.9 mmHg), daytime (78.0 vs. 83.3 mmHg) and night-
levels represent a risk factor for vascular disease even in
time (67.3 vs. 70.9 mmHg) diastolic blood pressure. These
young adults. In subjects aged 40−75 years, without previ-
effects on BP profile are consistent not only in hyperten-
ous history of CV disease or diabetes, with LDL-c concen-
sive patients, but also in normotensive patients, regardless
trations 70−189 mg/dL, the initiation of a statin therapy is
of the classes and the numbers of antihypertensive drug
suggested independently from sex and race since the ben-
administrated in free- or fixed-dose combinations (26).
efits in terms of relative risk reductions of major events in
These results may explain and further support the evi-
primary prevention do not differ between men or women
dence of a synergistic effect of statins and BP-lowering
or between different ethnicities. Intensity of statin treat-
therapies in reducing the development and progression of
ment should be adapted to the estimated 10-year CV risk.
atherosclerosis and the incidence of CV and cerebrovascu-
Because the relative risk reduction does not differ at dif-
lar events. In fact, these findings corroborate previous large
ferent LDL-c levels between 70−189 mg/dL, according to
epidemiological observations, such as those obtained in
several studies, the absolute benefit of statin therapy in
the Asian-Pacific Study (27), where the negative synergistic
primary prevention depends on the global 10-year esti-
effect of BP and cholesterol on myocardial infarction and
mated risk (22).
stroke was clearly demonstrated, and it was hypothesized
As observed in the aforementioned USPSTF recommen-
that a combined reduction of 10 mmHg systolic BP and
dations (23), a shared decision between patients and phy-
1 mmol cholesterol doubled the CV benefits.
sicians on starting statin therapy in subjects with a CV risk
of 7.5% or 5% to <7.5% is suggested. Physicians should
take into account potential benefits, adverse events and
individual preferences. CLINICAL TRIALS ON STATIN THERAPY
Additional factors should be also considered when under-
taking treatment decision. Among these, one should con- Numerous randomized controlled clinical trials have dem-
sider family history of premature onset of CV disease <55 onstrated the efficacy of statins in reducing CV morbidity
years of age in a first-degree male relative or <65 years of age and mortality, both in primary and secondary prevention
in a first-degree female relative, ankle-brachial index <0.9 and independently from age and sex. It should be noted
and also elevated lifetime risk of major events, considering that, regretfully, very often data and trends of BP during a
that the 10-year horizon might be not sufficient in some cir- trial are not reported, and a greater attention to the collec-
cumstances. In addition, the same guidelines recommend tion of these data should be encouraged.
166 Manual of Hypertension of the European Society of Hypertension
The Cholesterol Treatment Trialists’ (CTT) Collaboration have been obtained in a setting of satisfactory BP control
has analysed data from 27 trials involving 170,000 indi- (mean values 138/80 mmHg) in both groups, indicating
viduals treated with more or less intensive regimens. This that the effects of statins are additive to those of the anti-
analysis demonstrated that a reduction of 40 mg/dL of hypertensive regimen (37).
LDL-c is able to produce 10%, 20%, 23% and 17% reduc- The benefits of simultaneous modifications of risk fac-
tions of all-cause mortality, CV mortality, major coronary tors are particularly evident in subjects with impaired glu-
events and ictus, respectively, with more intensive statin cose metabolism. The co-administration of amlodipine
regimens being even more efficacious (28). The observed and atorvastatin produced greater reductions of both BP
benefits achieved statistical significance even after the first and inflammatory markers compared to those obtained
year of therapy and persisted for many years even after with each therapy administered separately. Indeed, the
treatment discontinuation. However, the benefits in terms amlodipine-atorvastatin combination produced a greater
of CV prevention became greater during each year in those decrease of 22.5 mmHg for systolic BP and 17.7 mmHg for
patients who remained on treatment. In this meta-analy- diastolic BP compared to 17.1 and 14.3 mmHg obtained
sis, statin therapy significantly reduced the risk of major with amlodipine monotherapy. The combination therapy
events even in individuals with 5-year risk lower than 10% also produced greater reductions of tumor necrosis factor
and without diabetes, chronic kidney disease and history (TNF) levels (2.59 pg/mL vs. 0.57 pg/mL in the amlodip-
of previous vascular disease. ine group) and of homeostasis model assessment (HOMA
A meta-analysis of eight controlled, lipid-lowering trials IR) (2.86 vs. 0.70 in the amlodipine group). HOMA-IR
involving 18,000 patients has shown a reduction of sys- changes significantly correlated with TNF-α changes
tolic BP between 1.3 and 6 mmHg in subjects who received (r = 0.38) during combination but not during amlodipine
lipid-lowering treatment (29). monotherapy (38). Subsequent studies confirmed that the
In non-placebo−controlled trials, both pravastatin and combination of atorvastatin to amlodipine therapy has an
atorvastatin (30,31) produced a mean reduction of 8 mmHg additive role in increasing arterial compliance and reduc-
for systolic BP and a mean reduction of 5 mmHg for dia- ing arterial stiffness and BP (39).
stolic BP levels. The obtained BP reduction was not related The synergistic beneficial role of antihypertensive and
to the mean decrease of cholesterol levels, thus confirming statin therapies in reducing CV risk is particularly relevant
the hypothesis that the BP-lowering effect of statins is inde- in secondary prevention, such as in patients with a history
pendent from their ability to lower LDL-c levels. of myocardial infarction.
Another meta-analysis has shown that statin treat- A sub-study from the IDEAL trial has investigated the
ment reduced systolic BP by 1.9 mmHg and diastolic BP effects of BP and LDL-c visit-to-visit variability on a com-
by 0.9 mmHg, with a greater effect in patients with higher posite endpoint of death from CV causes, nonfatal myocar-
baseline BP. Results obtained were even more marked dial infarction, revascularization or angina. The composite
in diabetic patients with hypercholesterolemia, with a endpoint was characterized by any CV event (any coronary
reduction of 3.7 and 0.8 mmHg for systolic and diastolic event or cerebrovascular event, peripheral vascular dis-
BP, respectively. These findings were independent of age, ease, heart failure) and individual endpoints of myocardial
length of the trial, baseline plasmatic concentrations of infarction, stroke, death and CV death evaluated separately
total and LDL cholesterol and antihypertensive medica- (40). The increase of about 11 mg/dL of LDL-c levels was
tions (32). associated with a significantly augmented incidence of
A sub-analysis of the Anglo-Scandinavian Cardiac any coronary event (7%), any CV event (8%), myocardial
Outcomes Trial (ASCOT) showed that after a 2.5-year fol- infarction (11%) and death (19%). For each increase in
low-up BP was significantly lower in patients treated with systolic BP variability of 7.2 mmHg, an increased risk of
atorvastatin than in those who received placebo (33). Similar any coronary event (15%), any CV event (16%), myocar-
data have been obtained by the San Diego Statin Study, in dial infarction (28%), stroke (33%), death from any cause
which treatment with simvastatin or pravastatin produced (28%) and from CV cause (19%) was detected.
a significantly greater reduction of BP compared to placebo, Both LDL-c and BP variabilities were independent of
with a maximum difference of 2.8/2.7 mmHg (34). each other in predicting any coronary event. However, the
In the Steno-2 study, intensive intervention on multiple group with high variability for both these risk factors had
risk factors (identified targets: levels of glycated haemoglo- a significant increase in any coronary event (HR 1.48), any
bin <6.5%, of total cholesterol <175 mg/dL and of triglyc- CV event (HR 1.43) and myocardial infarction (HR 1.87)
erides <150 mg/dL, BP <130/80 mmHg) had sustained compared to subjects with low variability of both LDL-c
beneficial effects on the rate of vascular complications and and blood pressure. Variability in systolic BP strongly
of CV and all-cause mortality (35). predicted the risk of stroke compared to the variability in
The ENCORE II study enrolled 226 patients with a LDL-c.
left coronary artery stenosis with the aim to evaluate the On the basis of the results of these trials, the American
potential synergism of lipid and BP-lowering therapies. College of Cardiology/American Heart Association 2013
The study demonstrated that the addition of nifedipine to Blood Cholesterol Guideline has stratified statin regimens
statin treatment significantly improved coronary endothe- into low- to high-intensity statins: (a) low-intensity statins,
lial function and inflammatory markers (36). such as simvastatin 10 mg daily, are able to produce a
In the ASCOT Lipid-Lowering Arm (ASCOT-LLA) trial, <30% reduction of cholesterol levels; (b) moderate-inten-
10,305 patients with hypertension and average total cho- sity statins, such as simvastatin 20–40 mg, atorvastatin
lesterol levels of 252 mg/dL were randomly assigned to 10–20 mg or rosuvastatin 5–10 mg daily, can reduce cho-
atorvastatin 10 mg daily or placebo. In patients treated lesterol concentration by a percentage between 30% and
with atorvastatin, 36% fewer fatal coronary events and <50%; (c) high-intensity statins, such as atorvastatin
nonfatal myocardial infarction occurred compared to the 40–80 mg or rosuvastatin 20–40 mg daily cause a >50%
placebo group. It must be emphasized that these results decrease in plasmatic cholesterol levels (23).
Dyslipidaemia in Hypertension 167
When high-intensity statin treatment cannot be under- Cardiovascular Disease Prevention in Clinical Practice developed
taken, the combination with ezetimibe (41) or alternative with the special contribution of the European Association for
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be considered, especially for high levels of cholesterol or lar disease in Europe: The SCORE project. Eur Heart J 2003; 24:
very high-risk patients who need to achieve very ambitious 987–1003.
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over the last 30 years from randomized controlled clinical Blood Cholesterol in Adults. Executive summary of the third report
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Section IV
Blood Pressure Measurements
OLD AND NEW OFFICE BLOOD
PRESSURE MEASUREMENT 21
APPROACHES
Riva-Rocci was aware of many of these deficiencies, from and people entering unexpectedly into the examination
the inception of systematic BP measurement (1): room. Environmental factors such as cold temperatures
(24), wintertime and short light hours (25) may also be
associated with higher OBP.
… It is enough to speak to the patient, invite him to
Initially, OBP should be determined in both arms,
read, or look at him suddenly, or perhaps it will take a
as there may be a difference between arms in OBP (26),
sudden noise, a carriage going past in the street, a shout which when consistent and sizeable (>10 mmHg) carries
of a loud but distant noise to make the blood pressure prognostic significance and points to more extensive vas-
rise, and not necessarily to the same extent in all cases. cular disease of some cause. However, it is a tricky finding,
as instruments for simultaneous two-arm measurements
Sources of variability include examiner factors, exam- are expensive and often unavailable (when available,
inee factors (20), intrinsic variability and seasonal they can be useful also for the purpose of evaluating the
variability (21) as well as other recognized and as-yet oscillometric ankle-brachial index (27)). Moreover, many
unrecognized factors. patients may falsely attribute variation between succes-
As noninvasive arterial BP measurement is indirect; sive measurements to inter-arm differences (28); therefore,
namely, pressure is measured within the bladder of the repeated examination of OBP in alternating arms may
manometer, presence of muscle tone in the arm may have prevent misclassification. If consistent, it is important to
a substantial effect. Hence the importance of arm support subsequently measure OBP in the arm with the higher
at the level of the heart to avoid not only gravitational but reading.
also other effects related to arm position (22). Comfortable Older patients, those with diabetes mellitus, and those
seating with the back supported, feet on the ground, not treated with medications, particularly α-blockers, should
crossed (23) and not hanging off an examination table, is be examined for orthostatic hypotension (a reduction of
also required for accurate readings. ≥20 mmHg systolic or ≥10 mmHg diastolic) after 1 and
Some sources of variability, when acknowledged 3 minutes of standing, because orthostatic hypotension is
(Table 21.1), are correctable. A common mistake is using common, symptomatic at times, antedates falls and inju-
a cuff too small for the arm, more frequent now due to ries, and has prognostic significance (29). Recently it was
the obesity epidemic. If the bladder is too short for the suggested that orthostatic hypertension, a BP rise of simi-
arm’s circumference, a greater pressure needs to be gener- lar magnitude, is associated with adverse outcome (30),
ated within it to occlude the artery, compared to the dis- though this is not a consistent finding (31).
tending pressure, thus yielding falsely elevated readings. OBP measurements in the presence of atrial fibrilla-
When such mistakes are recognized, they are correctable. tion (AF) are prone to error due to beat-to-beat variabil-
However, all too frequently this does not happen and the ity. Guidelines (although not most recent) recommend
mistake may be reiterated, and in such cases repeated mea- repeated auscultatory clinic measurements in patients with
surements will not improve accuracy. Occasionally mea- AF (32). Most validation studies of automated BP moni-
surement problems may be related to the examinee, who tors excluded subjects with irregular heart rhythm (33).
enters the examination room with a distended urinary Nonetheless, a recent small meta-analysis suggests that
bladder, in order not to miss his/her turn in queue. Other the oscillometric method is accurate for SBP, and possibly
factors that may elevate OBP inadvertently are speaking overestimates DBP (mean differences +0.5/+2.5 mmHg).
during OBP measurement, sitting with legs crossed (23), Correlation coefficients with the reference noninvasive
Source: Modified from Kallioinen N et al. J Hypertens 2017; 35(3): 421–441 (20).
Old and New Office Blood Pressure Measurement Approaches 173
method were r = 0.89 for SBP and r = 0.76 for DBP. way of manufacturers’ proprietary algorithms. Therefore,
Agreement of oscillometry with invasive BP measure- all oscillatory instruments need unbiased validation, also
ments in patients with AF was moderate in one study (34). in specific populations (e.g. children, severe obesity, preg-
In another, when three oscillometric measurements were nant women (41)). Given the plethora of producers, mod-
averaged and compared with intra-arterial readings, the els of even the same brand, and physical differences, not
biases of SBP and DBP did not significantly differ in the to mention a surfeit of validation methods and authorities,
presence or absence of AF (35). Currently, oscillometric it should not be surprising that not all models have been
devices are deemed acceptable for home and ambulatory validated successfully and many have not even attempted
monitoring of patients with AF, but not recommended for validation (42).
clinic setting (33). Despite the deficiencies of OBP measurement, it has
Another noteworthy aspect is the opportunity to detect served the vast majority of observational and randomized
asymptomatic AF during clinic BP measurement. Indeed, controlled trials. Moreover, even in the era of HBPM and
a NICE Medical Technology Guidance Committee rec- ABPM, OBP retains prognostic significance (9), hence is
ommended AF screening with a particular oscillometric here to stay, and we are destined to carry it out optimally.
device (36), and real-life assessment offered some support Instructions for such conduct, based on American Heart
for clinical utility (37). Association (43), and European Society of Hypertension
Devices also play a role in OBP measurement precision recommendations (44), are compiled in Table 21.2 (and
and accuracy. The auscultatory method is plagued with videotaped by Williams et al. (45)).
issues such as examiner’s hearing, prejudice and num- Recently, a model that includes three OBP measure-
ber rounding. The latter bias was addressed with random ments and clinical characteristics was developed that
zero sphygmomanometers, eventually found to be inac- predicts white-coat and masking effects with reasonable
curate (38). Given the phase-out of mercury sphygmoma- sensitivity and specificity. This may help triage patients’
nometers (which need verification of the zero Hg level) referral for out-of-office BP monitoring (46).
because of toxicity-related bans (39), we are left with aner-
oid sphygmomanometers requiring frequent calibration
due to time- and use-dependent decay of spring elastics
(40). All too frequently this recalibration is not performed. AUTOMATED OFFICE BLOOD PRESSURE
Oscillometric sphygmomanometers, commonplace these
days, are certainly devoid of prejudice, digit preference The recognition that white-coat hypertension is common
and auscultation capacity, but have other setbacks. These and may be related to the presence of the physician (or
instruments are based on detection of cuff oscillations nurse) (3,5,6), together with technical advances which
when pressure approaches SBP (in deflating oscillometry) allow multiple fully automated in-clinic measurements as
and recognition of maximal oscillations which indicate they do in ABPM, brought about a new concept for OBP
mean arterial pressure. DBP, however, is calculated by measurement: automated office blood pressure (AOBP).
Feature Recommendations
Patient preparation 1. Have the patient relax, sitting in a chair, feet on floor, back supported, for >5 min.
2. The patient should avoid caffeine, exercise and smoking for at least 30 min before measurement.
3. Ensure patient has emptied his/her bladder.
4. Neither the patient nor the observer should talk during the rest period or during the measurement.
5. Remove all clothing covering the location of cuff placement.
6. Avoid measuring while the patient is sitting or lying on an examining table.
Device preparation 1. Use a device that has been validated and ensure that the device is calibrated periodically.
2. Support the patient’s arm (e.g. resting on a desk).
3. Position the middle of the cuff on the patient’s upper arm at the level of the right atrium (the midpoint of the sternum).
4. Use the correct cuff size, such that the bladder encircles 80% of the arm, and note if a larger- or smaller-than-normal cuff
size is used.
5. Either the stethoscope diaphragm or bell may be used for auscultatory readings.
Technique 1. At the first visit record BP in both arms. Use the arm that gives the higher reading for subsequent readings.
2. Separate repeated measurements by 1–2 min.
3. For auscultatory determinations, use a palpated estimate of radial pulse obliteration pressure to estimate SBP. Inflate the cuff
20–30 mmHg above this level for the auscultatory determination.
4. For auscultatory readings, deflate the cuff pressure 2–3 mmHg/sec, and listen for Korotkoff sounds.
Documentation 1. Record SBP and DBP. If using the auscultatory technique, record SBP and DBP as onset of the first Korotkoff sound and
disappearance of all Korotkoff sounds, respectively, using the nearest even number.
2. Note the time of most recent BP medication taken before measurements.
3. Use an average of ≥2 readings obtained on ≥2 occasions to estimate the individual’s level of BP.
4. Provide patients their BP readings both verbally and in writing.
Source: Modified from Whelton PK et al. 2017 Hypertension 2017; 71(6): 1269–1324 (43).
174 Manual of Hypertension of the European Society of Hypertension
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ment. J Hypertens 2013; 31(6): 1131–1135.
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PULSE PRESSURE
22
DBP MBP
PERIPHERAL VERSUS CENTRAL PULSE
PRESSURE
PP amplification refers to the phenomenon of a widen-
Figure 22.1 Schematic representation of blood pressure ing in PP from the central aorta to the peripheral vascu-
fiduciary values. lature, most commonly to the brachial artery where BP is
conventionally measured. This PP widening occurs due
to an increase in SBP from central to peripheral arteries,
BP components (9). As with any component of BP, there is whereas DBP remains relatively similar between arterial
a continuum of risk, and establishing a threshold is arti- sites. Significant within-person variability in PP amplifi-
ficial. Nonetheless, scientific societies have proposed a cation can occur due to individual variation in the mag-
value of 60 mmHg as a threshold for elevated PP (13). The nitude of SBP differences between the aorta and brachial
pertinence of this value must be modulated by the meth- artery, which averages about 8 mmHg but can vary widely
odological issues raised later in this chapter and by the fact (e.g. <0 to >50 mmHg) (35) and with extreme differences
that PP differs according to where it is measured. of >100 mmHg observed among some patients with aortic
Young adults may exhibit high brachial PP in absence valve regurgitation (36).
of concomitant elevation in central aortic PP (14). This is The magnitude of PP amplification can be quantified
usually observed during so-called hyperkinetic states in as the ratio of PP between the proximal and distal loca-
early stages of essential hypertension (15). This phenom- tions, and using noninvasive methods, it has been shown
enon, later called ‘spurious hypertension’ (16), does not to decline from ≈1.7 in young adulthood to ≈1.2 in people
appear to be benign, as it is associated with higher rates of aged over 60 years owing to a relatively greater rise in central
hypertension in the future (17), abnormally raised stroke PP with ageing compared with brachial PP (37). Ultimately,
volume and aortic stiffness (18), as well as increased risk the value of central PP cannot be reliably determined
for future cardiovascular events and mortality (19). from measurements of brachial PP (37,38) and this has
There are multiple links between excessive PP and CVD several potential implications. Firstly, because diagnostic
risk. The first and most obvious is that PP is a hallmark of and hypertension management decisions may differ on the
ageing, and is thus associated to fatal and nonfatal CVD risk. basis of central compared with brachial BP values (39,40).
However, even after carefully adjusting for age, PP remains Secondly, central PP may respond differently to BP-lowering
significantly associated with CVD risk. This can be explained drugs compared with brachial PP (41), with most modern
by increased impedance and LV work during ejection (20,21) vasodilating antihypertensives having a greater central
ultimately leading to LV hypertrophy and LV functional PP-lowering effect, thus risk related to BP is overestimated
decline, for which PP (especially central PP) is one of the if only focusing on brachial BP (42). And finally, better esti-
main determinants. With advancing age, these processes are mates of risk may be derived from central PP compared with
paralleled with steeper decline in DBP, potentially leading conventional cuff PP (43–46). This makes pathophysiologi-
to impaired diastolic coronary perfusion (22). On the other cal sense given the target organs are exposed to central PP
hand, this view probably holds true only in very remod- rather than that in the arm (47), but nonetheless remains a
elled left ventricles (LVs) in the case of an acute drop in DBP controversial topic yet to be fully resolved (48,49).
because LV end diastolic pressure is close to DBP (23,24) and
is unlikely to occur in a more general population (25).
One other aspect of PP is the effect of PP on the trophic- HOW TO MEASURE PULSE PRESSURE
ity of arterial tissues. When compared to steady component
of BP (MBP), PP exerts a powerful trophic effect of the vas- Given that diagnostic and therapeutic decisions are made on
cular muscle cells, which increases metabolic activity and the basis of cuff measured BP, the accuracy of BP monitors is
proclivity for cell hypertrophy and proliferation (26). This a critical consideration. Unfortunately, most commercially
finding is confirmed in vivo since PP (central) is associated available BP monitors do not provide proof of measurement
with carotid hypertrophy and dilatation in man (27). These accuracy according to clinical validation standards (50). In
phenomenon in the large arteries promote atherosclerosis. 2017, a business concerned with testing and informing con-
PP within the large arteries also acts on small arteries. Since sumers on the validity of medical devices, reported that from
the pioneering works of Baumbach and Heistad (28–30), 2478 listed BP devices, only 441 (<20%) were appropriately
we know that excessive pulsatility is detrimental for intra- validated (50). Even using mercury sphygmomanometry,
cranial small arteries, leading to dilatation and hypertro- and among validated oscillometric BP devices, there is a ten-
phic remodelling. Similarly, the renal small arteries exhibit dency towards systematic underestimation of (intra-arterial)
an extreme sensitivity to increased pulsatility (31,32). brachial SBP but overestimation of DBP; altogether underap-
Physiologically, the stiffness of arteries increases mark- preciating the true brachial PP by an average 12 mmHg (35).
edly from the root of the aorta to medium-size muscular The flipside of this problem is that if an individual presents
Pulse Pressure 179
with high brachial PP (e.g. >60 mmHg) we can have reason- because they reduce cardiac output but increase central sys-
able confidence in diagnostic sensitivity. tolic loading. Drugs that lower PP can be difficult to identify
Growing interest towards attaining more accurate assess- on the basis of peripheral PP. Indeed, peripheral PP (usually
ment of risk related to BP has led to a burgeoning of com- brachial), incident and reflected waves coincide, and thus
mercial devices purporting to measure central aortic BP (51). it is difficult to discriminate a putative beneficial effect on
These employ a variety of methods, but with most seeking one component over the other. Identifying a differential
to synthesize a central aortic BP waveform using a general- effect of drugs on central versus peripheral arteries has been
ized mathematical transfer function applied to a peripheral a real change of paradigm (58,59). The first descriptions
BP waveform (i.e. at the brachial or radial artery). These were made by Kelly and O’Rourke when they reported that
noninvasive devices have helped gain valuable understand- guanylate trinitrate (GTN) administered during coronary
ing on central BP physiology, epidemiology and pharmacol- angiogram led to spectacular decrease in central SBP and
ogy, but a key problem has been reliance on the inaccurate virtually no change in brachial BP among some subjects
cuff SBP and DBPs to calibrate peripheral BP waveforms. (60). This concept led to the realisation of the ASCOT-CAFE
This imputes an error leading to marked underestimation of trial, where 2199 hypertensives randomized either to amlo-
derived central PP, and also results in co-linearity between dipine + perindopril of atenolol + thiazide therapy were
brachial SBP and central SBP such that there may be mar- studied for peripheral and central SBP and DBP. Despite not
ginal advantage of central BP as a prognostic tool. However, having baseline values, over time both groups coincided for
these issues appear to be rectifiable by applying different peripheral SBP and PP, whereas a marked 4 mmHg differ-
(re)calibration approaches (52–54). Recently, an interna- ence was observed in favour of amlodipine + perindopril
tional task force made recommendations on methods for on central SBP and PP reduction. This paralleled a larger
assessing and reporting the accuracy of central BP devices benefit, particularly for stroke in the amlodipine + per-
(55). Application of these recommendations to the measure- indopril arm with no direct demonstration of causality.
ment of central BP in a nationally representative population This seminal observation was confirmed and extended by
indicates that hypertension prevalence and control may be further clinical trials. The EXPLOR trial studied valsar-
significantly underestimated using conventional brachial tan + amlodipine compared to atenolol + amlodipine in a
cuff BP approach (56). However, more work is needed to forced titration scheme (59). The difference in central SBP
clarify the role of central BP devices in clinical practice. was 4 mmHg in favour of valsartan + amlodipine, dem-
onstrating that the adverse effect of atenolol on central BP
could not be reversed by associating a vasodilator. Whether
this effect on central BP translates into greater benefit is
HOW TO USE PULSE PRESSURE AND TO probable but remains to be proven (42,61).
‘TREAT’ PULSE PRESSURE
BP monitors usually provide only the SBP and DBPs as
these are the target values referred to in practice guidelines, CONCLUSION
whereas PP and MBP are seldom mentioned (13) even if
they may be more meaningful from a physiological point PP is an interesting parameter, directly linked to the pul-
of view. From the many epidemiological surveys which satile character of blood flow in arteries. Although the
have investigated PP, a threshold of 60 mmHg has been pathophysiology linked to PP elevation, i.e. increased arte-
proposed for brachial PP (Franklin); however, this value is rial stiffness and impedance to LV outflow, shed new light
highly dependent on the methodology used (office, 24 h on circulation, from a practical point of view, utilization of
ABPM, HBPM, oscillometric auscultatory, tonometry), so PP in clinical practice is hampered by the lack of precision
can only be regarded as indicative. A threshold central aor- of BP monitoring devices, the lack of representativity of
tic PP of ≥50 mmHg has been proposed as a target for inter- peripheral PP for the most interesting aspects of PP physi-
vention in one study (44), but this requires confirmation. ology and the lack of precision of techniques assessing
Treatment of secondary high PP is the treatment of its central PP. There are no trials in which treatment has been
cause; for example, correction of (aortic or mitral) valve directly targeted towards PP (or arterial stiffness), thus
regurgitation, anemia, or treatment of inflammation leads rendering the demonstration of superiority of treating PP
to improvement in PP. For essential high PP, then treatment over the classical index of SBP difficult to achieve. One of
is more complicated since no treatment has targeted arterial the main limits is methodologic, since we need peripheral
stiffness as a primary mechanism. Non-pharmacological BP to calibrate central BP monitors, and by this we induce
treatment is a key factor for improving arterial stiffness and huge collinearities which dilute the theoretic advantages
retards the increase in PP. Regular engagement in physi- of central BP over peripheral BP. New techniques which
cal activity acts through multiple mechanisms, including allow direct measure of stiffness and/or central PP, with-
improved metabolic balance, improved neurohormonal out calibration, should solve this issue at short term.
status (notably natriuretic peptides) and improved endo-
thelial function (55). Pharmacological treatments should
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CENTRAL BLOOD PRESSURE
23
Systole
Figure 23.1 Schematic representation of the role of arterial stiffness on assuring continuous blood flow through the
peripheral circulation, and how the aortic stiffening leads to increased SBP and PP. (Adapted from Briet M et al. Kidney Int
2012; 82: 388–400 (6). With permission.)
The ascending aorta and central arteries are distant from reflection pattern is thus complex but may be seen as a
reflecting sites, and the return of the reflected wave is ‘net’ or ‘effective’ reflection pattern, where all the forward
variably delayed depending on PWV and travelling dis- and backward running waves seem to add up to one single
tances (Figures 23.2 and 23.3) (17). In the aorta or cen- forward and backward wave, representing the global effect
tral arteries, the forward and reflected waves are not in of all reflections present (17). The phenomenon of wave
phase. In subjects with low PWV, reflected waves impact reflection can be quantified through the augmentation
on central arteries during end-diastole, increasing the index (AIx) – defined as the difference between the second
aortic pressure in early diastole and not during systole. (P2) and first (P1) systolic peaks (P2-P1 = AP, i.e. augmen-
This is physiologically advantageous, since the increased tation pressure) expressed as a percentage of pulse pressure
diastolic pressure boosts the coronary perfusion without (PP) (Figure 23.4).
increasing the LV pressure load. Thus, apart from a high PWV, changes in reflection sites
Pressure waves are reflected from the periphery, mainly can also influence central systolic blood pressure (SBP),
at branch points or sites of impedance mismatch. The PP and AIx. The major determinant of central SBP and
PP is, by definition, the forward pressure wave, since the
reflected wave can never be higher than the forward wave
(17). In clinical investigation, not only DBP and height,
which are related to total peripheral resistance and reflec-
Pbackward (reflected) Pforward
tion sites, but also age and aortic PWV are the main deter-
minants of AIx.
Recorded aortic Recorded peripheral
pressure wave pressure wave at
reflection sites AMPLIFICATION PHENOMENON
When SBP is recorded invasively and simultaneously in the
aortic arch and at multiple peripheral sites, it is possible
Tsh
The time interval of pressure to detect an ‘amplification phenomenon’, i.e. under rest-
Forward and backward
wave to pressures ing conditions in healthy men, brachial SBP is about 10%
and back from reflection sites are in phase: no time interval higher than aortic SBP (Figure 23.3). Indeed, in the pres-
ence of arterial stiffness gradient (aortic PWV < peripheral
Figure 23.2 Representation of forward and reflected PWV) partial pressure wave reflection occurs distant from
pressure wave traveling and the influence of their tim- microcirculation and returns at low PWV to the aorta in
ing and overlap on recorded aortic and peripheral pres- diastole, thus the reflected wave arrives back at the aortic
sure waves. Abbreviation: Tsh, time to shoulder. (Adapted root during late systole, whereas at the site of the periph-
from Briet M et al. Kidney Int 2012; 82: 388–400 (6). With eral artery (i.e. brachial artery), the pressure wave travels
permission.) rapidly and the reflected wave (from peripheral branch-
ing sites and small arteries) arrives at the recording site
Central Blood Pressure 185
120
Pressure (mmHg)
100
80
15
Reflected pressure
Aorta
m es
rie t
te ce
Micro-
te ui
10 ri
PWV 6 m/s
/s
ar tan
ar nd
Re s
s
V rte
rie
circulation
Co
sis
PW ge a
r
La
140
Pressure (mmHg)
120
80
15
Aorta
rie t
Micro-
te ce
m es
te ui
PWV 11 m\s
10 ri
ar nd
ar tan
Re s
/s
s
V rte
circulation
rie
Co
sis
PW ge a
r
La
Figure 23.3 Upper panel: In the presence of arterial stiffness gradient (aortic PWV < peripheral PWV) partial pressure
wave reflection occurs distant from microcirculation and returns at low PW V to the aorta in diastole maintaining
central-to-peripheral amplification. Partial pressure wave reflections limit the transmission of pulsatile pressure energy
to the periphery and protect the microcirculation. Lower panel: When the stiffness gradient disappears or is inverted
(aortic PWV > peripheral PWV), pulsatile pressure is not sufficiently dampened and is transmitted, thus damages the
microcirculation. In parallel, the central-to-peripheral pressure amplification is attenuated. (Adapted from Briet M et al.
Kidney Int 2012; 82: 388–400 (6). With permission.)
in early systole, raising brachial SBP; thus, central SBP is increasing myocardial pressure load (left ventricular
lower than distal SBP, leading to the so-called ‘central-to- hypertrophy) and oxygen consumption, decreasing the
peripheral amplification’. By contrast, when the stiffness diastolic blood pressure and subendocardial blood-
gradient disappears or is inverted (aortic PWV > periph- flow. Thus central SBP is higher in elderly subjects than
eral PWV), pulsatile pressure is not sufficiently dampened in young subjects and closer to the brachial SBP value,
at the central level, and the central-to-peripheral pressure reducing the difference (9). Indeed, at the site of the bra-
amplification is attenuated (9) (Figure 23.3). chial artery, arterial stiffness is not influenced by age (9),
The amplification phenomenon is attenuated by age- and the timing of forward and reflected waves is similar
ing (9) because of arterial stiffening. Indeed, by favour- to those in younger subjects. In conclusion, the true value
ing early wave reflections, arterial stiffening increases of central BP cannot be reliably estimated using standard
peak- and end-systolic pressures in the ascending aorta, brachial cuff BP (14,17,19).
186 Manual of Hypertension of the European Society of Hypertension
Table 23.1 Device and methods used for estimating central blood pressure, classified through the arterial segment used
for pressure wave recording
Year of first
publication Device Method Company Parameters
1997 Cardiovasc. Eng. Inc®* Tonometer, cardiac echo, Cardiovasc. Eng. cSBP, cPP, cAIx
impedence Zc, fP, bP
1984 Millar® strain gauge* Tonometer, direct Millar cSBP, cPP, cAIx
Source: Adapted from Laurent S, Boutouyrie P. How to estimate central blood pressure? In Dialogues in Cardiovascular Medicine, 2015.
*Apparatus used in pioneering epidemiological studies showing the predictive value of central BP for CV events.
Abbreviations: cSBP, central systolic blood pressure; cPP, central pulse pressure; cAIx, central augmentation index; rAIx, radial artery augmentation index; Zc,
characteristic impedence; fP, forward pressure wave; bP, backward pressure wave; Add. Infl., additional inflation; PVP, pulse volume plethysmography; N.A., not
available.
augmentation index as intermediate endpoints, that is, the the RR of total CV events for an increase of central PP by
higher the central pulse pressure and augmentation index, 10 mmHg was 1.14 (1.06–1.21). It was 1.09 (1.04–1.14) for
the higher the number of CV events. central SBP. The various mechanisms by which an increase
in central pulse pressure generates higher risk of cardiac
and cerebrovascular events have been described above.
CENTRAL BLOOD PRESSURE HAS AN Central BP can thus be considered as an intermediate end-
point for CV events.
INDEPENDENT PREDICTIVE VALUE
OF CV EVENTS
Since the early 2000s, several longitudinal studies have CENTRAL PULSE PRESSURE AS A SURROGATE
shown that central PP had independent predictive value ENDPOINT
for all-cause and CV mortality. Central augmentation
index and pulse pressure, either directly measured by A surrogate endpoint is a biomarker that is intended as a
carotid tonometry (23) or estimated using a transfer func- substitute for a clinical endpoint. In order to be consid-
tion from radial artery tonometry (31), were both indepen- ered as a surrogate endpoint of cardiovascular events, a
dent predictors of all-cause mortality in end-stage renal biomarker should satisfy several criteria, such as proof of
disease patients (23), in patients undergoing percutaneous concept, prospective validation, incremental value, clini-
coronary intervention and in the hypertensive patients of cal utility, clinical outcomes, cost-effectiveness, ease of
the CAFE study (31). use, methodological consensus and reference values.
Eleven studies performed in populations at various CV Although a large number of studies and several
risk, totalizing 5648 subjects with a mean follow-up of reviews (14,16,23,31) demonstrated that central PP was
3.8 y, were included in a meta-analysis (28). In six of them, increased in various pathophysiological conditions, and
188 Manual of Hypertension of the European Society of Hypertension
had predictive value for all-cause and CV mortality, only 10th, 25th, 75th and 90th percentiles for normal values, it
a marginal superiority of central PP over brachial PP for is possible to diagnose high-normal central BP, which is an
predicting CV events was observed in a meta-analysis (28), indication for a closer follow-up.
and there was no superiority of central SBP over brachial According to the 2013 ESH-ESC Guidelines (12), ‘no
SBP. Additional studies, not included in the meta-analysis, evidence is available that young patients with ISH benefit
also failed to show higher predictive values of central PP from antihypertensive treatment; on the contrary there are
compared to brachial PP (10). To our knowledge, no study prospective data that the condition does not necessarily
has demonstrated that patients at intermediate risk could proceed to systolic/diastolic hypertension. On the basis of
be reclassified into a higher or a lower CV risk, when cen- current evidence, these young individuals can only receive
tral BP (either PP or SBP) was measured (29). recommendations on lifestyle, but because available evi-
Large randomized clinical trials, aiming at reducing dence is scanty and controversial they should be followed
both central BP and CV events, are needed in order to infer closely’.
causality between central BP reduction and CV risk reduc-
tion. The only randomized intervention trial with record-
ing of central BP and CV events was the Conduit Artery
Function Evaluation (CAFE) study, an ancillary study of PHARMACOLOGY OF CENTRAL BLOOD
the ASCOT study (7) in 2199 patients with hypertension PRESSURE AND WAVE REFLECTION
and multiple CV risk factors (31). The CAFE study showed
that a therapeutic regimen based on amlodipine was more IN HYPERTENSION
effective than an atenolol-based regimen to lower central A large number of publications and several reviews
BP, despite similar brachial SBP between treatment groups. (4,5,10,13,20) reported the changes in central BP and
Because the ASCOT study (7) showed that the amlodip- wave reflections after various pharmacological treat-
ine-based regimen prevented more major CV events than ments. Pharmacological treatments which are able to
the atenolol-based regimen, it was tempting to attribute reduce central BP and wave reflections include (a) all
this superiority, at least in part, to a higher efficacy on the antihypertensive treatments, such as diuretics, beta-
reduction in central BP. However, such a conclusion can- blockers, ACE inhibitors, angiotensin II receptor block-
not be drawn since central BP was not measured at base- ers (ARBs) and calcium channel blockers (CCBs); (b)
line in the CAFE study (31), and thus no change in central treatments of congestive heart failure, such as ACE
BP could be calculated. inhibitors, nitrates and aldosterone antagonists; and (c)
There is an ongoing controversy on whether the lack of advanced glycation end-product (AGE)-breakers, such as
higher predictive value of central BP compared to brachial alagebrium (ALT-711).
BP reflects a true pathophysiological issue or is related to the
method used for central BP measurement, including calibra-
tion (19,26,27). To address the latter issue, an international
task force was convened (26) testing new and preceding DIFFERENTIAL CENTRAL AND BRACHIAL
devices in a uniform fashion with comparable protocols. BP RESPONSES TO ANTIHYPERTENSIVE
MEDICATIONS
REFERENCE VALUES AND GUIDELINES Whether pharmacological classes, and specific molecules
within a given pharmacological class, differ in their ability
Reference values for central BP (9) have been established in to lower central BP, has been addressed in several studies
18,183 healthy subjects and a larger population of 27,253 (4,5,10,13,20). Protogerou et al. (20) analysed the ability
subjects with CV risk factors. of drug treatment to lower central BP beyond the reduc-
The 2013 ESH-ESC Guidelines for the Management tion in peripheral (brachial) BP by computing the effects
of Hypertension (12) and a position paper from the of drugs on BP amplification, according to either its abso-
European Society of Cardiology (ESC) Working Group on lute (peripheral PP minus central PP, in mmHg) or relative
Peripheral Circulation (29) considered that although the (peripheral PP/central PP) expression. There are several
measurement of central BP and augmentation index is of mechanisms by which drugs may differently alter central
great interest for mechanistic analyses in pathophysiology, and peripheral BP, thus BP amplification. They include
pharmacology and therapeutics, more investigation is nec- large artery stiffness, vascular resistance, stroke volume
essary before recommending their routine clinical use. and heart rate.
The pharmacological classes which induce a greater
decrease in central SBP relative to brachial SBP, in other
words which increase SBP amplification are mainly angio-
ISOLATED HYPERTENSION tensin-converting enzyme inhibitors (ACEIs), ARBs and
IN THE YOUNG CCBs, whereas diuretics are less efficacious (5,10). Non-
vasodilating beta-blockers (such as propranolol and ateno-
A number of young, healthy males have elevated values of lol) are the least effective agents for reducing central SBP/
brachial SBP (above or equal to 140 mmHg) and normal PP. Instead of increasing SBP amplification, they reduce
values of brachial DBP (below 90 mmHg). Measurement it by inducing a lower decrease in central SBP relative to
of central BP may help diagnosing spurious hypertension brachial SBP (4,31). Mechanisms explaining the possible
if central SBP is normal, according to the reference values deleterious effects of beta-blockers in general, and ateno-
data (10). If there is no target-organ damage, then a sim- lol in particular, include the reduction in heart rate, the
ple follow-up is necessary (12). Since the reference values lack of reduction of total peripheral resistance and sym-
data (10) give for each decade of age and category of BP the pathetic drive, and a possible ‘pro-fibrotic effects’ on large
Central Blood Pressure 189
Figure 23.5 Differential effects of antihypertensive combination therapies on brachial SBP (a) and central SBP (b), deter-
mined during the CAFE (31), EXPLOR (4) and J-CORE (13) studies.
arteries. Nitrates, which are not indicated for hyperten- intima media thickness was principally determined by
sion, increase SBP amplification (5,10). the reduction in carotid PP after adjustment on brachial
Combination therapies exert also differential effects on PP, although no significant difference was observed
brachial and central BP (Figure 23.5). The available evi- between drugs (5). In a randomized study comparing
dence, originating from the CAFE (31), EXPLOR (4) and the effect of amlodipine/valsartan combination to amlo-
J-CORE (13) studies, indicates that this is a combination of dipine/atenolol combination on central and peripheral
CCB and either ACEI or ARB, which is the most effective BP and aortic stiffness over 6 months, the reduction in
for reducing central SBP, for a given reduction in brachial carotid-femoral PW V was positively associated with the
SBP. reduction in aortic SBP but not with the reduction in bra-
chial BP (4)
N° of N° of N° of N° of
subjects events subjects events
1.77† 1.80†
SH 2126 450 1790 403
0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0
Hazard ratio Hazard ratio
Figure 24.1 Hazard ratios for cardiovascular events and stroke associated with masked hypertension on daytime blood
pressure monitoring in participants with normotension or pre-hypertension. Participants with true normotension are the
reference group. Normotension (<120/80 mmHg) and pre-hypertension (120–139/80–89 mmHg) refer to the classification
based on the conventional blood pressure according to the JNC7/WHO-ISH criteria. Thresholds for daytime hypertension
were ≥135 mmHg systolic or ≥85 mmHg diastolic. The hazard ratios were adjusted for cohort, sex, age, body mass index,
smoking and drinking, serum cholesterol, history of cardiovascular complications and diabetes mellitus. Horizontal lines
denote the 95% confidence interval. Compared to pre-hypertension without masked hypertension, the hazard ratios associ-
ated with masked hypertension in prehypertensive subjects were 1.53 (95% confidence interval [CI], 1.23–1.91; P = 0.0001)
for the composite cardiovascular endpoint and 1.48 (CI, 1.01–2.16; P = 0.04) for stroke. (Reproduced with permission from
the study of Brguljan-Hitij J et al. Am J Hypertens 2014; 27: 956–965.)
Ambulatory Blood Pressure Measurement 193
0.5 1 2 4 8 0.5 1 2 4 8
Figure 24.2 Hazard ratios associated with masked hypertension (≥135/85 mmHg) on home blood pressure monitoring in
participants with optimal, normal or high-normal office blood pressure. Participants with optimal blood pressure without
elevated home blood pressure were the reference group. Systolic/diastolic thresholds for the conventional blood pressure
were optimal (<120/80 mmHg), normal (120–129/80–84 mmHg), and high-normal (130–139/85–89 mmHg). When a sys-
tolic or diastolic blood pressure was in a different category, the participant was assigned to the higher category. Systolic/
diastolic thresholds for hypertension on home measurement were ≥135/85 mmHg. MHT indicates masked hypertension.
The hazard ratios were adjusted for cohort, sex, age, body mass index, smoking, total cholesterol, diabetes mellitus,and
history of cardiovascular disease. Horizontal lines denote the 95% confidence interval. MHT indicates masked hyperten-
sion. The diamond represents the pooled estimate in all patients with MHT. The P value for heterogeneity was derived by
testing an ordinal variable in Cox proportional hazard regression coding for the three subgroups among patients with MHT.
(Reproduced with permission from the study of Asayama K et al. PLOS MED 2014; 11: e1001591 (47).)
cardiovascular endpoint and 3.02 (P = 0.01) for stroke preferred method for diagnosing hypotension, particularly
(Figure 24.2) (28). The corresponding hazard ratios asso- in seniors, in whom postprandial and postural hypoten-
ciated with masked hypertension in prehypertensive sion are common because of impairment of the autonomic
subjects were 2.08 (P < 0.0001) and 2.97 (P < 0.0001), nervous system and an attenuated baroreceptor reflex. The
respectively. Compared to pre-hypertension without diagnosis of symptomatic drug-induced hypotension is a
masked hypertension, the hazard ratios associated with key issue in patients who have a compromised arterial cir-
masked hypertension in prehypertensive subjects were culation, such as those with coronary and cerebrovascular
1.53 (P = 0.0001) for the composite cardiovascular end- disease, and fragile elderly patients (13). Fourth, whereas
point and 1.48 (P = 0.04) for stroke (Figure 24.2) (28). carotid atherosclerosis was associated with the home BP
These findings remained consistent, if masked hyperten- in Japanese, ABPM in the same cohort was a stronger pre-
sion was based on the 24-hour or nighttime BP (28). ABPM dictor of silent cerebrovascular disease (34). Finally and
also enhances risk stratification in apparently normoten- foremost, using home instead of ABPM misses the high-
sive people with optimal, normal or high-normal office risk diagnoses of masked or sustained hypertension in
BP, and who present with diabetes (29). over 25% of patients (35). Indeed, in 831 untreated out-
The probability of having masked hypertension patients (mean age, 50.6 years; 49.8% women), we mea-
increases with an office BP in the normal or high-normal sured office (three visits), home (7 days), and 24-hour
range (odds ratio [OR] 5.1 vs. optimal office blood pres- ABPM. We applied hypertension guidelines for the cross-
sure), age 40 years or older (OR 2.5 vs. being younger than classification of patients into normotension or white-coat,
40 years), overweight or obesity (OR 2.0), alcohol intake masked or sustained hypertension (Table 24.1). Based on
(OR 1.9), diabetes mellitus (OR 1.8) and smoking (OR office and home BP, the number (percentage) of patients
1.5). Other risk factors include a family history of hyper- with white-coat, masked and sustained hypertension was
tension in both parents, patients with multiple risk fac- 61 (10.3%), 166 (20.0%) and 162 (19.5%), respectively.
tors for cardiovascular disease, male sex and higher awake Using daytime instead of home BP confirmed the cross-
heart rate (30). classification in 575 patients (69.2%), downgraded risk
An issue of clinical importance is whether self-monitor- from masked hypertension to normotension (n = 24) or
ing of BP at home can replace ABPM as the gold standard from sustained to white-coat hypertension (n = 9) in 33
of out-of-office blood pressure measurement. The answer patients (4.0%), but upgraded the risk from normoten-
is negative. First, home BP measurement does not allow sion to masked hypertension (n = 179) or from white-coat
easy recording of nocturnal BP, the window of the day dur- to sustained hypertension (n = 44) in 223 (26.8%) (35).
ing which BP is most predictive of adverse cardiovascular Analyses based on the 24-hour instead of the daytime
outcome (14–20). Second, isolated nocturnal hyperten- ABPM were confirmatory. In adjusted analyses, both the
sion has a prevalence of 7% among Caucasians (26,31) urinary albumin-to-creatinine ratio (+20.6%; CI 4.4 39.3)
and of 10−11% among blacks (32) and Asians (26,31,32), and aortic pulse wave velocity (+0.30 m/s; CI 0.09–0.51)
and confers a risk equal to that of an elevated daytime BP were higher in patients who moved up to a higher risk cat-
(33). Only 24-hour ABPM makes diagnosing isolated noc- egory (35). Both indices of target-organ damage as well as
turnal hypertension straightforward. Third, ABPM is the the central augmentation index were positively associated
194 Manual of Hypertension of the European Society of Hypertension
Baseline ABPM
Figure 24.3 Flowchart for the use of ABPM in primary care. Abbreviation: CV, cardiovascular. (From Dolan E, O’Brien E. J
Clin Hypertens (Greenwich) 2017; 19: 218–220.)
In 2011, Lovibond et al. published a Markov model− and nurses, be it in primary or specialized care, have to
based probabilistic cost-effectiveness analysis which prove that they have acquired the skills necessary for
showed that in a hypothetical primary care population understanding the principles of BP measurement, cuff fit-
aged 40 years or older with screening BP measurements ting, monitor function and analysis and interpretation of
greater than 140 mmHg systolic and 90 mmHg diastolic ABPM recordings.
and a risk factor prevalence representative for the general
population, ABPM was the most cost-effective strategy
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pressure analysis. J Hypertens 1996; 14: 557–563. treatment based on conventional or ambulatory blood pres-
23. Steinhubl SR, Muse ED, Barrett PM, Topol EJ. Off the cuff: sure measurement. A randomized controlled trial. Ambulatory
Rebooting blood pressure treatment. Lancet 2016; 388: 749–750. Blood Pressure Monitoring and Treatment of Hypertension
24. Thijs L, Hansen TW, Kikuya M et al. The International Database Investigators. JAMA 1997; 278: 1065–1072.
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Outcome (IDACO): Protocol and research perspectives. Blood Press t reatment based on blood pressure measurement at home or in
Monit 2007; 12: 255–262. the physician’s office: A randomized controlled trial. JAMA 2004;
25. Kikuya M, Hansen TW, Thijs L et al. International Database 291: 955–964.
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Cardiovascular Outcomes Investigators. Diagnostic thresholds for Measurement, Reduction of Unnecessary Treatment Study
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vascular risk. Circulation 2007; 115: 2145–2152. reduces the need for antihypertensive drugs: A randomized, con-
26. Fan HQ, Li Y, Thijs L et al. International Database on Ambulatory trolled trial. Hypertension 2007; 50: 1019–1025.
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Investigators. Prognostic value of isolated nocturnal hypertension reanalysis. Hypertension 2006; 47: 29–34.
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27. Smirk FH. Observations on mortality of 270 treated and 199 ling study. Lancet 2011; 378: 1219–1230.
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Ambulatory Blood Pressure in Relation to Cardiovascular PLOS MED 2014; 11: e1001591.
HOME BLOOD PRESSURE
25
Advantages Limitations
■■ Large number of self-blood pressure measurements taken in the individual’s ■■ Most devices available on the market have not been
usual environment. validated for accuracy using an established protocol.
■■ More reproducible BP values than with office measurements. ■■ Misreporting (over- or under-) of BP readings by some
■■ Detection of white-coat and masked hypertension phenomena in both untreated patients.
and treated subjects. ■■ Need of user training (minimal with automated devices)
■■ Devoid of placebo effect. and medical supervision.
■■ Closer association with preclinical organ damage than with office BP ■■ May induce anxiety and too frequent monitoring in some
measurements. patients.
■■ Better prediction of cardiovascular events than with office BP measurements. ■■ Some patients may self-modify their drug treatment on
■■ Devoid of observer error, prejudice and bias with automated electronic devices. the basis of casual BP readings.
■■ Devoid of reporting bias of self-BP measurements by patients with electronic ■■ Measurements performed under standardized conditions
devices with automated memory, PC link or telemonitoring function. (sitting at home) do not reflect usual daily activities.
■■ Improves long-term patient compliance with drug treatment. ■■ Inability to monitor BP during nighttime sleep (possible
■■ Improves hypertension control rates. with some novel home monitors).
■■ Wide availability in most countries. ■■ Questionable accuracy of automated oscillometric
■■ Need of minimal training (with automated devices). devices in the presence of arrhythmias.
■■ Good acceptance by hypertensive patients for long-term use.
■■ Cost-effective.
OBP, particularly in cases with masked hypertension. computer through telephone or internet connection.
Additional analyses of the IDHOCO database showed Several studies suggest that tele-HBPM allows more reli-
home day-to-day BP variability to independently predict able and objective evaluation and is associated with higher
cardiovascular outcome (16). BP control rates and increased patient satisfaction, espe-
cially when accompanied with counselling support from
study personnel; however, its wide applicability and cost-
effectiveness require further research (21,22).
ROLE IN MANAGEMENT OF Automated BP measurement using the oscillometric
HYPERTENSION method in AF faces several difficulties (23). However, the
available evidence suggests that the oscillometric method
Because of its diagnostic accuracy and prognostic value, is feasible and appears to be accurate, at least for systolic
HBPM has a crucial role in the long-term management BP measurement, which is more important for AF patients,
of hypertension. This method motivates the patients by who are almost exclusively elderly (24). Screening for AF
increasing their awareness and rendering them actively with automated BP measurement is an attractive strategy
involved in their own monitoring and long-term follow- in the context of the guideline-recommended opportunis-
up. Several randomized controlled trials have shown that tic screening. A specific algorithm for AF detection dur-
treated hypertensives who perform HBPM have improved ing automated BP measurement has been developed and
long-term adherence to drug therapy, and thereby implemented in a novel oscillometric home BP monitor
improved hypertension control rates (17,18). (Microlife WatchBP Home-A) with satisfactory diagnos-
Two prospective studies compared HBPM versus ABPM tic accuracy (25). In 2013, the UK National Institute for
for treatment adjustment (19,20). The first, in 98 subjects Health and Care Excellence recommended this device for
followed for 6 months, found no difference in BP control AF screening in subjects ≥65 years (26).
when using HBPM or ABPM (19). The second randomized Accumulating evidence suggests that nighttime BP,
116 subjects to treatment initiation and titration based assessed by ABPM, is the most important aspect of the BP
either on HBPM alone or on combined use of OBP and profile in terms of prognosis (7). During the last decade,
ABPM (20). After a follow-up of 13.4 months, there was novel low-cost HBPM devices that allow automated night-
no difference between the two arms in BP decline and time BP monitoring have been developed. A recent meta-
hypertension control assessed by HBPM or ABPM and, analysis of six studies showed that nighttime HBPM is
more importantly, there was no difference in treatment- feasible, and compared to nighttime ABPM it presents
induced changes in several indices of preclinical target- similar BP values, has satisfactory agreement in detect-
organ damage (20). ing non-dippers and has a comparable relationship with
target-organ damage (27).
Reproducibility − ++ ++
Cost − − ++
CLINICAL INDICATIONS
The main clinical indications for HBPM include confirma-
training and more regular calibration, which usually are
tion of hypertension diagnosis, detection of white-coat
not feasible in general practice. Some automated wrist
and masked hypertension, identification of white-coat
devices have passed the internationally accepted valida-
reaction and masked hypertension effect in treated hyper-
tion protocols; however, these are regarded as less accurate
tensives, overcoming considerable variability of OBP over
than upper-arm devices, mainly because of anatomical
the same or different visits, identification of true and false
differentiations of the wrist, and difficulty in following
resistant hypertension, titration of BP-lowering medica-
the correct wrist position (at heart level and relaxed) (1–4).
tion and assessment of long-term BP control in treated
Updated lists of devices which have passed official vali-
hypertension (1–4).
dation protocols are available at several websites (www.
bhsoc.org; www.medaval.org; www.dableducational.org).
The use of a cuff with appropriate inflatable bladder size
DEVICES for the arm circumference of each individual is of equal
importance as the accuracy of the device (1–4). As a gen-
Validated automated electronic devices, especially those eral rule, the length of the inflatable bladder should cover
using an oscillometric algorithm and having an upper- 75–100% of the arm circumference and the width should
arm cuff, are currently recommended for HBPM, as they be about half of the length, yet some oscillometric devices
are relatively accurate, user friendly, relatively cheap, might give accurate measurements with a smaller cuff (1).
devoid of observer bias and require little training (1–4). Cuffs which are too small for the arm circumference tend
The accuracy of electronic BP monitors should be tested to overestimate BP (common in obese subjects), whereas
against conventional sphygmomanometry according to cuffs which are too large (in children or lean subjects) tend
established validation protocols (30–33). Unfortunately, to underestimate BP. It is generally recommended that sub-
most of the electronic BP monitors available on the mar- jects with arm circumference larger than 32 cm should use
ket have not been subjected to independent validation for a cuff larger than the standard size, while those with arm
their measurement accuracy. Aneroid or hybrid ausculta- circumference smaller than 24 cm should use a smaller
tory devices can also be used but require observer skills, cuff than the standard (1).
200 Manual of Hypertension of the European Society of Hypertension
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DAY-NIGHT RELATED EVENTS:
NIGHTTIME BLOOD PRESSURE 26
FALL AND MORNING BLOOD
PRESSURE RISE
Yamamoto et al. (24) demonstrated that the degree of of subjects reported a sleep duration perceived as usual
ambulatory BP reduction from day to night at the base- (group A), <2 hours less than usual (group B), 2–4 hours
line assessment was significantly (p < 0.01) smaller in the less than usual (group C), and >4 hours less than usual
group with subsequent cerebrovascular events than in the (group D). Daytime BP did not differ across the groups
group with no future events. (all p > 0.05). Nighttime BP increased from group A to D
In older patients with isolated systolic hypertension, (124/75, 126/76, 128/77, and 129/79 mmHg, respectively;
the Systolic Hypertension in Europe (Syst-Eur) study all p for trend <0.01). Over a median follow-up period of 7
found that cardiovascular risk increased with a higher years there were 356 major cardiovascular events and 176
night/day ratio of systolic BP (i.e. in patients more likely all-cause deaths. Incidence of total cardiovascular events
to be non-dippers) independent of the average 24-hour and deaths was higher in the subjects with a night/day ratio
BP (25). in systolic BP >10% compared with those with a greater
Similarly, Ohkubo et al. (26) showed an increased car- day-night BP drop in the group with perceived sleep dura-
diovascular mortality in ‘non-dippers’ (relative risk [RR]: tion as usual or <2 hours less than usual (both p < 0.01),
2.56, p = 0.02) and ‘reverse-dippers’ (RR: 3.69, p = 0.004) not in the group with duration of sleep ≥2 hours less than
in comparison with ‘dippers’. usual (all p not significant; Figure 26.1). Notably, in a Cox
Furthermore, in some patients BP is actually higher model, the independent prognostic value of nighttime BP
during night than during day. This phenomenon is usu- for total cardiovascular endpoints and all-cause mortality
ally referred as ‘reverse dipping’ and is associated with an disappeared in the subjects with perceived sleep depriva-
adverse cardiovascular outcome (27). tion ≥2 hours.
In this context, a recent analysis of the Progetto Finally, additional support to the prognostic indepen-
Ipertensione Umbria Monitoraggio Ambulatoriale dent importance of night BP measurements comes from
(PIUMA) Study confirmed on a large sample of 3792 sub- the evidence that absolute nighttime BP values are prog-
jects the detrimental effect of ‘reverse dipping’ in hyper- nostically superior to the daytime ones (29–32) and that
tension. Briefly, the rates of cardiovascular events were abnormal nighttime BP fluctuations may contribute to a
0.57 (95% CI: 0.36–0.88), 0.76 (95% CI: 0.63–0.92), 1.65 worse prognosis in hypertensive patients (33).
(95% CI: 1.37–1.98), and 3.06 (95% CI: 2.10–4.46) × 100 In this context, a large multinational cooperative data-
patient-years in the categories of extreme dippers, dippers, base including 7112 untreated hypertensive patients
non-dippers, and reverse dippers, respectively (log-rank enrolled in six prospective studies (33) demonstrated
χ2 = 74.8; p < 0.0001). After adjustment for multiple com- that nighttime BP variability (as estimated by standard
parisons, failure rate was higher in non-dippers ( log-rank deviation [SD]) was an independent predictor of all-cause
χ2 = 33.1; p < 0.0001) and reverse dippers (log-rank mortality, cardiovascular mortality, and cardiovascular
χ2 = 39.6; p < 0.0001) as compared with dippers, whereas events. In contrast, daytime BP variability was not an
extreme dippers and dippers did not differ significantly independent predictor of outcomes in any multivariable
(log-rank χ2 = 3.8; p < 0.052). model. Specifically, in fully adjusted models, a nighttime
Finalizing our discussion of the prognostic implica- systolic BP SD ≥12.2 mmHg was associated with a 41%
tions of a blunted or abolished fall in BP from day to greater risk of cardiovascular events, a 55% greater risk
night, at least three aspects need to be clearly detailed. of cardiovascular death, and a 59% increased risk of all-
First, the prognostic value of the diurnal BP changes is cause mortality compared with an SD <12.2 mmHg. The
comparable when using different clock-dependent or corresponding values for a diastolic BP SD of ≥7.9 mmHg
independent definitions of day and night (23). A recent were 48%, 132% and 77%, respectively. The addition of
analysis from our group (23) documented that total car- nighttime BP variability to fully adjusted models had a
diovascular events and all-cause mortality were simi- significant impact on risk reclassification and integrated
larly higher in non-dippers (night/day ratio of systolic discrimination for all outcomes (relative integrated dis-
BP >10% or >0%) than in dippers regardless of the defi- crimination improvement for systolic BP variability:
nition of day and night. Specifically, in a receiver-oper- 9% cardiovascular events, 14.5% all-cause death, 8.5%
ated characteristic (ROC) curve analysis of the night/day cardiovascular death; for diastolic BP variability: 10%
ratio of systolic BP on the occurrence of events, the area cardiovascular events, 19.1% all-cause death, 23% cardio-
under the ROC curve did not differ among the different vascular death, all p < 0.01).
definitions of day and night (large fixed-clock intervals,
narrow fixed-clock intervals, diary) for both total car-
diovascular events (p = 0.20) and all-cause mortality
(p = 0.78) (23). EARLY MORNING BLOOD PRESSURE
Second, nighttime BP may lose its prognostic signifi- SURGE
cance in hypertensive subjects with significant sleep dis-
turbances during overnight monitoring that may occur for Through ABPM, we know that BP usually follows a dis-
the compressive, tactile and sonorous stimuli produced by tinct circadian rhythm, characterized by a nocturnal
repeated cuff inflations (28). decline during sleep followed by an increase coincid-
Recent findings supported this hypothesis, suggesting ing with the time of awakening (26,27). In the last few
that the prognostic impact of day-night BP changes should years, there has been great interest in the early morning
be investigated, including the perceived quantity of sleep period by preventive medicine, since it became evident
as effect modifier in outcome analyses (28). Specifically, in that the onset of sudden death, myocardial infarction
a recent analysis of the PIUMA database we followed 2934 and stroke peaks in the first 4–6 hours post-awakening
initially untreated hypertensive subjects and we assessed (26,27).
the perceived quantity of sleep during overnight BP Since dynamic diurnal variations in pressor stress from
monitoring (28). Overall, 58.7%, 27.7%, 9.7% and 4.0% a nadir in the night to a peak in the morning (the morning
Day-Night Related Events 205
1.0
1.0
Event-free survival
0.9 0.9
0.8 Dippers (D) Dippers (D)
0.8
0.7 Non-dippers
Total CV events
Non-dippers 0.7
(ND) p = 0.59
0.6 (ND) p < 0.0001 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0 5 10 15 20 0 5 10 15 20
D (N. at risk) 1724 1072 389 79 0 225 149 56 18 0
ND (N. at risk) 795 484 170 31 0 171 109 45 10 0
1.0 1.0
Dippers (D) Dippers (D)
0.9 0.9
Event-free survival
Follow-up, years
Figure 26.1 Total cardiovascular events and all-cause mortality in dippers (night/day ratio in systolic blood pressure
≤10%) and non-dippers (night/day ratio in systolic blood pressure >10%) in relation to the perceived duration of sleep
during overnight blood pressure monitoring. The number of subjects entering each time interval is reported in the figure.
Abbreviation: CV, cardiovascular. (From Verdecchia P et al. Hypertension 2007; 49: 777–783, with permission (28).)
surge in BP) and some cardiovascular events all follow (40,41): (i) the sleep-through morning BP surge computed
the same temporal pattern, it has been hypothesized that as the difference between the average BP during the 2
a pathophysiologic relationship exists between hemody- hours following awakening and the lowest nighttime BP
namic aberrations such as the early morning BP surge and (i.e. the average of the lowest BP and the two readings
vascular damage (34–37). immediately preceding and after the lowest value), and
Some investigations have been conducted to explore the (ii) the pre-awakening morning BP surge as the difference
possible mechanisms of the morning surge in BP and its between the average BP during the 2 hours after awaken-
potential relationship to cardiovascular events (34–37). ing and the average BP during the 2 hours before awaken-
Increased sympathetic nervous system activity and acti- ing (Figure 26.2).
vation of the renin−angiotensin−aldosterone system Some studies performed in the past decade have found
(RAAS) may contribute to increase vascular resistance significant relations among the early morning BP surge
and the morning BP surge. Whether these mechanisms and vascular disease (42), cardiac hypertrophy (43) and
of morning BP elevation independently convey vascular white matter lesions of the brain (40).
harm is not clear, but of theoretical concern as it is known Of note, in a population of 519 older hypertensive sub-
that alpha-adrenergic stimulation and RAAS activation jects from Japan who contributed 44 stroke events, dur-
can increase vascular tone, coronary vasospasm and pro- ing an average follow-up of 41 months, a higher morning
thrombotic tendencies in the early morning period (34– BP rise (sleep-through morning surge ≥55 mmHg) was
37). Moreover, risk factors for a profile of excessive early associated with stroke risk independently of ambula-
morning hypertension include older age, excessive alcohol tory BP, nocturnal BP falls and silent cerebral infarct
and/or smoking, longer sleep times, later awakening times (p = 0.008) (40).
and cold weather climates (38,39). More recently, an analysis by the International Database
To date, the following two different estimates of the of Ambulatory Blood Pressure in Relation to Cardiovascular
morning surge in BP proved prognostic significance Outcome (IDACO) demonstrated that the morning surge
206 Manual of Hypertension of the European Society of Hypertension
A B
High morning BP surge High nocturnal fall in BP Low morning BP surge Low nocturnal fall in BP
X: time (hour) Y: Systolic, Diastolic (mmHg), HR (/min) X: time (hour) Y: Systolic, Diastolic (mmHg), HR (/min)
200 200 210 210
200 200
50 50 50 50
8 11 14 17 20 23 2 5 8 8 11 14 17 20 23 2 5 8
Figure 26.2 Estimates of the morning blood pressure surge, which proved prognostic significance in some reports. The
figure also suggests that day-night reduction in systolic blood pressure may be directly associated with the sleep through or
the pre-awakening systolic blood pressure surge (see text for details). Abbreviation: BP, blood pressure.
Yes No
White-coat
hypertension
Ambulatory hypertension
Intermediate
Low risk High risk
risk
Figure 26.3 Algorithm for interpretation of ambulatory blood pressure measurements in untreated hypertensive subjects.
Abbreviations: BP, blood pressure; ABPM, ambulatory blood pressure monitoring; PP, pulse pressure; SD, standard devia-
tion; *, European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines; **, American College of
Cardiology/American Heart Association guidelines.
simple (8,9,48), and clinicians should concentrate on values. In these subjects, drug treatment is highly recom-
ambulatory components, which proved to substantially mended (6) (Figure 26.3).
refine risk profiling over and beyond the BP level (6,49).
Evidence suggests that only the addition of ambulatory
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SHORT-TERM BLOOD
PRESSURE VARIABILITY 27
Figure 27.1 Different types of short-term BPV, their determinants and prognostic relevance. Arrows indicate an increase
in cardiovascular complications associated with an increased BPV. †Cardiac, vascular, and renal SOD; ‡BPV on a beat-by-
beat basis has not been routinely measured in population studies. Abbreviations: AHT, antihypertensive treatment; CV, car-
diovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; IHD, ischaemic heart disease; MA,
microalbuminuria; MI, myocardial infarction; SOD, subclinical organ damage.
1 min to 24 h). Indeed, it was through the use of 24-hour technology for the calibrated quantification of finger BP,
intra-arterial BP monitoring in ambulant subjects (the so- this device allows measuring BP levels on a beat-to-beat
called Oxford system) that these BP fluctuations occurring basis, providing the possibility to track fast variations in BP
on a beat-by-beat basis and over the 24-hour period were values either spontaneously occurring or during stimulated
first identified (16). These recordings allowed both the conditions in the laboratory setting (20). A portable version
identification of wake-to-sleep BP variations (i.e. noctur- of the Finometer (Portapres; Finapres Medical Systems,
nal BP fall during sleep followed by a rapid BP increase in Amsterdam, the Netherlands) (21) is currently available,
the early morning hours, with an additional BP decrease which permits a continuous, nonstationary measurement
in the early afternoon during siesta) and documentation of BP during 24 hours at the finger level in ambulant sub-
of fast changes in BP levels occurring during physical exer- jects and outside of the laboratory setting. Continuous BP
cise and under the effects of behavioural and emotional recordings performed within 24 hours represent the most
stimuli (17). Increasing concerns about the invasive nature accurate approach for the assessment of different indices of
and methodological difficulties of intra-arterial BP moni- very short- and short-term BPV (see below). However, the
toring led to the development of the vascular unloading difficulties in implementing continuous invasive record-
technique by Penaz and Wesseling (18) which paved the ings outside the laboratory setting in a daily life situation,
way to create the first noninvasive prototype for continu- the instability of measurements and the cost and technical
ous BP measurement using this principle (19). A device difficulties in performing noninvasive beat-by-beat record-
based on this method became commercially available as ings have thus far prevented this method from being widely
Finapres (TNO, Amsterdam, the Netherlands), with several used in clinical practice. While an accurate assessment of
subsequent devices being built based on the same prin- fast BP fluctuations occurring in the very short term is only
ciple (Finometer [Finapres Medical Systems, Amsterdam, possible through implementation of continuous beat-to-
the Netherlands], Nexfin HD [BMEYE B.V, Amsterdam, beat BP recordings, evaluation is also possible (although
the Netherlands], and Task Force Monitor [CNSystems, less precisely) through the use of intermittent, noninvasive
Graz, Austria]). Through the use of finger cuffs equipped 24-hour ABPM with intervals between measurements from
with an infrared photoplethysmograph and sophisticated 15 to 20–30 min (22,23). This allows the straightforward
Short-term Blood Pressure Variability 211
estimation of short-term BPV for the whole 24-hour period practice. Regarding the definition of the daytime (awake)
and separately for the daytime and nighttime subperiods and nighttime (asleep) periods, a study with ABPM in 330
(which represents a major advantage of 24-hour ABPM if participants showed that there was a high degree of agree-
the important prognostic value of nighttime BP changes is ment between the definitions of both periods by actig-
considered). Important aspects to be considered for estima- raphy and by self-reporting, with the narrow-fixed-time
tion of short-term BPV from ABPM include measurement periods representing an alternative acceptable approach
intervals and criteria for determining day- and nighttime (26). Editing of possible artefactual readings is not recom-
periods (predefined wide-fixed or narrow-fixed time peri- mended at present, but percent of automatically accepted
ods, self-reported diaries, actigraphy), as well as the BPV readings should be reported. Appropriate implementation
metrics to be analysed, and whether individuals’ behav- of ABPM according to current recommendations is critical
iours should be standardized in terms of daily activities, for the proper estimation of BPV indices, either for research
time in bed, working and resting hours, physical activity, purposes or in a clinical setting (24,27–30). Table 27.1 sum-
etc. Regarding determination of the interval between mea- marizes some important aspects regarding the assessment
surements and the minimum number of BP measurements of very-short- and short-term BPV in clinical practice.
to be obtained over 24 hours, the analysis of a large 24-hour
ABPM registry found 48 BP readings (spaced at 15- and
30-min intervals during day and night, respectively) to be
the minimum number of BP readings required to compute INDICES FOR ESTIMATION OF BLOOD
short-term BPV (i.e. as estimated by calculating average real PRESSURE VARIABILITY
variability [ARV]) without loss of prognostic information
(24). However, such a relatively small number of readings In general, indices for assessment of BPV over 24 hours can
may be responsible for inaccuracies, as shown by a simula- be classified into two main groups: (1) indices of overall vari-
tion study carried out on 24-hour intra-arterial recordings ability, focusing on faster BP variations occurring reading-
(25). Given that highly frequent measurements might cause to-reading over the 24-hour period, which assess either
discomfort, thus reducing compliance and acceptance of the frequency components of BP spectra in the frequency
ABPM, measurements at 15- to 20-minute intervals could domain, or in the time domain, the degree of dispersion,
be a reasonable compromise for BPV assessment in clinical the sequence or the instability of BP values over a certain
Table 27.1 Methods for assessment of very short- and short-term BPV
Characteristic features Very short-term BPV (beat by beat) Short-term BPV (within 24 h)
Method for BP measurement Continuous BP recordings in a laboratory setting Validated ABPM devices
or under ambulatory conditions
Measurement intervals Beat-to-beat 15–20-min intervals for day and night, respectively
A 15-min interval for the whole 24-h time desirable but
not always feasible
Number of measurements Variable depending on patient’s heart rate and Ideally 87–96, at least 72 valid measurements when
recording duration focusing on BPV
Duration of recording period Variable recording periods (1 min to 24 h) 24–48 h during a usual working day (usual physical
activity)
Advantages Beat-to-beat recordings allow assessment of indices Extensive information on 24-h BP profile (nighttime BP
of autonomic cardiovascular modulation dipping, morning surge)
Assessment of efficacy of antihypertensive drug treatment
over 24 h
Disadvantages Stability of measurements might not be guaranteed ABPM: Cannot be repeated frequently
outside the laboratory setting
Not well tolerated
Possibility of measurement artefacts
Not widely available
Difficult to standardize subject’s behaviour over 24 h
Abbreviations: BP, blood pressure; BPV, blood pressure variations; ABPM, ambulatory blood pressure monitoring.
212 Manual of Hypertension of the European Society of Hypertension
Figure 27.2 Indices for estimation of short-term BPV. Abbreviations: BPV, blood pressure variability; HF, high frequency;
LF, low frequency; VLF, very low frequency; SD, standard deviation; CV, coefficient of variation; VIM, variability indepen-
dent of the mean; wSD, weighted standard deviation; ARV, average real variability; MBPS, morning blood pressure surge.
period of time; and (2) indices for estimation of specific BPV the most commonly used index for assessment of BPV and
patterns, focusing on slower BP variations within 24 hours provides a measure of values dispersion over selected time
associated with circadian BP changes (i.e. day/night BP windows (24-hour, day and night), it is affected by trends
profiles) or with other behavioural factors (i.e. ‘siesta’; in BP (e.g. day-night change) and increases with increas-
awakening in the morning). See Figure 27.2. ing average BP values. To account for such a dependence of
SD and other absolute measures of BPV on mean BP levels,
the coefficient of variation (CV) (SD* 100/BP mean) may
be applied (25). Assessment of global 24-hour SD is sig-
INDICES FOR ASSESSMENT OF OVERALL nificantly influenced by both short-term and day-night BP
BLOOD PRESSURE VARIABILITY changes; that is, by components of 24-hour BPV known to
have opposite prognostic implications (see following para-
INDICES OF DISPERSION graphs). Thus whenever the focus is on short-term BPV over
A traditional approach for the estimation of very-short-term 24 hours, the contribution to overall 24-hour BP SD carried
BPV when using continuous beat-to-beat BP recordings con- by day-night BP changes has to be identified and removed.
sists in the calculation of the standard deviation (SD) of each This can be achieved through estimation of weighted 24-hour
half-hour mean BP value, followed by the calculation of the SD (wSD) which selectively removes the contribution pro-
average of these 48 half-hour SDs (‘within half-hour SD’) vided by night time BP fall to 24-hour SD, by weighting day-
(17). Alternatively, short-term BPV is obtained by calculating time and nighttime BP SD for the duration of the day- and
the SD of the average of the mean BP values for each of the nighttime periods, respectively, and by averaging the SD of
48 half hours in which the 24-hour recordings may be subdi- these two time subperiods (31). The corresponding weighted
vided. This other short-term BPV component (the so-called CV may be calculated as well. Variability independent of the
‘among half-hour SD’) is thought to reflect slightly slower cir- mean (VIM) excludes the effect of mean BP on BPV by apply-
cadian variations in BP. The first studies implementing these ing nonlinear regression analysis (i.e. plotting SD against
measures showed that short-term BPV increases proportion- mean) (32). For its estimation, it requires calculation of a
ally to the increase in mean BP levels, being greater during factor x from overall population data (32).
the daytime and during physical activity and lower during
the nighttime or during rest (25). These studies also showed
that compared to normotensive controls, hypertensive sub- INDICES OF BPV IN THE FREQUENCY DOMAIN
jects not only have higher mean BP levels but also greater An accurate estimation of spectral indices for assessment of
very-short-term BPV (within half-hour SD) and short-term very-short-term BPV in the frequency domain is only possible
BPV (among half-hour SD) (25). Short-term BPV may also from continuous beat-to-beat BP recordings (33). In addition
be estimated from noninvasive intermittent 24-hour ABP to calculation of SD and other traditional indices of BPV, con-
recordings at intervals from 15 to 20 minutes (22,23) by cal- tinuous BP recordings do indeed allow estimation of indices
culating 24-hour SD, and also the respective SD for the day- of autonomic cardiovascular modulation by applying power
and nighttime subperiods (22,25). Although SD represents spectral analysis. It decomposes the overall BP variance or
Short-term Blood Pressure Variability 213
power into its different components oscillating at different extreme readings of the distribution of BP values within
frequencies. The corresponding spectral indices are usually a given time window such as range (maximum-minimum
obtained by integrating the BP power spectrum over different BP), peak-and-trough values, peak size (maximum-mean
frequency bands and by focusing on those reported to have a BP), and trough size (mean-minimum BP). Although some
pathophysiological or clinical relevance. This is usually done studies have demonstrated their clinical value, a major
by computing BP spectral powers over a high-frequency (HF) limitation of these indices is that extreme readings are
band (power between 0.15 and 0.50 Hz), a low-frequency poorly reliable within a given distribution of values,
(LF) band (power between 0.15 and 0.07 Hz, centred around including ABPM data, e specially when focusing on indi-
0.1 Hz), and a very-low-frequency (VLF) band (power vidual subjects, being unstable and prone to show mea-
<0.07 Hz). The HF power usually reflects BP changes induced surement artefacts more than BP values recorded in the
by respiratory mechanics. The LF power mainly quantifies usual range.
oscillations generated by a resonance in the baroreflex loop,
with an important c ontribution by sympathetic modulation
(34). Evidence has been obtained of an adrenergic origin of
the VLF powers (35), which may be potentiated in case of INDICES FOR ASSESSMENT OF SPECIFIC
autonomic dysfunction by the inability of cardiovascular con- PATTERNS OF BLOOD PRESSURE VARIABILITY
trol mechanisms to ‘gate’ BP fluctuations around 0.1 Hz, as in WITHIN THE 24 HOURS
the case of arterial baroreceptors or cardiopulmonary recep-
tors denervation in the experimental animal. In addition, In addition to estimation of indices of overall variability
alterations in respiratory activity may contribute to the VLF (which allows assessment of faster BP variations occur-
power in pathological conditions like congestive heart failure ring reading to reading over the 24 hours), ambulatory
and obstructive or central sleep apnoea, due to the impact of BP recordings also allow estimation of slower fluctua-
so-called periodic breathing. Thus spectral BPV indices may tions within the 24 hours associated with circadian BP
yield information on the autonomic control of circulation, changes (the day/night cycle) or with other behavioural
on the baroreflex function and on pathological aspects of res- factors (e.g. ‘siesta’) (see Figure 27.2). One of the most
piration. Their assessment should be accompanied by assess- common among these indices of BPV estimated from
ment of the corresponding heart rate variability spectral 24-hour ABPM is the nocturnal BP fall. The reduction in BP
powers, which can provide complementary pathophysiologi- during the night can be expressed as percentage of day-
cally and clinically relevant information, and by the assess- time BP [Nocturnal BP fall = (Daytime BP – Nighttime
ment of respiratory frequency and depth. Residual variability, BP)*100/Daytime BP)] which is mathematically equiva-
another index of short-term BPV in the frequency domain, lent to the night/day ratio. When considering the degree
may be estimated not only from beat-to-beat continuous BP of nocturnal BP fall (dipping) subjects may be classified
recordings but also, although less precisely, from intermittent into four different categories: (1) normal dipping (fall in
24-hour ABP recordings at intervals from 15−20 min (22,23). nighttime systolic and diastolic BP between 10–20%),
It is computed in the frequency domain through spectral (2) non-dipping (or more precisely reduced d ipping,
analysis of 24-hour BP fluctuations by assessing the spectral with a fall in nighttime systolic and diastolic BP <10%),
power of faster BP fluctuations remaining in the 24-hour trac- (3) rising or ‘inverted dipping’ (increase in nighttime BP
ing after e xclusion of the slower circadian components (first compared to daytime values), and (4) extreme dipping
two harmonics) of the 24-hour BP profile. (BP fall during night >20%) (38). Another index of short-
term BPV that can be estimated from 24-hour ABPM
when focusing on differences between day and night and
INDICES OF SEQUENTIAL BP CHANGES which has been suggested to carry a prognostic value is
Average real variability (ARV) is an index of overall vari- the morning BP surge (MBPS). It is computed in different
ability based on readings sequence. It is computed as the ways, as a function of the different time points set by the
average of the absolute differences between consecutive BP researcher to define wake and sleep time periods. The
measurements over 24 hours. It focuses on the sequence of most commonly employed method is the calculation
BP readings, thus reflecting short-term, reading-to-reading, of the difference between the lowest BP value at night
within-subject variability in BP values (36). ARV has been and the highest BP value recorded shortly after awaken-
shown to be a more specific estimate of 24-hour BP vari- ing. However, when computed in this way, it is obvious
ability and a more effective predictor of outcome than SD. that correlation with nocturnal BP fall may represent a
Indeed, subjects with different 24-hour ABPM profiles may challenge in the interpretation of its impact on outcome
have similar SD but different ARV (27,36,37). ARV effectively data. Indeed, there are still issues to be defined regard-
removes the contribution of trends in mean BP to overall ing the best way of computing morning BP surge and
BPV and is correlated with mean BP levels. Other indices of its actual clinical value, due to the interference of the
overall variability based on reading sequence include time degree of nocturnal BP dipping both with morning BP
rate of BP fluctuations (similar to ARV but quantified as a surge estimates and with the assessment of its prognostic
function of time, to provide information also on speed of value. Other patterns of BP variations that can be evalu-
BP changes) and interval-weighted SD (similar to SD), both of ated from 24-hour ABPM are the siesta dipping (i.e. the BP
which take into account the interval between measurements, fall observed in populations where having an afternoon
giving greater weight to more distant pairs of readings. nap, i.e. siesta, is a common habit) and the postprandial
BP fall (supposedly due to splanchnic vasodilation after a
meal which, when excessive, leads to postprandial hypo-
INDICES OF INSTABILITY tension and may indicate altered autonomic function).
Short-term BP variability may also be assessed by esti- However, to date, no standards have been provided
mation of instability indices that take into account regarding the calculation of these indices.
214 Manual of Hypertension of the European Society of Hypertension
addressed the important issue of whether there are drugs of assessing BPV in clinical practice and of considering
able to specifically reduce BPV and whether such reduc- an elevated BPV as a possible target for treatment to fur-
tion is translated into an improved cardiovascular risk. ther improve prognosis. However, currently available
In the Natrilix SR versus Candesartan and Amlodipine in studies are characterized by a significant heterogeneity
the Reduction of Systolic Blood Pressure in Hypertensive in the methodology applied for estimating BPV indi-
Patients (X-CELLENT) Study, the effect of different ces, and although many indices of short-term BPV have
a ntihypertensive agents (candesartan, indapamide sus-
been shown to be of prognostic value, no interventional
tained release and amlodipine) on ambulatory BPV was longitudinal outcome study has yet been conducted spe-
examined. Amlodipine and indapamide were the only cifically addressing what short-term BPV levels should
agents associated with a significantly decreased ambula- be regarded as normal, and what short-term BPV level
tory BPV after a 3-month treatment (58). In another study should be achieved as target for antihypertensive treat-
in 2780 hypertensive subjects, it was shown that those ment. Similarly, no intervention study has yet explored
treated with calcium channel blockers or diuretics alone, the key question of whether a reduction in short-term
or in addition to other drugs, had significantly lower SD BPV by treatment translates into a better outcome.
of 24-hour systolic BP compared with those not treated
with these classes (59).
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EXERCISE BLOOD PRESSURE:
THE PROGNOSTIC IMPACT OF 28
EXERCISE SYSTOLIC
BLOOD PRESSURE
results indicated an ability of exercise blood pressure at were divided into quartiles based on peak systolic blood
moderate workload to provide early prognostic informa- pressure at 100W, and the risk of cardiovascular mortal-
tion in patients without hypertension. The predictive ity increased more than threefold in the highest quartile
value of exercise blood pressure seemed to be attenuated (200–270 mmHg, n = 489) compared to the lowest quar-
in the presence of hypertension, and most likely also end- tile (100–160 mmHg, n = 457). When adjusting for clas-
organ damage. sical cardiovascular risk factors, there was still a 1.5-fold
The Oslo Ischemia Study cohort is to our knowledge increased risk of cardiovascular mortality in the highest
the only cohort that has been followed with repeated exer- quartile compared to the lowest quartile (Figure 28.1).
cise tests over several years, according to a highly stan- Additional adjustments for physical fitness had minor
dardised protocol (10) and with long-term follow-up. The impact on the association. There was also a significantly
Oslo Ischemia Study included 2014 initially healthy men and independently increased risk of cardiovascular mor-
aged 40–59 years and has provided several publications tality when comparing the third quartile (180–195 mmHg,
on the prognostic value of exercise blood pressure regard- n = 545) to the lowest quartile.
ing cardiovascular disease. Participants had to perform a The risk of cardiovascular disease (fatal or nonfatal
symptom-limited, ECG-monitored bicycle test starting at myocardial infarction; angina pectoris; heart failure; fatal
a workload of 100W, equal to 600 kilopondmeter (kpm)/ or nonfatal stroke, either haemorrhagic or ischaemic;
min or 5.5 metabolic equivalents (METs). The test was transient ischaemic attack; abdominal aortic aneurysm;
performed on an electrically braked stationary bicycle peripheral artery disease and claudicatio intermittens)
with ergometer. After the initial 6 minutes, the workload also showed a significant and independent association
was increased with 50W every sixth minute. The partici- with systolic blood pressure at 100 W after 35 years of
pants were encouraged to continue exercising until near follow-up (Figure 28.2).
exhaustion or objective signs of cardiac ischemia appeared The finding of a significant association between exer-
on ECG. cise systolic blood pressure and cardiovascular mortality
Results from this cohort have previously shown that sys- is consistent with our previous findings from this cohort
tolic blood pressure at the moderate workload of 100W pre- and a recent meta-analysis and reviews regarding exer-
dicts coronary heart disease and cardiovascular mortality cise systolic blood pressure (5,8). It is our opinion that
in apparently healthy, middle-aged, Caucasian men after increased exercise systolic blood pressure should be
16 years of follow-up (10,11). The risk of cardiovascular regarded as a consistent and reliable predictor for car-
mortality was independent of resting systolic blood pres- diovascular mortality. The association for cardiovascular
sure after 21 years of follow-up (12). In the same cohort, a disease is not as strong compared with cardiovascular
temporal increase in exercise systolic blood pressure over mortality, and the results are cancelled out in the mul-
7 years has also been reported to predict long-term risk tivariate analysis by physical fitness (14). Nonetheless,
of coronary heart disease and mortality (13). The results the results of this study indicate that exercise systolic
remained robust and significant for exercise systolic blood blood pressure predicts cardiovascular disease indepen-
pressure on cardiovascular mortality when extending the dent of the classical cardiovascular risk factors. One rea-
follow-up from 21 years to 35 years (14,15). Participants son explaining the different predictive power of exercise
0.6
Q1:
0.5 Q2:
Proportion of participants with CVM
Q3:
Q4:
0.4
0.3
0.2
0.1
0.0
0 5 10 15 20 25 30 35
Observation time (Years)
Figure 28.1 Kaplan-Meier plot showing cardiovascular mortality (CVM) after 35 years in participants divided into
uartiles of SBP100W, Q1 (100–160 mmHg, red plot), Q2 (165–175 mmHg, green plot), Q3 (180–195 mmHg, blue plot) and
q
Q4 ( ≥ 200 mmHg, orange plot). N = 1999. CVM includes fatal myocardial infarction, stroke, ruptured aortic aneurysm and
sudden death. (From Mariampillai JE et al. Blood Press 2017; 26: 229–236. With permission.)
Exercise Blood Pressure 219
0.8
0.4
0.2
0.0
0 5 10 15 20 25 30 35
Observation time (Years)
Figure 28.2 Kaplan-Meier plot showing cardiovascular disease (CVD) after 35 years in participants divided into quar-
tiles of SBP100W, Q1 (100–160 mmHg, red plot), Q2 (165–175 mmHg, green plot), Q3 (180–195 mmHg, blue plot) and Q4
(≥200 mmHg, orange plot). N = 1999. Cardiovascular disease includes peripheral artery disease, abdominal aortic aneu-
rysm, claudicatio intermittens, fatal or nonfatal cerebral stroke, transient ischaemic attack, angina pectoris, fatal or nonfatal
myocardial infarction and heart failure. Abbreviation: CVD, cardiovascular disease. (From Mariampillai JE et al. Blood Press
2017; 26: 229–236. With permission.)
systolic blood pressure regarding cardiovascular mortality by heritage, hence justifying including the parameter in
and cardiovascular disease might be that the latter group the multivariate analyses.
contains ‘softer’ endpoints as angina pectoris and inter-
mittent claudication, possibly attenuating the results. It
is also possible that elevated systolic blood pressure dur-
ing exercise is a more potent inducer of atherosclerosis in
coronary and cerebral arteries, favouring cardiovascular
PHYSIOLOGY AND PATHOPHYSIOLOGY
mortality rather than cardiovascular disease including RELATED TO EXERCISE SYSTOLIC BLOOD
peripheral artery disease. PRESSURE
The risk of cardiovascular disease seems also to be
present at lower exercise systolic blood pressure. When During exercise, an increase in systolic blood pressure is
performing stepwise analyses comparing sustained eleva- considered to be a normal physiological response. The
tion of exercise blood pressure to exercise blood pressure hemodynamic changes are due to the increase in cardiac
persistently below incremental threshold values between output needed to meet the metabolic demands of the
160–195 mmHg, it seems that there is an increased cardio- exercising muscles, and roughly, systolic blood pressure
vascular risk already at 165 mmHg, independent of both increases with increasing workload. Why some individu-
resting systolic blood pressure and physical fitness (16). als show an exaggerated systolic exercise blood pressure
In the recent studies of exercise blood pressure from during exercise is not fully understood. The aetiology is
the Oslo Ischemia Study cohort, physical fitness and fam- most likely of vascular origin rather than due to left ven-
ily history of coronary heart disease have been included tricular hypertrophy and dysfunction, as often seen in
in the multivariate analyses, both being quite unusual exercise-induced hypotension (4). Insufficient reduction
adjustment variables in epidemiological analyses. The in total peripheral resistance due to failing vascular prop-
rationale for performing adjustments for physical fitness at erties and/or endothelial dysfunction has been proposed
maximal workload is that participants have different phys- (4,17,18). The exercise protocol in the Oslo Ischemia
ical capacity, and even though the exercise systolic blood Study was used by some of the authors of this paper,
pressure is measured at moderate workload, this workload showing a significantly higher total peripheral vascular
also represents different levels of the participants’ total resistance in men with exercise systolic blood pressure
capacity. Regarding family history of coronary heart dis- ≥200 mmHg (18).
ease, heritage is one of the most powerful predictors for It is not possible to determine the pathophysiological
cardiovascular disease. The results from our study are also mechanism for the association between exercise systolic
altered little when adding further adjustments in a model blood pressure and cardiovascular disease or mortality in
including the classical cardiovascular risk factors and fam- epidemiological studies. Therefore, exercise systolic blood
ily history. Most of the adjustments are therefore covered pressure might act as a marker for a yet unknown, or possibly
220 Manual of Hypertension of the European Society of Hypertension
a known (18), but not acknowledged, risk factor for cardio- workload representing maximal workload, greater effort
vascular disease and mortality. In subjects without hyper- might cause greater movement artefacts and disturbances
tension at rest, exercise blood pressure has been shown to which could result in unreliable values, at least when using
correlate to blood pressure responses during physical stress a noninvasive method. Diastolic blood pressure or pulse
in daily life (19), and consequently also associations with pressure is often not investigated in exercise studies due to
increased risk of future cardiovascular disease not discov- difficulties obtaining reliable results in an exercise setting
ered by blood pressure measurements after 5 minutes of with noninvasive measurements.
rest in supine or sitting position. Among individuals dem- Because maximum exercise capacity differs between
onstrating an exaggerated systolic blood pressure response participants, adjustment for physical fitness in addition
to exercise, both at maximal- or low-intensity effort, there to the classical cardiovascular risk factors is important.
is a greater prevalence of masked hypertension, which to Although 100W is considered to be a moderate workload,
some degree might explain the increased risk of cardiovas- some participants may show a physiologically increased
cular mortality (20). Another possibility is that moderate systolic blood pressure due to being closer to their maxi-
workload represents a physiological stressor, revealing fail- mum exercise capacity. This is reflected by the alterations
ing compensatory mechanisms not discovered under stan- in the results when introducing physical fitness in the mul-
dardised resting conditions, e.g. early vascular stiffness or tivariate model. In addition, exaggerated blood pressure in
exaggerated sympathetic response. Even though 100W is to athletes with high cardiorespiratory fitness does not seem
be considered as a moderate workload, the shift from rest to to have the same impact on end-organ damage and is thus
exercise without a more gradual increase in workload may unlikely to represent the same impact on cardiovascular
enhance the effect on blood pressure. If so, elevated exer- risk (5). Adjustments for physical fitness should therefore
cise systolic blood pressure must be regarded as a marker of be mandatory when studying the importance of systolic
disease rather than a risk factor for developing disease, as blood pressure levels at low-to-moderate intensity.
has been emphasized earlier (11). The importance of an exaggerated blood pressure
response to physical exercise is likely to be equal among
men and women (7,8), even though different gender-spe-
cific cutoff values for exercise blood pressure may exist.
EXERCISE SYSTOLIC BLOOD PRESSURE AT
DIFFERENT WORKLOADS AND IMPACT
OF PHYSICAL FITNESS CLINICAL ASPECTS OF EXAGGERATED
EXERCISE SYSTOLIC BLOOD PRESSURE
During the exercise test, systolic blood pressure is most
often measured at several different intensities or work- There is no agreement on what should be considered to
loads. If exercise systolic blood pressure is associated with be an inappropriate or exaggerated systolic blood pres-
cardiovascular disease and mortality, it is reasonable to sure response to exercise, and the threshold values have
believe that peak systolic blood pressure would have an only been arbitrarily defined (4). Some studies have
impact on risk prediction. In the recent reports from the used the 90th or 95th percentile, or systolic blood pres-
Oslo Ischemia Study, none of the results are altered by sure ≥210 mmHg for men and systolic blood pressure
peak systolic blood pressure, and systolic blood pressure ≥190 mmHg for women (22–24). Based on the findings in
at moderate workload seems to provide the important our studies, a larger proportion of the population might
prognostic information. This is consistent with other stud- have an increased risk of cardiovascular disease and mor-
ies, both from this cohort and other studies investigat- tality than earlier acknowledged by using the arbitrarily
ing exercise systolic blood pressure, including systematic defined limits referred to above.
reviews and meta-analysis by Schultz et al. (8,12), but dif- Exercise systolic blood pressure measurements are
fers from research on stroke from the Oslo Ischemia Study of uncertain clinical importance until threshold values
(21). Prestgaard et al. found that maximal systolic blood for exercise systolic blood pressure are defined. It is not
pressure during exercise predicts long-term risk of stroke known if intervention alters outcome in individuals with
and discusses the possibility that cerebral arteries are hypertensive response to exercise (19). Still, with the pre-
more susceptible to spikes in blood pressure, and thereby dictive power of exercise systolic blood pressure, exercise
are prone to earlier development of disease than coronary systolic blood pressure might be used in the overall risk
arteries. The meta-analysis by Schultz et al. is the first of assessment of individuals and in the future help clini-
its kind and shows a 4% increase in cardiovascular risk cians decide which individuals would benefit from regular
per 10 mmHg increase in exercise systolic blood pressure examinations and invasive, pharmacological or lifestyle
when comprising more than 46,000 patients followed for interventions. The discovery of exercise-induced hyper-
a mean of 15 years. For maximal systolic blood pressure, tension should at least lead to extensive assessment of
there was no significant association with cardiovascular masked hypertension and pre-hypertension with standard
events. One might speculate on why peak systolic blood office blood pressure measurement and ambulatory blood
pressure during exercise is cancelled out by other predic- pressure measurement, and treatment according to guide-
tors in most studies on cardiovascular events. One reason is lines if hypertension is revealed, as recommended by cur-
that peak systolic blood pressure is dependent on duration rent European hypertension guidelines (25).
and workload of exercise. This to a great extent depends Several aspects remain to be clarified regarding exer-
on how much effort each participant puts into the test, cise blood pressure and its prognostic impact on cardio-
which is based on subjective qualities differing between vascular risk estimation and before its implementation in
participants. In addition to difficulties reaching the proper clinical practice. The research on exercise blood pressure
Exercise Blood Pressure 221
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In order to further clarify the prognostic and diagnos- 21. Prestgaard E, Hodnesdal C, Engeseth K et al. Long-term predictors
of stroke in healthy middle-aged men. Int J Stroke. 2018; 13(3):
tic value of exercise blood pressure, there is urgent need 292−300.
to agree on standardised exercise protocols and measure- 22. Lauer MS, Levy D, Anderson KM, Plehn JF. Is there a relation-
ments; and to reach consensus on what a normal blood ship between exercise systolic blood pressure response and left
pressure response during exercise is, and also use this in ventricular mass? The Framingham Heart Study. Ann Intern Med
1992; 116: 203–210.
clinical, interventional trials. 23. Lauer MS, Pashkow FJ, Harvey SA et al. Angiographic and
prognostic implications of an exaggerated exercise systolic blood
pressure response and rest systolic blood pressure in adults under-
going evaluation for suspected coronary artery disease. J Am Coll
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ciency. BMJ 1918; 2: 366–368. sive response to exercise have impaired systolic function without
2. Dubach P, Froelicher VF, Klein J et al. Exercise-induced hypo- diastolic dysfunction or left ventricular hypertrophy. J Am Coll
tension in a male population. Criteria, causes, and prognosis. Cardiol 2004; 43: 848–853.
Circulation 1988; 78: 1380–1387. 25. Williams B, Mancia G, Spiering W et al. 2018 Practice guidelines
3. O’Neal WT, Qureshi WT, Blaha MJ et al. Systolic blood pressure for the management of arterial hypertension of the European
response during exercise stress testing: The Henry Ford Exercise Society of Hypertension (ESH) and the European Society of
Testing (FIT) Project. J Am Heart Assoc 2015; 4(5): pii: e002050. Cardiology (ESC). Blood Press 2018; 27: 314–340.
Section V
Organ Damage-Measurement/Clinical Value
CARDIAC DAMAGE FROM LEFT
VENTRICULAR HYPERTROPHY TO 29
HEART FAILURE
intramural coronary arteries and thereafter moves into Nonhemodynamic factors other than blood pres-
the interstitial space (6–8). The role of inflammatory cells sure, such as age, sex, race, body mass index, diabe-
and cytokines produced by the damaged myocardium in tes and dietary salt intake are operative in determining
the development of interstitial fibrosis has been recently who among the hypertensive patients develop LVH and
demonstrated (9), influencing the activity of the renin− to what degree LVM is increased. Obesity is a major risk
angiotensin−aldosterone system (RAAS). factor for LVH development: A 2 kg/m 2 increase in body
Collagen degradation is also impaired by the reduction mass index correlated with a 50% risk of increased LVM
of the activity of interstitial metalloproteinase-1 (MMP-1) in a cohort of elderly men and women (24). Obese hyper-
activity and by the enhanced production of tissue inhibitor tensive patients are characterized by expanded plasma
of metalloproteinases-1 (TIMP-1) in endothelial cells (8). volume and increased cardiac output, both imposing an
Several molecular mechanisms have recently been pro- additional hemodynamic load on the left (and right) ven-
posed to explain how hemodynamic and neurohumoral tricle (25,26); in addition, the secretion of proinflamma-
factors could induce the transition from hypertension tory cytokines may contribute to adipocyte necrosis, and
to LVH and then to chronic HF. Although some of these to the loss of vascular function contributing to LVH.
mechanisms could become new targets for pharmacologi- Epidemiological data clearly indicate that dietary salt
cal interventions, their importance has not yet been com- intake modifies the process of LVH in hypertensive sub-
pletely established (5,8). jects as well (27,28). This has been reported irrespective of
The postulated mechanisms that underlie cardiac dys- whether dietary salt intake has been assessed by measur-
function, alone or in combination, are hemodynamic ing 24-h urine sodium excretion in clinical stable condi-
load, decreased intrinsic myocardial contractility, adverse tions or by directly measuring the salt ingested with food.
chamber remodelling, impaired coronary hemodynamics, Of note, this relationship has been found to be indepen-
and ventricular fibrosis. dent of 24-h blood pressure, body weight and other clini-
The progressive increase in LV dimensions in patients with cal determinants of LVH (28,29). In normotensive and
LVH is aimed to achieve a contractile reserve under condi- hypertensive rats, high salt intake induced myocardial
tions of stress. The adaptation of LV geometry to maintain hypertrophy and fibrosis that was found to be related to
cardiac output, however, increases wall stress that further increased aldosterone synthase activity and production of
influences cardiac dilatation, and this has been considered aldosterone in the myocardium despite decreased plasma
the first step in the transition from cardiac hypertrophy to renin activity and lowered plasma aldosterone concentra-
cardiac failure (10). However, an interindividual variability tion in the systemic circulation (30). Most recent trials
in the magnitude of the increase in LV mass and change in have indicated that increases in intracellular sodium lead
geometry (ventricular dilation or wall thickening) has been to an up-regulation of growth-stimulating genes, thereby
observed and may be attributable to differences in the pres- directly inducing growth-stimulating signals.
sure load, concomitant medical conditions, neurohormonal Gender, race and genetic factors are also well established
activation or perhaps genetic influences (11). as nonhemodynamic factors that contribute to the devel-
opment of LVH. In the Framingham Study, LVM increase
was documented in a higher percentage of hypertensive
women than men (70% compared with 31%), a difference
PATHOGENESIS OF CARDIAC STRUCTURE which parallels the higher contribution of hypertension to
ADAPTATION the risk of chronic HF in women (31). In African Americans,
the prevalence of LVH is greater as compared to whites at
In arterial hypertension, elevated blood pressure is the fun- similar BP values (32). Several studies have further sug-
damental trigger to the sequence of biological events that gested that approximately 30% of the LVM variance is
lead to development of LVH. Statistically, only 10% of the genetically determined (33). Studies of genetic influence
variation in LVM could be accounted for based on office sys- of LVM have focused mainly on candidates’ genes that are
tolic BPs averaged over a 30-year period (12). LVM is more related to the RAAS, to the sympathetic nervous system or
closely related to average 24-h BPs (13,14), and even highly its receptors, and on components of the signal transduc-
sophisticated measurements of BP cannot fully account for tion mechanisms involved in cardiac hypertrophy.
the variance in LVM (15). The circadian pattern of blood The effect of sympathetic nervous system is evident in
pressure appeared to be of further importance. Despite experimental models and in human studies. Although in
similar mean ambulatory blood pressure values, ‘non-dip- pheochromocytoma LVH prevalence is relatively low, new
pers’ have increased LVM compared with individuals dis- studies applying the cardiac spillover methodology and
playing the usual circadian pattern (14,16). Overall, 24-h thereby assessing the direct effect of the sympathetic drive
mean BP and average daytime systolic BP – in most studies to the heart have found a close correlation between the
the best statistical correlates of LVM – account for about cardiac noradrenaline spillover and LVM (34). These find-
25% of observed variance in LVM (17,18) and the simplistic ings are in accordance with previous data demonstrating
view that only BP is a culprit of LVM has to be revised. It has that increased peripheral muscle sympathetic nerve activ-
been suggested that central SBP may be pathophysiologi- ity as measured by microneurography is elevated in hyper-
cally more relevant than brachial SBP for the pathogenesis tensive patients with LVH (34,35).
of cardiovascular disease (19). Central systolic BP has been More recently, the role of beta-3 receptors (36) in pro-
associated more closely with LVH and carotid atherosclero- tecting from cardiac fibrosis has been demonstrated; the
sis as markers of hypertensive organ damage than brachial stimulation of cardiac beta-3 receptors could influence
systolic BP in various populations (20–22). nitric oxide and oxidant stress-dependent paracrine sig-
Recently, it was observed that ambulatory central systolic nalling to fibroblasts, reducing collagen synthesis.
BP, measured by 24-h BP monitoring, tends to be superior Experimental and clinical trials highlight the role
to brachial ambulatory systolic BP in predicting LVH (23). of the RAAS in mediating LVH (37,38). In particular,
Cardiac Damage from Left Ventricular Hypertrophy to Heart Failure 227
Table 29.1 Proposed treatment for hypertension and hypertension and chronic heart failure/left ventricular hypertrophy, according to
ESC/ESH guidelines 2018
Uncomplicated hypertension
Among all antihypertensive drugs, ACE inhibitors, ARBs, beta-blockers, CCBs and diuretics (thiazides and thiazide-like drugs such as chlorthalidone
and indapamide) are indicated as the basis of antihypertensive treatment strategies.
It is recommended to initiate an antihypertensive treatment with a two-drug combination, preferably in an SPC. Exceptions are frail older patients and
those at low risk and with grade 1 hypertension (particularly if SBP is <150 mmHg).
Combination treatment is recommended for most hypertensive patients as initial therapy. Preferred combinations should comprise an RAS blocker
(either an ACE inhibitor or an ARB) with a CCB or diuretic.
Beta-blockers are combined with any of the other major drug classes when there are specific clinical situations, e.g. angina, post-myocardial infarction,
heart failure, or heart rate control.
If BP is not controlled with a two-drug combination, treatment should be increased to a three-drug combination, usually a RAS blocker with a CCB and
a thiazide/thiazide-like diuretic, preferably as an SPC.
If BP is not controlled with a three-drug combination, treatment should be increased by the addition of spironolactone or, if not tolerated, other diuretics
such as amiloride or higher doses of other diuretics, a beta-blocker, or an alpha-blocker.
In hypertensive patients with heart failure (with rEF or pEF), BP-lowering treatment should be considered if BP is ≥140/90 mmHg.
In patients with HFpEF, BP treatment threshold and target values should be the same as for HFrEF.
In patients with HFrEF, BP-lowering treatment comprises an ACE inhibitor or ARB, and a beta-blocker and diuretic and/or MRA if required.
Abbreviations: ESC/ESH, European Society of Cardiology/European Society of Hypertension; ACE, angiotensin converting enzyme; ARB, angiotensin receptor
blocker; CCB calcium channel blocker; SPC, single pill combination; RAS, renin angiotensin system; MRA, mineral receptor antagonist.
228 Manual of Hypertension of the European Society of Hypertension
LV dilatation
(BSA) and height should be applied according to gender criteria for the diagnosis of echocardiographic LVH have
and ethnic group (56). been proposed. These criteria are based on the distribution
The evaluation of geometric adaptation of the left ven- of LVM index in general population samples (average LVM
tricle to the increased hemodynamic load implies the cal- value plus one standard deviation in apparently healthy
culation of the relative wall thickness (or wall-to-radius population-based samples) or on the association between
[WTR] ratio, i.e. the ratio between LV end-diastolic wall increased values of LVM and occurrence of cardiovascular
thicknesses and diameter) and may significantly differ events in longitudinal studies. The presence of echocardio-
among hypertensive patients (57). A cutoff value of 0.43 graphic LVH is associated with an incidence of cardiovas-
permits categorization of an increase in left ventricu- cular events equal to or greater than 20% in 10 years (69).
lar mass as either concentric (RWT ≥0.43) or eccentric The American Society of Echocardiography and the
(RWT < 0.43) hypertrophy, and also allows the identifica- European Association of Echocardiography (ASE/EAE) have
tion of concentric remodelling, defined as a normal LVM published ranges for several echocardiographic parameters
with increased RWT ≥0.43 (45). derived from a population of about 500 multi-ethnic, nor-
These different LV geometric patterns are associated motensive and normal weight subjects, and the Pressioni
with different hemodynamic characteristics, and periph- Arteriose Monitorate E Loro Associazioni (PAMELA) study
eral resistances are greater in patients with concentric has provided new reference limits in an Italian population
geometry while cardiac index is increased in those with (70). A revision of previous diagnostic criteria will probably
eccentric hypertrophy (58). In addition, concentric remod- come from new ethnic- and gender-specific group reference
elling and eccentric and concentric hypertrophy all predict values from the EchoNoRMAL project (56). Real-time 3D
an increased incidence of cardiovascular disease, but con- echocardiography permits a more reliable measurement of
centric hypertrophy has consistently been shown to be the LVM, and its accuracy has been shown to compare favour-
condition that most markedly increases the risk, even in ably with that of cardiac magnetic resonance imaging (71).
very-high-risk patients (59–61). Recently, a new reclassifi- Similar to magnetic resonance imaging (MRI), not cur-
cation of LVH, based on LVM, RWT and LV dilatation has rently recommended for the assessment of hypertensive
been proposed in hypertensive patients (62). Eccentric LVH heart disease in clinical practice, 3D echocardiography
with increased LV chamber volume predicted increased has the advantage of not relying on geometric formulas for
risk for all-cause and cardiovascular mortality and cardio- calculating LVM but of measuring it directly. This allows
vascular events, while eccentric hypertrophy with normal greater accuracy and reproducibility in the evaluation of
LV chamber size did not. In contrast, both dilated and the LV structure and geometry in comparison with stan-
nondilated concentric LVH are associated with poor out- dard echocardiography. Numerous studies carried out in
come. The low-risk group of patients with relatively mild healthy subjects from different ethnic groups have inves-
eccentric LVH, no concentric geometry or dilatation had a tigated the accuracy of 3D echocardiography for LVM
similar risk of all-cause mortality or cardiovascular events measurements against MRI and have found an excellent
as patients with normal LVM. Verification of the enhanced correlation between the two methods (72). However, crite-
prognostic power of the four-group classification of LVH ria for prognostic significance of increased LV mass by 3D
in other populations is needed before recommending that echocardiography are not yet clearly established.
this more refined approach replace the established classi-
fication of LVH into eccentric and concentric subgroups.
Evaluating LVM increase by taking into account gender ASSESSMENT OF LV DIASTOLIC FUNCTION
and cardiac loading conditions has been proposed in order
to discriminate the amount of LVM adequate to compensate A large number of patients with typical symptoms of chronic
the hemodynamic load (adequate or appropriate) from the HF present a normal or only mildly impaired systolic func-
amount in excess to loading conditions (and therefore inap- tion but have evidence of diastolic dysfunction (73–77). In
propriate or not compensatory) (63). LVM is inappropriate hypertensive patients, diastolic dysfunction is character-
when the value of LVM measured in a single subject exceeds ized by alterations of LV relaxation and filling, which may
the amount needed to adapt to the stroke work for that precede abnormalities of systolic function; these abnormal-
given gender and body size. The degree of LV mass inap- ities should be interpreted according to the presence of LVH
propriateness is associated with structural and functional or concentric geometry in order to give a correct interpreta-
abnormalities, such as concentric LV geometry, reduced LV tion of LV diastolic function and filling pressure parameters.
ejection fraction and midwall shortening, and prolonged In fact, in patients with LVH or concentric remodelling, LV
LV relaxation, and with an increased rate of cardiovascu- relaxation is usually slowed, with a decrease in early dia-
lar events, both at baseline and during treatment (64). In stolic filling; in the presence of normal left atrial pressure, a
the Cardiovascular Health Study population, the hazard of greater proportion of LV filling is shifted from early to late
heart failure increased by 1% for each 1% increase in inap- diastole after atrial contraction. Therefore, the presence of
propriate LV mass and by 3% for each g/m2.7 increase in a predominant early filling in these patients should suggest
traditionally measured LV mass index, confirming that the the presence of increased LV filling pressures (78).
excess of LV mass portends impending heart failure (65). These aspects have become even more relevant owing to
Technical variability represents a potential limitation the increase of the elderly population in Western countries.
of echocardiographic measurement of LVM. An assess- Diastolic dysfunction can be observed in a greater percent-
ment of LVM reproducibility has shown that LVM changes age of patients with LVH. Increasing age, higher heart rate
of 10–15% may have biological significance in individual and obesity may worsen diastolic filling. Gender-related
patients (66). When changes in LVM inappropriateness are differences have been observed in the impact of impaired
evaluated, changes of 15–25% may reflect true change (67). diastolic relaxation on exercise capacity in hypertensives
Despite the fact that the relationship between LVM and inci- with LVH, and females could be more likely to have an
dence of cardiovascular events is continuous (68), several altered cardiac adaptation to physical activity than males.
230 Manual of Hypertension of the European Society of Hypertension
Figure 29.2 Relative risk reduction of heart failure (HF) in blood pressure-lowering in trials with no baseline heart failure
and with no or mild baseline heart failure. (From Thomopoulos C et al. J Hypertens. 2016 March;34(3):373–384.)
of an increased risk of atrial fibrillation, stroke, heart fail- the presence of a concentric LV geometry, LV midwall FS is
ure and mortality. This has been shown by the measure- considered a more appropriate index of LV systolic func-
ment of LA anteroposterior linear dimension by M-mode tion than conventional FS (98–100). The regression of LVH
from the parasternal long axis view and by the more accu- in patients with reduced midwall systolic performance is
rate evaluation of LA volume from 2D images. The mea- associated with a significant improvement of FS (101–103).
surement of LA volume is recommended both in clinical Left ventricular ejection fraction (LVEF), derived from
practice and in research studies, and most guidelines rec- 2D calculation of the LV end-diastolic volume (EDV) and
ommend the biplane area-length method. The 2013 ESH/ the LV end-systolic volume (ESV) according to the modi-
ESC hypertension guidelines and the EAE/ASE guidelines fied Simpson method (average of apical four- and two-
recommend a cutoff value of >34 mL/m2 for left atrial chamber views) is the most sensitive index of systolic
enlargement (94), while the 2018 ESH/ESC guidelines ventricular function, with a high prognostic value. LVEF
have further suggested the indexation of LA volume to values >55% define a normal systolic function, while a
height 2 for the evaluation of LA enlargement (45). slight or moderate reduction in systolic function is pres-
Compared to the conventional 2D approach, 3D echo- ent when EF values are between 45−55% and between
cardiography appears superior in the assessment of LA 35−45%, respectively; values below 35% identify patients
volume; at present, however, this application is limited to with severe LV systolic dysfunction.
research studies. The same consideration applies to several In the absence of major structural abnormalities, a
other parameters of LA function, based on 2D or 3D mea- single-plane measurement of the LV area is obtained from
sures, conventional and tissue Doppler or strain rate imag- the apical four-chamber window. The longitudinal myo-
ing (95,96). cardial systolic velocity (Sm), measured by tissue Doppler
LA reservoir and conduit function, assessed by volumet- imaging (TDI) at the mitral annulus level, has been pro-
ric and strain analysis, have been shown to be significantly posed as a reliable and accurate index of myocardial fibre
impaired in hypertensive patients when compared to nor- performance, independent of LV preload and afterload. In
motensive controls. normal conditions its value is higher than 8 cm/s and in
Some authors have found that all LA functions are severe pathological conditions is less than 5 cm/s.
reduced in hypertensive patients, while other investigators More recently, a 3D probe (multiplane) has become
reported decreased conduit and enhanced LA reservoir available and allows the calculation of LV volumes by the
and pump function (97). In addition, other researchers Simpson triplane method (104). The accuracy of 3D echo-
have demonstrated reduced LA reservoir and conduit, but cardiographic examination in the measurement of LV vol-
compensatory increased booster pump LA function. umes has been confirmed by comparison with MRI (105).
The newly developed 2D and 3D speckle tracking echo-
cardiography (a technique based on the analysis of inter-
ASSESSMENT OF LV SYSTOLIC FUNCTION ference patterns and natural acoustic reflections generated
by tissue motion which are ultimately resolved into angle-
LV dysfunction includes segmental and global alterations independent 2D and 3D strain-based sequences) represents
of LV that may differently affect pump function and prog- a valuable tool for the detection of subclinical systolic dys-
nosis. In uncomplicated hypertensive patients LV frac- function in the hypertensive setting and allows estimation
tional shortening (FS) and ejection fraction (EF) express of different directional strain components (106,107).
endocardial fibre shortening and are usually preserved or Left ventricular motion is rather complex and involves
even ‘supernormal’, mainly in the presence of concentric different types of movements: shortening, thickening,
geometry. However, midwall myocardial fibres contribute lengthening, rotation, twist and untwist. The best echo-
to a greater extent than subendocardial fibres to LV ejec- cardiographic method for evaluation of these compli-
tion, and the difference between the conventional and cated cardiac motions is speckle-tracking imaging (STI).
midwall indexes of LV systolic function is more evident Strain is only one of the STI parameters and represents
in the presence of a concentric LV geometry; therefore, in a percentage in changes of myocardial longitudinal
232 Manual of Hypertension of the European Society of Hypertension
diameter (longitudinal strain), circumference (circumfer- alterations in the repolarization could reflect the presence
ential strain) and thickness (radial strain) (108). Apical of reduced coronary perfusion.
rotation in the clockwise direction and basal rotation in It has been shown that the presence of LVH is associated
the counterclockwise direction enable efficient cardiac with structural and functional alterations in both large
contraction. Twist is the mathematical summation of the (115–117) and small arteries (118–121). Vascular struc-
absolute values of the basal and apical rotations. This tural changes are particularly evident in patients with con-
complex cardiac motion may be explained by cardiac layer centric remodelling and LVH (122–124).
architecture (109). LV myocardial wall consists of three The presence of vascular alterations is in large part
layers: endocardium, mid-myocardium and epicardium. responsible for reduced coronary reserve, consistently
Subendocardial and subepicardial myocytes have mostly observed in patients with LVH (125).
longitudinal direction, whereas mid-myocardial myocytes The concomitant atherosclerotic process of epicardial
are circumferentially directed. The assessment of global LV coronary vessels (126) and the structural alterations (127)
strain, and especially longitudinal strain, has been widely and rarefaction of small coronary vessels limit blood sup-
accepted in the clinical practice, because it is an angle- ply in a situation where oxygen request is increased due
independent, significantly less load- and age-dependent to the greater mass of tissue. An insufficient compensa-
than TDI, reproducible tool with high predictive value tory angiogenesis has been also demonstrated during the
in patients with a wide range of cardiovascular diseases development of adult LVH (128).
including arterial hypertension. STI strain rates are param- Wall motion abnormalities during a stress test have a
eters derived from global strain and illustrate systolic, high specificity for epicardial coronary artery stenosis
early and late diastolic LV function, similar to TDI indexes. assessed by angiography. In hypertensive patients with
Of all available strain parameters, LV global longitudi- LVH and/or microvascular disease, myocardial perfusion
nal strain certainly has the most importance and the great- abnormalities are frequently observed despite normal
est clinical utility. Recent studies showed that LV global coronary arteries at angiography (129). The use of echo-
longitudinal strain represents a good predictor of cardio- cardiographic imaging of wall motion abnormalities and
vascular and total morbidity and mortality in the hyper- of coronary flow reserve in the left anterior descending
tensive population or in the large group of patients with artery in order to distinguish the presence of obstruc-
high prevalence of different cardiovascular risk factors, of tive coronary artery disease (wall motion alterations and
which arterial hypertension was present in more than 40% reduced coronary flow reserve) from microvascular disease
(110). Arterial hypertension has an impact on all myocar- (reduced coronary flow reserve and normal regional wall
dial layers. Kim et al. (111) showed that all endocardial, motion) has been proposed (130).
midcardial and epicardial longitudinal strains were lower In the presence of LVH, the decrease of coronary perfu-
in hypertensive patients than in controls. Other authors sion in subendocardial layers may yield to myocyte necro-
showed that mostly endocardial and mid-myocardial lay- sis and reparative fibrosis (131), favouring the progression
ers are impaired in different hypertensive settings (i.e. to heart failure.
white-coat, masked and sustained hypertension). The Other extravascular mechanisms potentially respon-
available evidence regarding LV circumferential strain sible for impaired coronary reserve include changes in
in the hypertensive population is not consistent. Some wall tension, heart rate and contractility. In fact, oxygen
authors found significantly lower values of LV circumferen- requirements, as measured by the triple product (heart
tial strain, while others disagreed. Most of the circumferen- rate × LV mass × end-systolic stress) are progressively
tial changes found in hypertensive patients were ascribed increased in patients with LVH in comparison to patients
to LVH. However, our findings in prehypertensive and with normal LV mass and geometry (132).
white-coat hypertensive patients showed that LVH is not The reduction of the regulatory capacity of coronary
crucial for deterioration of circumferential strain. On the flow is greater during exercise, when oxygen demand
other hand, researches have also suggested that LV geome- increases. In fact, in resting conditions the reduction in
try, and particularly concentric and concentric-dilated LVH coronary flow reserve may not have important conse-
patterns, are responsible for worsening of LV circumferen- quences, but during exercise-induced increase in oxygen
tial strain (112). requirement it may become clinically relevant, producing
the clinical manifestations and favouring the progression
of LV dysfunction (133).
Functional alterations may occur and further deterio-
CONSEQUENCES OF LVH AND HF rate the vasodilator response of coronary microcirculation.
Functional alterations related to endothelial dysfunction
have been shown to precede morphological changes in the
LVH AND ISCHEMIA vascular wall and may trigger the development of vascular
remodelling (134,135) (Table 29.5).
LVH and failure are frequently associated to coronary All these observations suggest that LVH represents a
artery disease. Hypertension is one of the major risk fac- state of potential or actual myocardial ischemia.
tors for coronary atherosclerosis.
In the assessment of LVH by electrocardiographic crite-
ria, the use of the pattern of ‘definite LVH’, including S-T LVH AND VENTRICULAR TACHYARRHYTHMIAS
segment and T wave abnormalities, was strongly associ-
ated with an increase of the incidence in acute myocar- The clinical spectrum of hypertensive heart disease
dial infarction and sudden death (1,113,114). When using ranges from impaired coronary reserve, impaired filling,
the voltage criteria for LVH, a less strong association with impaired pumping function and ventricular remodelling
myocardial infarction was observed, suggesting that to cardiac arrhythmias such as ventricular ectopy and
Cardiac Damage from Left Ventricular Hypertrophy to Heart Failure 233
Myocardium
1-Average E/e’ >14
Myocyte hypertrophy 2-Septal e’ velocity < 7 cm/s or
Lateral e’ velocity <10 cm/s
Perivascular and interstitial fibrosis 3-TR velocity > 2.8 m/s
4-LA volume index > 34 ml/m2
Extravascular compression (wall stress increase and abnormal diastolic
filling)
Arteriolar rarefaction (or insufficient compensatory angiogenesis) Figure 29.3 Algorithm for diagnosis of LV diastolic dys-
function in subjects with normal LVEF. (Nagueh et al.
Endothelial dysfunction J Am Soc Echocardiogr 2016;29:277–314.)
Abbreviation: LVH, left ventricular hypertrophy.
Since numerous studies have documented that LVH per
se is associated with ventricular arrhythmias (139), one
atrial fibrillation. As early as 1984, Messerli reported that would expect that these ventricular arrhythmias would
hypertensive patients with LVH have a significantly greater disappear with reduction of LVH. In a double-blind study,
prevalence of premature ventricular contractions and com- the use of ACE inhibitors led to a significant reduction
plex ventricular arrhythmias than patients without LVH in LVH, and at the same time, to a marked reduction in
or normotensive subjects (136); this finding was later con- ventricular ectopy, whereas in the placebo group LVH pro-
firmed in large population-based studies (137,138). Hence, gressed and no changes in ventricular ectopy occurred
the presence of ECG criteria of LVH represents a risk of (144). In the Losartan Intervention For Endpoint reduc-
higher incidence of sudden death that is most prominent tion in hypertension (LIFE) study, the absence of in-treat-
in women (139). ment ECG LVH in hypertensive patients with baseline
On the basis of epidemiological observations, a patho- ECG LVH was associated with a reduced risk of sudden
physiological chain of evidence linking hypertension, cardiac death independent of antihypertensive treatment
LVH and sudden death has been proposed (137–141). regimen, blood pressure reduction, prevalent coronary
Furthermore, the Framingham cohort indicated that in heart disease, and other cardiovascular risk factors (145).
patients with LVH the presence of symptomatic ventricular Overall, reduction in ventricular ectopy has been found
arrhythmias was associated with a nearly twofold increase with the use of calcium antagonists, ACE inhibitors, angio-
in mortality (137). Hypertensive patients with LVH also tensin II receptor blockers and beta-blockers (143–145)
have more ventricular arrhythmias during the interval (Table 29.6). The fact that ventricular ectopy disappeared
from 6:00 am to noon, an interval when cardiac death is with three different drug classes makes it unlikely that the
most frequent (142). This observation and the evidence underlying mechanism is a direct antiarrhythmic effect of
of increased ventricular vulnerability detected by differ- any drug on the ectopically firing myocardium. The poten-
ent techniques (late potentials, ST depression on Holter tial proarrhythmogenic effect of diuretics is matter of
recording, programmed ventricular stimulation, changes concern, since diuretics have been shown to increase ven-
in the fibrillation threshold) support the link between ven- tricular ectopy both at rest and during exercise (146). This
tricular ectopy and cardiac sudden death in hypertensive
patients (138).
However, the mechanism by which LVH leads to Table 29.6 Proposed treatment of hypertension and coronary
increased arrhythmogenicity and ultimately to increased artery disease according to ESC/ESH guidelines 2018
mortality still remains to be elucidated. In a follow-up
trial of a geriatric population, hypertensive patients with- Target SBP to <130 mmHg if tolerated, but not <120 mmHg
out documented coronary artery disease but with echocar- In older patients (aged <65 years), target to an SBP range of
diographic LVH were more likely to experience ventricular 130–140 mmHg
fibrillation or sudden death than their counterparts with-
out LVH (31% vs. 10%) (143). Potential mechanisms are Target DBP to <80 mmHg, but not <70 mmHg
subendocardial ischemia, cardiac hypertrophy, high blood
pressure by itself, irregular hypertrophic pattern, fibrosis In hypertensive patients with a history of myocardial infarction,
within the myocardium (interstitial as well as perivascu- beta-blockers and RAS blockers are recommended as part of
lar) and the hypertrophic cardiac myocyte per se (Figure treatment
29.3). Furthermore, excessive activity of the sympathetic
In patients with symptomatic angina, beta-blockers and/or CCBs are
nervous system and the RAAS exert indirect or direct recommended
arrhythmogenic effects (141).
234 Manual of Hypertension of the European Society of Hypertension
In conclusion, drugs blocking the RAAS may reduce the diffuse interstitial myocardial fibrosis is accurately
risk of new-onset atrial fibrillation. Nevertheless, this effect assessed with post-contrast T1 mapping. In the future
has been mainly observed in high-risk patients particularly this technique will allow the assessment of the effects
in those with left ventricular dysfunction or LVH and in of different drugs on interstitial fibrosis in hypertensive
post-myocardial infarction patients. Most of the supportive patients.
data come from post hoc analyses (162). Recently published investigations for the first time
reported the beneficial effect of antihypertensive drugs
on LV global longitudinal strain in hypertensive patients
followed for 6 and 12 months, respectively, after introduc-
CLINICAL CONSEQUENCES OF CHANGES tion of antihypertensive therapy (169,170). The authors
OF LV MASS DURING reported significant improvement of LV global longitudi-
ANTIHYPERTENSIVE TREATMENT nal strain as well as parameters of LV diastolic function,
and in this way showed that mild deterioration of LV func-
Antihypertensive treatment is associated with a significant tion is reversible with appropriate and timely introduced
reduction in LVM. The magnitude of the decrease is related therapy.
to the baseline LVM (163); according to variability in LVM
measurements only changes >10–15% can be consid-
ered of biological relevance (66). The correlation between
changes of LVM and changes in clinic BP is modest and is PROGNOSTIC VALUE OF CHANGE OF LV
improved when 24-hour BP is considered (17). MASS DURING TREATMENT
Among all classes of antihypertensive drugs, ACE inhib-
itors, ARBs and calcium antagonists seem to be more effec- In hypertensive patients, LVH may predict the occurrence
tive as compared with beta-blockers (164). It should be of cardiovascular events, including myocardial infarction,
kept in mind, however, that in most studies patients were stroke, sudden death and heart failure. The incidence of
receiving a combination of drugs (usually with a diuretic) atrial fibrillation and of renal events, such as creatinine
and not monotherapy. In addition, the recent ESH/ESC doubling, estimated glomerular filtration rate <30 mL/
European guidelines (45) indicate initiation of antihyper- min/1.73 m2 or end-stage renal disease, are higher in the
tensive treatment in most patients with a combination of presence of LVH (171).
drugs, i.e. a RAS blocker plus a calcium-antagonist and/ Changes of LVM index during treatment, and not only
or a diuretic. The efficacy of antihypertensive treatment in the baseline value of LVM, may have prognostic relevance
inducing adequate and long-term blood pressure control (172). In the prospective randomized clinical study (LIFE),
seems more important than the choice of a specific class. it was shown that in patients with electrocardiographic
A normalization of LVM is more difficult and cannot be LVH, the absence of LVH during treatment was associated
always reached in women, obese or diabetic patients (165), with a lower incidence of cardiovascular events, while
elderly subjects with isolated systolic hypertension (166) the opposite was true for patients with no regression of
or patients with coronary artery disease, despite adequate LVH induced by long-term antihypertensive therapy
treatment. A normalization of LV geometry is also possible (173). Several other studies have confirmed the results of
and in the LIFE study a conversion of concentric to eccen- the LIFE study; these studies were performed in cohorts
tric LVH was reported in 34% of subjects, whereas only 3% of hypertensive patients with different demographic and
of patients with eccentric LVH transitioned to concentric clinical characteristics, with and without LVH at baseline,
LVH (167). In the ASCOT study a modest change in LVM treated according to the decision of their general practitio-
and persistence of elevated relative wall thickness were ner (Figure 29.4) (172,174–176).
observed from the first to the third year of therapy (168). Regression of LVH may have a prognostic significance
Several studies have also noted an improvement of midwall independent of blood pressure values, even when mea-
FS (102) and of diastolic function parameters in response to sured by 24-hour BP. Changes in LVM and in renal function
antihypertensive therapy. However, two studies have recently may independently predict the occurrence of cardiovascu-
shown no favourable changes in diastolic filling or E/e’ ratio lar events (176).
ratio, despite adequate BP control (168,169); in these studies, During antihypertensive treatment, the modifications
however, a limited, albeit statistically significant, decrease of of LV geometry, left atrial size, midwall FS and diastolic
LVM and no change in RWT were noted. dysfunction parameters have been also shown to be asso-
It is possible that the partial dissociation between struc- ciated with the incidence of cardiovascular events inde-
tural and functional changes during antihypertensive pendent of LVM change.
treatment may reflect, at least in part, the effect of treat- Therefore, although it must not be considered an abso-
ment on several factors influencing diastolic function, lute indication, in a patient with LVH at baseline it is rec-
including heart rate, humoral changes and extracellular ommended to repeat an echocardiogram after 12 months
matrix composition. of treatment, for the great amount of given information
The deposition of perivascular and interstitial fibrosis (45). During this time interval, the probability that the
has been noninvasively evaluated by some ultrasound degree of anatomic and/or functional changes indicates a
methods, showing that drugs interfering with the RAAS real biological modification is greatest.
may be particularly effective in inducing changes that In conclusion, in hypertensive patients, regression of
might reflect a decrease of myocardial tissue collagen LVH together with optimal BP control is associated with
content. Cardiac magnetic resonance may provide accu- a reduced incidence of myocardial ischemia, arrhythmias
rate and noninvasive assessment of regional myocar- and heart failure and therefore should be considered a spe-
dial fibrosis using late gadolinium enhancement, while cific goal of antihypertensive treatment.
236 Manual of Hypertension of the European Society of Hypertension
Study name Statistics for each study Events / Total Odds ratio and 95% Cl
Muiesan, 1995 0,136 0,052 0,355 –4,074 0,000 8/110 15/41 23/151
Verdecchia, 1993 0,448 0,215 0,934 –2,142 0,032 15/285 16/145 31/430
Cipriano, 2001 0,219 0,098 0,487 –3,722 0,000 8/218 32/216 40/434
Koren, 2002 0,376 0,162 0,873 –2,278 0,023 17/130 12/42 29/172
Muiesan, 2006 0,200 0,118 0,342 –5,907 0,000 31/321 40/115 71/436
Pierdomenico, 2008 0,150 0,080 0,281 -5,899 0,000 15/245 44/145 59/390
Gosse, 2012 0,282 0,162 0,490 –4,483 0,000 19/202 63/234 82/436
Figure 29.4 Studies evaluating the occurrence of CV events in hypertensive patients according to changes in LV mass.
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STRUCTURAL AND FUNCTIONAL
ASPECTS OF BRAIN DAMAGE 30
Cardiovascular Clinical
Silent cerebral damage
risk factors outcomes
Microaneurysms
microbleeds Haemorrhagic
stroke
LVH, LA , AF
Cardioembolic
Large arteries
stroke
PWV
HT
Atherosclerosis Ischaemic
remodelling stroke
WML, CMBs, lacunae
Early cognitive
Dementia
impairment
Figure 30.1 Pathophysiological mechanisms leading from hypertension to silent brain damage, and clinical outcomes.
HT, hypertension; LVH, left ventricular hypertrophy; LA, left atrium; AF, atrial fibrillation; PWV, pulse wave velocity.
Functional abnormalities
Reduced cerebral blood flow
Increased cerebrovascular resistance
Figure 30.2 White matter lesions and lacunar infarcts
Reduced cerebral vasomotor reactivity
Incipient cognitive impairment
shown as hyperintensities in brain magnetic resonance
imaging. Axial plane, fluid-attenuated inversion recovery
Structural abnormalities (FLAIR) image.
Vascular remodelling
Lacunar infarct: Small deep infarcts caused by penetrating arteriolar
occlusive disease
White matter lesions: Periventricular and subcortical white matter
Cerebral microbleeds: CMB are haemorrhagic lesions reflect-
lesions caused by subcortical hypertensive small vessel disease ing both ischaemic and haemorrhagic brain vascu-
Microbleeds: Punctate haemorrhagic lesions seen as homogeneous foci lopathy (Figure 30.3). They represent another sign of
in the brain parenchyma of low signal intensity on T2-weighted images hypertension-related cerebral small vessel disease.
They also participate as vascular factors in neurodegen-
erative disorders and can be seen on MRI, where they
images (Figure 30.2). Large artery stiffening and endothe- are defined as punctate homogeneous foci in the brain
lial dysfunction correlate with cognitive impairment and parenchyma of low signal intensity on T2-weighted
WML in elderly hypertensive subjects who present with images. It has been proposed that, depending on the
memory complaints, and the severity of WML is inversely location in the brain, CMB might have different aeti-
associated with memory function scores (5). ologies. Lobar microbleeds are seen in cerebral amyloid
Structural and Functional Aspects of Brain Damage 243
CEREBRAL ARTERIOSCLEROSIS
Figure 30.4 Lacunar infarct in the right thalamus
shown as a small hypointensity in brain magnetic reso- Lacunar infarction is the infarct subtype most closely
nance imaging. Axial plane, T1-weighted. and directly associated with hypertension due to its high
prevalence among clinical lacunar syndromes and the
244 Manual of Hypertension of the European Society of Hypertension
hypertensive lipohyalinotic changes seen in small pene- homocysteine metabolism and lipid metabolism, the angio-
trating vessels at necropsy (11). In other types of infarct, the tensin-converting enzyme (ACE) gene, and the endothelial
effect of hypertension is less direct and is mediated by its nitric oxide synthase gene, with conflicting results (18) that
effects on atherogenesis in large extracranial or intracranial may reflect methodological difficulties, since many studies
vessels. Lacunae are small infarcts, or occasionally, haem- were small and underpowered or required careful case-con-
orrhages related to Charcot-Bouchard microaneurysms. trol matching. Robust associations between candidate genes
The main current hypothesis on the association between and the occurrence of various features of cerebral small ves-
high BP and ischaemic WML is that longstanding hyper- sel disease, such as LI, intracerebral haemorrhage and WML,
tension causes lipohyalinosis of the media and thicken- have not yet been established (19).
ing of the vessel walls, with narrowing of the lumen of
the small perforating arteries and arterioles that nourish
the deep white matter (10). The perforating vessels, which
originate in the cortical and leptomeningeal arteries, HYPERTENSION, SMALL VESSEL DISEASE
have a relatively poor anastomotic system, which makes
the white matter vulnerable to cerebral ischemia. Low BP
AND COGNITIVE FUNCTION
has also been reported to be a risk factor for WML (10).
Hypertension may also cause disturbances in the blood- PATHOLOGICAL ASPECTS
brain barrier, leading to lesions in the white matter due
to cerebral oedema, the activation of astrocytes, and the The mechanisms by which vascular risk factors increase the
effects of destructive enzymes or other poisons which pass risk of cognitive impairment are not fully elucidated. As men-
through the damaged vessel walls (10). tioned, most of these factors, and especially hypertension,
Postmortem studies show that WML seen on MRI scans have been shown to be associated with subcortical lesions
are associated with degenerative changes in the arterioles seen on brain MRI: WML, LI, CMB (10,20) and EPS (21).
related to atherosclerosis, suggesting that cerebral arterio- Pathologically, this type of small vessel disease is prin-
sclerosis of the penetrating vessels is the main factor in the cipally characterised by loss of smooth muscle cells from
pathogenesis of ischaemic WML (10). Several studies have the tunica media, deposits of fibro-hyaline material, nar-
reported that WML are related to atherosclerosis, as indi- rowing of the lumen, and thickening of the vessel wall.
cated by increased common carotid intima-media thickness It is common and systemic, affects the kidneys and reti-
and carotid plaques, aortic atherosclerosis in abdominal nas, and is strongly associated with ageing, diabetes, and,
radiographs and arterial stiffness (12–14). In fact, arterial in particular, hypertension (10). For this reason, it is also
stiffness assessed using indicators such as the ankle-bra- named hypertensive small vessel disease.
chial index, pulse wave velocity, the cardio-ankle vascular On the other hand, there is increasing evidence con-
index and the augmentation index, is independently asso- necting cerebral hypoperfusion and neurodegeneration,
ciated with all components of cerebral small vessel disease specifically in Alzheimer’s disease and vascular dementia
including silent LI, WML and microbleeds (15). (1,22). In the Rotterdam Study (23), cerebral hypoperfu-
Several vascular risk factors have been linked with WML sion was shown to be either a risk or an aggravating factor
and it seems that the greater the number of vascular risk fac- in dementia. Chronic hypoperfusion is not only an epi-
tors for cerebrovascular disease, the greater the extent and phenomenon of brain tissue loss but actively promotes,
severity of WML. A review of more than 160 studies on WML initiates or accelerates neurodegeneration through mul-
found that, in studies with a multivariate analysis, diabe- tiple mechanisms, including the induction of oxidative
tes mellitus and hypertension were associated with WML, stress, amyloid beta accumulation and aggregation, tau
although the association with lipid abnormalities and smok- hyperphosphorylation, synaptic dysfunction, neuronal
ing was not so clear (10). WML have also been reported to loss, WML and neuroinflammation (24,25).
be associated with a history of stroke, LI, heart disease and
atrial fibrillation, which are frequently associated with both
hypertension and other vascular risk factors (10).
CHRONOPATHOLOGY
Long-term observational studies have reported that hyper-
ROLE OF GENETIC FACTORS IN THE tension during midlife increases the risk of cognitive
PATHOGENESIS OF VASCULAR CEREBRAL impairment later in life (3,26). In addition, there is some
evidence that antihypertensive drug treatment could play a
DAMAGE role in the prevention of cognitive impairment or vascular
A family history of cerebrovascular disease and stroke is dementia through BP control (27). By contrast, the effects
often perceived as a risk factor for stroke. The Framingham of late-life BP on the brain are complex and less clear. In
Heart Study found a positive association between a veri- fact, several studies, particularly in older individuals or
fied paternal or maternal history of stroke and an increased patients at high cardiovascular risk, suggest that lower BP
risk of stroke in offspring (16). Concordance rates in twin contributes to brain atrophy, cerebrovascular lesions and
studies have shown an almost fivefold increase in stroke more rapid cognitive decline (28).
prevalence in monozygotic twins compared with dizygotic
twins (17). However, the identification of individual caus-
ative mutations remains a challenge. The inheritance is CLINICAL ASPECTS
complex, multigenic, and heterogeneous. Associations with
polymorphisms have been investigated in a variety of candi- Cognitive impairment, defined as a progressive decline
date genes, including haemostatic genes, genes controlling in some cognitive functions that does not satisfy the
Structural and Functional Aspects of Brain Damage 245
diagnostic criteria of dementia, precedes at least 50% of 7. Potter GM, Doubal FN, Jackson CA et al. Enlarged perivascular
dementia onsets. Cognitive impairment may be assessed spaces and cerebral small vessel disease. Int J Stroke 2015; 10(3):
376–381.
by neuropsychological tests, as it is not necessarily evident 8. Huijts M, Duits A, van Oostenbrugge RJ et al. Accumulation of
in daily living. Cognitive decline can affect the memory or MRI markers of cerebral small vessel disease is associated with
other domains (perception, abstract thought, judgment, decreased cognitive function. A study in first-ever lacunar stroke
planning ability and attention). Dementia is characterised and hypertensive patients. Front Aging Neurosci 2013; 5: 72.
9. Begum A, Dewey M, Hassiotis A et al. Subjective cognitive com-
by an intellectual deterioration that includes memory loss plaints across the adult life span: A 14-year analysis of trends and
and one or more other neuropsychological alterations, associations using the 1993, 2000 and 2007 English Psychiatric
such as apraxia, agnosia and aphasia, which interfere with Morbidity Surveys. Psychol Med 2014; 44: 1977–1987.
social and occupational living. Mental alterations include 10. Pantoni L. Cerebral small vessel disease: From pathogenesis and
clinical characteristics to therapeutic challenges. Lancet Neurol
progressive memory loss, space and temporal disorienta- 2010; 9: 689–701.
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13. de Leeuw FE, de Groot JC, Oudkerk M et al. Aortic atherosclerosis
at middle age predicts cerebral white matter lesions in the elderly.
Stroke 2000; 31: 425–429.
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carotid arterial properties and cerebral white matter hyperintensi-
AND STROKE ties. Neurology 2017; 88: 2036–2042.
15. Saji N, Toba K, Sakurai T. Cerebral small vessel disease and arte-
Stroke is the third most-frequent cause of death after can- rial stiffness: Tsunami effect in the brain? Pulse (Basel) 2016; 3:
cer and heart disease in developed countries, and is one of 182–189.
16. Kiely DK, Wolf PA, Cupples LA et al. Familial aggregation of
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vascular dementia (29). High BP is a major risk factor for 17. Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD. A study of
stroke, and a continuous relationship between BP and the twins and stroke. Stroke 1992; 23: 221–223.
occurrence of stroke has been established (30,31). Cerebral 18. Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000;
123: 1784–1812.
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WML are an important prognostic factor for stroke, cog- vascular spaces are associated with cognitive function in healthy
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LARGE ARTERY DAMAGE:
MEASUREMENT AND 31
CLINICAL IMPORTANCE
PATHOPHYSIOLOGY OF CARDIOVASCULAR
PATHOPHYSIOLOGY OF LARGE ARTERY EVENTS
DAMAGE IN HYPERTENSION
A generally accepted mechanistic view is that an increase
in arterial stiffness causes a premature return of reflected
PATHOPHYSIOLOGY OF ARTERIAL STIFFNESS waves in late systole, increasing central pulse pressure and
AND WAVE REFLECTION thus systolic BP, and damages target organs (36). Systolic
BP increases the load on the left ventricle, increasing
Aortic stiffening accompanying age and cardiovascular myocardial oxygen demand. In addition, arterial stiff-
risk factors is caused by various phenomena, including ness is associated with left ventricular hypertrophy (LVH)
breaks in elastin fibres, cross-links of the elastin net- (5,31,35), a known risk factor for coronary events in nor-
work, accumulation of collagen, fibrosis, inflammation, motensive and hypertensive patients. The increase in
medial smooth muscle necrosis, calcifications and diffu- central PP and the decrease in diastolic BP may directly
sion of macromolecules within the arterial wall (13,17). cause subendocardial ischemia. The measurement of aor-
Although it is generally accepted that the major compo- tic stiffness, which integrates the alterations of the arterial
nents that contribute to arterial stiffening are extracellu- wall, may also reflect parallel lesions present at the site of
lar matrix (ECM) proteins such as elastin and collagens, the coronary arteries (6,12).
a second important component is vascular smooth mus- An increased arterial stiffness can increase the risk of
cle cells (VSMCs), the role of which has been underlined stroke through several mechanisms, including an increase
more recently (17). Indeed, both VSMC contraction and in central PP, influencing arterial remodelling at the site
changes in cell-ECM interaction, for instance through the of both the extracranial and intracranial arteries, increas-
architecture of cytoskeletal proteins and focal adhesions, ing carotid wall thickness and the development of steno-
can transfer the mechanical load from elastic components sis and plaques (24) and the prevalence and severity of
to stiff components, and thus increase the stiffness of the cerebral white matter lesions (8,38). The measurement of
wall material. aortic stiffness may also reflect parallel lesions present at
The stiffness of large arteries, including the aorta, repre- the site of cerebral vasculature. Thus, it is not surprising
sents the ability of large vessels to dampen the pulsatility that aortic stiffness is able to predict not only incident
of ventricular ejection and to transform a pulsatile pressure stroke (19) but also the functional outcome after stroke
248 Manual of Hypertension of the European Society of Hypertension
independent of classical risk factors (15). Another expla- usually obtained transcutaneously at the right common
nation is given by the differential input impedance in the carotid artery and the right femoral artery (i.e. ‘carotid-
brain compared with other systemic vascular beds (35). femoral’ PWV), and the time delay (Δt, or transit time) is
Finally, coronary heart disease and heart failure, which measured between the feet of the two waveforms (1,30,35)
are favoured by high PP and arterial stiffness, are also risk (Figure 31.1). The ‘foot’ of the wave is defined at the end of
factors for stroke (6,30). diastole, when the steep rise of the wave front begins. The
transit time is the time of travel of the ‘foot’ of the wave
over a known distance.
A variety of different waveforms can be used including
CLINICAL MEASUREMENTS OF ARTERIAL pressure (1,6,18), distension (3) and Doppler (11). The dis-
STIFFNESS AND WAVE REFLECTIONS tance (D) covered by the waves is usually assimilated to
the surface distance between the two recording sites, i.e.
Arterial stiffness can be evaluated at the systemic, regional the common carotid artery (CCA) and the common femo-
and local levels. In contrast to systemic arterial stiffness, ral artery (CFA). The direct distance (DD) is (CFA to CCA).
which can only be estimated from models of the circu- PWV is calculated as PWV = D (meters)/Δt (seconds).
lation, regional and local arterial stiffness can be mea- However, since the descending thoracic aorta is reached
sured directly and noninvasively at various sites along the by the pressure wave at the time another pressure wave,
arterial tree. A major advantage of the regional and local originating from the same cardiac contraction, arrives at
evaluations of arterial stiffness is that they are based on the carotid site, it has been recommended in a recent con-
direct measurements of parameters strongly linked to wall sensus paper (41) to measure the direct distance and apply
stiffness. Reviews have been published on methodologi- a 0.8 coefficient to take into account the shorter pathway
cal aspects (20,25). Table 31.1 gives the main features of of the pressure.
the various methods currently available, their respective Multiple devices using pressure waveforms recorded
advantages, and their theoretical, technical and practical simultaneously are validated to provide automated mea-
limitations (25). surement of PWV (25). Pressure waves can also be recorded
successively from different sites, and transit time deter-
mined from the R wave of the ECG. In order to increase ease
REGIONAL MEASUREMENTS OF ARTERIAL and acceptability, automatic cuff-based methods have been
STIFFNESS developed. Brachial-ankle PWV (baPWV) is calculated from
travelled distance and transit time, as described previously.
The aorta is a major vessel of interest when determining The measurement of baPWV includes a much longer trajec-
regional arterial stiffness for at least two reasons: the tho- tory of the pressure wave along the muscular arteries of the
racic and abdominal aorta makes the largest contribu- upper and lower limbs than along the aortic pathway, and
tion to the arterial buffering function (31,35), and aortic thus may not reflect the true ageing of the aorta. However,
pulse wave velocity (PWV) is an independent predictor the main assumption of the baPWV method, as well as other
of outcome in a variety of populations (11,18,27,28,30). two-site methods, is that the transit times of the pressure
However, all arterial sites have potential interest. Indeed, waves in the upper and lower limbs were comparable, and
the forearm circulation is where blood pressure is com- the impact of upper and lower limb pathways on aortic stiff-
monly measured, and the lower limb arteries are spe- ness measurement is limited (22). Thus, the net transit time
cifically altered by atherosclerosis. Measurement of local that is measured reflects mainly the aortic pulse transit time.
carotid stiffness may also provide important prognostic Using a similar cuff-based methodology for detecting the
information, since the carotid artery is a frequent site of pressure waveforms and an ECG recording, a cardio-ankle
atheroma formation. PWV can be calculated. The transit time can also be mea-
sured between two flow pulses simultaneously recorded by
continuous Doppler probes (11) or again sequentially with
TWO-SITE PULSE WAVE VELOCITY MEASUREMENTS ECG gating. The finger-toe PWV method is based on similar
The measurement of PWV is generally accepted as the most assumptions as brachial-ankle devices (32).
simple, noninvasive, robust and reproducible method with
which to determine arterial stiffness. Carotid-femoral
PWV is a direct measurement, and it corresponds to the SINGLE-SITE PULSE WAVE VELOCITY
widely accepted propagative model of the arterial system MEASUREMENTS
(30,35). Measured along the aortic and aortoiliac path- An increasing number of methods calculate PWV over a
way, it is the most clinically relevant, since the aorta and given arterial pathway from the analysis of the brachial
its first branches are what the left ventricle ‘sees’, and is pressure wave. Brachial pressure wave is determined with
thus responsible for most of the pathophysiological effects a brachial cuff. PWV is thus referred to as ‘single-site’ or
of arterial stiffness. Carotid-femoral PWV has been used ‘brachial cuff ’−derived PWV, and apparatus as ‘brachial
in epidemiological studies demonstrating the predictive cuff ’−based devices. As detailed later, PWV is estimated
value of aortic stiffness for CV events. from various parameters that are either measured or esti-
PWV is the speed of wave travel (C o) and intrinsically mated, but PWV is not directly measured between two arte-
represents arterial stiffness, according to the Bramwell- rial sites.
Hill formula: C o = √(V.dP/ρ.dV), where dV is the change Ambulatory measurement of BP and continuous moni-
in arterial volume (V), dP is the change in pressure driv- toring of ECG over 24 hours can be used to calculate the
ing the change in volume, and ρ is the density of fluid. QKD interval (25). The Arteriograph® system estimates
Aortic PWV is usually measured using the foot-to-foot PWV from a single-site brachial-cuff oscillometric deter-
velocity method from various waveforms (1). These are mination of the suprasystolic waveform at the brachial
Large Artery Damage 249
Table 31.1 Devices and methods used for determining regional, local and systemic arterial stiffness
Regional Stiffness
2002 Omron VP-1000® Pressure cuffs Aorta, ba PWVb Yes (2005) +++ Yes
2007 CAVI-VaSera® ECG + Pressure cuffs Aorta, ca PWVb Yes (2014) +++ Yes
Local stiffness
Systemic stiffness
Source: Adapted from Laurent S et al. Can J Cardiol 2016; 32: 669–679, with permission.
a Apparatus used in pioneering epidemiological studies showing the predictive value of aortic stiffness for CV events.
b cf, carotid-femoral; ba, brachial-ankle; ca, cardiac-ankle; aa, aortic arch; ft, finger-toe; PWV, pulse wave velocity.
d All superficial arteries, including particularly those mentioned; Ao, aorta; CCA, common carotid artery; CFA, common femoral artery; BA, brachial artery; RA,
radial artery; AA, ascending aorta; DA, descending aorta. FDA means agreement by FDA for the market, which is necessary for use in routine clinical practice,
but is not necessary for use in research centres. NA means not applicable. All apparatus have CE agreement by the European Community.
250 Manual of Hypertension of the European Society of Hypertension
CLINICAL IMPORTANCE
Common ΔL
femoral ARTERIAL DAMAGE IN HYPERTENSION AND
artery ASSOCIATED CLINICAL CONDITIONS
patient. Indeed, measurement of arterial stiffness may 21. Laurent S, Briet M, Boutouyrie P. Arterial stiffness and central
avoid patients being mistakenly classified as being at low pulse pressure as surrogate markers: Needed clinical trials.
Hypertension 2012; 60: 518–522.
or moderate risk, when they actually have an abnormally 22. Laurent S, Mousseaux E, Boutouyrie P. Arterial stiffness as an imag-
high arterial stiffness or central PP placing them within a ing biomarker: Are all pathways equal? Hypertension 2013; 62: 10–12.
higher risk group. 23. Laurent S, Boutouyrie P. On behalf of the Mechanism Vascular
Study Investigators. Dose-dependent inward arterial remodeling
and destiffening after olmesartan in hypertensive with metabolic
syndrome. Hypertension 2014; 64: 709–716.
24. Laurent S, Boutouyrie P. The structural factor in hypertension:
ACKNOWLEDGEMENTS Large and small artery alterations. Circ Res 2015; 116: 1007–1021.
25. Laurent S, Marais L, Boutouyrie P. The non-invasive assessment of
This work was supported by INSERM, Assistance-Publique vascular aging. Can J Cardiol 2016; 32: 669–679.
26. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines
Hopitaux de Paris, and Paris Descartes University. for the management of arterial hypertension: The Task Force for
the management of arterial hypertension of the European Society
of Hypertension (ESH) and of the European Society of Cardiology
(ESC). Eur Heart J 2013; 34: 2159–2219.
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4. Bossuyt J, Engelen L, Ferreira I et al. Reference intervals for 2010; 121: 505–511.
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8. Brisset M, Boutouyrie P, Pico F et al. Large vessel correlates of Hypertension. Lancet 2016; 388: 2665–2712.
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9. Campo D, Khettab H, Yu R et al. Measurement of aortic pulse Carotid-Femoral Pulse Wave Velocity in the Reference Values for
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MICROCIRCULATION
32
role of an increased lumen ration in the resistance vascu- alpha receptor stimulation (31). From a pathophysiologi-
lature, which maintains the elevated peripheral resistance cal perspective, changes in TPR in response to low/mod-
in hypertension. This is based on calculating resistance est stimulation appear to be a relevant parameter of TPR
from pressure and flow recordings and consequently cal- reactivity. More marked stimulation leading to five- or six-
culating an arbitrary radius from the fourth route of 1/R fold increases in TPR may lead to increased responsiveness
(Poiseuille’s law). The calculations indicate a constant nar- but these are unlikely to be relevant for the maintenance
rowing in vessel radius from maximal dilatation to maxi- or development of most hypertension. In other words, in
mal constriction in hypertension, which acts to amplify vivo studies do not actually support the hypothesis that
changes in resistance. This has been very controversial. A structural changes amplify vasoconstrictor responses
number of studies have consistently reported structural throughout the circulation.
changes predicted and described previously in small arter-
ies with an internal diameter between 200–300 µg from
patients with essential hypertension and in various animal
models with the disease. Such reports should strengthen REMODELLING AND HYPERTROPHY IN
this amplifier theory. However, direct supporting evidence THE CIRCULATION
needs the measurement of the lumen diameter of blood
vessels demonstrated to contribute to the control of resis- To understand how hypertension produces non-hyper-
tance in a vascular bed but under extremely rigorous con- trophic changes in small arteries, one must look at the
ditions (29). In this context, particular emphasis should be physiological role of the resistance vasculature. At normal
placed on measurement of diameter made at physiologi- pressures, these vessels exhibit a level of contraction (myo-
cal levels of tone. This has been carried out using studies genic tone), which is independent of neurohormonal influ-
of functional and structural characteristics of small mes- ences, and in functioning in this way the response enables
enteric arteries cannulated and pressurised in vitro. Such arteries to constrict or dilate in response to changes in
arteries have spontaneous myogenic tone at physiologi- upstream pressure. This process, known as the myogenic
cal pressures, which is a major determinant of diameter response, is only observed in smaller resistance arteries,
in the resistance vasculature unlike the upstream mesen- which mediate autoregulation of blood flow and stabilise
teric arteries frequently studied in hypertension research. capillary pressure. This ensures that target organs down-
Distal mesenteric arteries were pressurised to 63% of the stream are supplied with oxygenated blood at a constant
mean aortic pressure of each rat. It is the pressure recorded flow and pressure. Hypertrophy is observed in vessels
at this level of the mesenteric/intestinal vasculature in which do not possess myogenic tone, whereas in smaller
both rat strains indicating a location within the resistance resistance arteries, initial increase in pressure will bring
vasculature. In the absence of tone, SHR vessels had a about an increased myogenic constriction. If an individ-
reduced lumen diameter, although this was of borderline ual has untreated hypertension, then there will be pro-
significance. Nevertheless, a clear increase in wall lumen longed myogenic constriction as the resistance vasculature
ratio was observed. However, with spontaneous myogenic endeavours to protect the target organs downstream from
tone, lumen diameter became identical in the two strains, pressure-induced damage brought about by an increase in
and importantly remained identical as tone was increased blood flow. Prolonged vasoconstriction will lead to inward
throughout the complete noradrenaline concentration eutrophic remodelling and/or a reduced arterial distensi-
response curve (30). Such data do not support the hypoth- bility. The structural difference between large-conduit and
esis of an increased wall lumen ratio acting as an ampli- medium-sized arteries and downstream resistance vessels is
fier in hypertension. Studies in isolated segments of small apparent in many models of hypertension; for example, in
arteries or in isolated intact vascular beds can provide clear a hypertensive model brought on by chronic NO synthase
insights into basic mechanisms; however, these can only inhibition. In addition, the magnitude and duration of an
be considered as hypothesis-generating regarding the rele- increase in intraluminal pressure plays a role in determin-
vance of a particular mechanism. Surprisingly few studies ing the remodelling response.
have actually been carried out to date in intact conscious
animals, and overall the results are not consistent with
an amplifier hypothesis. In one of these, blood pressure
and total peripheral resistance responses to infusion of MOLECULAR MECHANISMS RESPONSE
the alpha agonist phenylephrine at two rates at the devel- FOR EUTROPHIC REMODELLING
opment phase of hypertension in SHRs aged 8–26 weeks
was compared with age-matched Wistar Kyoto (WKY) rats Eutrophic inward remodelling is a process of structural
before and after ganglionic blockade. At 16 weeks of age, adaptation observed in most forms of hypertension,
more complete dose-response curves to the alpha agonist including the onset of hypertension and milder hyperten-
methoxamine were constructed. Total peripheral resis- sive states. However, a few animal models of hyperten-
tance (TPR) responses to phenylephrine were significantly sion, such as a model developing hypertension independent
less in SHRs versus WKY rats at all ages in the study. The of the renin–angiotensin system (BPH-2 mice), demon-
higher infusion rate increased mean arterial pressure by strate hypertrophy as the predominating structural change.
approximately 80 mmHg and nearly doubled the TPR. In Inward eutrophic remodelling is a relatively fast functional
contrast, blood pressure and TPR responses to methox- adaptation observed after prolonged vasoconstriction and
amine were enhanced in SHRs in low rates of infusion but is thought to be an energetically favoured mechanism to
did not differ at the higher rates. Assuming that methox- preserve a lumen diameter for long periods. The process is
amine is the most specific alpha agonist, these results are also the preferred physiological mechanism by which wall
suggestive for functional rather than structural changes stress can be normalised while maintaining vasomotor
being contributory to the hyper-responsiveness to modest tone. Studies of the well-characterised TGR(mREN2)27
256 Manual of Hypertension of the European Society of Hypertension
rat, which develops fulminant hypertension from 4 weeks hypertrophy. These patients were selected as already hav-
of age, have demonstrated that eutrophic inward remodel- ing evidence of downstream target-organ damage because
ling occurs from 4 weeks and is dependent on the integrin they demonstrated microproteinuria and their myogenic
aVβ3, a multifunctional extracellular matrix (ECM) recep- tone was disordered (34). In other words, the onset of
tor (32). However, hypertrophy does begin to appear hypertrophy is a consequence of disruption of normal
between 6 and 8 weeks of age. This is important and is myogenic tone and the delivery of blood at a higher
discussed later. The ECM of resistance arteries is subject to perfusion pressure causing cellular damage. In the kidney,
tensile force exerted by blood pressure, which is trans- this would inevitably lead to a loss of filtration capability
ferred through integrins across the cell membrane and and protein leak. In terms of cardiovascular risk, recent
linked by molecular complexes to the cytoskeleton. data from Italy have demonstrated that there is an
Specific integrin subtypes are utilised initially for the increased risk of development of cardiovascular events in
mechanotransduction of pressure. Using peptides and spe- patients whose small arteries demonstrate hypertrophy
cific antibodies, it has been shown that integrins αVβ3 and rather than eutrophic inward remodelling (35). In vitro
α5β1 indirectly regulate the myogenic response by influ- studies support these considerations. It has been demon-
encing the control of calcium flow through ion channels; strated that the myogenic response of the middle cerebral
α5β1 is responsible for the initial calcium influx required artery from pre-stroke spontaneously hypertensive stroke-
to establish vascular tone, and αVβ3 mediates force main- prone rat (SHRSP) are impaired compared with the spon-
tenance by calcium sensitisation of contractile compo- taneously hypertensive rat (SHR) (36). This observation
nents. These integrins can form complexes which regulate would explain the deranged cerebral autoregulation that
cytoskeletal dynamics and maintain a vascular myogenic has been observed in the SHRSP before stroke occurs.
force at a given pressure (33). This is ameliorated if there is Also, this is associated with a redistribution of collagen
cytoskeletal disruption. Cytoskeletal proteins such as throughout the blood vessel wall. Other studies have dem-
heat-shock protein 27 (HSP27) activated by RhoA kinases onstrated that the myogenic component of renal autoregu-
have been shown to regulate myogenic tone. It is now clear lation is impaired in the fawn-hooded rat (FHR) (the
that RhoA signalling plays a central role in both calcium tubuloglomerular feedback component of renin autoregu-
sensitisation and regulation of actin dynamics in small lation is unchanged) compared with controls, thereby
artery remodelling. In contrast to molecular signalling causing glomerular hypertension and hyperfiltration,
mechanisms behind the vascular myogenic response, rela- which explains why the kidneys are susceptible to the del-
tively few data are available on the role of integrins and the eterious effects of moderate hypertension (37).
underlying biochemical pathways of the next stage of vas- Furthermore, the Brown Norway rat is normotensive but
cular adaptation for hypertension, which is the migration has a greater than normal life expectancy. However, when
of vascular smooth muscle cells towards a narrow lumen. hypertension is induced, these animals have a high inci-
Remodelling involves a migratory process following pro- dence of cerebral haemorrhage and mortality compared
longed vasoconstriction whereby existing vascular smooth with the Long-Evans rat (38). Also, the Brown Norway rat
cells reposition themselves in the vascular wall and thereby is very sensitive to hypertension-induced renal injury, and
produce a narrow lumen. A characteristic of migrating recently the myogenic component of renal autoregulation
cells in vitro is the presence of lamelopodial and filopodial has been found to be abnormal in normotensive Brown
protrusions containing focal adhesion kinase (FAK) which Norway rats (39). In vitro studies have demonstrated that
provide a substrate for other cytosolic proteins such as SrC the myogenic properties of middle cerebral arteries from
and interact with actin-associated cytoplasmic compo- the Brown Norway rat are impaired compared with the
nents. Recently it has been shown that the migration of Long Evans, which would explain the susceptibility of the
vascular smooth muscle cells of arteries in vivo is more Brown Norway rat to hypertension-induced cerebral
subtle, and is limited to elongation of tape in smooth mus- haemorrhage (40). Inhibition of the renin–angiotensin
cle cells and an increase in cellular overlap. It is thought system markedly delays the development of cerebral
that cytoskeletal rearrangements in subsequent force gen- haemorrhage and mortality in salt-loaded SHRSP (41). In
eration play a central role in these changes. The exact cel- the FHR, early angiotensin-converting enzyme (ACE)
lular signalling system is still unclear. Integrin αVβ3 is inhibition prevents renal damage, and this protection is
necessary for the pressure-induced inward remodelling associated with a normalisation of glomerular pressure
process but the rest of the biochemical sensing mechanism (42). The protective effect of ACE inhibition in the kidney
is still unclear. If the physiological response to a raised has been presumed to be a consequence of an inhibition of
blood pressure in small arteries is eutrophic inward remod- angiotensin II−induced efferent arteriolar myogenic tone.
elling, then the integrity of the circulation appears to be Of course, it could be argued that the effects of blood pres-
preserved until this breaks down. As indicated previously, sure lowering would be important on stroke development,
in the TGR(mREN2)27 rat there is evidence of the develop- and in consequence ACE inhibition is working by its anti-
ment of vascular wall hypertrophy in small arteries from hypertensive effects. However, dexamethasone or thyrox-
week 6 onwards. This rat model of hypertension develops ine increased blood pressure in the SHRSP to a greater
a severe form of the disorder, and indeed dams are unable extent than salt loading but stroke does not occur (43).
to breed if they do not receive antihypertensive medica- Also, the anti-stroke effect of captopril on salt-loaded
tion. Therefore, against this background it would appear SHRSP which occurs without an antihypertensive effect
that the breakdown of autoregulation (at the myogenic is unchanged when blood pressure is increased with
tone) is associated with the vascular wall developing a dexamethasone (43). Therefore, it seems that the renin−
growth response (hypertrophy) in an attempt to offset angiotensin system inhibition improves myogenic
the increased wall stress. Recent work on the small blood responses, and survival in salt-loaded SHRSP is largely
vessels of patients with type 2 (maturity onset) diabetes independent of changes in blood pressure, although this
mellitus has demonstrated that there is vascular wall remains to be confirmed.
Microcirculation 257
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ENDOTHELIAL DAMAGE
33
The reduced availability of NO observed in most of cytokine production (20). The contribution of mtROS to
these conditions was thought to depend upon a switch the global levels of ROS within endothelial cells might
in signalling from a NO-mediated silencing of cel- be particularly important in some conditions, including
lular processes toward activation by redox signalling obesity and diabetes mellitus as well as in physiological
(Figure 33.1). Reactive oxygen species (ROS), mainly ageing. In obesity and diabetes mellitus, an altered bal-
superoxide anions, are unstable molecules that can rap- ance between nutrient availability and demand for ATP
idly bind NO to form the highly reactive intermediate in favour of the former might cause a decrease in the
peroxynitrite (ONOO −). Thus, endothelial dysfunction rate of electron flow that prolongs the lifespan of reac-
is characterised by an increased consumption of NO and tive intermediates at Complexes I and III, ultimately pro-
formation of nitroso-compounds (16). This has multiple ducing a higher amount of superoxide anion (19,21). In
negative effects: reducing NO availability, having direct ageing, instead, several pieces of evidence suggest that
vasoconstrictor and cytotoxic effects and impairing the the mitophagy, the mechanism used by cells to eliminate
activity of the eNOS (16). Various enzymatic and non- damaged and dysfunctional mitochondria, is defective,
enzymatic sources of ROS have been described to be acti- leading to accumulation of dysfunctional mitochondria
vated in dysfunctional endothelial cells, smooth muscle that produce a larger amount of mtROS during their
cells and inflammatory cells within the arterial wall of physiological activity (22). Recent evidence seems to
patients exposed to cardiovascular risk factors, including confirm the key role of mtROS in mediating endothe-
nicotinamide adenine dinucleotide phosphate (NADPH) lial cell dysfunction by reduction of NO availability. In
oxidase, cyclooxygenase, xanthine oxidase and the same diabetic patients, circulating leukocytes and arterioles
eNOS (17) (Figure 33.1). The latter can contribute to ROS isolated from subcutaneous fat display higher mitochon-
generation when uncoupled, producing either anion drial ROS production and membrane hyperpolarisation
superoxide when there is a deficiency of its key cofac- (23,24). Furthermore, impaired endothelium-dependent
tor tetrahydrobiopterin, or hydrogen peroxide when its vasodilation in freshly isolated arterioles from patients
substrate l-arginine is deficient (18). Mitochondria ROS with diabetes is reversed by mild membrane depo-
(mtROS) has been identified as a major contributor to larisation or mitochondria-targeted antioxidants (23).
cellular ROS during endothelial cell activation. mtROS is Vascular dysfunction with age is a consequence of exces-
generated at Complex I and Complex III in the mitochon- sive superoxide-related oxidative stress, much of which is
drial electron transport chain (19) and, while historically of mitochondrial origin (25). Preclinical findings show
considered a toxic by-product of mitochondrial metabo- that oral supplementation of MitoQ (a potent mitochon-
lism, recent evidence suggests that it can act as a signal- drial targeted antioxidant) restores age-related decrease
ling molecule, directly contributing to proinflammatory of endothelial-dependent vasodilation in old mice (25),
Aggregation Inhibition
Platelets
Shear
TGFβ1 stress
Renin Thrombin AT-II Ach
ADP ET 5-HT Bk
T AT1 M P ETB S1 BK
Renin
Mitocondria
NADPH-oxidase PGI2 EDHF
ATG AT-I eNos NO
Cyclooxigenase Xanthine-
ACE ET-1 oxidase L-Arg
Endothelium
ETB TX
ETA cGMP
AT1 cGMP K+ Smooth
muscle
cells
Contraction
Relaxation
Figure 33.1 Molecular mechanisms involved in endothelial cell activation. Nitric oxide (NO) and other endothelium-
derived factors and their role in vascular homeostasis.
Endothelial Damage 263
and similar results have been reported in skeletal mus- Activated endothelial cells increase their expression of
cle feed arteries biopsied from older adult humans (26). selectins, VCAM-1, and intercellular adhesion molecule-1
Collectively, this evidence suggests that mtROS might (ICAM-1) (29,30). These molecules promote the adherence
represent an important therapeutic target to prevent or and migration of monocytes from the bloodstream to the
reduce endothelial cell damage related to exposure to subendothelial space, representing early events in the for-
some cardiovascular risk factors. mation of the atherosclerotic lesions (31) (Figure 33.2).
In the attempt to compensate for NO deficiency, endo- With prolonged or repeated exposure to cardiovascular
thelium-dependent vasodilation is partially maintained risk factors, the chronic activation of endothelial cells and
by the production of endothelium-derived vasodilators the switch to a pro-oxidant phenotype of the intracellu-
other than NO, such as prostanoids and other endothe- lar machinery may exhaust the capacity of cellular enzy-
lium-derived hyperpolarising factors (27). Endothelin-1 matic and nonenzymatic antioxidants, inducing further
(ET-1), by contrast, is a potent vasoconstrictor and mito- progression of the endothelial damage. In these condi-
genic peptide produced by endothelial cells, the expres- tions, the excess of ROS compared to the reduced antiox-
sion of which is normally upregulated in conditions of idant capacity can promote the interaction of ROS with
endothelial dysfunction. In essential hypertension, for all major intracellular macromolecules (lipids, proteins
example, it is possible to observe a relative increase of ET-1 and nucleic acids), favouring the loss of cellular integ-
vasoconstrictor tone compared to the vasodilatory effects rity and early cellular ageing. The increased formation of
of NO (28) (Figure 33.1). peroxynitrite (ONOO−) (Figure 33.2), resulting from the
Healthy endothelium
↓ ROS
NO NO NO NO ↓ EMPs
NO NO NO ↑ NO
NO
↓ S-Adhesion molecules
NO NO O NO
NO NO NO N ↓ Nitrotyrosines, MDA, etc.
Foam cells
Figure 33.2 Progression of endothelial damage. In normal vascular physiology, nitric oxide (NO) plays a key role in
maintaining the vascular wall in a quiescent state by inhibition of inflammation, cellular proliferation and thrombosis.
Exposure to cardiovascular risk factors switches the signal toward a pro-oxidant/-inflammatory state. Endothelial cells
adopt an activated phenotype, characterised by reduced NO availability, increased production of nitroperoxides (NOO−•)
and expression of cellular adhesion molecules. These events promote migration of inflammatory cells in the subendothelial
space and lead to initial endothelial cell damage, with release of endothelial microparticles (EMPs). In cases of prolonged
and/or repeated exposure to cardiovascular risk factors, endothelial cell damage progress leads to endothelial cell senes-
cence. Damaged endothelial cells detach from the vascular wall (circulating endothelial cells [CECs]) and are only partially
replaced by endothelial progenitor cells (EPCs) due to their dysfunctional/aged phenotype. This promotes accumulation of
further inflammatory cells in the subendothelial space that, following accumulation of lipids, sustains the local inflamma-
tory process by producing proinflammatory cytokines. This sequence of events ultimately leads to plaque formation.
264 Manual of Hypertension of the European Society of Hypertension
interaction between ROS and NO, leads to nitrosylation classic risk factors for atherosclerosis, alteration of endothe-
of cellular proteins, forming nitrotyrosine. This is used as lial/subendothelium cellular adhesion molecules, defec-
a robust marker of cellular oxidative stress (32–34), and tive binding to anchoring matrix proteins, and cellular
its concentration is increased after exposure of endothelial apoptosis with decreased survival of cytoskeletal proteins
cells to several activating stimuli (including TNF-α (35), (69,71,72). In normal steady-state conditions, the number
oxidized LDL (35), hypoxia (36) and altered shear stress of CECs in the bloodstream is very low, as endothelial
(37)) as well as with ageing in animal models (38–40) turnover is a very slow process in the absence of pathologi-
and in arterial endothelial cells of humans (41). In addi- cal stimuli, and nonviable CECs are rapidly cleared by the
tion to the nitration of tyrosine, which is irreversible, aged reticuloendothelial system. The level of CECs is expected
arteries also exhibit markers of lipid peroxidation such as to increase as a consequence of any type of damage to the
4-hydroxynonenal (4-HNE) or malodialdehyde (MDA) vessel wall (73). Indeed, several studies have demonstrated
and/or another reversible regulatory oxidative stress an increased number of CECs in patients with numerous
marker, glutathionylation, at cysteine residues (42–45). clinical conditions characterised by vascular involvement,
The ROS-mediated damage to major intracellular compo- ranging from cardiovascular risk factors (e.g. diabetes mel-
nents alters several cellular functions, ultimately resulting litus) (74), immune-mediated vasculitides (75) and sickle
in endothelial cell senescence or apoptosis and detach- cell disease crisis (76) to systemic infections (77). Based
ment of endothelial cells from the vascular wall. on this background, the level of CECs can be taken to
Circulating markers of this endothelial damage include represent an indicator of the ongoing systemic endothe-
endothelial microparticles (EMPs), and whole endothe- lial damage. While the number of CECs was considered a
lial cells (46,47) (Figure 33.2). Microparticles (MPs) are promising marker to characterise endothelial damage and
cell membrane-shedded submicron fragments ranging the risk of cardiovascular disease until a few years ago,
from 0.1−1.0 µm containing information such as mRNA, several drawbacks have limited its development in clinical
microRNAs (miRNAs), receptor, and specific proteins of the practice. Firstly, their very low numbers and complex phe-
parent cell. MPs are expressed by cells during cellular stress notype make their detection extremely difficult in periph-
and activation (48). Like other microparticles, endothe- eral blood, and several published techniques have shown
lial microparticles (EMPs) are anucleated vesicles formed different degrees of variability, reporting a wide range of
following cytoskeletal and membrane reorganisation, CEC values (0–7900 CEC/mL) in healthy subjects (78–82).
released in response to cell activation, injury, angiogenesis/ Secondly, CECs may also derive from sites of incompetent
neovascularisation and/or apoptosis (49). Ischaemia (50), angiogenesis, where tissue endothelial cells proliferate and
TNF-α (51), other inflammatory cytokines (52), reactive organise into immature leaky tubular structures that come
oxygen species (52), plasminogen activator inhibitor (53), into contact with the bloodstream (83). In these cases,
thrombin (54), camptothecin (55), C-reactive protein (56) CECs might represent a marker of endothelial cell prolif-
and uremic toxins (57) can induce in vitro EMP generation. eration rather than damage. Moreover, enhanced release
Conversely, endogenous NO dampens the release of EMPs of CECs might also take place during normal body growth
produced after stimulation with C-reactive protein (56). or at sites of tissue regeneration, either physiological (e.g.
Previous studies found elevated EMPs in several disease after menstruation) or pathological (e.g. wound healing).
conditions, including pre-eclampsia (58,59), severe hyper- Because of these limitations, the importance of CEC as
tension (60), acute coronary syndromes (61) and stroke markers of endothelial damage has been reconsidered,
(62). In patients with documented endothelial dysfunc- and not many studies have been published exploring their
tion, levels of circulating EMP are inversely correlated with capacity to predict evolution or reflect the severity of car-
the amplitude of flow-mediated dilatation, independently diovascular disease or endothelial dysfunction.
of age and blood pressure values (63–66). This evidence
suggests EMPs represent a reliable marker of pathological
processes involving the endothelium. Initially, EMPs were MECHANISMS INVOLVED IN ENDOTHELIAL
simply considered markers of endothelial cell activation REPAIR
and damage. More recently, it became clear that EMPs can
play a major role in inflammation, thrombosis and angio- The severity of endothelial damage depends not only on
genesis (67). These functions are mediated by the array of the extent of the injury, but also on the endogenous capac-
diverse molecules on their surface (with functions encom- ity for repair. While endothelial cells can replicate locally
passing coagulation, cell survival, inflammation, enhanced and replace those lost or damaged after endothelial injury,
oxidative stress, adhesion, proteolysis, remodelling, angio- it has been suggested that this mechanism of repair is not
genesis and tumour growth), as well as by their intracel- efficient enough to ensure endothelial integrity, particu-
lular proteins, nucleic acids and organelles. Once released larly when the endothelium is chronically exposed to the
into circulation, EMPs can thus exert functional effects on injurious action of cardiovascular risk factors (84). Over
cellular targets through surface membrane interactions the last 20 years, circulating endothelial progenitor cells
and/or fusion and delivery of its intravesicular cargo (68). (EPCs) have been identified as an effective and alternative
Circulating endothelial cells (CECs) are another marker mechanism for maintenance and repair of the damaged
which has been used to quantify endothelial damage, endothelium (85) (Figure 33.2). Endothelial progenitor
considering their number directly relates to the amount of cells originating from either bone marrow or other tissues
apoptotic endothelial cells in the vascular wall (69) (Figure (e.g. spleen, vessel wall, adipose tissue, placenta, etc.), have
33.2). They were first detected in the 1970s in smears of been classified into hematopoietic and nonhematopoietic
peripheral blood on the basis of their presumed morphol- progenitor cells (86). Several different phenotypes of EPCs
ogy (70). The mechanism of circulating endothelial cell have been identified based on the expression of different
detachment is only partially understood and is complex, surface antigens. Importantly, EPCs with different surface
involving many factors, such as mechanical injury, the phenotypes have shown the capacity to influence multiple
Endothelial Damage 265
aspects of the vascular biology, suggesting that these cells intracoronary infusion of substances that can cause vaso-
might have pluripotent functions and that their functional dilation through endothelial-dependent (acetylcholine)
destiny is defined by the biological niche where they are or -independent pathways (nitrates, papaverine). While in
called to operate. Irrespective of their origins and multiple healthy subjects the intracoronary infusion of endothe-
influences on the vascular biology, the most important lial agonists produces vasodilation, a paradoxical vaso-
characteristic of these cells is that they are capable of dif- constriction to acetylcholine of the epicardial arteries is
ferentiating into endothelial cells under specific conditions commonly observed in the presence of endothelial dys-
(85,87,88) and can contribute to the formation of capillary- function, due to the direct effect of the stimulating fac-
like networks (89). Multiple factors (cytokines released by tor on the smooth muscle rather than the endothelial cells
target tissue, growth factors, sex hormones, etc.) mobilise (96). This response was observed in essential hypertensive
EPCs to migrate from the bone marrow stroma into the patients also in the absence of angiographically detectable
blood circulation. As one of the most important factors reg- lesions (97–99).
ulating EPC mobilisation is NO and the activity of eNOS In healthy arteries, stimulation of endothelial α 2-
(90), the number of recruited EPCs can be impaired in adrenergic receptors due to activation of the sympathetic
patients with cardiovascular risk factors, thus contributing nervous system leads to release of NO and endothelium-
to the endothelial damage by reducing the repair capacity derived hyperpolarising factors, resulting in vasodilation.
of the endothelial monolayer. Indeed, the number of circu- In the presence of endothelial dysfunction, by contrast, the
lating EPCs is negatively associated with the Framingham activation of α1-adrenergic receptors on smooth muscle
risk score (91) and positively related to endothelial func- cells dominates the vascular response to the sympathetic
tion assessed at the level of both brachial (91) and coronary stimulation. Thus a reduced vasodilation with papaverine
arteries (92) in healthy subjects (91) as well as in patients administration (100), exercise (101) or cold pressure test
with coronary artery disease (93). The capacity of EPC to (102) is observed in patients with hypertension, mirroring
reflect endothelial health and damage is also confirmed the responses to acetylcholine (103).
by the evidence that many drugs used in cardiovascular
prevention and able to improve endothelial function also CORONARY MICROCIRCULATION
show positive effects on the circulating number of EPCs The measurement of coronary blood flow by Doppler flow
(94). Thus, current evidence supports the hypothesis that wires enables assessment of endothelial function in the
a reduced number of EPC marks both a deficient vascular coronary microcirculation by quantitative angiography
repair and a state of endothelial damage. during the intracoronary infusion of various endothelium-
dependent (acetylcholine and substance P) or -indepen-
dent (sodium nitroprusside and nitroglycerin) vasodilators
(104). The concomitant intracoronary infusion of NG -
METHODS FOR ASSESSING mono-methyl-l-arginine (L-NMMA, a potent inhibitor of
ENDOTHELIAL FUNCTION/DAMAGE the eNOS) also provides the opportunity to establish the
proportion of the vasomotor response due to the activity
of the eNOS and thus the NO availability (105). Although
VASCULAR REACTIVITY TESTS this test directly assesses coronary circulation, its invasive
nature limits its use to patients with advanced disease and
Early endothelial damage expressed in altered endothelial precludes repeated testing during serial follow-up. While
function is usually assessed by vascular reactivity studies other, noninvasive techniques are available to assess endo-
(95), defining the severity of the compromised response thelial function of the coronary microvasculature (includ-
of the endothelial cells to stimulating or inhibiting sub- ing positron emission tomography, myocardial perfusion
stances in several vascular regions and measuring the imaging and echocardiography) (104), the radiation expo-
vessel changes induced by experimental perturbation. sure, the reduced availability of the machines used for
Responses can be evaluated in the macrocirculation (bra- their assessment, the questionable reproducibility and
chial, radial, femoral and epicardial arteries) and microcir- the need for systemic administration of endothelial ago-
culation (peripheral muscle, subcutaneous or skin tissue, nists and antagonists limit their use in clinical practice.
coronary microcirculation). Nevertheless, it was shown that endothelial function in
coronary microcirculation has prognostic value in patients
with established coronary disease (100).
CORONARY EPICARDIAL AND MICROVASCULAR
FUNCTION
The first demonstration of endothelial dysfunction was PERIPHERAL TECHNIQUES FOR ASSESSING
obtained in atherosclerotic epicardial vessels by the intra- ENDOTHELIAL FUNCTION
coronary infusion of acetylcholine in 1986 (96). Although
tests of endothelial function in the coronary arteries are FLOW-MEDIATED DILATION OF THE BRACHIAL ARTERY
highly limited by their invasive nature, they have the The flow-mediated dilation (FMD) of the brachial artery
advantage to define the endothelial status directly in this is currently considered the gold standard, noninvasive
important vascular bed. technique for the assessment of endothelial function in
vivo. It measures the changes of the diameter of the bra-
EPICARDIAL ARTERIES chial artery induced by the reactive hyperaemia which
Quantitative angiography allows assessment endothe- follows 5-minute forearm ischemia induced by the blood
lium-dependent response of coronary circulation at the pressure cuff applied to the forearm (106) (Figure 33.3).
level of pericardial vessels (usually in the left descend- The increased share stress induced by the hyperaemia on
ing artery) by measuring coronary blood flow during the the vascular wall results in a local endothelial release of
266 Manual of Hypertension of the European Society of Hypertension
Figure 33.3 Flow-mediated dilation. Lab setup (left) and automated edge-detection system (right). (Adapted by permission
from Bruno RM, Picano E. Endothelial Function in the Stress Echocardiography Laboratory. Springer, Cham; 2015 (181).)
NO (107), which induces a vasodilation in a dose-depen- the fingertip of the same arm records the increase in arte-
dent fashion. Endothelium-independent vasodilatory rial blood volume, which is reflected by an increase in pul-
response can be tested by low-dose sublingual nitroglyc- satile arterial column changes. To account for any systemic
erin. Because of its noninvasive nature, the presence of drift in vascular tone during the test, the central device
clear indications to standardise each acquisition and its corrects this acquisition with the recordings obtained
high intra- and interobserver reproducibility, FMD has from a pneumatic probe applied to the contralateral arm,
been widely used in clinical research, testing the impact where no stimuli are applied.
of lifestyle and pharmacological interventions on endo- While digital vascular dysfunction is associated with
thelial function in both adults and children, particularly traditional and metabolic cardiovascular risk factors (114),
in the early preclinical stage of the disease when the several concerns have been raised about the capacity of
alterations of the vascular biology are more likely to be this index to reflect endothelial function, as augmentation
reversible (108). of the pulse amplitude after reactive hyperaemia involves
The greatest challenges of this technique include the changes in flow and in digital microvessel dilatation that
need for highly trained operators, the recruitment of large are only partly dependent on NO (115). Two large cross-
study populations for clinical studies due to the variabil- sectional studies (114,116) showed modest associations
ity and degree of response, the expense of the equipment between FMD and EnoPAT, suggesting that these two
(which not only includes the ultrasound machine but also methodologies are likely measuring different aspects of
a clamp to hold and adjust probe position, as well as a vascular biology.
computerized system to automatically measure brachial
artery diameter to minimize its variability) and the care FOREARM PLETHYSMOGRAPHY
required to minimize the effect of environmental or physi- By means of a strain-gauge applied to the distal part of the
ological influences (109,110). However, following stan- forearm and a blood pressure cuff positioned in the distal
dardised protocols and with appropriate training, FMD part of the arm which stops the venous outflow, this tech-
has been shown its high reproducibility also in multicen- nique measures the changes in the forearm blood volume
tre studies (111,112). induced by intra-arterial infusion of endothelial agonists
performed from a small polyethylene cannula inserted in
TECHNIQUES USED TO ASSESS ENDOTHELIAL FUNCTION the brachial artery. As the venous outflow is occluded dur-
IN THE PERIPHERAL MICROCIRCULATION ing each recording, any change in blood volume induced
While several techniques have been developed to mea- by infusion of an endothelial agonist reflects the change
sure microvascular endothelial function in the periph- in peripheral vascular resistances (reduced peripheral
eral microcirculation, the most validated and widely resistances = increase in flow = increased blood volume)
used include EndoPAT, forearm plethysmography and due to the stimulation of endothelial cell function. Based
micromyography. on these assumptions, endothelium-dependent vasodila-
tion is estimated by a dose-response curve to intra-arterial
ENDOPAT infusion of endothelial agonists (i.e. acetylcholine, brady-
This device has been developed to provide observer- kinin, methacholine, etc.), while endothelium-indepen-
independent measures of pulsatile arterial volume changes dent vasodilation is obtained by a dose-response curve to
by plethysmography (113). Using peripheral arterial intra-arterial sodium nitroprusside (117). Concomitant
tonometry, the machine captures beat-to-beat recordings infusion of L-NAME of vitamin C enables assessment
of the finger arterial pulse wave amplitude with pneumatic of the proportion of the endothelial response, which is
probes. Following the same principles as FMD, a pressure dependent on the activity of eNOS or the local amount of
cuff is placed on one forearm and inflated to a suprasys- oxidative stress (118).
tolic pressure to produce 5 minutes of ischaemia followed When studies are conducted in a quiet, temperature-
by reactive hyperaemia. The pneumatic probe applied to controlled room (22–26°C), with the subject resting in a
Endothelial Damage 267
comfortable supine position, measurement of forearm different cardiovascular risk factors and various manifes-
blood flow by strain gauge plethysmography compares tations of cardiovascular disease. While endothelial leu-
favourably with values obtained by other established kocyte adhesion molecules, including E-selectin, vascular
techniques (119,120). As this approach allows infusion of cell adhesion molecule-1 (VCAM-1) and intercellular adhe-
drugs at systemically ineffective rates, the forearm tech- sion molecule 1 (ICAM-1) reflect activation of the endo-
nique provides the capacity to explore the mechanisms thelium, either specifically (sE-selectin) or nonspecifically
underlying the endothelial dysfunction related to the (sVCAM-1, sICAM-1) (128), thrombomodulin (a protein
exposure to different cardiovascular risk factors, including C cofactor with anticoagulant activity) is released from
hypertension (27,121,122). On the other hand, the limi- injured endothelial cells and its soluble levels have been
tation of the forearm technique is its invasiveness (limit- shown to be a specific marker of endothelial cell damage
ing the number of patients enrolled and the possibility to (129). Soluble levels of thrombomodulin are associated
repeat testing frequently) and that is time-consuming (due with severity of coronary artery disease, stroke or periph-
to the complexity of the experimental design in assessing eral occlusive arterial disease, while are not increased in
dose-response curves to agonists and antagonists). healthy or asymptomatic subjects (127). von Willebrand
factor (vWF) is another protein expressed by activated
MICROMYOGRAPHY endothelial cells that acts as an endothelial ligand for
Micromyography was developed by Mulvany and Halpern platelet glycoproteins. vWF plays a vital role in mediat-
in the 1970s (123) and it was subsequently applied to vas- ing platelet adhesion to damaged arterial walls (130).
cular segments obtained from several animal models of Injured endothelial cells release vWF from endothelial
hypertension, and in several vascular districts (mesenteric, Weibel – Palade bodies; thus vWF is considered a marker
cerebral, coronary, renal, femoral, etc.) (124). There are two of endothelial damage, which is increased in cardiovascu-
major variants of this technique: wire micromyography lar diseases and predicts risk for ischaemic heart disease
and perfusion-pressure micromyography. Both techniques or stroke (131). All these proteins can be easily measured
allow investigation of morphological and functional char- in the peripheral blood using ELISA kits, and their assess-
acteristics of isolated resistance arterioles (lumen diameter ment requires minimal amounts of blood.
150–300 µm), taken from subcutaneous tissue obtained by
skin biopsies. Once cleaned of adherent connective tissue, CECs, EMPs AND EPCs
vessels can be investigated with the wire myograph or the Flowcytometry and immunobeads assays are the two tech-
pressurised myograph. Briefly, the first technique implies niques used to assess the number of CECs. In the flow-
that two wires are threaded through the vessel, while in cytometry assay, the whole blood or peripheral blood
the pressurised system the artery is slipped into two glass mononuclear cells are stained using monoclonal antibod-
microcannulae and exposed to a constant pressure (124). ies labelled with fluorescent probes that are specific for
Once mounted on the myograph, a dose-response curve endothelial antigens. The number of endothelial cells is
to acetylcholine is generated, and the amount of vascu- then counted at the flowcytometry based on the number
lar relaxation is quantified by a software. The perfusion- of cells with positive fluorescence (132). While this tech-
pressure micromyography allows application of different nique is relatively simple and enables a rapid assessment of
substances and transfection of small interfering RNA the number of CECs, the use of different antigens to iden-
(siRNA) (125,126) on the mounted arteries, thus enabling tify endothelial cells by different research groups and the
exploration of their effect on the endothelial-dependent lack of an international agreement on the protocols makes
vasodilation. As such, this technique enables identifica- impossible its application in clinical practice at present.
tion of the potential pathways involved in endothelial dys- The immunobeads assay, by contrast, is recognised as the
function in different pathological conditions. most accurate method to isolate and count CECs in periph-
eral blood (133). Antibodies specific for specific endothe-
lial antigens labelled with magnetic beads are incubated
CIRCULATING MARKERS with the whole blood. After this incubation, endothelial
As the endothelial damage seems to be directly involved cells are isolated using a magnet. These cells can be further
in the initiation, evolution and complications of athero- stained with other antibodies specific for endothelial cells
sclerosis, the availability of markers easily measured in the and are then counted at a fluorescent microscope.
peripheral circulation which could inform on the severity In contrast, assessment of the number and phenotype
of the endothelial damage could carry several advantages of EMPs and EPCs in peripheral blood by flowcytometry
and help the risk stratification of patients with hyperten- requires experience, making this measure feasible only in
sion. Indeed, assessment of direct products of endothelial trained laboratories. The use of fluorescent-labelled antibod-
cells that change when the endothelium is activated has ies is necessary to characterize the surface antigens of EMPs
been suggested to refine patient risk stratification (127). and EPCs, defining not only their numbers but also their
While this is a promising prospective, many of these cir- phenotypes (including origins, differentiation or activation).
culating markers are currently difficult and expensive to
measure. The additional challenges posed by the vari-
ability of the methods used for their assessment makes
translation to the clinical practice of the research evidence EVIDENCE OF ENDOTHELIAL
accumulated thus far very difficult. DYSFUNCTION/DAMAGE
SOLUBLE MARKERS OF ENDOTHELIAL CELL
IN HYPERTENSION
ACTIVATION/DAMAGE Homogeneous literature convincingly demonstrates
An increase in soluble markers of endothelial cell acti- the presence of endothelial damage in the hypertensive
vation and injury have been identified in subjects with patient (14,118). Early signs of this damage manifest in the
268 Manual of Hypertension of the European Society of Hypertension
form of endothelial dysfunction. An increased vascular the presence of increased E-selectin concentrations and
wall breakdown of NO is identified from the earliest stages reduced endothelium-dependent vasodilation in hyper-
of hypertension in humans as well as in experimental ani- tensive patients as compared to normotensive controls, no
mals. This is related to an increased production of ROS in significant correlation among the two endothelial param-
the vascular wall of hypertensive patients (118). Various eters was found (154). These data suggest that, at least in
enzymatic and non-enzymatic sources of ROS have been patients with essential hypertension, levels of E-selectin
described to be activated in endothelial cells, smooth mus- are mostly related to structural, rather than functional
cle cells and inflammatory cells within the arterial wall (endothelial), vascular changes.
of hypertensive patients, including nicotinamide adenine The different methods used to count the CECs have gen-
dinucleotide phosphate (NADPH) oxidase, cyclooxygen- erated conflicting results regarding their ability to mark
ase, xanthine oxidase and uncoupled eNOS (134–136). the endothelial damage in patients with hypertension.
Recent evidence suggests that mitochondria could also While some studies found a higher number of CECs in the
contribute to the increased levels of vascular wall ROS peripheral circulation of patients with hypertension com-
detected in hypertension (137). This could induce oxida- pared to normotensive subjects (155,156), these results
tive DNA damage in the mitochondria of endothelial and could not be replicated by other reports (157).
smooth muscle cells (138) that may affect the synthesis The need for more standardised protocols which
of components of the respiratory chain, leading to a fur- require extensive operator training has produced more
ther increase in mtROS production, ultimately initiating convincing evidence about the capacity of EMPs to char-
a vicious cycle. Interestingly, mutations in mitochondrial acterise the severity of endothelial damage in hyper-
DNA are also associated with increased risk of hyperten- tension. In the Framingham Heart Study, the number
sion (139–141), suggesting that these alterations might of EMPs was higher in patients with hypertension than
precede and be in the causal pathway for the disease initia- normotensive subjects. Another study by Preston et al.
tion and evolution. reported a significant increase in the amount of endo-
Although FMD and the microvascular techniques thelial and platelet microparticles in patients with severe
showed their ability to capture the presence of early arterial hypertension, and showed strong relationships
endothelial dysfunction in different vascular districts of between the amount of circulating EMPs and the level
hypertensive patients (14,98,118,142–147), the opportu- of both systolic and diastolic blood pressures (60). The
nity to use endothelial agonists or antagonists to manipu- hypothesis that EMPs can be used as circulating mark-
late endothelial function in the forearm plethysmography ers for endothelial injury following the hemodynamic
and the micromyography has enabled more complex stud- changes due to hypertension is further supported by
ies that not only confirmed the presence of endothelial studies in which increased levels of circulating EMPs
damage in hypertension, but also clarified the mecha- had been found in patients with pre-eclampsia (58,59)
nisms underlying the development of this damage. For and in patients with pulmonary hypertension (158–
example, using these techniques it was possible to con- 160). Importantly, EMPs have been linked also to the
firm that, while NO release has a strong influence on the decline of the glomerular filtration rate (161) and the
vasodilator response to of acetylcholine or bradykinin in degree of increased arterial stiffness (162) in hyperten-
the forearm of healthy subjects (12,148,149), in hyper- sive patients, suggesting they could be used to monitor
tensive patients the response to these agonists is not only the severity of the generalised endotheliopathy leading
blunted but also partially resistant to the inhibition of to the progression of micro- and macro-vascular compli-
the eNOS by L-NAME (118,143,150). This suggested that cations in arterial hypertension.
other endothelial-derived hyperpolarising factors could To understand the relationship between EPCs and
account for the endothelial response in hypertension (12). hypertension, it is important to consider that not only the
Further microvascular studies have confirmed that the number of circulating cells but also their function (in terms
reduced NO availability detected in hypertensive patients of repair capacity and survival) might provide important
was attributable to an excessive oxidative stress produc- clues on the evolution of the disease and its impact on the
tion, which causes NO breakdown (118). In the forearm endothelial biology. Indeed, current evidence suggests that
microcirculation it was suggested that the cyclooxygenase functional decline of EPCs occurs earlier and more com-
pathway actively interferes with NO availability and rep- monly than reductions in EPC quantity in patients with
resents a source of ROS (150). More recent experiments essential hypertension (163–166). Function of EPCs is
conducted in isolated small vessels from hypertensive dependent on NO availability and levels of oxidative stress
patients confirmed this finding and evidenced that cyclo- (167). Thus the early development of endothelial damage
oxygenase-2 could represent the main isoform able to act in the form of endothelial dysfunction might explain the
as a source of oxidative stress (136). In such a scenario, altered function of the EPC in patients with arterial hyper-
cytochrome P-450 2C9−derived EDHF might act as a par- tension. Increased levels of oxidative stress are also able
tial compensatory mechanism to sustain endothelium- to reduce EPC lifespan, stimulating further recruitment
dependent vasodilation (27). of EPCs from the bone marrow to repair this early endo-
Increased levels of E-selectin, VCAM and ICAM have thelial damage. However, with progression of the damage
been described by multiple research groups in patients associated with advanced hypertension and progressive
with hypertension (151–153). This increase seems to be exhaustion of the bone marrow regenerative capacities,
present from the earliest stage of the disease (153), sug- the number of EPCs might progressively decline, directly
gesting that these markers might be sensitive enough contributing to further progression of the damage. Indeed,
to detect the earliest stages of endothelial damage in the quantitative and functional declines of EPCs become
hypertension. However, a study conducted to assess more pronounced in the advanced stages of hypertension
the relationship between E-selectin levels and endo- (i.e. in patients with resistant hypertension, increased inci-
thelium-dependent vasodilation showed that, despite dence of adverse vascular events and end-organ damage)
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RETINAL CHANGES
34
by Mitchell-Wong combining grades 1 and 2 of the pre- association between venular widening (but not arterio-
vious classification in one stage (12). A further develop- lar narrowing) and incident stroke (16). Nevertheless, the
ment, with the aim to increase general reproducibility, assessment of A/V ratio is widely accepted as a measure of
used the imaging software Integrative Vessel Analysis hypertensive retinopathy in clinical research.
(IVAN) (University of Wisconsin, Madison, Wisconsin,
USA). This system conducts semi-automated measurement
of retinal arterioles and venules and derives its ratio (A/V
ratio) as the key parameter of the analysis. Unfortunately, SCANNING LASER DOPPLER
this system is not able to measure the retinal vascular wall FLOWMETRY
directly (7). Based on this work, the Atherosclerosis Risk in
Communities (ARIC) Study developed standardised pro- Beyond the inability to separately quantify arteriolar and
tocols to photograph and grade retinal vascular changes venular alterations, funduscopic photographs are also not
and to analyse their relationship with blood pressure, able to visualise the inner and outer wall of retinal vessels
target-organ damage and cardiovascular events. It has
(7). One promising approach was introduced to the field
been repeatedly shown that retinal alterations are strongly of hypertension by our study group in 2001. SLDF assesses
correlated with past, current and incident hypertension functional (i.e. perfusion) and structural (i.e. rearrange-
(7). In many large-scale longitudinal studies, associations ment of vascular smooth muscle cells) parameters of the
of directly assessed (generalised) arteriolar narrowing or retinal circulation at the same time (17). In brief, SLDF
a decreased A/V ratio (indirectly indicative of proposed is performed in the juxtapupillary area of the right eye,
arteriolar narrowing) with arterial hypertension were 2–3 mm temporal superior to the optic nerve at 670 nm
reported. The A/V ratio has also been shown to decline (Heidelberg Retina Flowmeter, Heidelberg Engineering,
with age, and turned out to be lower in current smokers Germany). An arteriole (80–140 µm) of the superficial
compared to nonsmokers. retinal layer in a retinal sample of 2.56 × 0.64 × 0.30 nm
In contrast, conflicting results with respect to the rela- is scanned within 2 seconds (one systolic and one diastolic
tion of retinal venules with hypertension were found. phase) and measured every 10 µm of this specific length of
Whereas some studies showed an association between the arteriole (Figure 34.1). The confocal technique of the
hypertension and venular narrowing, others demon- device ensures that only capillary flow of the superficial
strated a correlation between new onset of hypertension layer of 300 µm is measured.
and venular widening. This approach allows the in vivo measurement of the
Other retinal digital image analysis focused on the outer arteriolar diameter (OD) in reflection images and
evaluation of bifurcation of retinal vessels and found an the inner lumen diameter (ID) in perfusion images and
increase of tortuosity indices in treatment-naïve hyperten- thus the assessment of early vascular remodelling of reti-
sive patients compared to normotensive controls (13). nal arterioles by calculating wall-to-lumen ratio (WLR)
Regarding the association of A/V ratio and target-organ using the formula (OD-ID)/ID (18,19). There is evidence
damage, data are limited. In 1439 middle-aged African that WLR of retinal arterioles is closely related to the
American participants of the ARIC study, A/V ratio was micromyographic measurements of the media-to-lumen
associated with left ventricular hypertrophy, which was ratio of subcutaneous small arteries taken from bottom
partly explained by the coexistence of additional car- biopsies, which are known to predict cardiovascular events
diovascular risk factors (14). In contrast, in an Italian (20,21). There are further investigations pointing towards
study comprising 386 untreated and treated hyperten- evidence that retinal arterioles undergo similar changes
sive patients, no difference in A/V ratio between presence as peripheral and cerebral arterioles in hypertension,
and absence of hypertensive organ damage was found indicating that retinal abnormalities mirror structural
(15). Interestingly, the Rotterdam Study identified an and functional microvascular changes in hypertensive
Reflection image
Outer diameter (OD)
Perfusion image
Inner diameter (ID)
Figure 34.1 Scanning laser Doppler flowmetry (SLDF) of retinal arterioles: Scanned area with refection and perfusion
image, calculation of the wall-to-lumen ratio, cross-sectional area and wall thickness.
Retinal Changes 277
end-organs (9,22,23). It is noteworthy that SLDF does not with hypertension stage 1–2 (29). Six months after renal
require mydriatic drug application for pupil dilatation. On denervation, a decrease of pulsed RCF was observed in
the contrary, local application of tropicamide is known parallel to a decrease of blood pressure and heart rate,
to affect retinal perfusion and vascular tone and should suggesting a reduction of shear stress on the vascular wall
therefore not be applied when using SLDF (24). Reliability (30). The importance of these findings is emphasized by
of SLDF measurements have been repeatedly shown to be the most recent data that excessive flow pulsatility dam-
acceptable and similar to other biomarkers (coefficient of ages the cerebral microcirculation, leading to impaired
variation <10%) (18,25). cognitive function (31).
Figure 34.2 Scanning laser Doppler flowmetry (SLDF) for calculation of capillary rarefaction: Definition and calculation
of intercapillary distance and capillary area.
278 Manual of Hypertension of the European Society of Hypertension
cerebrovascular events had an increased WLR of retinal by 12% (46). Nevertheless, no validation of the method
arterioles compared to both treated hypertensive patients in respect to other available techniques (e.g. media-to-
and normotensive individuals. Moreover, treated hyper- lumen ratio of subcutaneous arterioles) is yet provided
tensive patients with poor blood pressure control showed (7). Of note, with adaptive optics imaging, RCF cannot
higher WLR than treated hypertensive patients with good be measured and thus dynamic measurements of flow in
blood pressure control (37). In addition, never-treated response to pharmacologic or physiologic stimulus cannot
hypertensive patients revealed higher WLR than normo- be assessed.
tensive individuals (23). A current consensus article from
the European Society of Hypertension (ESH) and European
Society of Cardiology (ESC) mentions retinal WLR as a
parameter for the noninvasive evaluation of the microvas- OPTICAL COHERENCE TOMOGRAPHY
culature and states that future studies will have to assess
the prognostic contribution of noninvasively assessing the Optical coherence tomography (OCT) has been developed
microvascular bed in patients with hypertension (38). for noninvasive cross-sectional imaging in an enhanced
resolution within an acceptable time period. OCT uses low-
coherence interferometry to produce a two-dimensional
image of optical scattering from internal tissue microstruc-
ADAPTIVE OPTICS IMAGING tures in a way that is analogous to ultrasonic pulse-echo
imaging (47). In addition to its diagnostic use in various
Adaptive optics imaging has been shown to be a reliable ophthalmologic diseases, OCT has emerged as tool to assess
method to noninvasively assess retinal microvascular structural compounds involved in neurodegeneration that
changes. The adaptive optics retinal fundus camera creates contribute to neurologic disability in a variety of central
a retinal image over time by recording scattered light from nervous system diseases (48). Currently, as a clinical tool,
a focused beam, and produces 4° × 4° high-resolution OCT is particularly useful for the structural measurement
fundus images (39). By continuous scanning of the retina of peripapillary retinal nerve fibre layer thickness, optic
in a raster, it is possible to take images of large areas at a nerve head volumetric analysis and macular anatomy (49).
faster rate (40 fundus images in 4 seconds) than with con- Schuster et al. proposed OCT-based retinal vessel analysis
ventional flash fundus imaging (40,41). Adaptive optics for the evaluation of hypertensive vasculopathy (50). They
imaging can be used to describe qualitative (e.g. hard exu- demonstrated a relationship between blood pressure and
dates, microaneurysms) and quantitative (e.g. capillary OCT-based arterial-venous ratio (11). However, data about
diameter, WLR) adaptive changes to increased blood pres- the retinal vessel parameters in arterial hypertension are
sure (42) (Figure 34.3). The feasibility and reproducibility limited. In an analysis of patients aged over 50 years, it
of retinal arteriole imaging was demonstrated in healthy was shown that mean arteriolar outer and inner diameter
individuals with several cardiovascular risk factors (43) did not differ between patients with (n = 103) and without
and in untreated hypertensive patients (44). It has also been hypertension (n = 83) but mean arterial wall thickness
shown that adaptive optics−based assessment of WLR was was significantly larger (51). This is in line with previous
positively correlated with age, mean blood pressure and findings using SLDF in never-treated hypertensive patients
body mass index (43). The quantitative measurements of compared to controls (23). In addition, in patients with
WLR measurements by adaptive optics imaging are close poor blood pressure control (BP ≥140/90 mmHg), calcu-
to those reported by SLDF (21,23,41). Analysis of WLR lation of OCT-measured WLR (0.396 ± 0.16) was simi-
using adaptive optics imaging in 1500 subjects showed lar to those measured using SLDF (37,51), but no direct
that a WLR higher than 0.31 is indicative of hypertension comparison has thus far been made. In addition, retinal
and a lumen diameter of less than 78 µm of masked hyper- microvascular damage assessed with OCT in patients with
tension (45). Adaptive optics imaging showed that barore- obstructive sleep apnoea (OSAS) and hypertension was
ceptor activation therapy reduced wall-cross-sectional area associated with OSAS severity (52).
Figure 34.3 Adaptive optics imaging: Analysis of retinal arterioles with measurement of inner and outer vessel diameter.
Retinal Changes 279
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Section VI
Integrated Diagnostic Aspects
THE INTEGRATED DIAGNOSTIC
APPROACH IN GENERAL 35
MEDICINE
Table 35.2 Factors other than office BP levels influencing prognosis used for stratification of total cardiovascular risk
Gender (men > women) Arterial stiffening: Pulse pressure (in the elderly) Cerebrovascular disease:
≥60 mmHg Ischaemic stroke; cerebral
haemorrhage; transient ischaemic
attack
Age Electrocardiographic LVH (Sokolow – Lyon index CHD: Myocardial infarction; angina;
>3.5 mV; RaVL >1.1 mV; Cornell voltage duration myocardial revascularization with
product >244 mV*ms) PCI or CABG
Smoking Echocardiographic LVH [LV mass index: men >50 g/m2.7; Heart failure, including heart failure
Family history of premature CVD (men women >47 g/m2.7 (height in m2.7); indexation for BSA with preserved EF
aged <55 years; women aged <65 may be used in normal-weight patients; LV mass/BSA
years) g/m2 >115 (men) and >95 (women)]
Diabetes
Familial or parental history of early-onset
hypertension
Early onset menopause
Sedentary lifestye
Psychosocial and socioeconomic factors
Total cholesterol and HDL-C Advanced retinopathy: haemorrhages or exudates, Symptomatic lower extremities
Uric acid papilloedema peripheral artery disease
Atrial fibrillation
Presence of atheromatous plaque
on imaging
Note: Factors were highlighted if the particular risk factor is evaluated by patient’s medical history (yellow), physical examination (orange), blood pressure
measurement (green), routine tests (blue) and additional tests (brown). Based on ESH/ESC 2013 and ESC/ESH 2018 Guidelines.
Table 35.3 Abnormalities on basal workup leading to the suspicion of secondary hypertension
Obstructive sleep Specific daytime and nighttime Abdominal obesity Increased plasma glucose Sleep study
apnea symptoms (e.g. snoring, fitful Increased neck circumference Lipid abnormalities
sleep, breathing pauses during Craniofacial abnormalities
sleep, daytime sleepiness)
Renal parenchymal History of urinary tract infection or Abdominal masses (in cases Presence of protein, Renal ultrasound
disease obstruction, haematuria, analgesic of polycystic kidney erythrocytes, or leucocytes
abuse; family history of kidney disease), skin pallor in the urine
disease Decreased GFR
Renal artery HT of abrupt onset, worsening or Abdominal bruit, bruits over Rapid deterioration in renal Renal duplex Doppler
stenosis – increasingly difficult to treat HT other arteries function (spontaneous or in ultrasonography
atherosclerotic Resistant or malignant HT response to RAA blockers)
Flash pulmonary oedema Hypokalaemia
Renal artery Early-onset HT (especially in Abdominal bruit, bruits over Rapid deterioration in renal Renal duplex Doppler
stenosis – FMD women) other arteries function (spontaneous or in ultrasonography
Worsening or increasingly difficult response to RAA blockers)
to treat HT Hypokalaemia
Resistant or malignant HT
FMD in other vascular beds or
history of spontaneous artery
dissection
Primary Muscle cramps or weakness Arrhythmias (especially atrial Hypokalaemia (spontaneous Aldosterone–renin
aldosteronism Resistant HT fibrillation) or diuretic-induced) ratio
HT and:
■■ Incidental adrenal mass
■■ OSA
■■ Family history of early-onset HT
and cerebrovascular events at
age <40 years
■■ First-degree relatives of patients
with primary aldosteronism
Cushing syndrome Rapid weight gain, polyuria, Typical body habitus (central Hyperglycaemia 24-h urinary free
polydipsia, muscle weakness, obesity, moon-face, buffalo cortisol
psychological disturbances hump), red striae, hirsutism, Excretion
bruising Low-dose
dexamethasone test
Source: Mancia G et al. J Hypertens 2013; 31: 1281–1357; Piepoli MF et al. Eur Heart J 2016; 37: 2315–2381; Luft FC. Hypertension 2001; 37: 350–356 (1–3).
Abbreviations: FMD, fibromuscular dysplasia; GFR, glomerular filtration rate; HT, hypertension; PPGL, pheochromocytoma/paraganglioma; RAA,
renin−angiotensin−aldosterone.
According to the recommendations established by the dia- plasma glucose concentration, estimation of blood concen-
betic associations, diabetes mellitus is diagnosed in such tration of glycated haemoglobin (HbA1c) should be also
hypertensive patients when in two different measure- performed (1,18).
ments FPG concentration is ≥7.0 mmol/L (126 mg/dL) It is well known that abnormal plasma glucose concen-
or plasma glucose concentration during the day is above trations are some of the most important risk factors for car-
11.0 mmol/L (198 mg/dL). In all subjects with elevated diovascular complications in hypertensive patients (1,18).
The Integrated Diagnostic Approach in General Medicine 287
Table 35.4 Physical examination for secondary hypertension, organ damage and obesity
■■ Auscultation of precordial or chest murmurs (aortic coarctation; aortic disease; upper extremity artery disease)
■■ Diminished and delayed femoral pulses and reduced femoral blood pressure compared to simultaneous arm BP (aortic coarctation; aortic disease;
lower extremity artery disease)
■■ Heart: heart rate, 3rd or 4th heart sound, heart murmurs, arrhythmias, location of apical impulse, pulmonary rales, peripheral oedema
■■ Peripheral arteries: absence, reduction, on asymmetry of pulses, cold extremities, ischaemic skin lesions
Evidence of obesity
■■ Waist circumference measured in the standing position, at a level midway between the lower border of the costal margin (the lowest rib) and
uppermost border of the iliac crest
Source: ESH/ESC 2013. Mancia G et al. J Hypertens 2013; 31: 1281–1357. With permission (36).
Abbreviations: BP, blood pressure; BMl, body mass index.
Elevated FPG concentration is often found in patients increased in hypertensive patients with elevated LDL-C
with secondary forms of arterial hypertension, as in concentration. In patients with arterial hypertension,
hypercortisolism, pheochromocytoma or to some extent it is recommended by the ESH/ESC guidelines to main-
also in primary hyperaldosteronisms (1,18). tain serum LDL-C cholesterol concentration <100 mg/
Elevated plasma glucose concentration should be also dL (<2.5 mmol/L). In patients with already existing coro-
taken into the consideration when the antihypertensive nary artery disease, serum LDL-C concentration should be
therapy is planned. It is well known that some antihyper- <70 mg/mL (1.8 mmol/L) and in those with the highest
tensive drugs may worsen glucose tolerance (especially risk of cardiovascular complications even lower, namely
thiazide or thiazide-like diuretics and beta-blockers). <55 mg/mL (1.8 mmol/L). Treatment with statins along
Therefore, these drugs should be prescribed with caution with appropriate dietary recommendation significantly
in subjects with arterial hypertension and diabetes mel- reduces cardiovascular risk in hypertensive patients; how-
litus or metabolic syndrome (1,18). ever, dose not reduce the progression of CKD (1,19).
because its calculation depends on 24-h urine collection, KDIGO 2012 guideline, measurement of the albumin-
for daily clinical practice, calculation (estimation) of cre- to-creatinine ratio along with morning urine sample is
atinine clearance (eGFR) is generally accepted. Most com- mandatory in all patients with newly diagnosed arterial
mon equations currently used are the Cockcroft-Gault, the hypertension. Urinary albumin excretion in the range
Modification of Diet in Renal Disease (MDRD) Study and 30–300 mg/g creatinine is recognized as a marker of sub-
the Chronic Kidney Disease Epidemiology Collaboration clinical target-organ damage. Based on CKD classification
(CKD-EPI) equations. MDRD equation is the most widely and the rate of albuminuria, an outcome of CKD patients
used formula in recent years. Many laboratories automati- can be assessed (Table 35.5) (20–24).
cally report eGFR based on MDRD equation addition-
ally to the creatinine measurements. CKD-EPI equation
is, however, more accurate in subjects with higher eGFR
levels (>60 mL/min/1.73 m2). In addition, CKD-EPI may ELECTROLYTES
serve as a better predictor of mortality or end-stage renal
disease (ESRD) than using the MDRD formula, therefore Estimation of serum sodium and potassium concentra-
KDIGO 2012 Clinical Practice Guidelines for the Evaluation and tion is mandatory in each patient with newly diagnosed
Management of Chronic Kidney Disease recommended CKD- arterial hypertension. These results are useful in the diag-
EPI equation for GFR estimation. Measurement of serum nosis of secondary forms of arterial hypertension (e.g.
concentration of cystatin C (low molecular weight-13 kDa- in patients with primary hyperaldosteronism) as well as
cysteine protease inhibitor, produced by all nucleated cells) in the long-term monitoring of side effects related to the
is a potential alternative to measurement of serum creati- antihypertensive therapy. Detailed differential diagno-
nine for estimating GFR. Measurement of cystatin C is less sis of hypokalaemia (serum potassium concentration
available and more expensive than measurement of serum <3.5 mmol/L) in patients with arterial hypertension is
creatinine and therefore is not routinely used for calculation given in Figure 35.1. Hyperkalaemia (serum potassium
of GFR. Estimated GFR <60 mL/min/1.73 m2 (and repeat- concentration >5.0 mmol/L) is usually caused by the
ing this value within 3 months) allocates these patients to antihypertensive therapy with direct inhibitors of the
the stage 3 or lower of the CKD classification (20–24). renin−angiotensin−aldosterone system (RAAS), includ-
Measurement of albuminuria is recommended in all ing ACEI, ARBs or mineralocorticoid receptor antagonists,
patients with arterial hypertension. The frequency of uri- as well as indirectly by inhibiting of RAAS with blockers
nary albumin excretion measurement depends on clini- of the beta-adrenergic receptors. Hyperkalaemia is most
cal situation and comorbidities (in patients with CKD, frequently found in hypertensive patients with advanced
it should be assessed at least annually). According to the CKD, diabetes mellitus, older age or treated simultaneously
A1 A2 A3
Prognosis of CKD by GFR
Normal to
and albuminuria categories: Moderately Severely
mildly
KDIGO 2012 increased
increased increased
Midly to moderately
G3a 45–59
decreased
Moderately to
G3b 30–44
severely decreased
Note: Green, low risk (if no other markers of kidney disease, no CKD); yellow, moderately increased risk; orange, high risk;
red, very high risk.
Source: According to Levin A, Stevens PE. Kidney Int 2014; 85: 49–61. With permission.
Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.
The Integrated Diagnostic Approach in General Medicine 289
Hypertensive patient
with hypokaliemia
Medical history
-diarrhea, vomiting, laxatives, diuretics
Decreased Increased
(<1 ng/mL/h) (≥1 ng/mL/h)
Figure 35.1 Diagnostic approach and differential diagnosis in a hypertensive patient with hypokalaemia.
with two or three different inhibitors of the RAAS and/ consequence of excessive production will be more prone to
or potassium supplementation. Hyponatremia (serum cardiovascular diseases compared to patients whose hyper-
sodium concentration <135.0 mmol/L) in patients with uricaemia is caused by reduced renal excretion or increased
arterial hypertension may be caused by the diuretic treat- tubular reabsorption of UA, which would predispose these
ment (especially by the thiazide or thiazide-like diuretics). patients for development of gout. Patients with hyperuri-
Hyponatremia is also a found in patients with a malignant caemia who manifest gout should be treated with an aim
form of arterial hypertension as well as in hypertensive to reduce serum UA below 6.0 mg/dL (357 µmol/L). This
patients with heart failure or in patients with hypothy- is especially important in patients with CKD and/or meta-
roidism. Hypernatremia (serum sodium concentration bolic syndrome. It is less clear whether the asymptomatic
>145.0 mmol/L) may be caused by primary hyperaldoste- hyperuricemia should be treated to the same target. Recent
ronism or by severe dehydration (6,25). randomised controlled trials suggested, however, a protec-
tive effect of urate-lowering therapy in preventing the pro-
gression of CKD. It seems that it is also true in reducing the
URIC ACID risk of cardiovascular complications, but large, randomised
trials are needed to prove this recommendation (26–29).
Measurement of serum uric acid (UA) concentration belongs
to the list of routine laboratory tests which should be per-
formed on each subject with arterial hypertension. It is espe-
cially important in patients with reduced kidney function ECG
(CKD stage 3–5) and/or treated with thiazide or thiazide-
like as well as loop diuretics. Normal serum UA concentra- A 12-lead electrocardiogram (ECG) is recommended in all
tions are lower in females (<6.0 mg/dL = 357 µmol/L) than hypertensive patients to detect left ventricular hypertro-
in males (<7.2 mg/dL = 428 µmol/L). An increasing body phy (LVH), left atrial dilatation, arrhythmias, or concomi-
of evidence suggests that asymptomatic hyperuricaemia tant heart disease (class I, level B recommendation) (1).
is an independent risk factor for cardiovascular complica- Although sensitivity of ECG in detecting LVH is low,
tions and CKD. The relationship between hyperuricaemia LVH detected by ECG has been found in observational
and the development of hypertension has been confirmed studies and clinical trials to be an independent predictor of
by several observational and experimental studies. It is also CV risk. Established ECG indices of LVH include (30–33):
suggested that levels of serum UA can be considered as a
marker of the oxidative stress associated with the activation ■■ The Sokolow-Lyon index (SV1 + RV5 >3.5 mV)
of xanthine-oxidase, which is essential in UA production. ■■ The modified Sokolow-Lyon index (largest
This hypothesis opens a new interpretation of the role of S-wave + largest R-wave >3.5 mV)
serum UA in the pathogenesis of cardiovascular and renal ■■ RaVL >1.1 mV
complications. Patients whose plasma levels of UA are the ■■ Cornell voltage QRS duration product (>244 mV*ms)
290 Manual of Hypertension of the European Society of Hypertension
Accordingly, ECG may also be used to detect (1): hypertensive subjects should undergo basal workup for sec-
ondary forms of hypertension, but the younger the patient
■■ Patterns of ventricular overload or ‘strain’ and the higher and more resistant to the antihypertensive
■■ Ischaemia therapy BP levels exist, the more thorough the pursuit for
■■ Conduction abnormalities identifiable causes should be (35). In middle-aged or elderly
■■ Left atrial dilatation hypertensive subjects, greater attention should be directed
■■ Arrhythmias, including atrial fibrillation to the assessment of global CV risk, since those subjects are
at higher risk of immediate CV events. As described in this
chapter, in most patients this can be achieved by BP mea-
surement, assessment of medical history including family
SCREENING EVALUATION FOR history, physical examination, and routine tests. These con-
stitute the integrated diagnostic approach in hypertensive
SECONDARY HYPERTENSION patients, easily implanted in general medicine settings.
Although secondary causes of hypertension can be diag-
nosed in a relatively small proportion of hypertensive
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MANAGEMENT OF
HYPERTENSION BY THE 36
HYPERTENSION SPECIALIST AND
THE HYPERTENSION
EXCELLENCE CENTRES
Bojan Jelaković
socioeconomic factors are involved in the clinical expres- blood pressure control which should improve health and
sion and aggravation of hypertension to be neglected, reduce costs. Hypertension specialists have to initiate,
and often these factors are better handled by the family organise and coordinate nationwide surveys on hyperten-
doctor than by the university specialists (4,5). Thus, the sion, salt intake and obesity, etc., collecting relevant recent
final answer to the question of whether hypertensiology data which should be the basis for healthcare programmes.
is separate speciality is − yes. Several arguments favour In addition, hypertension specialists must be involved in
this conclusion. Hypertension is (1) highly prevalent in the education of patients, nurses and physicians as well as
the general population (the highest prevalence of chronic- pharmacists, who should become regular partners in the
noncommunicable diseases with increasing trend); (2) a team (7). The next important task at the national level is
major cardiovascular and cerebrovascular risk factor; (3) to work on improvement of blood pressure control, bring-
an established renal risk factor; (4) one of the major causes ing new knowledge and making sophisticated diagnostic
of disability; (5) a huge economic burden to all societies; methods and therapeutic procedures available and part of
(6) a complex entity where hypertension specialists should routine clinic work. Finally, hypertension specialists must
be capable of solving the most complicated cases, but also serve as ‘interplayers’ between hospital physicians, gen-
should serve as a consultants in many other cases being eral practitioners, nurses, pharmacists, health insurance
linked among various specialities. companies and ministries of health and industry (pharma
Thus far, hypertension is not recognised as a medical field and food). Actions to prevent cardiovascular/renal disease
on its own by the vast majority of governments and national should be incorporated into everyone’s lives, starting in
physicians’ chambers and is not considered a discipline sui early childhood and continuing through adulthood and
generis, for example, diabetology (1–5). Until hypertension senesce (class IIa, level B, grade strong) (Table 36.1) (8,9).
is acknowledged as a separate medical discipline, young Two groups of healthcare providers are crucial in manag-
physicians, lacking motivation and financial incentives, ing hypertension at the national level – nurses and general
will be attracted by other recognised medical specialties practitioners. Nurse-coordinated prevention programmes
and will be reluctant to enter the field of hypertension. should be well integrated into the healthcare system (class
Aside from all other previously mentioned facts, stop- IIa, level B, grade strong) (8,9). The physician in general
ping this brain drain from the field of hypertension (2) practice is the key person to initiate, coordinate and provide
was one of the reasons why the European Society of long-term follow-up. The critical task is to properly commu-
Hypertension decided to start with its own programme on nicate with the individual patient. Hypertension specialists
hypertension specialists. should be involved in plans and implementation of actions
where both groups are key players. Patients with cardiac/
renal disease may participate in self-help programmes to
increase or maintain awareness of the need for risk factor
HYPERTENSION SPECIALIST management, for maintaining physical fitness, or for dili-
gent self-management of therapy (class IIa, level B, grade
PROGRAMME strong) (8,9). One important task is to develop patients’
educational materials which might increase their under-
WHY DO WE NEED HYPERTENSION standing and facilitate physician-patient communication.
SPECIALISTS AND WHAT SHOULD THEY DO? Hypertension specialists must be involved in regularly
publishing patient-oriented journals which will educate
Hypertension specialists have opportunities to improve patients, increasing their awareness and responsibility.
blood pressure control at global, national and local levels. The most common barriers to guideline implementation
are government or local health policy (40%), patient com-
pliance (36%), lack of time (23%) and lack of communica-
GLOBAL LEVEL tion (immeasurable). Hypertension specialists must work
Hypertension is so complex that one must be aware that on better communication between hospital specialists
every hypertension specialist could not develop superb
competence in all areas. Hypertension specialists rep-
resent a diverse group of board-certified physicians (7). Table 36.1 Actions to prevent cardiovascular disease
Importantly, this group collectively must be engaged in
designing, implementing, and monitoring patient-centred, Target group Action
evidence-based, cost-efficient best practice approaches to School, −− Conveying the pleasures of healthy nutrition and
all levels of health protection – primordial (prevention of kindergarten joys of physical activity
lifestyle risk factors), primary (prevention of vascular and −− Education on devastating effects of smoking and
target-organ damage in subjects with established risk fac- alcohol
tors), and secondary (prevention of recurrent events) (7).
One recent example where hypertension specialists have Adults −− Risk-adjusted prevention
a crucial role is an ongoing survey on blood pressure con- −− Nurse-based activities
trol in ESH Excellence Centres (BP-Control study in ESH −− Importance of general practitioners
Excellence Centres). −− Involvement of pharmacists in the team
−− Hospital-based programme
−− Society-based programme
NATIONAL LEVEL −− Non-personal interventions (mass media)
Hypertension specialists have opportunities to work on
Legislative −− Ban smoking, reduce salt content in bread, meat
improvement of blood pressure control at the national activities products, etc.
level. They can develop and coordinate strategies beyond
Management of Hypertension by the Hypertension Specialist and the Hypertension Excellence Centres 295
and general practitioners, and they should ensure that all secondary form of hypertension. In addition, many sub-
patients with cardiovascular/renal disease be discharged jects are underdiagnosed, inadequately followed up, or
from the hospital with clear guideline-oriented treatment undertreated. Screening programmes and education of
recommendations to minimise adverse events (class I, physicians and patients should be the tasks of hyperten-
level B, grade strong) (8,9). sion specialists among general practitioners.
It was shown in several studies that the presence of a
pharmacist improves medication adherence. Hypertension HOSPITAL HYPERTENSION SPECIALIST
specialists should coordinate programmes which will Hypertensives with refractory hypertension, those with
enable pharmacists to become valuable partners in the severe or difficult-to-control hypertension, suspicion of
team, starting from education to enhancing commu- secondary forms of hypertension and patients who are
nication between pharmacists, nurses and physicians, noncompliant should be referred to a hospital hyperten-
and working on financial incentives. The main task for sion specialist who has access to other experts and facilities
pharmacists should be providing education of patients for various laboratory and imaging investigations. Usually,
on proper blood pressure measurements, a healthy life- hospital hypertension specialists work in ESH Excellence
style, and together with general practitioners and nurses, Centres of Hypertension. Evaluation and treatment of
increasing patient and family engagement. Many hyper- difficult-to-treat hypertensives, secondary forms of hyper-
tensive patients have multiple comorbidities with the tension and resistant hypertensives are the main tasks of
need for complex polypharmacy regimens, thus the next the hospital hypertensive specialist. The multidisciplinary
task for pharmacists is to explain the need for taking so approach is important as many (the majority of) patients
many drugs, inform patients when to take each drug, and have clusters of chronic diseases that are not efficiently
warn them about side effects and possible interactions addressed by disease-specific management strategies (1–
(7). Pharmacists should communicate with physicians 7,10). For instance, patients with resistant hypertension
and nurses, reporting to them any remark that could have frequently have obesity, sleep apnoea syndrome, chronic
impact on better blood pressure control. kidney disease or high salt intake; some have cognitive
Figure 36.1. presents a scheme on a network where dysfunction or dementia, while others are noncompli-
hypertension specialists have a central role. Such care ant. Various hypertension specialists should be part of the
networks could enable many return visits to be organ- team, including either interventional cardiologists or radi-
ised via telemedicine, as a few minutes ‘face to face’ on a ologists. However, they also should be involved in educa-
computer and might provide enough information to make tion of patients and be engaged in all other activities at the
most decisions for stable follow-up patients (1). However, global and national level. Hypertension specialists must
in many circumstances it is more important to have in- work on better communication between hospital special-
person contact between two human beings. Again, lack ists and general practitioners, and shared care should be
of time, which is a frequent problem for physicians and introduced and encouraged (Figure 36.1) (6).
nurses, could be bridged over with the help of educated
pharmacists.
WHO CAN BE A HYPERTENSION SPECIALIST?
LOCAL LEVEL The Hypertension Specialist Programme was organised
GENERAL PRACTITIONER HYPERTENSION SPECIALIST by the European Society of Hypertension in 2000 to
Most patients with hypertension need little investiga- identify hypertension specialists in Europe, to contrib-
tion, and in many of them blood pressure control can ute to the training of these specialists, and to improve
be achieved by monotherapy or a two-drug regime the treatment of hypertension and thus obtain better
(6,10). However, those patients should also be carefully prevention of cardiovascular and kidney diseases (11)
monitored, as hypertension is a dynamic entity that can (Figure 36.2). ESH Hypertension Specialists have to be
change characteristics either because of ageing and long- selected from among physicians who have long-time
time duration of disease or because of developing some experience, multidisciplinary knowledge and expert
Pharmacist
Patient
General
Nurse
physician
Hypertension
specialist Multidiscplinary
Multidisciplinary team (individual)
approach
Good communication !
ISH ESH
scientific council Advanced educational
ESH summer ESH HT ESH web ESH
-positive view course master research grants
school specialist educational
ESH establishment on HT courses
EI escorial activities projects
1983 1988 1989 1991 1995 1999 2000 2001 2002 2003 2005 2006 2007 2009
skills to effectively deal with complex and difficult cases to a hypertension clinic. They must describe their medi-
of clinical hypertension and related disorders (11). The cal division and the entire hypertension unit/centre,
purpose of this programme is to qualify and identify and inform the ESH council of hypertension research
practitioners who have broad knowledge of hyperten- projects/grants/fellowships in which they have been or
sion and the proven ability to apply this knowledge to are currently involved. Finally, each applicant is asked
the expert care of hypertensive patients (11). Eligibility to describe extra hospital practice. All members in good
criteria for recognition as a hypertension specialist of standing and who have been a hypertension specialist
ESH are listed in Box 36.1. for 5 years should apply for re-accreditation. Specialists
Nomination is based on credits obtained through par- should fulfil at least three of the following six criteria
ticipation in scientific meetings and teaching courses (required in the last 3 years): (a) participation in ESH
endorsed by ESH (Box 36.2). Applicants should have annual meetings; (b) participation in ESH teaching activ-
acquired 10 credits for A and 10 credits for B. Credits ities (summer school or advanced course); (c) participa-
must be documented and uploaded, and submitted in the tion in ESH-endorsed local meetings; (d) participation
online process. When describing practice activity in hyper- in ESH distance-learning activities; (e) publication in
tension, an applicant should provide data on: (a) num-
ber of years of experience in the clinical management of
hypertensive patients; (b) percentage of practice devoted
to the care of hypertensive patients; (c) estimated number
of consultations per month for hypertension-related dis-
orders; (d) estimated number of evaluations performed BOX 36.2 CREDITS NEEDED TO COLLECT
per month for possible secondary hypertension assigned FOR RECOGNITION OF THE STATUS
OF HYPERTENSION SPECIALIST
Figure 36.3 Map of countries where the ESH Excellence Centres are located in Europe and the Middle East.
(primary care or institutions/hospitals) who have special However, the final shape and structure of an ESH BP-VP
interest and expertise in hypertension (14). The coordi- Clinic may depend on the objectives, which may dif-
nation of the interaction with these ESH BP-VP Clinics is fer among clinics and different local healthcare systems,
at the Excellence Centre level. One Centre of Excellence and may change with time. Good BP-VP Clinics may not
can be associated with several ESH BP-VP Clinics with necessarily address all the possible purposes described
European recognition. The Centres of Excellence and the below. In addition to aforementioned tasks, ESH BP-VP
ESH BP-VP Clinics allow the organisation of a network Clinics should establish a database management system
aiming to improve the accuracy of diagnosis and manage- and computer software to collect, store and retrieve data
ment of hypertension and to be involved in multicentre in structured way with the aim to facilitate prompt moni-
clinical research activities. The main tasks are shown in toring implement and interpret office and out-of-office BP
Box 36.6 and the main requirements in Box 36.7 (14). measurements.
Management of Hypertension by the Hypertension Specialist and the Hypertension Excellence Centres 299
BOX 36.6 MAIN TASKS FOR THE ESH BLOOD PRESSURE AND VASCULAR PROTECTION CLINIC
ABPM ACR
of the DASH diet was more pronounced in hypertensive cardiovascular risk, it may be prudent to conduct exercise
patients and in African Americans. Efficacy of the DASH stress testing before commencing a training program, and
diet has been confirmed in subsequent studies (63,79); to gradually increase exercise intensity and duration over
thus the DASH diet can be recommended for hypertensive time.
patients. In hypertensive individuals, endurance training on
a bike three or seven times per week at 70% maximum
work capacity for 1 month each reduced blood pressure
by 11/9 and 16/11 mmHg, respectively (95). More mod-
REDUCED ALCOHOL CONSUMPTION erate levels of exercise, for example, walking, may also
AND SMOKING CESSATION be effective (96,97). In a meta-analysis of 72 trials in
which exercise was the only intervention, blood pressure
Cross-sectional studies documented increased blood pres- decreased on average by 3/2 mmHg in the overall popula-
sure and hypertension risk with higher levels of alcohol tion and by 7/5 mmHg in hypertensive patients (98). A
intake (80). In a large survey of 30,000 individuals, blood meta-analysis that included several forms of exercise pro-
pressure increased by 0.9/0.6 mmHg per daily drink in tocols found a blood pressure reduction of 3.5/2.5 mmHg
men and 2/1 mmHg in women who consumed two or with endurance training, 1.8/3.2 mmHg with dynamic
more drinks (81). A J-shaped association between alcohol resistance training, and 10.9/6.2 mmHg with isomet-
intake and blood pressure was reported by some but not all ric resistance training (99). A meta-analysis of studies
studies (82). Moderation of alcohol consumption reduced assessing antihypertensive responses to dynamic resis-
blood pressure in normotensive men (83). In heavy drink- tance training showed that blood pressure decreased at
ers with hypertension, the reduction of alcohol consump- least as much as with aerobic exercise training. Greater
tion reduced blood pressure by 14/7 mmHg at two 2 years’ blood pressure reductions occurred in individuals with
follow-up, while no changes occurred in the control group higher resting blood pressure, approximately 6/5 mmHg
(84). In another randomized trial, however, a reduction in hypertensives and 3/3 mmHg in individuals with pre-
from 432 to 230 g alcohol per week for 6 months decreased hypertension, and in non-white individuals (100). Blood
blood pressure only by 2/2 mmHg (85). Two meta-analyses pressure reduction with endurance training and with
calculated that a reduction of alcohol consumption may dynamic resistance training is greater in hypertensive
reduce blood pressure by approximately 4/2 mmHg (49,86). patients compared with normotensive individuals (100).
In summary, moderation in alcohol intake to two drinks However, a recent meta-analysis in young adults with pre-
per day in men and one to two drinks per day in women is hypertension and hypertension suggested that guideline-
a sensible recommendation for hypertensive patients. recommended exercise interventions may have a transient
Smoking increases the relative risks for coronary heart blood pressure-lowering effect that may not be sustained
disease in hypertensive individuals with low or high cho- in the longer term (101).
lesterol levels by 3.0 and 9.7 in men and 2.3 and 15.9 in In patients with treatment-resistant arterial hyperten-
women, respectively (87). Some studies suggested that sion, treadmill training for 8–12 weeks reduced systolic
chronic smokers have similar blood pressure (88), and and diastolic daytime ambulatory blood pressure by 6/12
in the case of light smokers even lower blood pressure and 3/7 mmHg, respectively (102). The result is of special
than nonsmokers (89). However, the finding that day- interest because these patients are at particularly high car-
time ambulatory blood pressure was increased in smok- diovascular risk. In summary, increased levels of physical
ers whereas office blood pressure was similar in smokers activity reduce blood pressure and cardiovascular mortal-
and nonsmokers may explain the earlier findings (90). ity in hypertensive patients (103). Exercise intensity and
Furthermore, smoking may diminish the response to anti- the exact type of exercise need to be tailored to the ability
hypertensive therapy (91), thus smoking cessation should of the patient and require individualized counselling.
be recommended in all patients. Besides the possible posi-
tive role on blood pressure and blood pressure treatment,
the reduction of cardiovascular risk through smoking ces-
sation speaks for itself (92,93). However, nicotine is highly CONCLUSIONS
addictive, and therefore simple advice to stop smoking
rarely suffices. Behavioural interventions, nicotine replace- There is abundant evidence that lifestyle changes and
ment therapy or other pharmacological smoking cessation dietary measures are effective to prevent the development
aids may be considered. of hypertension and reduce blood pressure in hyperten-
sive patients. Figure 37.3 summarizes the most commonly
recommended non-pharmacological measures. Additional
measures such as relaxation methods and others are on
EXERCISE the horizon but are less well characterized than those
described in this chapter (4). Lifestyle modification coun-
A large body of epidemiological studies demonstrated that selling should be offered to all patients with or at risk of
physical fitness is associated with reduced cardiovascular hypertension, and particularly in those with additional
morbidity and mortality. Multimodal interventions inte- cardiovascular risk factors. The main challenge remains
grating physical exercise are included in recent European the optimal implementation of such lifestyle strategies.
guidelines on cardiovascular disease prevention (94). Apart from advice from healthcare professionals, govern-
While earlier recommendations often focused on aero- ment legislation and regulation as well as societal change
bic exercise, now the specific benefits of endurance and will be necessary to aid patients in choosing and sustain-
strengthening exercises are recognized. Depending on ing healthy lifestyle decisions.
308 Manual of Hypertension of the European Society of Hypertension
HT
DASH diet
NT
HT Systolic
Sodium restriction
to 1.8 g per day Diastolic
NT
HT
Potassium supplementation
(50 mmol per day)
NT
HT
Exercise (120–150 minutes/week
of walking, jogging or biking)
NT
HT
Alcohol restriction from
3–6 to 1–2 drinks per day
NT
0 –5 –10 –15
∆ blood pressure (mmHg)
Figure 37.3 Estimates of blood pressure-lowering effects of commonly recommended non-pharmacological interventions.
The results are based upon the data presented in this chapter. It should be recognized, though, that blood pressure-lowering
effects of combinations of these measures are not necessarily additive.
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THE PROTECTIVE
CARDIOVASCULAR EFFECTS OF 38
ANTIHYPERTENSIVE TREATMENT
* Professor Alberto Zanchetti died in March 2018, after sending his chapter in collaboration with Dr. Thomopoulos. His contribution to the whole series
of the ESH books on hypertension has been outstanding. He will be sadly missed by his colleagues and friends.
312 Manual of Hypertension of the European Society of Hypertension
Absolute risk
Difference reduction
Trials SBP/DBP Standardized RR Standardized RR per 1000 pts/5 years
Outcome (n) (mmHg) (95% CI) (95% CI) (95% CI)
Figure 38.1 Relative and absolute risk reduction of various outcomes in trials of blood pressure lowering. Analysis includ-
ing intentional and non-intentional trials exclusively in hypertensive patients. Abbreviations: CHD, coronary heart disease;
CI, confidence intervals; CV, cardiovascular; DBP, diastolic blood pressure; HF, heart failure; n, number; NNT, number
needed to treat; pts, patients; RR, Mantel-Haenszel risk ratios; SBP, systolic blood pressure. Standardized RR is to an SBP/
DBP reduction of 10/5 mmHg. The column Absolute Risk Reduction reports number (and 95% CI) of events prevented every
1000 patients treated for 5 years with a standardized RR. NNT are numbers (and 95% CI) of patients needed to treat for 5
years to prevent one event. (From data in Thomopoulos C et al. J Hypertens 2014; 32: 2285–2295.)
contemporary medicine. Meta-regression analyses have mmHg) was first raised in 2009 (7), when we called
also shown that the risks of stroke, heart failure and car- attention to the fact that the few trials conducted in the
diovascular death are related in a semi-logarithmic way 1970s–1980s to what was then defined as ‘mild’ hyperten-
to the extent of the systolic, diastolic and pulse pressure sion could not be taken as reliable evidence supporting
reductions, without a preference for any of these blood treatment of grade 1 hypertension, as patients included
pressures (Figure 38.2) (4). in the ‘mild’ hypertension trials had been recruited on
the basis of DBP values only (often in a range much wider
than the 90–99 mmHg range now used for grade 1 hyper-
tension). Furthermore, in most of the ‘mild’ hypertension
INITIATION OF ANTIHYPERTENSIVE trials SBP was not considered among recruitment criteria,
TREATMENT and in some of them SBP could be as high as 200 mmHg.
In 2012, a Cochrane collaboration tried to overcome
Despite the overwhelming evidence of the benefits of this difficulty by making an individual patient meta-anal-
blood pressure-lowering treatment, trial-based evidence ysis of the ‘mild’ hypertension trials including only data
about the systolic blood pressure threshold at which treat- from those patients whose blood pressure values were in
ment should be initiated is weak. The 2013 ESH-ESC the grade 1 range (8). This meta-analysis was unable to
guidelines (6) give a strong recommendation (class I, level show a significant reduction in the risk of any cardiovascu-
A) to promptly initiate antihypertensive drug treatment ‘in lar outcome alone or in combination. Although based on a
individuals with grade 2 and 3 hypertension with any level small number of patients and events (e.g. only 30 strokes)
of cardiovascular risk’, but advise to consider ‘initiation these negative results were widely publicized as warning
of antihypertensive drug therapy in grade 1 hypertensive against overtreating grade 1 hypertension, and obviously
patients at low to moderate risk only when blood pressure influenced the cautious attitude all guidelines had when
is within this range at several repeated visits or elevated discussing management of grade 1 hypertension.
by ambulatory blood pressure criteria, and remains within Since 2013, new analyses of available data have been
this range despite a reasonable period with lifestyle mea- conducted. The Blood Pressure-Lowering Treatment
sures’ (6). Despite all these precautions, this recommenda- Trialists’ Collaboration (BPLTTC) made an attempt to
tion is classified only as class IIa (conflicting evidence and/ increase the number of patients and events by including
or divergence of opinion) and level of evidence B. other individuals from other trials with baseline SBP/
The issue about the poor level of evidence favouring DBP in the grade 1 range (9). This extended meta-analysis
active blood pressure lowering in individuals with sys- showed significant reductions in stroke, major cardiovas-
tolic blood pressure (SBP)/diastolic blood pressure (DBP) cular events, cardiovascular and all-cause mortality. The
values within what is usually defined grade 1 (or stage 1) BPLTTC conclusions, however, were limited by the fact
hypertension (SBP 140–159 mmHg and/or DBP 90−99 that about 50% of the added individuals were already
The Protective Cardiovascular Effects of Antihypertensive Treatment 313
1.0
p = 0.55
0.7 p = 0.028
p = 0.28 Stroke
0.4 p < 0.001 CHD
RR
p = 0.069 HF
CV death
All-cause death
0.1
0 –10 –20 –30 –40
D-SBP (mmHg)
RR
p = 0.061
0.1 0.1
0 –10 –20 –25 0 –5 –10 –15
D-DBP (mmHg) D-PP (mmHg)
Figure 38.2 Relationships of outcome reductions to the extent of blood pressure reductions. Metaregressions of risk ratios on
absolute blood pressure differences (active treatment group minus placebo or less active treatment group) in 47 trials of inten-
tional blood pressure lowering. Regressions relative to stroke are in green; CHD in blue; HF in red; CV death in orange; All-
cause death in brown. Abbreviations: CHD, coronary heart disease event; CV, cardiovascular; D-DBP, diastolic blood pressure
difference; D-PP, pulse pressure difference; D-SBP, systolic blood pressure difference; HF, heart failure; RR, Mantel-Haenszel
risk ratios. (From Thomopoulos C et al. J Hypertens 2014; 32: 2285–2295, by courtesy of Journal of Hypertension.)
under some blood pressure-lowering treatment at base- groups). Also, in the 8975 patients of this meta-analysis,
line, and therefore could not be correctly defined as grade blood pressure-lowering treatment significantly decreased
1 hypertensive patients. Furthermore, most of the indi- the risk of stroke, coronary events, the composite of stroke
viduals added were diabetic, with the consequence that and coronary events and all-cause death (Figure 38.3b).
the total cardiovascular risk in the placebo group of the Absolute risk reduction was large, amounting to 21 strokes,
BPLTTC meta-analysis (6.2% cardiovascular death in 10 34 major cardiovascular events and 19 deaths prevented
years) was beyond the limits of low-moderate risk (which every 1000 patients treated for 5 years (10).
normally is <5%). The results of this meta-analysis (10) have been further
Another, more powerful meta-analytical approach has supported by the recently published results of the Heart
recently been followed by our group. Among all blood pres- Outcomes Prevention Evaluation (HOPE)-3 trial (11),
sure-lowering trials, we have chosen those in which patients which has shown a significant 27% reduction of major car-
had been randomized in absence of current treatment, in diovascular outcomes in patients at an intermediate level
order to avoid incorrectly labelling hypertension grade. We of cardiovascular risk with baseline SBP values higher than
identified 32 trials (including 104,359 patients) that could 143.5 mmHg (mean 154 mmHg).
be classified as investigating grade 1, 2 or 3 hypertension on On the whole, despite the absence of a large random-
the basis of the average baseline blood pressure in each trial ized placebo-controlled trial specifically investigating
(10). Significant reductions of the risk of all major cardio- blood pressure-lowering treatment in patients with grade
vascular outcomes were found to be induced by blood pres- 1 hypertension at low to moderate cardiovascular risk,
sure lowering at all grades of hypertension with no trend the data of our meta-analysis (10) and the results of the
toward different relative risk reductions at different hyper- HOPE-3 subgroup analysis (11) provide a much stronger
tension grades. In particular, six trials in 16,036 individuals evidence-based support in favour of initiating active drug
were classified as on grade 1 hypertension, and their meta- treatment in grade 1 low-moderate risk hypertensives (12)
analysis showed significant reductions in the risk of stroke, than the arguments that could be used in the 2013 ESH-
coronary events, the composite of stroke and coronary ESC guidelines (6).
events, cardiovascular and all-cause deaths (Figure 38.3a). A related question is whether there is evidence support-
As some of these trials included patients at high cardiovas- ing initiation of antihypertensive treatment in individuals
cular risk, another meta-analysis was done only including with blood pressure values in the range defined as high-
trials or trial subgroups with mean baseline SBP/DBP values normal or pre-hypertension (SBP 120–139 mmHg, DBP
in the grade 1 range and a low to moderate cardiovascular 80–90 mmHg), and whether a decision should depend
risk (<5% cardiovascular death in 10 years in the control on the level of their cardiovascular risk. We have recently
314 Manual of Hypertension of the European Society of Hypertension
Absolute
(b) Events
Baseline Difference risk reduction NNT
(n/patients)
Trials SBP/DBP SBP/DBP RR Standardized RR Standardized RR 1000 pts/5 years 5 years
Outcome (n) (mmHg) (mmHg) Treated Controls (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
Stroke 4 146/91 –7.1/–4.5 71/4061 110/4012 0.58 (0.34–0.99) 0.33 (0.11–0.98) –21 (–26, –1) 47 (39, 1301)
CHD 5 145/91 –6.5/–4.2 114/4729 129/4246 0.75 (0.58–0.96) 0.68 (0.48–0.95) –12 (–18, –2) 86 (55, 531)
Stroke + CHD 4 146/91 –7.1/–4.5 159/4061 227/4012 0.69 (0.57–0.85) 0.51 (0.36–0.75) –34 (–43, –19) 29 (23, 54)
CV death 4 146/91 –7.1/–4.5 53/4061 74/4012 0.71 (0.50–1.01) 0.57 (0.32–1.02) –9 (–14, +1) 110 (72, –2223)
All-cause death 4 146/91 –7.1/–4.5 90/4061 133/4012 0.67 (0.51–0.87) 0.53 (0.35–0.80) –19 (–25, –8) 54 (40, 119)
0.1 0.2 0.5 1 2 5
Active better Control better
Figure 38.3 Effects of blood pressure lowering in trials of grade 1 hypertension. Meta-analyses of trials in which average
baseline SBP/DBP were in the range 140–159/90–99 mmHg (all trials without or minimal baseline antihypertensive drugs
at randomization). (a) All grade 1 trials independent of total cardiovascular risk. (b) Only grade 1 trials or trial subgroups at
low-moderate risk. Abbreviations: CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure;
RR, risk ratios. Standardized RR is to an SBP/DBP difference of 10/5 mmHg. (From Thomopoulos C et al. J Hypertens 2014;
32: 2296–2304, by courtesy of Journal of Hypertension.)
identified 24 randomized controlled trials providing data than 130 mmHg in high cardiovascular risk patients (e.g.
on 47,991 individuals with high-normal or normal blood post-stroke or post-myocardial infarction) and in hyper-
pressure in absence of baseline treatment. When these tri- tensives with diabetes, was unsupported by trial evidence
als were stratified according to total cardiovascular risk, or supported by controversial evidence. As a consequence,
no significant benefits were found in those including indi- the 2013 ESH-ESC guidelines (6) recommended a SBP tar-
viduals at low-moderate risk (less than 5% cardiovascular get of less than 140 mmHg in most groups of hyperten-
mortality in 10 years), whereas a significant reduction in sive patients (those at low-moderate cardiovascular risk,
stroke risk was found in those trials including individu- those with diabetes, those with previous stroke or tran-
als at high-very high cardiovascular risk, mostly because sient ischaemic attack, those with coronary heart disease,
of symptomatic cardiovascular disease (13) (Figure 38.4). those with diabetic or nondiabetic chronic renal disease),
In conclusion, only individuals with symptomatic cardio- though with a different class of recommendation and a
vascular disease should consider blood pressure-lowering different level of available evidence (6).
treatment when their blood pressure is in the high-normal Since 2013 new data and new analyses have become
and normal range. available. In 2014 we published a meta-analysis of 32
blood pressure-lowering trials (including 128,232 individ-
uals), showing that risk of all outcomes could be signifi-
BLOOD PRESSURE TREATMENT TARGETS cantly reduced when SBP in the treated group was lowered
to mean values less than 150 mmHg and compared to SBP
Although the target values to which blood pressure should values above 150 mmHg in the control group, and when
be brought by drug treatment to optimize treatment bene- it was lowered to mean values less than 140 mmHg in the
fits is of prominent interest for the patients and the treating treated group and compared to values above 140 mmHg in
physician, it is surprising that, among the large number of the control group. However, when SBP values below were
antihypertensive treatment trials (as many as 72), so few compared to SBP above the cutoff of 130 mmHg, only
(only 14) have compared the effects of more versus less stroke and all-cause death were significantly reduced (10).
intense blood pressure-lowering treatment, and even less In November 2015, the results of a large National
have investigated precise SBP or DBP targets. Institutes of Health (NIH)-sponsored trial comparing a
When we first reviewed the subject in 2009 (7), we SBP goal of less than 120 mmHg with the usual goal of
showed that the recommendation frequent in guidelines less than 140 mmHg were published (16). The Systolic
current at the time (14,15), namely, to lower SBP to less Blood Pressure Intervention Trial (SPRINT) was stopped
The Protective Cardiovascular Effects of Antihypertensive Treatment 315
Figure 38.4 Relative risk and absolute risk reduction of various morbidity and mortality outcomes in individuals with
high-normal or normal blood pressure: Comparison of individuals at low-moderate (L-M) and high-very high (H-VH)
cardiovascular risk. Risk ratios (RR) are standardized to an SBP/DBP difference of 10/5 mmHg. Rectangles at the right
represent absolute risk reductions expressed as number (and 95% confidence intervals) of events prevented every 1000 indi-
viduals treated for 5 years with a standardized RR. P-values for heterogeneity refer to differences in standardized risk ratios
and, respectively, absolute risk reductions between individuals at low-moderate versus high-very high cardiovascular risk.
Abbreviations: CHD, coronary heart disease; CV, cardiovascular; DBP, diastolic blood pressure; HF, heart failure; H-VH, high-
very high; L-M, low-moderate; n, number; pts, patients; RR, risk ratio; SBP, systolic blood pressure. (From Thomopoulos C
et al. J Hypertens 2017; 35: 2150–2160, by courtesy of Journal of Hypertension.)
early because of a significant reduction of the primary all outcomes were lower than 1, hence there was no indi-
endpoint in the group with more intense blood pressure- cation of a J-shaped relationship of the risk of any major
lowering treatment. The results of SPRINT have been outcome with achieved SBP, at least down to values several
received with obvious interest but have also raised some mmHg below 130.
perplexities. Among the latter, it has been found surpris- Since the publication of the 2013 ESH-ESC guidelines,
ing that stroke, the cardiovascular outcome known to be our meta-analyses have also provided further evidence
most sensitive to blood pressure decrease, was not signifi- on the DBP target: both meta-analyses of trials in which
cantly reduced in SPRINT. The most important benefit of achieved mean DBP values were below 90 mmHg in
the lower blood pressure goal in SPRINT was a marked the actively treated group and above 90 mmHg in the
reduction in heart failure risk, which may have resulted control group, and below and above 80 mmHg showed
from a larger use of diuretics and renin−angiotensin significant reductions of all major outcomes (10,19).
system blockers in the group with lower blood pressure Admittedly, in trials in which DBP achieved values
(17). The point has also been raised that the blood pres- below (vs. above) 80 mmHg, SBP also achieved signifi-
sure measurements in SPRINT may hardly be compara- cantly lower values in the active versus placebo treat-
ble with those used in other trials (as well as in current ment groups, and it is therefore difficult to ascribe the
medical practice), because in SPRINT blood pressure was benefit of morbidity and mortality risk reduction to the
measured by an automatic device in absence of a doctor lower DBP rather than to the lower SBP. In any case,
or nurse, and the reported values were likely lower than our meta-analyses (10,19) show that DBP values several
those to be expected by the use of conventional office mmHg lower than 80 mmHg are at least safe, being asso-
blood pressure (18). ciated with a reduction rather than an increase in cardio-
After the publication of SPRINT, we have updated our vascular risk.
meta-analysis of blood pressure-lowering trials stratified In conclusion, the recommendations given in 2013 by
according to the three different cutoffs of achieved SBP all major guidelines (6,21) to achieve SBP and DBP targets
(below and above 150, 140 and 130 mmHg). The meta- lower than 140 and, respectively, 90 mmHg can be placed
analysis now includes 35 trials on 138,452 individuals and now, thanks to new meta-analyses, on much firmer ground,
shows (Figure 38.5) that lowering SBP below 130 mmHg and therefore with a greater strength. The additional rec-
can significantly reduce most types of outcomes (stroke, ommendation can now be given that achieving SBP val-
coronary events, cardiovascular and all-cause death); how- ues lower than 130 mmHg and DBP values lower than
ever, absolute outcome reduction was definitely smaller 80 mmHg appears safe and can be associated with some
than at higher SBP cutoffs (19), and permanent treatment further benefit, provided addition of drugs or dose increase
discontinuations for adverse events were significantly are not incrementing adverse events and consequently the
greater (20). It should be emphasized, however, that even risk of permanent treatment discontinuation (20). Whether
for SBP values less than 130 mmHg mean risk estimates of these recommendations are valid for all phenotypes of
316 Manual of Hypertension of the European Society of Hypertension
Figure 38.5 Effects of blood pressure lowering in trials of active treatment versus placebo and more versus less intense
treatment (considered together), stratified in three strata with mean SBP achieved by active or more intense treatment versus
mean SBP achieved in the placebo or less intense treatment: 140–149 versus >150 mmHg; 130–139 versus >140 mmHg;
<130 versus >130 mmHg. Standardized RR is to an SBP/DBP difference of −10/−5 mmHg. The histograms of the column
Absolute Risk Reduction represent the numbers (and 95% CI) of events prevented every 1000 patients actively or more
intensely treated for 5 years using the standardized RR. The two columns headed P-value for trend refer, the first, to the
standardized RR, and the second to Absolute Risk Reduction. Mean SBP/DBP achieved in the three strata of achieved SBP
were (from above downward): 143.3/76.4 versus 157.1/82.1; 137.2/81.0 versus 144.3/84.8; 125.8/76.3 versus 134.9/79.4.
Abbreviations: BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; DBP, dia-
stolic blood pressure; HF, heart failure; pts, patients; RR, Mantel-Haenszel risk ratio; SBP Systolic blood pressure. (From
Thomopoulos C et al. J Hypertens 2016; 34: 613–622, by courtesy of Journal of Hypertension.)
hypertension, and particularly in the elderly or in second- drug costs (older drugs are commonly cheaper than newer
ary prevention, remains to be ascertained by further stud- ones) or on the assumption of specific protective properties
ies, such as the ongoing Stroke in Hypertension Optimal of some agents independent of the blood pressure-lowering
Treatment (SHOT) trial (17), and further analyses. action or on the frequency of adverse effects, and different
recommendations have been given in different guidelines.
However, there have been a very large number of ran-
domised controlled trials (RCTs) comparing the effects
ARE THERE CLINICALLY RELEVANT on fatal and nonfatal cardiovascular events of different
classes of antihypertensive agents between themselves
DIFFERENCES IN THE PROTECTIVE or with placebo, and we have recently completed and
CARDIOVASCULAR EFFECTS OF DIFFERENT published three different sets of meta-analyses that help
CLASSES OF ANTIHYPERTENSIVE DRUGS? doctors in making informed decisions (22). The body of
evidence available consists of (i) 55 RCTs comparing in
There are a number of pharmacologically different classes of 195,267 individuals the effects on cardiovascular events
blood pressure-lowering drugs that, because of this property, of each of the five major classes of antihypertensive drugs
have been widely used in treating arterial hypertension. The (diuretics, beta-blockers, calcium antagonists, angioten-
existence of multiple classes and their discovery and intro- sin-converting enzyme (ACE) inhibitors and angiotensin
duction into therapeutic usage at different times have often receptor blockers) versus placebo (23); (ii) 50 RCTs directly
stimulated experts at developing and discussing ranks or (head-to-head) comparing the cardiovascular disease risk
orders of choice or step-care systems, based sometimes on of at least two different classes of drugs (24); and (iii) 38
The Protective Cardiovascular Effects of Antihypertensive Treatment 317
(a) (b)
Each class vs. Placebo Each class vs. all other classes
D BB CA ACEI ARB D BB CA ACEI ARB
Stroke Stroke
CHD CHD
HF HF
CV death CV death
Figure 38.6 Comparisons of each of five major classes of antihypertensive agents versus placebo and B, comparisons
of each class versus all other classes on seven major outcomes and treatment discontinuations because of adverse events.
The effect of each drug class indicated on the top of the columns versus the comparator (a: placebo, b: all other drugs) are
indicated as follows: green, better effect; yellow, non-significant difference in effect; red, worse effect. Abbreviations: D,
diuretics; BB, beta-blockers; CA, calcium antagonists, ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin
receptor blockers. CHD, coronary heart disease events; CV, cardiovascular; HF, Heart failure. (From data in Thomopoulos C
et al. J Hellenic Soc Hypertens 2017; 26: 160–165; Thomopoulos C et al. J Hypertens 2015; 33: 195–211; Thomopoulos C et al.
J Hypertens 2015; 33: 1321–1341.)
318 Manual of Hypertension of the European Society of Hypertension
important task of practicing physicians, together with an 16. The SPRINT Research Group. A randomized trial of intensive
increasing use of two or three drug combinations in single versus standard blood-pressure control. N Engl J Med 2015; 373:
2103–2116.
pills. Reducing the number of pills to be taken daily has 17. Zanchetti A, Liu L, Mancia G et al. ESH-CHL-SHOT trial investi-
been shown to improve adherence and increase the rate of gators. Continuation of the ESH-CHL-SHOT trial after publica-
blood pressure control. tion of the SPRINT: Rationale for further study on blood pressure
targets of antihypertensive treatment after stroke. J Hypertens
2016; 34: 393–396.
18. Kjeldsen SE, Lund-Johansen P, Nilsson PM et al. Unattended
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1206–1252.
THE NEPHROPROTECTIVE EFFECT
OF ANTIHYPERTENSIVE 39
TREATMENT
(19), increased fat accumulation in the renal sinus (‘fatty outcome with a systolic BP target <120 mmHg versus a tar-
kidney’) (20) or sympathetic hyperactivity (21). However, get of <140 mmHg (44). In consequence, it was proposed
elevated BP and the amount of albumin present in urine to extrapolate BP targets currently recommended in the
are the two most relevant factors facilitating the progres- general population (<140/90 mmHg) to those patients
sion of renal failure till ESRD (11). Together, BP and albu- with CKD who do not have elevated albuminuria (8,9).
minuria are related to the progression of arteriosclerosis Nevertheless, considering that increased urinary albumin
and target-organ damage (22,23) and are independent risk excretion is associated with higher cardiovascular and renal
factors for cardiovascular and all-cause mortality (24). In risk, guidelines suggested a BP target ≤130/80 mmHg for
recent years, some parameters related to blood pressure patients with CKD and increased albuminuria, both with
have been linked to progression of kidney damage and and without diabetes (3,8).
cardiovascular risk: increased aortic pulse pressure that Recently, the publication of the renal data of the Systolic
could be associated with alteration of renal hemodynam- Blood Pressure Intervention Trial (SPRINT), showed that
ics through the pulsatile characteristic of BP (25), the visit- targeting SBP to values <120 mmHg compared with
to-visit BP variability as an independent determinant of <140 mmHg reduced rates of major CV events and all-
deterioration of renal function (26), and the influence of cause death without evidence of effect modifications by
out-of-office BP values on progression of renal and cardio- CKD or deleterious effect on the main kidney outcome
vascular disease (27,28,29). Moreover, new methods to (45). However, more intense BP lowering resulted in more
estimate renal function could contribute to a better identi- frequent episodes of acute kidney injury (AKI), in most
fication of high-risk patients (30–33). cases mild in nature and with a total recovery (46) and in
The renoprotection provided by antihypertensive agents increased risk for incident CKD events, but this was out-
depends on their capacity to lower systemic BP and also weighed by cardiovascular and all-cause mortality ben-
on their specific effects on renal hemodynamics (34). This efits (47). The new Guidelines of the American College of
effect could positively or negatively influence intraglomer- Cardiology and the American Heart Association (48) con-
ular pressure through the facilitation of the transmission sider that attaining BP values below 130/80 mmHg is an
of an uncontrolled systemic BP that, as we know, is present adequate goal for patients with CKD.
in many patients with CKD even while on treatment and/
or through the effect opening or closing the efferent arteri-
ole (34). A meta-analysis of 11 randomized controlled trials
assessed the effect of systolic BP (SBP) on the renal outcome RECENT TRIALS FOCUSING ON RENAL
in 1860 patients with nondiabetic renal disease (35). The OUTCOMES
lower risk for progressive renal disease was observed when
SBP ranged from 110 to 129 mmHg. Higher levels of SBP RAAS blockade is strongly recommended by most recent
were associated with a sudden increase in renal risk, regard- guidelines as the initial regimen of choice for renoprotec-
less of the drug used. Values of achieved SBP < 110 mmHg tion based on the results of several clinical trials and meta-
were, interestingly, associated with an increased renal risk, analyses that have, with hardly any exception, revealed
consistent with the potential negative renal effects of a larger reductions in proteinuria as well as a diminished
drastic reduction in renal perfusion pressure when renal velocity of progression to the development of renal end-
vasculature has suffered the consequences of a maintained points with RAAS blockade as compared with other anti-
elevation of BP and nephrosclerosis has developed (36). hypertensive regimens in both diabetic and nondiabetic
Independently of the level of BP attained, antihypertensive nephropathies (49). As an example, the previously men-
regimens that include an angiotensin-converting enzyme tioned meta-analysis conducted by Jafar et al. (35) suggests
inhibitor (ACEi) were more effective than regimens with- that ACE inhibition was associated with overall relative
out it for slowing the progression of nondiabetic renal risk reductions of 30–40% for doubling of serum creati-
disease. Similar data were found in a secondary analysis nine and/or ESRD in nondiabetic nephropathy, with the
of the Irbesartan Diabetic Nephropathy Trial (IDNT); the greater benefits being seen in patients with heavier pro-
risk for reaching a renal endpoint in diabetic nephropathy teinuria. Such data indicate that the greater renoprotec-
is reduced progressively and continuously at lower levels tion that is observed with RAAS blockade is mediated by
of the achieved SBP. An optimal renoprotective effect was BP-independent mechanisms.
demonstrated for SBP between 120−130 mmHg, with no Similar positive results with suppression of the RAAS,
further benefits below 120 mmHg (37). beyond BP control, were seen in the patients included in the
Previous guidelines for kidney disease recommended a Reduction of Endpoints in NIDDM with the Angiotensin
BP target <130/80 mmHg for all patients with CKD, irre- II Antagonist Losartan (RENAAL) and IDNT studies in
spective of the level of urine protein (1,7,8), based on obser- patients with overt diabetic nephropathy, and two angio-
vational data in general population and in patients with tensin receptor blockers (ARBs), losartan and irbesartan,
renal disease (38,39,40). Since the publication of previous were compared to placebo and placebo or amlodipine,
guidelines, several manuscripts have emphasized that tight respectively (50,51). The advantage of RAAS suppression
BP control may have adverse effects (41,42). Moreover, sev- was also demonstrated for the prevention of the devel-
eral recent trials have not shown a benefit of lower BP targets opment of overt diabetic nephropathy in the Irbesartan
in patients without proteinuria. In the African American in Patients with Type 2 Diabetes and Microalbuminuria
Study of Kidney Disease and Hypertension, there was a (IRMA) study (52). This study showed that treatment with
benefit associated with the lower BP target among patients the ARB irbesartan was more effective than placebo in pre-
with a urine protein/creatinine ratio (PCR) >220 mg/g, but venting the development of macroalbuminuria and also
not among those with a lower PCR (43). Similarly, in the in favouring regression to normoalbuminuria in microal-
Action to Control Cardiovascular Risk in Diabetes trial, no buminuric patients with type 2 diabetes, despite a similar
benefit was found with regard to the primary composite BP control.
The Nephroprotective Effect of Antihypertensive Treatment 321
The concept of nephroprotection during dual blockade meta-analysis shows that in those not primarily devoted
of RAAS with combination therapy of an ACEi and an ARB to renal function this was not the case, in particular when
or with either of these two and aliskiren have been dis- Antihypertensive and Lipid-Lowering treatment to pre-
carded because of the absence of positive results in differ- vent Heart Attack Trial (ALLHAT), which mostly drove
ent trials (8,48). the result of the meta-analysis due to the high number of
In recent years, aldosterone is regarded as a mediator patients included, is considered (64). With respect to the
of progressive renal damage (53). It is therefore relevant time of follow-up, it is well recognized that, only in the
that aldosterone antagonists reduce proteinuria in patients presence of albuminuria, short follow-up periods of 2–5
with chronic kidney disease, even if they are already on a years are adequate to show potential differences in renal
RAAS blocker (54,55). In a meta-analysis, the addition of protection (65). Preliminary data with longer follow-up
an aldosterone antagonist to an ACEi or an ARB, decreased periods indicate that suppression of the RAAS is required
proteinuria by an estimate of 30–40% (55). A limiting fac- for a better renal protection (66).
tor for the wide use of aldosterone antagonists is linked Even so, data from trials devoted to hypertension and
with the risk of inducing hyperkalaemia, which becomes a to renal disease have come to clarify the positive role of
prominent concern as renal function deteriorates (54,55). calcium antagonists in renal protection when used either
The recent appearance of new potassium binders could alone or in combination with drugs suppressing the RAAS
facilitate the maintenance of RAAS blockade including an (67). More recently, the Delapril and Manidipine for
ACEi or an ARB plus an aldosterone blocker in patients Nephroprotection in Diabetes (DEMAND) trial failed to
with stage 3–4 or more advanced CKD (56) because of slow GFR decline after 3.8 years of median follow-up, but
their capacity to control increases in serum potassium that safely ameliorated CVD, retinopathy and neuropathy in
impede adequate RAAS blockade. hypertensive type 2 diabetic patients receiving combined
These data indicate that a better degree of suppression manidipine and delapril therapy (68). It has also been
of the RAAS is obtained with the combination therapy shown that patients with hypertension or established CVD
but leave open the possibility that doses higher than those and CKD seem to be particularly good responders to the
normally used for each component could be equally posi- suppression of the RAAS (69,70) and to the administration
tive as the combination at lower doses (57). In this sense, of a statin (71) and aspirin (72). The Anglo-Scandinavian
recently published data have shown that up-titration of the Cardiac Outcomes Trial – Blood Pressure-Lowering Arm
dose of an ARB improves its capacity to diminish albumin- (ASCOT-BLPA) showed a 15% reduction of development
uria (58,59). Up-titration of the dose of an ARB is impor- of renal impairment in high-risk hypertensive patients
tant because the only head-to-head comparison between receiving a combination of amlodipine and perindo-
an ACEi and an ARB, performed in the Diabetics Exposed pril (73). Moreover, the Avoiding Cardiovascular Events
to Telmisartan and enalaprIL (DETAIL) study (60) for the through Combination Therapy in Patients Living with
long-term renal outcome in mostly microalbuminuric type Systolic Hypertension (ACCOMPLISH) trial showed that
2 diabetics, showed that telmisartan offered comparable patients with hypertension, chronic kidney disease, and
nephroprotection to enalapril. These new options, together minimal or no albuminuria who achieved blood pressure
with a multifactorial approach, should be considered of 130/80 mmHg with an initial combination of benaz-
because the traditional chronic RAAS suppression does not epril plus amlodipine have lower rates of cardiovascular
seem to consistently maintain its protective capacity on the events and slower progression of chronic kidney disease
development and evolution of albuminuria both in dia- than do patients treated with a combination of benazepril
betic and nondiabetic hypertensive patients (61). plus hydrochlorothiazide (74).
a radical change in the treatment of these patients. 16. Park M, Shlipak MG, Katz R et al. Subclinical cardiac abnormali-
Studies like Empagliflozin Cadiovascular Outcomes and ties and kidney function decline: The multi-ethnic study of
atherosclerosis. Clin J Am Soc Nephrol 2012; 7: 1137–1144.
Mortality in Type 2 Diabetes (EMPA-REG [85,86]), The 17. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet 2012;
Canagliflozin Cardiovascular Assessment Study (CANVAS 380: 756–766.
(87)), Liraglutide Effect and Action in Diabetes: Evaluation 18. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease
of Cardiovascular Outcome Results (LEADER (88,89)) after acute kidney injury: A systematic review and meta-analysis.
Kidney Int 2012; 81: 442–448.
and the Trial to Evaluate Cardiovascular and Other Long- 19. Terata S, Kikuya M, Satoh M et al. Plasma renin activity and the
term Outcomes with Semaglutide in Subjects with Type 2 aldosterone-to-renin ratio are associated with the development of
Diabetes (SUSTAIN-6 [90]) trials have shown very positive chronic kidney disease: The Ohasama Study. J Hypertens 2012; 30:
results for major adverse cardiovascular events (MACE) 1632–1638.
20. Foster MC, Hwang SJ, Porter SA et al. Fatty kidney, hyperten-
and progression of renal disease which are accompa- sion and chronic kidney disease. The Framingham Heart Study.
nied, among other positive mechanisms, by a significant Hypertension 2011; 58: 784–790.
decrease in body weight and BP. Both mechanisms par- 21. Vink EE, de Jagr RL, Blankestijn PJ. Sympathetic hyperactivity in
ticipate in the improvement in MACE, albeit the descent is chronic kidney disease: pathophysiology and (new) treatment
options. Curr Hypertens Rep 2013; 15(2): 95−101.
rather modest (around 5 mmHg in SBP and less than 5% 22. Turner ST, Rule AD, Schwartz GL et al. Risk factor profile for
in body mass index) (39). chronic kidney disease is similar to risk factor profile for small
In summary, strict BP control, adequate suppression artery disease. J Hypertens 2011; 29: 1796–1801.
of the RAAS, and an integral protection of the increased 23. Shah AM, Lam CSP, Cheng S et al. The relationship between
global CV risk are required in every patient presenting renal impairment and left ventricular structure, functions and
ventricular-arterial interaction in hypertension. J Hypertens 2011;
with any stage of CKD. 29: 1829–1836.
24. Oh SW, Baek SH, Kim YC et al. Mild decrease in estimated
glomerular filtration rate and proteinuria are associated with
all-cause and cardiovascular mortality in the general population.
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ANTIHYPERTENSIVE DRUG
CLASSES 40
Drug Half-life (h) Daily frequency of administration Usual dosing range (mg/day) Renal elimination (%)a
Fosinoprilb 12 1 10–40 50
Lisinopril 12 1 10–40 80
a Renal impairment (6), particularly if severe with an eGFR is <30 mL/min/1.73 m2 may require cautious use and dose adjustment of drugs. This may generally
apply to drugs for which the renal elimination rate is at least 50%.
b Prodrug.
Table 40.2 Pharmacokinetic characteristics and dosage of selected angiotensin receptor blockers (ARBs)
Telmisartan 24 1 20–80 –
this enzyme with concomitant drugs (e.g. azole antimy- the sympathetic nervous system resulting in tachycardia
cotics) will increase losartan levels but decrease EXP-3174, (2). Therefore, formulations and compounds with delayed
while inducers like rifampin will increase the clearance of onset and longer duration of action have replaced the
both losartan and EXP3174. Telmisartan may cause vari- rapid- and short-acting oral medications. DHPs were clas-
able increases in serum digoxin levels, mandating moni- sified into first, second, third or fourth generation DHP
toring digoxin levels during concomitant therapy (2). CCBs based on their sequence of development and dura-
tion of action. The first generation comprises the original
ADVERSE EFFECTS formulations of nifedipine and nicardipine (8). Their clini-
ARBs are very well tolerated and associate with treatment cal use was significantly limited by rapid onset and short
discontinuation rates due to adverse events that are similar half-life, which predispose to adverse effects. Subsequent
to placebo treatment and lower than those observed with generations of DHP CCBs comprise either first-generation
all other antihypertensive drugs (4,7). Hence cough and drugs with longer-acting formulations or CCBs with novel
angioedema are not associated with ARB treatment. All chemical structures and increasingly longer half-lives.
other aspects for adverse effects mentioned above for ACE
PHARMACOKINETICS AND DOSING
inhibitors apply also to ARBs.
CCBs have a high first-pass effect, high plasma protein bind-
ing and extensive metabolism (3). During repeated oral
CALCIUM CHANNEL BLOCKERS administration, bioavailability and half-life may increase
MECHANISM OF ACTION because of saturation of hepatic metabolism. Both metabo-
Calcium channel blockers (CCBs) inhibit the influx of lism and pre-systemic clearance of all CCBs are mediated
extracellular calcium through L-type channels located on by CYP3A4. In addition, all CCBs are also a substrate of
the vascular smooth muscle, cardiac myocytes, and cardiac P-glycoprotein (P-gp), an efflux transporter. Importantly,
nodal tissue (sinoatrial and atrioventricular nodes) (1). however, only verapamil and diltiazem exhibit a sig-
The inhibition of inward calcium flux causes relaxation nificant inhibiting effect on both CYP3A4 and P-gp. This
of vascular smooth muscle cells and results in vasodila- results in their potential to cause adverse drug–drug inter-
tion and lowering of BP. In cardiac muscle, contractility is actions when verapamil and diltiazem are administered
reduced and conduction velocities in cardiac nodal tissue together with drugs that are substrates of CYP3A4 and/or
are slowed (2). P-gp. In this situation, plasma concentrations of the other
substrates will rise, thereby increasing their toxicity (1).
CLASSIFICATION OF CCBs For example, verapamil and diltiazem increase the risk of
There are two main groups of CCBs, the dihydropyridine- myopathy of some statins, nephrotoxicity of cyclosporine
type (DHP) CCB (e.g. nifedipine and amlodipine) and the and tacrolimus, digoxin toxicity, and increased plasma con-
non-dihydropyridine type (non-DHP), which can be fur- centrations of novel oral anticoagulants (NOACs), thereby
ther subdivided into benzothiazepines, such as diltiazem, increasing the risk for bleeding events. On the other hand,
and phenylalkylamines, such as verapamil (Table 40.3). the use of CYP3A4 and/or P-gp inhibitors can increase the
The CCBs are a chemically diverse group with a common plasma concentrations of all CCBs and thus impair their
mechanism of action, however they differ in their relative tolerability (1).
selectivity toward cardiac versus vascular L-type calcium
channels (8). Whereas DHPs are more vasoselective than ADVERSE EFFECTS
non-DHP, non-DHPs have a more negative chronotropic The CCBs are generally well-tolerated drugs. Their adverse
and inotropic effect than DHPs. Being potent arterial vaso- effects derive from their pharmacologic properties (2).
dilators, particularly rapid- and short-acting DHP CCBs Gastrointestinal adverse effects include gastroesophageal
exhibit the potential of baroreflex-mediated activation of reflux, slowed gastrointestinal transit and constipation
328 Manual of Hypertension of the European Society of Hypertension
Table 40.3 Pharmacokinetic characteristics and dosage of selected calcium channel blockers
CCB—Dihydropyridines
Nifedipine LA 2 1 30–120 –
CCB—Non-dihydropyridines
Abbreviations: SR, sustained release; LA, long acting; ER, extended release; IR, immediate release.
a See Table 40.1; -, indicates almost no renal elimination.
(particularly with verapamil). Gingival hypertrophy can beta-adrenoceptors (beta 1, beta 2 and beta 3) in a compet-
occur with all CCBs. Flushing, headache, tachycardia itive way. Beta-blockers differ in their receptor selectivity
and peripheral oedema are more common with DHP. and the presence of additional intrinsic sympathomimetic
Peripheral oedema is not due to fluid retention but occurs activity (ISA) (1). Beta-blockers with ISA are generally not
because of the imbalance between upstream arteriolar recommended anymore. Surprisingly, the mechanisms by
vasodilatation and downstream venoconstriction, which which beta-blockers lower BP are still not fully understood,
causes transudation of fluid from the vascular compart- and several modes of action are likely to be involved. A
ments into the dependent tissues. It is dose-dependent and basic short-term mechanism is reducing cardiac output by
not responsive to diuretic therapy, and can be treatment- their negative chronotropic and inotropic effects, which is,
limiting. Oedema can slowly resolve without intervention however, accompanied by increased peripheral resistance
but is alleviated adding an RAS blocker. Verapamil and due to baroreceptor stimulation. Long-term lowering of BP
diltiazem are negative inotropic and dromotropic agents, occurs because of late lowering of peripheral vascular tone
which is the basis for their use as heart rate-lowering drugs that may occur due to the resetting of baroreceptors. Other
as alternatives to beta-blockers (2). possible mechanisms include inhibition of renin secretion
from the kidneys with a subsequent decrease in plasma
Ang II and catecholamine levels, and a central reduction
CONTRAINDICATIONS AND PRECAUTIONS in sympathetic outflow leading to reduction in vasomo-
The non-DHPs can induce severe bradycardia, impairment tor tone. An effect on prejunctional beta receptors has also
of sinoatrial and atrioventricular conduction and depres- been suggested, leading to a reduction in norepinephrine
sion of contractility; therefore, they are contraindicated release, hence adrenergic drive (2).
in patients with high-grade sinoatrial or atrioventricular
block and in severe left ventricular dysfunction (8). Non-
DHPs should not be combined, unless needed in selected CLASSIFICATION OF BETA-BLOCKERS
patients with arrhythmias, with beta-blockers because of Currently used beta-blockers can be divided into three
their shared negative effects on sinoatrial or atrioventricu- groups (2) (Table 40.5) based on their pharmacodynamics
lar nodes (Table 40.4). properties:
Table 40.4 Compelling and possible contraindications to the use of antihypertensive drugs
Mineralocorticoid receptor Acute or severe renal failure (eGFR < 30 mL/min/1.73 m2) Caution when eGFR is <45 mL/min/1.73 m2
antagonists Hyperkalaemia
used in approved doses. Overall, cardioselectiv- heart failure and liver cirrhosis) (9). They cross the blood−
ity of these drugs is still weak, dose-dependent and brain barrier to a greater extent causing an increased
decreases with higher doses. incidence of central side effects. Hydrophilic agents are
3. Beta-blockers with additional vasodilatory effects. eliminated unchanged by the kidney and tend to have lon-
Carvedilol and labetalol exhibit additional vasodila- ger half-lives (6–24 h) and more stable plasma concentra-
tory effects by blocking adrenergic alpha 1 receptors tions; e.g. atenolol and bisoprolol. They do not (or only to a
in arteries, while both compounds are non-selec- small extent) cross the blood–brain barrier, and their dos-
tive blockers of both beta 1 and beta 2 receptors. age may require adjustment in renal impairment (1).
Nebivolol is the beta-blocker with the highest beta 1 Beta-blockers are, to a varying degree, substrates of
selectivity and induces its vasodilatory effect by acti- CYP450 (e.g. CYP2D6) enzymes and can therefore be
vating nitric oxide (NO). The vasodilation enhances affected by drug interactions (1). Compounds eliminated
the BP-lowering effect of these compounds and may via metabolism in the liver (e.g. metoprolol and carvedilol)
improve their tolerability and metabolic profile. have a greater potential for drug interactions compared
to compounds renally excreted such as atenolol or biso-
prolol. Alcohol, phenytoin, rifampicin and phenobarbi-
PHARMACOKINETICS AND DOSING tal, as well as smoking, induce hepatic CYP450 enzymes
Wide variability exists in the pharmacokinetics of beta- and may decrease plasma concentrations and elimination
blockers and their lipophilic or hydrophilic properties (3). half-lives of lipophilic beta-blockers. Multiple daily dos-
Most of the drugs are well absorbed after oral administra- ing is required for several beta-blockers in order to provide
tion; peak concentrations occur 1–3 hours after ingestion. 24-hour BP-lowering effects (9). However, slow release or
Beta-blockers vary in the degree of elimination by the kid- long-acting formulations have been developed for some
ney or the liver. Lipophilic agents are eliminated primar- beta-blockers with short half-lives to allow once-daily dos-
ily by hepatic metabolism and tend to have relatively short ing. Abrupt discontinuation of beta-blockers after chronic
plasma half-lives; for example labetalol, metoprolol, pin- treatment should be avoided since it can lead to rebound
dolol and propranolol. These drugs exhibit wide interin- symptoms (BP and heart rate increase, arrhythmias and
dividual variability in bioavailability and may accumulate angina) due to upregulation of beta adrenoceptors during
in patients with reduced hepatic blood flow (i.e. congestive chronic treatment (1).
330 Manual of Hypertension of the European Society of Hypertension
Beta-blockers − Noncardioselective
Beta-blockers − Cardioselective
(ii) long term, and (iii) chronic. In the short-term phase arrhythmias) and was linked to their pro-diabetic effect.
(i.e. first 2–4 weeks), reductions in BP occur due to the The risk of hypokalaemia increases in combination with
decrease in plasma volume which reduces cardiac out- several other drugs (amphotericin B, beta 2-adrenergic
put. A countereffect elicited by consecutive rise in plasma agonists and loop diuretics).
renin and transient increase in peripheral vascular resis- Other electrolyte disturbances: Hypomagnesaemia, hypo-
tance opposes the BP-lowering effect. During the long- natraemia and hypercalcaemia.
term phase, BP is still lowered due to a gradual reduction Metabolic: Hyperglycaemia and dyslipidaemia, i.e.
in peripheral vascular resistance, while cardiac output and increase in total cholesterol, low-density lipoprotein cho-
plasma volume return to pretreatment levels. A chronic lesterol and triglyceride levels, and decrease in high-den-
antihypertensive effect is reached after about 2 months sity lipoprotein cholesterol.
due to a persistent reduction in peripheral resistance, Hyperuricemia: Thiazides, being sulphonamide-related
where a new steady state of reduced total body sodium organic acids, compete with uric acid for secretion by the
and BP is established (2). same transporter (rOAT1) at the proximal tubule. This
leads to increased reabsorption of uric acid and increase in
CLASSIFICATION serum urate levels.
Despite their structural variation, thiazide and thiazide-
like diuretics could be still considered as one group shar-
ing a similar mode of action. Thiazide diuretics include CONTRAINDICATIONS AND PRECAUTIONS
hydrochlorothiazide and bendroflumethiazide, while Although gout has been generally considered as a contra-
indapamide, chlorthalidone and metolazone are thiazide- indication for the use of thiazide diuretics, they might be
like diuretics (3). still used with caution in affected patients, particularly
when thiazides are needed to control BP in otherwise
PHARMACOKINETICS AND DOSING high-risk resistant patients and when uric acid can be con-
Thiazides are rapidly absorbed from the gastrointes- trolled by specific drug treatment (Table 40.4).
tinal tract and are highly bound to plasma proteins.
Most of them are excreted unchanged by active secre-
tion at the proximal tubules (1). Hepatic metabolism LOOP DIURETICS
is almost nonexistent except for indapamide, which MECHANISM OF ACTION
u ndergoes extensive metabolism by CYP3A4. Thiazides Loop diuretics exert their effects at the thick ascend-
exert a diuretic effect within 1–3 h that lasts for 12–24 h. ing limb of the loop of Henle, where they inhibit Na+/
Chlorthalidone, indapamide and metolazone are longer- K+/2Cl−cotransporter (NKCC). Loop diuretics are more
acting drugs, with a longer half-life and larger volume potent diuretics than thiazides, but they are shorter acting,
of distribution (due to binding to erythrocytes) than causing reflex stimulation of the RAS, which attenuates
hydrochlorothiazide. Thiazides at conventional dosages their BP-lowering efficacy (10). Because of their pharma-
are ineffective in patients with severe renal impairment codynamics and kinetic profile, they have no place in the
(eGFR <30 mL/min/1.73 m 2) because the reduced GFR routine management of hypertension in patients with
limits the filtered Na+ load reaching the distal tubule. normal renal function. They should replace thiazides,
In such patients, loop diuretics are preferred for man- however, if eGFR is <30 mL/min/1.73 m2 or their use is
agement of hypertension because of their more proxi- required to control volume status of patients; e.g. with
mal site of action. Whereas higher dosages were used in severe oedema (2).
the past, e.g. 50–200 mg of hydrochlorothiazide, there
was a successful development to reduce the recom-
mended dose of t hiazide-type diuretics to minimize their PHARMACOKINETICS AND DOSING
adverse effects. Low-dose treatment with thiazide diuret- All loop diuretics are rapidly absorbed from the gastro-
ics is particularly effective in combination therapy with intestinal tract, followed by extensive binding to plasma
other antihypertensive agents, particularly RAS blockers proteins. They exert their peak effect after 1–1.5 h. Oral
(10). Indapamide and chlorthalidone are more potent absorption of bumetanide and torsemide is high even in
BP-lowering agents when compared to hydrochlorothia- patients with severe oedema so that their effects are more
zide on milligram basis, and provide a longer duration predictable than those of furosemide; the latter shows
of action due to their greater half-lives (particularly for variable gastrointestinal absorption (3). Elimination var-
chlorthalidone). Despite this, their tolerability profile is ies also between loop diuretics (Table 40.6). Furosemide
not impaired. is predominantly eliminated by the kidney, while torse-
mide is significantly metabolized by CYP450 enzymes
ADVERSE EFFECTS and eliminated by the hepatic route. Consequently, the
Thiazides have various biochemical adverse effects that half-life of furosemide is prolonged in advanced renal
are mainly dose dependent. They share several adverse dysfunction, while the half-life of torsemide is doubled in
effects with beta-blockers: both drug classes may worsen hepatic dysfunction. Torsemide can be administered once
glucose intolerance and dyslipidemia, particularly when daily (1).
combined in treatment. Thiazide diuretics decrease lith-
ium renal excretion and increase the risk of lithium tox-
icity. Unlike loop diuretics, they increase renal calcium ADVERSE EFFECTS
reabsorption and thus decrease calciuresis (10). Most of the selected adverse effects described for thiazide
Hypokalaemia: Thiazides induce hypokalaemia, which diuretics apply also to loop diuretics with gradual differ-
may have a negative impact on their cardiac safety (cardiac ences. A significant difference is the disparate effect on
332 Manual of Hypertension of the European Society of Hypertension
Table 40.6 Pharmacokinetic characteristics and dosage of selected thiazide and loop diuretics
Loop diuretics
Clinical CV event
Heart failure Diuretic, BB, ACE inhibitor, ARB, mineralocorticoid receptor antagonists
Aortic aneurysm BB
Atrial fibrillation, prevention Consider ARB, ACE inhibitor, BB or mineralocorticoid receptor antagonist
Other
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BB, beta-blocker; BP, blood pressure; CV, cardiovascular; ESRD, end-stage
renal disease; ISH, isolated systolic hypertension; LVH, left ventricular hypertrophy.
Antihypertensive Drug Classes 333
calcium handling with loop diuretics increasing calcium Consequently, further research with this compound was
excretion (2). halted, and currently no trials are available on cardiovas-
cular or renal outcome events in hypertension that sup-
port its use. Direct-acting vasodilators are a heterogeneous
group of drugs, among which hydralazine and minoxi-
ADDITIONAL ANTIHYPERTENSIVE DRUGS dil are most frequently used. Their use is associated with
tachycardia and fluid retention and other significant side
The preferred use of the drugs discussed above in spe- effects, and thus use is restricted to special conditions.
cific conditions is summarized in Table 40.7. Additional
drugs, that can be used in patients with treatment-resis-
tant hypertension or other conditions are summarized in
Table 40.8. The additional treatment with low-dose spi-
ronolactone (25−50 mg daily) has recently been shown DEVELOPMENT OF NOVEL
to be more effective than the alpha-blocker doxazosin or ANTIHYPERTENSIVE DRUGS
beta-blocker bisoprolol when added as the fourth drug
to patients with resistant hypertension already treated Although effective antihypertensive agents are avail-
with a RAS-blocker, CCB, and thiazide-like diuretic (11). able on the market, hypertension is still not sufficiently
Centrally active drugs such as clonidine or moxonidine are controlled in a majority of patients. There is a need for effec-
less frequently used because of their poorer tolerability. tive treatment strategies in patients with resistant hyper-
Methyldopa is used because of its safety for treatment of tension, those with comorbidities, or patients intolerant
hypertension in pregnancy. Aliskiren is the first nonpep- to the available drugs. In addition to the drugs mentioned
tide, currently available orally active direct renin inhibi- in this chapter, several novel drugs for the treatment of
tor (12). Because renin inhibition overcomes the reactive hypertension or associated diseases are c urrently being
renin release observed during use of ACE inhibitors or developed at either the preclinical or clinical stage. These
ARBs, this concept was considered advantageous when tar- new agents with novel targets have applications that may
geting the RAS. However, during late-stage clinical devel- extend beyond protection against cardiovascular diseases
opment, aliskiren was predominantly studied on top of and target-organ damage. A summary of the compounds
treatment with another RAS-blocker (i.e. during dual RAS and their status of development is given in Table 40.9;
blockade), and these trials generated unfavourable results. f urther details were recently reported (13).
Potassium-sparing diuretics/ Block aldosterone receptor in distal tubule Hyperkalaemia, worsening renal
Mineralocorticoid receptor in the kidney leading to natriuresis and function, metabolic acidosis,
antagonists potassium retention gynecomastia, impotence
■■ Spironolactone 25–50
■■ Eplerenone 25–50
Potassium-sparing diuretics Blocks directly the epithelial sodium channel Hyperkalaemia, abdominal pain,
■■ Amiloride (ENaC) within the distal tubule of the 5–10 nausea
kidney natriuresis and potassium retention
Centrally acting sympatholytic Reduce sympathetic outflow centrally by Bradycardia, somnolence, dry
agents/Alpha-2 agonist stimulating presynaptic α2 receptors and/ mouth
■■ Clonidine or imidazoline receptors 0.1–0.8
■■ Moxonidine 0.2–0.4
■■ Rilmenidine 1–2
■■ Alpha-Methyldopa 500–2000
Direct renin inhibitor Reduces plasma renin activity with Diarrhea, cough, changes in renal
■■ Aliskirin subsequent reduction of angiotensin I 150–300 function
and angiotensin II
Table 40.9 Selected novel drugs in the treatment of hypertension and their status of development
Pharmaceutical
Therapeutic group/ Selected clinical industry/
category Mechanism of action Drug/compound Status trial number developer
ACE2 activator Activating RAS counter- APN01 (rhACE2) Phase I NCT00886353 Apeiron Biologics
regulatory system GSK 2586881 Phase II NCT01597635 GlaxoSmithKline
(rhACE2)
Mineralocorticoid Anti-aldosterone effect BAY 94–8862 Phase IIb NCT01807221 Bayer HealthCare
receptor antagonist (Finerenone) Phase IIIa NCT01874431
NCT02540993
NCT02545049
Dual-acting Dual blockade of RAS and LCZ696 (Sacubitril/ Approved NCT00549770 Novartis
angiotensin the natriuretic peptide Valsartan) Phase III NCT01785472 Pharmaceuticals
receptor-neprilysin system Phase IV NCT01920711
inhibitor NCT02690974
NCT02754518
NCT02887183
Dual acting Dual blockade of the SLV-306 (Daglutril) Phase II NCT00160212 Solvay
endothelin- natriuretic peptide system NCT00160225 Pharmaceuticals
converting and endothelin
enzymes-neprilysin -1-mediated
inhibitor vasoconstriction
Nitric oxide donor Vasodilation AZD 3582 Phase IIIb NCT00662896 NicOx
■■ CINOD (Naproxcinod) Preclinical n.a ---
■■ Soluble Guanylate YC-1 Phase III NCT00810693 Bayer-HealthCare
cyclase stimulator BAY-63-2521 Phase II NCT00863681
(Riociguat) NCT02744339
Intestinal Na+/H+ Impaired intestinal sodium AZD1722 (Tenapanor) Phase II NCT01847092 Ardelyx
exchanger 3 absorption SAR218034 Preclinical NCT02675998 ---
inhibitor n.a.
Abbreviations: NCT, indicates the clinical trial number registered at ClinicalTrials.gov; n.a., not applicable; CINOD, cyclo-oxygenase-inhibiting nitric-oxide donator.
a In diabetic kidney disease.
b In arthritis.
7. Unger T. Pharmacological properties of angiotensin II antago- treatment for drug-resistant hypertension (PATHWAY-2): A
nists: Examining all the therapeutic implications. JRAAS 2001; randomised, double-blind, crossover trial. Lancet (London) 2015;
2(Suppl 2): S4–S7. 386(10008): 2059–2068.
8. Godfraind T. Discovery and development of calcium channel 12. Rahuel J, Rasetti V, Maibaum J et al. Structure-based drug design:
blockers. Front Pharmacol 2017; 8: 286. The discovery of novel nonpeptide orally active inhibitors of
9. Frishman WH, Alwarshetty M. Beta-adrenergic blockers in sys- human renin. Chem Biol 2000; 7(7): 493–504.
temic hypertension: Pharmacokinetic considerations related to 13. Kreutz R, Algharably E. Novel drugs in the treatment of hyper-
the current guidelines. Clin Pharmacokinet 2002; 41(7): 505–516. tension. In: Tsioufis C, Schmieder R, Mancia G (eds). Updates in
10. Brater DC. Diuretic therapy. N Engl J Med 1998; 339(6): 387–395. Hypertension and Cardiovascular Protection. Springer, Switzerland;
11. Williams B, MacDonald TM, Morant S et al. Spironolactone versus 2016: 157–178.
placebo, bisoprolol, and doxazosin to determine the optimal
SINGLE-PILL COMBINATION
TREATMENTS IN HYPERTENSION 41
Michel Burnier
Overall
Risk ratio
Study (95% CI) % Weight
Dezii CM et al. 2000 0.74 (0.65, 0.84) 17.5
Dezii CM et al. 2000 0.71 (0.62, 0.80) 17.6
Eron JJ et al. 2000 0.78 (0.55, 1.11) 4.3
Geiter LJ et al. 1987 0.88 (0.55, 1.42) 2.5
Melikian C et al. 2002 0.50 (0.35, 0.71) 4.2
Melikian C et al. 2002 0.47 (0.22, 1.01) 1.0
NDC dataset, 2003 0.81 (0.77, 0.86) 29.0
Su WJ et al. 2002 0.89 (0.51, 1.57) 1.8
Taylor AA et al. 2003 0.74 (0.67, 1.81) 22.1
Overall 0.74 (0.69, 0.80) 100.0
0.1 1 10
Risk ratio
Favours fixed-dose Favours free-drug
combinations combinations
Heterogeneity chi2 = 14.49 (p = 0.07) Publication bias (Egger’s) p = 0.43
Figure 41.2 Effect of fixed-dose combination versus free-drug combination on the risk of noncompliance to medication
regimens. Complete references of publications indicated in the figure can be found in the original paper by Bangalore et al.
(From Bangalore S et al. Am J Med 2007; 120(8): 713–719.)
single-pill combinations. When nonspecific side effects approach to improve BP control by reducing the compen-
occur, it may become more difficult to identify which com- satory sodium reabsorption in the distal segments of the
ponent of the combination is responsible. Finally, one may nephron (26). However, associations of diuretics contain-
expose patients with a low cardiovascular risk to unneces- ing a potassium-sparing agent must be used cautiously in
sary therapy when prescribing single-pill combinations as patients with reduced renal function and should not be
first-line therapies (21), and there is a risk of hypotension prescribed to patients with severe renal insufficiency or
if patients miss several doses and restart, for example, on pre-existing hyperkalaemia.
a triple combination. Today, dual combinations containing an RAS blocker
and a diuretic (thiazide, chlorthalidone, indapamide)
belong to the most frequently used associations in the
management of hypertension. There is strong physiologi-
SINGLE-PILL DUAL COMBINATIONS cal rationale for this association. Indeed, the negative
sodium balance induced by the diuretic triggers the release
Today, there is a very large choice of single-pill combina- of renin and the production of angiotensin II. Hence the
tions associating two antihypertensive drug classes avail- maintenance of BP becomes angiotensin II-dependent. In
able on the market. They generally combine drug classes this context, blockade of the reactive activation of the RAS
recommended as first-line therapy by international guide- enhances the BP-lowering effect of diuretics. Conversely,
lines such as diuretics, beta-blockers, CCBs and RAS block- the diuretic-induced stimulation of aldosterone leading to
ers (angiotensin-converting enzyme inhibitors [ACEi] or hypokalaemia is blunted with the administration of the
angiotensin receptor blockers [ARB]) (22). Combinations RAS blocker, therefore preserving an intact potassium bal-
including centrally active drugs are also available in some ance (19,27). This combination is generally well tolerated,
countries. and several studies have demonstrated that the association
Each of these single-pill combinations has a good ratio- of an RAS blocker and a diuretic is superior to a high dose
nale to justify its use in clinical practice. Thus the asso- of the RAS blocker alone to lower BP. Recently, the issue
ciation of a potassium-sparing diuretic (spironolactone, of which is the best diuretic has been the topic of some
amiloride or triamterene) with a thiazide diuretic enables discussions. Indeed, there is some clinical evidence that
one to limit the potassium losses and the thiazide-induced chlorthalidone reduces cardiovascular events in hyper-
hypokalaemia. The correction of hypokalaemia may tension better than hydrochlorothiazide (HCTZ) (28),
reduce the risk of cardiac and metabolic complications and and differences in potency between HCTZ and chlortha-
sexual impotence, which is in part mediated by the thi- lidone in favour of the latter have been clearly demon-
azide-induced hypokalaemia (23), and limit the benefits strated (29). However, almost all combinations associate
of lowering BP (24). Clinically, the association of diuretics an RAS blocker with low doses of HCTZ except for azil-
has been found to be equally effective in reducing cardio- sartan, which has been developed in association with
vascular events as a CCB-based therapy (nifedipine GITS) chlorthalidone, and perindopril, which is associated with
(25). A recent study in patients with resistant hypertension low doses of indapamide (30,31). This latter is effective in
has suggested that combining diuretics is also a useful lowering BP (32) and/or preventing cardiovascular events
340 Manual of Hypertension of the European Society of Hypertension
(30). Recent comparative studies have shown that the SPC ASCOT trial compared an amlodipine-based therapy to an
of azilsartan modoxomil and chlorthalidone induces a atenolol-based therapy with the possibility to add perin-
greater fall in 24-h ambulatory BP than azilsartan/HCTZ dopril to amlodipine and HCTZ to atenolol. The CCB-RAS
(33) or olmesartan/HCTZ (34) (Figure 41.3). blocker association was superior in preventing cardiovas-
In recent years, the combination of an RAS blocker cular events and reducing cardiovascular mortality. Since
and a CCB in a single pill has become very popular. The then, several other single-pill combinations associating an
main advantage of this combination is that the coad- ACE inhibitor or an ARB or a renin inhibitor with amlo-
ministration of the RAS blocker significantly reduces dipine or another CCB such as lercanidipine have been
the incidence of peripheral oedema induced by the CCB launched for the treatment of hypertension (20).
(35,36). The sudden enthusiasm for this combination These trials may suggest that the CCB/RAS blocker
comes essentially from the results of the ACCOMPLISH combination is superior to the traditional association of
trial (Avoiding Cardiovascular Events in Combination RAS blocker or beta-blocker with a diuretic. However, one
Therapy in Patients Living with Systolic Hypertension), has to consider the characteristics of patients enrolled in
which compared the fixed combination of benazepril/ these studies before extrapolating the results to the entire
amlodipine to the fixed association of benazepril/HCTZ. hypertension population. Thus, although these studies
Despite a similar reduction in BP, the former was superior were conducted in high cardiovascular risk patients, the
in reducing cardiovascular as well as renal events in high ACCOMPLISH trial included essentially patients of African
cardiovascular risk patients (37,38). In this trial, the bena- American origin. Thus, the results of ACCOMPLISH may
zepril/amlodipine single-pill combination reduced the rel- not be applicable to all populations around the world. In
ative risk of cardiovascular events by 20% and the relative one study conducted in elderly patients with hyperten-
risk of progression of chronic kidney disease by 48%. The sion, the combination of an ARB + CCB was reported to be
clinical benefits of combining an RAS blocker and a CCB as effective as the same ARB + diuretic to control BP and
in a single pill were also supported by the results of the to prevent cardiovascular events, although fewer patients
INVEST [INternational VErapamil SR- Trandolapril] and developed side effects with the ARB + CCB combination
ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) tri- (41). Another Japanese study compared the combinations
als (39,40). These two trials did not used fixed-dose combi- of a CCB plus an ARB or a diuretic or a beta-blocker and
nations but compared the efficacy and clinical benefits of a reported no significant difference between the three combi-
therapeutic strategy based on an CCB as first-line therapy nations in terms of BP control and prevention of cardiovas-
and an RAS blocker as the second line of treatment to the cular complications (42,43). In another set of experiments,
older strategy starting with a beta-blocker as first-line ther- Stergiou et al. examined the additional BP-lowering effect
apy and diuretic as second-line. The INVEST trial assessed of adding a diuretic, a CCB or an ACE inhibitor on top of
the clinical benefits of the verapamil SR ± trandolapril an ARB in patients uncontrolled with the maximal dose
on cardiovascular events in patients with coronary heart of the ARB alone (44). Although all three drugs added to
disease, and the control group received atenolol ± HCTZ. the ARB lowered BP, only the addition of the CCB or the
Both strategies were equally effective in terms of preven- diuretic induced a significant decrease in BP, enabling an
tion of cardiovascular events but there were fewer new increase in the percentage of patients under control. This
cases of diabetes in the verapamil/trandolapril group. The observation further confirms the initial hypothesis that
combining drugs with different modes of action is prefer-
able to an increase in dose or combining drugs acting on
the same mechanism of BP control. In this respect, one has
0 to mention that combining an ACE inhibitor and an ARB
AZL-M/CLD 40/25 mg
–5 AZL-M/CLD 80/25 mg or a renin inhibitor is no longer recommended by guide-
–10 OLM-HCTZ 40/25 mg lines because of the increased risk of acute renal failure and
SBP change (mmHg)
Triple combinations
of triple combinations should therefore be encouraged to and all patients on the quadpill reached the target BP of
intensify the treatment of patients with uncontrolled BP <140/90 mmHg, whereas under placebo only three partici-
on a well-dosed bi-therapy or to simplify the therapeutic pants were well controlled. Side effects were more frequent
regimen in patients receiving triple free-drug combina- with the quadpill, but they were relatively mild and only
tions. One advantage of these triple combinations is the one patient stopped the quadpill. A small meta-analysis of
ability to progressively increase the treatment while stay- clinical studies having investigated combinations of quar-
ing on the same initial drugs in different clinical condi- ter doses previously accompanied the study. This analysis
tions associated with hypertension, as suggested recently showed a range of BP decrease of 5/2–7/5 mmHg systolic/
by Volpe et al. (54). In general, patients are reassured of diastolic BP. A second analysis by the same authors con-
continuing drugs that they know they tolerated. firmed these figures (56) (Figure 41.4), suggesting that only
a combination of four drugs at very low dose (1/4) is supe-
rior to a monotherapy. This new concept may be of interest
but its position in the management of hypertensive patients
THE QUARTER-DOSE QUADRUPLE remains to be defined in a larger number of patients. Thus
COMBINATION THERAPY CONCEPT far, the dataset is small, few patients have been treated and
for a short period of time. Several questions remain unan-
Australian investigators have recently developed the con- swered with this approach, such as the strategy to adopt in
cept of the quadpill, which consists of combining four active the case of intolerance to one of the compounds, even at
antihypertensive substances at very low dose in a single low dose, or the next treatment step if BP remains uncon-
pill. This principle has been evaluated in a randomized, trolled. Whether the quadpill is superior to a dual fixed
double-blind placebo-controlled, crossover study pub- low-dose combination should also be investigated.
lished in 2017 (55). The quadpill contained 37.5 mg irbe-
sartan, 1.25 mg amlodipine, 6.25 mg hydrochlorothiazide
and 12.5 mg atenolol. The primary endpoint of the study
was the decrease in 24-h ambulatory BP at 4 weeks. Only SINGLE-PILL COMBINATIONS IN
a small number of 18 patients with hypertension were HYPERTENSION GUIDELINES
enrolled in this crossover study. After correction for the pla-
cebo effect, systolic ambulatory BP decreased by 19 mmHg. For many decades, recommendations for the initia-
At baseline, 24-h ambulatory BP was 154/90 mmHg, tion of antihypertensive treatments were to start with
¼ dose group Trials Participants Reduction in DBP and 95%CI (mmHg) Reduction in SBP and 95%CI (mmHg)
Favours ¼ dose agent(s) Favours standard dose Favours ¼ dose agent(s) Favours standard dose
Figure 41.4 Comparisons of single, dual, and quadruple quarter-dose therapy compared with standard-dose monother-
apy on blood pressure reductions. Single quarter-dose therapy was less efficacious than standard-dose monotherapy; dual
quarter-dose therapy showed an equivalent blood pressure-lowering effect compared with standard-dose monotherapy.
Only one study with quadruple quarter-dose therapy versus standard-dose monotherapy showed a substantially greater
blood pressure reduction in the quarter-dose group. (From Bennett A et al. Hypertension 2017; 70(1): 85–93.)
342 Manual of Hypertension of the European Society of Hypertension
a monotherapy to avoid having patients who responded 16. Burnier M, Brede Y, Lowy A. Impact of prolonged antihyperten-
adequately to a single drug taking more pharmacologi- sive duration of action on predicted clinical outcomes in imper-
fectly adherent patients: Comparison of aliskiren, irbesartan and
cal agents than necessary. This approach changed in the ramipril. Int J Clin Pract 2011; 65(2): 127–133.
2013 ESH/ESC hypertension guidelines with the possibil- 17. Weber MA, Julius S, Kjeldsen SE et al. Blood pressure dependent
ity to start on a combination therapy in patients with a and independent effects of antihypertensive treatment on clinical
high cardiovascular risk or in patients with elevated base- events in the VALUE Trial. Lancet 2004; 363(9426): 2049–2051.
18. Ram CV. Fixed-dose triple-combination treatments in the man-
line BP (57). Today, even this approach is questioned, and agement of hypertension. Manag Care 2013; 22(12): 45–55.
some experts suggest that there is a need to readdress the 19. Kochar M, Guthrie R, Triscari J et al. Matrix study of irbesartan
approach to antihypertensive treatment owing to the poor with hydrochlorothiazide in mild-to-moderate hypertension. Am
BP control rate worldwide. In their view, antihyperten- J Hypertens. 1999; 12(8 Pt 1): 797–805.
20. Burnier M, Vuignier Y, Wuerzner G. State-of-the-art treatment of
sive fixed-dose combinations should be prescribed earlier, hypertension: Established and new drugs. Eur Heart J 2014; 35(9):
including as first line in patients with a low cardiovascular 557–562.
risk and mild forms of hypertension. This new strategy is 21. Angeli F, Reboldi G, Mazzotta G et al. Fixed-dose combination
now under discussion, as it might help to shrink the cur- therapy in hypertension: Cons. High Blood Press Cardiovasc Prev
2012; 19(2): 51–54.
rent gap between antihypertensive use and BP target con- 22. Waeber B, Feihl F, Ruilope LM. Fixed-dose combinations as initial
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to patient selection. Drugs 2009; 69(13): 1761–1776.
23. Alderman MH, Piller LB, Ford CE et al. Clinical significance of
incident hypokalemia and hyperkalemia in treated hypertensive
patients in the antihypertensive and lipid-lowering treatment to
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THE J-CURVE PHENOMENON
42
40 20
35
Unadjusted relative hazard, x 800,000
Incidence of primary outcome, %
30 15
25
20 10
15
10 5
0 0
≤60 61–70 71–80 81–90 91–100 101–110 >110
Diastolic blood pressure, mmHg
Figure 42.1 Relationships between different achieved levels of diastolic blood pressure and the incidence of the primary
outcome (first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke) (column), expressed as per-
centage and unadjusted relative hazard (line) in the International Verapamil-Trandolapril Study trial (INVEST). (Adapted
from Messerli FH et al. Ann Intern Med. 2006; 144(12): 884–893.)
The J-Curve Phenomenon 347
their study sample by SBP, McEvoy et al. found an excess risk increased for the combined outcome, cardiovascular
risk among those with SBP >=120 mmHg, which is a death, and all-cause death except stroke.
pulse pressure >60 mmHg, which in turn is a marker for In contrast, in the 9361 patients of SPRINT (Systolic
advanced disease of the vascular tree (15). Among patients Blood Pressure Intervention Trial), the HR for a compos-
with a DBP <60 mmHg, elevated levels of highly sensi- ite outcome of MI, acute coronary syndrome not result-
tive cardiac troponin-T were more prevalent compared to ing in MI, stroke, acute decompensated heart failure or
a DBP of 80–89 mmHg, suggesting ongoing and chronic death from cardiovascular causes with intensive treatment
subclinical myocardial damage. (mean SBP 121.5 mmHg over follow-up) was 0.75 (95%
In line with these results, in 10,001 patients with CI, 0.64–0.89; p < 0.001) compared to the standard-treat-
CAD of the Treating to New Targets (TNT) Trial over ment arm with a mean SBP of 134.6 mmHg (20). Even
a follow-up of 4.9 years, a time-dependent, nonlinear, among the 2510 patients older than 75 years, intensive
multivariate Cox proportional hazard model identified treatment resulted in an HR for the composite outcome of
a nadir of 146.3/81.4 mmHg where the event rate for a 0.66 (95% CI 0.51–0.85) compared to standard treatment.
composite of death from coronary disease, nonfatal MI, However, these benefits came at the cost of an increase
resuscitated cardiac arrest, and fatal or nonfatal stroke in secondary chronic kidney disease (HR 3.14, 95% CI
was l owest (16). 1.66–6.37, p < 0.001) and blood pressure measurement in
SPRINT was unique and cannot be compared with other
studies (21). Interestingly, when looking at baseline DBP, a
post hoc analysis showed a U-shaped association with the
RANDOMISED CONTROLLED TRIALS AND hazard of the primary outcome, but the effects of intensive
THE J-CURVE SBP intervention on the primary outcome was not influ-
enced by baseline DBP level (p for interaction 0.83) (22).
In 18,790 patients with hypertension of the HOT (Hyper
tension Optimal Treatment) trial, designed to determine
whether different DBP targets led to different rates of
major cardiovascular events (MI, stroke, cardiovascu- J-CURVE IN CEREBROVASCULAR DISEASE
lar death), the lowest incidence of major cardiovascular
events occurred at a mean achieved DBP of 82.6 mmHg, If low DBP were simply a marker of poor vascular health,
and the lowest risk of cardiovascular mortality occurred and not eo ipso responsible for adverse outcomes, low DBP
at 86.5 mmHg. In high-risk patients with evidence of would independently be associated with cerebrovascular
coronary ischemia, there was an 22% increase in the risk events, too. However, this association is less robust. In
of MI when the DBP was <80 mmHg compared with the 6287 subjects of the Rotterdam Study, a J-shaped rela-
<85 mmHg (17). tion was found between both systolic and diastolic blood
In the VALUE (Valsartan Antihypertensive Long-term pressure and the incidence of stroke. For DBP, the increase
Use Evaluation) trial, there is a trend to an increased inci- of the risk in the lowest category (DBP <65 mmHg)
dence in MI with a nadir of DBP at 79 mmHg for patients compared with the reference was statistically signifi-
without, and 76 mmHg for patients with CAD. However, cant (23). In the 4736 patients of the SHEP (the Systolic
this interaction did not attain statistical significance. Of Hypertension in the Elderly Program) study, the benefit of
note, there was an increase in the ratio of MI to stroke treatment with a calcium channel blocker or diuretic dis-
with lower DBP, indicating target organ heterogeneity in appeared in patients who developed diastolic hypotension
that the optimal on-treatment DBP for cerebroprotection (DBP <70 mmHg), and DBP <55 mmHg was associated
seems to be below that for cardioprotection (18). with a higher risk of ischaemic cardiac events, but also
In a recent post hoc analyses of two randomised tri- with stroke (24). In the 20,330 patients aged ≥50 years of
als (19), ONTARGET (Ongoing Telmisartan Alone and in the PROFESS (Prevention Regimen for Effectively Avoiding
combination with Ramipril Global Endpoint Trial ACE- Second Strokes) trial, the risk for first recurrence of stroke
inhibitors) and TRANSCEND (Telmisartan Randomised of any type was higher in the group with SBP <120 mmHg
Assessment Study of ACE Intolerant), a mean DBP (adjusted HR 1.29; 95% CI 1.07–1.56) compared to SBP
<=70 mmHg in 5352 patients was associated with a >140 mmHg (25).
greater risk of the composite primary outcome (cardiovas- This is in contrast to data from the PROGRESS
cular death, MI, stroke, and hospital admission for heart (Perindopril Protection Against Recurrent Stroke) study,
failure) (HR 1.31, 95% CI 1.20–1.42), MI (1.55, 1.33–1.80), where the association of stroke incidence with achieved
hospital admission for heart failure (1.59, 1.36–1.86) and follow-up SBP level was strong and continuous with no evi-
all-cause death (1.16, 1.06–1.28) compared to the 14,305 dence of a J-curve in the range from 112−168 mmHg. A sim-
patients with a DBP 70–80 mmHg. A pretreatment and ilar pattern was found for DBP levels from 72−102 mmHg.
mean on-treatment DBP of about 75 mmHg was associ- Furthermore, no such J-curve for stroke was found in a
ated with the lowest risk. In the 4052 patients with a SBP post hoc analysis of INVEST (13). And in the recent Action
less than 120 mmHg on treatment, the risk of the com- to Control Cardiovascular Risk in Diabetes (ACCORD)
posite cardiovascular outcome (adjusted HR 1.14, 95% CI trial in 4733 diabetic patients randomised to conventional
1.03–1.26), cardiovascular death (1.29, 1.12–1.49), and all- or intensive SBP lowering treatment, the HR for fatal and
cause death (1.28, 1.15–1.42) were significantly increased nonfatal stroke in those assigned to an intensive systolic
compared to the 16,099 patients in whom SBP was 120– BP lowering (mean achieved BP of 119.3/64.4 mmHg) was
140 mmHg during treatment. Interestingly, mean achieved 0.59 (95% CI 0.39–0.89, p = 0.001) compared to those
SBP more accurately predicted outcomes than baseline randomised to conventional treatment (mean achieved
or time-updated SBP, and was associated with the lowest BP 133.5/70.5 mmHg). These conflicting results can be
risk at approximately 130 mmHg, and at 110–120 mmHg explained by the point-of-no-return hypothesis with
348 Manual of Hypertension of the European Society of Hypertension
regard to BP management. In the REGARDS (Reasons for Inhibitor] with ACEI [Angiotensin-Converting Enzyme
Geographic and Racial Differences in Stroke) cohort, (26) Inhibitor] to Determine Impact on Global Mortality
during 6.3 years of follow-up, individuals taking three and Morbidity in Heart Failure) trial, all-cause mortality
antihypertensive drugs and a systolic BP below 120 mmHg rates were highest in patients with the lowest SBP (33).
were at a higher risk for stroke (HR 2.48 [1.63–3.77]) than However, these patients had the same benefits over enala-
those with SBP <120 on no antihypertensive medications. pril as patients with higher baseline SBP (HR for the pri-
mary endpoint 0.88 (0.74–1.06) in patients with baseline
SBP <110 mmHg and 0.81 (0.65–1.02) in those with a
SBP >140 mmHg (p for interaction = 0.55).
J-CURVE IN THE ELDERLY POPULATION In 1130 patients with heart failure with preserved ejec-
tion fraction (HFpEF, LVEF ≥50%), Lee et al. (30) found
Such a point of no return might play its role in the elderly a J-curve for mortality with a nadir of 127.9/72.7 mmHg.
population, too. In the PARTAGE (Predictive Values of In 1802 propensity-matched patients with HFpEF and
Blood Pressure and Arterial Stiffness in Institutionalized a SBP at discharge of <120 vs. ≥120 mmHg, the hazard
Very Aged Population) study, in 1127 nursing home resi- ratio for all-cause mortality was significantly higher for
dents older than 80 years, a significant interaction for all- SBP <120 mmHg at 30 days (HR 2.07, 95% CI 1.45–2.95;
cause mortality in propensity-score−matched subsets was p < 0.001), at 1 year (HR 1.36, 95% CI 1.16–1.59; p < 0.001),
found between low SBP and treatment with two or more and at 6 years (HR 1.17, 95% CI 1.05–1.30; p = 0.005)
BP-lowering agents (adjusted HR 2.05, 95% CI 1.37–2.48, with a J-shaped curve in the restricted cubic spline plot
p < 0.001) (27). Their hypertension may not always have of the 3906 prematched patients (34). Importantly, cur-
been well controlled and have resulted in vascular damage. rent guidelines, recommending lowering BP in heart fail-
Thus, hypertensive target organ disease and alterations in ure patients as low as in hypertensive patients without
the vascular tree were no longer amenable to regression, heart failure, are based on evidence that management of
and further BP lowering resulted in adverse events. In con- hypertension lowers incident heart failure, but not on evi-
trast, among the 2636 community-dwelling participants dence that lowering BP improves outcome of heart failure
of SPRINT elderly (mean age 79.9 years, 37.9% women), patients (21,35) (Figure 42.2). Reverse causality might be
there was a 33% relative risk reduction for all-cause mor- the underlying mechanism; low blood pressure may sim-
tality in the intensive treatment arm (21) (Table 42.1). ply be an epiphenomenon of impaired cardiac function.
Similar phenomena have been described for other heart
failure risk factors such as obesity, cholesterol or smoking
(36–38).
J-CURVE IN HEART FAILURE
In 1049 patients with acute heart failure requiring hospi-
talisation, there was an inverse linear relationship between REVERSE CAUSALITY
SBP at admission and mortality over a follow-up of 18
months. In patients with LVEF ≤40%, every 10-mmHg 1. Chronic illness. Several pathophysiologic mechanisms
decrease in SBP was associated with a 16% increase in mor- have been proposed to explain the existence of a
tality (28). On the other hand, in patients with HFpEF, the J-curve. The J-curve with increased mortality with low
relationship was nonlinear, resulting in a J-shaped curve. blood pressure could be an epiphenomenon related
In another cohort of 56,942 patients aged 79.7 years (SD to underlying chronic illness, being a mere marker
22.8) admitted for acute heart failure, higher DBP levels of this illness thereby increasing mortality (39). In a
were associated with lower 30-day and 1-year mortality meta-analysis of 40,233 hypertensive patients from
rates in unadjusted analysis that persisted after adjustment seven randomised trials, a positive J-curve relation-
for baseline characteristics and SBP values (29). ship between DBP as well as SBP and both fatal
In 2584 patients with heart failure with reduced cardiovascular and noncardiovascular mortality
ejection fraction (HFrEF, LVEF ≤40%), Lee et al. (30) was found. The authors concluded that the J-curve
reported a J-curve association between mortality and on- relationship is possibly attributed to poor health,
treatment BP with a nadir at 136.0/76.6 mmHg. Low BP because it was independent of either treatment or
is frequently encountered in HFrEF and it is associated type of events (40). This paradoxical association with
with poor outcomes. This brings up the question whether lower BP and increased mortality has sometimes also
there is an optimal BP level for dosing neurohormonal been explained in terms of patient frailty. The highest
blockers or whether one should uptitrate to the maxi- drop in BP can be found in individuals who are most
mal tolerable dose. In post hoc analysis of randomised at risk of adverse outcomes because of underlying
controlled trials, such medication still showed benefit in illness over follow-up. In a UK cohort with 144,403
patients with low BP. In the COPERNICUS (Carvedilol patients >=80 years of age registered with family
Prospective Randomized Cumulative Survival) trial, practices, Ravindrarajah et al. (41) showed an accel-
although patients with the lowest SBP were at the high- erated decline of SBP in the last 2 years of life. They
est risk of an event, they experienced the greatest abso- showed that elderly patients with SBP <120 mmHg
lute benefit from treatment with carvedilol (31). In the did have higher risks of mortality than those with
CHARM (Candesartan in Heart Failure: Assessment of SBP of 120–139 mmHg, independent of frailty. The
Reduction in Mortality and Morbidity) trial, baseline pattern of accelerated decline was identical in patients
SBP and DBP did not modify the effect of candesartan on on and off antihypertensive medication, with the
all-cause mortality (32). In PARADIGM-HF (Prospective relative odds of SBP <120 mmHg in the last 3 months
Comparison of ARNI [Angiotensin Receptor-Neprilysin of life than 5 years previously in treated (odds ratio
Table 42.1 Summary of selected clinical studies reporting assocation between blood pressure and adverse endpoints
ARIC (15) 2016 11,565 56.7 121 73 Yes 21 Yes No Yes DBP <60
CLARIFY (14) 2016 22,672 65.2 133.7 78.2 Yes 5 (median) Yes No Yes SBP 120
/DBP 70
Cruickshank (6) 1987 2145 55 na 109 Yes 6.1 Yes No No DBP 85–90 (in ischaemic
patients only), SBP in
patients >=60 years
137–148 mmHg
Fagard (50) 2007 4695 70 173 85 Yes 1–8 Yes Yes Yes DBP 70–75 in patients
with CAD
Hansson (51) 1998 18,790 62 170 105 Yes 3.8 Yes Yes (SBP) No (cardiovascular) SBP 138.8 mmHg, DBP
86.5 mmHg
Lee (30) 2017 5625 68 131 78 Yes 2.2 – – Yes SBP 132.4
DBP 74.2
Lindblad (7) 1994 2574 59 157 92 Yes 7.4 Yes – – DBP 90–95
ONTARGET/TRANSCEND (19) 2008 30,937 66.5 142 82 Yes 4.6 (median) Yes No Yes SBP 120
DBP 70
Pepine (49) 2003 22576 66 149 86 Yes 2.7 Yes Yes Yes DBP 76.4–85.8
SPRINT (22) 2016 9361 67.9 140 78 Yes 3.3 (median) Yes No Yes –
TNT (16) 2010 10,001 61 131 78 Yes 5.5 Yes Yes (DBP) Yes SBP 146.3, DBP 81.4
VALUE (18) 2016 15,244 67 150 86 Yes 4.2 Yes No – SBP 128, DBP 75
Wilhelmsen (48) 1987 6569 40–60 na 107 No 3.9 Yes Yes Yes DBP 86–89
Abbreviations: Na, not available; SBP, systolic blood pressure; DBP, diastolic blood pressure.
The J-Curve Phenomenon 349
350 Manual of Hypertension of the European Society of Hypertension
HFpEF HFrEF
Low
blood
pressure
Poor
Low tissue
output perfusion
Figure 42.2 Potential pathophysiologic mechanism resulting in a J-curve in heart failure with preserved ejection fraction
(HFpEF) and heart failure with reduced ejection fraction (HFrEF) and its respective hallmarks: a much-debated vicious cycle.
[OR] 6.06, 95% CI 5.4–6.81) and untreated patients outcome only as DBP decreased, suggesting that patients
(OR 6.31, 95% CI 5.3–7.52). who had revascularisation before enrolment tolerated
2. Heart failure. Low blood pressure may be an epiphe- lower DBP relatively better than those who did not have
nomenon of impaired cardiac function (42), even revascularisation (13). However, the data are not unequiv-
though previous studies have controlled for left ocal. In the CLARIFY cohort, no significant effect modifi-
ventricular function (16,43). However, only randomi- cation was found with previous revascularisation and the
sation can ensure that comparison of groups is similar primary outcome (14). In the TNT trial (16), a significant
with respect to the underlying risk. interaction between SBP with prior bypass surgery was
3. Increased pulse pressure. Last but not least, the J-curve found (p interaction 0.004) with higher event rates at low
might be an epiphenomenon of increased arterial SBP after bypass surgery; however, reverse causality can-
stiffness, marking advanced vascular disease and not be excluded.
thereby increasing mortality (44). Pulse pressure is
an independent risk factor for CAD irrespective of
SBP. In a pooled analysis of individual patient data
from three large trials involving approximately 8000 CONCLUSION
patients, a 10 mmHg wider pulse pressure increased
A large body of evidence shows that there is a J-curve in
the risk of major cardiovascular complications
hypertension. The J-shaped curve seems particularly
(p < 0.001). At any given level of SBP, the risk also
prominent in CAD, and less so in cerebrovascular disease.
increased with lower DBP (p = 0.001) (45). Therefore,
However, to conclusively document its pathogenesis, pro-
low DBP might simply be a surrogate for poor vas-
spective properly randomised controlled trials are needed.
cular heath. There seems to be an inverse relation-
ship between DBP and CAD (i.e. the lower the DBP
the greater the risk of CAD), but such is not the case
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A POLYPILL FOR GLOBAL
CARDIOVASCULAR PREVENTION: 43
CURRENT DATA AND FUTURE
PERSPECTIVES
communicable disease which affected patients all over the patients, 18% did not fill their cardiac medications even
world, especially in LMICs, with very low accessibility to once in the 4 months after discharge from hospital (31).
effective antiretroviral treatment, at a time where antiret- These percentages represent summary estimates, and there
roviral therapy effectively led to the chronification of the are substantial differences in adherences to specific CV
disease. Two decades later, the antiretroviral polypill has medications, even among those prescribed for the same
effectively controlled the HIV pandemia based on three CV condition.
simple benefits: accessibility, adherence and cost-effective-
ness. The current CV landscape calls for a similar strategy
to contain what has become the leading cause of death
worldwide, responsible for over 17 million deaths world- CLINICAL IMPACT OF MEDICATION
wide in 2011 and expected to reach 24 million deaths by NONADHERENCE
2030. The sanitary, social and economic costs of this reality
call for simple solutions to contain this grave burden. The Lack of adherence has been associated with an increase
CV polypill represents one of these strategies, which should in long-term CV events, including acute MI (AMI), stroke,
be included within an integrated public health approach to CV mortality, and all-cause mortality (32,33). In a meta-
promote healthy lifestyles, correct CV risk factors and effec- analysis conducted with data from the European Union,
tively implement CV therapies in high-risk patients. lack of adherence was identified as the cause of 13 CVD
deaths per 100,000 inhabitants, and 9% of all CVD
deaths were attributed to nonadherence. Good adherence
is associated with a 20% lower risk of CVD and a 35%
THERAPEUTIC ADHERENCE: PREVALENCE reduction in all-cause mortality (12). In a recent study
AND CLINICAL IMPACT of 90,869 Medicare beneficiaries who had prescriptions
for ACE inhibitors/ARBs, beta-blockers and statins, after
Medication nonadherence, defined as a patient’s passive AMI hospitalization, adherence was measured by propor-
failure to follow a prescribed drug regimen, remains a sig- tion of days covered during 180 days following hospital
nificant concern for healthcare professionals and patients. discharge. The authors used proportional hazards models
Medication adherence represent a person’s behaviour, and to estimate hazard ratios of mortality for groups adher-
it depends on multiple factors related to the patient, the ent to two, one, or none of the therapies versus group
health system, the disease, the treatment and socioeco- adherent to all three therapies. Only a striking 49% of
nomic factors (Figure 43.1). the patients adhered (PDC >80%) to all three therapies.
On average, one-third to one-half of patients do not Compared with being adherent to all three therapies, mul-
comply with prescribed treatment regimens (28). In tivariable-adjusted hazard ratios for mortality were 1.65
a meta-analysis of 20 observational studies involving (95% CI: 1.54−1.76) for being nonadherent (PDC <80%)
376,162 patients, a summary estimate of the prevalence of to all three therapies (34). In another study carried out
poor adherence across multiple drug classes as measured by Bansilal et al. that included patients who had experi-
by pharmacy refill data was 43% (12). The World Health enced an AMI or had atherosclerosis and were treated with
Organization has reported similar figures of adherence statins and ACE inhibitors, AMI patients with full adher-
both to CV and non-CV medications (29). In secondary ence had 27% fewer events compared to their nonadher-
prevention, adherence to medication has been reported to ent counterparts, and 19% fewer events than patients with
be below the 50% mark 6 months following the CV event partial adherence. In patients with atherosclerosis, a 44%
(30), but alarmingly even in the immediate aftermath of reduction in events was observed compared to nonadher-
acute cardiac events adherence is suboptimal. In a popu- ent patients, and a 24% reduction compared to partially
lation cohort of 4591 post-myocardial infarction (MI) adherent patients. In terms of costs, lack of adherence
is associated with a long-term increment of $907/year/ and used for primary and secondary prevention of ath-
patient (33). Finally, a recent Swedish nationwide cohort erosclerosis. Two large prospective, randomized clinical
study of 601,527 users of low-dose aspirin for primary or trials are underway to assess the benefit on outcomes of
secondary prevention showed that patients who discontin- the use of a polypill in primary prevention, the HOPE-4
ued aspirin had a higher rate of CV events than those who study, (NCT01826019) as well as in secondary prevention,
continued (multivariable-adjusted hazard ratio, 1.37; 95% the SECURE (Secondary prEvention of CardiovascUlar
CI, 1.34–1.41), corresponding to an additional CV event disease in the Elderly trial), a European collaborative proj-
observed per year in 1 of every 74 patients who discon- ect funded by the EU Framework Programme for Research
tinue aspirin (35). Data from meta-analysis cohort regis- and Innovation, Horizon 2020 (NCT02596126).
tries or prospective cohort studies consistently shows the
overwhelming clinical impact (and economic burden) of
medication nonadherence in major adverse events, most ACCESSIBILITY
of which are preventable on the basis of following the pre-
scribed treatment regimen. Nearly 80% of all CV deaths take place in LMICs, where
Based on the results of the studies measuring the impact access to medication is dismal (reports from the PURE
of the polypill on adherence and risk factor control, the studies show 8–14% accessibility to antiplatelets, statins
recent guidelines have included the polypill as one of and antihypertensive medication in secondary preven-
the most effective strategies to improve adherence. This tion with figures dropping to the low single digits in rural
has been the case of the 2016 European Guidelines on areas) (42).
CV disease prevention (36), as well as the recently pub-
lished 2017 ST elevation MI guidelines (37). Recently, the
Spanish consensus document on the clinical use of the
polypill issued a series of recommendations related to ADHERENCE
adherence. Major recommendations included establish-
ing good doctor-patient communication and relation- The polypill has been consistently shown in clinical tri-
ships, agreeing on the therapeutic plan with the patient to als including different populations to be the single most
improve their commitment and involvement, simplifying efficient (and certainly scalable) strategy to significantly
the therapeutic regimen, periodically assessing therapeu- improve adherence. Four trials reported the effect of polyp-
tic adherence and implementing adherence reinforcement ills on adherence, which was 44% higher in the polypill
strategies over time (38). Similarly, the Chilean Society of group than in the comparator group (p < 0.001) (8,43–45).
Cardiology, the Argentine Society of Cardiology and the Interestingly, participants with low baseline adherence
Argentine Federation of Cardiology recommended the use were more likely to show improvements in adherence with
of polypills to increase adherence (39). polypills than were participants with high baseline adher-
ence levels. This finding supports the position that polyp-
ills can be used to reduce inequities that manifest in lower
baseline medication adherence rates in disadvantaged pop-
EVIDENCE OF THE CLINICAL USE OF A ulations (46).
CARDIOVASCULAR POLYPILL:
ACCESSIBILITY, ADHERENCE, RISK RISK FACTOR CONTROL
FACTOR CONTROL, COST-EFFECTIVENESS
Thirteen trials (7638 participants) reported the effect on
AND PATIENT PREFERENCE systolic blood pressure, which was 6.3 mmHg lower in the
The low adherence to prescribed CVD drugs and the polypill group than in the comparator group (p < 0.001).
impact on secondary prevention has prompted investiga- Eleven trials (6565 participants) reported the effect on
tors to evaluate strategies for improvement. Such strate- total cholesterol, which was 0.6 mmol/L lower in the
gies can be implemented through the development of polypill group (p < 0.001) (41). Because most trials that
government health policies and interventions in routine included risk factor changes had short-term follow-up,
clinical practice. One of these strategies is treatment sim- the differences seen between the polypill and comparator
plification, as it can be assumed that any strategy aimed at groups were not maintained long enough to manifest dif-
simplifying treatment, such as the polypill, will result in ferences in clinical event rates.
improved adherence.
The recently published 2017 Cochrane systematic review
synthesized the evidence on the use of the polypill and COST-EFFECTIVENESS
included 13 polypill trials (9059 participants) done in 32
countries that investigated the effect of different combina- At the health system level, although increasing drug use
tions compared with usual care, placebo, or active compar- increases short-term costs, it leads in the long term to a
ator that had been published up to 2016 (40). decrease in the number of significant CV events and costs
Polypill trials have been designed as phase 2 studies associated with hospitalization and treatment of the
to investigate pharmacodynamics and short-term and event. The net result is a reduction in healthcare costs. A
medium-term safety of the polypills (41). These trials were systematic review found that adherence greater than 80%
not powered to detect differences in clinical outcomes is associated with a reduction in expenditure of up to 18%
(Table 43.1). The rationale for use of a phase 2 design has (47). A mathematical model applied to the economic con-
been largely based on the understanding that the compo- sequences of the lack of adherence in chronic diseases
nents of polypills have been widely accepted, approved, showed that long-term adherence reduces costs of medical
Table 43.1 Clinical trials using a cardiovascular polypill for primary and secondary CV prevention
Trial/Sample size/Principal
investigator(s) Population Polypill composition Outcomes Status
Primary prevention
Indian Polycap Study (TIPS) Men and women aged 40–80 y without Aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, Feasibility; effect on risk factor Completed
n = 2053 CVD and with at least 1 CV risk factor in hydrochlorothiazide 12.5 mg, atenolol 50 mg levels; safety and tolerability
Yusuf S, Pais P India
Poly-Iran: Phase II Study of Heart Polypill Men and women aged 50–80 y without Aspirin 81 mg, hydrochlorothiazide 12.5 mg, Effect on risk factor levels; safety Completed
Safety and Efficacy in Primary Prevention indications or contraindications for aspirin, enalapril 2.5 mg, atorvastatin 20 mg and tolerability
of CV Disease BP-lowering drugs, and statins in Iran
n = 475
Marshall T, Malekzadeh R, Malekzadeh F
Combination Therapy Trial Age >40 y without CVD and with estimated Aspirin 75 mg, simvastatin 10 mg, lisinopril 10 mg, Effect on estimated 10-y total Completed
n = 200 10-y total CVD risk score >20% in hydrochlorothiazide 10 mg (Red Heart Pill 2b) CVD risk score
Furberg C, Mendis S, Soliman EZ. Sri Lanka
IMProving Adherence using combination Established CVD or 5-year risk ≥15% Aspirin 75 mg, simvastatin 40 mg, and lisinopril Effect on Adherence to Completed
therapy (IMPACT) 10 mg with either atenolol 50 mg or recommended drugs and mean
n = 497 hydrochlorothiazide 12.5 mg change in blood pressure and
Rodgers A, Selak A. LDL-chol at 12 months
Indian Polycap Trial (TIPS)-3 Primary prevention with estimated yearly Polycap; dose to be chosen after completion of the Major CVD events; Estimated study
n = 5000 CVD event rate of >1% using the TIPS-K trials neurocognitive function completion date:
Yusuf S, Pais P, Xavier D, Liu L. INTERHEART risk score in China and India January 2019
356 Manual of Hypertension of the European Society of Hypertension
Heart Outcomes Prevention Evaluation Primary prevention in men aged >55 y and Rosuvastatin 10 mg, candesartan 16 mg/ Major CVD events; Completed
(HOPE)-3 women aged >65 y with at least 1 CV risk hydrochlorothiazide 12.5 mg (2 × 2 factorial neurocognitive function; renal
N = 12.500 factor and women aged >60 y with at design) function
Yusuf S, Lonn E least 2 risk factors and with average BP
and cholesterol levels in 22 countries
Secondary prevention
FOCUS Trial in Secondary Prevention Survivors of myocardial infarction in Spain Aspirin 100 mg, simvastatin 40 mg, ramipril 2.5, Adherence; feasibility; effect on Completed
Phase 1: n = 2000, Phase 2: n = 800 and Latin American countries 5, 10 mg (Trinomia) risk factor levels; safety and
Fuster V tolerability
Use of a Multidrug Pill in Reducing CV Established CVD or high-risk primary Aspirin 75 mg, atenolol 50 mg, simvastatin 40 mg, Adherence; effect on risk factor Completed
Events/n = 2000/ prevention (5-y CVD risk of >15%) in lisinopril 10 mg (RedHeart pill 1) or aspirin 75 mg, levels; safety and tolerability;
Thom SA, Rodgers A India, Netherlands, UK hydrochlorothiazide 12.5 mg, simvastatin40 mg, CVD events (secondary
lisinopril 10 mg (Red Heart pill 2) outcome)
SECURE Post MI over 65 years old Aspirin 100 mg, atorvastatin 20 or 40 mg, ramipril Composite MACE: Estimated study
Secondary Prevention Spain, France, Italy, Germany, Poland, 2.5, 5, 10 mg (Trinomia) revascularization, CV death, completion date:
N = 3206 Czech Republic, Hungary. ischaemic stroke, recurrent MI May 2020
Fuster V
Castellano JM
A Polypill for Global Cardiovascular Prevention 357
care by reducing hospitalizations and admissions to the The HOPE-3 study explored the role of three drugs, the
emergency room, despite the increased pharmaceutical RAS angiotensin-receptor blocker (ARB) candesartan, the
expenditure (48). Various pharmaco-economic models thiazide diuretic hydrochlorothiazide (HCTZ), and a 10-mg
have been published comparing the use of a polypill strat- dose of rosuvastatin into one pill. HOPE-3 enrolled more
egy versus usual care. The polypill has been shown to be than 12,000 people from around the world, including men
cost-effective even in the most adverse models due to its over age 55 years and women over age 65 years with at least
effect on clinical outcomes based on improved adherence, one risk factor for heart disease. The study had a 2 × 2 facto-
and risk factor control (49,50). rial design. In the first arm of the study (57), participants
were randomly assigned to receive placebo or a low dose
of a candesartan/hydrochlorothiazide combination. Then,
PATIENT PREFERENCE in the second arm (58), they were again randomly assigned
to receive rosuvastatin 10 mg or placebo. Investigators
Various trials of polypills versus usual care have reported analysed the blood pressure changes, then the cholesterol
data on acceptability of the polypill concept to physicians changes, and finally blood pressure and cholesterol levels
or patients, or both, participating in these trials (46). in those who received both treatments versus placebo (59).
Although subject to social desirability bias (whereby par- In HOPE-3’s first arm (57), those who received BP-
ticipants might report favourably to be seen in a better lowering treatment consisting of candesartan 16 mg/day
light), the overwhelming response was favourable towards and hydrochlorothiazide 12.5 mg/day did not have sig-
use of a polypill in routine clinical practice. Further addi- nificantly fewer occurrences of a composite of CV-related
tional studies surveyed patients and physicians who were death, nonfatal MI, or nonfatal stroke (the first co-primary
not involved in clinical trials with similar positive response outcome) a mean of 5.6 years later compared with those
to the polypill concept. The most commonly mentioned who received placebo (4.1% vs. 4.4%, respectively). The
advantages were the ease and convenience of taking pills, second co-primary outcome, which added heart failure,
cost-saving benefits and improved safety from simplifying, cardiac arrest or revascularization to the composite, was
and therefore decreasing confusion about, pill regimens. also not significantly different between the groups (4.9%
vs. 5.2%). However, prespecified subgroup analysis, which
divided baseline systolic BP into thirds, showed that the
participants with upper-third measurements (>143.5
CLINICAL USE OF THE POLYPILL mmHg) receiving candesartan/hydrochlorothiazide did
meet the co-primary outcomes.
In the second arm (58), the participants who were ran-
POLYPILLS FOR PRIMARY PREVENTION domized to rosuvastatin 10 mg/day also met both pri-
mary outcomes versus placebo (p = 0.002 and p < 0.001
The clinical indication of a polypill is largely determined for both group comparisons, respectively) and had a 24%
by the specific composition of the available polypills. lower risk for CV events.
Currently, the Fuster polypill (which includes aspirin The trial’s third arm (59) assessed patients random-
100 mg, atorvastatin 20 or 40 mg, and ramipril 2.5, 5 or ized to rosuvastatin plus candesartan/hydrochlorothia-
10 mg), is first-in-class and has been approved for com- zide versus rosuvastatin plus placebo versus candesartan/
mercialization in more than 50 countries. In this current hydrochlorothiazide plus placebo versus two placebos.
scenario, treatment with the polypill could be indicated The findings showed that those who received both of the
in primary prevention patients with a high or very high treatment drugs together had significantly lower rates of
CV risk (determined by risk charts, presence of diabetes or the first primary outcome versus the double-placebo group
subclinical vascular disease, including carotid atheroma (3.6% vs. 5.0%, respectively, p = 0.005), as well as the sec-
plaques, low ankle-brachial pressure index or chronic ond primary outcome (4.3% vs. 5.9%, p = 0.003).
renal failure, high calcium score, or presence of abdomi- The results of this trial indicate that the use of low-dose
nal aortic aneurysm) and low risk of bleeding with ASA statin therapy with rosuvastatin 10 mg is superior to pla-
in diabetic patients older than 50 years with at least one cebo in reducing long-term CV events in an intermediate-
associated CV risk factor including smoking, hyperten- risk population (CV event rate ∼1%/year). On the other
sion, dyslipidemia, low LDL-C or microalbuminuria. hand, a fixed-dose combination of candesartan 16 mg +
This rationale is based on the HOPE study (51), which HCTZ 12.5 mg daily was not superior to placebo in reduc-
showed a benefit in the primary prevention of diabetic ing CV events despite a 6-mmHg decrease in SBP and a
patients treated with ramipril, and also on recommenda- 3-mmHg decrease in DBP. There was effect modification
tions from clinical guidelines on the management of dia- by baseline SBP such that patients who truly had hyper-
betic patients (52), and in diabetic patients older than 50 tension (i.e. SBP >143.5 mmHg) appeared to benefit with
years with chronic renal disease and macroalbuminuria or combination treatment. A fixed-dose combination of all
microalbuminuria. The data are based on various studies three drugs appeared to have CV benefits that were mostly
that demonstrate the renal protection of the renin−angio- similar to those observed with rosuvastatin compared
tensin system (RAS) blockers in primary prevention in with placebo. In the subset of patients ≥70 years, there was
diabetic patients (53,54), and on some clinical guidelines no signal of differential cognitive decline with all three
recommendations on the management of diabetic patients strategies compared with placebo.
(54,55). Finally, the polypill may be used in patients with Many features of this trial deserve comment. First, it was
high CV risk and clinical or subclinical ventricular dys- designed as a practical trial, with few mandatory visits to
function, in whom ramipril would be prescribed for the titrate medications based on cholesterol or BP response.
cardiac pathology (56), and statin and aspirin for the high This might thus lend itself well to a ‘polypill’ approach
CV risk. for large populations but lowering of LDL-C and/or BP
358 Manual of Hypertension of the European Society of Hypertension
could have been greater if these were periodically assessed lisinopril and another containing aspirin, simvastatin,
and dosages adjusted accordingly, particularly for the lisinopril and hydrochlorothiazide. Over a median fol-
BP-lowering arm. Second, rather than enrolling patients low-up of 15 months, the polypill group exhibited a sig-
based on baseline values of LDL-C or BP, they were enrolled nificant improvement in adherence to treatment than the
based on their baseline risk for CV events. This has been usual care group (86% vs. 65%, p < 0.01), an even larger
endorsed by the most recent lipid guidelines and was also improvement occurring in patients with lower adherence
recently observed in the SPRINT trial for BP lowering. to treatment at baseline. The improved adherence was
These results thus provide further validation of the 2015 accompanied by a significantly greater reduction of sys-
lipid guidelines approach. Next, the trial enrolled patients tolic BP (−2.6 mmHg) and LDL-cholesterol (−4.2 mg/dL)
from many different countries, with close to 50% of Asian while no significant differences in serious adverse or CV
ethnicity. Since these countries have a progressively larger events between groups were observed.
burden of CVD, these results may be more broadly gen- The Improving Adherence using Combination Therapy
eralizable. For the BP arm, it is unclear if the use of other (IMPACT) trial (43) randomized more than 500 patients
agents such as chlorthalidone or amlodipine would have with established CV disease or a high CV risk (>15% risk
demonstrated a benefit rather than HCTZ/candesartan. of an event over 5 years) to usual care (free combinations)
or two different polypill strategies (aspirin, simvastatin,
lisinopril and atenolol or hydrochlorothiazide) accord-
POLYPILLS FOR SECONDARY PREVENTION ing to an open-label study design and with self-measured
adherence as the primary endpoint. BP and cholesterol
The polypill has been predominantly investigated in reductions were non-significantly different between the
the context of secondary CV prevention, particularly two treatment groups and so were serious adverse and CV
in patients with a previous MI, for a number of reasons. events. This was not the case for adherence, however, which
First, in patients with established CV disease the efficacy after 12 months from randomization was 46% and 81%
of drug-related correction of several CV factors (antiplate- in the usual and polypill treatment strategy, respectively,
let, BP-lowering and lipid-lowering treatments) has been the difference being statistically significant (p < 0.001).
unequivocally proven by randomized trials (60–62), and Similar observations were made in the Kanyini Guidelines
a greater protective ability has usually been documented Adherence with Polypill (Kanyini GAP) open-label trial
when these drugs are used in combination (63). Two, (45) in which more than 600 patients with a risk profile
compared to primary prevention, secondary prevention and a polypill composition similar to those of the UMPIRE
is characterized by a more favourable NNT ratio; that is, trial showed, after one-and-a-half years from initial ran-
by a greater number of hospitalizations and events saved domization to treatment, a much greater adherence to the
for a given number of treated patients, with thus a more polypill-based strategy than to the usual free combination
favourable cost-benefit ratio, at least over a midtime treat- care (70% vs. 47%, p < 0.0001). This was unexpectedly not
ment duration. Finally, despite its high economic burden accompanied by a greater BP and serum cholesterol reduc-
for the healthcare system, in patients with CV disease con- tion, a finding possibly accounted for by the more limited
trol of CV risk factors is still largely ineffective (64) due to power of the study compared to that provided by the much
under-prescription of a number of drugs with documented higher number of patients available for the UMPIRE trial.
protective effects, low treatment compliance and, in devel- Further interesting evidence has more recently been
oping countries, limited availability of medicaments and obtained by research conducted in Spain from the Centro
unaffordable treatment costs. Nacional de Investigationes Cardiovasculares (CNIC) in
In the last 10 years, several studies have shown that the collaboration with Ferrer International. The Fuster polyp-
polypill strategy can favourably affect CV prevention in ill, containing aspirin (100 mg), simvastatin (40 mg) and
patients with established CV disease. The second Indian ramipril at various doses (2.5, 5 or 10 mg) was extensively
Polycap Study (TIPS-2) (6) made use of ramipril, ateno- tested in preclinical and clinical studies to document a
lol, hydrochlorothiazide, simvastatin and aspirin (supple- similar efficacy with the free association of its individual
mented by potassium) in a single capsule (half-dose of the components (65,66). It was thereafter tested in a random-
drugs) and compared its effects to the administration of two ized study on about 700 patients with a history of MI (8).
capsules (full doses of the drugs) for 8 weeks in more than Compared to a 9 months separate administration of the
500 patients with CV disease or type 2 diabetes. Compared three drugs, the polypill group showed similar effects on
to one capsule, two Polycap capsules significantly reduced BP (on-treatment systolic value 129.6 vs. 128.6 mmHg),
BP by a further 2.8/1.7 mmHg, total serum cholesterol by serum LCD-cholesterol (89.9 vs. 91.7 mg/dL), serious
7.2 mg/dL and LDL-cholesterol by 6.6 mg/dL, with a cal- adverse events (23% vs. 21%) and death (0.3% in either
culated reduction in the relative risk of coronary disease of group). In line with other studies, however, adherence to
69% and stroke of 57%. Discontinuation of treatment was treatment as measured by both self-reported question-
low and similar in the two groups (6.9% and 7.8%, respec- naire and by pill counting was significantly better in the
tively) showing that the Polycap had a good tolerability. polypill than in the group in which drugs were given sepa-
The use of a multidrug pill in reducing CV events rately, the difference amounting to 22% (50.8% vs. 41.0%,
(UMPIRE) trial (44) has assessed whether a polypill strat- p = 0.019). Similar findings have been obtained with a
egy lowered BP and serum cholesterol in several thou- second polypill also containing aspirin and ramipril at
sand patients with established or at high risk (>15% over various doses, but replacing simvastatin with atorvas-
5 years) of developing CV disease, the primary goal being tatin 20 mg, with the addition of the information pro-
to determine whether this might be associated with an vided by careful in vitro and in vivo studies which have
improved adherence to treatment. Two polypill types were shown the safety, tolerability and bioequivalence of all
used, depending on the extent of baseline comorbidities: its components with the drugs given separately (67). This
a polypill containing aspirin, simvastatin, atenolol and has led this polypill to receive in 2014 the approval of the
A Polypill for Global Cardiovascular Prevention 359
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MANAGING ADVERSE EFFECTS
AND DRUG INTOLERANCE 44
common and expected side effects, which are associated with the individual the possibility of drug re-challenge,
with very mild and potentially temporary symptoms as well as the possibility to try the use of other drugs of
related to the initiation of the drugs. Patient awareness the same class before permanently omitting this specific
regarding their non-harmful nature, the reassurance on class of medication.
their reversibility upon drug discontinuation, as well as Multiple drug intolerance in blood pressure-lowering
clear guidance about when further contact with the treat- drugs is a rare but difficult to handle condition. There is
ing physician is needed, are reasonable actions in daily only one available study regarding the management of
clinical practice in order to minimize drug treatment dis- unpredictable responses of antihypertensive drugs, based
continuation, patient’s low adherence to optimal drug use on a retrospective analysis (33) in a small population with
(daily uptake in the proposed dose) and patient lost to the multiple drug intolerance in blood pressure-lowering
upcoming follow-up. Particularly, in difficult to treat or drugs. We propose a modified treatment algorithm for
resistance hypertension − in need of four or five differ- multiple drug intolerance, based on a five-step approach
ent classes of blood pressure-lowering drugs in order to focusing on alternative blood pressure-lowering methods
achieve blood pressure treatment goals − the cost of any and/or alternative root of drug administration until the
expected unavoidable minor side effect (e.g. mild − or patient is relieved from the symptoms:
even substantial − ankle oedema due to calcium channel
blocker use) versus the benefit of effective blood pressure Step 1: Introduction of alternative blood pressure-lower-
control and cardiovascular risk reduction should be clearly ing methods (beyond drugs, diet and exercise) such as
addressed. We should bear in mind, though, that for any device-guided breathing and transcendental meditation.
single drug addition to the therapy, 4% more patients (Step 1 can be used in combination with all the following steps.)
discontinue their medication in 5 years (13). Step 2: Use of fractional doses of conventional medications
In adherence with good clinical practice, in any case by halving or quartering tablets; use of combinations
physicians should inform all patients regarding the likeli- (double, triple etc.).
hood of an adverse effect while on blood pressure-lower- Step 3: Use of liquid drug formulations.
ing medication. Interacting with hypertensive individuals Step 4: Use of transdermal antihypertensive medication.
and educating them on: (i) the need for and importance of Step 5: Consider use of alternative blood pressure-lowering
antihypertensive treatment; (ii) the mode of drug admin- regiments.
istration and actions; (iii) the possible adverse effects
in order to recognize in an early stage any drug-related Individuals with intolerance to multiple antihyperten-
adverse effect; and (iv) the pitfalls of dosage or medication sive drugs may have panic attacks, anxiety and depres-
altering without expert consultation, are factors associated sion disorders (25) and might benefit from psychiatric
with better patient compliance (12). evaluation.
Step 4: How to deal with a developed expected adverse effect.
When dealing with an expected adverse event that has
already occurred, the physician should take into consider- CONCLUSIONS AND PERSPECTIVES
ation the following. It is highly reasonable to consider that
an expected adverse event is directly and causally related Adverse effects caused by blood pressure-lowering drugs
to specific type of drug. It is reasonable that in the case are not uncommon but are usually mild. They are impor-
of a minor adverse effect that is dose dependent and/or tant because they are associated with treatment discontin-
can be prevented with the precautions discussed above in uation or low adherence. Preventive management of side
steps 1–3, the drug might be reintroduced (after tempo- effects should be integrated in the initial design of treat-
rary discontinuation) in the treatment strategy, potentially ment strategies. Future studies focusing on the potential
at a lower dose, if considered to be indispensable. This superiority of ultra-low doses of multidrug combinations
option should be discussed in detail with the hypertensive to minimize side effects should be carried out. A five-step
individual. algorithm for the management of multiple drug intoler-
In cases of adverse effects efficiently classified as severe ance in arterial hypertension is proposed; however very
allergic reaction of immunological basis, a class contradic- limited data on this issue are available and future studies
tion should be labelled (22,23). should shed more light on this phenomenon.
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ADHERENCE TO TREATMENT
IN HYPERTENSION 45
Michel Burnier
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
Percent adherent Percent adherent
Figure 45.1 Persistence to therapy in primary and secondary cardiovascular prevention. (From Naderi SH et al. Am J Med
2012; 125(9): 88–7e1.)
Table 45.1 Advantages and limits of methods used to assess adherence to therapy
associated with a poor adherence (10,15). However, this from nonadherent hypertensive patients from the United
approach assumes that patients take their drugs adequately Kingdom and the Czech Republic (26).
every day, which is not always the case. Moreover, patients As noted in a recent review, the ideal method to assess
may use different pharmacies to obtain their medications. drug adherence in clinical practice should ‘provide a reli-
Thus, the monitoring system should cover all sources of able capture, storage, analysis, and communication of dos-
medication delivery. ing history data in ways that make it difficult or impossible
Two methods actually provide very interesting and reli- for patients or trial staff to censor or otherwise manipulate
able information on drug adherence: electronic monitor- the data’ (16). Nowadays, three methods are close to fulfill-
ing, and direct measurements of plasma or urinary drug ing these criteria: the retrospective analysis of prescription
levels. The former gives very interesting dynamic informa- refill records, analysis of chemical markers of drug expo-
tion on adherence and is based essentially on the fact that sure, and automatic electronic monitoring of adherence.
if the pillbox is not open, the drug is not taken. However,
it does not prove ingestion when the box was opened (16).
In contrast, direct measurements of drugs ascertain drug
intake, but the information obtained with drug levels is RISK FACTORS OF POOR ADHERENCE
only punctual (17). The fact that electronic monitoring IN HYPERTENSION
systems do not prove the medication was taken is often
seen as a major limitation of these devices. Yet in our expe- Hypertension is a disease than can be treated but rarely
rience, one has to admit that it is rare that a patient opens cured. Thus patients must be informed that therapy will be
the pillbox every day and throws the medication away over maintained for the rest of their life. The long-term manage-
several months. Thus, information gathered with the elec- ment of hypertension generates many obstacles that may
tronic monitoring is quite reliable provided the monitor- affect the capacity of patients to stay on therapy. As illus-
ing is performed long enough (at least several months). As trated in Table 45.2, these obstacles can find their origin in
far as drug measurements are concerned, positive results the treatment itself, in the patient’s beliefs, in the attitude of
confirm that some drug has been taken, but physicians the physician and in the quality of the healthcare system. The
obtain no information on when the drug was taken and first obstacle is acceptance of the diagnosis and the difficulty
how often doses were missed between consultations, and for some patients to initiate a lifelong treatment program for
this may limit the interpretation of the results. In fact, a silent disease. Depending on the quality of the information
although measurements of drug levels tend to become they receive, patients may not be motivated. This is the rea-
popular, for example in patients with resistant hyperten- son persistence to antihypertensive therapy is low in newly
sion (17–23), this approach may be affected by the white- treated patients and declines further in following years. One
coat adherence bias, according to which patients tend to study, in which persistence with antihypertensive therapy fell
improve their adherence a few days before and after a con- to 75% in the first 6 months after treatment and continued to
sultation (24). Thus if patients are informed that blood or decline over the next 3 years to 55%, illustrated this observa-
urine will be taken to measure drug levels, which should tion perfectly (27). Later, patients are confronted with the first
be done ethically, the method may be of limited interest. side effects of prescribed drugs. In the absence of symptoms
Moreover, chemical methods are costly and labour inten- before treatment, side effects may not be accepted and tol-
sive. Nonetheless, recent studies using this methodological erated. With time, the treatment scheme may become more
approach without informing patients have clearly dem- complex. Indeed, it is well recognized that 70% of patients
onstrated that drug adherence is particularly low among will need more than one drug to reach the target BP recom-
patients with resistant hypertension. Interestingly, mea- mended by guidelines. However, the more drugs patients
suring drug levels appears to improve adherence to ther- receive, the lower the persistence (28,29). Eventually, patients
apy, as shown in Figure 45.3 (25,26). These results come may be exposed to delayed side effects such as sexual dys-
from a retrospective analysis of about 300 urine samples function. These factors will further decrease the motivation
372 Manual of Hypertension of the European Society of Hypertension
SBP DBP
80
P = 0.002 P = 0.005
60
Change in BP (mmHg) 40
20
–20
–40
–60
–80
Figure 45.3 Changes in blood pressure in relation to changes in urinary adherence ratio based on urinary drug
levels (ratio of detected to prescribed antihypertensive medications). (From Gupta P et al. Hypertension 2017; 70(5):
104–1048.)
to remain under treatment, and for many patients the neces- Besides these therapy-related factors, several other bar-
sity of pursuing the treatment will be questioned, leading in riers and risk factors for interrupting treatment have been
most cases to a discontinuation of therapy. identified (Table 45.2). These barriers come from the
Interestingly, a recent meta-analysis by Simpson et al. patient him/herself but also from the family, the physi-
has shown that patients with excellent adherence to ther- cian, the nature of the treatment and the healthcare sys-
apy have a globally positive attitude towards all preven- tem. The main factors affecting long-term adherence are
tive recommendations for a better health (30). Thus, these depression, other comorbidities, personal as well as family
patients with healthy behaviours have a better survival beliefs on hypertension and on the necessity of treatment,
even if they receive a placebo, as demonstrated recently in lack of knowledge about hypertension, cost of medica-
the post hoc analysis of a heart failure trial (31). However, tions, use of alternative medicines, memory problems in
it is also important to note that in some cases, good adher- elderly patients and poor quality of life.
ence may have also damaging effects if the drug has serious Several studies have clearly identified the characteris-
adverse effects and the patient continues to take them. Two tics of patients at high risk of nonadherence to treatment.
examples are the use of nonsteroidal anti-inflammatory These are essentially young, active men, hypertensive
drugs and antiarrhythmic agents (30). patients of African American origin, elderly patients with
cognitive dysfunction and a low income (32,33). Gender
does not seem to be a major determinant in all circum-
Table 45.2 Factors associated with an increased risk of poor
stances, even though studies have suggested that adher-
adherence
ence to therapy is better in females than males. Differences
in comorbidities, types of treatment and severity of hyper-
■■ Age and sex (young men at higher risk) tension may account for some of the gender differences
■■ Elderly patients with cognitive impairment reported in many surveys (34). The same is true for educa-
■■ Personal and family beliefs tional level. The healthcare system per se, and particularly
■■ Asymptomatic nature of hypertension the copayment, also has a major impact on the long-term
■■ Understanding of the benefits of treatment persistence of patients treated for hypertension. Thus it is
■■ Lower socioeconomic status very important for physicians to identify these high-risk
■■ Cost of treatments and copayments factors, as strategies can be developed to prevent any inter-
■■ Severity of disease ruption of therapy, as will be discussed later in this review.
■■ Number of drugs and complexity of treatment
■■ Drug tolerability (acute and long-term side effects)
■■ Efficacy on blood pressure control
■■ Family support ADHERENCE IN HYPERTENSION
■■ Physician-patient relationship
■■ Depression and comorbidities
It is well recognized that adherence to medication is an
important determinant of the BP response to treatment and
Adherence to Treatment in Hypertension 373
hence of the clinical benefits of antihypertensive therapies. not lower BP as expected, physicians have only two choices:
In the last two decades, many clinical studies and meta-anal- either the patient is a true nonresponder to therapy or the
yses have assessed drug adherence in patients with essential patient is not taking his/her drug as recommended thus being
hypertension and also in patients with uncontrolled hyper- a non-adherer. In the former situation, the patient has a true
tension or apparent resistant hypertension (17,23,33,35). In resistance to treatment, whereas in the latter, it is only appar-
all conditions, adherence to therapy was highly variable but ent or pseudo-resistance. In the absence of adequate tools to
particularly low among patients with uncontrolled hyper- measure adherence, physicians have only one option, and
tension, with almost 80% nonadherence in this subgroup that is to consider the patient as a nonresponder. Therefore,
(33). In many early studies, the assessment was done using they will probably increase the drug doses or add another
the Medication Event Monitoring System (MEMS) which drug in order to achieve the therapeutic targets. However, if
enables one to follow adherence on a day-to-day basis for adherence is the real problem, adding new drugs will only
a long time period (35,36). These studies were aimed at not aggravate the situation. One study actually confirmed that
only defining adherence in hypertension but also at inves- nonadherent hypertensive patients have not only a higher
tigating the ability of the monitoring system to support BP but also a greater number of prescribed drugs (22).
drug adherence. Interestingly, the same observations were With the recent development of new interventional
made more recently with measurement of drugs in the urine approaches for the management of patients with resistant
(20,23). The finding of a high adherence in many studies hypertension, a renewed interest for resistant hypertension
may be due to the measurement bias, as adherence tends to and its causes has emerged, including adherence to therapy
increase as soon as it measured. With the use of the MEMS (46,47). Several analyses have investigated the potential
system, which provides a dosing history, many interesting causes of apparent resistance to drug therapy in hyperten-
aspects of the adherence process can be seen. The first and sion. Not surprisingly, poor drug adherence emerged as
probably the most important one is that drug adherence is one important factor of pseudo-resistance (17). Yet, as of
a very dynamic process, which cannot be summarized with a today, the true incidence of poor adherence remains largely
single number. Indeed, patients are adherent for some peri- unknown in this patient population because adherence is
ods and less adherent at other times, for example during not measured adequately. Thus, published figures range
weekends and holidays. Second, it is very difficult to define between 10−50% (17,18,20,23,38). In our experience,
a cutoff point above which drug adherence is sufficient and using electronic monitoring of drug adherence, about one-
acceptable. Indeed, in the literature, the arbitrary cutoff of third of patients with resistant hypertension had adherence
80% is often used to define good adherence, but it is obvi- problems leading to uncontrolled hypertension (38,48).
ous that 80% can be obtained in several ways with different More recently, several studies have been conducted among
clinical impacts − for example, missing 1 day every 5 days hypertensive patients with uncontrolled BP or candidates to
or 1 week every 5 weeks. Moreover, the impact of missed renal denervation to assess drug adherence using measure-
doses on BP control and risk reduction depends largely on ments of either urinary or blood concentrations of drugs
the pharmacological profile of the prescribed drug, and (18,20,21,23). They confirmed high percentages of partial
particularly on the duration of action (37). This is why pre- or total nonadherence (sometimes greater than 50%). These
scribing long-acting medications in patients at risk of poor figures are important and may well be underestimations,
adherence is generally recommended. Thirdly, many inves- as they do not take into account the white-coat adher-
tigators have tried to demonstrate a correlation between the ence phenomenon discussed earlier in this review (24). In
level of BP achieved under treatment and the percentage of hypertensive patients with coronary heart disease, resistant
doses taken. Associations between adherence to antihyper- hypertension also appears to be common (38%) and to be
tensive drug therapy and BP control have been obtained but associated with a worst cardiovascular prognosis (49).
they have generally been very weak (38–40). In fact, there In any case, poor adherence is a real concern in resistant
are many good reasons why this type of correlation should hypertension. Unfortunately, adherence to therapy remains
not be very high. Indeed, high BP values are frequent in largely underdiagnosed in clinical studies despite the avail-
nonadherent hypertensive patients, but also in adherent ability of adequate noninvasive methods. In recent studies,
patients insufficiently or inadequately treated. some investigators have used the directly observed treat-
Despite many of these limitations, evidence gathered ment (DOT) or ‘tablet feed’, which is commonly used in the
from large databases usually confirms that patients with management of tuberculosis, to evaluate the role of poor
good adherence have better BP control (33,39). Moreover, adherence in mediating uncontrolled BP (50). Although
highly persistent hypertensive patients have a greater a small number of patients participated in some of these
reduction of their cardiovascular risk than those inter- studies, the studies clearly showed that many patients nor-
rupting their treatment (41,42). Finally, good adherence to malize their BP when the treatment is given under control.
antihypertensive medications has been associated with a In a larger group of 102 patients, 65% of patients achieved a
significant reduction of the risk of cardiovascular events systolic BP <140 mmHg at any point immediately prior to
such as coronary heart disease, congestive heart failure or after drug ingestion (51). In the United Kingdom, clinics
and cerebral diseases (29,43–45). dedicated to the DOT system have been installed with some
success (52). Thus, taken together, these new data confirm
that adherence to the drug regimen is a critical issue in
resistant hypertension. We believe that a good assessment
ADHERENCE IN RESISTANT of adherence in patients not responding to drug therapy is
HYPERTENSION essential in order to make rational therapeutic decisions. To
this purpose, methodologies to monitor adherence should
Apparent resistance to therapy is one clinical situation in be implemented in hypertension reference centres as sug-
which the question of drug adherence becomes particularly gested recently (17). Yet as of today, the main limitation is
important. When the prescribed antihypertensive drugs do the lack of cheap and easy-to-use methods of monitoring
374 Manual of Hypertension of the European Society of Hypertension
adherence in clinical practice. Measurements of urinary or the approaches may include the patient, the therapeutic regi-
plasma drug levels and electronic monitoring are the most men, physicians and the healthcare system.
adequate methods that can be recommended today. The first and certainly the most important step to sup-
port long-term adherence is to carefully inform the patient
on the goals of therapy and on the means to achieve the
therapeutic objectives. In order to be motivated and stay
STRATEGIES TO IMPROVE DRUG on therapy, patients need to know the risks linked to their
ADHERENCE IN HYPERTENSION disease, and to consider them as serious. This has been well
illustrated in patients with chronic kidney diseases who
A critical meta-analysis of the multiple strategies to improve may need to take up to 15 pills a day (54). In this study,
drug adherence in hypertension and chronic diseases has the patient’s perception of the burden of the disease was
been published recently (53). In this analysis, the standard- a major determinant of persistence. Patients have to know
ized mean difference effect size is only 0.290 comparing the BP goals and the effects expected from therapy. They
treatment and control groups. Larger effect sizes are found also have to be informed on the means to achieve these
for habit-based and behavioural-targeted (vs. cognitive- goals, to acquire specific competences and to develop a set
focused) interventions. The most effective interventions of personal strategies to reach the targets, to cope with the
appear to be those delivered face to face by physicians disease and to autoregulate their actions. Finally, they have
or by pharmacists and administered directly to patients. to believe in their personal efficacy. Thus, among all strate-
Effect sizes are smaller in studies with older participants. gies to improve adherence, empowerment of the patient is
Interestingly, the authors recommend focusing interven- critical (55). In this respect, a recent study has shown that
tions on behavioural strategies, especially habit-based inter- self-monitoring and even self-titration of drugs by patients
ventions, rather than on cognitive strategies designed to results in a significantly lower BP control at 1 year even
change knowledge and beliefs. As illustrated in Table 45.3, in high cardiovascular risk patients (56). Home BP moni-
toring (HBPM) is also a good recommendation in patients
who have difficulties with their treatment and are at high
risk of not staying on therapy. A systematic review of the
Table 45.3 Approaches and methods available to support the published literature on the effects of HBPM on medication
adherence to therapy adherence has confirmed the benefits of this approach
Treatment
on adherence to therapy (57). Today, the use of home
BP monitoring is increasing, and this strategy is strongly
■■ Simplifying treatment schedules (e.g. twice to once daily dosing) endorsed by the European Society of Hypertension (58).
■■ Reduce number of drugs using single-pill combinations On their side, physicians also need to be motivated and
■■ Prefer long-acting agents and drugs with the least side effects should avoid medical inertia and show patients that they
■■ Use drugs in favourable packages with calendar (blister vs. bottle) are eager to achieve the BP goals in order to preserve their
■■ Use of reminders (medication dispenser, organizers, telemonitoring …) patients’ health (59).
■■ Stop any unnecessary treatment One can also act on the prescribed regimen to sup-
port drug adherence over time. Both the number of
Healthcare providers drugs patients receive and the dosing frequency have
■■ Regular discussions on adherence and its barriers
a major impact on persistence (60–62). Several studies
■■ Provide clear instructions to patients
have demonstrated that simplifying the drug regimen
■■ Collaborate with other providers (pharmacists, nurses, …) with the use of fixed-dose combinations has a positive
■■ Healthcare provider education on adherence (medical students, impact on adherence and persistence (63–67). A recent
physicians, nurses, pharmacists…) meta-analysis confirmed that simplification of therapy is
■■ Improve communication skills of healthcare partners an effective therapeutic approach in hypertension that
■■ Good interpersonal relationship between provider and patient improves adherence, though the impact on BP control
■■ Increase the frequency of appointments in case of low adherence is relatively modest (66). This finding was confirmed in
■■ Regular monitoring of adherence during treatment (electronic a Cochrane analysis of different strategies to improve
monitoring, urinary drug levels…) adherence in hypertension (68). However, a recent survey
■■ Give positive feedbacks to patients among Swedish hypertensive patients has shown that in
patients started on a combination therapy, drug persis-
Patient empowerment tence at 2 years was not superior, and surprisingly, per-
■■ Educate patient to self-management
haps even inferior (32). Regarding the adaptation of drug
■■ Discuss the patient’s believes and barriers to adherence therapy, the prescription of combinations of long-acting
■■ Use of home BP monitoring drugs, which blunt the effect of isolated missed doses,
■■ Use of tele-monitoring systems is preferable. Studies have shown that BP is more likely
■■ Propose tips for maintaining adherence (at work, during holidays..) to remain adequately controlled despite the omission of
■■ Increase the family involvement and education one or two doses if the antihypertensive drug has a long
half-life (37).
Other approaches Several other tools can support drug adherence in
hypertensive patients (69). These include the use of orga-
■■ Improve the access to care
nizers, recalls using telephones or emails, rewards, spe-
■■ Reduce or suppress co-payments
cial packages and behavioural interventions. All of these
■■ Increase the social support
tools have been shown to have some positive effect on
■■ Counselling
■■ Home visits
drug adherence, but the effect size is rather small, in the
order of 4−11%. The most effective way to support drug
Adherence to Treatment in Hypertension 375
adherence and improve persistence during a long period be improved only by recruiting more untreated hyper-
is probably to monitor drug adherence continuously, for tensive patients and supporting drug adherence. To this
example with an electronic monitoring system such as the purpose, there is an urgent need to develop new method-
MEMS, or with the use of repeated drug measurements. ologies or devices enabling detection and monitoring of
The use of such devices enables one to obtain real data drug adherence in order to provide physicians with reli-
on patient adherence and allows a discussion between the able information on which they can build their therapy
physician and patient on adherence data. Unfortunately, and support their patients in their efforts to achieve their
the MEMS device is used essentially in clinical trials and therapeutic goals, and hence reduce the risk of cardiovas-
very few hospitals or reference centres are using them as cular complications.
a clinical tool. However, the MEMS device can be used
in clinical centres for a relatively modest cost (16). In
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RESIDUAL RISK IN
TREATED PATIENTS 46
Giuseppe Mancia
0.9
0.8 0.9
Probability
Probability
0.7
0.6 0.8
Follow-up BP: NBP 145/93
0.5 T-HBP 145/89
p = 0.0001 p = 0.0001
0.4 0.7
0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22
Years Years
Figure 46.1 Long-term (>20 years) cumulative probability of overall survival and survival free from coronary events (CHD)
in 686 men treated for hypertension and almost at BP target compared to 8100 men taken from the General Prevention
Study in Sweden. Abbreviations: T-HBP, treatment–high blood pressure; NBP, normal blood pressure. (From Andersson OK
et al. BMJ 1998 July 18; 317(7152): 167–171, by permission.)
with a more conservative attitude in the elderly in which increased incidence of orthostatic hypotension, which
the recommended systolic target is between 140 and may increase the risk of injurious falls and bone fractures,
150 mmHg (4). More recent trials, as well as recent large particularly in the elderly (25). Third, serious side effects
meta-analyses, suggest that lowering BP to values just are also the most important reason for treatment discon-
above or below 130/80 mmHg may incrementally protect tinuation (26), which is also more frequent at lower BP
most patients with high BP (18,19), and that this may be targets (27) and is known to be accompanied by a marked
the case also if in the older patient strata (>65 years of increase of disease and mortality (28). Ideally, the optimal
age) systolic BP is reduced to the 130–139 rather than to BP target should be established on an individual basis, a
the 140–149 mmHg range (20). More rigorous BP targets goal which is unfortunately beyond what cardiovascu-
may thus represent another means to reduce the residual lar medicine can presently do. The position of the new
risk of treated hypertensive individuals, although with the European guidelines on optimal target BP values for treat-
caveat that in real life an indiscriminate adoption of lower ment is presented in a separate chapter.
BP targets may generate inconveniences that can poten-
tially reduce their benefits. First, in patient subgroups, for
example, those with coronary heart disease, systolic BP
reductions to <130 mmHg have been reported to be accom- FAILURE TO GUIDE TREATMENT BY OUT-
panied by a J-curve−like increase in the incidence of most OF-OFFICE BP
CV events (21), a phenomenon that seems to be common
to most hypertensives if BP is reduced to <120/70 mmHg 24-h mean and home BP have a limited relationship with
(22). Second, BP reductions and lower BP targets are office BP, this being even more the case for the office and
accompanied by a marked increase in the incidence of seri- out-of-office BP changes induced by treatment (29–31).
ous side effects (20,22,23), with adverse consequences for An example is given in Figure 46.2 which shows that in a
patients’ health. One example is the increased incidence large number of hypertensive patients the 24-h mean and
of renal ischemia associated with lower BP targets, which office systolic BP changes induced by treatment exhib-
leads to the development of chronic kidney disease (20), ited a correlation coefficient of 0.43, a value compatible
ultimately increasing CV risk as well (24). Another is the with marked difference between these two sets of values
(31). Because ambulatory and, to a lesser extent, home
BP have a steeper and closer relationship with CV events
Table 46.1 Factors possibly involved in the high residual CV and mortality than office BP (32), the possibility exists
risk of treated hypertensive patients that founding treatment on out-of-office or combined
in- and out-of-office BP, rather than office BP alone, lead
■■ Genetic profile to a greater reduction of CV events and mortality, with
■■ Poor control of associated metabolic risk factors thus a greater protection and a lower residual risk of the
■■ Suboptimal BP targets
treated hypertensive individuals. At present, however,
■■ Failure to guide treatment by out-of-office BP
this has never been tested by an appropriate trial, and
■■ Inadequate control of short- and long-term (visit-to-visit) BP
evidence is also not available on a number of important
variability
■■ Late initiation of antihypertensive treatment
related issues. It is not known, for example, whether addi-
tion of out-of-office to office BP substantially improves
Residual Risk in Treated Patients 381
40 INADEQUATE CONTROL OF BP
VARIABILITY
20
24 h SBP change (mmHg)
24 h SD SBP (mmHg)
14
0
n = 266 12
r = –0.45
p <0.01
–15 10
B T
Figure 46.3 The left panel shows the correlation between the change of 24-hour systolic blood pressure (SBP) variability
induced by antihypertensive treatment and the variability before treatment (individual data from 266 patients). The right
panel shows the average variability value before (B) and during treatment (T). Variability is expressed as the standard devia-
tion (SD9 of the 24-hour mean SBP). (From Mancia G et al. Blood Press 4(3): 148–156, by permission.)
382 Manual of Hypertension of the European Society of Hypertension
10.6 160
12 135.9 135.3 135.2 135.0 135.7
8.3 140
mmHg
8 6.4
%
3.9 120
4
100
0 80
(n) 5758 5758 5758 5758 5758 (n) 5758 5758 5758 5758 5758
Figure 46.4 The left panel shows the quintiles of visit-to-visit SBP variability in the patients of the ONTARGET and
TRANSCEND trials. The right panel shows the corresponding mean SBP values. Variability was measured as the coefficient
of variation of mean on-treatment SBP as obtained from five visits spaced by several month interval. Symbols as in the pre-
ceding figures. (From Mancia G et al. Hypertension 2017 November; 70(5): 938–948, by permission.)
value were associated with a greater incidence and risk of mean BP values (Figure 46.4) (42). Furthermore, and most
CV outcomes. It has since been shown by a large number of importantly, evidence has been obtained that visit-to-
other trial or cohort analyses, which have further reported visit BP variability adds its prognostic role to the one of
greater visit-to-visit BP variability values to adversely affect mean on-treatment BP, a combined use of reduction in
renal and other (e.g. cognitive function) outcomes as well both BP mean and BP variability reflecting a greater CV
(36,41). It should be emphasized that these data suffer risk reduction (Figure 46.5) (42). Finally, post hoc analy-
from their post hoc nature, and thus by their comparisons sis of large clinical trials has shown that the risk of CV
of groups that differ at baseline for several variables as well outcomes decreases progressively as the number of visits
as for their overall CV risk. They are also limited by the in which office BP is found to be controlled increases,
frequent quantification of BP variability by the standard independently of the mean BP value achieved over the
deviation, a measure notoriously not independent on the years of treatment (Figure 46.6) (43–45). This provides
mean BP value (42). However, in a few studies the adverse clear support to the hypothesis that temporal inconsis-
prognostic role of visit-to-visit BP variability has been con- tency of chronic BP control by treatment also represents
firmed by variability measures independent on the mean a determinant of the residual risk of treated hypertensive
(36,41) and even documented, particularly for the lethal patients, and that its minimization by more effective long-
events, by comparison of groups with similar on-treatment term treatment strategies should thus be pursued. Indeed,
Primary endpoint
68 68
60 60
Change, hazard ratio
* (P < 0.0001)
40 40
*
(P < 0.0001)
20 20
(P = 0.13)
*
0 0
–20 –20
Quintiles 1 2 3 4 5 Quintiles 1 5
(ref) (ref)
Figure 46.5 The left panel shows the hazard ratio for cardiovascular morbidity and mortality (primary endpoint of the
ONTARGET and TRANSCEND trials) data for quintiles of on-treatment visit-to-visit SBP variability (SBP-CV), on-treatment
SBP mean and the two sets of quintiles combined in patients of Figure 46.4. The right panel shows the difference in the
hazard ratio between quintile 5 and 1 for the above three sets of data. Quintiles 1 and 5 represent the lowest and highest
values, respectively. Symbols as in preceding figures. (From Mancia G et al. Hypertension 2017 November; 70(5): 938–948,
by permission.)
Residual Risk in Treated Patients 383
19.8
20
All patients
11.3
10.8
10 9.2
8.1
Adjustment for
baseline covariates
5 and on-T mean BP
Figure 46.6 Relationship between the percentage of visits in which blood pressure (BP) was reduced to <140/90 mmHg
and the incidence of the primary endpoint (cardiovascular morbidity and mortality) in patients of the INVEST trial. Data
from the whole trial population and for its diabetic fraction. Data were adjusted for the mean BP systolic and diastolic value
during the treatment (T) period. (From Mancia G et al. Hypertension 2007; 50(2): 299–305, by permission.)
Clinic BP 24 h
80 80
60 60
%
40 40
20 20
0 0
1 2 3 4 All years 1 2 3 4 All years
Year Year
Figure 46.7 Percentage of hypertensive patients of the ELSA study in whom treatment achieved control of office (clinic) BP
(<140/90 mmHg) or 24-hour mean BP (<125/80 mmHg). Control is shown for any given year of treatment and for patients
in whom it was achieved in all 4 years. Symbols as in preceding figures. (From Mancia G et al. J Hypertens 2007 May; 25(5):
1087–1094, by permission.)
384 Manual of Hypertension of the European Society of Hypertension
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tes. Evidence against or in favour of an aggressive approach. 40. Rothwell PM, Howard SC, Dolan E et al. Prognostic significance
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Section VIII
Special Conditions
ETHNIC FACTORS IN
HYPERTENSION 47
In Hispanic Americans, the lower control rates result pri- MESA not currently taking antihypertensives showed, that
marily from lack of awareness and treatment (11), whereas compared with whites, blacks had 28% lower PRA and
in blacks, awareness and treatment are at least as high as in 17.4% lower aldosterone (20).
whites, but hypertension is more severe, and some agents Recent data point to a central role for the balance
are less effective at BP control (9). between nitric oxide (NO) bioavailability and creatinine
Furthermore, treatment-resistant hypertension is more kinase (CK) activity (21). The NO and CK systems share a
prevalent in adults of African descent in the United States common precursor in l-arginine and display antagonizing
than in other ethnicity groups (12). effects with mutual inhibition. NO inhibits CK, lowers BP
Ethnicities differ significantly also in terms of other and promotes cardiovascular health (21). High CK activ-
cardiovascular risk factor prevalence. African Americans ity is thought to promote salt retention and vascular con-
have a high prevalence of obesity, diabetes and hypercho- tractility, with low renin as an epiphenomenon. Patients
lesterolemia (13). In Mexican American men and women, of African ancestry are reported to have low NO bioavail-
high rates of obesity (36.5 and 42.6%, respectively) and ability (22), high CK activity (21) and low l-arginine (23),
hypercholesterolaemia (51.7 and 36.9%) were noted (14). with restored NO bioavailability upon l-arginine supple-
As seen in blacks and Hispanics, hypertension is often mentation (24).
present with other comorbid conditions in the Asian The prevalence of risk factors for hypertension may also
patients. Diabetes, in particular, occurs often in the Asian differ between ethnic groups within the same race. In the
population, and develops at an earlier age relative to European Project on Genes in Hypertension (EPOGH),
Europeans (15). white Europeans from six centres located in different
countries had divergent characteristics in terms of lifestyle
factors, i.e. dietary sodium intake or alcohol consump-
tion (25,26). The EPOGH demonstrated that phenotype-
PATHOPHYSIOLOGIC CONSIDERATIONS genotype associations strongly depend on host factors
such as gender, but also lifestyle, in particular salt intake
African Americans do have a greater increase in BP for as reflected by the 24-h urinary excretion of sodium, that
a given exposure to dietary sodium and have a greater is at least partially determined by the ethnicity (27,28)
frequency of salt sensitivity compared with European and may translate into divergent BP levels and BP-related
Americans. The Dietary Approaches to Stop Hypertension target-organ damage (29,30).
(DASH)-sodium diet trial (16) was designed to determine
whether or not sodium reduction would further improve
the BP reduction achieved with the DASH diet. The great-
est benefit was seen in the African American hypertensive END-ORGAN DAMAGE AND CLINICAL
participants consuming the 1500-mg per day DASH- COMPLICATIONS
sodium diet. In this group, systolic BP was lowered by
12.6 mmHg compared with 9.5 mmHg in the European Cross-sectional studies (31) have documented that blacks
American hypertensive participants on the same diet (16). have a steeper increase in left ventricular mass with each
Obesity contributes significantly to hypertension risk in unit of increase in BP as compared to whites.
all populations, particularly racial and ethnic minorities These effects may also be observed when indices of
(9). The excess prevalence of salt sensitivity among African left ventricular hypertrophy are assessed based on ECG
Americans relates to the increased frequency of obesity recording. Odili et al. (32) analysed blacks from sub-
in this population. It has been demonstrated in both Saharan Africa and Flemish whites. In both ethnicities,
Caucasians and African Americans that obesity is linked the precordial QRS voltage sums, combined or not with
to salt sensitivity. Low dietary potassium intake contrib- the limb voltages, and the voltage-duration products were
utes to salt sensitivity, as high levels of potassium intake positively associated with both office and home systolic
diminish the pressor effect of salt in salt-sensitive African BP; however, the slopes of these associations were up to
Americans (17). three times steeper in blacks than in whites.
Data demonstrating lower prevalence of hypertension The current state of knowledge indicates that the preva-
among populations of African descent from the Caribbean lence of left ventricular remodelling or hypertrophy is not
and rural continental Africa relative to those in the United only higher (33) but also has more deleterious effects (34)
States (18) support the hypothesis that environmen- among blacks.
tal factors play an important role in the development Morbidity and mortality attributed to hypertension are
of hypertension in blacks living in the United States. In also more common in blacks and Hispanic Americans
a standardized evaluation of populations in West Africa than in whites. Blacks have 1.3-times greater risk of nonfa-
(Nigeria and rural and urban Cameroon), the Caribbean tal stroke, 1.8-times greater risk of fatal strokes, 1.5-times
(Jamaica, St. Lucia and Barbados), and the United States greater risk of heart failure (HF), and 4.2-times greater risk
(Chicago), the hypertension rate was directly related to of end-stage renal disease (ESRD) (35). Studies have shown
increasing Westernization, with increasing prevalence that Hispanic Americans also have an increased cardiovas-
from rural Cameroon (15.4%) to urban Cameroon (19.1%) cular risk compared with non-Hispanic whites (11).
to the United States (32.6%); regression analysis found The four to five times greater risk for developing chronic
that 70% of the geographic variation in hypertension prev- kidney disease (CKD) or ESRD in hypertensive blacks has
alence was attributable to two characteristics, body mass been linked to unique genetic polymorphisms, includ-
index (BMI) and the sodium:potassium ratio (18). ing MYH9 and apolipoprotein L1 gene (APOL1), which is
In African Americans, low-renin, salt-sensitive hyper- found primarily with African ancestry and associated with
tension may be genetically based (19). Plasma renin activ- focal segmental glomerular sclerosis and hypertensive
ity (PRA) and aldosterone in 1021 participants in the kidney disease (36).
Ethnic Factors in Hypertension 391
Early hypertension onset and premature CV disease in in preventing heart failure (43). Blacks have a greater risk of
blacks may be related to blunted nocturnal BP declines, angioedema with ACE inhibitors (43), and Asian Americans
starting in childhood and exacerbated with age (36,37). have a higher incidence of ACE inhibitor – induced cough
Wang et al. recently reported ethnic differences in the (44). ACE inhibitors and ARBs are recommended more
longitudinal effect of ambulatory BP measured multiple generally as components of multidrug antihypertensive
times in youth and young adults over a 15-year period. regimens in blacks with CKD (9), with the addition of
Beginning at adolescence, African Americans had higher beta-blockers in those with heart failure (9). Beta-blockers
systolic and diastolic BP at night and during the day com- are recommended for treatment of patients with coronary
pared with European Americans. African Americans had heart disease who have had a myocardial infarction. Most
a more rapid increase in systolic BP with ageing and a sig- patients with hypertension, especially blacks, require ≥2
nificantly greater nocturnal BP compared with European antihypertensive medications to achieve adequate BP con-
Americans. Importantly, non-dipping of nocturnal BP trol. A single-tablet combination that includes either a
began very early, at 10 years of age (36,37). diuretic or a calcium antagonist may be particularly effec-
tive in achieving BP control in blacks. Racial and ethnic dif-
ferences should not be the basis for excluding any class of
antihypertensive agent in combination therapy (9).
ANTIHYPERTENSIVE TREATMENT Patients of African ancestry as a group respond better
to calcium blockers and diuretics, while the response to
beta-adrenergic blockade and inhibition of the ACE is
LIFESTYLE CHANGES attenuated (45). Brewster and colleagues systematically
reviewed the international contemporary literature on
Lifestyle modification (i.e. weight reduction, dietary mod- pharmacotherapy in persons of African ancestry and con-
ification and increased physical activity) is particularly cluded the response was superior in blacks for thiazide-
important in blacks and Hispanic Americans for preven- like diuretics and calcium channel blockers, as compared
tion and first-line or adjunctive therapy of hypertension. to beta-adrenergic blockers and ACE inhibitors/ARBs.
However, the adoption of lifestyle recommendations is Overall, as compared to genetic markers, self-defined
often challenging in ethnic minority patients because of ancestry appeared to be the best predictor of individual
poor social support, limited access to exercise opportuni- responses to antihypertensive drugs (46). Nevertheless,
ties and healthy foods, and financial considerations (9). the same authors recently cautioned that there was also a
High BMI, especially abdominal obesity, may explain large degree of overlap in BP lowering between blacks and
much of the variation of hypertension and CV dis- whites, providing caution for making therapeutic deci-
ease among groups. In a retrospective study of 150,753 sions based solely upon ethnicity (race) (47).
California adults, Asians had the lowest BMI among all Brewster et al. in their systematic review searched for
groups, but the impact of increasing BMI on the risk of the explanation of the differential clinical efficacy of
hypertension and diabetes was significantly greater in antihypertensive drugs in patients of African ancestry.
Asians; for each one unit increase in BMI, Asians were sig- Pharmacokinetics, plasma renin and genetic polymor-
nificantly more likely to have hypertension (OR 1.15; 95% phisms did not well predict the response of patients of
CI 1.13–1.18) compared to non-Hispanic whites, blacks, African ancestry to antihypertensive drugs. The magni-
and Hispanics (38). tude of the effects of variation in single-candidate genes
Especially in blacks, there is strong evidence for the on antihypertensive drug responses appeared to be very
DASH diet (high in fresh fruits and vegetables and low-fat modest, accounting for only a small percentage of total
dairy products) (39), Mediterranean eating patterns, and variation in response. No unique mutation was by itself
sodium restriction (40). predictive of the therapeutic response to these drugs, and
even the combined effects of polymorphisms did not
account for enough variation in response to be clinically
PHARMACOTHERAPY useful (46).
While some argue that the persistent racial and ethnic
In black hypertensive patients, compared with hyperten- differences in hypertension control is due to less aggressive
sion in other ethnicities, the disorder in often more severe, treatment in blacks, fewer or less effective medications, or
more resistant to treatment, and leads to earlier end-organ genetic and other physiological factors making medica-
damage and premature death, as described above. Thus, tions less effective for blacks than whites (47), others sug-
hypertension seems to be a more aggressive disease in gest that differences in social and healthcare environments
patients of African ancestry. This has important implica- account for substantial disparities (47). Characteristics of
tions for the choice of an antihypertensive agent. local environmental factors such as neighbourhood pov-
In blacks, thiazide-type diuretics and calcium channel erty, crime rates, availability of healthy foods and racial
blockers are more effective in lowering BP when given as isolation contribute to disparities in BP control (47).
monotherapy or as initial agents in multidrug regimens Health behaviours are significant contributors to hyper-
(41). In addition, thiazide-type agents are superior to drugs tension disparities. Adherence to hypertension treat-
that inhibit the renin-angiotensin system (i.e. angiotensin ment recommendations is lower in black compared with
converting enzyme [ACE] inhibitors, angiotensin-receptor white individuals (48) and dissimilarities in medication
blockers [ARBs], renin inhibitors, and beta-blockers) for adherence are linked with hypertension control dispari-
prevention of selected clinical outcomes in blacks (42). The ties (49). Prospective, longitudinal analysis of the preva-
calcium antagonist amlodipine is as effective as chlorthali- lence of cardiovascular health metrics among 5310 blacks
done and more effective than the ACE inhibitor lisinopril in (63.5% women) from the Jackson Heart Study showed that
reducing BP, CV disease and stroke events but less effective only 19% engaged in adequate physical activity, 18% had
392 Manual of Hypertension of the European Society of Hypertension
adequate BP, and 14% had a normal BMI. Meeting ideal American Heart Association Task Force on Clinical Practice
dietary intakes was rare (0.9%), with extremely low preva- Guidelines. J Am Coll Cardiol 2017 7; 71(6): e13–e115.
10. Yoon SS, Carroll MD, Fryar CD et al. Hypertension prevalence
lence of achieving sodium (0.2%) and wholegrain (4.1%) and control among adults: United States, 2011–2014. NCHS Data
recommendations (50). Brief 2015; (220): 1–8.
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Americans in clinical studies in sufficient representative Hispanics in the antihypertensive and lipid-lowering treatment to
prevent heart attack trial. Hypertension 2007; 50(5): 854–861.
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do not provide specific guidance for treating hypertension prevalence and disparities of obesity and other cardiovascular
in Hispanic patients. Given the clustering of hyperten- disease risk factors in three racial/ethnic groups of USA adults.
Adv Prev Med 2012; 2012: 172423.
sion with obesity, diabetes, and metabolic syndrome in 14. Daviglus ML, Talavera GA, Avilés-Santa ML et al. Prevalence of
Hispanics and the role of the renin−angiotensin system major cardiovascular risk factors and cardiovascular diseases
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sin system inhibitors are postulated as the most suitable United States. JAMA 2012; 308(17): 1775.
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medications (51). prevalence of diabetes in Asian countries. World J Diabetes 2012;
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nationally by culture or ethnic group and whether the reduced dietary sodium and the dietary approaches to stop hyper-
research could inform interventions to improve adherence. tension (DASH) diet. N Engl J Med 2001; 344(1): 3–10.
17. Morris RC, Sebastian A, Forman A, et al. Normotensive salt sen-
Included studies came from 16 countries. Nonadherence sitivity: Effects of race and dietary potassium. Hypertension 1999;
to hypertension treatment often resulted from patients’ 33: 18–23.
understanding of the causes and effects of hypertension; 18. Cooper R, Rotimi C, Ataman S, et al. The prevalence of hyper-
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and MYH9 genes is associated with chronic kidney disease among antihypertensive drugs. Hypertension 2004; 43(3): 566–572.
Nigerians. Int Urol Nephrol 2013; 45(2): 485–494. 46. Brewster LM, Seedat YK. Why do hypertensive patients of African
37. Wang X, Poole JC, Treiber FA, Harshfield GA, Hanevold CD, ancestry respond better to calcium blockers and diuretics than to
Snieder H. Ethnic and gender differences in ambulatory blood ACE inhibitors and β-adrenergic blockers? A systematic review.
pressure trajectories results from a 15-year longitudinal study in BMC Med 2013; 11(1): 141.
youth and young adults. Circulation 2006; 114(25): 2780–2787. 47. Seedat YK, Brewster LM. What role does African ancestry play in
38. Wong RJ, Chou C, Sinha SR, et al. Ethnic disparities in the how hypertensive patients respond to certain antihypertensive
association of body mass index with the risk of hypertension and drug therapy? Expert Opin Pharmacother 2014; 15(2): 159–161.
diabetes. J Community Health 2014; 39(3): 437–445. 48. Kressin NR, Orner MB, Manze M, et al. Understanding contribu-
39. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the tors to racial disparities in blood pressure control. Circ Cardiovasc
effects of dietary patterns on blood pressure. N Engl J Med 1997; Qual Outcomes 2010; 3(2): 173–180.
(4641): 1117–1124. 49. Bosworth HB, Powers B, Grubber JM et al. Racial differences in
40. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on blood pressure control: Potential explanatory factors. J Gen Intern
lifestyle management to reduce cardiovascular risk: A report of Med 2008; 23(5): 692–698.
the American College of Cardiology/American Heart Association 50. Djoussé L, Petrone AB, Blackshear C, et al. Prevalence and changes
Task Force on practice guidelines. J Am Coll Cardiol 2014; 63(25 over time of ideal cardiovascular health metrics among African-
Part B): 2960–2984. Americans: The Jackson Heart Study. Prev Med 2016; (617): 111–116.
41. Wright JT. Outcomes in hypertensive black and nonblack patients 51. Guzman NJ. Epidemiology and management of hypertension in
treated with chlorthalidone, amlodipine, and lisinopril. JAMA the Hispanic population: A review of the available literature. Am J
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42. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodip- 52. Marshall IJ, Wolfe CDA, McKevitt C. Lay perspectives on hyper-
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RESISTANT HYPERTENSION:
MEDICAL TREATMENT 48
of drugs, and the risk of drug−drug interactions should be detect dehydration, hypokalaemia, hyponatraemia, hypo-
taken into account for the treatment (5,14,15). volaemia or renal dysfunction.
General measures
• Take into account cardiovascular or other comorbid conditions (chronic kidney disease), age, sex, ethnicity, drug-drug
interactions, contraindications, previous side effects.
• Use fixed-dose combinations in a single pill, home BP monitoring, regular appointments, and the help of nurses,
pharmacists and patient’s family, to improve adherence to treatment.
• Regular monitoring of plasma electrolytes (K and Na) and creatinine (or cystatin C) concentrations.
clonidine was low. The patients randomized to clonidine atenolol), an alpha-blocker and a centrally acting alpha-
had more frequent somnolence. agonist is preferred (Figure 48.1). Beta-blockers can be
In summary, RHTN is commonly a salt-retaining state, used particularly in patients with coronary artery disease,
most likely due to inappropriate aldosterone secretion (45). heart failure, arrhythmia or chronic kidney disease (3–5).
MR blockade by spironolactone overcomes the salt retention Direct vasodilators (hydralazine or minoxidil) should
and resistance of hypertension to treatment. Spironolactone be avoided, because they may induce fluid retention and
(25–50 mg/day) should be used in patients with RHTN but tachycardia (3–5). Dual RAS blockade with ACEI and
restricted to those with an eGFR ≥45 mL/min and a plasma ARBs or with direct renin inhibitors should not be used
potassium concentration ≤4.5 mmol/L (Figure 48.1), par- (3,4) because such combinations (i) are not effective for
ticularly in cases of a compelling indication, such as heart lowering BP 47, and (ii) are associated with a higher risk of
failure, in accordance with guidelines (3,4,28). When spi- hyperkalaemia, hypotension and acute renal failure (48).
ronolactone is contraindicated or not tolerated, bisoprolol The complexity of the multidrug therapeutic regimens
(42), doxazosin (42), amiloride (45) or clonidine (46) can used in patients with RHTN increases the likelihood of
be used for the treatment of RHTN (Figure 48.1). drug-related side effects and may contribute to the lack
The efficacy of spironolactone to reverse sodium over- of adherence to treatment of patients who may be taking
load and thus to lower BP in patients with RHTN may be large numbers of other drugs for comorbid conditions.
enhanced by using a combination of loop diuretics and thia-
zides at low doses, or sequential nephron blockade (sequen-
tial administration of 25 mg/day spironolactone, followed
by 20 and then 40 mg/day furosemide, and 5 mg/day IMPROVING THE EFFICACY OF
amiloride) on top of a triple therapy including a low dose ANTIHYPERTENSIVE TREATMENTS
of 12.5 mg of hydrochlorothiazide, as shown in a French
study (47). However, although well tolerated in this trial,
sequential nephron blockade strategy requires the careful DETECTING NONADHERENCE AND IMPROVING
monitoring of renal function, serum electrolyte levels and
fluid status, for the detection of dehydration, hypokalae-
ADHERENCE TO ANTIHYPERTENSIVE
mia, hyponatraemia, hypovolaemia or renal dysfunction. TREATMENT
Nonadherence to antihypertensive medications and
lifestyle measures is a key contributing factor to RHTN
FURTHER ADDITION OF ANTIHYPERTENSIVE (49,50). Nonadherence is associated with poor cardio-
TREATMENTS: SEEKING SPECIALIST ADVICE vascular prognosis (51,52). Several disease-, physician-,
treatment- and patient-related factors, either alone or in
Specialist advice should be sought at a dedicated tertiary combination, promote nonadherence to treatment and are
BP clinic if BP remains uncontrolled (3–5). At this stage, common to all chronic diseases, including hypertension
a stepwise addition of a beta-blocker (with exception of (49,50).
398 Manual of Hypertension of the European Society of Hypertension
ambulatory blood pressure monitoring. Hypertension 2011; 57: 36. Tamargo J, Segura J, Ruilope LM. Diuretics in the treatment of
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15. Vongpatanasin W. Resistant hypertension: A review of diagnosis ing furosemide and hydrochlorothiazide in patients with hyper-
and management. JAMA 2014; 311: 2216–e2224. tension and stage 4 or 5 chronic kidney disease. J Clin Hypertens
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INTERVENTIONAL THERAPIES
FOR ESSENTIAL HYPERTENSION 49
resistant hypertension (6). The device was implanted in all The preliminary Barostim neo trial was a single-arm
participants, and BAT was engaged in a 2:1 fashion either open-label study on 30 patients with RHTN in whom
for the first 6 months (active group) or in a delayed man- device programming was individually tailored (10).
ner after the 6-month visit (control group). At 6 months, Resultant decreases in BP were similar to bilateral ther-
decreases in clinic systolic BP by 16 mmHg in the active apy. At 6 months, a significant decrease in clinic BP by
group and 9 mmHg in the control group (p = 0.08) were 26 ± 4/12 ± 2.5
mmHg was documented. Significant
recorded, with sustained efficacy at 12 months (7). The decreases were also observed in patients with prior RDN,
trial failed the acute 6-month responder efficacy endpoint similar to the other BAT studies. The study documented
(>10 mmHg systolic BP drop) but not the ancillary end- a pacemaker-like safety profile, with all of three compli-
point of subjects attaining a systolic BP below 140 mmHg cations associated with the generator pocket. However, a
(42% in the treatment group vs. 24% in the control group). limitation of most BAT studies is the utilization of office
Of interest, a post hoc analysis revealed that right-sided BP for the efficacy endpoint. A recent uncontrolled study
unilateral BAT had a greater effect on BP compared to on 51 patients with resistant hypertension who underwent
bilateral or left-sided BAT (8). The study, however, raised treatment with the Barostim neo showed that 24-h BP was
safety concerns related to surgical complications and facial significantly reduced by 8 ± 6/5 ± 2 mmHg at 6 months
nerve injury. (11). The Barostim neo Hypertension Pivotal Trial is a ran-
Data from the 6-year open follow-up of 383 patients domised controlled trial on resistant hypertension patients
included in any of the three trials provide long-term that will shed more light on the safety and efficacy of the
efficacy and safety data of the device (9). Office BP fell from system (clinicaltrials.gov/NCT01679132).
179 ± 24/103 ± 16 mmHg to 144 ± 28/85 ± 18 mmHg
(p < 0.0001), and the greatest BP drop was documented
at 6 months and sustained thereafter. The treatment effect
was more evident in patients with heart failure signs and MOBIUSHD
smaller in those with isolated systolic hypertension. About
The MobiusHD (Vascular Dynamics, Inc.) is an endovas-
a quarter of patients were able to reduce their median drug
cular, nitinol, self-expanding cuboid stent that is unilater-
number by half. The procedure proved overall safe. Out
ally applied to the carotid sinus through the less invasive
of a total of 335 serious adverse events recorded, 26 were
endovascular femoral approach (Figure 49.2). The device
related to the procedure or the system and included gen-
increases carotid sinus wall strain by inducing geometric
erator migration, lead malfunction or migration and epi-
changes at the level of the carotid bulb, without affecting
sodes of hypotension.
pulsatile or laminal flow. As the increased wall strain is
sensed as increased pressure, the device amplifies barore-
ceptor sensitivity and feedback in order to lower sympa-
BAROSTIM NEO thetic activity and BP.
Recently, the results of the Controlling and Lowering
The Barostim neo (CVRx) is a second-generation, improved Blood Pressure with the MobiusHD-First in Man (CALM-
version of the Rheos device and features a smaller pulse FIM_EUR) study were reported (12). The study was a mul-
generator with a longer-lasting battery and a simpler, sin- ticentre, open-label, safety and proof-of-principle trial in
gle-button, 2-mm lead that is unilaterally placed at the patients with severe resistant hypertension (mean office BP
right carotid sinus (Figure 49.1). The surgical procedure, 184/109 mmHg on a mean of 4.4 drugs). Exclusion criteria
performed under conscious sedation, has an improved
safety profile due to the need for only a small incision
for electrode placement and no exposure of the external
carotid artery.
included possible baroreflex failure or autonomic neuropa- to maintain the baseline BP, eventually leading to its reduc-
thy. Lowering of BP was already evident in the first 24 hours tion. On the other hand, the increased cardiac preload
after implantation. Significant reductions in office and 24-h leads to higher right atrial and pulmonary capillary wedge
BP were documented (24/12 mmHg and 17/14 mmHg respec- pressure that may attenuate the baroreceptor reflex (along
tively) at 6 months. The few serious adverse events included with sympathetic activation) as well as trigger the release of
episodes of hypotension and wound infection. Blinded, natriuretic peptides. Furthermore, a central AV anastomosis
sham-controlled trials (clinicaltrials.gov/NCT02804087) reduces effective arterial blood volume to a new baseline
shall investigate the device safety and efficacy further. without depleting other volume capacitance spaces, and
thus without neurohormonal activation. This is of particu-
lar interest for the ageing aorta, where the stress-strain curve
shifts to the left; after the anastomosis, for any increase in
CENTRAL ILIAC ARTERIOVENOUS intravascular volume, a milder increase in BP is expected,
ANASTOMOSIS restoring arterial compliance (18).
While other interventional therapies of hypertension The ROX AV coupler (ROX Medical) is a nitinol-based, self-
primarily target the SNS, the central iliac arteriovenous expanding device resembling a coronary stent with shape
(AV) anastomosis seeks to add a low-resistance, high- memory, allowing it to adopt a preformed figure after
compliance venous segment to the arterial tree in order deployment (Figure 49.4). The implantation procedure is
to reduce systemic vascular resistance and restore the performed in the catheterization laboratory or the endo-
Windkessel model of elastic aortic function (Figure 49.3). vascular operating room. In the beginning, a 4F arterial
The concept of the creation of a fixed-calibre central AV and 11F venous sheath are placed in either the right or left
fistula was initially developed for patients with chronic common femoral artery and ipsilateral vein, with a 2-cm
obstructive pulmonary disease. The desired effect was to height difference. A crosshair spiral guidewire is advanced
increase central venous oxygenation as well as oxygen sat-
uration in pulmonary shunts not participating in exchange
of gases (13). Moderate results regarding exercise capacity Placement between
along with adverse events restricted the interest in further external iliac artery and vein
development of the procedure for this indication (14).
(a)
The creation of an AV fistula results in blood flow parallel
to the systemic circulation, leading to a reduction in sys-
temic vascular resistance and cardiac afterload (15). It is well
known that peripheral AV fistulae in haemodialysis patients
are accompanied by decreases in BP and peripheral resis-
tance (16,17). However, BP reduction due to the shunt in
turn leads to sympathetic activation. The increase in venous
return and sympathetic activation result in an increase in
cardiac output. The percentage of the cardiac output that the
shunt holds needs therefore to reach a threshold over which
any increase in systemic resistance and cardiac output fail
through the arterial sheath to mark the desired anastomo- NCT02895386). The primary endpoint of the study shall
sis location, 2–4 cm above the femoral head. At that point, be the mean ambulatory systolic BP change at 6 months.
the external iliac artery should be free of calcium and have This trial, along with a running global registry (clinical-
a diameter of at least 5 mm, while the space between artery trials.gov/NCT01885390), are expected to clarify the effi-
and vein should be less than 3 mm. A micropuncture cross- cacy and accompanying cardiac adaptations of the device,
ing needle is then introduced through the venous sheath as well as provide better understanding of the potential
in order to pierce through the venous and arterial walls. A adverse events, that apart from venous stenosis include
crossing wire is advanced through the crossing needle, and high output sequelae and venous stenosis.
the latter is removed. The ROX coupler delivery system,
featuring a flexible tip, is then advanced over the cross-
ing wire, and the arterial arms of the coupler are deployed OTHER INTERVENTIONAL TREATMENTS
first. The final anastomotic passage of a 4 mm diameter is
achieved with the inflation of a balloon catheter within A number of impressive interventional modalities for
the coupler. Fluoroscopic guidance is used to optimize the treatment of HTN are currently under investigation.
the procedure and ensure correct positioning and sizing Research data are very limited and mostly at a phase I or
of the anastomosis. Eventually, the device allows for con- II trial level, and carefully designed studies are needed to
trolled shunting of 800–1000 mL/min. A significant asset identify their clinical use.
of the AV coupler is the direct assessment of procedural
success through visualization with contrast, palpation of
a thrill, auscultation of a bruit and most importantly, by
the instant drop in systolic BP, which is reversible with bal- CAROTID BODY ABLATION
loon reocclusion. The anastomosis itself is reversible with
The carotid bodies are peripheral chemoreceptors at the
the use of a covered stent.
bifurcations of the common carotid arteries that are very
Following trials of patients with pulmonary disease
sensitive to small changes in blood flow, oxygen, carbon
showing significant reductions in BP (19), principal study
dioxide and pH. Inappropriate activation of the carotid
data involve patients with significantly uncontrolled
bodies, accompanied by sympathetic overactivity, has
hypertension. Contraindications have included previous
been observed in hypertension and sleep apnoea. Bilateral
thromboembolism and pulmonary hypertension or high
resection was performed in the past for the treatment
pulmonary capillary wedge pressure, secondary hyperten-
of asthma but was abandoned due to decreased efficacy
sion and renal denervation within the previous 6 months.
(23). Unilateral surgical carotid body resection has been
The ROX CONTROL HTN study was a multicentre safety
recently proposed for BP lowering, acting through a reduc-
and efficacy, open-label trial on 83 patients with uncon-
tion in afferent sympathetic activity from the carotid body
trolled systolic BP (office BP at 175/100 mmHg) randomised
(24). The procedure is performed under general or local
1:1 to coupler implantation plus current drug treatment or
anaesthesia with sedation, and it involves isolation of tis-
drug treatment alone (20). Significant reductions in the cou-
sue within the intercarotid septum, ligation at the saddle
pler group, unlike the control group, were observed in the
of the bifurcation and excision of the septal tissue.
intention to treat analysis at 6 months in both office and
In a proof-of-concept study in 15 patients with resistant
24-h systolic BP (by 27 ± 24 mmHg and 14 ± 19 mmHg
hypertension (mean office systolic BP:168 ± 7 mmHg on
respectively, p < 0.0001 for both). Highly significant BP
5.7 drugs), the procedure was shown to be of acceptable
reductions were also observed in patients who had previ-
safety, and ventilatory response to hypoxia was main-
ously undergone RNA. In a post hoc analysis of the trial
tained (25). Overall, no significant change was observed
data, it was also shown that the anastomosis reduces BP to
in BP, but a significant decrease was noted in the eight
a similar extent in patients with either combined or isolated
responders with high carotid tone (by 23/12 mmHg) along
systolic hypertension (21). A total of 25 procedure- or device-
with a decrease in muscle sympathetic activity. An endo-
related events were recorded that resolved without sequelae.
vascular as well as a chemical block approach to carotid
There were no cases of coupler migration or spontaneous
body modulation are under investigation (clinicaltrials.
closure reported. However, 29% of participants developed
gov/NCT02099851 and NCT02519868, respectively).
lower-extremity oedema in the following months due to
iliac vein stenosis and were treated with venoplasty.
More recently, the available 1-year results of the active
treatment group of the ROX CONTROL HTN study DEEP BRAIN STIMULATION
were published (22). A sustained reduction in office
and ambulatory systolic BP (by 25.1 ± 23.3 mmHg and The periaqueductal and periventricular grey matter has
12.6 ± 17.4/15.3 ± 9.7 mmHg respectively, p < 0.0001 for been shown to be associated with heart rate and BP in
both) was noted. Rates of venous stenosis were again high animals. The potential use of deep brain stimulation for
(33% of patients) and all cases were treated with venous BP lowering was first identified in patients with neuro-
stenting. Overall, the stenosis develops upstream from the pathic pain (26). A number of case reports have shown that
conduit as a result of venous intima hyperplasia due to tur- continuous deep brain stimulation with multipolar elec-
bulent flow. It is more often on the left side and is associ- trodes, surgically implanted with a magnetic resonance-
ated with ipsilateral limb swelling and an increase in BP. guided stereotactic approach, may lead to significant and
The promising results have given the green light for the sustained drops in BP (27,28). An accompanying reduction
CONTROL HTN-2, a randomised, sham-controlled (arte- in muscle sympathetic nerve activity has been noted. The
rial puncture) study of up to 500 uncontrolled hyper- proposed mechanisms include a resetting of neural net-
tensive patients (office systolic BP >155 mmHg) that is works that manage sympathetic outflow and a decrease in
expected to be completed in 2019 (clinicaltrials.gov/ systemic vascular resistance.
Interventional Therapies for Essential Hypertension 405
which are influenced by the ‘placebo’, the sham-controlled The Prague-15 study compared RDN with use of the
design is proposed. Addressing the abovementioned need, Symplicity catheter (n = 52) to intensive pharmacologi-
the sham-controlled study in RDN, Symplicity HTN-3 cal therapy with spironolactone (n = 54) in patients with
was conducted (45). In the trial 535 patients with resis- resistant hypertension. There was a significant reduction
tant hypertension were randomised 2:1 to RDN or sham- of 24-h BP at 6 months της (−8.6 mmHg; p < 0.001 in
RDN. Antihypertensive medication remained stable for at the RDN compared to −8.1 mmHg, p = 0.001 in the drug
least 2 weeks before the procedure. The primary endpoint group) while there was no significant difference between
of safety was reached, but not efficacy, since the predeter- groups (54). Based on these results, RDN was not superior
mined 5 mmHg cutoff point of difference in office sys- in BP reduction efficacy but the number of antihyperten-
tolic BP between the two arms was not met (45). In the sive drugs was higher in the group of non-interventional
RDN group, systolic BP was reduced by −14.1 mmHg and therapy (54). Along the same lines, in the OSLO study with
by −11.7 mmHg in the sham-group. Similarly there was a stepwise drug therapy based on the use of the HOTMAN
2-mmHg difference in the ambulatory BP achieved after device and strict compliance control it was shown that
6 months with the patients after RDN presenting a drop after 6 months office and ambulatory BP reduction was
of 6.7 mmHg and the sham group a decrease of 4.7 mmHg greater in the non-RDN group, with the limitation of the
(45). The frequent and not predefined in terms of drug small number of participants and the use of the imped-
classes and time-point changes in antihypertensive medi- ance system (55).
cation, the relatively small number of ablations performed
per patient, the problems of reduced compliance and the
great reduction of BP in the sham group are important lim- CONCLUSIONS AND CONSENSUS FOR THE
itations for Symplicity HTN-3 (46–48). Subsequent analy-
sis revealed that patients with arterial stiffness as reflected NEXT RDN TRIALS
by higher pulse pressure were not responders to RDN, After the publication of Symplicity HTN-3, subsequent
and greater reductions in office and ambulatory SBP were comprehensive subanalysis of the results along with inter-
observed in those patients with a higher number of abla- esting new preclinical data regarding the location and dis-
tions and when lesions were created in a four-quadrant tribution of renal fibres in the renal arterial wall improved
pattern (45–48). These findings influenced future sham- the insight on the potential confounding factors that may
controlled studies to include a more structured approach explain, at least partially, the unexpected BP responses in
for ensuring compliance, drug intake, titration of therapy both RDN and sham ablation groups as well as the huge
and effective ablation by RDN in sham-controlled RDN variability in BP response post RDN (47,56–59). The list
studies (49). of these confounders includes incomplete denervation,
poor antihypertensive medication stability and adherence,
selection of non-appropriate population and selection of
OTHER FIRST-GENERATION SHAM- office BP as endpoint of RDN efficacy (47,56). In addition,
CONTROLLED TRIALS pioneer studies have shown that the highest average num-
ber of nerves was observed in the proximal and middle
In the Symplicity HTN-3 aftermath, subsequent sham-con- segments of the renal artery and the lowest in the distal
trolled smaller trials showed that RDN is at least equally segments (60,61), while the mean distance from the lumen
effective to intensive pharmacotherapy in lowering BP in to the nerve was the longest in the proximal and the lowest
patients with resistant hypertension (50,51). These studies in the distal segments. Moreover, reports have suggested
suggested that it is essential to monitor technical success that RDN distally in the renal vasculature, and more spe-
during the intervention and assess compliance to certain cifically, in the branches, results in greater noradrenaline
medications throughout the studies (50,51). Another most reduction (56–61). These points are of importance since
recent sham-controlled trial using external application they changed our perspective towards RDN trial method-
of ultrasound energy for RDN compared to drug therapy ology and overall design, which is reflected to the recent
showed no difference in office and ambulatory BP between sham-controlled studies.
treatment arms (52).
SECOND-GENERATION SHAM-CONTROLLED
STUDIES COMPARING STANDARD STEPWISE RANDOMISED TRIALS
PHARMACOLOGICAL THERAPY AND RDN
In order to address the confounders of RDN therapy, three
In the Renal Denervation in Hypertension (DENER-HTN) randomised sham-controlled trials have been designed and
study, 106 patients with resistant hypertension were ran- presented using radiofrequency (SPYRAL HTN-OFF and
domised to either standard stepwise therapy with pre- ON-MED studies) and ultrasound ablation (RADIANCE
determined doses of certain drugs (indapamide 1.5 mg, HTN SOLO) (52,62–63). The SPYRAL HTN-OFF Med and
remipril 10 mg or irbesartan 300 mg) and amlodipine the SPYRAL HTN-ON Med had as primary endpoints the
10 mg daily for 4 weeks plus spironolactone 25 mg, biso- change in 24-h ambulatory blood pressure at 3 months
prolol 10 mg, prazosine 5 mg and rilmenidine 1 mg (53). (OFF-MED) and 6 months (ON-Med), while the SPYRAL
There was a −5.9 mmHg difference in the daytime ambu- HTN ON-MED study required patients to be treated with
latory BP in the RDN group compared to drug therapy at a consistent mono or double- or triple-therapy antihyper-
6 months. In this well-designed trial, the severity of hyper- tensive regimen, whereas the SPYRAL HTN OFF-MED and
tensive disease was less and baseline BP lower than in the the RADIANCE HTN SOLO study included drug ‘naïve’
Symplicity HTN-2 study population (43,53). patients or patients after a 3–4 week drug washout period
Interventional Therapies for Essential Hypertension 407
(52,62,63). The studies randomise patients with combined both patients and physicians remain blinded to randomi-
systolic-diastolic hypertension (with special attention sation for 6 months at least, and for efficacy and safety the
to exclude isolated hypertension phenotype) to RDN or follow-up is extended to 3 years.
sham procedure. In the SPYRAL HTN-OFF MED trial, all patients were
The two proof-of-concept SPYRAL HTN studies reported off any antihypertensive medication for 4 weeks before
their results at an interim analysis when 80 patients were randomisation with office BP >150/90 mmHg, and ambu-
included (62,63). The SPYRAL trials were proof-of-concept latory BP >140 mmHg systolic (24-h average) (62). A suit-
trials to justify larger, powered trial, while the RADIANCE able renal artery anatomy and an estimated glomerular
HTN-SOLO trial randomised a total of 146 patients and filtration rate >45 mL/min/1.73 m2 was needed. SPYRAL
had the statistical power to detect a difference of 6 mmHg HTN-ON Med included patients with the same BP criteria
in daytime ambulatory systolic BP between the RDN and as in SPYRAL HTN-OFF Med, but one to three antihyper-
the sham group (52). The follow-up phases were at the tensive medications were allowed (on average 2.2 medica-
time-points of 2 months (RADIANCE HTN-SOLO), 3 tions) (62). In the SPYRAL HTN-OFF Med, office BP was
months (SPYRAL HTN-OFF MED) and 3 and 6 months 162/100 mmHg and 24-h BP was 152/99 mmHg, and in
(SPYRAL HTN-ON MED), respectively. In the three trials, the SPYRAL HTN-ON Med office BP was 164/101 mmHg
and 24-h BP was 151/97 mmHg (62,63).
Regarding the SPYRAL multielectrode catheter (Med
tronic, Galway, Ireland) with quadrantic vessel contact, it
is an over-the-wire system that uses radiofrequency-energy
designed to target the main distal and branch renal arter-
ies with diameter >3 mm by applying energy simultane-
ously through four electrodes for 60 seconds (Figures 49.6
and 49.7). In both studies, more than 45 ablations were
performed per patient (62,63).
In the SPYRAL HTN-OFF Med trial, 24-h ambulatory
BP was reduced by 5.5/4.8 mmHg in the RDN group
and 0.5/0.4 mmHg in the sham group after 3-month
follow-up. The mean baseline-adjusted difference (primary
objective) in ambulatory BP between the RDN and the
sham groups was −4.6/−4.3 mmHg for 24-h ambulatory
BP (p = 0.0528/p =
0.0028) in the SPYRAL HTN-OFF
Med trial (Figure 49.8) (62). In the SPYRAL HTN-ON
Med, 24-h a mbulatory BP was reduced in the RDN group
by −4.8/−4.3 mmHg after 3 months and −9.0/−6.0 mmHg
after 6 months, compared to changes of −0.2/−0.6 mmHg
Figure 49.6 The SPYRAL (Medtronic Inc.) multi- and −1.6/−1.9 mmHg in the sham group, respectively. The
electrode catheter used in the SPYRAL HTN-OFF and meandifferencein24-hambulatoryBPintheSPYRALHTN-ON
HTN-ON MED studies. Med (6 months) was −7.0/−4.3 mmHg (p = 0.0059/0.0174)
(Figure 49.9) (63). The mean baseline-adjusted differences
(a) (b)
Figure 49.7 (a) The SPYRAL catheter in the stem of the left main renal artery (Prof. Tsioufis personal archive). (b) The
SPYRAL catheter in a branch of the left renal artery (Prof. Tsioufis personal archive).
408 Manual of Hypertension of the European Society of Hypertension
–10
∆ –5.0 mmHg ∆ –4.4 mmHg –10.0 ∆ –4.9 mmHg
–12 (–9.9, –0.2) (–7.2, –1.6) (–15.1, –4.9) (–8.5, –1.4)
P = 0.04 P = 0.002 P <0.001 P = 0.008
–14
∆ –7.7 mmHg
(–14.0, –1.5) RDN
P = 0.02
Figure 49.8 The 3-month results of the SPYRAL HTN-OFF MED sham-controlled trial.
in office BP between the RDN and the sham group were compliance with the requirement to be off antihypertensive
7.1/−5.0 mmHg (p = 0.0212/0.0076) in SPYRAL HTN-OFF medications at baseline and 3 months was 85.5% (62). In
Med and −6.6/−4.2 mmHg (p = 0.0250/0.0190) in the these lines, in the SPYRAL HTN-ON MED study, adherence
SPYRAL HTN-ON MED. There was a stable reduction of 24-h to antihypertensive drugs was similar between groups and
BP in the RDN group whereas this was not present in the drug antihypertensive drugs not prescribed by physicians were
intervention arm, suggesting an ‘always-on’ effect of RDN detected in 10–15% of patients at each time point (63).
on BP levels due to the fact that pharmaceutical treatment is Regarding safety, there were no adverse events though
influenced by daily action and complicated by intolerances, the reported follow-up (62,63). This proof-of-concept
dosing frequency and levels of adherence (63). SPYRAL study provided the evidence for larger pivotal
In the SPYRAL HTN-OFF MED study, drug testing was studies with this RDN system.
done at baseline and at 3 months to identify whether In the RADIANCE HTN-SOLO, all patients were off anti-
patients were taking any antihypertensive medications. At hypertensive medication, and inclusion criteria were office
baseline, 92.1% (35 of 38) of patients in the renal dener- BP ≥140/90 mmHg and ambulatory BP ≥135/85 mmHg
vation group and 88.1% (37 of 42) in the sham control (daytime) and an estimated glomerular filtration
group had no evidence of antihypertensive medication rate >40 mL/min/1.73 m2 (63). Baseline office BP was
use (p = 0.72) (62). At 3 months, for available data, 94.3% 154/99 mmHg and 24-h BP was 144/88 mmHg (52).
(33 of 35) of patients in the renal denervation group and The RADIANCE-HTN trial used a low-pressure water-
92.7% (38 of 41) in the sham control group had no anti- filled cooling balloon catheter that delivers ultrasound
hypertensive medications detected (p >0.99) (62). Overall energy to thermally ablate the renal sympathetic nerves
(a) 24 h SBP 24 h DBP Office SBP Office DBP (b) 5 Renal denervation
Sham control
Change in 24 h SBP (mmHg)
–7.4 (–12.5 to –2.3) –4.1 (–7.8 to –0.4) –6.8 (–12.5 to –1.1) –3.5 (–7.0 to 0) 0
p = 0.0051 p = 0.0292 p = 0.0205 p = 0.0478 –0.7
–4.3 –1.8
0 –5
Change in BP from baseline to 6 months (mmHg)
n = 36 n = 36 n = 36 n = 36 n = 38 n = 40 n = 38 n = 40 –8.8
–2 –1.6 –10
–1.7
–1.9
(–5.2 to 2.0) –2.6 (–4.2 to 0.9)
(–4.7 to 0.9)
p = 0.365 (–6.7 to 1.6) p = 0.188 –15
–4 p = 0.172
p = 0.215
5
–5.2
–6
Change in 24 h DBP (mmHg)
Figure 49.9 The results of the SPYRAL HTN-ON MED sham-controlled trial. (a) Reduction of 24 hour and office blood
pressure in the renal denervation and sham control groups; (b) changes in 24 hour systolic and diastolic blood pressure at
3 and 6 months follow-up.
Interventional Therapies for Essential Hypertension 409
Systolic Diastolic
Figure 49.10 The 2-month results of the RADIANCE-HTN SOLO sham-controlled trial. (a) Change in daytime ambulatory
blood pressure. (b) Change in 24-h ambulatory blood pressure.
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ATRIAL FIBRILLATION AND
ARTERIAL HYPERTENSION 50
significantly more frequent than in patients without LVH In another cross-sectional study (32) that included
(11.1% vs. 1.1%) (22). 102 patients (52 on sinus rhythm, 50 on AF) systolic and
In addition, LVH influences the effectiveness of antico- diastolic BP did not significantly differ in patients with
agulant therapy. In a post hoc analysis, the Randomised sinus rhythm and AF, independently of the method of
Evaluation of Long-term anticoagulation therapY (RE-LY) measurement. Although the within-subject variability of
Study, LVH was associated with lower antithrombotic effi- the oscillometric measurements was higher in patients
cacy of warfarin, but not of dabigatran (23). It also seems with AF compared to those with sinus rhythm, the biases
that the hypercoagulable state during AF could induce of systolic and diastolic BP did not significantly differ in
atrial fibrosis and further enhance AF. Spronk et al. (24), the presence or absence of AF. A few more studies have
in an experimental study, showed that in isolated rat atrial assessed the use of ABPM in patients with stable AF.
fibroblasts, thrombin enhanced the phosphorylation However, the number of participants was small. In these
of the pro-fibrotic signalling molecules Akt and Erk and studies, the average of successful BP readings ranged from
increased the expression of transforming growth factor β1 80−94% (33–35).
(2.7-fold) and the proinflammatory factor monocyte che- Taking all of this into consideration, we could support
moattractant protein-1 (6.1-fold) by activating protease- the fact that oscillometric devices can be accurate in mea-
activated receptor (PAR)-signalling pathways. They also suring SBP but not DBP. Since AF is encountered more fre-
demonstrated that all effects could be attenuated by the quently among the elderly, an age group for which current
thrombin inhibitor dabigatran. Furthermore, they indi- guidelines recommend BP thresholds only for SBP levels,
cated that in goats with AF, treated with nadroparin tar- we may also use these devices for BP measurement in
geting the factor Xa−mediated thrombin generation, the patients with AF, knowing, however, the limitation regard-
complexity of the AF substrate was lower than in control ing DBP readings (31,36).
animals, and the arrhythmogenic burden also. Given the
fact that novel (new) oral anticoagulants (NOACs) are able
to act at the level of both the coagulation cataract and the
PAR-signalling pathway (25), unlike vitamin K antagonists DETECTION OF ATRIAL FIBRILLATION IN
(VKAs), it can be said that NOACs may not only prevent PATIENTS WITH ARTERIAL HYPERTENSION
strokes but also alter the substrate for AF (24).
Both atrial AF and AH share common risk factors such According to the Framingham Heart Study, the lifetime
smoking, diabetes mellitus, obesity and alcohol consump- risk for development of AF is 1 in 4 for men and women
tion, leading to the development of both diseases (29). 40 years of age and older (37). Based on this finding, the
Thus it is not a surprise that in all recent AF trials, namely Framingham researchers developed an algorithm to define
RELY, ROCKET-AF (Rivaroxaban Once Daily Oral Direct an individual’s absolute risk of developing AF within the
Factor Xa Inhibition Compared with Vitamin K Antagonist next 10 years (38). They used a predictive model relying on
for Prevention of Stroke and Embolism Trial in Atrial risk factors associated with AF occurrence, like SBP.
Fibrillation), AVERROES (Apixaban versus Acetylsalicylic The early diagnosis of AF is crucial due to the high risk
Acid to Prevent Strokes) and ARISTOTLE (Apixaban for of cardiovascular events in patients with AF. However,
reduction in stroke and other ThromboemboLic events in in about one-third of the cases, AF can be totally asymp-
AF), the presence of AH ranged from 49−90% of the indi- tomatic (17,39). In the ALFA Study (40) that enrolled 756
viduals with AF (23,26–28), highlighting the fact that AH patients with electrocardiographically documented AF,
and AF frequently coexist. subdivided into paroxysmal (<7 days), chronic (last epi-
sode >1 month) and recent onset AF (persistent >7 days
and <1 month) symptoms were present only in 88.6% of
the patients. More specifically, 16.2% of the participants
DIAGNOSIS OF ARTERIAL HYPERTENSION with permanent AF reported no obvious symptoms, while
IN PATIENTS WITH ATRIAL FIBRILLATION − 5.4% of patients with the paroxysmal form of the arrhyth-
BLOOD PRESSURE MEASUREMENT mia were asymptomatic. According to current ESH/ESC
guidelines (41), all hypertensive patients should undergo
Several sphygmomanometer types − aneroid, hybrid and palpation of the pulse at rest to determine heart rate and
the oscillometric − are validated to properly measure BP to to search for arrhythmias, especially AF. A 12-lead ECG
assess hypertensive burden and proceed to the therapeutic should be part of the routine tests since it can detect
management of the hypertensive patient (30). Automatic arrhythmias like AF, although this procedure must be car-
oscillometric devices in particular are useful since they ried out by appropriately trained personnel. The Screening
also permit out-of-office BP measurements (home or 24-h for Atrial Fibrillation in the Elderly (SAFE) trial (42) that
ambulatory BP measurements [ABPM]). These devices are took place in the UK pointed out that the primary care pro-
programmed to calculate mean BP levels relying on the fessionals (general practitioners and practice nurses) could
oscillometric principle and therefore to evaluate SBP and not reliably diagnose AF on an electrocardiogram. Current
DBP levels by using a specific algorithm (30). However, ESH/ESC guidelines (41) also recommend additional tests
measurements obtained by automatic oscillometric in patients with history or physical examination suggestive
devices may not be accurate in patients with AF, as they of arrhythmic events. In case of suspected exercise-induced
encounter several points assessed as mean arterial pres- arrhythmias, a stress ECG test should be considered.
sure. Unfortunately, there are few studies in the literature However, the existence of AF episodes cannot be ruled out
addressing this issue. According to a meta-analysis (31) by these tests, since it is not certain that patients will pres-
that enrolled 566 patients with sustained AF, automated ent AF during these diagnostic procedures.
devices (oscillometric or automated Korotkov) appear to Thus in patients at high risk for the development of
be accurate in measuring SBP but not DBP. AF as well as in patients with cryptogenic stroke, more
Atrial Fibrillation and Arterial Hypertension 413
extended and reliable AF screening is necessary. Serial stroke and systemic embolic events (SEE) and the degree
ECGs, prolonged ECG monitoring (e.g. for 72 hours or of hypertension, in patients with AF, receiving ximelaga-
more − ECG Holter monitoring), skin patch recorders for tran (a direct oral thrombin inhibitor discontinued due to
extended continuous ECG monitoring or implantation hepatic toxicity). They concluded that event rates mark-
of loop recorders can enhance the detection of AF (42). edly increased at SBP levels of > or = 140. Likewise, the
Furthermore, oscillometric BP devices with a specific algo- ARISTOTLE (Apixaban for Reduction in Stroke and Other
rithm for the detection of AF may be useful tools in screen- Thromboembolic Events in Atrial Fibrillation) trial that
ing for AF at multiple time points during the day. Recently, included 18,201 patients with AF indicated that BP levels
in a meta-analysis of a total of 2332 individuals with AH, >140/90 mmHg at any point during the trial were inde-
Verberk et al. (43) investigated the use of a specific algo- pendently associated with a substantially higher risk of
rithm for AF detection during automated BP measurement stroke or systemic embolism (SE) (50). Moreover, from a
held by oscillometric devices. They concluded that AF retrospective analysis of the ROCKET AF trial, it has been
detection with routine automated BP measurements is a indicated that the adjusted risk of stroke or SE increased
reliable screening tool in the elderly. They also stated that significantly for every 10-mmHg increase in screening SBP
the accuracy of the procedure depended on the number of (51). Similar findings were collected from a substudy of
the measurements. Thus, taking three sequential readings the RELY trial that included hypertensive patients with AF.
with at least two detecting AF gave the highest diagnostic Every 10-mmHg increase in mean BP and SBP was associ-
accuracy. ated with an increase by 6–7% in the risk of stroke (52).
Hypertensive patients tend to routinely measure BP levels Many studies have also indicated the fact that anti-
several times during a day or week. Thus these devices can hypertensive treatment is associated with a remarkable
be a useful tool in revealing arrhythmic events especially in reduction in stroke incidence (53), irrespectively of the
the elderly. Of course, the use of such devices cannot alone medication used (46). It has also been indicated that
be sufficient for the diagnosis of AF, which requires electro- higher BP reduction is related to higher protection against
cardiographic confirmation (ECG, Holter, etc). stroke (46). The PROGRESS (The Perindopril Protection
Finally, in patients with rhythm management devices, against Recurrent Stroke Study) trial, which included
the interrogation of the device may reveal periods of AF. The patients with a history of a cerebrovascular event, showed
Asymptomatic Atrial Fibrillation and Stroke Evaluation in that the reduction of SBP from about 165 mmHg to about
Pacemaker Patients and the Atrial Fibrillation Reduction 115 mmHg was associated with a progressive reduction in
Atrial Pacing Trial (ASSERT) included 2580 hypertensive the incidence of ischaemic stroke (54). Furthermore, the
patients older than 65 years old, with permanent pace- reduction of SBP by 12–14 mmHg from an initial value of
maker or defibrillator and no history of AF, who were at least 140 mmHg was associated with 70–88% reduction
monitored for 3 months in order to detect subclinical of the risk of intracranial haemorrhagic event. Patients on
atrial tachyarrhythmias. Subclinical atrial tachyarrhyth- antithrombotic therapy with an SBP more than 160 mmHg
mias had been detected by the pacemaker in 10% of the were approximately six times more likely to suffer from
individuals (44). Moreover, in The Relationship between intracranial bleeding compared to patients with an SBP of
Daily Atrial Tachyarrhythmia Burden from Implantable 115 mmHg (55).
Device Diagnostics and Stroke Risk (TRENDS Study), Thus, fine BP regulation is a very significant part of the
a prospective, observational study that enrolled 3045 management of AF patients (56). According to current ESC
patients with ≥1 stroke risk factor (heart failure, arterial guidelines for the management of AF, it is recommended to
hypertension, age ≥65 years, diabetes, or prior thrombo- use angiotensin-converting enzyme inhibitors (ACEi) and
embolic event) and permanent pacemakers or defibril- angiotensin II receptor blockers (ARBs) in order to prevent
lators that monitor atrial tachycardia (AT)/AF burden. the new onset of AF in patients with AH and cardiac target-
Patients with longstanding persistent AF or re-entrant organ damage (42). Several studies have indicated the fact
supraventricular tachycardias were excluded. During a that the inhibition of the renin–angiotensin–aldosterone
mean follow-up of 1.4 years, AF was detected in 24% of system can be protective regarding structural remodelling
the individuals (45). of the LV, atrial dilatation and fibrosis, and therefore could
prevent AF (57–64). However, these findings have been
obtained from retrospective secondary analyses of the tri-
als and concern patients with heart failure or LVH (65–70)
TREATMENT OF ARTERIAL only, as these results were not established in patients with
HYPERTENSION IN PATIENTS WITH AF and no LVH or LV dysfunction (68–69). In conclu-
ATRIAL FIBRILLATION sion, current ESC guidelines for the management of AF
suggest using these drugs in patients with heart failure
AH is major risk factor for stroke. Uncontrolled high BP and reduced ejection fraction as well as in hypertensive
levels are associated with high risk of ischaemic stroke patients with LVH.
as well as intracranial bleeding (46–48). The coexistence Moreover, according to the current ESH/ESC guidelines
with AF further increases these risks. (41), beta-blockers and non-dihydropyridine calcium
In current ESC guidelines for the management of AF, antagonists are recommended as antihypertensive agents
increased BP levels represent a significant risk factor in in patients with atrial fibrillation and high ventricular
the CHA 2DS2-VASc (resting BP >140/90 mmHg) and response rates. It is also confirmed by several studies that
HASBLED (SBP>160 mmHg) scores predisposing for beta-blockers as well as mineralocorticoid antagonists
thromboembolic and haemorrhagic events (40). In the are effective in preventing the new onset of AF in patients
SPORTIF (Stroke Prevention using an ORal Thrombin with heart failure and reduced ejection fraction (71,49).
Inhibitor in atrial Fibrillation) III and IV trials (49), the Therefore there are many options regarding the drugs that
researchers investigated the possible connection between can be used in treating AH in patients with AF. It should
414 Manual of Hypertension of the European Society of Hypertension
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THE DIABETIC/OBESE
HYPERTENSIVE PATIENT 51
(INCLUDING METABOLIC
SYNDROME)
Vasilios Kotsis
Extracellular fluid volume is expanded, resulting in a (β-cell failure) that has been decline more than 50% of
hypertensive adjustment of the pressure natriuresis provid- normal at diagnosis. Excessive deposition of fat within
ing a model of hypertension due to volume overload (17). the visceral adipose tissue and ectopic fat within muscle,
Increased plasma renin activity (PRA), plasma angioten- liver and pancreas impair these organ functions (26).
sinogen, angiotensin II and aldosterone levels have been Adipocytes are an active endocrine organ that secretes
reported in obesity (18). Renin−angiotensin system (RAS) numerous inflammatory cytokines that can have para-
has a regulatory mechanism from preventing extreme crine and systemic hormonal effects and lower levels of
variations in arterial pressure caused from changes in salt protective anti-inflammatory adipocytokines such as adi-
intake and determines obesity-related BP as a salt-sensitive ponectin (27). Increased secretion of TNFα, interleukins,
condition (19). Obesity is accompanied by high levels of plasminogen activator inhibitor-1, and retinol-binding
circulating insulin and reduced sensitivity to the metabolic protein-4 and secretion of macrophage chemoattractant
actions of insulin. Insulin exhibits a sodium-retaining protein-1 (MCP-1) drives macrophage infiltration of adi-
effect through its direct action on the renal tubules, and pose tissue (28). Insulin has antilipolytic effects by sup-
chronic hyperinsulinemia has been associated with vaso- pressing lipase activity within adipose tissue. Insulin
constriction (20). Insulin resistance also down-regulates resistance increases output of FFAs into the circulation for
nitric oxide (NO) synthesis and increases vascular and ectopic uptake, predominantly by liver and muscle. The
systemic inflammation (21) that can cause endothelial liver stores excessive fat that causes hepatic steatosis and
dysfunction. Biologically active derivatives generate from subsequent nonalcoholic fatty liver disease (NAFLD) (29).
adipose cells, including reactive oxygen species, proinflam- Increased FFA secretion from adipose tissue may exceed
matory and inflammatory molecules (interleukin-1β [IL- the liver’s capacity to synthesize triglycerides, leading to
1], interleukin-6 [IL-6], tumour necrosis factor-α [TNFα], diacylglyceride (DAG) formation. Failure of hepatic glu-
C-reactive protein [CRP]) and angiogenetic factors (vas- cose output to suppress both fasting and after meals is the
cular endothelial growth factor [VEGF]) promote vascular hallmark of metabolic disturbance in type 2 DM result-
damage, endothelial dysfunction and hypertension (22). ing in hyperglycaemia. Similar inflammatory processes
The intestinal microbiota and changes in intestinal perme- take place within the pancreas in obesity and drive β-cell
ability have been reported as potential triggers of inflam- apoptosis and dysfunction (30).
mation in obesity (14,23).
Genome-wide association studies have established more
than 175 common variants for type 2 DM and obesity, DEFINITION OF HYPERTENSION IN DIABETES
but with little shared genetic aetiology accounting only
for 15/20% of known heritability (24). Genetic suscepti- The definition of hypertension in diabetes differs between
bility to type 2 DM is mediated through effects on both societies, but the most common definition is BP values
insulin release and insulin sensitivity. Epigenetic effects higher than 130 mmHg for systolic and 80 for diastolic
seem to have an important role impairing b-cell function, (Figure 51.1) (31,32), and J-curve is unlikely to occur until
and BMI is more predictive of diabetes than any of the these BP values, except for very aged populations that
common risk alleles identified by genome-wide associa- have important vascular damage (33). The diabetic patient
tion studies. Lifestyle factors such as chemical exposures, should have orthostatic BP measured (34), as the coexis-
diet, physical activity and age can also affect gene expres- tence of diabetic neuropathy may exaggerate orthostatic
sion (25). Type 2 DM combinates a progressive defect in hypotension. In obesity, the definition of hypertension is
insulin action (insulin resistance) and insulin secretion BP greater than 140/90 mmHg.
Diagnosis of hypertension should be done with the cohort reported that obesity per se is also one of the stron-
correct cuff size (large adult or extra-large) because of the gest risk factors for new onset of CKD (47). Kidney impair-
increased circumference of the obese subject’s arm (35). ment in obesity starts with glomerular hyperfiltration,
This cuff size should also be used for out-of-office BP mea- which is observed before the appearance of glomerulo-
surements (home BP measurements or ambulatory BP megaly or renal dysfunction; thus it could be considered
monitoring) for correct measurements (31). Out-of-office an early marker of obesity-related kidney disease. The pri-
BP is important in the diagnosis of obesity-induced hyper- mary histologic features in obesity are relatively few lesions
tension because white–coat hypertension is highly preva- of focal-segmental glomerulosclerosis, profound glomeru-
lent in obese subjects (11). lomegaly due to glomerular hyalinosis and fibrosis, as well
as lipid accumulation in the glomeruli and adhesion to
Bowman’s capsule (16). Diabetic nephropathy starts with
glomerular basement membrane thickening followed by
TARGET-ORGAN DAMAGE IN DIABETES/ mesangial expansion, nodular sclerosis and finally glomer-
OBESITY ulosclerosis. In clinical praxis diabetic nephropathy can be
detected either as increased e-GFR or microalbuminuria in
HEART AND VESSELS the early stages of the disease, followed by proteinuria that
Obesity increases blood volume and cardiac output, lead- can reach the nephrotic syndrome values and reduction
ing to excess venous return to heart. Shear stress dilates in e-GFR hypofiltration leading to end-stage renal disease
left and right ventricle walls and eventually reduces left (ESRD). Obesity, hypertension and diabetes are the most
ventricular pump strength. Obesity-induced hyperten- common causes of ESRD in Western countries (48).
sion may also in part explain the development of left ven-
tricle hypertrophy (36). Atherosclerosis, lipotoxicity and
endothelial dysfunction promote coronary artery disease
(CAD) and myocardial infarction. Myocardial fibrosis TREATMENT OF HYPERTENSION
and atherosclerosis can be accelerated by insulin resis- IN THE DIABETIC/OBESE PATIENT
tance and adipokine release in both obesity and diabetes.
Obesity increases the risk of heart failure (37,38). Obesity LIFESTYLE MODIFICATION
is also an independent risk factor for the development of WEIGHT MANAGEMENT
atrial fibrillation (39,40). The MADIT-II study shows that Lifestyle interventions constitute behavioural modifica-
a BMI >30 kg/m2 is an independent risk factor for ven- tions and hypocaloric diets. Behavioural therapy is based
tricular tachyarrhythmias, and obesity and diabetes are on self-monitoring of food intake, increased physical
associated with an increased risk of sudden cardiac death activity, stimulus control, problem solving and relapse
(41). Conditions that may trigger cardiac fibrosis are the prevention. Studies have shown that self-monitoring of
upregulation of the renin angiotensin system, transform- food intake and weekly measurement of body weight are
ing growth factor (TGF)-β, endothelin, leptin and other important factors of short- and long-term weight loss (49).
inflammatory mediators. Insulin resistance contributes Although these interventions are commonly recommended
to left ventricular hypertrophy, and abdominal fat dis- in patients with obesity, diabetes and hypertension, aver-
tribution increases the adrenergic tone and altered reflex age weight loss is modest, and most patients regain weight
control mechanisms contributing to cardiac work and within months to a few years. The Mediterranean diet is
to increased ventricular arrhythmia susceptibility (39). known for its beneficial metabolic effects and for its ability
Obstructed sleep apnoea is a condition characterized by to delay need for drug therapy in newly diagnosed type 2
hypoxaemia, hypercapnia, reoxygenation, sleep depriva- DM patients (50). Energy-restricted diets have beneficial
tion, alteration in intrathoracic pressure and arousal. The effects on reducing hypertension, dyslipidemia and type
pathophysiological results of this condition include sym- 2 DM. Very-low-energy diet can be useful to reduce total
pathetic activation, metabolic dysregulation, endothelial cardiovascular risk and T2D. Such diets may reverse type
dysfunction, systemic inflammation, hypercoagulability 2 DM, as reported in the DIRECT trial that used a very
and left atrial enlargement that increase the risk of atrial low caloric diet (825–853 kcal/day formula diet for 3–5
fibrillation, stroke and sudden cardiac death (42). Finally, months), followed by stepped food reintroduction for 2–8
obesity and diabetes increase the risk of stroke from accel- weeks and structured support for long-term weight loss
erating atherosclerosis and/or thromboembolism that may maintenance (51). This intervention resulted in achieving
result in arterial occlusion or rupture. Electrocardiogram remission to a nondiabetic state in half of the study popu-
(ECG) may detect CAD, left ventricular hypertrophy and lation, and patients were off antidiabetic drugs the next
arrhythmias, but echocardiography is more sensitive in year. A modest weight loss of 5–10% seems to be necessary
the diagnosis of left ventricular hypertrophy. Other exams to reduce haemoglobin A1c (HbA1c) levels and decrease
that might be performed in patients with diabetes, obesity the use of hyperglycaemic-, hypertension- and lipid-low-
and hypertension are stress ECG or echo and 24-h Holter ering medications as observed after 1 year in the Look
ECG to detect possible CAD or arrhythmias. Obesity AHEAD study (52). Diet choice should always be based
is also associated with increased arterial stiffness (43), on the patient’s individual food preferences, lifestyle and
increased carotid artery intima media thickness (44,45), medical condition to ensure sustained diet adherence.
flow-mediated dilation and early vascular ageing (46).
of moderate aerobic exercise in combination with three prevention after coronary heart disease). Newer vasodilat-
weekly sessions of resistance training to increase muscle ing beta-blockers may have attenuated effects on insulin
strength (53). Cardiorespiratory fitness (CRF) assesses the sensitivity.
functional capacity of an individual is measured as maxi-
mal oxygen consumption (VO2max), estimated from the
peak work rate achieved on a treadmill, and is a strong and PHARMACOLOGICAL TREATMENT FOR
independent marker of cardiovascular risk (39). Obesity
with low CRF is associated with increased CV risk factors OBESITY, HYPERTENSION AND DIABETES
such as hypertension and diabetes. The ‘fat-and-fit’ con- MELLITUS
cept may reclassify obese subjects’ individual CV risk (54),
suggesting that overweight but not fit may have higher risk Antiobesity agents have shown to help patients with
than obese but fit patients. type 2 DM to achieve weight-loss goals and to improve
Hb1Ac-levels. Targeting obesity can improve glycaemic
control and should represent the first approach in the
management of type 2 DM. The primary focus of diabe-
PHARMACOLOGICAL TREATMENT FOR OBESITY tes management is the prevention of additional weight
AND HYPERTENSION gain. Most of the traditional antidiabetic drugs promote
weight gain and make the task of successful management
Antiobesity agents are recommended for patients with of overweight or obese individuals with T2D a challeng-
obesity-related comorbidity (e.g. hypertension, type 2 ing task. Metformin and dipeptidyl peptidase-IV (DPP-IV)
DM with a BMI at least 27 kg/m2) (30,53,55). In Europe, inhibitors are weight-neutral glucose-lowering drugs (30).
orlistat and liraglutide 3 mg licensed for obesity may have Newer glucose-lowering agents, including sodium-glucose
some beneficial effects on hypertension. Angiotensin- cotransporter 2 (SGLT2)-inhibitors and GLP1-analogues,
converting enzyme (ACE) inhibitors, angiotensin receptor support weight loss and should be the preferred choice
blockers (ARBs), and long-acting calcium channel block- of treatment for obese type 2 DM individuals. In patients
ers (CCBs) are preferred (30). These drug classes have neu- with type 2 DM and hypertension, empagliflozin (56),
tral effect on weight gain. RAS inhibition may also have canagliflozin (57) and dapagliflozin (58) reduced body
beneficial effects on glucose metabolism and may prevent weight and BP versus placebo, irrespective of the use of
progression to type 2 DM, and CCBs have at least a neutral other antihypertensive drugs. Liraglutide and dulaglutide,
effect on glucose metabolism. Thiazide-like diuretics may GLP1 receptor analogues tested in patients with type 2 DM
worsen glucose metabolism and their use may be appro- and high cardiovascular risk reduced body weight and SBP
priate when other combinations fail. Mineralocorticoid but increased DBP and heart rate compared to placebo.
receptor antagonists may be used in resistant obese hyper- Empagliflozin (59), canagliflozin (57) and liraglutide (60)
tensives (35). Treatment with beta-blockers promotes reduced CV risk in patients with type 2 diabetes mellitus.
weight gain, limiting their utility in the treatment of Combining exenatide with dapagliflozin was superior to
patients with obesity except for the absolute indications either drug alone for weight loss and SBP reduction (61)
(heart failure with reduced ejection fraction or secondary (Figures 51.2 and 51.3).
Figure 51.2 Obesity, hypertension and diabetes. (Modified from Kotsis et al. J J Hypertens 2018 July; 36(7): 1427–1440.)
The Diabetic/Obese Hypertensive Patient (Including Metabolic Syndrome) 421
Figure 51.3 Obesity, hypertension and diabetes. (Modified from Kotsis et al. J J Hypertens 2018 July; 36(7): 1427–1440.)
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HYPERTENSION IN CHILDREN
AND ADOLESCENTS 52
adolescents. The prevalence of elevated UAE is not promi- increased risk for depression and anxiety in comparison
nent in obese children (2.4%) and when it is increased, it to their normotensive and/or non-overweight peers (41).
depends mainly on metabolic factors (33). While the sig- Neurocognitive studies of children have focused prin-
nificance of microalbuminuria in paediatric essential HTN cipally on cognitive domains of attention and working
has yet to be established, routine urinary albumin assess- memory, executive functions and recall of newly learned
ment is recommended by the ESH Guidelines (2,3). information. However, paediatric reports to date have
Hypertension-induced abnormalities in arterial struc- been limited to database and single-centre studies (42).
ture and function are important because they underlie The practical implications of the potential neurocognitive
many adverse effects. Assessment of vascular damage, deficits associated with HTN in childhood are not clear. It
however, received little attention prior to the advent of the is even less clear whether there would be any implications
advanced ultrasound technology which permits nonin- for longer-term cognitive reserve and ultimate cognitive
vasive study of vascular walls and lumen. Intima-media decline in later life (43,44). Meanwhile, clinicians should
thickness measurement at the carotid artery is the most be aware of these emerging concerns. Arterial HTN should
common of the methods to assess structural abnormali- be ruled out routinely in children with deteriorating cog-
ties. Since intima-media thickness is influenced by age and nitive function, and referral for neurocognitive testing
sex during childhood and adolescence (34), measured val- should be considered in children with HTN who are strug-
ues should be related to percentiles or expressed as stan- gling academically.
dard deviation scores.
Ultrasound examination of the carotid arteries with
measurement of intima media thickness and/or the pres-
ence of plaques has been shown to predict the occurrence WHEN TO INITIATE ANTIHYPERTENSIVE
of both stroke and myocardial infarction, independently of TREATMENT
traditional CV risk factors (35). In the few paediatric stud-
ies available, intima-media thickness tends to be increased Currently the initial treatment for children and adoles-
in hypertensive children and adolescents compared to cents with less severe HTN and those with primary HTN
normotensive controls (36,37), although one study did and no hypertensive target-organ damage involves life-
not observe differences among normotensives, white-coat, style modifications: weight reduction, exercise and dietary
masked or sustained hypertensives (19). Moreover, a rela- intervention (3). Weight reduction has been shown to be
tionship between intima-media thickness and endothelial an effective therapy for obese children with HTN. Weight
function has been established in the Cardiovascular Risk in reduction in children is a goal that is difficult to achieve in
Young Finns Study (38). The impact of other cardiovascular the long run. Exercise helps to reduce systolic and diastolic
risk factors besides HTN, such as cholesterol levels or smok- BP levels as well as it does weight. Diets with a high intake
ing, needs to be considered in the interpretation of intima- of fruits, vegetables, low-fat dairy and whole grains while
media thickness levels, since these have been associated reducing the intake of foods high in saturated fat and
with intima-media thickness as well (39). The International refined sugar are recommended. Dietary salt restriction
Childhood Cardiovascular Cohort Consortium demon- has a very important place in the control of BP. The current
strated that individuals with persistently elevated BP from recommendation for adequate daily sodium intake is only
childhood to adulthood had increased risk of carotid 1.2 g/day for 4- to 8-year-olds and 1.5 g/day for children
atherosclerosis. This risk was reduced if elevated BP dur- older than that.
ing childhood resolved by adult age (40). Moreover, mea- Although conservative measures clearly can reduce
surement is not trivial and is subject to some observer BP, these options are often insufficient for achieving the
bias. Hence, despite the increasing evidence for its predic- treatment goal. The decision to initiate pharmacologic
tive value in cardiovascular disease, carotid intima-media treatment in the first or second decade in the absence of
thickness assessments have not yet been recommended symptoms and in otherwise healthy individuals is not
universally for routine clinical use (2,3). easy, since the long-term consequences of untreated HTN
Traditional diagnostic procedures to assess early organ and the benefits of therapy remain unknown. For these
damage in the central nervous system included neuro- reasons, a definitive indication for initiating pharmaco-
logic and ophthalmologic clinical evaluation, electroen- logic treatment should be ascertained before medication
cephalography and, in emergency cases, cranial magnetic is prescribed in a child or adolescent. The indications for
resonance image to exclude intracranial haemorrhage or antihypertensive therapy are symptomatic HTN, second-
cerebral oedema. Magnetic resonance imaging has largely ary HTN, hypertensive target-organ damage, diabetes and
replaced the computerized tomography scan, due to its persistent HTN despite non-pharmacologic measures (3).
better detection of small silent brain infarcts, microbleeds
and white matter lesions (2,3).
As paediatric HTN is on the rise, there has been
increased interest in evaluating its impact on neurocogni-
HOW TO INTRODUCE ANTIHYPERTENSIVE
tive function. There is now emerging evidence that chil- PHARMACOLOGICAL TREATMENT, AND
dren with HTN manifest neurocognitive differences when GOALS TO ACHIEVE
compared with normotensive controls, potentially repre-
senting early signs of hypertensive target-organ damage In making pharmacological treatment decisions for chil-
to the brain. Preliminary evidence suggests that children dren, clinicians previously had to adapt the results of adult
with HTN may manifest deficits on measures of neuro- trials in selecting antihypertensive agents. This approach,
cognition. They have an increased prevalence of learning although possibly effective in lowering BP, is fraught with
difficulties and have altered cerebrovascular reactivity. problems, especially the unknown differences in both the
Children with HTN associated with obesity may be at metabolism and adverse effect profiles of these drugs in
Hypertension in Children and Adolescents 429
children versus adults, as well as the unknown long-term risk factors. Then, above and beyond BP values in an indi-
effects of antihypertensive medications on the growth vidual subject, it is necessary to monitor the impact of
and development of children. Off-label use, with all of its antihypertensive treatment in the development or regres-
implied risks, has often been the only option available to sion of HTN-induced early end-organ damage. Among the
physicians who treated children with HTN. potential intermediate endpoints, LVH seems to be the
No particular class of antihypertensive drugs has been most useful in this age group. Assessment and monitor-
shown to be superior to another in terms of its effect in ing of these intermediate objectives may play an impor-
children. In some cases, the choice of antihypertensive tant role in providing scientific evidence for delineating
agent depends on the underlying cause. When choosing the best antihypertensive treatment to apply. Although
among the available therapies, the clinician must also con- improvement in the intermediate endpoints may be fol-
sider efficacy, dosing availability and frequency, adverse lowed by a substantial reduction of risk, the potential dif-
effects and cost. Taking into account that compliance is a ferences in success among the different classes of drugs is
very important issue, if BP control can be achieved with a still a matter of debate.
single drug that is taken once a day, it will improve com- In some patients, in whom treatment is accompanied
pliance and should be taken into consideration when the by effective BP control for an extended period, it may be
initial agent is chosen. If monotherapy is introduced, and possible to reduce the number and dose of drugs. This
after titration BP control is not achieved, the next step is may particularly be the case if BP control is accompanied
to add a second drug. The choice of the drug to be added by healthy lifestyle changes, such as weight loss, exercise
needs to look for additive antihypertensive activity and habits and a low-fat and low-salt diet, which remove envi-
to buffer potential secondary effects. Therapy must be ronmental pressor influences. Reduction of medications
monitored closely both for efficacy and potential adverse should be made gradually, and the patient should fre-
effects. Efficacy in reducing BP values should be monitored quently be checked because of the risk of reappearance of
by using both office and out-of-office BP measurements. HTN.
The goal of treatment for HTN is to decrease the short-
and long-term risks of cardiovascular, neurological and
renal disease. Reducing BP alone is insufficient to obtain FUTURE PATHS
this objective; the issues of obesity, hyperlipidaemia,
smoking and glucose intolerance must also be addressed Several unmet knowledge gaps about BP and its conse-
if present. quences in children and adolescents remain. A growing
The target BP goal in children with uncomplicated body of evidence supports the concept that high-normal
primary HTN and no hypertensive target-organ damage BP is not benign and is likely to be associated with the
should be <95th percentile for gender, age and height but presence of early target-organ damage. This raises the
it is probably wiser and safer to aim at a BP below the 90th question of whether the 95th percentile criteria for HTN
percentile, provided this goal can be attained by well-tol- capture current and subsequent cardiovascular disease
erated treatment. For children with chronic renal disease, risk and if it is possible to detect early biomarkers that her-
diabetes or hypertensive target-organ damage, the goal ald the progression to higher BP values.
BP should be <75th percentile (3). Evidence for this was Besides BP values, better knowledge about the natural
established in the prospective randomized ESCAPE Trial, history of early organ damage is necessary. The assess-
which showed better 5-year renal survival in children ment of organ damage needs to be optimized, looking for
with chronic kidney disease when strict BP control below early markers, not only for diagnosis but also for assessing
the 50th percentile of mean arterial pressure was aimed changes during treatment.
for (45). Perinatal programming opens up new ways to under-
After starting treatment, the frequency of office BP read- stand the early-life origins of diseases such as HTN and
ings depends on the severity of HTN and on the given BP diabetes, but also introduces relevant challenges in under-
goal. Stage 2 HTN or stage 1 in the presence of cardiac or standing the potential mechanisms involved. Making
renal failure needs to be monitored weekly until the goal careful phenotypic observations and pairing them with
is achieved. In subjects with diabetes or organ damage, a molecular markers will need to be integrated into pro-
monthly check may be appropriate. At-home BP monitor- spective studies. Newer tools of molecular medicine are
ing can help in long-term control and even improve com- increasingly available and have the potential to deepen
pliance. Twenty-four-hour ambulatory BP monitoring is our understanding of these intriguing associations.
recommended in cases of resistant HTN, progression of Developing insights into the interactions among clus-
organ damage despite apparent good BP control and in tering cardiometabolic risk factors in target-organ injury
those with frequent circadian variability abnormalities, will contribute to a more accurate estimation of the under-
chronic renal failure and diabetes mellitus. Female patients lying cardiovascular pathology among adolescents with
of childbearing potential should be counselled about the elevated BP. Understanding the interactions among all of
need to use an effective method of contraception when these factors in the development of target-organ damage
treatment with an angiotensin-converting enzyme inhibi- is critical.
tor or angiotensin receptor blocker is indicated, because In children and adolescents, pivotal information
exposure to these drugs, especially in the first trimester, remains unanswered, and therefore a plan of action needs
may have adverse effects on the developing fetus (46). to be developed, looking for a definition of HTN, appro-
The success of a given antihypertensive treatment, priate goals, and ambulatory BP-guided therapy to obtain
however, is difficult to estimate solely by the extent of BP greater reductions in organ damage compared to office BP.
reduction, in part due to the impact of BP values on risk, Better knowledge of all of these may contribute to opti-
which depends on the existence of underlying organ dam- mizing interventions, reducing organ damage and improv-
age and the coincident influence of other cardiovascular ing long-term prognosis.
430 Manual of Hypertension of the European Society of Hypertension
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HYPERTENSIVE EMERGENCIES
AND URGENCIES 53
EPIDEMIOLOGY
Hypertensive emergencies occur in up to 2–3% of hyper-
tensive patients (19–21) with a progressive decrease in
mortality rate over the past 4 decades. Among hyperten-
sive ‘crises’, the prevalence of hypertensive emergencies
and urgencies is about 25 and 75%, respectively.
In patients with both hypertensive emergencies and urgen-
cies, the incidence of cardiovascular (CV) events is still high
(20,22,23). In the United States, increasing age, male sex
and a higher Charlson Comorbidity Index were among the Figure 53.1 Example of papilledema. Image taken with
stronger predictors of mortality for patients hospitalized for a a smartphone device for fundoscopy.
hypertensive emergency (24). In the Studying the Treatment
of Acute hypertension (STAT) registry, a 6.9% hospital mortal-
ity and 37% 90-day readmission rate were reported in hyper-
tensive emergencies (17); readmission for hypertension was TREATMENT IN HYPERTENSIVE URGENCY
significantly associated with lack of compliance to the antihy-
pertensive treatment, substance abuse and dialysis (25). The best therapeutic approach is the oral administration
Recently, among patients presenting in an office setting with of antihypertensive drugs, aimed to lower BP gradually
a hypertensive urgency (26), a low percentage (0.7%) were over 24–48 hours (1–3,10). A short stay in an observation
referred to the emergency room. Patients with renal disease, unit is usually appropriate, without the need of hospi-
African American race, and higher SBP and DBP were more tal admission; a short-term outpatient visit by a hyper-
frequently hospitalized, without a more favourable outcome. tension specialist is strongly suggested (Figure 53.2). A
The optimal screening, treatment and follow-up inter- recent study evaluating 58,535 patients with a hyperten-
vals, as related to the short-term and long-term clinical sive urgency (26) showed that 65% of patients admitted
outcomes, need to be addressed in the future (5). to the ED had uncontrolled hypertension at 6 months
follow-up.
The reduction in BP should be gradual, as no benefit,
but potential harm, may be associated with a too-rapid BP
INITIAL EVALUATION decrease due to a rightward shift in the pressure/flow auto-
In all patients with an acute increase in BP, a complete regulatory curve in critical arterial beds (32,33). The use
history (with particular attention to pre-existing hyper- of a calcium-antagonist or a combination of antihyperten-
tension and target-organ damage [TOD]) and an accurate sive drugs may favour an effective BP reduction and can
physical examination are mandatory (10). BP should be be considered for the initial approach, while all guidelines
measured according to guidelines; a significant difference recommend against the use of sublingual administration
in BP between the two arms should raise the suspicion of of nifedipine, as it induces an unpredictable, often too-fast
aortic dissection. Repeated measurements of BP should be and large decrease in BP (34). In patients with a hyper-
taken, since in about 30% of patients a spontaneous reduc- tensive urgency, a similar BP reduction was obtained by
tion in BP is observed after a 20–30 minutes of rest (27). treatment with a low dose of telmisartan and by bed rest
Alcohol consumption, some food ingestion (liquorice), the (35), underlying the efficacy of resting in managing hyper-
use of illicit substances (cocaine) (28) or drugs (in particular tensive urgency, mainly in those with emotional stress or
corticosteroids and mineralocorticoids, oestrogens, NSAIDs, sympathetic overactivity (36).
cyclosporine, carbamazepine, metoclopramide and angio-
genesis inhibitors) should be investigated. Urine analysis,
creatinine, urea, electrolytes and a full blood count, an elec- TREATMENT IN HYPERTENSIVE
trocardiogram and a chest radiogram should be obtained. EMERGENCY
Further investigations including echocardiography (29,30),
brain CT scan, thoracic and abdominal ultrasound or CT In hypertensive emergencies, the NHLBI, the 2013 ESH/
scan, and vascular ultrasound should be performed accord- ESC guidelines (1) and the 2017 multisociety AHA/ACC
ing to the clinical presentation. A fundoscopic examination guidelines (3) suggest a similar approach and recommend
(17,31) is part of the examination; in addition to traditional reducing mean BP by ≤25% for the first hour, and then
ophthalmoscopy, the use of new smartphone devices seems to 160/100–110 mmHg by 2–6 hours with subsequent
promising in identifying grade 3–4 Keith–Wegener retinopa- gradual normalization in 24–48 hours. The admission
thy (31) (Figure 53.1). to an ICU for observation and continuous BP monitoring
Hypertensive Emergencies and Urgencies 433
Clevidipine is a third-generation calcium antagonist drive, reflex response to cerebral ischaemia and mental
inhibiting selectively extracellular calcium influx through stress may explain the BP rise. However, a high baseline BP
the L-type channel, relaxing smooth muscle of small arter- should not always be considered deleterious, and the use
ies and reducing peripheral vascular resistance. The advan- of antihypertensive drugs for BP reduction is not always
tages of clevidipine are the blood metabolism, the very advisable in patients with acute ischaemic stroke (49). In
short (1-minute) half-life and the rapid titration (42,47) with the CATIS trial (China Antihypertensive Trial in Acute
minimal effects on stroke volume, cardiac output or heart Ischaemic Stroke), BP reduction with antihypertensive
rate. In the PRONTO study (48) clevidipine reduced SBP and medications did not reduce the likelihood of death and
improved dyspnoea more effectively than standard treat- major disability at 14 days or hospital discharge compared
ment did, with a reduction in the need of additional IV anti- with the absence of hypertensive medication (50).
hypertensive drugs and in the total dose of furosemide. In In the early (the first 24–48 hours) phase of ischaemic
AHF, several other promising drugs including ularitide, an stroke, a BP fall may be critical, reducing cerebral perfusion,
analogue of urodilatin, and serelaxin, a recombinant version extending the ischaemic area and inducing irreversible dam-
of human relaxin-2, are currently under investigation (18). age due to the loss of cerebral flow autoregulation; therefore,
The use of morphine is controversial, despite the evi- during the first 24–48 hours, a high BP may be seen as a com-
dence that morphine has vasodilator properties and may pensatory mechanism until the autoregulation is restored.
reduce preload and the sympathetic drive, and also it Conversely, in the later phase, a smooth rate of BP reduction is
decreases dyspnoea. recommended in order to reduce the risk of cerebral oedema,
Noninvasive ventilation may be used to relieve symp- haemorrhagic transformation, stroke recurrence and CV com-
toms in patients with pulmonary oedema and severe respi- plications. Unfortunately, in acute ischaemic stroke it is very
ratory distress, or in those patients who fail to improve difficult to anticipate the effect of BP changes on cerebral per-
with pharmacological therapy (41). fusion, even when a thrombolytic agent is administered.
The American Stroke Association (ASA) recommends
that only BP values repeatedly above 220/120 mmHg
ACUTE STROKE should be treated with intravenous either labetalol or
sodium nitroprusside, unless there are other indications
Hypertension is common in the first hours after ischaemic for antihypertensive therapy (congestive heart failure,
and haemorrhagic stroke. myocardial infarction, aortic dissection) (49).
The BP target during the acute phase of an ischaemic
stroke should not be a normal BP, but rather 180 mmHg
ISCHAEMIC STROKE systolic–105 mmHg diastolic in previously hypertensive
patients and 160–180/90–100 mmHg in previously normo-
Hypertension is a common early finding in patients with tensive patients (49); a reasonable goal would be to lower BP
an acute ischaemic stroke. The increase in BP usually fol- by approximately 15% during the first 24 hours after onset
lows the onset of cerebral ischaemia and is transient (24– of stroke. Different targets are proposed in patients eligible
48 hours). Impaired neurogenic CV control, autonomic for treatment with intravenous thrombolytics or other acute
dysregulation, baroreflex failure, increased sympathetic reperfusion intervention (49) (Table 53.1), while no specific
Table 53.1 Treatment of ischaemic and haemorrhagic stroke according to baseline and target BP
Ischaemic stroke
Patients on chronic antihypertensive SBP/DBP >220/120 mmHg SBP 180–220 mmHg DBP Give antihypertensive therapy
treatment <120 mmHg (labetalol first choice)
Haemorrhagic stroke
recommendations for target BP are given for patients treated fluctuations on cerebral blood flow. In this regard, trans-
with endovascular therapy. dermal agents have inconsistent absorption and efficacy,
A systematic meta-analysis of studies evaluating the although stable cerebral perfusion has been observed dur-
effect of BP lowering in early ischaemic stroke (51) has ing glyceryl trinitrate administration (60).
included 13 clinical trials, showed no differences in the Intravenous labetalol is indicated as a first-line agent for
primary outcome (unfavourable outcome at 3 months or at BP control in ischaemic or haemorrhagic stroke, because
trial endpoint) and in secondary outcomes, both at short it has a rapid onset of action and is associated with stable
(modified Rankin scale 3–6 and 2–6, all-cause mortal- cerebral perfusion.
ity and serious adverse events) and long term (recurrent Urapidil is an alpha-blocker with a central sympatho-
stroke, recurrent vascular events, modified Rankin score lytic effect mediated via stimulation of serotonin 5HT1A
2–6, all-cause mortality). receptors in the central nervous system. Intravenous
A subgroup subanalysis of the CATIS trial (52) has urapidil was suggested to have a potential role in the
compared the outcome in 4071 acute ischaemic stroke management of acute stroke, although no studies have
patients with elevated SBP who received antihyperten- specifically investigated the efficacy of urapidil in stroke
sive treatment or discontinued all antihypertensive medi- management. In the Intensive Blood Pressure Reduction
cations during hospitalization, and the primary (death in Acute Cerebral Haemorrhage (INTERACT) study, 47%
and major disability) and secondary outcomes (modified of patients randomized to intensive BP reduction were
Rankin score, recurrent stroke, vascular disease events, treated with urapidil (61).
and all-cause mortality) were not significantly different Intravenous agents such as hydralazine or enalapril have
between the treatment and control groups after 2 weeks or been included as treatment options in stroke guidelines.
at hospital discharge. Death or major disability, recurrent Hydralazine, however, may be difficult to titrate, with
stroke, and vascular events were significantly reduced at unpredictable effects (62), and may reduce cerebral perfu-
the 3-month follow-up in the antihypertensive treatment sion through systemic vasodilatation (63). Enalapril was
group only among participants who received treatment first-line therapy in the CATIS trial, without an increase in
between 24 and 48 hours. adverse events (50).
Some randomized, controlled studies are currently ongo- Nitroprusside is rarely used in acute stroke for BP reduc-
ing, testing the use of transdermal glyceryl-trinitrate (The tion in the emergency department setting, despite its rapid
Rapid Intervention with Glyceryl Trinitrate in Hypertensive onset of action, because it needs careful and continuous
Stroke Trial-2, RIGHT-2) (53) given in the ambulance dur- monitoring and carries a small risk of thiocyanate and cya-
ing the first 4 hours after the onset of an acute ischaemic nide toxicity, although this side effect is seen more com-
stroke, and the effects of early BP-lowering treatment and monly with excessive dosing and prolonged use.
compares SBP 130–140 mmHg versus SBP <180 mmHg in Nicardipine has been included in recent guidelines for
patients treated with intravenous alteplase (54). stroke management (49) and was used in the ATACH-2
study. A systematic review of 10 studies comparing nicar-
dipine and labetalol treatment in hypertensive emergen-
HAEMORRHAGIC STROKE cies has shown comparable efficacy and safety, in spite of
more predictable and consistent BP control with nicardip-
Prevalence of haemorrhagic strokes is 15% of patients. ine than with labetalol (64). Nicardipine has been shown
Patients with intracerebral haemorrhage (ICH) often have to decrease BP more smoothly than sodium nitroprusside
elevated BP, associated with increased risk of death, disabil- or labetalol and to be associated with less BP variability,
ity or neurological deterioration. Increased BP is related to with stable brain oxygen tension (65–68). Clevidipine
haematoma growth (55) and formation of cerebral oedema. could represent an alternative to nicardipine, although
Haematoma expansion is a frequent complication of ICH, it has not been as well studied in stroke as nicardipine.
occurring in 30% of patients (mainly in the first 24 hours).
Intensive BP lowering in acute ICH is safe and feasible
and may be associated with reduced haematoma growth. ACUTE AORTIC DISSECTION
Rapid BP lowering after a moderate-volume ICH does
not alter peri-haematoma cerebral blood flow (56). In the Arterial hypertension is associated with a higher attribut-
INTERACT-2 (Intensive Blood Pressure Reduction in Acute able risk for acute aortic dissection, in addition to more
Cerebral Haemorrhage Trial-2) study, intensive lowering of rare genetic syndromes as well as arterial inflammatory
BP did not result in a significant reduction in the rate of the diseases (69). In the setting of the ED, the incidence of acute
primary outcome of death or severe disability but improved aortic dissection is approximately 1 in 10,000 patients,
functional outcomes (57). The ATACH-2 (Antihypertensive and only 25% of patients present with the classical pain
Treatment in Acute Cerebral Haemorrhage 2) tested the of sudden onset or ripping/tearing quality, inter-arm BP
same BP targets in ICH as INTERACT-2, starting treatment difference and widened mediastinum on chest radiograph.
at earlier time points (58); the results suggest that intensive Type A dissections of the ascending aorta, according to the
SBP reduction is associated with a higher occurrence of seri- Stanford classification, are more common, entail a much
ous adverse events within 3 months after randomization, worse prognosis and may progress proximally, causing
without providing an incremental clinical benefit. Blunting hemopericardium with cardiac tamponade, acute aortic
fluctuations in SBP in patients with ICH and an acute hyper- valve regurgitation and acute myocardial infarction; Type
tensive response may confer a treatment benefit indepen- A and type B dissections may also include aortic intramu-
dently of the magnitude of SBP lowering (58,59) (Table 53.1). ral haemorrhage and penetrating aortic ulcer (69).
The choice of the best drugs for BP reduction in isch- Prompt aortic imaging by transoesophageal echocardiog-
aemic or haemorrhagic stroke should be based on a few raphy, CT scan with intravenous contrast or MRI may con-
principles, including rapidity of action, titration and no firm (or reasonably exclude) the diagnosis (69), and surgical
436 Manual of Hypertension of the European Society of Hypertension
team consultation may be lifesaving. Concomitantly, medi- 9. Shantsila A, Dwivedi G, Shantsila E et al. Persistent macrovas-
cal therapy is mandatory to control heart rate (goal <60 cular and microvascular dysfunction in patients with malignant
hypertension. Hypertension 2011; 57: 490–496.
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13. Baron SL, Steege AL, Marsh SM et al. CDC health disparities and
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HYPERTENSION ASSOCIATED
WITH PERIPHERAL ARTERY 54
DISEASE
Denis L. Clement
PREVALENCE
CLINICAL ASPECTS Data on prevalence differ considerably depending on gen-
der, age and criteria used to define PAD (4,5). If only the
The symptoms of PAD have historically been categorized typical symptom of intermittent claudication is taken into
by Fontaine in Europe and further detailed by Rutherford account, a prevalence figure of 5% in the adult popula-
in the United States (3). The most typical clinical picture in tion is usually proposed. At the age of 70, it increases to
such patients is intermittent claudication: pain in the calf at least 10%, according to the Rose Angina Questionnaire.
while walking; the pain disappears at rest. According to the However, as said above, many patients are asymptomatic
Fontaine classification, intermittent claudication is class II. or present with atypical symptoms that could significantly
It should be mentioned that more and more atypical pre- alter the figures on prevalence (Box 54.1).
sentations occur, especially in female patients (Box 54.1). Until recently, it was accepted that PAD is less prevalent
Diagnosis of PAD is made by an association of com- in women (5). This is probably true in patients under 50
plaints, palpation of pulses and by measuring the ankle- years but after this, prevalence significantly increases, and
brachial index (ABI) (systolic blood pressure measured often worse cases are detected.
at the ankle divided by systolic pressure measured at the As far as the association of hypertension with PAD is
brachial artery). The lower the index, the more advanced concerned, data are surprisingly scarce. The general state-
is the occlusive process in the extremity. Values between ment is that hypertension is accompanied by a two- to
0.5 and 0.9 indicate light to moderate stenosis; however, threefold increase in the risk of intermittent claudication
at 0.5 critical limb ischaemia is present or likely to appear. (6–8); on the other hand, PAD patients often present with
The diagnosis can be further expanded by ultrasound high blood pressure, especially systolic blood pressure,
imaging, and if interventional treatment is considered, due to increased stiffening of the arteries (9).
440 Manual of Hypertension of the European Society of Hypertension
18. Sigvant B, Lundin F, Wahlberg E. The risk of disease progression prevention of death, myocardial infarction, and stroke in high
in peripheral arterial disease is higher than expected: A meta- risk patients. BMJ 2002; 324: 71–86.
analysis of mortality and disease progression in peripheral arte- 29. CAPRIE Steering Committee. A randomised, blinded, trial of
rial disease. Eur J Vasc Endovasc Surg 2016; 51: 395–403. clopidogrel versus aspirin in patients at risk of ischaemic events
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tion paper from the European Society of Cardiology Working physiological walking distance in patients with intermittent
Group on peripheral circulation: Endorsed by the Association claudication.] [Article in French] Ann Cardiol Angéiol 2001; 50:
for Research into Arterial Structure and Physiology (ARTERY) 175–182.
Society. Atherosclerosis 2015; 241(2): 505–532. 31. Spengel F, Clement D, Boccalon H et al. Findings of the
20. Lane JS, Magno CP, Lane KT et al. Nutrition impacts the preva- Naftidrofuryl in Quality of Life (NIQUOL) European Study pro-
lence of peripheral arterial disease in the United States. J Vasc Surg gram. Int Angiol 2002; 21: 20–27.
2008; 48: 897–904. 32. Espinola-Klein C, Weisser G, Jagodzinski A et al. Beta-blockers in
21. Clement DL. Occlusive arterial diseases in the lower limbs: patients with intermittent claudication and arterial hypertension:
Physiologic principles and guidelines to methods of investigation Results from the nebivolol or metoprolol in arterial occlusive
and treatment. Int Angio 1984; 3: 57–65. disease trial. Hypertension 2011; 58: 148–154.
22. Hiatt WR. Medical treatment of peripheral arterial disease and 33. Stevens JW, Simpson E., Harnan S. et al. Systematic review of the
claudication. N Engl J Med 2001; 344: 1608–1621. efficacy of cilostazol, naftidrofuryl oxalate and pentoxiphylline
23. Murphy TP, Cutlip DE, Regensteiner JG et al. Supervised exercise for the treatment of intermittent claudication. Br J Surg 2012; 99:
versus primary stenting for claudication resulting from aortoiliac 1630–1638.
peripheral artery disease: Six-month outcomes from the claudica- 34. Polonia J, Monteiro J, Almeida J et al. High salt intake is inde-
tion: Exercise Versus Endoluminal Revascularization (CLEVER) pendently associated with a higher risk of cardiovascular events.
study. Circulation 2012; 125: 130–139. A 12 years evaluation of a hypertensive cohort. J Hypertens 2015;
24. Antoniou GA, Fisher RK, Georgiadis GS et al. Statin therapy in 33(Suppl 1): e71.
lower limb peripheral arterial disease: Systematic review and 35. Yusuf S, Sleight P, Pogue J. et al. Effects of an angiotensin-converting-
meta-analysis. Vascul Pharmacol 2014; 63: 79–87. enzyme inhibitor, ramipril, on cardiovascular events in high-
25. Kumbhani DJ, Steg PG, Cannon CP et al. Statin therapy and risk patients. The Heart Outcomes Prevention Evaluation Study
long-term adverse limb outcomes in patients with peripheral Investigators. N Engl J Med 2000; 342: 145–153.
artery disease: Insights from the REACH registry. Eur Heart J 2014; 36. Yusuf S, Teo KK, Pogue J et al. Telmisartan, ramipril, or both in
35(41): 2864–2872. patients at high risk for vascular events. N Engl J Med 2008; 358:
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353–361. with reduced major adverse cardiovascular events among patients
27. Giugliano RP, Pedersen TR, Park JG et al. Clinical efficacy and with critical limb ischemia. Vasc Med 2015; 20: 237–244.
safety of achieving very low LDL-cholesterol concentrations 38. Novo S, Abrignani MG, Pavone G et al. Effects of captopril and
with the PCSK9 inhibitor evolocumab: A prespecified second- ticlopidine, alone or in combination, in hypertensive patients
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1962–1971. 39. Bogaert M, Clement DL. Lack of influence of propranolol and
28. Antithrombotic Trialists’ Collaboration. Collaborative meta- metoprolol on walking distance in patients with chronic intermit-
analysis of randomised trials of antiplatelet therapy for tent claudication. Eur Heart J 1983; 4: 203–204.
HYPERTENSION IN PREGNANCY
55
Renata Cífková
Systolic blood pressure ↓4–6 mmHg All bottom at 20–24 weeks, then rise
gradually to pre-pregnancy values at term
Diastolic blood pressure ↓8–15 mmHg
Cardiac output ↑33–45% Peaks in early 2nd trimester, then until term
GESTATIONAL HYPERTENSION
DEFINITION OF HYPERTENSION
IN PREGNANCY Gestational hypertension is pregnancy-induced hyperten-
sion, with or without proteinuria, complicating 6–7% of
The definition of hypertension in pregnancy was not uni- pregnancies and developing only after 20 weeks of ges-
form for a long time (2,16,17). It used to include an eleva- tation; it is characterized by poor organ perfusion and
tion in BP during the second trimester from a baseline usually resolves within 42 days postpartum. Gestational
reading in the first trimester, or to pre-pregnancy levels, but hypertension associated with significant proteinuria
a definition based on absolute BP values (SBP ≥140 mmHg (>0.3 g/24 h in a 24-h urine collection or ≥30 mg/mmol
or DBP ≥90 mmHg) is now preferred (2,17). urinary creatinine in a spot random urine sample) is
Most of the obstetric literature distinguishes mild known as pre-eclampsia.
and severe hypertension rather than grades used by the Pre-eclampsia is a pregnancy-specific syndrome that
European Society of Hypertension and the European occurs after mid-gestation, defined by de novo appearance
Society of Cardiology (ESH-ESC; 2,8). of hypertension, accompanied by new-onset proteinuria.
It is a systemic disorder with both maternal and fetal man-
ifestations. Pre-eclampsia was classically defined as a triad
of hypertension, oedema and proteinuria, but oedema
CLASSIFICATION OF HYPERTENSION is no longer considered part of the diagnostic criteria, as
IN PREGNANCY it occurs in up to 60% of normal pregnancies and is no
longer included because of the lack of specificity. Overall,
Hypertension in pregnancy is not a single entity but com- pre-eclampsia complicates 5–6% of pregnancies, but this
prises (2,8,18): figure increases to up to 25% in women with pre-existing
hypertension. Risk factors for developing pre-eclampsia
■■ Pre-existing hypertension are given in Table 55.2.
■■ Gestational hypertension Pre-eclampsia remains one of the three most fre-
■■ Pre-existing hypertension plus superimposed gesta- quently cited causes of maternal death and is responsible
tional hypertension with proteinuria for an estimated 64,000 deaths a year worldwide (19).
■■ Antenatally unclassifiable hypertension Developing countries have had persistently higher rates of
Hypertension in Pregnancy 447
Table 55.3 Basic laboratory investigations recommended for monitoring patients with hypertension in pregnancy
Hemoglobulin and hematocrit Hemoconcentration supports diagnosis of gestational hypertension with or without proteinuria. It indicates
severity. Levels may be low in very severe cases because of hemolysis.
Platelet count Low levels <100,000 × 109/L may suggest consumption in the microvasculature. Levels correspond to severity
and are predictive of recovery rate in postpartum period, especially for women with HELLP syndrome.
Serum AST, ALT Elevated levels suggest hepatic involvement. Increasing levels suggest worsening severity.
Serum LDH Elevated levels are associated with haemolysis and hepatic involvement. May reflect severity and may predict
potential for recovery postpartum, especially for women with HELLP syndrome.
Urinalysis Dipstick test for proteinuria has significant false-positive and false-negative rates. Positive dipstick results ( ≥1)
should prompt further investigations including albumin/creatinine ratio. Negative dipstick results do not rule
out proteinuria, especially if DBP ≥90 mmHg.
Urinary albumin/creatinine (ACR) Can be quickly determined in a single-spot urine sample; a value <30 mg/mmol can reliably rule out
proteinuria in pregnancy. Values ≥30 mg/mmol identify significant proteinuria.
Proteinuria (24-hour urine collection) Standard to quantify proteinuria, but often inaccurate. If in excess of 2 g/day, very close monitoring is
warranted. If in excess of 3 g/day, delivery should be considered.
Serum uric acid Elevated levels aid in differential diagnosis of gestational hypertension and may reflect severity.
Serum creatinine Levels drop in pregnancy. Elevated levels suggest increasing severity of hypertension; assessment of 24-hour
creatinine clearance may be necessary.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HELLP, Hemolysis, Elevated Liver enzyme levels, and Low Platelet count; LDH, lactate
dehydrogenase.
Hypertension in Pregnancy 449
and symptoms are quite variable but not specific, with mother (41). Small and frequently poorly designed stud-
hypertension being one of the most prominent signs. If ies have recently suggested that therapy of mildly elevated
undiagnosed, maternal and fetal mortality is around 50%; BP may prevent progression to pre-eclampsia (42,43). Even
on the other hand, early detection and proper treatment for women with BP elevation sufficient to justify therapy
during pregnancy decrease the maternal and fetal mor- for their own benefit, it is not clear whether it is beneficial
tality to <5 and <15%, respectively. For the biochemical for or detrimental to the fetus. In several studies, treat-
diagnosis, plasma or urinary metanephrines are the test of ment of hypertensive women resulted in an increased risk
choice since they have the highest sensitivity and the high- of growth restriction in their infants (44). It is not known
est negative predictive value. For reliable localization, mag- whether this is the inevitable consequence of lower BP dur-
netic resonance imaging is the most suitable technique, ing pregnancy or if it is due to excessive pressure decreases
with a sensitivity of more than 90%. When a pheochromo- or too specific drugs.
cytoma is diagnosed, it should be removed by laparoscopic
adrenalectomy after 10–14 days of drug pretreatment as
in nonpregnant patients (alpha-adrenoreceptor blockade
combined with beta-adrenergic blockade started some NON-PHARMACOLOGICAL MANAGEMENT
days later). If the pheochromocytoma is diagnosed in the AND PREVENTION OF HYPERTENSION
third trimester, the patient should be managed until the IN PREGNANCY
fetus is viable using the same drug regimen as for regu-
lar surgical preparation. Cesarean section with tumour Non-pharmacological management (45) of hyperten-
removal in the same session or at later stage is then pre- sion in pregnancy has a limited role because randomized
ferred, since vaginal delivery is possibly associated with studies of dietary and lifestyle interventions showed only
higher mortality. minimal effects on pregnancy outcomes. A short-term
hospital stay may be required for confirming the diag-
nosis of and ruling out severe gestational hypertension
(pre-eclampsia), in which the only effective treatment is
MANAGEMENT OF HYPERTENSION delivery. Management, depending on BP, gestational age
IN PREGNANCY and presence of associated maternal and fetal risk factors,
includes close supervision, limitation of activities and
The majority of women with pre-existing hypertension some bed rest in the left lateral position.
in pregnancy have mild to moderate hypertension (140– A normal diet without salt restriction is advised, particu-
179/90–109 mmHg) and are at low risk for cardiovascular larly close to delivery, as salt restriction may induce a low
complications within the short time frame of pregnancy. intravascular volume. Increased energy and protein intake
Women with essential hypertension and normal renal are not beneficial in the prevention of gestational hyperten-
function have good maternal and neonatal outcomes; sion. Although weight reduction may be helpful in reduc-
they are candidates for non-drug therapy because there ing BP in nonpregnant women, it is not recommended
is no evidence that pharmacological treatment results in during pregnancy in obese women, as weight reduction
improved neonatal outcome. Some women with treated can be associated with reduced neonatal weight and slower
pre-existing hypertension are able to stop their medication subsequent growth in infants of dieting obese mothers.
in the first half of pregnancy because of the physiological However, as maternal obesity can result in negative
fall in BP during this period. However, close monitoring outcomes for both women and fetuses, guidelines for
and if necessary, resumption of treatment, are essential. healthy ranges of weight gain in pregnancy have been
There are not sufficient data regarding treatment of established. In pregnant women with normal body mass
hypertension in pregnancy, as pharmaceutical compa- index (BMI <25 kg/m2), the recommended weight gain
nies have been reluctant to test drugs in this small mar- is 11.2–15.9 kg; for overweight pregnant women (BMI
ket with a high potential of litigation. Childbearing 25.0–29.9 kg/m2) it is 6.8–11.2 kg; and for obese pregnant
potential without reliable contraception is an exclusion women (BMI ≥30 kg/m2) the recommended weight gain is
criterion in basically all clinical trials testing antihyper- <6.8 kg (46).
tensive drugs. Pharmaceutical companies are not willing Regular exercise might be continued with caution.
to take any, even a small risk, and as no data are available Calcium supplementation (1.5–2 g orally) is recom-
for most of the antihypertensive drugs marketed over the mended for prevention of pre-eclampsia in women with
last 20 years, the vast majority of newer antihypertensive low dietary calcium intake (<600 mg/d) (47) from the first
drugs is strictly contraindicated in pregnancy. antenatal clinic visit.
The only trial of treatment of hypertension in pregnancy In a multicentre randomized clinical trial of effect
with adequate infant follow-up (7.5 years) was performed of fish oil in a high-risk population of pregnant women
more than 30 years ago with alpha-methyldopa, now with pregnancy complications, fish oil supplementation
rarely used in nonpregnant women (37,38). Past clinical delayed the onset of delivery in low and middle, but not in
trials also have not supported a beneficial effect on preg- high, fish consumers (48).
nancy outcome of treating mild hypertension. There has Fish oil supplementation as well as vitamin and nutrient
been no reduction in perinatal mortality, placental abrup- supplements have no role in the prevention of hypertensive
tion, or superimposed pre-eclampsia (39,40). All these disorders. Some studies with vitamin C and vitamin E sup-
trials are subject to criticism, including small numbers, plementation were associated with more frequent low birth-
starting the drug too late in pregnancy, or flawed study weight (<2.5 kg) and adverse perinatal outcome (49–52).
design; however, no other data are available. These studies There has been considerable controversy regarding the
have led to recommendations to treat only on the basis of efficacy of low-dose aspirin for the prevention of pre-
BP sufficiently elevated to pose a potential acute risk to the eclampsia. Despite a large meta-analysis reporting a small
450 Manual of Hypertension of the European Society of Hypertension
■■ First pregnancy
TREATMENT OF MILD TO MODERATE
■■ Age 40 years or older
■■ Pregnancy interval of more than 10 years HYPERTENSION
■■ Body mass index (BMI) of 35 kg/m2 or more at first visit
The benefits of antihypertensive therapy for mildly to
■■ Family history of pre-eclampsia
moderately elevated BP in pregnancy (<160/110 mmHg)
■■ Multiple pregnancy
have not been demonstrated in clinical trials. Recent
reviews including a Cochrane analysis concluded there
are insufficient data to determine the benefits and risks of
PHARMACOLOGICAL MANAGEMENT antihypertensive therapy for mild to moderate hyperten-
OF HYPERTENSION IN PREGNANCY sion (defined as 140–169 mmHg SBP and 90–109 mmHg
DBP) (62–64). Of note, with antihypertensive treatment
The value of continued administration of antihypertensive there seems to be less risk of developing hypertension (risk
drugs to pregnant women with chronic hypertension con- ratio 0.50 with a number-needed-to-treat of 10), but no
tinues to be an area of debate. While there is a consensus difference in outcomes of pre-eclampsia, neonatal death,
that drug treatment of severe hypertension in pregnancy preterm birth and small-for-gestational-age babies with
is required and beneficial (57), treatment of less severe treatment (61).
hypertension is controversial. Although it might be ben- In the absence of randomized controlled trials, rec-
eficial for the mother with hypertension to reduce her BP, ommendations can only be guided by expert opinion.
lower BP may impair uteroplacental perfusion and thereby International and national guidelines vary with respect to
jeopardize fetal development. Much uncertainty about the thresholds for starting treatment and BP targets in preg-
benefits of BP lowering in pregnant women with mild pre- nancy. The suggestion in the 2007 ESH/ESC Guidelines
existing hypertension stems from published trials too small (65) of considering drug treatment in all pregnant women
to detect a modest reduction in obstetric complications. with persistent elevation of BP >150/95 mmHg is sup-
All antihypertensive drugs have either been shown or ported by more recent US data, which show an increasing
are assumed to cross the placenta and reach the fetal cir- trend in the rate of pregnancy-related hospitalizations with
culation. However, none of the antihypertensive agents stroke − especially during the postpartum period − from
in routine use have been documented to be teratogenic, 1994−2007 (66), and by an analysis of stroke victims
although angiotensin-converting enzyme (ACE) inhibi- with severe pre-eclampsia and eclampsia (67). Despite
tors, angiotensin II antagonists, and aliskiren, a direct lack of evidence, the 2013 Task Force reconfirms that phy-
renin inhibitor, are fetotoxic. sicians should consider early initiation of antihyperten-
While the goal of treating hypertension is to reduce sive treatment at values >140/90 mmHg in women with
maternal risk, the agents selected must be efficacious and (i) gestational hypertension (with or without proteinuria),
safe for the fetus (6,58). (ii) pre-existing hypertension with the superimposition of
Hypertension in Pregnancy 451
could explain, at least in part, the increased risk for cardio- 20. Ventura SJ, Martin JA, Curtin SC et al. Births: Final data for 1999.
vascular disease in later life in these women (73). Natl Vital Stat Reports 2001; 49: 1–100.
21. Irgens HU, Reisater L, Irgens LM et al. Long term mortality of
On the other hand, women who go through pregnancy mothers and fathers after pre-eclampsia: Population-based cohort
without developing hypertension are at reduced risk of study. BMJ 2001; 323: 1213–1217.
becoming hypertensive in later life when compared to 22. Hiett AK, Brown HL, Britton KA. Outcome of infants delivered
nulliparous women. Thus, pregnancy may offer a window between 24 and 28 weeks’ gestation in women with severe pre-
eclampsia. J Matern Fetal Med 2001; 10: 301–314.
into the future cardiovascular health of women that is 23. The Genetics of Pre-eclampsia (GOPEC) Consortium. Babies,
unavailable in men. pre-eclamptic mothers and grandparents: A three-generation
phenotyping study. J Hypertens 2007; 25: 849–854.
24. Roberts JM. Pregnancy related hypertension. In: Creasy RK,
Resnik R (eds.) Maternal Fetal Medicine. 4th ed. WB Saunders,
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DRUG-INDUCED HYPERTENSION
56
Direct vasoconstriction
Immunosuppressants ■■ Multiple factors including ■■ Pre-existing hypertension Discontinuation may not lead to
Ciclosporin decreased NO ■■ Concurrent corticosteroids a reduction in BP levels
■■ Systemic and renal ■■ Co-prescription with CCBs (caution as some lead to
vasoconstriction erythromycin paradoxical increase in
■■ Salt and fluid retention ■■ Poor renal function ciclosporin levels)
Alternative immunosuppressants
Sympathomimetics
(Continued )
Drug-Induced Hypertension 457
Table 56.1 (Continued ) Summary of drugs leading to hypertension based on the pathophysiology
Appetite suppressants
Sibutramine
Herbal supplements
Ephedra
Bitter orange
Other drugs
associated with a pressor effect and subsequent hyperten- oestrogens also act directly on mineralocorticoid receptors
sion in a number of studies, including patients with coro- and influence 11-β-hydroxysteroid dehydrogenase activity.
nary artery disease (16,17). Discontinuation usually sees the BP returning to baseline
over a number of weeks, but it can take over 6 months. If
antihypertensive agents are needed, then angiotensin con-
verting enzyme inhibitors (ACEIs) or angiotensin-2 recep-
SEX HORMONES tor blockers (A2RBs) are useful but their use needs to be
outweighed by the risk of potential pregnancy and fetal
The combined oral contraceptive pill results in hyperten- abnormalities. BP elevations are not seen with hormone-
sion in 5% of users. The minimum amounts of hormones replacement therapy and the progesterone-only pill (21).
at which this is seen is 50 mg oestrogen and 1–4 mg proges- Testosterone leads to androgen receptor agonism, which
tins (18). However, even lower doses of the combined oral will elevate BP through the resulting salt and volume reten-
contraceptive pill (containing 20–35 mg of oestrogens) tion. This is not seen when testosterone is given to men
can increase BP by 8 mmHg (19). Elevations in BP leading with hypogonadism. Indeed, in this group, BP improves
to hypertensive crises have also been reported. Risk factors by 23/16 mmHg and there is a reduction in cardiovascu-
predisposing to the development of hypertension include lar risk (22). Anabolic androgenic steroids are synthetic
hypertension during pregnancy, a family history of hyper- molecules derived from testosterone and are used in vari-
tension, elevated body mass index, and diabetes mellitus ous medical conditions. They are also used by people to
(18). The underlying mechanism is related to increased enhance exercise performance and for cosmetic reasons.
hepatic angiotensinogen production and its downstream They can lead to hypertension and other cardiovascular
effects with eventual aldosterone activation of the min- abnormalities; for example, left ventricular dysfunction,
eralocorticoid receptors (20). This is not the only effect, aortic stiffness and atherosclerosis (23,24). Aortic stiffness
however, as spironolactone alone is not enough to con- may persist years after discontinuation of androgens, lead-
trol the elevations in BP. It is postulated that high-dose ing to increased cardiovascular risk (24). Taurine helps to
458 Manual of Hypertension of the European Society of Hypertension
attenuate these effects in animal models (23). Danazol is a diastolic BP from baseline of greater than 20 mmHg is an
semisynthetic androgen used in the management of endo- indication for treatment regardless of whether the recom-
metriosis and hereditary angioedema. It is also a perfor- mended levels where treatment is indicated are reached.
mance-enhancing drug misused by exercise enthusiasts. It Chemotherapeutic agents cannot be discontinued or
can lead to elevated BP, which resolves on discontinuation. reduced in the majority of cases, but hypertension treat-
ment needs to be managed as a priority, as comorbidities
are independent contributors for poor prognosis in cancer
patients. Any antihypertensive agent can be used for treat-
CHEMOTHERAPEUTIC AGENTS AND ment but dihydropyridine CCBs are effective especially for
IMMUNOSUPPRESSANTS the short-acting drugs. Verapamil, diltiazem and nifedip-
ine should be avoided, as they can provoke VEGF secretion
Cancer patients are now living longer and are likely to die (31). Antihypertensive medication may be less effective
from non-cancer−related illnesses, including cardiovascu- with bevacizumab and rarely discontinuation may be nec-
lar disease (25). The recognition and management of both essary for uncontrolled hypertension. Good control of pre-
cardiovascular risk and disease in these patients is there- existing hypertension may also help alleviate any further
fore becoming more important. Of all the comorbid condi- worsening of hypertension and the potential for associ-
tions, hypertension is the most frequent in patients with ated cardiotoxicity.
cancer (25–27). Chemotherapeutic agents that are com- The immunosuppressant ciclosporin can result in neph-
monly associated with hypertension include alkylating rotoxicity and hypertension. Hypertension develops in
agents, demethylation inhibitors and vascular endothelial 50–80% of patients who receive ciclosporin after kidney,
growth factor (VEGF) inhibitors (27,28). Of the alkylat- heart or liver transplantation (41). One year after renal
ing agents, cyclophosphamide, isophosphamide, cisplatin transplantation, the incidence is 32.7−81.6% (42,43). Loss
and busulfan have all been associated with hypertension. of nocturnal dipping in ambulatory BP is seen along with
VEGF is a heparin-binding glycoprotein with high affinity systolic and diastolic hypertension (43). Hypertension
for endothelial cells. The VEGF inhibitors can be divided may also result from increased SNS activity, increased
into two groups, both of which can induce hyperten- renal proximal tubular reabsorption of sodium, changes
sion: the VEGF monoclonal antibody bevacizumab, and in the production of vasodilating prostaglandins, stimulat-
small molecules that inhibit tyrosine kinase (normally ing the RAAS axis and through direct effects (41). Risk fac-
stimulated by VEGF), such as sunitinib and sorafenib. It tors for hypertension with ciclosporin include pre-existing
is not surprising that these drugs lead to hypertension, as hypertension, concurrent corticosteroid therapy and poor
both VEGF and tyrosine kinase are involved in modula- renal function (42). Hypertensive crises with encephalop-
tion of vascular function through nitric oxide regulation. athy induced by ciclosporin have also been described (42).
Other putative pathophysiological mechanisms include The diastolic BP correlates with the trough levels of ciclo-
induction of rarefaction of the microvasculature, loss of sporin, suggesting some dose response, and hypertension
antioxidative effects, activation of endothelin-1, sodium may improve with dose reduction. Discontinuation may
retention, stimulation of the sympathetic nervous system not always lead to a reduction in BP levels to baseline.
(SNS) activity, increased production of vasoconstrictors Preferred antihypertensive medications include CCBs but
and activation of the renin−angiotensin−aldosterone sys- avoid non-dihydropyridine CCBs as they can result in a
tem (RAAS) (29,30). The overall result is endothelial dys- paradoxical increase in ciclosporin levels through cyto-
function and changes in the microvasculature. chrome p450 inhibition. An alternative calcineurin inhib-
The overall incidence of hypertension is 32% using itor is tacrolimus, which has less hypertensive tendency
VEGF inhibitors (31). VEGF inhibitors are associated with but can lead to salt and fluid retention. Other immunosup-
grade 3 or higher hypertension in 10–20% of patients at pressants such as rapamycin and mycophenolate mofetil
the starting dose (31). Bevacizumab leads to hyperten- do not result in hypertension.
sion in 17–31% of patients (31,32). It can result in de novo
hypertension in 22% and worsening of hypertension in
18.7% (33). Hypertensive crises occur in 1% and include
reversible posterior leukoencephalopathy syndrome RECOMBINANT HUMAN
(34). The median time to develop hypertension is 131 ERYTHROPOIETIN
days (range 7–316 days) (35). In comparison, sorafenib
leads to hypertension in 23.4% (severe hypertension in One in three recombinant human erythropoietin (EPO)
5.7%) and sunitinib in 21.6% (28). Elevated BPs are dose users will develop hypertension, which can present as
dependent and can be seen as early as 24 hours of start- new-onset hypertension, worsening of pre-existing hyper-
ing therapy and are reversible on stopping. The half-life of tension or in the form of a hypertensive crises (44). Risk fac-
bevacizumab is 20 days, so patients need to have their BP tors include pre-existing hypertension and a family history
monitored for a minimum of 3 months after discontinua- of hypertension. This is a dose-dependent effect and can
tion of therapy. Actual changes in BP for bevacizumab are become apparent after 2−16 weeks (45). The pathophysi-
quoted at around 10/6 mmHg in the first 60 days (median) ology is complex and not just related to increased blood
and for sorafenib changes in 24-hour BP monitoring of viscosity. Increased production of endogenous pressors,
8.2/6.5 mmHg have been described (36,37). reduced responsiveness to vasodilators and arterial mod-
Bevacizumab leads to a higher incidence of hyper- elling have all been described (44). EPO can also increase
tension when used in combination with 5-fluorouracil cytosolic calcium concentrations, leading to reduced nitric
(38,39). Hypertension can also occur with ocular admin- oxide−mediated vasodilation (44). Hypertension induced
istration of bevacizumab (40). Such is the risk that the by EPO can be treated with a single antihypertensive agent
Joint National Commission advocates that a change in the in 42% of patients (46). General management consists of
Drug-Induced Hypertension 459
treatment with diuretics, and dialysis may need to be con- effects making it useful in anaesthesia. It acts on central
sidered. Venesection can also help for those patients with α2-adrenergic receptors and leads to elevated BP at high
more resistant hypertension. doses and reduced BP at low doses.
cardiovascular system. This has led to its use being contra- (73–75). When alcohol is taken with the anti-abuse drug
indicated in patients with severe uncontrolled hyperten- disulfiram, the resulting reaction also elevates BP.
sion. Patients who are on mirabegron should have their
blood pressure checked before starting and at regular
intervals after.
CAFFEINE
Acute ingestion of 200–300 mg caffeine in caffeine-naive
HERBAL SUPPLEMENTS subjects leads to increases in systolic and diastolic BPs
of 8.1 and 5.7 mmHg, respectively (76). Elevations of
Herbal supplements are available readily and many do 10 mmHg after 2–3 cups have been reported, and an aver-
not have robust data regarding their safety and/or efficacy. age increase of 4–5/3 mmHg (77). These effects are seen 1
Supplements associated with elevations in BP include hour after ingestion and peak at 3 hours. The mechanism
ephedra (including ma-huang), St John’s Wort, yohimbine, includes increased sympathetic activity, raised catechol-
ginseng and bitter orange (64). Ephedra consists of vari- amine levels and antagonism of endogenous adenosine
ous alkaloid and nonalkaloid components such as ephed- (76). With chronic use, the BP changes are less apparent.
rine and pseudoephedrine. Ephedra has been associated
with hypertensive emergencies and deaths, and some
supplements contain caffeine (65,66). Ephedra-containing
ephedrine alkaloids have now been banned in a number MISCELLANEOUS DRUGS AND TOXINS
of countries due to these adverse effects. The underly-
ing mechanisms for many herbal supplements remain l-dopa and yohimbine lead to sympathomimetic activity
unknown, but ephedra and bitter orange are α-1 agonists through presynaptic changes, which leads to hyperten-
and elevate BP by up to 10 mmHg (67). Ginger root has sion (78). Physostigmine when given orally also activates
been shown to have a pressor effect in animals, and a case central sympathetic activity, leading to elevated BP. The
report has suggested it can elevate BP in humans (64). A disease modifying antirheumatic drug leflunomide results
drug interaction between diuretics and gingko can also in increased BP in up to 5–10% of users (79). Systemic
lead to hypertension (68). Vitamin A and its derivatives antifungals such as ketoconazole lead to hypertension
and iron in overdose can all elevate BP. through mineralocorticoid effects (80). Growth hormone
and thyroid hormones can increase BP by both meta-
bolic and cardiac effects. There is associated tachycardia,
and vascular remodelling occurs with prolonged use.
ILLICIT DRUGS Thyrotropin-releasing hormone is also associated with an
acute increase in BP. Midodrine, a prodrug of the sympa-
Cocaine leads to acute hypertension through adrenergic thomimetic agent desglymidodrine, acts on peripheral-α
overactivity. It inhibits the peripheral reuptake of norepi- receptors and leads to elevations in BP. Atypical antipsy-
nephrine, resulting in synaptic neurotransmitter accu- chotics − for example clozapine and olanzapine − are also
mulation leading to excessive stimulation of adrenergic associated with hypertension, but this may be the result of
receptors. The result is BP elevation through vasocon- their effects on weight gain and precipitation of the meta-
striction, amongst other SNS effects. Regular users have bolic syndrome (81). Metoclopramide and prochlorpera-
higher baseline systolic BP. Nevertheless, it is the acute zine can transiently increase BP levels when they follow
users who run the risk of sudden, dangerously elevated cisplatin therapy. Metoclopramide can also increase BP
levels of BP. This is seen within 15 minutes of use and is when there is an occult pheochromocytoma. Lead, thal-
more enhanced when cocaine is taken intranasally (69). lium, cadmium and arsenic can all lead to raised BP (82–
Furthermore, presence of pre-existing hypertension can 84). Venom from scorpions and the black widow spider
result in much higher BP elevations. Management usually leads to massive catecholamine discharge, which elevates
consists of benzodiazepines and sublingual nitroglycerin. BP (85). Organophosphates bind to nicotinic receptors,
More severe cases are likely to require intravenous therapy, leading to elevated BPs (86).
and the agents of choice are nitroglycerin, nitroprusside,
or phentolamine. It is important to avoid β-blockers, as
these can lead to unopposed α-adrenergic receptor stimu-
lation, which can exacerbate the situation. CONCLUSION
There is a broad spectrum of drugs that can elevate BP
in a manner which can be transient or persistent. The
ALCOHOL underlying mechanisms are widespread. In many cases,
discontinuation of the drug or dose reduction will lead to
Heavy drinkers have a higher prevalence of chronic hyper- resolution of hypertension. In some cases, this is not possi-
tension (70–72). Excessive alcohol intake also results ble and antihypertensive therapy is needed. Drug-induced
in resistance to antihypertensive treatments. The effect hypertension that does not resolve on discontinuation
appears to be dose dependent. The prevalence of alcohol- of the medication raises the risk of longer-term cardio-
induced hypertension varies, and rates of 7–11% have been vascular illness. Given the potential for both short- and
reported (70,71). Proposed mechanisms include impaired long-term adverse outcomes, drug-induced hypertension
baroreflex activity, increased sympathomimetic activity, merits greater awareness amongst clinicians and should
cortisol hypersecretion, activation of RAAS and abnor- be actively sought for and carefully managed in affected
mal vasoconstriction through effects on calcium channels patients.
Drug-Induced Hypertension 461
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HYPERTENSION IN PATIENTS
WITH ADVANCED CHRONIC 57
KIDNEY DISEASE
Table 57.2 Possible blood pressure targets for patients with kidney disease, according to available evidence from trials with renal and/or
cardiovascular primary endpoints
Source: Modified from Sarafidis PA, Ruilope LM. Kidney Int 2014; 85: 536–546. With permission.
a As evident from MDRD study B trial phase and MDRD long-term study.
c Following extrapolation of data from in nondiabetic CKD studies and post hoc or observational analyses in diabetic CKD.
In patients with diabetic CKD, a post hoc analysis of the (p = 0.19) and stroke (p = 0.50) but a 38% significantly
Reduction of Endpoints in NIDDM with the Angiotensin lower risk of heart failure, 27% lower total mortality
II Antagonist Losartan (RENAAL) study, which included and 43% lower cardiovascular mortality. Patients in the
1513 patients with type 2 diabetes, hypertension and intensive-treatment group more frequently developed
macroalbuminuria (mean SCr 1.9 mg/dL and median ACR hypotension (2.4% vs. 1.4%, p = 0.001), syncope (2.3%
1237 mg/g) and compared the effects of losartan or pla- vs. 1.7%, p = 0.05), electrolyte abnormalities (3.1% vs.
cebo on CKD progression, showed that baseline SBP of 2.3%, p < 0.001), and acute kidney injury (4.1% vs. 2.5%,
140–159 mmHg increased risk for ESRD or death by 38% p < 0.001) (33). A recent SPRINT report (34) included the
(p = 0.05) compared to SBP <130 mmHg. In a multivari- subpopulation of patients with CKD (eGFR 20–60 mL/
ate model, every 10-mmHg rise in baseline SBP increased min/1.73 m2) which was considerably high (n = 2646).
the risk for ESRD or death by 6.7% (p = 0.007), whereas After a median of 3.3 years, the primary outcome was
the same rise in DBP decreased the risk by 10.9% (p = 0.01) non-significantly lower in the intensive group (HR 0.81;
(30). A relevant post hoc analysis of achieved BP and renal 95% CI: 0.63–1.05), but the intensive group had a lower
outcomes from the Irbesartan Diabetic Nephropathy mortality rate (HR 0.72; 95% CI: 0.53–0.99). The prespeci-
Trial (IDNT) (which included 1590 patients with type 2 fied main kidney outcome, defined as the composite of
diabetes, hypertension, and proteinuria >900 mg/day, to ≥50% decrease in eGFR from baseline or ESRD, occurred
compare the effects of irbesartan, amlodipine and pla- in 15 intensive group and 16 standard group participants
cebo) showed that SBP >149 mmHg was associated with (HR 0.90; 95% CI: 0.44–1.83). The overall rate of serious
a 2.2-fold increase in the risk for doubling SCr or ESRD adverse events did not differ between treatment groups.
compared with SBP <134 mmHg and follow-up achieved These results must be interpreted with caution, since the
SBP most strongly predicted renal outcomes; moreover, SPRINT trial was not powered to study renal outcomes,
progressive lowering of SBP down to 120 mmHg improved included few proteinuric patients, and, especially with pre-
renal and patient survival, but <120 mmHg, all-cause mature termination of the trial, the number of renal events
mortality increased (31). Based on evidence like the above were small. If anything, the above results rather support
and since progression of renal injury is believed to follow the use of the <130/80 mmHg in all individuals with CKD
the same pathways once proteinuria develops, it has been for cardiovascular and mortality benefit, as patients with
argued that in patients with proteinuric diabetic nephrop- CKD in the intensive group of SPRINT had lower cardio-
athy (particularly >1 g/day), the above BP targets for non- vascular and all-cause mortality rates and similar rates of
diabetic CKD should apply (6,7,18,29,32). the prespecified composite renal outcome.
Recently, the ACC-AHA BP High Blood Pressure Clinical
Practice Guideline proposed a level of 130/80 mmHg for
the diagnosis and management of hypertension in all USE OF ANTIHYPERTENSIVE AGENTS IN CKD
individuals, including those with CKD (17). This change Following implementation of the lifestyle modifications
is mainly generated from the results of the Systolic Blood recommended for all hypertensive individuals (35), with
Pressure Intervention Trial (SPRINT) in which 9361 particular attention paid to sodium restriction, as dis-
hypertensives of increased cardiovascular burden but not cussed elsewhere (8,36), use of antihypertensive agents
diabetes or prior stroke were randomized to intensive (SBP in CKD patients should aim to not only effectively lower
<120 mmHg) or standard treatment (SBP <140 mmHg) BP, but also to slow nephropathy progression and reduce
based on automated office BP measurements (33). The the risk of cardiovascular disease. ACEIs and angioten-
SPRINT trial was terminated earlier than scheduled, as sin receptor-1 blockades (ARBs) are the antihypertensive
the rate of the primary composite outcome (MI, acute agents that most consistently have been found in renal
coronary syndrome not resulting in MI, stroke, acute outcome trials to reduce the rate of CKD progression, an
decompensated HF or death from cardiovascular causes) effect proportionate to proteinuria reduction in protein-
was significantly lower in the intensive-treatment group uric diabetic and nondiabetic nephropathy (8,37), and are
compared with the standard-treatment group (HR 0.75; thus suggested as first-line treatment in these individuals
95% CI: 0.64–0.89; p < 0.001). Patients in the intensive- (6,7,21,35). Herein, we briefly discuss the evidence from
treatment group had a non-significant lower risk of MI outcome trials on the use of major antihypertensive drug
466 Manual of Hypertension of the European Society of Hypertension
classes in proteinuric nephropathies. It has to be noted, death. The mean rate of decline of creatinine clearance was
however, that in hypertensive patients without protein- −5.5, −6.8, and −6.5 mL/min/1.73 m2 per year in the irbe-
uria and relatively preserved eGFR (i.e. >70–75 mL/ sartan, placebo and amlodipine groups, respectively (44).
min/1.73 m2), there is no evidence from outcome trials Post hoc analyses of the above two trials investigated the
on additional renoprotective benefit of RAS blockade. A relationship of baseline proteinuria and reductions in pro-
detailed discussion on the latter field is beyond the scope teinuria during follow-up with the outcome. In RENAAL
of this chapter and can be found elsewhere (18). baseline proteinuria had a nearly linear relationship with
the risk for the primary outcome. Further, for every 50%
BLOCKERS OF THE RENIN−ANGIOTENSIN− reduction in albuminuria in the first 6 months, there was a
ALDOSTERONE SYSTEM 36% reduction of the primary endpoint and a 45% reduc-
In nondiabetic proteinuric nephropathy, ACEI use was tion for ESRD at study end (45). In IDNT, every twofold
studied in the Ramipril Efficacy In Nephropathy (REIN)-2 increase in baseline proteinuria doubled the risk of the pri-
study, where patients with mean SCr of 2.4 mg/dL and pro- mary endpoint. Irrespective of treatment group, this risk
teinuria >3 g/day were randomized to ramipril or placebo; was cut in half with every 50% reduction in proteinuria
ramipril showed significant reductions in proteinuria, GFR at 1 year (46). These results clearly supported the value of
decline and the risk of SCr doubling or ESRD compared proteinuria as an intermediate outcome in patients with
to placebo. The risk of kidney disease progression was overt diabetic nephropathy. It must be noted that there
still significantly reduced after adjustment for changes in are currently no outcome data supporting differences
systolic and diastolic BP (38). In the AASK trial analysed in renoprotection between ACEIs and ARBs. This was
above, patients treated with ramipril had a 36% reduction exemplified in the Diabetics Exposed to Telmisartan And
in the composite endpoint of 50% reduction of GFR, ESRD enalapril (DETAIL) study, which compared the effects of
or death compared to amlodipine, and a 22% reduction enalapril and telmisartan in 250 patients with type 2 dia-
compared to metoprolol (26). Of particular importance betes, hypertension and UAE between 11 and 999 µg/min.
also is the study from Hou et al., who randomized 224 and showed the two drugs having similar effects on GFR
Chinese patients with SCr levels 3.1–5.0 mg/dL (274.3– change, UAE, BP, and the rates of ESRD, cardiovascular
442.5 µmol/L) and persistent proteinuria [mean UAE of events and all-cause mortality (47).
1600 mg/day (1.6 g/day)] to receive 20 mg of benazepril The scarcity of effective means to halt the progression
per day or placebo on top of conventional antihyperten- of proteinuric CKD led to several research efforts to evalu-
sive therapy. Benazepril was associated with a 43% reduc- ate the effects of aggressive RAS blockade (37). Short-term
tion in the risk of the primary endpoint (doubling of SCr, randomized studies in patients with micro- or macroal-
ESRD, or death), a 23% decrease in the rate of decline in buminuria have shown that use of a single RAS-blocker
renal function and 2.5 times greater reduction in protein- in ultra-high dose (i.e. 2–3 times the maximum dose for
uria compared to placebo after 3.4 years, benefits that were hypertension) could reduce UAE more effectively than
not attributable to better BP control (39). A meta-analysis conventional doses without important side effects (48,49).
by the AIPRD Study Group in nondiabetic CKD showed Similarly, combination treatment of ACEIs and ARBs
that regimens including an ACEI were associated with a reduced proteinuria more than single blockade at maxi-
31% reduction in progression to ESRD and 30% reduction mum doses (50,51). However, the premature termination
in the combined endpoint in doubling of SCr or progres- of the two outcome trials in this area has provided defi-
sion to ESRD (40). nite results against the use of combined RAS blockade. In
In patients with diabetes, the use of an ACEI or an ARB particular, the Aliskiren Trial in Type-2 Diabetes Using
is generally recommended for hypertension treatment Cardiorenal Endpoints (ALTITUDE) study compared the
due to the fact that these agents have positive or neutral effects of combination of aliskiren and ACEI or ARB versus
effects on glycaemic and lipid control (41). The eminent ACE or ARB alone on cardiovascular and renal outcomes in
Collaborative Group Study examined the effects of capto- 8561 patients with type 2 diabetes. ALTITUDE was prema-
pril versus placebo in 409 type 1 diabetic patients with turely terminated at 69% of events (52). The components
albuminuria ≥0.5 g/day and SCr ≤2.5 mg/dL. After 3 of the primary outcome did not differ between groups,
years, treatment with captopril led to 43% reduction in with the exception of resuscitated cardiac arrest; the main
the risk of the primary endpoint of doubling of SCr, 50% differences between groups was the proportion of patients
reduction in the combined endpoint of death, need for with hyperkalaemia (11.2% vs. 7.2%), and hypotension
dialysis and transplantation as well as 30% reduction in (12.1% vs. 8.3%) (p < 0.001 for both) (52). The Veterans
UAE compared to placebo (42). In the RENAAL study dis- Affairs Nephropathy in Diabetes (VA NEPHRON-D) study
cussed above, losartan-treated patients had a 35% reduc- aimed to randomize 1850 patients with diabetes, eGFR
tion in the urinary albumin-to-creatinine ratio along 30–90 mL/min/1.73 m2 and ACR >300 mg/day to com-
with a 16% reduction in the primary endpoint of dou- bination of losartan and lisinopril versus losartan alone.
bling of SCr, progression to ESRD or death. The median The study was stopped due to safety concerns after 1448
rate of decline in estimated clearance was 4.4 and 5.2 mL/ patients were randomized with a median follow-up of
min/1.73 m2/per year in the losartan and placebo group, 2.2 years. No difference in the primary endpoint of eGFR
respectively (43). Similarly, in the IDNT study, after a change, ESRD or death (HR with combination therapy
mean follow-up of 2.6 years, proteinuria was decreased by 0.88; 95% CI: 0.70–1.12; p = 0.30) (Figure 57.1), mortal-
33% in the irbesartan group versus 6% in the amlodipine ity or cardiovascular events were noted with combination
group and 10%, in the placebo group. Treatment with irbe- therapy, whereas risk of hyperkalaemia (6.3 vs. 2.6 events
sartan also resulted in a 20% reduction compared to pla- per 100 person-years p < 0.001) was increased (53). The
cebo and 23% reduction compared to amlodipine in the above results clearly indicate that use of combined use
primary composite outcome of doubling of SCr, ESRD or of ACEI with ARB or aliskiren is not indicated in CKD
Hypertension in Patients with Advanced Chronic Kidney Disease 467
A primary endpoint
100 Percent of patients (95% CI)
90 5.7 (4.1–7.8) 18.7 (15.6–22.3) 30.4 (26.1–35.3) 42.4 (34.8–50.8) Losartan + placebo
0
0 6 12 18 24 30 36 42 48 54
Months since randomization
No. at risk
Losartan + placebo 724 641 543 453 335 238 149 75 14
Losartan + lisinopril 724 631 534 457 347 245 139 69 10
Figure 57.1 Kaplan–Meier Plot of cumulative probabilities of the primary endpoint in the VA NEPHRON-D trial. The
primary endpoint was the first occurrence of a change in the eGFR (decline of ≥30 mL/min/1.73 m 2 if the initial estimated
GFR was ≥60 mL/min/1.73 m 2 or a decline of ≥50% if the initial estimated GFR was <60 mL/min/1.73 m 2), end-stage renal
disease or death. (From Fried LF et al. N Engl J Med 2013; 369: 1892–1903. With permission.)
patients. It should be noted, however, that since the main use of finerenone is currently tested in two outcome trials
concern of this combination is hyperkalaemia leading to in individuals with diabetic CKD.
cardiac arrhythmias, it is not impossible for the issue to be
re-examined in the future, given the recent release of well- OTHER ANTIHYPERTENSIVE CLASSES
tolerated potassium-lowering agents (54). The two different subtypes of calcium channel block-
Addition of a mineralocorticoid-receptor-antagonist to ers, non-dihydropyridine (non-DHPCCB) and dihydro-
patients already on ACEI or ARB is suggested as another pyridine (DHPCCB) have been shown to have divergent
option for renoprotection, since plasma aldosterone is ele- effects on proteinuria. In patients with overt diabetic
vated in CKD and may independently contribute to renal nephropathy, non-DHPCCBs (verapamil, diltiazem) were
injury (55), whereas use of ACEIs or ARBs does not nec- associated with reductions in proteinuria and the rate
essarily result in maintained reductions in plasma aldo- of CrCl decline that were greater than those with ateno-
sterone (56). Addition of spironolactone in proteinuric lol (66,67) and no different to those with lisinopril (66),
patients receiving ACEIs or ARBs reduced proteinuria in with similar BP control in the various groups. In another
several pilot studies (57–60). Similarly, eplerenone added cohort of patients with diabetic nephropathy, followed
to an ACEI further reduced UAE in patients with hyperten- for 21 months, a DHPCCB, nifedipine XL, produced no
sion and left ventricular hypertrophy (LVH) (61). Increase change in proteinuria, whereas diltiazem resulted in a pro-
of serum potassium to more than 5.5 mEq/L, is always a teinuria reduction of about 60% (68). The mechanism for
case of concern (62,63) and when such agents are used, this difference relates to the fact that DHPCCBs produce
serum potassium must be followed closely, and a dose afferent arteriole dilation (69). This relates to increased
adjustment of the concomitant conventional diuretic ther- renal blood flow and gives the mistaken impression of
apy should be considered. A detailed study randomized preserved renal function but comes at the expense of fur-
81 patients with diabetes, hypertension and macroalbu- ther increased intraglomerular pressures and permeability
minuria already on lisinopril 80 mg, to losartan 100 mg, to albumin, which leads to poorer long-term renal out-
spironolactone 25 mg or placebo for 48 weeks (64). comes. Further evidence to support lack of renoprotective
Compared to placebo, ACR decreased by 34.0% with spi- properties of DHPCCBs come from multicentre trials. As
ronolactone and by 16.8% with losartan; ambulatory BP, mentioned above, in the IDNT trial, amlodipine was asso-
creatinine clearance (CrCl), sodium and protein intake, ciated with a 6% increase in proteinuria versus baseline
and glycaemic control did not differ between groups. and a 23% higher incidence of the primary endpoint com-
Serum potassium was higher with either spironolactone pared to irbesartan (44). In the nondiabetic population of
or losartan (yet on average <5.2 mEq/L in all groups). A the AASK trial, the 58% increase in proteinuria seen at 6
new aldosterone-blocker with the potential for less hyper- months in those treated with amlodipine correlated with
kalaemia, finerenone, was recently tested in 823 diabetic a greater incidence of the composite endpoint of a ≥50%
patients with micro- or macroalbuminuria randomized reduction in GFR, ESRD and/or death when compared to
to finerenone 1.25, 2.5, 5, 7.5, 10, 15 and 20 mg/d or pla- those treated with ramipril who had a 20% reduction in
cebo for 90 days (65). ACR significantly decreased by 21%, proteinuria (70). Data from the REIN-2 study also ques-
24%, 33% and 38% relative to baseline, whereas hyper- tion the ability of DHPCCBs to help towards regression of
kalaemia leading to discontinuation was up to 3.2% with renal function deterioration in proteinuric kidney disease
finerenone. Based on the above promising findings, the even by means of BP lowering (71). However, as noted also
468 Manual of Hypertension of the European Society of Hypertension
above, a detrimental effect of DHPCCBs in renal progres- >130/80 mmHg (6). However, observational studies sug-
sion is not apparent in patients without proteinuria and gest that peridialytic BP measurements have a flat or ‘U’
preserved eGFR, as noted in the ALLHAT trial (72) or in curve association with cardiovascular events or mortal-
combination with ACEI, as noted in the ACCOMPLISH ity, with hazard ratios not increasing at the SBP range
trial (73). Overall, these notions are in keeping with the of 110–180 mmHg, in contrast to what is expected from
aforementioned observations about ACE inhibitors, i.e. observations in the general hypertensive population (81).
in advanced kidney disease with proteinuria the focus Previous studies suggested that low BP in hemodialysis is
should be both BP and proteinuria reduction with the use associated with early mortality and deaths of primarily
of proper agents, whereas in early kidney disease the focus noncardiac origin, indicating poor physiological reserve
should be BP control (37). and frailty due to comorbid conditions (82). However,
As most patients with CKD and proteinuria would need these findings largely reflect the poor validity of peridi-
a combination of two or more antihypertensive agents to alytic BP recordings per se to describe the true BP load,
reach the aforementioned BP goals, and renal function due to reasons ranging from inadequate implementation
deterioration is accompanied with salt and water reten- of standardized measurement techniques to the well-
tion, diuretics are usually necessary in patients with CKD documented BP fluctuations during the interdialytic BP
(6,37). It is not uncommon for BP to remain refractory interval (83–85). Indeed, BP measurements pre-, during
to treatment without the use or with inappropriate dos- and post-dialysis are not made for diagnostic reasons
ing of diuretics (74). Although diuretics have not been but to exploit a major hemodynamic metric like BP in
directly shown to reduce urine proteinuria beyond the order to assess cardiovascular stability before, during and
amount that is expected due to BP reduction, a potential immediately after the dialysis procedure (86). Factors
benefit of diuretics relates to helping preserve the anti- leading to inaccurate BP pre- and post-hemodialysis
proteinuric effects of ACEIs or ARBs, which are blunted readings may include white-coat effect, limited time for
with high-salt diets (75,76). Thiazide diuretics (with the fear or anxiety for correct arteriovenous fistula needling,
exception of metolazone) become less effective when previous bilateral upper limb attempts of arteriovenous
GFR falls below 40 mL/min/1.73 m 2 (77). In GFR below fistulae and unknown validity of most oscillometric
that level, a loop diuretic (i.e. furosemide, torasemide, devices attached to commercially available hemodialy-
etc.) is rather necessary. If furosemide is used, adequate sis machines. Furthermore, the intermittent nature of
dosing (i.e. 2–3 times instead of once-daily) is necessary hemodialysis as a form of renal replacement therapy is
to achieve optimal BP control, as it has a very short dura- long known to be associated with wide fluctuations in a
tion of action (3–6 h). wide range of metabolic, electrolyte and hemodynamic
Finally, there is no direct evidence that conventional parameters (87), including a particular pattern of BP
β-blockers provide additional renoprotective effects. In changes during the interdialytic interval in the major-
overt diabetic nephropathy non-DHPCCBs produced ity of patients, with progressive increase in BP during
greater proteinuria reductions than atenolol (67,78). In the interdialytic interval and rapid decrease during the
patients with type 2 diabetes in the UKPDS 39 study there dialysis session following sodium and water accumula-
were not significant differences between captopril and tion and removal, respectively. Thus, truly high BP vari-
atenolol in the level of BP achieved, incidence of overt ability (pre- to post-dialysis and day-by-day variability)
nephropathy and doubling of creatinine, data suggesting in response to fluctuations in volume status and other
that any renoprotective effect is due to BP lowering (79). parameters during the intra- and interdialytic periods,
The Glycemic Effects in Diabetes Mellitus: Carvedilol- is another important issue that complicates the accurate
Metoprolol Comparison in Hypertensives (GEMINI) trial diagnosis of hypertension (88). Defining hypertension
showed that carvedilol was associated with significant with predialysis BP becomes even more complex in the
reductions in the risk of microalbuminuria development 5–15% of patients having the ‘paradoxical’ phenomenon
in hypertensive type 2 diabetic patients compared to of intradialytic hypertension, i.e. increase in BP during or
metoprolol (80). These findings, however, were not con- immediately after hemodialysis (89).
firmed by a trial in proteinuric CKD. Therefore, β-blockers In contrast to the above, elevated SBP measured
are suggested to be used in patients with advanced CKD at home or with ABPM monitoring has been associ-
mainly for BP reduction (37). Second-line antihyperten- ated with target-organ damage, such as LVH, as well
sive agents, such as α-blockers, centrally acting agents and as mortality (84,90–92). The use of ABPM has also the
others, are also necessary in several patients with advanced advantage of recording BP during nighttime, which is
CKD to achieve BP control. particularly relevant, as the presence of a non-dipping
nocturnal BP pattern is very common among dialysis
patients and has been associated with LVH (88,93) and
increased risk of all-cause and cardiovascular mortality
HYPERTENSION IN PATIENTS WITH ESRD (94). Thus, many experts suggest that ABPM is the gold-
UNDER DIALYSIS standard method for the diagnosis and management of
hypertension in hemodialysis patients, which should
be probably the first population where BP definition
DEFINITION AND EPIDEMIOLOGY should not be based on office recordings (83,84,95,96).
To this end, a recent consensus paper on hypertension in
Defining hypertension in ESRD patients under mainte- hemodialysis patients, which embodies a joint effort of
nance dialysis is challenging. In the 2005 NKF-KDOQI the European Renal Association-European Dialysis and
guidelines, hypertension was defined as pre-hemodialysis Transplant Association (ERA-EDTA) and the European
BP levels >140/90 mmHg or post-hemodialysis BP levels Society of Hypertension (ESH), proposed a definition for
Hypertension in Patients with Advanced Chronic Kidney Disease 469
hypertension based on out-of-dialysis BP measurements treatment), the prevalence of hypertension was 88%.
(Table 57.3) (86). When defining hypertension using a BP load of more
than 30% of values >140/90 at daytime or >120/80 at
nighttime during 24-hour ABPM, the estimated preva-
EPIDEMIOLOGY OF HYPERTENSION IN lence was 69%. The average 24-hour BP in this study was
HEMODIALYSIS PATIENTS 139 ± 19/81 ± 11 mmHg, suggesting again that if the cur-
Previous efforts on hypertension prevalence in dialysis rently proposed definition of average SBP ≥135 and/or
defined hypertension based on peridialytic BP measure- DBP ≥85 mmHg in ABPM or antihypertensive treatment
ments (86). Using definitions for hypertension such as (103) was used instead, hypertension prevalence would
pre-hemodialysis MAP ≥114 mmHg or use of antihyper- also exceed 70–80% (102). Of note, 53% of patients in
tensive agents (97), pre-hemodialysis SBP ≥140 mmHg this study were non-dippers and an additional 9% were
and/or DBP ≥90 mm (98) and 1-week average pre-hemo- reverse-dippers. Small studies comparing the ambula-
dialysis SBP >150 mmHg and/or DBP >85 mmHg, or tory BP profile between patients treated with automated
use of antihypertensive agents (99) prevalence was esti- peritoneal dialysis (APD) versus continuous ambula-
mated to 70–88%, while concordant control was achieved tory peritoneal dialysis (CAPD) showed that the average
at 30–70% (86). A previous study on the prevalence of 24-hour BP did not differ between the treatment modali-
hypertension in 369 African American hemodialysis ties (104,105). Volume overload is frequently more marked
patients using ABPM (44-hour interdialytic ambula- in peritoneal dialysis than in hemodialysis patients (106)
tory SBP ≥135 mmHg and/or DBP ≥85 mmHg or use of and these patients require antihypertensive drugs more
antihypertensive medications) found that 82% of the frequently (65%) than hemodialysis patients (38%,
patients were hypertensives, and control of hyperten- p < 0.001). In this regard, a strict volume control policy
sion was achieved only in 38% of these patients (100). could reduce the need of antihypertensive medication also
The only information on a Caucasian population comes in peritoneal dialysis patients. As the cyclic variations in
from a recent study in 160 hemodialysis patients from our volume status and in several other metabolic parameters
group, where the prevalence of hypertension (defined as in patients receiving peritoneal dialysis are absent, it has
SBP ≥130 or DBP ≥80 mmHg during the 44-hour inter- been hypothesized that BP control and BP diurnal varia-
dialytic period or use of antihypertensive agents) was tion may be substantially different compared to hemodi-
88.8% and 19.6%, and 11.5% had white-coat effect or alysis. One study testing this hypothesis (107) compared
masked hypertension accordingly (101). the 44-hour BP profile of 22 hemodialysis patients with
that of 24 patients treated with CAPD, showing mean
44-hour SBP and DBP to be similar between the groups,
EPIDEMIOLOGY OF HYPERTENSION IN PERITONEAL but daytime BP on the dialysis day was lower and night-
DIALYSIS PATIENTS time BP on the dialysis-off day to be higher in hemodi-
The prevalence of hypertension among patients on perito- alysis patients. Further, a dipping pattern was much lower
neal dialysis was evaluated in a cross-sectional study (102). in hemodialysis patients (18% vs. 88%) (107). Another
Using the WHO/ISH 1999 definition of hypertension study including 33 hemodialysis and 27 peritoneal dialy-
(SBP ≥140 or DBP ≥90 mmHg, or use of antihypertensive sis patients showed that diurnal BP pattern (i.e. dipping
Table 57.3 Diagnosis of hypertension in dialysis patients proposed by the EURECA-m working group of the ERA-EDTA and the
Hypertension and the Kidney working group of the ESH
Hypertension in dialysis patients should be defined on the basis of home BP or ABPM measurements, as follows:
■■ Home BP in hemodialysis: An average BP ≥135/85 mmHg for measurements collected in the morning and in the evening over 6 non-dialysis days
(covering a period of 2 weeks). Measures should be performed in a quiet room, with the patient in seated position, back and arm supported, after
5 minutes of rest, and with two measurements per occasion taken 1–2 minutes apart.
■■ Home BP in peritoneal dialysis: An average BP ≥135/85 mmHg over 7 consecutive days with measurements collected as above.
■■ ABPM in hemodialysis: An average BP ≥130/80 mmHg over 24-hour monitoring during a mid-week day free of hemodialysis. Whenever feasible
ABPM should be extended to 44-hours, i.e. covering a whole mid-week dialysis interval.
■■ For hemodialysis patients no recommendation can be made on the basis of pre-dialysis or post-dialysis BP. When neither ABPM nor home BP
measurements are available in these patients, the diagnosis can be made on the basis of office BP measurements taken during the dialysis interval,
i.e. the average of three measurements with 1–2 minutes interval obtained in the sitting position by trained personnel after at least 5 minutes of
quiet rest. The threshold of office BP ≥140/90 mmHg recommended by current guidelines for the definition of hypertension in CKD patients can be
used for hemodialysis patients.
■■ For peritoneal dialysis patients, office BP ≥140/90 mmHg obtained as described immediately above can be used for the diagnosis of hypertension.
Source: Modified from Sarafidis PA et al. J Hypertens 2017; 35: 657–676. With permission.
Abbreviations: BP, blood pressure; ABPM, ambulatory blood pressure monitoring; EURECA-m, European Renal and Cardiovascular Medicine working group; ERA-
EDTA, European Renal Association-European Dialysis and Transplant Association; ESH, European Society of Hypertension.
470 Manual of Hypertension of the European Society of Hypertension
Alx (%)
∆ Day (2)-Day (1)
Alx(75) (%)
PATHOGENESIS ∆ Day (3)-Day (2)
PWV (m/s)
The major pathophysiologic mechanism of hypertension
development in hemodialysis patients is sodium and water 0 1 2 3 4 5 6
overload (8). In CKD, the kidney’s ability to control water
and sodium homeostasis is severely impaired, particularly Figure 57.2 Changes in aortic blood pressures, wave
in hemodialysis patients with little or no residual renal reflections and arterial stiffness parameters between the
function (109). Due to the intermittent nature of renal first and the second interdialytic day D[Day(2)-Day(1)],
replacement therapy, hemodialysis patients are subjected in comparison with relevant changes between the sec-
to sodium and fluid accumulation and BP elevation in pro- ond and the third interdialytic day D[Day(3)-Day(2)].
portion to weight gain during the interdialytic interval, a Abbreviations: AoSBP, aortic systolic blood pressure;
phenomenon superimposed on BP circadian variation AoDBP, aortic diastolic blood pressure; AoPP, aortic
(110–112). The inter-dialysis increase in BP is not limited pulse pressure; AIx, augmentation index; AIx(75), heart
to brachial BP but extends to other critical hemodynamic rate-adjusted AIx; PWV, pulse wave velocity. (Reprinted
parameters like aortic BP (110), and the peripheral and with permission from Koutroumbas G et al. Nephrol Dial
central BP burden is accentuated during the long dialysis Transplant 2015; 30: 2046–2053.)
interval, again in proportion to fluid overload (112,113).
Until fluid and sodium overload is removed during dialy-
sis, a rise in peripheral vascular resistance would sustain
hypertension in these individuals. weight gain (113). Subsequent studies with ABPM record-
Sympathetic overactivity is another major cause of ings from our group further confirmed the above, show-
hypertension in ESRD. Efferent sympathetic discharge rate ing a continuous increase in wave reflection indices and
is doubled in hemodialysis patients with in situ native kid- central BP in both the 2-day and 3-day interdialytic inter-
neys but normal in hemodialysis patients after bilateral vals with minimal increase in PWV (110,112). Of note,
nephrectomy (114). Bilateral nephrectomy of failed kid- the above findings were associated with a greater increase
neys produces sustained reductions in peripheral vascular in aortic SBP and DBP when moving from the second to
resistance and dramatic BP decrease (115). Recent obser- the third than when moving from the first to the second
vations where renal denervation substantially reduced BP day of the large intradialytic interval, suggesting a pro-
in small series of hemodialysis patients with severe resis- gressive BP increase with increasing time from the last
tant hypertension support the above (116,117). Activation dialysis (Figure 57.2) (112).
of RAS is also involved, as clinical studies show increase Endothelial dysfunction could also cause BP eleva-
in plasma renin activity (PRA) and plasma aldosterone tion in ESRD. Patients with CKD show markedly reduced
from pre- to post dialysis, suggesting that residual func- NO-dependent vasodilation, possibly due to reduced pro-
tioning nephrons in dialysis patients retain their ability to duction of NO (123). This reduction in NO bioavailability
sense acute changes in sodium intravascular volume sta- in ESRD may result from high circulating levels of asym-
tus in response to ultrafiltration (118,119). Overactivation metric dimethylarginine (ADMA), an endogenous NO
of SNS and RAS may be particularly relevant for patients synthase inhibitor (124). Other mechanisms involved in
with intradialytic hypertension (89). hypertension occurrence in hemodialysis patients include
Arterial stiffness is particularly accelerated in ESRD sleep apnoea, which provokes nocturnal hypoxemia and
patients and is independently associated with high sys- sympatheticotonia (89), as well as the use of medications
tolic BP, LVH and increased all-cause and cardiovascular which induce BP elevation, such as erythropoietin-stimu-
mortality in hemodialysis patients (120,121). An analy- lating agents (8).
sis including 125 hemodialysis patients showed that
log of PW V presented linear relationship with BP (each
log increase in PWV was associated with 20.3, 7.2 and TREATMENT OF HYPERTENSION IN PATIENTS
12.8- mmHg increases in SBP, DBP and PP [pulse pres- ON DIALYSIS
sure], respectively), but also increasing PWV blunted the
circadian amplitude of SBP and PP (122). A study evaluat- Management of hypertension in dialysis patients is com-
ing acute changes in arterial stiffness indexes during the plex. Focusing on correction of the primary pathogenetic
interdialytic periods showed that augmentation index mechanism, i.e. sodium and volume excess, by carefully
(AIx) and central PP is increased during both 3-day and implementing a series of non-pharmacological measures in
2-day interdialytic intervals; aortic and brachial PWV order to achieve the dry weight for each individual patient
was unchanged in these short time frames. The increase and to avoid intradialytic sodium loading, is considered
in AIx was 30% greater during the 3-day than during central (Table 57.4). However, since 95% of patients are
the 2-day interval and was associated with interdialytic already hypertensive and the vast majority are receiving
Hypertension in Patients with Advanced Chronic Kidney Disease 471
dialysis sessions is necessary to ensure BP control in these effect on cardiovascular outcomes is examined in relatively
patients (134). few studies, as in the case of other antihypertensive classes
(86,134). One randomized study (Fosinopril in Dialysis
[FOSIDIAL]) has prospectively evaluated the effects of
USE OF ANTIHYPERTENSIVE AGENTS IN PATIENTS fosinopril (up to 20 mg/day t.i.d) and placebo therapy
ON DIALYSIS on cardiovascular events (152). Almost 400 hemodialy-
After the above strategies are properly implemented, the sis patients with or without hypertension but with LVH
introduction of drug treatment can further help in achiev- were included and followed-up for 4 years. Hypertensive
ing the optimum BP. All major antihypertensive classes patients on fosinopril had a higher drop in pre-dialysis
with the exception of diuretics can be considered in hyper- SBP (fosinopril 11.7; placebo 5.4 mmHg; p = 0.002), but
tension management in hemodialysis patients (103,148), hazard ratios for the primary endpoint of fatal and non-
as the use of agents from these classes was associated with fatal CV events was similar between the fosinopril and
reduced cardiovascular risk (Table 57.5). The choice of a placebo groups (RR: 0.93; 95% CI: 0.68–1.26) (152). In a
specific antihypertensive drug should be based on the meta-analysis of smaller studies comparing RAAS block-
patient’s comorbid conditions and the pharmacologic ers versus other classes, placebo or no treatment in hemo-
characteristics of the agent, including dialyzability (134). dialysis found similar hazard ratios for the two patient
None of the antihypertensive classes has been proven supe- groups (153). From the three studies included in this meta-
rior in controlling BP levels compared to another (149), analysis, the first randomized 80 patients to candesartan
as no comparative studies with the use of ABPM exist. (4–8 mg/day) or nothing, and after 19 months patients on
Further, no study has compared the effectiveness of anti- candesartan had significantly lower cardiovascular events
hypertensive treatment with that of strict control of water and mortality (16.3% vs. 45.9%, p < 0.01 and 0% vs.
and sodium balance with non-pharmacologic measures 18.9%, p < 0.001, respectively) (154). Another open-label
(125). However, accumulated evidence from clinical trials study randomized 360 hemodialysis patients with hyper-
suggests that the BP-lowering effect of antihypertensive tension to ARB or nothing. No difference was noted in pre-
drug treatment was associated with significant improve- hemodialysis BP changes between the start and the end of
ment in cardiovascular mortality in patients undergo- the study in the two study arms, but ARB use was associ-
ing hemodialysis. Results from a systematic review of ated with lower cardiovascular event occurrence (HR 0.51;
five randomized controlled studies indicated that among 95% CI: 0.33–0.79) (155). Finally, in a more recent study,
1202 patients, those receiving drug treatment (ACEI, ARB, 469 hypertensive hemodialysis patients were randomly
β-blocker or CCB) had 31% lower risk of cardiovascular assigned to olmesartan (10–40 mg/day) or other treat-
events occurrence and all-cause mortality compared to ment, but olmesartan was not associated with significant
those not receiving drugs or receiving placebo (150). In reductions in cardiovascular risk (HR 1.00; 95% CI: 0.71–
another meta-analysis of eight randomized controlled tri- 1.40) or mortality (HR 0.97; 95% CI: 0.62–1.52) (156).
als including 1679 patients, it was shown that lowering Overall, a superiority of ACEIs and ARBs over other anti-
SBP by 4.5 mmHg and DBP by 2.3 mmHg with the use hypertensive drugs has not been demonstrated until now
of ACEI, ARB, β-blocker or CCB was associated with 29% in dialysis patients, and antihypertensive treatment per se
lower cardiovascular and all-cause mortality (151). rather than the use of a RAS-blocker could be the factor
reducing cardiovascular risk (86). Importantly, almost all
BLOCKERS OF THE RENIN−ANGIOTENSIN− ARBs are not dialyzed and do not require dosage modifica-
ALDOSTERONE SYSTEM tion in dialysis, whereas ACEIs have differences regarding
The RAS blockers class is used as in hemodialysis patients, their dialyzability.
mostly due to continuation of hypertension treatment The effect of mineralocorticoid-receptor antagonists
before dialysis, or for other comorbidities. However, their (MRAs) in hemodialysis patients compared to other
Table 57.5 Outcome trials with major antihypertensive classes in patients on dialysis
ACE-inhibitors In the FOSIDIAL trial in HD patients with LVH (152) fosinopril did not reduce cardiovascular events and mortality
compared to placebo.
ARBs In HD patients, losartan/valsartan/candesartan reduced cardiovascular events and mortality compared to treatment
not including ACEIs/ARBs (154,155).
In the OCTOPUS trial in HD patients with hypertension (156), olmesartan did not reduce cardiovascular events or
mortality compared to treatment not including ACEIs/ARBs
MRAs In two trials in HD and PD patients, spironolactone reduced cardiovascular events and mortality compared to no
additional treatment or placebo (158,159).
β-blockers In HD patients with dilated cardiomyopathy carvedilol reduced mortality compared to placebo (161).
In the HDPAL trial in HD patients with hypertension and LVH (162) thrice-weekly atenolol reduced cardiovascular
events compared to thrice-weekly lisinopril.
Calcium channel blockers In HD patients with hypertension amlodipine reduced cardiovascular events compared to placebo (165).
Abbreviations: FOSIDIAL, Fosinopril in Dialysis trial; HD, hemodialysis; HDPAL, Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril trial; LVH,
left ventricular hypertrophy; OCTOPUS, Olmesartan Clinical Trial in Okinawa Patients under Dialysis Study; PD, peritoneal dialysis.
Hypertension in Patients with Advanced Chronic Kidney Disease 473
antihypertensive drugs classes has also recently been peripheral vascular disease (H: 0.53; 95% CI: 0.31–0.93)
studied. A study of 76 dialysis patients with refractory (165). At the end of this study pre-hemodialysis BP was sig-
hypertension randomized subjects to 12-week treatment nificantly lower in the amlodipine study group compared
with spironolactone (25 mg/day) or placebo and showed to baseline, but not in placebo; occurrence of hypoten-
reduced 24-hour ambulatory BP by 12.5/7 mmHg in the sive episodes was similar between the two groups (165).
spironolactone group (157). The Dialysis Outcomes Heart Importantly, CCBs are practically not removed during
Failure Aldactone study (DOHAS) compared the effects of standard hemodialysis and their pharmacokinetics are
adding 25 mg of spironolactone versus standard of care in unchanged in ESRD and thus can be dosed once-daily in
309 hemodialysis patients (158). After 3 years, spironolac- these patients (160). Data on non-DHPCCB in hemodialy-
tone greatly reduced the risk of death or hospitalization for sis patients are practically absent; their use should at least
cardiovascular event (HR 0.38; 95% CI: 0.17–0.83), with- follow the recommendations for the general population
out significantly lowering BP levels from baseline to the (86).
end of the study. The incidence of drug discontinuation
due to serious hyperkalaemia was 1.9% (158). Another
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BLOOD PRESSURE
MANAGEMENT IN ACUTE 58
STROKE
Table 58.1 Randomized clinical trials: blood pressure management and outcome in acute ischaemic stroke
ACCESS (8) 342 Candesartan Mean SBP 6–24 h after No significant reduction No difference in Barthel Index at
admission ≥200 mmHg or DBP 3 months. No difference in
≥110 mmHg cerebrovascular events at
Mean SBP 24–36 h after 12 months. Reduced mortality
admission ≥180 mmHg or DBP and vascular events at 12 months
≥105 mmHg in favour of candesartan.
SCAST (9) 2029 Candesartan SBP >140 mmHg. ↓SBP 5 mmHg and ↓DBP No difference in mRS or stroke
Fixed dose-escalation schedule 2 mmHg on day 7 recurrence at 6 months.
CHHIPS 179 Oral labetalol or SBP >160 mmHg ↓SBP 14 mmHg and ↓DBP No difference in death or
(11) lisinopril or 7 mmHg with lisinopril at dependency rate at 2 weeks.
placebo 24 hours
COSSACS 763 Continuation of SBP <200 mmHg and ↓SBP 13 mmHg and ↓DBP No difference in death or
(12) home DBP <120 mmHg 8 mmHg at 2 weeks dependency rate at 2 weeks.
medications No difference in stroke recurrence
at 6 months.
CATIS (13) 4071 ACE-I, CCB, SBP of 140–200 mmHg ↓SBP 8.1 mmHg and ↓DBP No difference in death or disability
diuretics 3.8 mmHg at 24 h, ↓SBP rate at 14 days after
(predefined 9.3 mmHg and ↓DBP randomization. No difference in
algorithm) 4.0 mmHg at 7 days mRS at 3 months.
ENOS (14) 4011 Glyceryl trinitrate SBP of 140–220 mmHg ↓SBP 7.0 mmHg and ↓DBP Significant BP lowering,
(transdermal) 3.5 mmHg at 24 h, ↓SBP acceptable safety but not
9.5 mmHg and ↓DBP improvement in functional
5.0 mmHg on day 7 outcome
Abbreviations: n, number of patients; h, hours; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; mRS, modified Rankin scale; ACE-I,
angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker.
In the ACCESS study (Acute Candesartan Cilexetil 36 hours of symptoms onset to labetalol, lisinopril or pla-
Therapy in Stroke Survivors), 339 patients with acute IS cebo (11). There were no differences in the primary endpoint
and BP values greater than 180/105 mmHg were random- of 14-day death, dependency, early neurological dete-
ized to oral candesartan or placebo within 36 hours after rioration and serious adverse events. However, 3-month
admission and maintained on study drug for 7 days after mortality showed a trend favouring active treatment.
randomization (8). The two groups did not differ regard- This preliminary observation remains to be confirmed
ing functional outcome and risk of stroke recurrence at by a larger phase III trial. In the COSSACS (Continue or
3 and 12 months, respectively. However, candesartan sig- Stop Post-Stroke Antihypertensives Collaborative Study)
nificantly reduced mortality and vascular events during study, 763 patients with ischaemic (95%) or haemorrhagic
the 12-month follow-up. The superiority of candesartan stroke (5%) were randomized to continue or to stop their
versus placebo over the secondary endpoint of the study antihypertensive treatment prior to stroke onset (12). The
triggered the design of a larger study. In the SCAST study continuation of previously administered antihypertensive
(Scandinavian Candesartan Acute Stroke Trial), a phase III treatment in acute stroke patients was not associated with
RCT, 2029 patients with acute IS (85%) or ICH (15%) and improved mortality or disability at 2 weeks and 6 months
SBP (>140 mmHg) were randomized to oral candesartan of follow-up.
or placebo using a design similar to ACCESS (9). The com- The most recently published studies were the CATIS and
posite endpoint of major cardiovascular events did not dif- ENOS trials. The CATIS (China Antihypertensive Trial in
fer between the two groups at 6 months. However, patients Acute Ischaemic Stroke) study included 4071 patients with
treated with candesartan had a worse functional outcome IS within 48 hours of symptom onset and SBP levels of
compared to those receiving placebo. In addition, a SCAST 140–220 mmHg (13). Patients were randomized to an SBP
substudy showed that in patients with moderate to severe reduction target of 10–25% within 24 hours of randomiza-
carotid artery disease treated with candesartan, progres- tion and a BP of <140/90 mmHg within 7 days with the
sive stroke occurred more frequently than in the placebo use of agents of angiotensin-converting enzyme inhibi-
group (10). tors, calcium channel blockers and diuretics according to
Two more studies investigating the same research ques- a predefined algorithm versus no antihypertensive treat-
tion in the United Kingdom have reported similar results. ment. The two groups did not differ regarding the primary
The CHHIPS (Randomized Stroke and Stroke Hypotension) composite endpoint of death and dependency rate at 14
study randomized 179 patients with ischaemic (85%) or days and the secondary endpoint of functional disability
haemorrhagic stroke (15%) and SBP (>160 mmHg) within at 3 months. However, when antihypertensive therapy was
Blood Pressure Management in Acute Stroke 481
started >24 hours of symptoms onset there was a signifi- consensus, extrapolating the findings from thrombolysis
cant reduction of the primary endpoint in the treatment trials in the setting of myocardial infarction. The most
group. important observational study supporting the associa-
Finally, in ENOS (Efficacy of Nitric Oxide in Stroke) tion of high BP values and adverse outcome in patients
trial, 4011 patients with ischaemic or haemorrhagic stroke with acute IS treated with intravenous thrombolysis is
and SBP (140–220 mmHg) were allocated to treatment the SITS-ISTR (Safe Implementation of Thrombolysis
with transdermal glyceryl trinitrate or placebo within in Stroke – International Stroke Thrombolysis Register)
48 hours of stroke onset and for 7 days (14). The admin- study (15). This study showed that BP levels during the
istration of glyceryl trinitrate did not improve functional first 24 hours following intravenous thrombolysis were
outcome at 3 months compared with placebo. In contrast positively and linearly associated with the risk of intrace-
to the CATIS trial, a prespecified subgroup analysis of rebral haemorrhage. Moreover, during the first 24 hours
ENOS demonstrated that the early onset of active therapy, post-thrombolysis, a U-shaped relationship was observed
within 6 hours of ictus, was associated with a favourable between BP values and mortality and disability. An SBP of
functional outcome and fewer deaths. Thus, the optimal 141–150 mmHg was associated with the more favourable
timing of antihypertensive therapy initiation during the outcome.
acute phase of IS remains controversial.
The U-shaped relationship between baseline BP values
and outcome revealed that both markedly elevated and
low BP values (<120 mmHg) are associated with poor out- INTRACEREBRAL HAEMORRHAGE
come. Thus it could be theoretically assumed that raising
Similar to acute IS, the optimal management of post-stroke
BP might be beneficial in selected patients. Studies in ani-
hypertension in patients with intracerebral haemorrhage
mal models have demonstrated that the administration of
(ICH) is still uncertain. Although elevated BP declines
phenylephrine after stroke improved cerebral blood flow
spontaneously within the first days after ICH onset and
and reduced cerebral oedema in the territory of the infarc-
aggressive BP reduction may decrease cerebral perfusion
tion. Unfortunately, no RCTs have evaluated the safety and
pressure in the area surrounding haematoma leading to
efficacy of treatment-induced hypertension in the setting
neurological worsening, most arguments are in favour of
of acute ischaemic stroke. The available evidence derived
BP lowering. Observational studies have illustrated that
from retrospective and small randomized studies suggests
elevated BP is associated with increased risk of death,
that raising BP up to 20% with intravenously administered
disability or neurological deterioration in patients with
phenylephrine in selected acute IS patients is safe and may
acute haemorrhagic stroke (6,16). In addition, some stud-
be associated with neurological improvement. The best
ies have demonstrated that increased BP is related to hae-
studied candidates for induced hypertension are those
matoma growth and to cerebral oedema formation (7,17).
with large perfusion deficits caused by steno-occlusive
Haematoma expansion is a frequent complication of ICH,
disease who are not eligible for thrombolytic or interven-
occurring in 30% of patients with haemorrhagic stroke,
tional treatments.
whilst one-third of them develop the expansion within
Despite several published RCTs, the optimal BP manage-
3 hours of ICH (18). Several studies have reported that
ment in acute IS patients is still unclear. The neutral results
haematoma enlargement is associated with neurological
of all trials regarding the effect of BP lowering on death and
deterioration and poor outcome (19,20). Haematoma vol-
dependency in the setting of acute stroke demonstrate that
umes greater than 30 mL are related to increased mortality
either reducing BP is not of benefit or the study designs were
rates (60–90%) at 1 month after ICH (21). Of note, the
inappropriate to reveal positive associations between BP
INTERACT1 study revealed that for each 1-mL increase in
modulation and outcome. Stroke is a complex disease and
haematoma expansion, the risk of death and dependency
the ‘one size fits all’ approach in terms of BP lowering in IS
increases by 5% (22). Hence this has prompted some
may not be valid. Future studies should take into account
researchers to conclude that haematoma growth might
IS subtypes (separate evaluation of large and small vessel
be the biological link between elevated BP and mortality.
disease strokes), timing of administration (early adminis-
The possible beneficial effects of early BP-lowering treat-
tration <24 h), route of therapeutic manipulation (intrave-
ment on haematoma enlargement and outcome after ICH
nously, easily titrated agents), recruitment of patients with
have led to the conduction of RCTs aiming to determine
higher SBP values (>160 mmHg) and targeting greater SBP
the safety and efficacy of early BP management on haema-
goals (<150 mmHg). These trials may provide adequate sci-
toma expansion and hard outcomes such as mortality and
entific basis for more evidence-based treatment decisions
disability (Table 58.2).
regarding BP management in acute IS patients.
Table 58.2 Randomized clinical trials: Blood pressure management and outcome in acute intracerebral haemorrhage
INTERACT-1 (23) 404 <6 h since onset, SBP 140 mmHg vs. 180 mmHg Reduction in haematoma growth at 24 h
(150–220) mmHg
ICH-ADAPT (26) 75 <24 h since onset, 150 mmHg vs. 180 mmHg No significant difference in perihematoma CBF
SBP >150 mmHg
ATACH-1 (24) 60 <6 h since onset, 170–200 mmHg in the first cohort Neurologic deterioration and serious adverse
SBP ≥170 mmHg of patients; 140–170 mmHg in events were below the prespecified safety
the second cohort; 110– thresholds, and the 3-month mortality rate was
140 mmHg in the third cohort lower than expected in all SBP tiers.
INTERACT-2 (28) 2794 <6 h since onset, SBP 140 mmHg vs. 180 mmHg No significant reduction in the rate death or
(150–220) mmHg severe disability. Improved functional
outcomes (ordinal analysis of mRS) with
intensive lowering of blood pressure.
ATACH-2 (29) 1000 3 and 4.5 h since onset, at <140 (110–139) mmHg vs. Not lower rate of death or disability.
least one reading of 140–179 mmHg Significantly higher rates of renal adverse events
SBP ≥180 mmHg at 7 days in the aggressive BP-lowering group.
Abbreviations: n, number of patients; h, hours; BP, blood pressure; SBP, systolic blood pressure; CBF, cerebral blood flow; mRS, modified Rankin Scale.
within 6 hours of ICH onset and randomized them to (Intracerebral Haemorrhage Acutely Decreasing Arterial
either intensive BP treatment (SBP target <140 mmHg Pressure Trial) assessed the impact of aggressive BP low-
within 1 hour of randomization and maintaining it for the ering on CBF and provided strong arguments against
next 7 days) or guideline-based management of BP (SBP this hazard (26). A total of 75 patients with acute haem-
target <180 mmHg) (23). The choice of antihypertensive orrhagic stroke and SBP >150 mmHg were randomly
treatment was determined by the investigator’s prefer- assigned within 24 hours of onset to an SBP goal of less
ence. The aim of the study was to assess safety, efficacy than 150 mmHg or less than 180 mmHg. The SBP target
(proportional change in haematoma volume at 24 hours) had to be achieved within 1 hour from randomization by
and clinical outcomes (death or disability) of treatment at means of intravenous antihypertensive agents. The aim of
90 days. The rates of serious adverse events, neurological the study was to investigate the effect of intensive versus
deterioration and poor clinical outcome did not differ sig- standard BP-lowering treatment on perihematomal CBF,
nificantly between the two groups. Furthermore, intensive which was measured by performing computed tomogra-
BP reduction attenuated proportional haematoma growth phy perfusion imaging at 2 hours post-randomization in
at 24 hours, not significantly though. both groups. The results showed that intensive BP treat-
In the prospective, open-label, ATACH1 (Antihyper ment was not associated with impairment of perihema-
tensive Treatment of Acute Cerebral Haemorrhage) study, tomal CBF compared to the standard treatment group,
60 patients with acute haemorrhagic stroke and SBP > contradicting the theory of cerebral ischaemia induced by
170 mmHg were randomized, within 6 hours of symp- BP lowering in ICH patients. Moreover, a post hoc analysis
tom onset, into one of three SBP target levels: 170–199, of ICH-ADAPT reported that early aggressive BP lowering
140–169 and 110–139 mmHg (24). Patients were treated was not associated with perihematomal oedema growth
with intravenous nicardipine for achieving and maintain- (27). These findings remain to be confirmed by a larger
ing BP goals for 24 hours. The study aimed to determine ongoing phase II trial (ClinicalTrials.gov ICH-ADAPT II,
feasibility, safety (neurological deterioration at 24 hours NCT02281838).
and serious adverse events at 72 hours) and efficacy (dis- The promising observations regarding safety and feasi-
ability or death at 90 days) of intensive BP reduction. The bility from INTERACT1 and ATACH1 studies has led to
mortality at 3 months was lower than expected across all the conduction of two large RCTs, aiming to investigate
SBP levels and the rates of serious adverse events and neu- the impact of early aggressive BP lowering on clinical out-
rological deterioration were below the prespecified safety come in acute ICH.
thresholds. A post hoc analysis of ATACH1 trial did not INTERACT2 was an international, prospective, ran-
reveal any significant associations between different SBP domized, open-label, blinded endpoint trial (28). The
levels and haematoma expansion (25). study randomized 2839 ICH patients with SBP levels
Both pilot trials demonstrated that intensive BP lower- between 150−200 mmHg within 6 hours of onset to an
ing in the setting of acute ICH is safe and feasible and may intensive (SBP <140 mmHg, achieved within 1 hour and
be associated with reduced haematoma growth. However, maintained for 7 days) or a guideline-recommended SBP
the opponents of this treatment strategy are concerned target (SBP <180 mmHg). The choice of antihypertensive
that the already compromised cerebral blood flow (CBF) in treatment was based on the local availability of antihy-
the perihematomal area due to the compression of small pertensive agents. The composite primary outcome of the
arteries by the haematoma and the associated oedema will study was death or major disability, defined as a modi-
be further reduced by aggressive BP lowering, leading sub- fied Rankin Scale (mRS) score of 3–6 at 90 days, whilst
sequently to perihematomal ischaemia. The ICH-ADAPT the secondary outcomes included ordinal analysis of the
Blood Pressure Management in Acute Stroke 483
primary endpoint, all-cause mortality, health-related increased intracranial pressure, who are at increased risk
quality of life, duration of hospitalization, living in resi- for cerebral hypoperfusion.
dential care facility, haematoma expansion, neurological
deterioration and serious adverse events. At 3 months,
the rates of death and severe disability did not differ sig-
nificantly between the two groups, although the primary GUIDELINES
outcome was reduced by 25% in the intensive compared
to the guideline treatment group. The effects of intensive
BP control on the primary outcome were consistent across ISCHAEMIC STROKE
all prespecified subgroups. However, ordinal analysis
The American Heart Association/American Stroke
demonstrated a significantly favourable functional out-
Association (AHA/ASA) and the European Stroke
come for patients randomized to intensive BP-lowering
Organization (ESO) have released guidelines regarding the
treatment compared to their counterparts. Furthermore,
management of high BP in the acute phase of IS (31,32).
intensive BP treatment was safe and associated with sig-
Both authorities recommend that in acute IS patients who
nificantly better health-related quality of life than stan-
are not candidates for thrombolysis, BP should not be
dard BP treatment. In contrast, the two groups did not
lowered unless BP levels exceed 220/120 mmHg (thresh-
differ significantly in terms of all-cause mortality and
old values recommended by consensus). If repeated BP
haematoma expansion.
measurements reveal SBP >220 mmHg and/or DBP >
The most recent RCT, ATACH2, was a multicentre,
120 mmHg, pharmacological intervention is indicated,
open-label, blinded endpoint trial, which randomly
and BP should be reduced by no more than 15% in order
assigned 1000 patients with acute ICH (haematoma vol-
to avoid profound BP falls that have been associated
ume <60 mL) and increased SBP levels >180 mmHg to
with neurological and functional worsening. Immediate
an aggressive SBP target (110–139 mmHg) or a standard
onset of antihypertensive treatment is recommended in
SBP target (140–179 mmHg) within 4.5 hours of symptom
patients with acute stroke and target-organ damage such
onset by means of intravenous nicardipine (29). The trial
as acute myocardial infarction, left ventricular heart fail-
was designed to evaluate the potential benefits obtained
ure, acute renal failure, aortic dissection and hypertensive
with tight compared to standard SBP targets on the pri-
encephalopathy, independent of BP levels. Intravenous
mary (death or severe disability [mRS >3] at 3 months)
administration of antihypertensive drugs is superior to
and secondary outcome measures (all-cause mortality,
oral administration due to easier titration and better BP
health-related quality of life, haematoma growth, neuro-
management under close BP monitoring (Table 58.3).
logical deterioration and serious adverse events). The two
Sublingual administration of nifedipine should be avoided
groups did not differ significantly regarding the primary
because of the risk of abrupt BP drop and possible isch-
and secondary outcomes of the study. Aggressive treat-
aemic steal. Regarding the optimal timing of restarting
ment group demonstrated non-significantly lower rates of
antihypertensive treatment in acute IS patients with BP
haematoma growth. Moreover, patients in the intensive
levels below 220/120 mmHg and without comorbid condi-
group presented increased rates of any serious adverse
tions requiring acute antihypertensive therapy, the recently
events at 3 months and significantly higher rates of renal
published AHA guidelines for management of high BP in
adverse events at 7 days after randomization compared to
adults recommend that initiating or reinitiating antihyper-
the standard group. Thus, the results of ATACH2 trial sug-
tensive treatment within 48–72 hours after stroke onset is
gest that aggressive BP-lowering treatment in acute ICH is
not effective to prevent death or dependency (33).
not effective and potentially harmful.
In acute IS patients eligible for thrombolysis, immediate
A recent meta-analysis of the aforementioned studies
parenteral antihypertensive treatment should be initiated
demonstrated that aggressive BP lowering in the setting
if SBP >185 mmHg and/or DBP >110 mmHg, and BP levels
of acute ICH is safe, reduces the risk of ICH expansion
should be maintained at desired levels (SBP <180 mmHg
(though not statistically significant) but does not improve
and DBP <105) during and for at least 24 hours after the
functional outcome and mortality at 3 months (30).
thrombolysis. During this period, BP should be closely
Thus, the optimal management of BP at the acute phase
monitored, every 15 minutes for 2 hours from the ini-
of ICH remains still unresolved. The safety of aggressive
tiation of the thrombolysis, then every 30 minutes for 6
BP lowering demonstrated in INTERACT2 was not con-
hours and then every hour for the next 16 hours.
firmed by the ATACH2 study. Moreover, both trials failed
to meet their primary and secondary outcomes of reduc-
ing death, severe disability and haematoma expansion at
3 months, with the exception of the favourable functional INTRACEREBRAL HAEMORRHAGE
outcome observed in the ordinal analysis of disability in
INTERACT2 for aggressively treated ICH patients. The fail- The novel findings of randomized controlled trials
ure of both trials to demonstrate a clear clinical benefit (INTERACT1, ATACH1, INTERACT2 and ICH-ADAPT)
from intensive BP lowering could be attributed to several have influenced the AHA/ASA and the ESO and forced
methodological aspects such as recruitment of patients at them to modify the previously published recommenda-
low risk for haematoma expansion, heterogeneity in man- tions on BP management in acute haemorrhagic stroke.
agement of hypertension, different admission SBP values Currently, the AHA/ASA guidelines, published in 2015,
and time-window for inclusion in the study. Future trials for the management of spontaneous intracerebral haem-
should further investigate the optimal BP target in patients orrhage recommend that for ICH patients with elevated
with acute ICH in terms of hard outcomes, as well as the SBP between 150−220 mmHg, early SBP lowering to
effect of aggressive BP lowering on haematoma expansion 140 mmHg is safe and may improve functional outcome
especially in ICH patients with large haematomas and (34). In a similar way, the ESO guidelines, published in
484 Manual of Hypertension of the European Society of Hypertension
Table 58.3 Proposed antihypertensive agents for the management of arterial hypertension in acute stroke patients
Intravenously
Labetalol 10–20 mg over 1–2 min, may repeat or double every 10 min (maximum 300 mg)
Nicardipine 5 mg/h infusion as initial dose, titrate to desired effect by increasing 2.5 mg/h every 5 min (maximum 15 mg/h)
Nitroprusside 0.5 µg/kg/min as initial dose with continuous BP monitoring
Uradipil 10–50 mg, followed by 4–8 mg/h
Nitroglycerin 5 mg, followed by 1–4 mg/h
Esmolol 500 µg/kg loading dose; maintenance use 50–200 µg/kg/min
Subcutaneously
Clonidine 0.15–0.30 mg
Transdermally
Glyceryl trinitrate 5 mg
Sublingually
Lisinopril 5 mg
Orally
Angiotensin converting inhibitors or angiotensin II receptor blockers with or without diuretic (secondary stroke prevention)
2014, state that in patients with acute ICH, early (within 6 9. Sandset EC, Bath PM, Boysen G et al. The angiotensin-receptor
hours of onset) aggressive BP lowering (SBP <140 mmHg blocker candesartan for treatment of acute stroke (SCAST): A
randomised, placebo-controlled, double-blind trial. Lancet 2011;
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11. Potter JF, Robinson TG, Ford GA et al. Controlling hyperten-
patients and forced the recently published AHA and the sion and hypotension immediately post-stroke (CHHIPS): A
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BLOOD PRESSURE
MANAGEMENT IN THE 59
CHRONIC POST-STROKE PHASE
1994 when the trial was initiated. This resolved the issue
in normotensive subjects with cerebrovascular disease that THRESHOLD FOR BLOOD PRESSURE
previous trials had left unanswered. LOWERING AND OPTIMAL TARGET
In the PROGRESS trial, combination therapy with per-
indopril plus indapamide produced consistently larger BLOOD PRESSURE IN SECONDARY
reductions in the risk of stroke (43%, 95% CI 30−54%) PREVENTION OF STROKE
compared to single-drug therapy with perindopril (5%,
95% CI −19 to 23%, non-significant reduction), and it With regard to threshold for blood pressure lowering, a
is likely that the large differences in treatment effect rep- subsidiary analysis of the PROGRESS trial investigated
resent the benefits of greater blood pressure reduction the effects of randomised treatment on recurrent stroke
with combination therapy with perindopril plus indap- by baseline blood pressure levels (Figure 59.2) (17). Blood
amide compared to single-drug therapy with perindopril pressure lowering with combination therapy of perindo-
(12/5 mmHg vs. 5/3 mmHg) (13). pril plus indapamide produced similar risk reductions in
Several randomised controlled trials completed after each of subgroups defined by baseline systolic blood pres-
PROGRESS have reported the effects of blood pressure low- sure of less than 120, 120−139, 140−159 and 160 mmHg
ering on recurrent stroke. The Felodipine Event Reduction or greater (p homogeneity = 0.5) and those defined by
(FEVER) study has also demonstrated a trend towards baseline diastolic blood pressure of less than 80, 80−89,
reduction in recurrent stroke in a subset of 2368 patients 90−99 and 100 mmHg or greater (p homogeneity = 0.2).
with a history of stroke or TIA (relative risk reduction 18% The effects of single-drug therapy with perindopril alone
[95% CI −12 to 40%]), associated with a modest reduc- were also comparable across these subgroups (p homoge-
tion in blood pressure (4.0/1.8 mmHg), obtained with neity = 0.2 and 0.8 for systolic and diastolic blood pres-
a calcium channel blocker (CCB) felodipine (15). While sure, respectively), but consistently greater benefits were
many trials completed after PROGRESS have broadly con- observed with combination compared to single-drug
firmed our findings, the results of the Prevention Regimen therapy. It is clear that blood pressure-lowering treatment
For Effectively Avoiding Second Strokes (PRoFESS) study should be considered routinely for patients with a history
(16), which was published in 2008, were less positive. of stroke or TIA, irrespective of their blood pressure.
The PRoFESS trial investigated the effects of an angio- With regard to optimal target blood pressure, large-scale
tensin receptor blocker (ARB) telmisartan in addition to observational studies have demonstrated clear associa-
standard care for secondary prevention of stroke among tions between blood pressure and initial stroke (18,19). A
20,322 patients with recent ischaemic stroke. Active treat- systematic review of observational studies performed by
ment lowered blood pressure by 4/2 mmHg and reduced the Prospective Studies Collaboration demonstrated that
the risk of recurrent stroke by 5% (95% CI −4 to 14%). lower blood pressure levels are continuously associated
Although telmisartan did not confirm significant ben- with lower risks of fatal stroke down to very low blood pres-
efit, factors that might have contributed to the negative sure levels (as low as 115/75 mmHg) (18). A continuous
outcome include the small difference in blood pressure relationship of blood pressure with the outcome ‘fatal and
between randomised groups, a large number of patients non-fatal stroke’ was also observed down to levels as low as
with a history of large artery infarction (30%), and the 115/75 mmHg in a systematic review performed by the Asia
frequent use of ACE inhibitors (37%), that had already Pacific Cohort Studies Collaboration (19). More limited evi-
achieved a moderate degree of blood pressure control at dence from studies in patients with a history of cerebrovas-
baseline (144/84 mmHg). The Secondary Prevention of cular disease has also suggested that lower blood pressure
Small Subcortical Strokes (SPS3) trial was the first trial to levels are associated with lower risks of stroke recurrence. A
investigate the effects of intensive blood pressure lowering large-scale observational study demonstrated that the rela-
with target systolic blood pressure levels of <130 mmHg tionship between blood pressure levels and recurrent stroke
among 3020 patients with symptomatic lacunar infarction. was strong and continuous down to levels of 130/80 mmHg
After 1 year, mean systolic blood pressure was 11 mmHg (20). In addition, an observational analysis of PROGRESS
lower in the intensive blood pressure-lowering group than showed that the lowest risk of recurrent stroke was observed
in the control group. Non-significant rate reductions were amongst individuals who achieved a follow-up blood pres-
observed for the primary outcome of total recurrent stroke sure of approximately 115/75 mmHg (Figure 59.3) (17).
(hazard ratio [HR] 0.81, 95% CI 0.64−1.03), while the rate Similar relationships were observed for both ischaemic
of intracerebral haemorrhage was reduced significantly stroke and intracerebral haemorrhage (Figure 59.3) (17). In
(0.37, 0.15−0.95). Non-significant associations for total contrast, an observational analysis from PRoFESS demon-
stroke in SPS3 might be attributable to limited statistical strated slight increase in the risks of recurrent stroke among
power due to smaller number of events than expected (277 patients who achieved systolic blood pressure levels of less
vs. more than 500 events). than 120 mmHg (21), although the modest increase in very
Our updated meta-analysis of 23 randomised controlled low systolic blood pressure levels disappeared after exclu-
trials (17 active vs. control, 3 more vs. less intensive, and sion of patients within 6 months from stroke onset. These
3 ARB vs. CCB) including PROGRESS, FEVER, PRoFESS observational data suggest that, in chronic, stable phase
and SPS3 with a total of 49,195 patients demonstrates that after stroke, lower blood pressure levels are continuously
blood pressure-lowering treatment clearly reduced the risk associated with lower risks of recurrence, down to very low
of recurrent stroke (relative risk reduction [RRR] 22%, blood pressure levels (115 mmHg systolic).
95% CI 12−30%) (Figure 59.1). Thus, the totality of the There are also a few randomised controlled trials which
evidence, including the findings from PRoFESS and SPS3, investigated the benefits and harms of intensive blood pressure
confirms that blood pressure-lowering treatment reduces lowering towards lower systolic blood pressure levels in sec-
the risk of stroke recurrence among patients with cerebro- ondary prevention of stroke. As described in the previous sec-
vascular disease. tion of this chapter, SPS3 trial demonstrated non-significant
Blood Pressure Management in the Chronic Post-Stroke Phase 489
Figure 59.1 Meta-analysis of 16 randomised controlled trials of blood pressure lowering for secondary prevention of
stroke. Solid boxes represent estimates of trials; areas of the boxes are proportional to the inverse variance of the estimates;
vertical lines represent 95% CI; diamonds represent estimates and 95% CI for overall effects. Overall estimates of effect and
95% CI were calculated using random-effects models and inverse variance weighting.
0.25 0.5 1 2
Hazard ratio (95% CI)
Figure 59.2 Effects of blood pressure lowering with combination therapy of perindopril plus indapamide on stroke by
baseline blood pressure. Solid boxes represent estimates of hazard ratio for stroke; areas of the boxes are proportional to the
inverse variance of the estimates; vertical lines represent 95% CI. (Adapted from previously published figures with permis-
sion from Wolters Kluwer Health.)
490 Manual of Hypertension of the European Society of Hypertension
0.16
4
Annual rate (%)
0.08
0.04
2
0.02
1 0.01
100 120 140 160 180 100 120 140 160 180
Systolic blood pressure (mmHg) Systolic blood pressure (mmHg)
Figure 59.3 Annual rates of ischaemic stroke and intracerebral haemorrhage according to achieved follow-up systolic
blood pressure levels. Annual incidence rates and P values were controlled for age, sex, smoking, diabetes, study treatment
and combination therapy. Solid boxes represent estimates of annual incidence rates of stroke. Centres of the boxes are placed
at the estimates of annual incidence rates and at median values of systolic blood pressure; areas of the boxes are proportional
to the number of events. Vertical lines represent 95% confidence intervals. p trend = 0.0005 for ischaemic stroke, <0.0001
for intracerebral haemorrhage. (Reproduced with permission from Wolters Kluwer Health.)
reduction in recurrent stroke (HR 0.81; 95% CI 0.64−1.03) patients with severe large artery occlusive diseases. Among
among patients who received intensive blood pressure lower- patients with severe occlusive disease of extracranial and
ing with target systolic blood pressure levels of <130 mmHg intracranial large arteries, cerebral perfusion may depend
among 3020 patients with symptomatic lacunar infarction. on blood pressure, and intensive blood pressure-lowering
The Prevention After Stroke—Blood Pressure (PAST-BP) treatment may lead to ischaemic stroke via hemodynamic
(22) and the pilot Prevention of Decline in Cognition after mechanisms. As patients with stenosis in large arteries are
Stroke Trial (PODCAST) (23) also investigated the effects of also likely to have atherosclerotic lesions in various large
intensive blood pressure lowering (target systolic blood pres- arteries including coronary, renal and peripheral arter-
sure level <130 mmHg for PAST-BP and <125 mmHg for ies, intensive blood pressure lowering may result in hypo-
PODCAST) in the setting of secondary prevention of stroke. perfusion and subsequent damage in various organs. An
However, there are limited number of recurrent stroke events observational study of the Warfarin-Aspirin Symptomatic
because of relatively small sample size and short follow-up Intracranial Disease (WASID) trial investigated the asso-
duration (PAST-BP: 529 patients for 1 year, PODCAST: 83 ciation between blood pressure and ischaemic stroke
patients for 2 years). When SPS3, PAST-BP and PODCAST are among 567 patients with cerebrovascular disease due to
pooled, there is marginally significant 18% reduction (95% angiographically verified 50–99% stenosis of a large artery
CI −2 to 35) in the risk of recurrent stroke associated with (26). Among patients with moderate large artery stenosis
intensive blood pressure lowering with target systolic blood (50–69%), systolic blood pressure was associated with
pressure <130 mmHg (P = 0.076) (Figure 59.1). Definitive increased risk of ischaemic stroke. Among patients with
evidence of intensive blood pressure lowering for prevention severe large artery stenosis (70–99%), in contrast, sys-
of stroke will be provided by ongoing trials such as Recurrent tolic blood pressure was not significantly associated with
Stroke Prevention Clinical Outcome Study (RESPECTS), the risk of ischaemic stroke. Furthermore, a meta-analy-
the Stroke in Hypertension Optimal Treatment Trial (ESH- sis of European Carotid Surgery Trial (ECST) and North
CHL-SHOT) and Triple Therapy Prevention of Recurrent American Symptomatic Carotid Endarterectomy Trial
Intracerebral Disease EveNts Trial (TRIDENT). Meanwhile, (NASCET) investigated the association of systolic blood
in keeping with the current international guidelines (24,25), pressure and stroke among patients with cerebrovascular
we would recommend that blood pressure should be lower to disease and severe, symptomatic stenosis (70% or more) in
less than 130/80 mmHg in patients with stroke or TIA. both carotid arteries and found that lower systolic blood
pressure was associated with increased risks of stroke (27).
These results suggest that intensive blood pressure lower-
ing may be harmful among patients with severe, symp-
PATIENTS WITH LARGE ARTERY tomatic stenosis in both sides of the cerebral circulation.
STENOSIS For patients at high risk of cardiovascular disease, it would
be useful to provide comprehensive screening of clini-
A contentious area of blood pressure-lowering treatment cal and subclinical atherosclerotic lesions in coronary,
in chronic post-stroke phase is the risks and benefits in renal, peripheral and other arteries as well as carotid and
Blood Pressure Management in the Chronic Post-Stroke Phase 491
intracranial arteries. If there is severe occlusive or stenotic would be ACE inhibitors plus thiazide-like diuretics,
large artery disease, treatment of the arterial lesions may which was shown to be effective in the PROGRESS trial
be taken into consideration before starting intensive blood (13). Combination of ACE inhibitor and CCB as confirmed
pressure-lowering treatment. by Anglo-Scandinavian Cardiac Outcomes Trial – Blood
Pressure-Lowering Arm (ASCOT-BPLA) (36) and Avoiding
Cardiovascular Events through Combination Therapy in
Patients Living with Systolic Hypertension (ACCOMPLISH)
DIFFERENT CLASSES OF BLOOD trial (37), ARB and CCB, ARB and diuretics, and CCB and
PRESSURE-LOWERING DRUGS AND diuretics are also recommended by guidelines for manage-
COMBINATION THERAPIES ment of hypertension (25).
antihypertensive treatment in patients having already suffered 26. Turan TN, Cotsonis G, Lynn MJ et al. Relationship between blood
from stroke: Gathering the evidence. Stroke 1997; 28: 2557–2562. pressure and stroke recurrence in patients with intracranial
13. PROGRESS Collaborative Group. Randomised trial of a a rterial stenosis. Circulation 2007; 115: 2969–2975.
perindopril-based blood pressure lowering regimen among 6,105 27. Rothwell PM, Howard SC, Spence JD For the Carotid
individuals with previous stroke or transient ischaemic attack. Endarterectomy Trialists’ Collaboration. Relationship between
Lancet 2001; 358: 1033–1041. blood pressure and stroke risk in patients with symptomatic
14. Arima H, Chalmers J. PROGRESS: Prevention of recurrent stroke. carotid occlusive disease. Stroke 2003; 34: 2583–2592.
J Clin Hypertens (Greenwich) 2011; 13: 693–702. 28. The Heart Outcomes Prevention Evaluation Study Investigators.
15. Liu L, Wang Z, Gong L et al. Blood pressure reduction for the Effects of an angiotensin-converting-enzyme inhibitor, ramipril,
secondary prevention of stroke: A Chinese trial and a systematic on cardiovascular events in high-risk patients. N Engl J Med 2000;
review of the literature. Hypertens Res 2009; 32: 1032–1040. 342: 145–153.
16. Yusuf S, Diener HC, Sacco RL et al. Telmisartan to prevent 29. Trenkwalder P, Elmfeldt D, Hofman A et al. The Study on
recurrent stroke and cardiovascular events. N Engl J Med 2008; COgnition and Prognosis in the Elderly (SCOPE)—major CV events
359: 1225–1237. and stroke in subgroups of patients. Blood Press 2005; 14: 31–37.
17. Arima H, Chalmers J, Woodward M et al. Lower target blood 30. Schrader J, Luders S, Kulschewski A et al. Morbidity and mortality
pressures are safe and effective for the prevention of recurrent after stroke, eprosartan compared with nitrendipine for second-
stroke: The PROGRESS trial. J Hypertens 2006; 24: 1201–1208. ary prevention: Principal results of a prospective randomised
18. Prospective Studies Collaboration. Age-specific relevance of usual controlled study (MOSES). Stroke 2005; 36: 1218–1226.
blood pressure to vascular mortality: A meta-analysis of indi- 31. Zanchetti A, Julius S, Kjeldsen S et al. Outcomes in subgroups of
vidual data for one million adults in 61 prospective studies. Lancet hypertensive patients treated with regimens based on valsartan
2002; 360: 1903–1913. and amlodipine: An analysis of findings from the VALUE trial.
19. Asia Pacific Cohort Studies Collaboration. Blood pressure and J Hypertens 2006; 24: 2163–2168.
c ardiovascular diseases in the Asia-Pacific region. J Hypertens 32. Ogihara T, Nakao K, Fukui T et al. The optimal target blood pres-
2003; 21: 707–716. sure for antihypertensive treatment in Japanese elderly patients
20. Rodgers A, MacMahon S, Gamble G et al. Blood pressure and with high-risk hypertension: a subanalysis of the Candesartan
risk of stroke in patients with cerebrovascular disease. BMJ 1996; Antihypertensive Survival Evaluation in Japan (CASE-J) trial.
313: 147. Hypertens Res 2008; 31: 1595–1601.
21. Ovbiagele B, Diener HC, Yusuf S et al. Level of systolic blood 33. Blood Pressure Lowering Treatment Trialists’ Collaboration.
pressure within the normal range and risk of recurrent stroke. Effects of different blood-pressure-lowering regimens on major
JAMA 2011; 306: 2137–2144. cardiovascular events: Results of prospectively-designed over-
22. Mant J, McManus RJ, Roalfe A et al. Different systolic blood views of randomised trials. Lancet 2003; 362: 1527–1535.
pressure targets for people with history of stroke or transient isch- 34. Law MR, Wald NJ. Use of blood pressure lowering drugs in
aemic attack: PAST-BP (Prevention After Stroke—Blood Pressure) the prevention of cardiovascular disease: meta-analysis of 147
randomised controlled trial. BMJ 2016; 352: i708. randomised trials in the context of expectations from prospective
23. Bath PM, Scutt P, Blackburn DJ et al. Intensive versus guideline epidemiological studies. BMJ 2009; 338: b1665.
blood pressure and lipid lowering in patients with previous 35. Chow CK, Teo KK, Rangarajan S et al. Prevalence, awareness,
stroke: Main results from the pilot ‘Prevention of Decline in treatment, and control of hypertension in rural and urban
Cognition after Stroke Trial’ (PODCAST) randomised controlled communities in high-, middle-, and low-income countries. JAMA
trial. PLOS ONE 2017; 12: e0164608 . 2013; 310: 959–b1968.
24. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ 36. Dahlöf B, Sever PS, Poulter NR et al. Prevention of cardiovascular
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for events with an antihypertensive regimen of amlodipine adding
the prevention, detection, evaluation, and management of high perindopril as required versus atenolol adding bendroflumethia-
blood pressure in adults: A report of the American College of zide as required, in the Anglo-Scandinavian Cardiac Outcomes
Cardiology/American Heart Association Task Force on Clinical Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre
Practice Guidelines. Hypertension 2017; 71(6): 1269–1324. randomised controlled trial. Lancet 2005; 366: 895–906.
25. Williams B, Mancia G, Spiering W et al. 2018 ESC/ESH Guidelines 37. Jamerson K, Weber MA, Bakris GL et al. Benazepril plus amlodip-
for themanagement of arterial hypertension. J Hypertens 2018; 36: ine or hydrochlorothiazide for hypertension in high-risk patients.
1953–2041. N Engl J Med 2008; 359: 2417–2428.
THE POST-TRANSPLANT PATIENT
WITH HYPERTENSION 60
120
40 50
110
100
20 25
90
0 0 80
Before After Before After Before After
Nephrectomy Nephrectomy Nephrectomy
Figure 60.1 Muscle sympathetic nerve activity (MSNA), calf vascular resistance (CVR) and mean arterial pressure (MAP) in
six renal transplant recipients before and after native kidney nephrectomy. Horizontal bars indicate mean values. (Adapted
from Hausberg M et al. Circulation 2002; 106: 1974–1979, with permission.)
are responsible for sustained sympathetic activation in 0.8% in recipients from living donors (39). Noninvasive
patients with end-stage renal disease and renal allograft techniques such as color-coded Duplex ultrasound or mag-
recipients (Figure 60.1) (38). netic resonance angiography allow to reliably establish the
Fifth, stenosis of the kidney graft artery causes hyper- diagnosis of kidney graft artery stenosis.
tension in 2–7% of renal transplant patients despite techni- Finally, rare causes of hypertension in kidney transplant
cal progress in surgical procedures such as the use of aortic patients, such as post-transplant erythrocytosis (40) due
patches and improved perfusion techniques before trans- to unregulated secretion of erythropoietin from the graft,
plantation (Figure 60.2). Major causes of graft artery ste- or genetic factors possibly linked to the graft (41), have to
nosis are immunologic factors related to rejection but also be considered.
infection (e.g. cytomegalovirus infection) and nonimmu-
nologic factors such as hyperlipidaemia (39). Pre-existent
atherosclerosis of the graft artery particularly in elderly
donors favours the development of hemodynamically rel- IMPACT OF HYPERTENSION IN KIDNEY
evant stenosis. The risk of developing graft artery stenosis TRANSPLANT RECIPIENTS
increases with cold ischaemia time. In a survey by Patel
et al., the prevalence of kidney graft artery stenosis was Hypertension is of prognostic relevance for both patient
4.1% in recipients from cadaveric donors, contrasting with and graft survival. Patients with end-stage renal disease
Figure 60.2 Transplant renal artery stenosis in one patient leading to graft failure and severe hypertension. Graft failure
resolved and hypertension improved after successful angioplasty with stenting.
496 Manual of Hypertension of the European Society of Hypertension
are characterized by a large burden of cardiovascular dis- a major if not the most important factor determining the
ease (42). Hypertension in these patients is particularly progression of renal failure. The same could be demon-
related to atherosclerotic disease with alterations of large strated in kidney transplantation in animal models and in
artery elastic wall properties and endothelial function. As humans. Kidney transplant recipients, particularly those
summarized by London and co-workers, increased large with already impaired graft function, often have an inad-
artery stiffness results in increased cardiac afterload, thus equate number of functionally intact nephrons (30). The
left ventricular hypertrophy, and at the same time reduced consequences are hyperfiltration with excessive glomeru-
diastolic perfusion—both leading to an increased risk of lar protein excretion and subsequent interstitial and glo-
coronary events (43). Structural alterations of large arter- merular inflammation, and finally scarring, which results
ies are paralleled by cardiac hypertrophy (25). Indeed, in a further reduction of the number of functional neph-
Blacher et al. could demonstrate that increased large artery rons. This vicious circle is accelerated by hypertension
stiffness is an independent predictor of cardiovascular and which increases glomerular filtration pressure and causes
overall mortality in patients with end-stage renal disease endothelial damage and therefore substantially contrib-
(44). These issues are not resolved by successful kidney utes to enhanced filtration of macromolecules across the
transplantation. McGregor and co-workers could show capillary barrier (47).
that echocardiographic abnormalities (i.e. left ventricular Opelz and co-workers (48) have published an impres-
hypertrophy) at the time of kidney transplantation predict sive analysis where systolic blood pressure 1 year after
survival of allograft recipients (45). Our group could show transplantation was strongly related to long-term graft
that left ventricular hypertrophy and structural altera- survival (Figure 60.3), even when corrected for patients
tions of large arteries persist after kidney transplantation dying with a functioning graft. Importantly, the relation
despite effectively treated hypertension (24). Moreover, was stronger for systolic than for diastolic or mean arterial
large artery stiffness measured during the first year after pressure. Since systolic blood pressure is better related to
transplantation is an independent factor predicting sub- functional and structural arterial damage than diastolic or
sequent cardiovascular morbidity in kidney transplant mean blood pressure (49), this suggests that arterial injury
patients (46). Cardiovascular mortality in kidney trans- predicts kidney graft survival. From the correlation anal-
plant patients is approximately four times higher than ysis, no definite conclusions can be made as to whether
observed in an age- and sex-matched general population, hypertension is a marker or a cause of arterial injury and
and hypertension could be identified as a major determi- graft loss in kidney transplant patients. However, several
nant of the excess mortality (42). observations suggest that hypertension is a cause of graft
Hypertension is related to endothelial cell injury, loss. First, the above-cited relationship between blood
although endothelial damage in kidney transplant patients pressure and graft survival was also observed in recipi-
is multifactorial (23). Endothelial injury may be a link ents of living related donors who had excellent human
between hypertension and progressive graft dysfunction leucocyte antigens (HLA) matching and no rejection epi-
after kidney transplantation. In patients with chronic renal sodes, thus who were unlikely to have lost their grafts due
disease of diabetic and nondiabetic origin, hypertension is to immunologic causes. Second, the outcome of vascular
90
% Grafts surviving
80
<120 n = 2173
70 120-129 n = 3424
130-139 n = 5243
140-149 n = 3627
60 150-159 n = 2336
160-169 n = 1007
170-179 n = 584
50 ≥180 n = 814
0
0 1 2 3 4 5 6 7 8
Years
Figure 60.3 Depicted is kidney graft survival as function of systolic blood pressure 1 year after transplantation. The
analysis included only those patients with graft survival of at least 1 year and no rejection episode during the first year after
transplantation. (Adapted from Opelz G et al. Kidney Int 1998; 53: 217–222, with permission.)
The Post-Transplant Patient with Hypertension 497
rejection episodes appears to be aggravated by hyperten- amlodipine to have a more pronounced antihypertensive
sion (50). Third, animal models allow separation of the effects than lisinopril in renal allograft recipients (62).
effects of immunologic factors and hypertension on graft Glomerular filtration rate increased with amlodipine,
damage and clearly identify hypertension as cause of kid- whereas it remained unchanged during lisinopril treat-
ney graft loss (51). From the available observations, we ment. In this crossover study, patients were treated for
suggest that target blood pressure for hypertensive kidney 2 months with each drug. In a similar crossover design,
transplant recipients (but also for other solid organ trans- Sennesael et al. compared perindopril and amlodipine in
plant recipients) should be less than 130/80 mmHg. This 10 renal allograft recipients and found no significant dif-
is supported by current KDIGO guidelines (52) and also ferences in blood pressure reduction or renal function (63).
from current guidelines on target blood pressure in hyper- Curtis et al. (64) and Abu-Romeh et al. (65) both showed
tensive patients with high cardiovascular risk (53,54)— a slight decrease in glomerular filtration rate with the ACE
present in the majority of solid organ t ransplant recipients. inhibitor but not with the calcium antagonist. However,
these two studies comprised only treatment periods of less
than 1 month. Grekas et al. showed that combination ther-
apy of a calcium antagonist with an ACE inhibitor in renal
ANTIHYPERTENSIVE THERAPY IN allograft recipients for 2 months results in superior blood
KIDNEY TRANSPLANT RECIPIENTS pressure control, reduction in proteinuria and no signifi-
cant change in glomerular filtration rate when compared
Early studies demonstrated the sodium-dependency of to antihypertensive therapy with a calcium antagonist
hypertension in kidney transplant recipients (11). This con- alone (66). Taken together, ACE inhibitors appear as effec-
cept has proven true to date. Diuretics are effective antihy- tive as calcium antagonists with regard to blood pressure
pertensive drugs after kidney transplantation, and they are reduction and preservation of graft function. The effects of
particularly useful in patients with impaired graft function the ACE inhibitor quinapril and those of the beta-blocker
(55). Beta-blockers have also been proven effective. atenolol on blood pressure and graft function were com-
In the 1990s, calcium channel blockers were recognized pared in cyclosporine-treated hypertensive kidney trans-
as very effective drugs for the treatment of hypertension in plant recipients (67). Quinapril and atenolol were equally
renal transplant patients. They combine vasodilating with effective in the treatment of post-transplant hypertension
natriuretic properties, lower blood pressure substantially in renal allograft recipients. Renal transplant function did
and counteract cyclosporine-induced hypoperfusion (56). not differ between patients treated with quinapril and with
Therefore, they can be expected to exert some nephropro- atenolol. In neither group could a significant deterioration
tective action after renal transplantation. Rahn et al. (57) of renal allograft function be observed at the end of the
evaluated the effects of the calcium antagonist nitrendip- 24 months’ treatment period. However, when compared
ine on graft function in renal transplant patients receiv- to the changes in the atenolol group, quinapril-treated
ing cyclosporine during an observation period of 2 years. renal allograft recipients showed a significant reduction of
Indeed, they observed a protective effect of nitrendipine proteinuria and urinary albumin excretion at the end of
on graft function which was independent of the blood the 24 months’ observation period (Figure 60.4).
pressure-lowering effect. From these studies, it appears that ACE inhibitors are
Initially, ACE inhibitors were only administered to a equally effective but apparently not better than other
relatively small proportion of renal transplant patients and classes of antihypertensive drugs such as calcium channel
used with great caution. Indeed, several reports exist on blockers or beta-blockers with regard to the preservation
acute renal failure in renal transplant recipients after admin- of allograft function in hypertensive kidney transplant
istration of ACE inhibitors. In some cases, this was attribut- patients. However, a major limitation of all these stud-
able to renal artery stenosis of the graft (58). Ahmad et al. ies is a relatively short observation period. ACE inhibitors
observed serious impairment of graft function induced by but not the other antihypertensive drugs unequivocally
captopril in renal transplant patients receiving cyclospo- showed a reduction in proteinuria. Therefore, it is con-
rine even in the absence of renal artery stenosis (59). Also, ceivable that after a longer observation period beneficial
Murray et al. observed enalapril-associated acute graft effects of ACE inhibitors—and possibly angiotensin recep-
failure in cyclosporine-treated kidney transplant recipi- tor blockers—as compared to other classes of antihyper-
ents (60). This phenomenon could be explained by addi- tensive drugs may appear with respect to graft function.
tive adverse effects of cyclosporine and ACE inhibitors on In favour of this argues the following: First, a progressive
glomerular hemodynamics with a subsequent s ubstantial decline in graft function was found to correlate with the
decrease in glomerular filtration pressure. amount of protein excreted in the urine (31,33). Hohage
However, several recent trials could prove the effectiveness et al. observed a negative influence of even mild protein-
and safety of ACE inhibitors after kidney transplantation. uria (less than 1 g per day, Figure 60.5) on long-term graft
Several studies compared the effects of calcium chan- survival in renal transplant patients (68). Second, Barnas
nel blockers with those of ACE inhibitors in renal trans- et al. observed a beneficial effect of the ACE inhibitor lisin-
plant patients. Mourad et al. (61), van der Schaaf et al. (62), opril on graft function in those renal transplant patients
Sennesael et al. (63), Curtis et al. (64) and Abu-Romeh with chronic allograft dysfunction in whom proteinuria
et al. (65) compared the effects of an ACE inhibitor with decreased after initiation of ACE inhibitor treatment (69).
those of a calcium antagonist in cyclosporine-treated renal Third, in many large studies on the effects of ACE inhibi-
transplant patients. None of these studies showed adverse tors on the progression of chronic renal disease, reduction
effects for the ACE inhibitors. Mourad et al. showed after of proteinuria precedes and consistently correlates with
a treatment period of 30 months a similar degree of the nephroprotective effect (70,71). Reduction of protein-
renal protection and reduction of arterial pressure with uria was observed early, a significant benefit of ACE inhibi-
lisinopril and nifedipine (61). Van der Schaaf et al. found tors on the course of renal function that often appeared
498 Manual of Hypertension of the European Society of Hypertension
0 100
(mg/day)
80
p < 0.05
–500
70
100
60
∆ Urinary albumin
50
(mg/day)
50
0 1 2 3 4 5
0
Years after transplantation
–40
0 12 24
is generally severe, especially when calcineurin inhibi-
Time (months)
tors are used. Combination of multiple antihypertensive
drugs is required for adequate blood pressure control, for
Figure 60.4 Changes in urinary total protein, albumin
e xample, c ombination of a diuretic, a calcium antagonist
and 1-microglobulin excretion in hypertensive renal and an ACE inhibitor or beta-blocker.
transplant patients treated with quinapril or atenolol. Studies investigating calcineurin inhibitor withdrawal
*p < 0.05 for trend, group × time interaction. (Data from after kidney transplantation are under way. Some reports
Hausberg M et al. Hypertension 1999; 33: 862–868.) clearly demonstrate a pronounced decrease in blood pres-
sure after discontinuation of calcineurin inhibitors (76,77).
However, calcineurin inhibitor withdrawal may also nega-
only after 2 years of treatment. This is consistent with the tively affect graft survival since associated with a higher
idea that excessive glomerular protein filtration leads to rate of late chronic antibody-mediated rejection (78,79).
increased reabsorption in the proximal tubulus with sub-
sequent perinuclear organelle overload and upregulation
of vasoactive and inflammatory genes. These processes
contribute to tubulo-interstitial injury and scarring (72). CONCLUSIONS
Genetic variants of the renin−angiotensin system in renal
transplant recipients may contribute to the rate of progres- Hypertension is common in solid organ transplant recipi-
sion of chronic graft nephropathy (73). ents, especially with the use of modern immunosuppres-
Fourth, two retrospective studies suggest a beneficial sive drugs such as cyclosporine. In kidney transplant
effect of ACE-inhibitors and angiotensin receptor blockers recipients, hypertension is of major prognostic relevance
on graft survival in renal transplant recipients. Heinze and for graft survival but also for the incidence of cardiovas-
co-workers observed a 10-year graft survival rate of 59% in cular events. Also, in nonrenal solid organ transplant
ACEI/ARB users versus 41% in nonusers (p < 0.001) (74). recipients, hypertension emerges as a significant prognos-
However, functional graft survival (adjusted for death with tic factor. Effective antihypertensive therapy is mandatory,
functioning graft) did not differ between groups in that and is possible by combinations of different classes of
study. We observed significantly increased functional graft a ntihypertensive drugs.
survival in renal transplant patients receiving long-term
treatment (>2 years) with ACE-inhibitors or angiotensin
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Nephron 1997; 75: 160–165.
Section IX
Secondary Hypertension:
Diagnosis and Treatment
RENOVASCULAR HYPERTENSION
61
Figure 61.1 Examples of atherosclerotic renal artery stenosis (left) and fibromuscular dysplasia (right).
in patients with renal FMD. However, it remains possible inflatable cuff around the vessel. Initially, when the pres-
that a patient has essential hypertension with FMD being sure distal to the stenosis is still within the autoregulatory
an ‘innocent’ bystander. Assuming that patients with ‘true’ range, intrarenal vasodilation will ensure that renal blood
RVH are those in whom BP is normalized after correction flow is maintained and as long as intraglomerular pressure
of RAS, it was already clear from early studies that the remains sufficiently high to guarantee an adequate glo-
prevalence of RVH was rather low in patients with ARAS, merular filtration rate (GFR), the kidney may still function
varying from 6−19% (12–14). Technical improvements in properly. Nevertheless, due to the intrarenal vasodilation
angioplasty did not appreciably change these figures, since the pressure distal to the stenosis will fall further so that
in a very recent study the rate of hypertension cure in a the transstenotic pressure gradient will increase. This cre-
cohort of 126 patients (77.2% with ARAS) was 11.1% and ates, as it were, a tighter stenosis, and because less of the
7.9% at 12 months after revascularization when assessed systemic pressure is now transmitted to the glomeruli, GFR
by office and home BP (15). In contrast with ARAS the rate may be jeopardized. However, the lower pressure at the
of BP normalization after RAS correction is 30–50% in level of the juxtaglomerular apparatus will also stimulate
patients with renal FMD (16). the RAS which in turn raises postglomerular resistance,
Finally, we must acknowledge that the presence of a RAS thereby maintaining glomerular filtration. Angiotensin
does not always lead to hypertension. Indeed, in the early II also acts on other (dilated) vessels to raise renal vas-
days unselected autopsy studies already failed to show a cular resistance to the extent that distal renal artery pres-
relationship between accidentally found RAS and hyper- sure is restored as much as possible so that the stenosis
tension in a substantial number of cases (17,18). More effect is attenuated (26,27). The restoration of poststenotic
recently, an autopsy study reported several renal artery pressure and/or renal vascular resistance then shuts off
lesions which were apparently not suspected on clinical further renin stimulation (27). It follows that the func-
grounds and which were not associated with hypertension tional impact of a renal artery stenosis, or for that mat-
during life. In a general population older than 65 years ter the hemodynamic significance of it, largely depends
and without renal disease, a prevalence of 6.8% was noted on the resistance to flow in the distal renal vasculature.
(19). Lastly, there are also clinical studies showing inciden- The competition between the autoregulatory mechanisms
tal RAS in normotensive patients (20,21). favouring vasodilation and the vasoconstrictor action of
The opposite is also true in that there are more complica- angiotensin II appears to be most conspicuous with rela-
tions of hypertension in patients with than in patients with- tively mild degrees of stenosis that are not confounded by
out RAS. Indeed, in the study by Kalra et al. among patients significant changes is systemic pressure.
who were found to have ARAS, there was a threefold increase More severe forms of stenosis will produce a longer-
in new-onset cardiovascular events with respect to the gen- lasting stimulation of the RAS and hypertension. To pre-
eral population (6). In a cross-sectional study comparing serve GFR as much as possible, efferent vascular resistance
patients with and without ARAS, the same authors found will also be enhanced. Consequently, hydrostatic pressure
that only 5.1% of those with ARAS had normal cardiac in the peritubular capillaries falls, which promotes sodium
structure and function and a significantly greater cardio- reabsorption. In addition, the activation of the renin sys-
vascular morbidity (22). In addition, in patients with renal tem will lead to secondary stimulation of aldosterone.
FMD the prevalence of atherosclerotic plaques in carotid The latter contributes to enhanced retention of sodium of
arteries was greater than in controls matched for BP level water by the stenotic kidney and to the loss of potassium.
and hypertension duration (23). Therefore, the relationship If sufficient volume expansion ensues, this reduces renin
between RAS and hypertension remains enigmatic, and again, so that eventually a complex interplay between
perhaps the idea should be entertained that RAS may exert hemodynamic and volume factors keeps the pressure at a
detrimental cardiovascular effects also via mechanisms not high level. When the stenosis becomes so tight that even
related to BP elevation (24). a substantial rise in systemic pressure cannot overcome
the resistance, the kidney will face progressive ischaemia
with loss of tissue and severe functional impairment. At
the later stages of (experimental) renal artery stenosis, the
PATHOPHYSIOLOGICAL renin system has no major role anymore in the elevation
CONSIDERATIONS of BP and is hypertension-sustained by other, less well-
understood mechanisms such as enhanced sympathetic
Basic concepts in the pathophysiology of RAS take a reduc- activity and vascular hypertrophy. Only when the hyper-
tion in renal blood flow as the starting point. Since blood tension evolves into the malignant phase does BP again
flow to any tissue depends heavily on perfusion pressure, become renin-dependent.
such as the pressure gradient across the organ, one would It should be emphasized that the pathophysiology as
assume that, at least in theory, renal blood flow will not be outlined above has been derived from experimental sit-
affected until the stenosis is so tight that perfusion pres- uations which are only a remote reflection of what hap-
sure has become too low. Early observations in experi- pens in humans. Aside from rare acute occlusions of the
mental animals suggested that the renal arterial luminal renal artery, in man ARAS is a progressive disorder which
diameter must be reduced by at least 70–80% before mea- slowly evolves over time (28), and the same is true for FMD
surable reductions in perfusion pressure and blood flow (29). This allows the kidney enough time to completely
develop (25). However, what happens to a kidney with a adapt to alterations in flow. Moreover, a wide spectrum of
stenotic artery depends not only on the degree of the ste- renovascular abnormalities is possible, ranging from mild
nosis, but also on how acutely this develops, and on the unilateral disease to severe bilateral stenosis. Even when
autoregulatory potential of the organ. Most of our knowl- there is stenosis on only one side, if and how hyperten-
edge on the sequence of events comes from animal experi- sion develops depends on the function of the contralateral
ments in which RAS was produced by placing a clip or an kidney. When this contralateral kidney is still fully intact,
506 Manual of Hypertension of the European Society of Hypertension
it may get rid of the excess volume retained by the other imaging (40) and results of studies carried out in patients
kidney, and it may suppress its own renin release. It is pos- with ARAS before and after revascularization using this
sible, therefore, that under those conditions BP will rise technique confirm the relationship between the degree of
only mildly or not at all. However, once this kidney gets renal hypoxia and the markers of inflammation released
damaged by an elevated BP itself, it will no longer be able from the stenotic and contralateral kidney (41).
to compensate for the disturbed function of the stenotic
kidney. The hypertension, which was initially primar-
ily renin-dependent, now becomes increasingly volume-
dependent. Such a volume dependency also dominates CLINICAL ASPECTS
the clinical picture when both kidneys are supplied by a
stenotic artery. Atherosclerotic RAS and renal FMD differ with respect
Another point to consider is that in man, the kidney to patient characteristics and prognosis. Severe or recent-
responds differently to a stenosis caused by atheroscle- onset hypertension, abdominal bruit, male gender, flash
rotic lesions as compared to an FMD-related stenosis. The pulmonary oedema, hypercholesterolaemia, loss of renal
limited data available suggest that kidneys from patients function after treatment with an ACE inhibitor (ACEI)
with FMD are more like those of patients with essential or an angiotensin receptor antagonist (ARA), a history of
hypertension and not so much prone to reductions in flow tobacco use and atherosclerosis elsewhere in the body are
as atherosclerotic kidneys (30,31). This corresponds with clinical clues which may arouse the suspicion of ARAS.
clinical observations showing that severe renal impair- This diagnosis may also be suspected in elderly patients,
ment is common in atherosclerotic renovascular disease with hypertension and renal dysfunction as key symp-
but not so much in FMD (10). toms. However, one should be cautious to reject ARAS in
Because RAS takes a long time to develop, it is difficult a patient who does not meet any of the above-mentioned
to decide when it has reached hemodynamic significance. criteria. Clinical prediction rules, such as the one proposed
One report relating renin release to pressure gradients (42) and validated (43) by Krijnen et al., may assist the phy-
across the stenosis indicates that such gradients must sician in the selection of patients who need to be investi-
exceed 10–20 mmHg before renin release is activated gated further, but even then, the chance of a positive result
(32). However, in this study an acute graded stenosis was is not much greater than 30%. On the other hand, the odds
superimposed upon an existing stenosis. Moreover, renin of finding a lesion in the renal arteries markedly increases
responses may have been blunted by concurrent medica- in preselected patient groups (Table 61.1) and when several
tion. The impact of the stenosis per se remains, therefore, clinical signs coexist. For instance, the combination of age
enigmatic. above 60 years, diastolic BP greater than 110 mmHg and
In addition to the classical ‘hemodynamic’ understand- a serum potassium <3.3 mEq/L is associated with a nine-
ing of RVH pathophysiology, a number of recent studies, fold increase in the likelihood of finding an ARAS (44).
mostly in animals, point to hypoxia as the key player in Regardless of whether ARAS is found accidentally or after
causing progression of renal damage in the poststenotic a deliberate search, or whether it is associated with hyper-
kidney (33). Kidneys are highly oxygenated organs, and tension or not, the long-term prognosis of patients with
sufficient oxygenation for physiological functions can be this abnormality is not very favourable (6,21,45), although
preserved despite some reduction in blood flow in patients this may be related to a concurrent decline in renal func-
with ARAS (34). However, when critical hypoxia develops tion more than to the RAS per se (46). Although renal
as a result of long-lasting, severe RAS a number of proin- impairment is frequently seen in patients with ARAS, pro-
flammatory, prooxidant and profibrinogenic mechanisms gression to renal atrophy and renal failure occurs in ‘only’
are activated, leading to loss and remodelling of renal about 20% of cases (47) but it doubles when ARAS is more
microvasculature, tubulointerstitial fibrosis, renal scarring than 75% at the time of diagnosis (48).
and dysfunction (33). Among the many cytokines involved FMD is still considered to be a disease that affects
in these processes, the vascular endothelial growth fac- mainly young women, although this paradigm is subject
tor (VEGF) as well as the endothelial progenitor cells to debate, especially since we encounter an increasing
(EPC) seem to be the more relevant (35,36). From these number of older and male patients with FMD (49). Surely,
experimental studies, several findings emerge that can be if one looks for FMD only in young females, the asso-
translated to patients with RAS. First is that the kidney ciation becomes a self-fulfilling prophecy, which tends
contralateral to the stenotic one is affected by the similar to deny that older women who are first diagnosed with
humoral changes, supporting the notion that the ischaemic hypertension at a later age may have had the disorder all
kidney is the source of factors that can have detrimental of their lives. However, it is important to recall that there
effects on the systemic circulation. This interpretation is are remarkable clinical differences between patients with
in agreement with the observations that reversal of experi- multifocal and unifocal FMD. Indeed, the latter form is
mental RVH restores coronary microvascular function relatively more frequent in men, is diagnosed much earlier
and architecture (37) and that for the same level of BP, the (on average at 15–20 years before) and is associated with
alterations of the microcirculation in patients with RVH are more severe hypertension that responds better to revascu-
more severe than in those with essential hypertension (38). larization (16). Thus far, no clues have been identified that
Second, after restoration of renal blood flow, the regression are sensitive and specific enough to alert the physician to
of hypoxia-induced changes in renal microvessels is only the diagnosis of FMD, but an association that is increas-
partial, delayed and not dependent on BP. This finding goes ingly being recognized as important is that between FMD
along with the observation that in patients with ARAS the and pre-eclampsia (50). FMD and smoking were also found
recovery of GFR in the dilated kidney takes place progres- to be associated, but the mechanisms underlying this rela-
sively (39). Nowadays, renal tissue oxygenation is mea- tionship are unclear (51). As pointed out above, one may
surable with blood-oxygen level–dependent (BOLD) MR also suspect renal FMD to be present when FMD has been
Renovascular Hypertension 507
found in another vascular territory, for instance in the due to technical imperfections and/or poor quality of test
carotids (52). As for ARAS, the combination of quite spe- characteristics, it may simply be that the pathophysiologi-
cific clinical signs (abdominal bruit, early onset of severe cal concepts upon which the tests were based are wrong.
hypertension, renal asymmetry) are strongly suggestive of For instance, renography with or without ACE inhibition
severe renal FMD, and in our opinion, worth investigating has proven to be too unreliable for the diagnosis of (func-
directly with intra-arterial angiography. tional) renal artery stenosis even though the rationale of
the test seems sound. Rather than dismissing the test as
being inaccurate, we may have to conclude that the test
WHOM TO SCREEN AND HOW? result represents a mechanistic phenomenon that we do
not yet fully understand.
To screen patients for RAS, one can perform either a func- Intra-arterial digital subtraction angiography remains
tional or an anatomical (imaging) test. While the latter is the gold standard to confirm or exclude the diagnosis of
supposed to identify a culprit lesion, the former should RAS. In experienced centres, this procedure may be com-
detect a disturbance in physiological functions such as renal bined with determination of pressure gradients, intra-
blood flow or renin release. Unfortunately, so far no consen- vascular ultrasound and/or renal vein renin sampling.
sus has been reached on which test is preferable or in which Lateralization of renin may point towards a significant
sequence they should be applied. Although functional tests stenosis on the affected side and may predict a favourable
would be ideal from a theoretical point of view, they have response to dilation and/or stent placement. However, the
proven to be of limited value in the workup of patients in number of exceptions is simply too high to make this a
whom renal artery stenosis is suspected (53). Several years reliable test. In fact, the renal vein/renin ratio is more use-
ago, Radermacher and associates suggested that the intra- ful to detect patients with a totally occluded renal artery
renal resistance index, measured by duplex ultrasonogra- who will benefit from nephrectomy than for identifying
phy, could fairly accurately predict the response to renal patients in whom BP will fall after revascularization (60).
angioplasty or surgery (54) and thus provide information Today, measurements of pressure gradients across the ste-
about the hemodynamic significance of a stenosis. At least nosis at baseline and during dopamine-induced hyperae-
in patients with unilateral ARAS, there is a close correlation mia (61,62) are being advocated more and more as the best
between the resistance index and the translesional pressure method to ascertain whether a stenosis is hemodynami-
gradient (55). Also, other velocimetric indexes like accelera- cally significant or not, but evidence that this is the better
tion and acceleration time that are less influenced by such tool is still lacking.
confounding factors as age, intraparenchymal artery dis-
tensibility and renal function accurately detect ARAS and
FMD with greater than 50% luminal reduction and have TREATMENT
the additional advantage of reflecting the technical success
of revascularization procedures as well as the restenosis
of the dilated vessel (56,57). However, even though ultra- REVASCULARIZATION
sound represents the best available noninvasive procedure,
it has not gained widespread acceptance, perhaps because it Treatment options include surgery (reconstructive or
requires specific operator skills. bench), percutaneous transluminal renal angioplasty
Imaging techniques include CTA and MR angiography (PTRA) with or without stenting and medical therapy.
(MRA), both of which have reasonable sensitivity and There has been only one prospective study which com-
specificity, although with the limitation of a modest repro- pared reconstructive surgery to angioplasty in patients
ducibility (49). An obvious advantage of MRA is that no with unilateral ARAS (63). Despite better patency of the
contrast material is needed, but this technique tends to renal arteries after surgery, the outcome in terms of BP and
overestimate the degree of stenosis and may miss FMD. It renal function after 2 years was similar. Together with the
is safe but occasionally a patient turns out to be allergic improvement in PTRA and stent procedures, this has led to
to gadolinium. By and large, CTA seems to be a bit more a substantial decline in operative procedures for the treat-
reliable than MRA but adverse reactions to contrast mate- ment of atherosclerotic RAS. The question then is whether
rial may be a problem, particularly in elderly or diabetic PTRA is any better than conventional (medical) treatment.
patients or those with proteinuric CKD (58). Moreover, Unfortunately, this issue has not yet been settled. Four
CT-angiography better visualizes small calcifications, major prospective randomized trials have evaluated the
thereby providing a more accurate discrimination of FMD effect of PTRA with or without stenting on top of medi-
lesions versus atherosclerotic ones. Taken together, for cal treatment as compared to that of medical treatment
the time being CTA probably is the best widely available alone. These are DRASTIC (64), STAR (65), ASTRAL (66)
screening test for RAS, although duplex ultrasound may and CORAL (7). At first glance, none of these trials showed
be considered in specialized centres with extensive experi- any clear benefit of PTRA with or without stenting over and
ence with this modality. A promising alternative to have a above the effect conferred by medical treatment. Of course,
kind of ‘in vivo’ histology of artery lesions with an invasive despite great technical achievements, it is still possible that
investigation is to combine intravascular ultrasound with in some cases after an angioplasty intervention, procedure-
optical coherence tomography (OCT), a technique that related factors (e.g. undetected dissection) help to sustain
provides high-resolution cross-sectional images and per- renal ischaemia rather than ameliorating it, but this would
mits a comprehensive visualization of the inside of the ves- not be likely to explain the lack of effect in the whole trial.
sel with evaluation of RAS severity and morphology (59). On the other hand, the trials have been severely criti-
Why is it that imaging techniques provide better over- cized for a variety of methodological limitations, of which
all results than functional tests? Although we are inclined sample size and patient selection are the most important
to believe that the lack of accuracy of functional tests is (67,68). In 2016, an expert panel systematically reviewed all
508 Manual of Hypertension of the European Society of Hypertension
data concerning the comparative effectiveness and safety of in GFR in the contralateral kidney. In any case, treatment
PTRA plus stenting, surgical revascularization, and medi- with these drugs should be closely monitored, particularly
cal therapy to treat ARAS in regard to clinically important in the early phases, with serum creatinine and potassium
outcomes (69). The overall conclusion of this analysis was measurements, and treatment should be suspended when-
that the strength of the evidence is low so that there is no ever there is an increase in creatinine >20% above baseline
or only a minimal clinically important difference between values (77). The majority of these deteriorations in renal
these treatments with regard to outcome or BP control. In function are seen in patients with RAS in a single function-
other words, we do not know whether mechanical treat- ing kidney or in those with bilateral RAS, and represent a
ment of the stenosis is good or bad. Van der Niepen and strong indication to attempt revascularization.
co-workers also reviewed the evidence and concluded that There are several good reasons to use beta-adrenergic−
the trials fell short of including the right type of patients blocking compounds alone or in combination with ACEIs
(70). They appropriately stated that the results of the trials and ARAs to treat patients with RVH. One is that sympa-
argue against indiscriminately revascularizing all patients thetic overactivity is recognized in hypertensive patients
with ARAS. Nevertheless, there are probably subgroups of with ARAS (78). In addition, beta-blockers suppress the
patients who would benefit more than others from such neurally mediated component of renin release and, at vari-
treatment (69–71). The same reasoning applies also to the ance with ACEIs and ARAs, have neutral effects on renal
possibility of rescuing renal function. While in patients function (79). A recent retrospective study has shown that
with almost normal GFR, like those in the CORAL study beta-blockers reduce mortality in patients with renovas-
(on average 58 mL/mL), the expected benefits are small, in cular disease (80) as they do in the general CKD popu-
those with more advanced CKD (stage 4–5), the increase in lation (81). Calcium channel blockers are advantageous
GFR after restoration of renal blood flow may be substan- because of their vascular protective properties, but their
tial (72). In these patients, postponing revascularization use is limited by side effects and in the setting of incipient
to a later stage may abolish its beneficial effects because or overt heart failure. Diuretics are contraindicated in RVH
the ischaemia-induced intrarenal lesions have become irre- because they can exacerbate the hyperactivity of the RAS.
versible. Moreover, the revascularization has the additional However, loop diuretics may be needed in patients with
advantage of reducing the number of hospitalizations and bilateral RAS or in the late, volume-dependent stages of
improving heart failure control (73,74). For the time being, RVH and when kidney function is markedly deteriorated.
it is wise to select for angioplasty those patients with ARAS Aldosterone antagonists are very effective in resistant
in whom hypertension is resistant to treatment or who hypertension but must be used with caution if patients are
respond to a lowering of BP with a decline in renal kid- already on treatment with ACEIs or ARAs because of the
ney function, whereas revascularization is mandatory in risk of inducing a further fall in GFR and dangerous hyper-
patients with bilateral ARAS and flash pulmonary oedema. kalaemia. Preliminary evidence from uncontrolled studies
In patients with FMD, angioplasty is still the treatment suggests that also statins and antiplatelet drugs may have
of choice, although the effects are less clear-cut than once beneficial effects in patients with ARAS (82,83).
thought. As mentioned earlier, in a systematic analysis
of 47 angioplasty studies and 23 surgery studies in FMD
patients, Trinquart and co-workers concluded that the CONCLUSIONS
probability of being cured was approximately 30−50%
and inversely associated with age (16). Renal angioplasty After decades of intensive and painstaking research, the
can be particularly rewarding in children in whom an relationship between RAS and hypertension remains elu-
adequate control of BP is very difficult despite the use of sive. There are no clinical signs, biomarkers or imaging
several antihypertensive drugs (75). investigations to establish with certainty that RAS is the
cause of high BP. In young patients, and particularly in
many of those with unifocal FMD, the role of RAS is evident,
MEDICAL TREATMENT considering the high rate of hypertension cure seen after
revascularization. In most middle-aged or elderly patients
All patients with hypertension associated with RAS should ARAS seems to be superimposed on essential hypertension
be treated intensively with medical therapy. Unfortunately, and aggravates an already extensive atherosclerotic burden
there is no consensus on the optimal medical treatment. rather than being the aetiology of BP elevation. Thus, not
ACEIs, ARAs, calcium channel blockers and beta-blockers unexpectedly, in the majority of these patients the restora-
can all be used in the treatment of these patients. However, tion of renal blood flow results, at best, in some improve-
in several studies the antagonists of the RAS were found ment of BP control, whereas the outcome may be somewhat
to be superior to other classes of antihypertensive agents, better in rescuing renal function in patients with advanced
achieving BP goals in more than 80% of cases (47). renal insufficiency. Notwithstanding the importance of
Moreover, in observational studies treatment with ACE the recent large randomized clinical trials that addressed
inhibitors was associated with increased survival during the value of renal angioplasty versus medical treatment,
several years of follow-up (76). The drawback of ACEIs and the decision of whether to proceed to revascularization in
ARAs is that reducing angiotensin II formation or antago- individual patients with RAS cannot be taken according to
nizing its action prevents the most relevant compensatory their results with the logic ‘one treatment fits all’. Rather,
mechanism that maintains glomerular filtration pressure this decision rests on the responsibility of the clinician in
in poststenotic kidneys. Thus, in patients with unilateral charge and should be based on a number of factors that
RAS, treatment with ACEIs and ARBs may occasionally lead include age, type and severity of RAS, comorbidities, over-
to substantial decrements in single kidney function. When all cardiovascular risk profile, efficacy of and adherence
serum creatinine is measured, this loss of function may to medical therapy and, by no means equally important,
be underestimated because of the compensatory increase expectations and wishes of the patient.
Renovascular Hypertension 509
48. Tollefson DF, Ernst CB. Natural history of atherosclerotic renal stenosis. Dutch Renal Artery Stenosis Intervention Cooperative
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14(3): 327–331. 65. Bax L, Woittiez AJ, Kouwenberg HJ et al. Stent placement in
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puted tomographic angiography and magnetic resonance angiog- renal function: A randomized trial. Ann Intern Med 2009; 150(12):
raphy for diagnosing renal artery stenosis. Ann Intern Med 2004; 840–848, W150-1.
141(9): 674–682, discussion 82. 66. Wheatley K, Ives N, Gray R et al. Revascularization versus medi-
50. Vance CJ, Taylor RN, Craven TE et al. Increased prevalence of pre- cal therapy for renal-artery stenosis. N Engl J Med 2009; 361(20):
eclampsia among women undergoing procedural intervention for 1953–1962.
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1105–1110. revascularization for atherosclerotic renovascular disease. Curr
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PRIMARY ALDOSTERONISM
62
Case detection
(ARR above cutoff and/or logistic discriminat function score [LDFS] > 50%)
Yes No
Positive
PA likely
Yes No
Refer to third level center for subtyping by AVS Target medical treatment
Figure 62.1 Diagnostic workup of primary aldosteronism. The clinical pre-screening should allow identification of
patients with a high pre-test probability of primary aldosteronism in whom to perform the screening tests. The latter should
be highly sensitive in order not to miss cases; thus they carry a high false positive rate. The most used such screening test
is the ARR, which carries important quantitative information. In patients with a high ARR (for example, higher than 100
when measured from PAC [ng/dL] and PRA [ng/m/h]) and/or a LDFS >90%, we proceed directly to subtype differentiation
by adrenal vein sampling (see text). In those with an ARR at baseline (for example between 26 and 100 when measured from
PAC [ng/dL] and PRA [ng/m/h]) and/or a LDFS between 50−90%, we repeat the screening tests under carefully standard-
ized conditions and then proceed to subtyping if the ARR and/or the LDFS are confirmed to be raised. This approach is in
line with that suggested in the Endocrine Society Practice Guidelines, which, however, recommend a confirmatory test in
patients with equivocal ARR results. Abbreviations: ARR, aldosterone:renin ratio. LDFS, logistic discriminant function score;
AVS, adrenal vein sampling.
of only the latter variables, but also because they make use of words, if the ARR value (determined under standardized
the absolute value of these variables (49,50). Therefore, these conditions) is noticeably raised, a biochemical diagnosis
strategies have the additional advantage of providing an esti- of PA can be made and there is no need for further testing.
mate of the individual patient’s probability of developing PA, Therefore, one can proceed directly to referring the patient
which enables the clinician to decide, based on this prob- for subtyping following a simplified diagnostic algorithm
ability, whether to proceed with further testing. One such (Figure 62.1). This means a remarkable simplification of
function has been published and can easily be implemented the workup, which saves a good deal of time and money
for use in commercially available worksheets and adapted for the management (53).
for decision-making in clinical practice (50). It has also been In the largest study, where the diagnosis of APA was
implemented in an ARR app. In fact, one problem commonly used as the gold standard and the investigators used
encountered by physicians when dealing with the laboratory receiver operating characteristic (ROC) curves and the
report of renin and aldosterone entails the different meth- Youden index, the optimal cutoff which corresponded to a
ods and units used in the different laboratories. To overcome sensitivity of 80.5% and a specificity of 84.5% of the ARR
these difficulties, we have created an application, the ARR (calculated from PAC and PRA in ng/dL/ng/mL/h) was 26
app, which is described in detail elsewhere (51). (27), with lower cutoff values increasing sensitivity at the
Notwithstanding its many limitations, the ARR still expense of specificity. With use of an automated chemi
remains the most popular test because of its simplicity. luminescent assay that provides measurement of PAC and
Despite some pessimistic expectations, we found that DRC at the same time, the corresponding cutoff was 2.06
when repeated under carefully standardized conditions it (calculated from PAC in ng/dL and DRC in mUI/L), as
shows a considerable within-patient reproducibility (52). ascertained in a prospective study of a large cohort of PA
Moreover, it conveys quantitative information, which is patients (48). With this cutoff, the sensitivity for the iden-
commonly neglected when the ratio is interpreted in a tification of APA was 92%, the specificity 91.6%, and the
purely categorical way, e.g. as positive or negative. In other area under the ROC curve, an estimate of overall accuracy,
514 Manual of Hypertension of the European Society of Hypertension
The oral sodium loading test, the saline infusion test, the
captopril challenge test and the fludrocortisone with salt Na+ intake below median
loading test have been put forward as ‘confirmatory’ tests. 20.8%
100
In reality, what they actually serve for is to exclude false
positive results, because at the prevalence rate commonly
encountered at hypertension centres their negative predic-
tive (exclusion) value largely exceeds their positive predic- 75
tive (confirmatory) value (56,57).
The general purpose of these tests is to demonstrate that
the excess secretion of aldosterone is autonomous from the
(%)
50
renin–angiotensin system, but unfortunately this premise is
false inasmuch as in many patients with idiopathic hyper-
aldosteronism and also with APA, aldosterone secretion is 25
dependent on angiotensin, as shown in the aforementioned
PAPY study (Figure 62.2) (61). Relying on these tests can
thus lead to missing several patients with curable APA, who
show suppressible aldosterone excess after blunting the lev- 0
0 25 50 75 100
els of renin (62–65). According to a recent very large study,
Prevalence (%)
the diagnostic gain provided by one such test, the captopril
challenge, was negligible over an ARR performed in care- Na+ intake above median
fully standardized conditions (53). Thus, as mentioned ear- 17.2%
100
lier, once a markedly raised ARR, for example >100 (when
using PAC in ng/dL and PRA in ng/mL/h), has been found,
it is justified to proceed directly with AVS if the patient is
willing to pursue a surgical cure (52), an approach shown 75
in Figure 62.1 that is consistent with the suggestion of the
latest Endocrine Society guidelines to skip the confirmatory
tests in patients with a florid PA phenotype (41).
(%)
50
If one preferred to perform a ‘confirmatory’ test any-
way, it has to be considered that at a low sodium intake
the saline infusion test is more accurate than the captopril Pos. pred. value
25
test, which should therefore be used only after increasing Neg. pred. value
sodium intake to >6.3 g NaCl per day (65). Moreover, as SIT = Open symbols
mentioned earlier, both tests are more specific than sen- CAT = Closed symbols
sitive at their optimal cutoff values in referred patients 0
(Figure 62.3) (49,65). This feature means that these tests 0 25 50 75 100
are more useful to exclude, rather than confirm, the Prevalence (%)
Figure 62.3 The plot shows that for two of the so-called
90 ‘confirmatory’ tests, the saline infusion test (SIT) and the
captopril test (CAT) at the prevalence of PA rate commonly
seen at referral centres, the negative predictive value of
75
Plasma aldosterone (ng/dL)
15
6.75
6.91
0 presence of PA, and therefore they should be regarded as
PH APA IHA exclusion rather than as confirmatory tests (65). Finally,
(n=197) (n=47) (n=73) some experts contend that the fludrocortisone with salt
loading test would be the most specific exclusion test (55)
Figure 62.2 The plot shows the PAC values after saline in and should be a gold standard test, but this test has been
the patients with primary (essential) hypertension (PH), abandoned at most centres because it requires a costly hos-
APA (confirmed by the four corners criteria) and idio- pitalization for surveillance of the patient, owing to the
pathic aldosteronism (IHA) of the PAPY study. Please note risk of worsening hypertension and hypokalaemia.
the huge overlap of values both below and above the cut- Some clinicians prefer the measurement of urinary aldo-
off that makes this test unreliable in attributing patients to sterone because they hold it to provide an estimate of aldo-
one group or another. (Reproduced with permission from sterone production integrated over 24 hours. However, only
Rossi GP et al. J Hypertens 2007; 25: 1433–1442.) 15–20% of the aldosterone excreted in urine is 18-glucuro-
nide, which is the substance usually measured to assess the
516 Manual of Hypertension of the European Society of Hypertension
excretion of aldosterone in the urine. In fact, aldosterone the surgically documented side in 59%. Despite the over-
is mainly metabolized to tetra-hydro-aldosterone, which all poor accuracy of CT and MRI in detecting unilateral
implies that if the laboratory does not take proper precau- disease, adrenal imaging seemed to perform well in the
tions to measure all forms of aldosterone, only a small frac- patients younger than 35 years of age, but there were only
tion of aldosterone is being measured, particularly if the six patients with these features (72).
pH of urine is not kept close to 1. For these reasons, the A more recent German study reached similar con-
measurement of urinary aldosterone does not furnish an clusions concerning the poor performance of imaging.
accurate estimate of the true aldosterone secretion in all Despite AVS demonstration of lateralized disease, MRI
laboratories, which probably explains why in some centres and CT showed bilaterally normal adrenals in 17% and
urinary aldosterone was not found to discriminate between 9% of the cases, respectively (10). Unilateral enlargement
patients with and without PA as well as expected. of the non-hypersecreting adrenal gland was seen in 3%
and 12% of the patients, respectively. In addition, bilateral
pathology was seen in 17% and 22% of the patients with
lateralized PA. Therefore, quite reasonably the authors
IMAGING OF PRIMARY concluded that: (i) the assessment of adrenal microadeno-
ALDOSTERONISM mas is the main limitation of adrenal CT, (ii) both CT and
MR imaging have a poor accuracy in predicting unilateral
According to guidelines, all PA patients should undergo an disease, and therefore (iii) AVS remains the essential diag-
imaging test, preferably by CT, for two main reasons: (i) to nostic step to identify patients who may benefit given uni-
exclude carcinoma, which are usually large and display lateral laparoscopic adrenalectomy.
Hounsfield units >15, and (ii) to identify adrenal venous
drainage, thus offering some guide to the interventionist per-
forming AVS (67,68). Compelling evidence, however, exists
that imaging alone is insufficient to refer the patient to sur- SUBTYPE DIFFERENTIATION BY AVS
gery: in 2004, a Mayo Clinic study examining the diagnos-
tic accuracy of a CT-based strategy for the subtyping of PA, Given the fallacies of the imaging tests, AVS remains
using cosyntropin-stimulated AVS as a reference test, found the key technique for diagnosing unilateral production
concordant results between tests in only 53.1% of the cases, of aldosterone (41,68), but it is expensive, technically
unilateral disease at AVS in 22.2% CT-negative cases, and uni- demanding, and carries a very small, but not negligible,
lateral mass at CT with bilateral or contralateral disease at AVS risk of adrenal vein rupture (69,73). As an indication for
in 24.7% of the cases (69). Relying on CT alone would there- adrenalectomy, AVS should only be used in patients with
fore have led to denial of curative adrenalectomy to 22% of unequivocal biochemical evidence of PA in whom the sur-
the patients and to unnecessary or inappropriate adrenalec- gically incurable forms of mineralocorticoid excess have
tomy in 24%. These findings led the authors to conclude that been excluded (Figure 62.4) (74). Furthermore, patients
AVS is essential to distinguish between unilateral and bilateral selected to undergo AVS must be candidates for general
PA. Common experience, anecdotal reports (8), and count- anaesthesia and surgery, and must be willing to achieve
less further studies support this conclusion. In 2009, Kempers long-term cure of PA with adrenalectomy.
et al. retrospectively analysed 38 studies comprising a total of The Endocrine Society guidelines state that AVS is the
950 patients with the aim of determining the diagnostic accu- ‘standard test to differentiate unilateral from bilateral
racy of imaging for the subtyping of PA (70). A major limita- causes of [PA]’ (41). Accordingly, as we consider unethi-
tion of this study was the lack of follow-up data in the articles cal undertaking of surgery without evidence of lateralized
that could be examined, which rendered it impossible to aldosterone secretion, at my institution we offer AVS to all
confirm that adrenalectomies were performed appropriately. patients before adrenalectomy. By contrast, some centres
Importantly, 38% of the patients showed discordant results advocate a discriminating use of AVS and contend that this
between AVS and CT/MRI. If only CT/MRI had been used to test might not be needed in patients <35 years old with soli-
determine lateralization, inappropriate adrenalectomy would tary unilateral apparent adenoma on CT scan (75), based
have occurred in 15% of the patients where AVS showed a on the premise that the prevalence of non-functioning ade-
bilateral cause. Furthermore, inappropriate exclusion from noma (incidentaloma) increases with age, and therefore an
adrenalectomy would have occurred in 19% where AVS adrenal mass in a patient <35 years old with PA ‘must be
showed unilateral secretion, and adrenalectomy on the wrong an APA’. The logical ground of this reasoning is, however,
side would have occurred in 4%. The authors concluded that weak because the hyperaldosteronism and incidentaloma
CT/MRI misdiagnosed the cause of PA in 38% of the patients, are independent conditions, which means that one does
and that relying only on CT/MRI can lead to inappropriate not exclude the other, and vice-versa. Moreover, the rarity
treatment of many patients with PA.. of incidentaloma before age 40 years does not mean that an
A larger 19-year single-centre experience in patients adrenal node in a patient with PA is automatically an APA,
who underwent unilateral adrenalectomy for the treat- as PA can be attributable to micronodular bilateral adrenal
ment of PA supports similar conclusions, with the caveat hyperplasia or to a small APA that is invisible on CT scan
that long-term postoperative follow-up was obtained only and is contralateral to the identified node.
in 54% of the 263 patients (71). In the patients submitted Moreover, familial hyperaldosteronism type I, II, III and
to adrenalectomy for presumptive unilateral disease, the IV, which cause bilateral adrenocortical hyperplasia due
overall effective cure rate of PA was 96%. In the biochemi- to germ-line mutations (76,77), are best treated medically
cally cured PA patients, hypertension was cured in 42% as they are not surgically curable. Thus, whenever there
and improved 46%; moreover, PA was not cured with uni- is a family history of PA, use long PCR or sequencing to
lateral adrenalectomy only in 4% of the patients. AVS was exclude the presence of such familial forms before offering
97% accurate, while adrenal imaging was concordant to AVS to the patients.
Primary Aldosteronism 517
Yes No
Adrenalectomy is indicated anyhow
and/or AVS not
Adrenalectomy is contraindicated indicated
and/or
The patient refuses AVS and agrees to take a 25%-50%
chance of having the wrong adrenal removed
and/or
The patient has familial hyperaldosteronism type 1-4
No
Yes
The patient accepts a
No AVS not
chance of unsuccessful AVS
and a 0.5% risk of complications indicated
Yes
Perform AVS
Figure 62.4 Flow chart for selecting the patients with primary aldosteronism to be submitted to adrenal vein sampling.
As considerable experience is required for the perfor- The measurement of PCC, besides that of PAC, in adrenal
mance and interpretation of AVS, this test should only vein blood is used for calculation of the selectivity index
be done in tertiary referral centres. An in-depth discus- (74), which helps in confirming catheter placement and cor-
sion of the issues surrounding the use of AVS is provided recting for dilution during sampling (85). This measurement
elsewhere (74,78), and only the key information is given is also crucial for calculating the lateralization index (78),
herein to enable practicing physicians to prepare their for example, the PAC:PCC ratio on the dominant side over
patients for AVS and to select appropriate referral centres the PAC:PCC ratio on the contralateral side of the adrenal
for their patients with PA. gland, which usually provides an accurate diagnosis (74).
First, to minimize the chance of false results, AVS should Cosyntropin stimulation facilitates the ascertainment
be undertaken after the withdrawal, if feasible, of all con- of selectivity but has a confounding effect on the lateral-
founding drugs or after tapering treatment that reduces ization index (86), which means that the value of aldoste-
the levels of aldosterone as indicated for the screening test rone levels after ACTH stimulation can lead to the removal
(Table 62.4). Second, hypokalaemia, if present, should be of the wrong adrenal gland. Therefore, this stimulation
corrected, or after tapering treatment, before AVS, as hypo- should be used only at centres with a low success rate in
kalaemia reduces aldosterone secretion and therefore can achieving selective cannulation (87). For a discussion of
minimize lateralization, thus increasing the chances of the pros and cons of using cosyntropin the readers are
false negative results. Third, use of bilaterally simultaneous referred to a recent debate (88).
catheterization during AVS (79,80) avoids generating arti- Assessment of the results of AVS as a lateralization index
ficial differences between the adrenal glands owing to the ignores a finding that is widely recognized but seldom
different timing of the blood sampling during AVS, which reported and discussed. The secretion of hormones from
is a stressful situation (79). Bilaterally simultaneous cath- the contralateral adrenal gland is rarely suppressed to lev-
eterization is essential particularly when AVS is performed els similar to peripheral values and is most often higher
without adrenocorticotropic hormone (ACTH) stimula- than the peripheral values. Moreover, experimental studies
tion. Fourth, a major source of variation in the interpreta- have shown that aldosterone secretion persists even during
tion of AVS results is the difficulty of catheterizing the right prominent sodium loading and studies using in situ hybrid-
adrenal vein, which is short and sometimes shares a com- ization and immunohistochemistry have shown persistent
mon egress with inferior accessory hepatic veins. In the aldosterone synthesis in the adrenal cortex surrounding an
letter condition, mixing of adrenal blood with liver blood APA (89,90). Notwithstanding these limitations, some have
dilutes the plasma cortisol concentration (PCC) and PAC proposed a contralateral suppression index (calculated as a
(81), and thus AVS can show levels of cortisol and aldoste- PAC:PCC ratio in the contralateral [nondominant] adrenal
rone that are even lower than peripheral values owing to gland lower than the PAC:PCC ratio in the peripheral vein
liver metabolism of the steroids. Superselective catheter- or the infrarenal inferior vena cava) (91), but the accuracy
ization of the right adrenal vein after identification of the of this index for the identification of unilateral causes of PA
hepatic vein by CT (74,82), or after rapid measurement of remains to be conclusively proven to data (74).
cortisol levels in the adrenal vein during AVS (83,84), can Hence, to address the several issues that remain contro-
circumvent this problem. versial and/or unresolved in the interpretation of results
518 Manual of Hypertension of the European Society of Hypertension
Factor PAC Renin ARR False positive rate False negative rate
Medications
β-blockers ↓ ↓↓ ↑ ↑↑ ↓
NSAIDs ↓ ↓↓ ↑ ↑ ↓
K+-losing diuretics ↑ ↑↑ ↓ ↓ ↑
K+-sparing diuretics ↑ ↑↑ ↓ ↓ ↑
Potassium status
Hypokalaemia ↓ →↑ ↓ ↓ ↑
Potassium loading ↑ →↑ ↑ ↑ ↓
Sodium status
Sodium depletion ↑ ↑↑ ↓ ↓ ↑
Sodium loading ↓ ↓↓ ↑ ↑ ↓
Ageing ↓ ↓↓ ↑ ↑
Other conditions
Renal impairment → ↓ ↑ ↑ ↓
Pregnancy ↑ ↑↑ ↓ ↓ ↓
Renovascular ↑ ↑↑ ↓ ↓ ↑
Malignant ↑ ↑↑ ↓ ↓ ↑
Note: β-blockers reduce levels of renin but affect PAC relatively less, thus raising the ARR (47); therefore it is better to stop administering them at least 3–4 weeks
before the assay, as failure to do so increases the false positive rate. Drugs that raise the PRA more than PAC, such as diuretics and mineralocorticoid receptor
antagonists, should be withdrawn (at least 3–4 and 6 weeks before, respectively) to reduce the rate of false negative diagnoses. Angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers and renin inhibitors raise renin and reduce aldosterone secretion. Therefore, they reduce the ARR and markedly increase
the false negative rate. Because of this, they also should be withdrawn at least 3–4 weeks before performing the ARR.
a Renin inhibitors lower PRA but raise DRC. This effect would be expected to increase false positives when renin is measured as PRA, and false negatives for renin
measured as DRC.
Abbreviations: ARR, aldosterone: renin ratio; DRC, direct active renin; PAC, plasma aldosterone concentration; PRA, plasma renin activity.
from AVS, the Adrenal Vein sampling International Study of antihypertensive medication needed for obtaining the
has gathered on >2500 AVS studies carried out at centres target blood pressure (in DDD), and the median (RAND-
scattered across Europe, Asia and North America. This 36) physical or mental scores did not differ significantly
study has shown that AVS is being offered not to all but between the groups exposed to the two diagnostic strate-
only to a variable proportion of PA patients, even though gies. This led the authors to conclude that the increased
the rate of major complications is extremely low (0.57%), healthcare costs related to AVS were not justified by
thus dispelling the idea that AVS is dangerous (91). improvements in the quality of life, a claim that was not
A challenge to the overwhelming evidence and the new, as similar statements were made before by at least two
current guidelines recommendation to perform AVS in retrospective observational studies (93,94), Unfortunately,
all patients with PA came by results of a recent prospec- this trial has so many limitations that its conclusions are
tive, randomized, controlled study of 184 patients, who hardly acceptable. The most important of these limitations
received either an AVS-based or a CT-based treatment (92), regards the selection of the patients, the choice of the pri-
which reported that after 1 year follow-up the intensity mary endpoints, the suboptimal use of AVS and the total
Primary Aldosteronism 519
lack of adequate statistical power, as recently discussed in hypertension and requiring bilateral adrenalectomy (102).
depth (95). The primary endpoint (DDD 1 year post inter- After this seminal report, other mutations were found
vention) was a not a proper outcome measure inasmuch which led to a novel classification of familial hyperaldo-
as AVS fattened by adrenalectomy is not recommended to steronism, besides the glucocorticoid-remediable form
lower the intensity of drug treatment necessary for obtain- known for some decades (under revision (76)). To date,
ing target blood pressure, but rather to cure patients from genetic testing is performed for research purposes and is
PA. A worthier analysis would have compared biochemi- advised only for ruling out the need of AVS as discussed
cal resolution of PA, correction of hypokalaemia, and a above. However, the recent report that APA with some
rise in renin/fall in aldosterone into the normal range as KCNJ5 mutations respond to macrolides and their deriva-
primary endpoints, plus levels of complete remission of tives without antibiotic activity can open a new avenue
hypertension/partial remission/no change, or increase, as toward personalized medical treatment of PA (103,104), a
clinical endpoints. Notably, in the AVS and the CT group, hypothesis that is being tested in the MAPA Study (105).
persistent PA at 1-year follow-up, was found in 11% and
20% of the adrenalectomized patients, respectively, which
is in striking contrast with the biochemical cure rate
between 96−100% seen in larger AVS-based studies even TREATMENT
by exploiting a much longer follow-up (21) and in a large
retrospective international survey (96). As regards power, Laparoscopic adrenalectomy is currently the best treatment
the authors calculated the sample size needed to achieve for PA patients with lateralized aldosterone excess. It can be
80% power to detect a difference in DDD between groups, performed during a short hospital stay at a very low opera-
assuming a 1.8 SD, was 81 patients per arm for a two-sided tive risk (106–108). At our institution, we follow the recom-
α = 0.05. Because their patients went into subgroups of 46 mendation from the Endocrine Society guidelines, that a
(in medical and surgical arms), only 46 patients under- lateralized aldosterone secretion should be demonstrated
went adrenalectomy in both arms. With this smaller sam- before undertaking surgery in patients who are candidates
ple size, the power of the study was reduced to ∼50%, e.g. for general anaesthesia and wish to achieve long-term cure
equivalent to tossing a coin. The authors’ interpretation of (41). In our hands, when guided by demonstration of lat-
those findings that ‘Treatment of primary aldosteronism eralized aldosterone excess at AVS, unilateral laparoscopic
based on CT or AVS did not show significant differences adrenalectomy almost invariably provides correction of
in intensity of antihypertensive medication or clinical the biochemical changes of PA (21,87); and the cure rate
benefits for patients after 1 year of follow-up … chal- of hypertension (patients who are cured or experience a
lenges the current recommendation to perform AVS in all marked improvement) is ∼82% (21). Even when antihyper-
patients with primary aldosteronism’ (18) is a straightfor- tensive treatment cannot be withdrawn after adrenalectomy,
ward example of reverse ‘spin’ (97), e.g. to report that one the number and/or the doses of antihypertensive drugs can
approach was not beneficial while in fact it is (95). The be markedly decreased and/or resistant hypertension can be
superiority of AVS-guided adrenalectomy over CT in terms resolved. Predictors of hypertension cure include young age,
of biochemical outcome, albeit not of clinical outcome in female sex, a short history of hypertension and no evidence
a recent retrospective multi-centre survey (98), and also of of CV damage, including the absence of vascular remodel-
clinical outcome has also been found in the largest registry ling (26,109) and renal chronic kidney disease (110). The
of patients submitted to AVS worldwide (99). wide variation of results in the literature is probably because
at some centres adrenalectomy is performed on the basis of
imaging alone that, as mentioned before, can be misleading
in a substantial proportion of patients (111,112). Of inter-
C11METHOMIDATE POSITRON EMISSION est, at a centre in Brisbane, Australia, adrenalectomy was
also associated with a considerable improvement in several
TOMOGRAPHY indexes of quality of life (113). Hence, the overall available
C11methomidate positron emission tomography seems to evidence supports the concept that the sooner the diagno-
be a promising alternative approach to AVS to the dem- sis is made and adrenalectomy is performed, the better the
onstration of lateralized aldosterone excess, but this tech- outcome.
nique requires a facility for the preparation of the tracer, On the whole, the common reasons of failure to cure PA
which has a very short half-life, and therefore could only be are an inaccurate diagnosis (AVS was not performed or its
developed at large tertiary referral centres (100). Whether results were incorrectly interpreted) and, more frequently,
C11methomidate positron emission tomography could iden- the concurrence of primary hypertension and/or chronic
tify the majority of APAs, which are quite small, remains to kidney disease (114). As PA and primary (essential) hyper-
be proven. The same applies to use of a chemokine receptor tension are both highly prevalent, 20–30% of patients
type 4 (CXCR4)-specific ligand used for molecular imaging would be expected to have primary hypertension concur-
of APA in one study of only nine patients (101). rent with PA, which cannot be cured by adrenalectomy.
For patients who are not candidates for surgery or do
not show lateralized aldosterone excess, mineralocorticoid
receptor antagonists, such as spironolactone, canrenone,
GENETIC TESTING potassium canrenoate and eplerenone (which is more selec-
tive, but also more expensive, weaker and shorter acting
An exome sequencing of 24 APA allowed the discovery of than the other antagonists and is not generally available)
somatic mutations in the Kir3.4 gene encoding the KCNJ5K are a reasonable alternative to adrenalectomy. Novel potent
channel, which were thereafter identified in few families and specific mineralocorticoid receptor antagonists are also
with bilateral adrenal hyperplasia causing drug-resistant being developed (115). Results from pilot studies suggest
520 Manual of Hypertension of the European Society of Hypertension
that these novel antagonists can effectively control blood prevented by mineralocorticoid receptor antagonists. Horm Metab
pressure in patients with PA and decrease left ventricular Res 2010; 42(6): 458–465.
7. Rocha R, Rudolph AE, Frierdich GE et al. Aldosterone induces a
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and heart) remains to be conclusively proven. Gynecomastia 8. Weber KT, Brilla CG, Campbell SE, Reddy HK. Myocardial fibrosis
and impotence, which are not rare in men receiving miner- and the concepts of cardioprotection and cardioreparation.
J Hypertens Suppl 1992; 10: S87–S94.
alocorticoid receptor antagonists for a long time, are dose- 9. Brilla CG, Pick R, Tan LB et al. Remodeling of the rat right and
dependent side effects. Hence, the use of reduced doses in left ventricles in experimental hypertension. Circ Res 1990; 67:
combination, if necessary, with other agents, such as long- 1355–1364.
acting calcium channel blockers (some of which also have 10. Rossi GP, Sacchetto A, Pavan E et al. Remodeling of the left ventri-
cle in primary aldosteronism due to Conn’s adenoma. Circulation
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mize these side effects. Angiotensin-converting enzyme 11. Rossi GP, Bello VD, Ganzaroli C et al. Excess aldosterone is associ-
inhibitors and angiotensin receptor blockers can be particu- ated with alterations of myocardial texture in primary aldosteron-
larly useful, as they effectively control the stimulation of ism. Hypertension 2002; 40: 23–27.
12. Farquharson CA, Struthers AD. Aldosterone induces acute endo-
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PHEOCHROMOCYTOMA AND
PARAGANGLIOMA 63
INTRODUCTION PREVALENCE
The terminology of chromaffin cell tumours is sometimes The prevalence of PPGLs in hypertensive populations is
confusing when pheochromocytoma and paraganglioma low (0.2–0.6%), but higher in selected patient groups such
are interchangeably used. The term pheochromocytoma as those with an adrenal incidentalomas (5%) (1,3,4,6–8).
should be reserved for chromaffin cell tumours of the A recent study from the Netherlands showed that, prob-
adrenal gland, while the term paraganglioma should be ably due to more intensified diagnostics, the age-standard-
used for extra-adrenal chromaffin cell tumours. This dis- ized incidence rate has increased over the last two decades
tinction is clinically relevant because these tumours not by nearly 50%. As PPGLs may also go unrecognized, its
only differ in location but also in clinical presentation, prevalence in autopsy studies is 0.05% (1,3,4,6–10).
genetic background and malignant potential. In children with hypertension, the prevalence of PPGL
Pheochromocytomas arise from the adrenal medulla is approximately 1.7% and PPGLs more frequently have a
(80−85%), while sympathetic paragangliomas arise from hereditary background (70%). Recently, in a large group
chromaffin cells associated with the paravertebral ganglia of patients it has been demonstrated that children show
of the sympathetic chain (15−20%). Paragangliomas can higher prevalence than adults of hereditary (80% vs. 53%),
also originate from cells associated with the parasym- extra-adrenal (66% vs. 35%), multifocal (33% vs. 13.5%),
pathetic nervous system, and these tumours are usually metastatic (49.5% vs. 29%) and recurrent (29.5% vs. 14%)
located in the neck and skull base (1). PPGLs (11).
The degree and patterns of catecholamine secretion
largely account for the clinical presentation and hemody-
namic features. About half of adrenal tumours produce CLINICAL PRESENTATION
a combination of noradrenaline and adrenaline, and the
other half nearly exclusively noradrenaline (2,3). In con- The clinical presentations of PPGLs are highly variable,
trast, most paragangliomas (PPGLs) located in the thorax, leading to its designation as the ‘great mimic’, or ‘the dis-
abdomen and pelvis produce exclusively noradrenaline. ease with the multiple faces’ (12,13). There are numerous
This is due to the lack in extra-adrenal chromaffin tissue of reports in the literature of highly unusual presentations of
the enzyme PNMT that converts noradrenaline into adren- PPGLs. Some patients may be completely asymptomatic,
aline. Other paragangliomas produce a mixture of nor- while in others PPGL can be confused with many other
adrenaline and dopamine and some exclusively dopamine disorders that display similar cardiovascular, abdominal,
(2,3). The paragangliomas located in the neck and skull neurologic or metabolic signs and symptoms.
base are typically hormonally inactive except for mild pro- Excessive production and high levels of circulating cat-
duction of dopamine and rarely noradrenaline (1). echolamines are responsible for the classical symptoms of
Because pheochromocytomas and PPGLs are rare and hyperadrenergic spells, including tachycardia, headache
may have severe and even fatal cardiovascular consequences, and sweating, which may occur spontaneously or may be
the clinician needs a high awareness and early consideration provoked by different physical or chemical triggers (e.g.
of the presence of such tumour. When correctly diagnosed general anaesthesia, medications and other) (1,3,4). The
and treated, most of PPGLs are curable. When undiagnosed frequency of spells may vary from several times per day to
or improperly treated, they can have fatal consequences. a few times per month. The episodes may occur suddenly
In contrast, when a PPGL is diagnosed and managed by a and unexpectedly − in 80% of the cases they commonly
highly experienced clinical team, the tumour can be success- last less than 1 hour, then subside gradually and lead to
fully resected with minimal perioperative mortality (4,5). exhaustion of the patient.
524 Manual of Hypertension of the European Society of Hypertension
Phaeochromocytoma
Cardiovascular system
Vessels Heart
- Myocardial infarction
- Hypertensive crisis - Hemodynamic collapse
- Aortic dissection - Heart failure
- Multisystem crisis - Pulmonary oedema
- Cardiac arrest
Figure 63.1 Cardiovascular manifestations of pheochromocytoma. (From Prejbisz A et al. J Hypertens 2011; 29(11):
2049–2060. With permission.)
Recent studies have shown that the classic triad occurs PPGL, with more recent attention to an increasing number
more rarely than usually assumed. Diabetes and weight of cases with Tako-Tsubo cardiomyopathy (8,17,18).
loss are other signs of the hyperadrenergic state (1,3,4). In addition to catecholamine excess, PPGLs have been
The excessive adrenergic stimulation of the cardiovascu- found very rarely to secrete neuropeptide Y, chromogranin
lar system may produce paroxysmal hypertension, which A, vasointestinal peptide, serotonin, calcitonin, parathy-
appears to be less frequent than observed in previous roid hormone-related protein, adrenocorticotropic hor-
studies. Approximately one-half of patients have sustained mone or interleukin-64. This can result in typical clinical
hypertension, whereas the other 50% suffer from parox- features related to these hormones, for example, diarrhoea
ysmal hypertension. Normotension is typical for head in the case of vasointestinal peptide secretion.
and neck paragangliomas (1). Because catecholamines can Finally, some patients can present with a metastatic
inhibit peristalsis, PPGL may be associated with severe PPGL with symptoms resulting from tumour infiltration
constipation and even enteric pseudo-obstruction or ileus. and distant metastatic lesions (e.g. bone pain in the case of
Mesenteric arterial vasoconstriction due to excessive cat- osseous metastasis).
echolamines may result in ischaemic enterocolitis with Symptoms of catecholamine excess can be further mim-
intestinal necrosis (4). icked by hyperthyroidism, panic attacks, hypoglycaemia
PPGLs can present with a plethora of life-threatening and alcohol withdrawal symptoms, and these conditions
cardiovascular manifestations, including hypertensive cri- should therefore be considered in patients with spells sug-
sis, myocardial infarction, shock and multisystem failure gestive of excessive catecholamine production. Sudden
(Figure 63.1). Most of these life-threatening cardiovascu- cessation of clonidine or beta-blocker therapy may also
lar presentations of PPGLs result from a rapid and massive cause PPGL-like symptoms due to the rebound effect of
release of catecholamines from the tumour (8,14–16). catecholamines (1,3,4,7).
Rarely, patients with a PPGL present with low blood pres-
sure or even shock that may then precede a multisystem
crisis. Sinus tachycardia with palpitations as the present-
ing symptom is the most prevalent abnormality of cardiac WHICH PATIENTS SHOULD BE SCREENED
rhythm in PPGL, but tumours can also be associated with FOR PPGL?
more serious ventricular arrhythmias or conduction distur-
bances (8). Reversible dilated or hypertrophic cardiomy- Clinicians should base their decision for biochemical screen-
opathy are other well-established cardiac manifestations of ing for a PPGL on signs and symptoms or other tumour
Pheochromocytoma and Paraganglioma 525
Symptoms
is exceptional, while using the LC-ECD method several b Pharmacodynamic interference leading to increased levels affecting all
for false-positive test results cause pharmacodynamical namic interference increase the dopamine metabolite 3-methoxytyramine
interference such as cocaine, tricyclic antidepressants and affecting all analytical methods.Abbreviations: MAO, monoamine oxi-
dase; MN, metanephrine; NMN, normetanephrine; ++, clear inerease;
MAO-inhibitors (2,20,22) (Table 63.2).
+, mild increase; −, no increase.
To avoid any false-positive test result of metanephrines,
it would be ideal to discontinue all medications in each
patient but that is not feasible in all patients from the prac- tumour size and tumour location. A predominant meta-
tical point of view. An alternative option is to discontinue nephrine production usually indicates that the tumour is
medications before sampling only if the initial test results located in one or both adrenals, while significant meta-
are elevated (2,20,22). nephrine production is never the case in extra-adrenal
Dietary factors are another source of potential false- chromaffin cell tumours (1,2,22). Some studies have sug-
positive test results that has frequently been mentioned. gested in the past that increases in urinary dopamine may
Indeed, several food products containing large amounts predict metastatic disease. In recent years, however, it has
of biogenic amines such as banana, pineapple, nuts and become clear that increments in plasma MTY provide a
cereals may increase the levels of metanephrines, but not much better predictor of the presence of metastatic PPGLs
to such extent that they cause false-positive test results. than urinary dopamine. For this reason, plasma MTY is
Dietary restriction of consuming food products contain- regarded as a promising biomarker of metastatic PPGL and
ing biogenic amines is only indicated for the measurement its measurement should be pondered in all patients at risk
of the dopamine metabolite MTY (22). for metastatic PPGLs (7,20,22,25).
All patients with positive test results should receive As documented by several studies, measuring meta-
appropriate follow-up according to the clinical presenta- nephrines in plasma and urine can also be indicative of
tion and magnitude of increased values. Additional testing the kind of hereditary syndrome that may be associated
such as the clonidine suppression test is indicated in those with PPGLs. The underlying mutations are characterized
cases with borderline elevated test results that cannot be by different biochemical profiles, and the biochemical
explained by faulty sampling conditions or patient prepa- results may therefore guide the priorities in genetic testing
ration or the use of interfering medication. The clonidine (Figure 63.2). This is elaborated further in the paragraph
test serves to distinguish true-positive from false-positive on genetic testing.
elevations of plasma normetanephrine. This test has an Tumours due to mutations in the RET (rearranged dur-
excellent diagnostic specificity (100%) and sensitivity ing transfection, a protooncogene associated with multiple
(97%), although it has not yet been validated in more pro- endocrine neoplasia [MEN] type 2A) and NF1 (neurofibro-
spective studies (1,20,22). matosis type 1) genes show predominant increases in meta-
In addition to the use of metanephrines for the diagnosis nephrine. In contrast, tumours due to von Hippel–Lindau
of PPGLs, they may also serve as biomarkers for estimating disease (VHL) and familial paraganglioma syndrome
Pheochromocytoma and Paraganglioma 527
Mutation
Disease (phenotype MIM numbers) Genes rate (%)a Main features
Neurofibromatosis type 1 (162200) NF1 3 Café-au-lait spots, neurofibromas, axillary and inguinal
freckling, Lisch nodules, osseous lesions, optic gliomas,
mainly pheochromocytomas
Multiple endocrine neoplasia type 2 RET 6 2A: Medullary thyroid cancer, primary
(171400; 162300) hyperparathyroidism, PPGL
2B: Medullary thyroid cancer, PPGL, Marfanoid habitus,
mucocutaneous neuromas, gastrointestinal
ganglioneuromatosis
von Hippel–Lindau disease (193300) VHL 7 Central nervous system or retinal hemangioblastomas,
renal cell carcinoma, PPGL pancreatic neuroendocrine
tumours and cysts, endolymphatic sac tumours, papillary
cystadenoma of the epididymis and broad ligament
Familial pheochromocytomas (173300; TMEM127 1 Mainly pheochromocytomas, rare renal cancers mainly
613403; 154950) MAX 1 PPGL
Leiomyomatosis and renal cell cancer FH 1 Cutaneous and uterine leiomyomas, type 2 papillary
(150800) renal carcinoma, rare PPGL
Source: From Favier J et al. Nat Rev Endocrinol 2015; 11(2): 101–111. With permission.
Abbreviations: GIST, gastric stromal tumours; MIM, Mendelian inheritance in man; PPGL, paraganglioma and/or pheochromocytoma.
a The mutation rate is the percentage of patients with PPGL with mutations in the gene concerned.
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Section X
Additional Aspects
FOLLOW-UP OF THE
HYPERTENSIVE PATIENT 64
was found that the annual number of return visits was 12-month follow-up period (14) and patients in the inter-
more than twofold higher in patients with three or more vention group had significantly lower office and ambula-
comorbidities compared to those without other condi- tory BP values.
tions (8). However, exactly why more frequent visits are
required and whether they translate into better long-term
outcomes remains unclear. CONTROLLED BLOOD PRESSURE
Once BP control is achieved, less frequent follow-up visits
are reasonable. A limited number of studies, however, pro-
UNCONTROLLED BLOOD PRESSURE vide evidence in this context.
A randomised clinical trial of 609 patients with controlled
Several observational studies and one randomised study BP treated by family practitioners in Canada compared the
have evaluated the impact of visit frequency on BP control equivalence of 3-month and 6-month follow-up visits in
in hypertensive patients with uncontrolled BP. terms of BP control, patient satisfaction and adherence to
In a cohort of 429 hypertensive patients from two therapy (15). During a follow-up period of 33.6 months,
urban family practices, the average return visit interval there were no significant differences between the two
for patients with uncontrolled BP patients was 71.2 days, groups in mean BP, BP control rates, patient satisfaction or
while the corresponding interval for those with controlled adherence to treatment, indicating that 6-month visit inter-
BP patients was 84.1 days (p < 0.001) (9). Of major clini- vals might be appropriate for patients with controlled BP.
cal importance, decrease in systolic BP was significantly It should be mentioned, however, in both treatment arms
greater with shorter return visit intervals. Another large the actual between-visit time was much shorter than origi-
retrospective study analysed the data of more than 5000 nally planned (2.16 months for the 6-month group and
hypertensive patients with type 2 diabetes treated by 1.89 months for the 3-month group), thereby challenging
primary care physicians (10). BP control was achieved
the conclusions that can be drawn from this study.
after a median of 1.5 months in patients with visit inter-
vals of less than 1 month, while a median of 12.2 months
was needed in patients with visit intervals of more than 1
month (p < 0.0001). A large retrospective study evaluated EFFECT OF VISIT FREQUENCY ON
a cohort of more than 25,000 patients with type 2 diabetes CARDIOVASCULAR OUTCOMES
treated for 9 years by primary care physicians (11). BP con-
trol (<130/85 mmHg) was achieved after a median of 1.3 The aforementioned studies indicate that more frequent
months in patients visiting their physician more frequently return visits translate into significant benefits in surro-
(1−2 weeks) compared to 13.9 months in those with less gate endpoints such as overall BP control rates and time
frequent (3−6 months) visits (p < 0.001). In multivariate to achieving BP control. However, they do not attest to
analysis, doubling time between visits was associated with whether these intermediate benefits are associated with
an 87% increase in median time to achieve BP control. A long-term cardiovascular risk reduction.
retrospective study of almost 100,000 participants with A large population-based retrospective cohort study
newly diagnosed hypertension from the Kaiser Permanente in 90,000 patients with hypertension treated in British
Insurance System in California found that mean follow- primary care practices between 1986 and 2010 provides
up was significantly longer in patients with uncontrolled information about the impact of delays in follow-up visits
compared with patients with controlled BP (292.9 vs. on cardiovascular events and death (16). During a median
232.2 days) (12). The average number of visits was higher follow-up period of 37.4 months, almost 10,000 partici-
in the controlled compared with the uncontrolled group pants suffered a nonfatal cardiovascular event or died.
(4.1 vs. 3.1 visits) and the likelihood of reaching BP control It was found that when time to follow-up visit exceeded
decreased with increasing intervals between visits. Indeed, 2.7 months, risk of cardiovascular events was increased
visit intervals >180 days were associated with the lowest by 18% (p < 0.001). Likewise, a gradual risk increase was
likelihood of achieving BP control, while visit intervals observed with delays in treatment intensification. Similar
<2 weeks were associated with the highest likelihood of associations were observed when only the mortality risk
achieving target BP. Another retrospective study evaluated was studied.
the association between visit frequency and time to BP
control in almost 3000 patients younger than 40 years of
age with incident hypertension treated in primary care − CRITICAL EVALUATION
an important patient group who experience lower control
rates compared with elderly patients (13). This study also Overcoming clinical inertia through treatment intensifica-
showed that shorter visit intervals were associated with tion is probably a major factor for better BP control with
better BP control rates during a 2-year follow-up period. greater frequency of visits. Other factors such as intensive
Interestingly, the corresponding rates of initiation of drug lifestyle modification and better adherence to antihyper-
therapy were lower (21%) in the frequent visit group (com- tensive therapy appear to be equally important.
pared to 29% in less-frequent visit groups). Prompt BP control has been associated with significant
The data above all derive from observational stud- cardiovascular benefits in several studies. In the VALUE
ies with inherent limitations. The only randomised trial, rapid BP control (within 6 months) was associated
controlled study comes from a small cohort of 156 hyper- with decreased rates of cardiovascular events, irrespective
tensive patients with uncontrolled BP treated by fam- of treatment allocation (amlodipine or valsartan) (17).
ily physicians in Canada. This study compared frequent Likewise, in the open extension of the Systolic Hypertension
visits (every 2 weeks for 16 weeks) with usual care for a in Europe (Syst-Eur) Trial, immediate BP control was
Follow-Up of the Hypertensive Patient 537
associated with reduced risk of cardiovascular events com- Primary care physicians and hypertension specialists
pared with delayed BP control (18). More recently, similar are facing increasing workloads worldwide. Innovative
findings were observed in the ADVANCE-ON study, the interventions that include other healthcare professionals
open follow-up observation phase of the Action in Diabetes such as pharmacists and nurses, the use of eHealth tech-
and Vascular Disease: Preterax and Diamicron Modified nologies such as mobile phones and other devices to mon-
Release Controlled Evaluation (ADVANCE) trial (19). On itor patients remotely, and the involvement of patients and
the other hand, a potentially significant barrier to increased their relatives through self-monitoring and home BP tele-
visit frequency in real-life practice might be the increased monitoring might not only reduce physicians’ workload
demand for healthcare resources in primary care (20–22). but also significantly improve BP control and cardiovas-
Therefore, innovative ways of delivering healthcare should cular outcomes. Team-based care has indeed been found
be explored where more frequent visits are required. to be associated with significantly greater reductions in
The opinions and beliefs of practicing physicians are BP and increased rates of BP control compared to usual
of paramount importance for the implementation of care (27). We would like to focus on the roles of pharma-
guideline recommendations, particularly where guide- cists and nurses in hypertension management.
lines are vague or not provided at all. In the context of
follow-up of hypertensive patients, a few older studies
shed light on this issue. A study of 50 general practitioners
in South Glamorgan, Wales, assessed their opinions on PHARMACISTS
visit frequency for patients with uncomplicated controlled
Pharmacists are highly accessible in most parts of the
hypertension (23). On average, doctors thought that
world and often build long-term relationships with
hypertensive patients should be followed up every 14.8
patients. Their role in hypertension management includes
weeks; however, a wide range of responses was observed,
regular BP monitoring, patient education on lifestyle mod-
with visit frequency every 2 weeks to once a year. The
ification, advice on adherence to therapy and feedback to
main factors guiding these decisions were BP severity,
the treating physician. Of equal importance, pharmacists
age, and prior antihypertensive therapy. Another study
can also play an important role in a holistic approach to
evaluated visit frequency and its determinants among 457
the prevention and treatment of cardiovascular diseases
patients in UK during a 14-year follow-up period (24). The
through improving control of other cardiovascular risk
mean and the median intervals between visits were 113
factors such as diabetes, dyslipidemia, smoking and obe-
and 91 days, respectively. The between-visit interval was
sity (28–31).
mainly affected by the severity of hypertension and the
Several studies evaluated the impact of pharmacist
duration of follow-up. The background of primary care
involvement on adherence to antihypertensive therapy
physicians might also play a role. In a study of 273 female
and BP control. A meta-analysis of 19 randomised con-
physicians in Canada, it was found that community prac-
trolled trials with more than 14,000 participants demon-
tice physicians scheduled more frequent follow-up visits
strated greater BP reduction compared with usual care (32).
than physicians with academic appointment (25).
Another recent meta-analysis pooled data from 63 studies
A recent study simulated the impact of three inter-
evaluating the effects of pharmacist-led chronic disease
vention strategies on BP control using national survey
management (33). In 15 studies, pharmacist-led compared
data and validated the findings in two large clinical tri-
with usual care was found to be associated with similar
als (Antihypertensive and Lipid Lowering Treatment to
numbers of clinical events, similar health-related quality
Prevent Heart Attack Trial [ALLHAT] and VALUE) (26).
of life and similar number of hospitalisations, urgent care
Enhanced treatment intensification had the greatest
and visits to the emergency department. Mixed findings
impact on BP control followed by increased visit frequency
were observed for patient satisfaction, office visits and cost
and increased adherence. When all three interventions
outcomes, while BP control was more likely to be achieved
were optimised, appropriate BP control was predicted to
with pharmacist-led care. A recent randomised controlled
be achieved in 95% of hypertensive patients, highlighting
study of 248 patients in Alberta, Canada, where pharma-
the importance of follow-up frequency in hypertension
cists prescribe drugs, request laboratory tests after appro-
treatment strategies.
priate training and communicate prescription changes to
Whilst all these data provide evidence of the importance
the treating physician, showed that pharmacist interven-
of tailored follow-up strategies for BP control and cardiovas-
tion was associated with greater systolic BP reduction and
cular outcome, specific guidance cannot be provided at this
increased probability of achieving BP control (34).
point in time. The overarching evidence that more frequent
Appropriate education and training of pharmacists in
visits are associated with better outcomes should, however,
accurate BP measurement and hypertension management
be taken into account in the care of individual patients.
are paramount for wide-range implementation of such
strategies, and expanding the role of community pharma-
cists requires significant changes in the health network
WHO SHOULD FOLLOW UP ON and legislation changes in many countries.
PATIENTS WITH HYPERTENSION?
NURSES
Should all patients with hypertension be followed
up by primary and secondary care physicians? What Nurses have traditionally been involved in the measure-
is the role of allied healthcare professionals in long- ment of BP and provide advice on lifestyle modification
term management? Will eHealth and mHealth have an and adherence to antihypertensive therapy. The closer and
impact on patient management? more relaxed relationship between nurses and patients
538 Manual of Hypertension of the European Society of Hypertension
results in lower BP values obtained by nurses compared messaging on BP during a 6-month follow-up period (49).
to physicians (35) and longer conversations focused on No significant differences between participants with or
prevention (36). Nurses have been granted the author- without text messaging were found in systolic or diastolic
ity to prescribe medicines, to be reimbursed for primary BP or in BP control rates, while only a marginal benefit
care services and to admit patients to hospital in several in compliance to therapy was observed with intervention.
parts of the world. Generally, more evidence on the effec- Clearly, the quality of studies in this field must be further
tiveness of nurse-led services in terms of BP control and improved in order to impact on clinical care.
cardiovascular outcomes is required (37).
A large randomised controlled trial found no differ-
ences in patient outcomes between primary care physi-
cians and nurse practitioners who had similar authorities MOBILE APPLICATIONS
and responsibilities (38). Other studies in community set-
Smartphone devices have revolutionised modern com-
tings both in Europe and the US also failed to demonstrate
munication and are used by the majority of adults world-
significant benefits of nurse-led clinics (39–41). In con-
wide, with constantly increasing numbers of elderly users.
trast, several small studies have shown beneficial effects
Health-related smartphone applications represent a fast-
with nurse-led practices, attributed to stricter implemen-
growing field, rendering mobile health (mHealth) an
tation of guideline recommendations and adherence to
attractive approach for the management of chronic dis-
therapeutic protocols, and more regular follow-up visits. A
eases (50–52). mHealth applications are widely accepted,
meta-analysis of 33 studies reported that nurse-led inter-
with more than half of smartphone owners using at least
ventions − through a stepped-treatment algorithm, nurse
one mHealth application (53), including the assessment of
prescribing or community monitoring − were associated
heart rate, atrial fibrillation, physical activity, sleep quality
with greater systolic BP reductions compared to usual care.
and BP. Smartphone applications may be used in hyper-
A sub-analysis of six studies in primary care also demon-
tension management through recording and storing BP
strated that nurse-led clinics showed greater reduction of
values inserted manually, automatic transmission of mea-
BP compared with usual care (42). The benefits of nurse-led
surements from the device to the smartphone, and more
clinics compared with physician-led care are even greater
impressively, by turning the smartphone into a BP device
in diabetic patients with hypertension (43). The most
permitting cuffless BP measurements (54). All applications,
recent meta-analysis pooled data from studies evaluating
however, have several limitations, with the major drawback
the effects of community-based nurse-led interventions
being the limited accuracy of cuffless measurements (55).
in patients with chronic conditions (44). This analysis of
A recent statement of the American Heart Association on
10 studies with almost 4000 participants revealed that
mHealth applications in cardiovascular disease included
compared with usual care, nurse-led interventions were
BP management among the potential aspects for interven-
associated with a trend towards lower BP. When nurses
tion, favouring the applications but also highlighting the
were specifically trained and studies were of adequate size
lack of standardisation (56). Recently, the ESH endorsed
(>200 participants), statistically significant BP reduction
ESH CARE (57); this mobile application facilitates the
favouring nurse-led interventions was observed in patients
collection and the transmission of BP measurements and
with diabetes for systolic BP and in patients with cardio-
information about drug therapy as well as feedback from
vascular disease for diastolic BP (44).
physicians. Moreover, educational information is pro-
vided on hypertension and its cardiovascular complica-
tions. Another application has been developed for patients
DIGITAL INTERVENTION with suspected primary aldosteronism and has recently
been endorsed by ESH (58).
Interactive digital interventions are internet-based pack-
ages delivered to the patient either by computer or by
phone, which provide health information, focussing on
behavioural modification and decision support, and allow HOME BLOOD PRESSURE TELEMONITORING
remote monitoring by physicians. Self-management of
hypertension guided by interactive digital intervention Home BP monitoring is encouraged by most hyperten-
can lead to improved education and BP control in hyper- sion guidelines in order to ensure patient engagement and
tensive patients (45). improve BP control. Home BP telemonitoring includes
A recent meta-analysis of seven randomised controlled transmission of measurements to a healthcare provider
trials pooled data from more than 1200 participants and through various remote methods.
revealed that interactive digital interventions were associ- Home BP telemonitoring compared with usual care has
ated with significantly greater BP reduction compared with been found to be associated with increased frequency of
usual care (46). However, the benefits were not consistent treatment intensification (59). A systematic review in 2013
among all studies, and it remains unclear whether BP revealed that telemonitoring was associated with better BP
reduction is sustained and whether it translates to cardio- control and improvements in the physical components of
vascular risk reduction. In a meta-analysis of 51 studies, quality of life when compared to usual care (60). However,
digital health interventions were found to be associated the healthcare costs per patient were approximately 600€
with significant reductions in cardiovascular risk and car- greater for those undergoing telemonitoring, and there was
diovascular outcomes (47). A Cochrane meta-analysis of no consistent effect on treatment adherence (60). A more
the impact of mobile phone messaging on facilitation of recent meta-analysis of 46 randomised studies with almost
self-managing chronic disease identified only one ran- 14,000 participants found that home BP telemonitoring was
domised controlled study for the management of hyper- associated with significant reductions in systolic and diastolic
tension (48) − a small study evaluating the effect of text BP, along with improved control of hypertension (61). Home
Follow-Up of the Hypertensive Patient 539
BP telemonitoring with additional support compared with ago (66,67). This has been achieved through the successful
telemonitoring alone was associated with a trend towards implementation of multicomponent approaches, including
reduced BP levels. Several patient characteristics have been physician education, incentives, performance measure-
identified as predictors of better outcomes with telemoni- ments, algorithms, team-based strategies, patient educa-
toring, including younger age, higher baseline diastolic tion and patient aids (68–71).
BP, reduced salt intake, fewer antihypertensive drugs and
absence of diabetes mellitus (62).
Despite evidence supporting the use of home BP tele-
monitoring in the management of arterial hypertension, WHAT SHOULD BE DONE AT FOLLOW-UP
this approach is not widely used in contemporary clini-
cal practice. Potential barriers include uncertainties about
VISITS?
data security and infrastructure limitations and the lack
of simple, cost-effective and user-friendly systems that Should follow-up visits focus on blood pressure mea-
are required to gain wide acceptability by both healthcare surement or are other investigations required? Is there
professionals and patients. Moreover, financial incentives
guidance on the frequency of such assessments? How is
for healthcare professionals are needed in order to make
the care of hypertensive patients embedded in manage-
telemonitoring attractive for physicians, pharmacists and
nurses (63). Patients seem keen to use telemonitoring and ment of other cardiovascular risk factors?
find it easy to perform but question its utility and ask for
enhanced feedback by physicians; lack of familiarity with The main incentive for achieving long-term optimal BP
technology, out-of-town jobs and hobbies are identified by control lies in the tight relationship between BP and cardio-
patients as potential obstacles to implementation (64). vascular events (72). Hypertension remains a key risk factor
for coronary artery disease, cerebrovascular events, left ven-
tricular hypertrophy and congestive heart failure, and con-
tributes to other complications including peripheral artery
VIRTUAL CLINICS disease, chronic kidney disease, retinopathy and aortic dis-
section. Where these conditions are present at first diagnosis
Involvement of allied health professionals and eHealth of hypertension it may be important to monitor and treat
technologies has the potential to reduce face-to-face visits them. In patients without overt target-organ damage, how-
to primary care physicians or hypertension specialists. At ever, one may argue that the risk of developing complications
the same time there may be increased demand for health- is reasonably low in those with optimally controlled BP.
care professionals to review ambulatory data and feedback
to patients and other members of the healthcare team.
These tasks will require dedicated and protected time,
probably in the form of virtual clinics involving a multidis- INITIAL EVALUATION AND MONITORING
ciplinary team where all available information is reviewed, AT FOLLOW-UP
and individualized diagnostic and therapeutic approaches
are discussed. Without sufficient time allocated to man- Guidelines and healthcare systems differ considerably in
agement of data that are not directly acquired by the physi- their recommendations and resources to support initial eval-
cian, these new approaches are bound to fail and possibly uation of patients with hypertension. Evidence suggests that
even to pose a risk to patients with hypertension. ambulatory BP monitoring, serum creatinine, albuminuria
and ECG are cornerstones of the workup at first presenta-
tion, followed by further tests in cases of abnormal results,
in younger patients or where suspicion of secondary hyper-
CRITICAL EVALUATION: LESSONS FROM THE tension is high. These investigations are in fact the general
UK AND THE US recommendations in the NICE guidelines (73). Other guide-
lines, including those by ESH/ESC, also discuss the value
Although physicians dominate hypertension care in most of further investigations that look into subclinical organ
European countries, some healthcare systems explore alter- damage as assessed, for example, by measurement of endo-
native modes of hypertension care. A recent survey among thelial function, pulse wave velocity and carotid intima-
117 general practices in South West England sheds light media thickness (3). Whether an evidence-based minimal
on the organisation of hypertension care in the UK and its workup is employed or if more comprehensive assessments
impact on BP control (65). Most practices (73%) changed will be performed depends critically on the local setup and
their hypertension care arrangements, mainly through the available resources, where the latter are often primar-
strengthened roles of healthcare assistants (19.4%), nurses ily driven by research interests. In any case, however, the
and nurse-led clinics (16.7%) and pharmacists, including degree of initial workup will often determine the tests and
pharmacist-led clinics (4.2%). In 2.8% of surveyed prac- investigations during long-term management, where initial
tices, however, 6-monthly follow-up was changed to annual assessments are often more detailed than those at follow-up.
checkup. BP control rates tended to be higher with shared-
care teams compared with single-professional-led practices
(81.6% vs. 79.5%) and were higher in dispensing versus
nondispensing facilities (82.7% vs. 79.7%; p < 0.007). In TREATMENT OF BLOOD PRESSURE
the US, the Veterans Affairs and Kaiser Permanente are AND CARDIOVASCULAR RISK
two large healthcare systems that have achieved substan-
tial BP control during the last two decades. BP control rates Hypertension should not be seen in isolation. Management
today exceed 80% compared to less than 50% a decade of hypertension should be part of a multifaceted approach
540 Manual of Hypertension of the European Society of Hypertension
to control cardiovascular risk factors and will therefore In our own practice, and this would be in keeping with
extend to management of diabetes, dyslipidaemia, body recommendations of major guidelines (3,4), we assess
weight, advice on lifestyle and particularly on smoking serum electrolytes, creatinine, glucose or HbA1c and albu-
cessation. Often these factors will be taken into account in minuria at least annually, a lipid profile every 2–3 years
one comprehensive visit in primary care settings, and we and ECG every 3–5 years. More important than any rigid
have discussed above that such services can benefit from investigation schedules, however, is taking the time to
the input of allied healthcare professionals, including update a patient’s medical history and to watch out for
pharmacists and nurse specialists, as well as from eHealth any symptoms of organ damage, change in BP, and keep-
and mHealth systems. ing in mind the possibility that patients with essential
In contrast, secondary hypertension services are often hypertension are not protected from developing secondary
specialist clinics that focus on specific areas such as endo- hypertension later in life.
crine or renovascular hypertension and are less likely to
deliver a holistic approach to the patient but favour special-
ist diagnosis and treatment of a small range of conditions.
It is therefore not possible to provide general recommen- SUMMARY AND CONCLUSIONS
dations on the extent of risk management in the follow-up
of patients with hypertension, but it is important to ensure We are aware that the present chapter provides less detailed
that at least one member of the wider healthcare team information and less specific guidance than other contri-
not only addresses BP but also other cardiovascular risk butions to this book. In summarising the available evi-
factors; in many cases this will be a primary care p
hysician dence we have highlighted the lack of robust data and the
together with their practice team. rather sketchy recommendations in contemporary guide-
lines, which mainly focus on acute investigations and
treatment rather than long-term management.
A few factors should, however, be obvious from the
RECOMMENDED TESTS AND INVESTIGATIONS above considerations. First, it generally appears that more
AT FOLLOW-UP VISITS frequent follow-up is associated with better adherence, BP
control and fewer cardiovascular events. Second, there is
The initial phase in the treatment of patients with hyperten- no disadvantage to the outcome of patients if follow-up
sion will be highly personalised and depends on BP levels, involves or is even led by allied healthcare professionals;
response to treatment and presence of any organ damage. in fact, studies have shown that there may be benefits with
Investigations during this period are often driven by spe- regard to BP control and risk factor management. The asso-
cific therapeutic steps such as assessment of renal function ciated cost savings are another factor that should be taken
and potassium levels in patients treated with angiotensin- into account. Third, both patients and healthcare profes-
converting enzyme inhibitors or diuretics. Findings beyond sionals realise the potential of eHealth technologies, but
high BP such as presence of diabetes or dyslipidaemia will their widespread use in routine clinical care is not cur-
require their own specific follow-up investigations. It is evi- rently foreseen; weaknesses of available systems include
dent that physicians are well aware of such specific inves- limited user-friendliness, uncertainties about time and
tigations that are determined by symptoms and findings cost savings, and the need to fundamentally reorganise
from other tests, and seek specialist advice where indicated. clinical services in order to make best and safest use of this
The follow-up of patients after the initial workup and potential. Finally, the exact nature of follow-up visits will
at a time when BP is well controlled, however, remains an depend on a number of factors including level of BP con-
area that is less well defined. We have already referred to trol, cardiovascular complications and local and national
this in much more detail above when we reviewed the evi- setup of hypertension services and available resources.
dence on follow-up intervals, and it is not surprising that Scientific contributions often end with a statement that
clear-cut recommendations on investigations at follow-up further research is needed. Nowhere is this truer in the
are as vague as recommendations on follow-up intervals. It treatment of patients with hypertension than in follow-up
is, however, commonly agreed that the focus of long-term and long-term management. We encourage readers to sys-
management should lie in cardiovascular risk manage- tematically audit their local practice and develop research
ment and adherence to therapy in addition to assessment proposals into this important area of clinical medicine.
of BP and, at intervals, limited investigations into hyper-
tension or treatment-associated complications.
With regard to BP, the majority of patients will not
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2018 ESC/ESH GUIDELINES FOR
THE MANAGEMENT OF 65
ARTERIAL HYPERTENSION
THE TASK FORCE FOR THE MANAGEMENT OF ARTERIAL
HYPERTENSION OF THE EUROPEAN SOCIETY OF CARDIOLOGY
AND THE EUROPEAN SOCIETY OF HYPERTENSION*
* Text reproduced from Journal of Hypertension (2018; 36:1953-2041) and European Heart Journal (2018; 39:3021-3104). Permission for reproduction
provided by the European Society of Hypertension.
† Bryan Williams and Giuseppe Mancia contributed equally to the document.
‡ Professor Zanchetti died toward the end of the development of these Guidelines, in March 2018. He contributed fully to the development of these
Guidelines, as a member of the Guidelines’ Task Force and as a section co-ordinator. He will be sadly missed by colleagues and friends.
544 Manual of Hypertension of the European Society of Hypertension
Classes of
recommendations Definition Suggested wording to use
Class I Evidence and/or general agreement that a given treatment or procedure is beneficial, Is recommended/is indicated
useful, effective.
Class III Evidence or general agreement that the given treatment or procedure is not useful/ Is not recommended
effective, and in some cases may be harmful.
Each member of the Task Force was assigned specific met collectively and corresponded intensively with one
writing tasks, which were reviewed by section co-ordinators another between meetings. Before publication, the docu-
and then by the two chairs, one appointed by the ESC and ment was reviewed by European reviewers selected by
the other by the ESH. The text was developed over approxi- the ESC and ESH, and by representatives of ESC National
mately 24 months, during which the Task Force members Cardiac Societies and ESH National Hypertension Societies.
WHAT IS NEW AND WHAT HAS CHANGED IN THE 2018 ESC/ESH ARTERIAL HYPERTENSION
GUIDELINES?
Changes in recommendations
2013 2018
Diagnosis Diagnosis
Office BP is recommended for screening and diagnosis of hypertension. It is recommended to base the diagnosis of hypertension on:
■■ Repeated office BP measurements; or
■■ Out-of-office BP measurement with ABPM and/or HBPM if logistically
and economically feasible.
An SBP goal of <140 mmHg is recommended. ■■ It is recommended that the first objective of treatment should be to
lower BP to <140/90 mmHg in all patients and, provided that the
treatment is well tolerated, treated BP values should be targeted to
130/80 mmHg or lower in most patients.
■■ In patients <65 years it is recommended that SBP should be lowered
to a BP range of 120–129 mmHg in most patients.
BP treatment targets in older patients (65–80 years) BP treatment targets in older patients (65–80 years)
An SBP target of between 140–150 mmHg is recommended for older In older patients (≥65 years), it is recommended that SBP should be
patients (65–80 years). targeted to a BP range of 130–139 mmHg.
BP treatment targets in patients aged over 80 years BP treatment targets in patients aged over 80 years
An SBP target between 140–150 mmHg should be considered in people An SBP target range of 130–139 mmHg is recommended for people
older than 80 years, with an initial SBP ≥160 mmHg, provided that older than 80 years, if tolerated.
they are in good physical and mental condition.
A DBP target of <90 mmHg is always recommended, except in patients A DBP target of <80 mmHg should be considered for all hypertensive
with diabetes, in whom values <85 mmHg are recommended. patients, independent of the level of risk and comorbidities.
Continued
546 Manual of Hypertension of the European Society of Hypertension
Initiation of antihypertensive therapy with a two-drug combination may It is recommended to initiate an antihypertensive treatment with a
be considered in patients with markedly high baseline BP or at high two-drug combination, preferably in a SPC. The exceptions are frail
cardiovascular risk. older patients and those at low risk and with grade 1 hypertension
(particularly if SBP is <150 mmHg).
Mineralocorticoid receptor antagonists, amiloride, and the alpha-1 Recommended treatment of resistant hypertension is the addition of
blocker doxazosin should be considered if no contraindication exists. low-dose spironolactone to existing treatment, or the addition of further
diuretic therapy if intolerant to spironolactone, with either eplerenone,
amiloride, higher-dose thiazide/thiazide-like diuretic or a loop diuretic,
or the addition of bisoprolol or doxazosin.
In case of ineffectiveness of drug treatment, invasive procedures such as Use of device-based therapies is not recommended for the routine treatment
renal denervation and baroreceptor stimulation may be considered. of hypertension, unless in the context of clinical studies and RCTs, until
further evidence regarding their safety and efficacy becomes available.
Recommendation Grading
Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CAD, coronary artery disease; CVD, cardiovascular disease; DBP, diastolic
blood pressure; HBPM, home blood pressure monitoring; HMOD, hypertension-mediated organ damage; RCT, randomized controlled trial; SBP, systolic blood
pressure; SPC, single-pill combination.
New sections/recommendations
When to suspect and how to screen for the causes of secondary hypertension
Management of hypertension emergencies
Updated recommendations on the management of BP in acute stroke
Updated recommendations on the management of hypertension in women and pregnancy
Hypertension in different ethnic groups
The effects of altitude on BP
Hypertension and chronic obstructive pulmonary disease
Hypertension and AF and other arrhythmias
Oral anticoagulant use in hypertension
Hypertension and sexual dysfunction
Hypertension and cancer therapies
Perioperative management of hypertension
Glucose-lowering drugs and BP
Updated recommendations on cardiovascular risk assessment and management: using the SCORE system to assess risk in patients without CVD; the
importance of HMOD in modifying cardiovascular risk; and the use of statins and aspirin for CVD prevention
New concepts
BP measurement
Wider use of out-of-office BP measurement with ABPM and/or HBPM, especially HBPM, as an option to confirm the diagnosis of
hypertension, detect white-coat and masked hypertension and monitor BP control
Less conservative treatment of BP in older and very old patients
Lower BP thresholds and treatment targets for older patients, with emphasis on considerations of biological rather than chronological
age (i.e. the importance of frailty, independence, and the tolerability of treatment)
Recommendation that treatment should never be denied or withdrawn on the basis of age, provided that treatment is tolerated
A SPC treatment strategy to improve BP control
Preferred use of two-drug combination therapy for the initial treatment of most people with hypertension
A single-pill treatment strategy for hypertension with the preferred use of SPC therapy for most patients
Simplified drug treatment algorithms with the preferred use of an ACE inhibitor or ARB, combined with a CCB and/or a thiazide/
thiazide-like diuretic, as the core treatment strategy for most patients, with beta-blockers used for specific indications
Continued
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 547
Abbreviations: ABPM, ambulatory blood pressure monitoring; ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BP,
blood pressure; CCB, calcium channel blocker; CVD, cardiovascular disease; HBPM, home blood pressure monitoring; HMOD, hypertension-mediated organ dam-
age; SCORE, Systematic COronary Risk Evaluation; SPC, single-pill combination.
The relationship between BP and cardiovascular and renal Normal 120–129 and/or 80–84
events is continuous, making the distinction between normo-
tension and hypertension, based on cut-off BP values, some- High normal 130–139 and/or 85–89
what arbitrary [2,4,8]. However, in practice, cut-off BP values
are used for pragmatic reasons to simplify the diagnosis and Grade 1 hypertension 140–159 and/or 90–99
decisions about treatment. Epidemiological associations
between BP and cardiovascular risk extend from very low Grade 2 hypertension 160–179 and/or 100–109
levels of BP (i.e. SBP >115 mmHg). However, ‘hypertension’
is defined as the level of BP at which the benefits of treatment Grade 3 hypertension ≥180 and/or ≥110
(either with lifestyle interventions or drugs) unequivocally
outweigh the risks of treatment, as documented by clinical Isolated systolic ≥140 and <90
hypertensionb
trials. This evidence has been reviewed (see section ‘When to
initiate antihypertensive treatment’ for detailed discussion of Abbreviation: BP, blood pressure.
hypertension diagnostic thresholds) and provides the basis a BP category is defined according to seated clinic BP and by the highest
for the recommendation that the classification of BP and level of BP, whether systolic or diastolic.
definition of hypertension remain unchanged from previous b Isolated systolic hypertension is graded 1, 2, or 3 according to systolic BP
ESH/ESC Guidelines (Table 65.3) [15–17]. values in the ranges indicated. The same classification is used for all ages
Hypertension is defined as office SBP values at least from 16 years.
140 mmHg and/or diastolic BP (DBP) values at least
90 mmHg. This is based on evidence from multiple RCTs
that treatment of patients with these BP values is beneficial
(see section ‘Treatment of hypertension’). The same classi-
fication is used in younger, middle-aged, and older people, PREVALENCE OF HYPERTENSION
whereas BP centiles are used in children and teenagers, in
whom data from interventional trials are not available. Based on office BP, the global prevalence of hyper-
Details on BP classification in boys and girls 16 years or less tension was estimated to be 1.13 billion in 2015 [5],
of age can be found in the 2016 ESH Guidelines for children with a prevalence of over 150 million in central and
and adolescents [18]. Eastern Europe. The overall prevalence of hypertension
in adults is around 30–45% [12], with a global age-
standardized prevalence of 24 and 20% in men and
CLASSIFICATION OF BLOOD PRESSURE women, respectively, in 2015 [5]. This high prevalence
of hypertension is consistent across the world, irre-
Classification of BP spective of income status, that is in lower, middle and
higher income countries [12]. Hypertension becomes
Recommendation Classa Levelb progressively more common with advancing age, with
a prevalence of more than 60% in people aged more
It is recommended that BP be classified as I C than 60 years [12]. As populations age, adopt more sed-
optimal, normal, high–normal, or grades 1–3
entary lifestyles, and increase their body weight, the
hypertension, according to office BP.
prevalence of hypertension worldwide will continue
Abbreviation: BP, blood pressure. to rise. It is estimated that the number of people with
a Class of recommendation. hypertension will increase by 15–20% by 2025, reach-
b Level of evidence. ing close to 1.5 billion [19].
548 Manual of Hypertension of the European Society of Hypertension
Asymptomatic HMOD
Arterial stiffening:
Pulse pressure (in older people) 60 mmHg
Carotid–femoral PWV >10 m/s
ECG LVH (Sokolow–Lyon index >35 mm, or R in aVL ≥11 mm; Cornell voltage duration product >2440 mm*ms, or Cornell voltage >28 mm in men
or >20 mm in women)
Echocardiographic LVH [left ventricular mass index: men >50 g/m2.7; women >47 g/m2.7 (height in m2.7); indexation for BSA may be used in
normal-weight patients; left ventricular mass/BSA g/m2 >115 (men) and >95 (women)]
Microalbuminuria (30–300 mg/24 h), or elevated albumin–creatinine ratio (30–300 mg/g; 3.4–34 mg/mmol) (preferentially on morning spot urine)b
Abbreviations: BSA, body surface area; CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular
filtration rate; HDL-C, HDL cholesterol; HFpEF, heart failure with preserved ejection fraction; HMOD, hypertension-mediated organ damage; LVH, left ventricular
hypertrophy; PWV, pulse wave velocity; SCORE, Systematic COronary Risk Evaluation; TIA, transient ischaemic attack.
a CV risk factors included in the SCORE system.
b Proteinuria and reduced eGFR are independent risk factors. See Table 65.6 for cardiovascular risk modifiers.
considerations: not all features of HMOD are included in hypertension and helps identify high-risk or very high-risk
the SCORE system (CKD and established vascular disease hypertensive patients who may otherwise be misclassified
are included) and several hypertensive HMODs (e.g. car- as having a lower level of risk by the SCORE system [42].
diac, vascular, and retinal) have well established adverse This is especially true for the presence of left ventricular
prognostic significance (see section ‘Clinical evaluation hypertrophy (LVH), CKD with albuminuria or proteinuria,
and assessment of hypertension-mediated organ dam- or arterial stiffening [43] (see section ‘Clinical evaluation
age in patients with hypertension’) and may, especially if and assessment of hypertension-mediated organ damage
HMOD is pronounced, lead to a high cardiovascular risk in patients with hypertension’). The impact of progres-
even in the absence of classical cardiovascular risk fac- sion of the stages of hypertension-associated disease (from
tors; the presence of HMOD is common and often goes uncomplicated through to asymptomatic or established
undetected [38]; and the presence of multiple HMODs in disease), according to different grades of hypertension
the same patient is also common, and further increases and the presence of cardiovascular risk factors, HMOD, or
cardiovascular risk [39–41]. Consequently, the inclu- comorbidities, is illustrated in Figure 65.1 for middle-aged
sion of HMOD assessment is important in patients with individuals.
550 Manual of Hypertension of the European Society of Hypertension
Table 65.5 Ten-year cardiovascular risk categories (Systematic COronary Risk Evaluation system)
Hypertensive LVH
Abbreviations: BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; LVH, left ventricular
hypertrophy; TIA, transient ischaemic attack; PAD, peripheral artery disease; SCORE, Systematic COronary Risk Evaluation.
Table 65.6 Risk modifiers increasing cardiovascular risk Table 65.7 Correction factors for the Systemic COronary Risk
estimated by the Systemic COronary Risk Evaluation (SCORE) Evaluation (SCORE) cardiovascular risk estimates in first-genera-
system tion immigrants to Europe
Social deprivation, the origin of many causes of CVD Region of origin Multiplication factor
Obesity (measured by BMI) and central obesity (measured by waist Southern Asia 1.4
circumference)
Sub-Saharan Africa 1.3
Physical inactivity
Caribbean 1.3
Psychosocial stress, including vital exhaustion
Western Asia 1.2
Family history of premature CVD (occurring at age <55 years in men
and <60 years in women) Northern Africa 0.9
Treatment for infection with human immunodeficiency virus Source: Piepoli MF et al. Eur Heart J 2016;37:2315–2381.
Atrial fibrillation
Obstructive sleep apnoea syndrome Cardiovascular risk is strongly influenced by age (i.e. older
people are invariably at high absolute cardiovascular risk).
Source: Piepoli MF et al. Eur Heart J 2016;37:2315–2381. In contrast, the absolute risk of younger people, particu-
Abbreviations: BMI, body mass index; CKD, chronic kidney disease; CVD, larly younger women, is invariably low, even in those
cardiovascular disease. with a markedly abnormal risk factor profile. In the latter,
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 551
BP (mmHg) grading
Hypertension
Other risk factors,
disease High normal Grade 1 Grade 2 Grade 3
HMOD, or disease
staging SBP 130–139 SBP 140–159 SBP 160–179 SBP 180
DBP 85–89 DBP 90–99 DBP 100–109 or DBP 110
No other risk
Low risk Low risk Moderate risk High risk
factors
Stage 1
Moderate to
(uncomplicated) 1 or 2 risk factors Low risk Moderate risk High risk
high risk
Low to Moderate to
≥ 3 risk factors High Risk High risk
Moderate risk high risk
Established CVD,
Stage 3
CKD grade ≥ 4, or
(established Very high risk Very high risk Very high risk Very high risk
diabetes mellitus
disease)
with organ damage
Figure 65.1 Classification of hypertension stages according to blood pressure levels, presence of cardiovascular risk fac-
tors, hypertension-mediated organ damage, or comorbidities. Cardiovascular risk is illustrated for a middle-aged male.
The cardiovascular risk does not necessarily correspond to the actual risk at different ages. The use of the SCORE system is
recommended for formal estimation of cardiovascular risk for treatment decisions. Abbreviations: BP, blood pressure; CKD,
chronic kidney disease; DBP, diastolic blood pressure; HMOD, hypertension-mediated organ damage; SBP, systolic blood
pressure; SCORE, Systematic COronary Risk Evaluation.
relative risk is elevated even if absolute risk is low. The use impute out-of-office BP values into risk calculators that
of ‘cardiovascular risk age’ has been proposed as a useful have been calibrated according to office BP readings. These
way of communicating risk and making treatment deci- various limitations should be kept in mind when estimat-
sions, especially for younger people at low absolute risk ing cardiovascular risk in clinical practice.
but with high relative risk [35]. This works by illustrating
how a younger patient (e.g. a 40-year-old) with risk factors
Hypertension and cardiovascular risk assessment
but low absolute risk has a cardiovascular risk equivalent
to a much older person (60 years) with optimal risk factors; Recommendation Classa Levelb
thus, the cardiovascular risk age of the younger patient is
60 years. The cardiovascular risk age can be automatically CV risk assessment with the SCORE system is I B
calculated using HeartScore (www.heartscore.org). recommended for hypertensive patients who
A second consideration is that the presence of concomi- are not already at high or very high risk
tant disease is often recorded in a binary way in cardiovas- due to established CVD, renal disease, or
cular risk assessment systems (e.g. diabetes, yes/no). This diabetes, a markedly elevated single risk
does not reflect the impact of the severity or duration of con- factor (e.g. cholesterol), or hypertensive LVH
[33,35].
comitant diseases on total cardiovascular risk. For example,
long-standing diabetes is clearly associated with high risk, Abbreviations: CVD, cardiovascular disease; LVH, left ventricular
whereas the risk is less certain for recent-onset diabetes [34]. hypertrophy; SCORE, Systematic COronary Risk Evaluation.
A third conundrum specific to hypertension is what BP a Class of recommendation.
validated according to standardized conditions and pro- to the standardized conditions recommended for a valid
tocols [44]. BP should initially be measured in both upper measurement of office BP. Improper measurement of office
arms, using an appropriate cuff size for the arm circumfer- BP can lead to inaccurate classification, overestimation of
ence. A consistent and significant SBP difference between a patient’s true BP, and unnecessary treatment.
arms (i.e. >15 mmHg) is associated with an increased
cardiovascular risk [45], most likely due to atheromatous
vascular disease. Where there is a difference in BP between UNATTENDED OFFICE BLOOD PRESSURE
arms, ideally established by simultaneous measurement,
MEASUREMENT
the arm with the higher BP values should be used for all
subsequent measurements. Automated multiple BP readings in the doctor’s office
In older people, people with diabetes, or people with improve the reproducibility of BP measurement, and if
other causes of orthostatic hypotension, BP should also the patient is seated alone and unobserved, the ‘white-coat
be measured 1 and 3 min after standing. Orthostatic effect’ (see section ‘White-coat hypertension’) can be sub-
hypotension is defined as a reduction in SBP of at least stantially reduced [48] or eliminated [49]. Moreover, the BP
20 mmHg or in DBP of at least 10 mmHg within 3 min of values are lower than those obtained by conventional office
standing, and is associated with an increased risk of mor- BP measurement and are similar to, or even less than, those
tality and cardiovascular events [46]. Heart rate should provided by daytime ambulatory blood pressure monitor-
also be recorded at the time of BP measurements because ing (ABPM) or home blood pressure monitoring (HBPM)
resting heart rate is an independent predictor of cardio- [50]. Use of unattended office BP measurement in a recent
vascular morbid or fatal events [47], although heart rate is clinical trial [the Systolic Blood Pressure Intervention Trial
not included in any cardiovascular risk algorithm. Table (SPRINT)] [51] generated controversy about its quantitative
65.8 summarizes the recommended procedure for routine relationship to conventional office BP measurement (which
office BP measurement. It is emphasized that office BP is has been the basis for all previous epidemiological and clin-
often performed improperly, with inadequate attention ical trial data); its feasibility in routine clinical practice has
also been questioned. Presently, the relationship between
BP readings obtained with conventional office BP mea-
Table 65.8 Office blood pressure measurement surement and unattended office BP measurement remains
Patients should be seated comfortably in a quiet environment for 5 min
unclear, but available evidence suggests that conventional
before beginning BP measurements. office SBP readings may be at least 5–15 mmHg higher than
SBP levels obtained by unattended office BP measurements
Three BP measurements should be recorded, 1–2 min apart, and [52]. There is also very limited evidence on the prognos-
additional measurements only if the first two readings differ by tic value of unattended office BP measurements, that is
>10 mmHg. BP is recorded as the average of the last two BP readings. whether they guarantee at least the same ability to predict
outcomes as conventional office BP measurements [53].
Additional measurements may have to be performed in patients with
unstable BP values due to arrhythmias, such as in patents with AF, in
who- m manual auscultatory methods should be used as most
automated devic-es have not been validated for BP measurement in OUT-OF-OFFICE BLOOD PRESSURE
patients with AF.a MEASUREMENT
Use a standard bladder cuff (12–13 cm wide and 35 cm long) for Out-of-office BP measurement refers to the use of either
most patients, but have larger and smaller cuffs available for larger HBPM or ABPM, the latter usually over 24 h. It provides
(arm circumference >32 cm) and thinner arms, respectively. a larger number of BP measurements than conventional
office BP in conditions that are more representative of
The cuff should be positioned at the level of the heart, with the back
daily life. Recent position papers and practice guidelines
and arm supported to avoid muscle contraction and isometric
exercise-dependent increases in BP.
provide comprehensive details for ABPM [54] and HBPM
[55], and are briefly summarized below [54,56].
When using auscultatory methods, use phase I and V (sudden reduction/
disappearance) Korotkoff sounds to identify SBP and DBP, respectively.
undertaken, an alarming number of people (>50%) were weeks), depending on the severity of BP elevation and
unaware they had hypertension [12,98]. This high rate whether there is evidence of CVD or HMOD. Conversely,
of undetected hypertension occurred irrespective of the in patients with BP elevation in the grade 1 range, the
income status of the countries studied across the world. period of repeat measurements may extend over a few
All adults should have their BP recorded in their medi- months, especially when the patient is at low risk and
cal record and be aware of their BP, and further screen- there is no HMOD. During this period of BP assessment,
ing should be undertaken at regular intervals with the cardiovascular risk assessment and routine screening tests
frequency dependent on the BP level. For healthy people are usually performed (see section ‘Definition, classifica-
with an optimal office BP (<120/80 mmHg), BP should tion, and epidemiological aspects of hypertension’).
be remeasured at least every 5 years and more frequently These Guidelines also support the use of out-of-office BP
when opportunities arise. In patients with a normal measurements (i.e. HBPM and/or ABPM) as an alternative
BP (120–129/80–84), BP should be remeasured at least strategy to repeated office BP measurements to confirm the
every 3 years. Patients with high–normal BP (130–139/ diagnosis of hypertension, when these measurements are
85–89 mmHg) should have their BP recorded annually logistically and economically feasible (Figure 65.2) [99].
because of the high rates of progression of high–normal This approach can provide important supplementary clini-
BP to hypertension. This is true also for people in whom cal information, for example detecting white-coat hyperten-
masked hypertension is detected. sion (see section ‘White-coat hypertension’), which should
be suspected, especially in people with grade 1 hyperten-
sion on office BP measurement and in whom there is no
CONFIRMING THE DIAGNOSIS OF evidence of HMOD or CVD [100] (Table 65.11). A particu-
lar challenge is the detection of masked hypertension (see
HYPERTENSION section ‘Masked hypertension’). Masked hypertension is
BP can be highly variable, thus the diagnosis of hyper- more likely in people with a BP in the high– normal range
tension should not be based on a single set of BP read- in whom out-of-office BP should be considered to exclude
ings at a single office visit, unless the BP is substantially masked hypertension (see Table 65.8). Out-of-office BP
increased (e.g. grade 3 hypertension) and there is clear measurements are also indicated in specific circumstances
evidence of HMOD (e.g. hypertensive retinopathy with (see section ‘Clinical indications for out-of-office blood
exudates and haemorrhages, or LVH, or vascular or renal pressure measurements’ and Table 65.11).
damage). For all others (i.e. almost all patients), repeat
BP measurements at repeat office visits have been a long-
standing strategy to confirm a persistent elevation in BP, CLINICAL INDICATIONS FOR OUT-OF-OFFICE
as well as for the classification of the hypertension status BLOOD PRESSURE MEASUREMENTS
in clinical practice and RCTs. The number of visits and
the time interval between visits varies according to the Out-of-office BP measurements are increasingly used,
severity of the hypertension, and is inversely related to especially HBPM but also ABPM, to confirm the diag-
the severity of hypertension. Thus, more substantial BP nosis of hypertension. Out-of-office BP measurement
elevation (e.g. grade 2 or more) requires fewer visits and provides important complementary information, as dis-
shorter time intervals between visits (i.e. a few days or cussed above. The clinical indications for out-of-office
Out-of-office BP
Consider masked measurement
hypertension (ABPM or HBPM)
Use
either to
confirm
diagnosis
Indications for
ABPM or HBPM see Table 65.11
Figure 65.2 Screening and diagnosis of hypertension. ABPM, ambulatory blood pressure monitoring; BP, blood pressure;
HBPM, home blood pressure monitoring.
556 Manual of Hypertension of the European Society of Hypertension
BP measurement
BP measurements are shown in Table 65.11. HBPM is
also increasingly used by patients to monitor their BP Recommendations Classa Levelb
control, which increases their engagement and may
improve their adherence to treatment and BP control Screening programmes for hypertension are I B
[61,101,102]. It is likely that, with increased availability recommended. All adults (18 years or older)
and lower cost of these devices, this will become more should have their office BP measured and
commonplace. recorded in their medical file, and be aware of
their BP [12,98].
Other BP measures and indices (pulse pressure, IIb C Physical examination provides important indications
BP variability, exercise BP, and central BP) may of potential causes of secondary hypertension, signs
be considered but are not often used for routine of comorbidities, and HMOD. Office BP and heart rate
clinical use at present. should be measured as summarized in section ‘Blood pres-
They may provide useful additional information sure measurement’.
in some circumstances and are valuable tools Measurements of office BP on more than one occasion
for research. are usually required to confirm the diagnosis of hyperten-
Abbreviations: ABPM, ambulatory blood pressure monitoring; AF, atrial
sion unless HBPM or ABPM is used to confirm the diagno-
fibrillation; BP, blood pressure; HBPM, home blood pressure monitoring.
sis (see section ‘Blood pressure measurement’).
a Class of recommendation. Details of the requirements for a comprehensive clinical
b Level of evidence. examination are outlined in Table 65.13, and this should
be adapted according to the severity of hypertension and
clinical circumstances. Suggested routine clinical investi-
gations are outlined in Table 65.14.
CLINICAL EVALUATION AND
ASSESSMENT OF HYPERTENSION-
MEDIATED ORGAN DAMAGE IN ASSESSMENT OF HYPERTENSION-MEDIATED
PATIENTS WITH HYPERTENSION ORGAN DAMAGE
HMOD refers to structural or functional changes in arter-
CLINICAL EVALUATION ies or end organs (heart, blood vessels, brain, eyes, and
kidney) caused by an elevated BP, and is a marker of pre-
The purpose of the clinical evaluation is to establish the clinical or asymptomatic CVD [112]. HMOD is common
diagnosis and grade of hypertension, screen for potential in severe or long-standing hypertension, but can also be
secondary causes of hypertension, identify factors poten- found in less severe hypertension. With wider use of imag-
tially contributing to the development of hypertension ing, HMOD is becoming increasingly apparent in asymp-
(lifestyle, concomitant medications or family history); tomatic patients [43]. Cardiovascular risk increases with
identify concomitant cardiovascular risk factors (includ- the presence of HMOD, and more so when damage affects
ing lifestyle and family history); identify concomitant dis- multiple organs [16,113,114]. Some types of HMOD can
eases and establish whether there is evidence of HMOD or be reversed by antihypertensive treatment, especially
existing cardiovascular, cerebrovascular or renal disease. when used early, but with long-standing hypertension,
HMOD may become irreversible despite improved BP
control [115,116]. Nevertheless, BP-lowering treatment is
MEDICAL HISTORY still important as it may delay the further progression of
HMOD and will reduce the elevated cardiovascular risk
A thorough medical history (Table 65.12) should address of these patients [116]. Although poor technical provision
in particular: and cost may limit the search for HMOD in some countries,
558 Manual of Hypertension of the European Society of Hypertension
Table 65.12 Key information to be collected in personal and family medical history
Risk factors
■■ Family and personal history of hypertension, CVD, stroke, or renal disease
■■ Family and personal history of associated risk factors (e.g. familial hypercholesterolaemia)
■■ Smoking history
■■ Dietary history and salt intake
■■ Alcohol consumption
■■ Lack of physical exercise/sedentary lifestyle
■■ History of erectile dysfunction
■■ Sleep history, snoring, sleep apnoea (information also from partner)
■■ Previous hypertension in pregnancy/pre-eclampsia
Abbreviations: AF, atrial fibrillation; BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; HMOD, hypertension-mediated organ
damage; TIA, transient ischaemic attack.
Table 65.13 Key steps in physical examination Table 65.14 Routine workup for evaluation of hypertensive
patients
Body habitus
■■ Weight and height measured on a calibrated scale, with calculation Routine laboratory tests
of BMI
■■ Waist circumference Haemoglobin and/or haematocrit
Echocardiography To evaluate cardiac structure and function, when this information will influence treatment decisions
Carotid ultrasound To determine the presence of carotid plaque or stenosis, particularly in patients with cerebrovascular disease
or vascular disease elsewhere
Abdominal ultrasound and Doppler To evaluate renal size and structure (e.g. scarring) and exclude renal tract obstruction as possible underlying
studies causes of CKD and hypertension
Evaluate abdominal aorta for evidence of aneurysmal dilatation and vascular disease
Examine adrenal glands for evidence of adenoma or phaeochromocytoma (CT or MRI preferred for detailed
examination); see section ‘Secondary hypertension’ regarding screening for secondary hypertension
Renal artery Doppler studies to screen for the presence of renovascular disease, especially in the presence of
asymmetric renal size
Abbreviations: ABI, ankle-brachial index; CKD, chronic kidney disease; CT, computed tomography; eGFR, estimated glomerular filtration rate; HMOD, hypertension-
mediated organ damage; LEAD, lower extremity artery disease; LVH, left ventricular hypertrophy; MRI, magnetic resonance imaging; PWV, pulse wave velocity.
it is recommended that basic screening for HMOD is per- whom will be at moderate-risk and at higher risk if HMOD
formed in all hypertensive patients and more detailed is detected. Moreover, a risk-conditioning effect of HMOD
assessment is performed when the presence of HMOD will also be important in younger hypertensive patients
might influence treatment decisions. The various investi- who are invariably classified as low risk according to the
gations to establish HMOD are shown in Table 65.15. SCORE system. In addition, detecting HMOD in younger
patients with grade 1 hypertension provides unequivocal
evidence of hypertension-mediated damage and indicates
USING HYPERTENSION-MEDIATED ORGAN a clear need for BP-lowering treatment in patients who may
DAMAGE TO HELP STRATIFY RISK IN HYPERTENSIVE be reluctant to be treated. For the same reason, the pres-
PATIENTS ence of HMOD in a patient with high–normal BP would
As discussed in section ‘Definition, classification, and also provide a rationale to consider BP-lowering treatment.
epidemiological aspects of hypertension’, hypertensive Another important consideration is whether the pres-
patients with documented CVD, diabetes, CKD, grade 3 ence of a specific manifestation of HMOD (e.g. LVH or
hypertension, or marked cholesterol elevation (e.g. famil- CKD) might influence the selection of drug treatment for
ial hypercholesterolaemia) are already at high or very high hypertension. This was considered important in the previ-
cardiovascular risk (10% risk of a fatal event). Thus, the ous guidelines [17], but is now considered less important.
presence of HMOD is unlikely to influence treatment, as In patients more likely to have HMOD (i.e. those with high
these patients should already receive lifestyle interven- grade 1 or grade 2–3 hypertension), we now recommend
tions, BP-lowering medications, statins, and in some cases initial treatment with a combination of two drugs, usu-
antiplatelet therapy, to reduce their risk [35] (see section ally an angiotensin-converting enzyme (ACE) inhibitor or
‘Managing concomitant cardiovascular disease risk’). angiotensin receptor blocker (ARB) in combination with a
The main advantage of detecting HMOD is that it may calcium channel blocker (CCB) or thiazide-type diuretic,
reclassify a patient’s SCORE risk assessment from low to which would be the optimal treatment for all manifesta-
moderate or from moderate to high risk [117]. The specific tions of HMOD (see section ‘Treatment of hypertension’).
impact of HMOD [114] with regard to the reclassification
of risk estimation according to the SCORE system has not
been clearly defined. The SCORE system already takes
account of the grade of hypertension as SBP is included CHARACTERISTICS OF HYPERTENSION-
in the risk calculation. Moreover, CKD and the presence MEDIATED ORGAN DAMAGE
of vascular disease on imaging are already specified as
high or very high risk (Table 65.5). Conditioning of the THE HEART IN HYPERTENSION
risk score by the presence of HMOD will be most impor- Chronically increased left ventricular workload in hyper-
tant in middle-aged patients with hypertension, many of tensive patients can result in LVH, impaired left ventricular
560 Manual of Hypertension of the European Society of Hypertension
PULSE WAVE VELOCITY Serum creatinine, eGFR and ACR should be documented
Large artery stiffening is the most important pathophysi- in all hypertensive patients, and if CKD is diagnosed,
ological determinant of isolated systolic hypertension and repeated at least annually [159]. One negative urinary dip-
agedependent increase in pulse pressure [148]. Carotid- stick test does not rule out albuminuria, in contrast to a
femoral pulse wave velocity (PWV) is the gold standard normal ACR [160].
for measuring large artery stiffness [149]. Reference values
for PWV are available in healthy populations and patients
at increased cardiovascular risk [150]. A PWV more than HYPERTENSIVE RETINOPATHY
10 m/s is considered a conservative estimate of significant The prognostic significance of hypertensive retinopathy by
alterations of aortic function in middle-aged hyperten- fundoscopy has been well documented [161]. Detection
sive patients [149]. The additive value of PWV above and of retinal haemorrhages, microaneurysms, hard exudates,
beyond traditional risk factors, including SCORE and the cotton wool spots, and papilloedema is highly reproduc-
Framingham risk score, has been suggested by several ible, indicates severe hypertensive retinopathy, and is
studies [151]. However, routine use of PWV measure- highly predictive of mortality [161,162]. In contrast, evi-
ment is not practical and is not recommended for routine dence of arteriolar narrowing, either focal or general,
practice. and arteriovenous nicking at early stages of hypertensive
retinopathy have less predictive value [163], and limited
ANKLE–BRACHIAL INDEX interobserver and intraobserver reproducibility, even
Ankle-brachial index (ABI) may be measured either with with experienced observers [164]. Fundoscopy should be
automated devices, or with a continuous wave Doppler performed in patients with grade 2 or 3 hypertension or
unit and a BP sphygmomanometer. A low ABI (i.e. <0.9) hypertensive patients with diabetes, in whom significant
indicates lower extremity artery disease (LEAD), is usu- retinopathy is more likely. Fundoscopy may be considered
ally indicative of advanced atherosclerosis [152], and has in other hypertensive patients. The increasing emergence
predictive value for cardiovascular events [153], being of new techniques to visualize the fundus through smart-
associated with an almost two-fold greater 10-year cardio- phone technologies should increase the feasibility of more
vascular mortality and major coronary event rate, com- routine fundoscopy [165].
pared with the overall rate in each Framingham category
[153]. Even asymptomatic LEAD, detected by a low ABI,
THE BRAIN IN HYPERTENSION
is associated in men with a high incidence of cardiovas-
cular morbid and fatal events, approaching 20% in 10 Hypertension increases the prevalence of brain dam-
years [153,154]. Routine use of ABI is not recommended age, of which transient ischaemic attack (TIA) and stroke
in hypertensive patients, but should be considered in are the most dramatic acute clinical manifestations. In
patients with symptoms or signs of LEAD, or in moderate- the asymptomatic phase, brain damage can be detected
risk patients in whom a positive test would reclassify the by MRI as white matter hyperintensities, silent micro-
patient as high-risk. infarcts, (most of which are small and deep, i.e. lacunar
infarctions), microbleeds and brain atrophy [166,167].
White matter hyperintensities and silent infarcts are
THE KIDNEY IN HYPERTENSION associated with an increased risk of stroke and cogni-
Hypertension is the second most important cause of CKD tive decline due to degenerative and vascular dementia
after diabetes. Hypertension may also be the present- [166–169]. Availability and cost do not permit the wide-
ing feature of asymptomatic primary renal disease. An spread use of brain MRI for the evaluation of hypertensive
alteration of renal function is most commonly detected patients, but white matter hyperintensity and silent brain
by an increase in serum creatinine. This is an insensitive infarcts should be sought in all hypertensive patients
marker of renal impairment because a major reduction with neurological disturbances, cognitive decline, and,
in renal function is needed before serum creatinine rises. particularly, memory loss [168,169]. A family history
Furthermore, BP reduction by antihypertensive treat- of cerebral haemorrhage at middle age and early-onset
ment often leads to an acute increase in serum creatinine dementia should prompt MRI. Cognitive impairment in
by as much as 20–30%, especially with renin–angioten- older patients is, at least in part, hypertension-related,
sin system (R AS) blockers, which has a functional basis and cognitive evaluation tests should be considered in the
and does not usually reflect manifest renal injury, but clinical assessment of hypertensive patients with a his-
the long-term clinical significance is unclear [155,156]. tory suggestive of early cognitive impairment. The Mini-
The diagnosis of hypertension-induced renal damage is Mental State Examination has been the most widely used
based on the finding of reduced renal function and/or method in clinical trials, but is now being superseded by
the detection of albuminuria. CKD is classified accord- more sophisticated cognitive tests that are more suitable
ing to estimated glomerular filtration rate (eGFR), cal- for routine clinic visits [170].
culated by the 2009 CKD-Epidemiology Collaboration
formula [157].
The albumin:creatinine ratio (ACR) is measured from
a spot urine sample (preferably early morning urine), HYPERTENSION-MEDIATED ORGAN DAMAGE
and is the preferred method to quantify urinary albumin REGRESSION AND CARDIOVASCULAR RISK
excretion. A progressive reduction in eGFR and increased REDUCTION WITH ANTIHYPERTENSIVE
albuminuria indicate progressive loss of renal function, TREATMENT
and are both independent and additive predictors of
increased cardiovascular risk and progression of renal As discussed above, HMOD assessment may play a role in
disease [158]. stratifying the risk of patients with hypertension. In posthoc
562 Manual of Hypertension of the European Society of Hypertension
Table 65.18 Sensitivity to detect treatment-induced changes, reproducibility and operator independence, time to changes, and
prognostic value of changes provided by markers of hypertension-mediated organ damage
Abbreviations: CMR, cardiac magnetic resonance; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HMOD, hypertension-mediated organ
damage; IMT, intima–media thickness; LVH, left ventricular hypertrophy; PWV, pulse wave velocity.
Echocardiography: I B
■■ Is recommended in hypertensive patients when there are ECG abnormalities or signs or symptoms of LV dysfunction [42,134].
■■ May be considered when the detection of LVH may influence treatment decisions [42,134]. IIb B
Continued
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 563
Blood vessels
Measurement of PWV may be considered for measuring arterial stiffness [109,189]. IIb B
Measurement of ABI may be considered for the detection of advanced LEAD [153,190]. IIb B
Kidney
Measurement of serum creatinine and eGFR is recommended in all hypertensive patients [180]. I B
Renal ultrasound and Doppler examination should be considered in patients with impaired renal function, albuminuria, or for IIa C
suspected secondary hypertension.
Fundoscopy
Is recommended in patients with grades 2 or 3 hypertension and all hypertensive patients with diabetes. I C
Brain
In hypertensive patients with neurological symptoms and/or cognitive decline, brain MRI or CT should be considered for IIa B
detecting brain infarctions, microbleeds, and white matter lesions [168,169].
Abbreviations: ABI, ankle-brachial index; CKD, chronic kidney disease; CT, computed tomography; eGFR, estimated glomerular filtration rate; HMOD, hypertension-
mediated organ damage; LEAD, lower extremity artery disease; LVH, left ventricular hypertrophy; MRI, magnetic resonance imaging; PWV, pulse wave velocity.
a Class of recommendation.
b Level of evidence.
of decline in renal function in most hypertensive patients to RCTs in patients with grade 1 hypertension and low–
makes the demonstration of potential benefits of BP lower- moderate-risk (five RCTs, 8974 patients), demonstrated a
ing difficult. Consequently, the protective effect of BP reduc- significant reduction in all major cardiovascular events by
tion on kidney function can be less obvious and has been BP-lowering drug treatment [combined stroke and coro-
restricted to patients with diabetes or CKD, in whom there nary artery disease (CAD) reduced by 34%, and all-cause
is a faster rate of disease progression [203]. Some, but not mortality by 19% for an SBP reduction of 7 mmHg] [8].
all, RCTs have also shown a protective effective of BP low- A third analysis demonstrated a benefit of BP lowering in
ering on the progression of CKD towards end-stage renal reducing death and CVD in patients with a baseline BP
disease in both diabetic and nondiabetic nephropathy [2]. 140/90 mmHg or higher, but not when baseline BP was
The recommendations that follow are based on outcome lower [201]. These findings have been supported by the
evidence from RCTs; however, it must be acknowledged results of a subgroup analysis of the Heart Outcomes
that RCTs based on clinical outcomes have limitations, the Prevention Evaluation (HOPE)-3 trial, showing a signifi-
most important of which are that the data are largely lim- cant 27% reduction in major cardiovascular outcomes
ited to older and high-risk patients, preferentially recruited in patients at intermediate cardiovascular risk and base-
to increase statistical power, and over a relatively short line SBP values in the grade 1 hypertensive range [i.e.
duration of follow-up, rarely beyond 5 years. This means >143.5 mmHg (mean 154 mmHg)] when SBP was lowered
that recommendations for life-long treatment for younger by drug treatment by a mean of 6 mmHg [212].
and lower risk patients are necessarily based on consid- Based on these new data, this Task Force now recom-
erable extrapolation. Big data, now being collected by mends that lifestyle advice should be accompanied by
national health system registries, health insurance compa- BP-lowering drug treatment in patients with grade 1
nies, and prolonged observational follow-up of RCTs, are hypertension at low–moderate cardiovascular risk.
becoming an important source of long-term information
on the effects of chronic treatment [204], which adds to
that provided by observational studies over several decades INITIATION OF BLOOD PRESSURE-LOWERING DRUG
[205–207]. Such evidence suggests that the benefit of con- TREATMENT IN OLDER PEOPLE WITH GRADE 1
tinued treatment is maintained over decades [206]. HYPERTENSION
Discussion about the treatment of ‘the elderly’ or ‘older’
people has been complicated by the various definitions of
older age used in RCTs. For example, older was defined as
WHEN TO INITIATE ANTIHYPERTENSIVE more than 60 years in the earliest trials, then as 65, 70 and
TREATMENT finally 75 [51] or 80 years [213] in later trials. Chronological
age is often a poor surrogate for biological age, with con-
RECOMMENDATIONS IN PREVIOUS GUIDELINES sideration of frailty and independence influencing the
All guidelines agree that patients with grade 2 or 3 hyper- likely tolerability of BP-lowering medications. For the pur-
tension should receive antihypertensive drug treatment poses of this guideline, the ‘old’ are defined as at least 65
alongside lifestyle interventions [208]. Guidelines are years and the ‘very old’ as at least 80 years. The previous
also consistent in recommending that patients with grade Guidelines [17] noted that all available evidence on cardio-
1 hypertension and high cardiovascular risk or HMOD vascular event reduction by BP lowering in older patients
should be treated with BP-lowering drugs. There has been was obtained in patients whose baseline SBP was at least
less consistency about whether BP-lowering drugs should 160 mmHg, and there is strong evidence that these patients
be offered to patients with grade 1 hypertension and low– should be offered BP-lowering drug treatment [210,214].
moderate cardiovascular risk or grade 1 hypertension in Undoubtedly, there are RCTs showing outcome ben-
older patients (>60 years), or the need for BP-lowering efits with BP-lowering treatment in older patients whose
drug treatment in patients with high–normal BP levels baseline BP was in a lower SBP range, but these patients
[17,209,210]. This uncertainty relates to the fact that low- were often on background antihypertensive treatment,
risk patients with high–normal BP or grade 1 hyperten- thus they cannot be defined as having true grade 1 hyper-
sion have rarely been included in RCTs, and that in older tension. This is also the case for the data recently pub-
patients, RCTs have invariably recruited patients with at lished from the SPRINT trial, which included a cohort of
least grade 2 hypertension. New analyses and RCT data patients older than 75 years, in whom more intense BP
have become available in these important areas and are lowering reduced the risk of major cardiovascular events
discussed below. and mortality [51,215]. However, in most RCTs showing
a protective effect of BP-lowering treatment in patients
with an untreated baseline BP in the grade 1 hypertension
DRUG TREATMENT FOR PATIENTS WITH GRADE 1 range, older patients were well represented. This was fur-
HYPERTENSION AT LOW-MODERATE ther supported by the recent HOPE-3 trial, which showed
CARDIOVASCULAR RISK beneficial effects of BP lowering on cardiovascular out-
Recent meta-analyses show significant treatment-induced comes in patients, many with grade 1 hypertension (SBP
reductions in cardiovascular events and mortality in >143 mmHg and mean BP 154 mmHg), whose mean age
patients with grade 1 hypertension [8,201,211]. However, was 66 years, and in whom only 22% had prior treatment
the first of these analyses included a substantial number of hypertension [212].
of patients who had grade 1 hypertension despite exist- The evidence supports the recommendation that older
ing treatment, and were therefore likely to have had ini- patients (>65 years, including patients over 80 years)
tial BPs above the grade 1 range. Furthermore, many of should be offered BP-lowering treatment if their SBP is at
the patients had diabetes and were therefore at high car- least 160 mmHg. There is also justification to now recom-
diovascular risk [211]. The second meta-analysis, limited mend BP-lowering treatment for old patients (aged >65 but
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 565
not >80 years) at a lower BP (i.e. grade 1 hypertension; SBP cardiovascular events (relative risk 0.90; 95% con-
140–159 mmHg) [201]. BP-lowering drugs should not be fidence interval 0.84–0.97), but was not associated
withdrawn on the basis of age alone. It is well established with an increased survival (relative risk 0.98; 95%
that BP-lowering treatment withdrawal leads to a marked confidence interval 0.89–1.07) [201]. Thus, the benefit
increase in cardiovascular risk. This was exemplified in older for treating people with high–normal BP appears
patients by a recent subgroup analysis of the Hypertension marginal and, if present, appears to be restricted to
in the Very Elderly Trial (HYVET) [213], reporting that in those at very high cardiovascular risk and established
patients aged at least 80 years, cardiovascular risk reduc- CVD, especially CAD.
tion was greatest in those who continued treatment rather
than in those whose treatment was discontinued [216]. As We recommend that patients with high–normal BP and
stated above, all of the above recommendations relate to low–moderate cardiovascular risk should be offered life-
relatively fit and independent older patients, because physi- style advice, because this reduces their risk of progress-
cally and mentally frail and institutionalized patients have ing to established hypertension and may further reduce
been excluded in most RCTs of patients with hypertension their cardiovascular risk. These patients should not be
[214]. Further details of the treatment of hypertension in offered BP-lowering drug treatment. Nevertheless, based
older patients and very old patients is provided in section on the data from the HOPE-3 trial, drug treatment may
‘Hypertension in older patients (Age 65 years)’. be considered in these patients if their BP is close to the
hypertension diagnostic threshold of 140/90 mmHg, after
a prolonged attempt to control BP with lifestyle changes.
INITIATION OF BLOOD PRESSURE-LOWERING DRUG
BP-lowering drugs may be considered for patients with
TREATMENT IN PATIENTS WITH HIGH-NORMAL
high–normal BP and established CVD, especially CAD. In
BLOOD PRESSURE these patients, monotherapy may be sufficient.
The previous (2013) Guidelines [17] recommended not to
initiate antihypertensive treatment in people with high–
normal BP and low–moderate cardiovascular risk. This SHOULD BLOOD PRESSURE-LOWERING DRUG
recommendation is further supported by new evidence: TREATMENT BE INITIATED ON THE BASIS OF BLOOD
PRESSURE VALUES OR THE LEVEL OF TOTAL
1. In all RCTs (including SPRINT) [51] and meta-analy- CARDIOVASCULAR RISK?
ses [2] that have reported reduced major outcomes by Two recent meta-analyses of RCTs [8,218] have shown that
lowering ‘baseline’ BP in the high–normal range, the when BP-lowering data are stratified according to cardiovas-
‘baseline’ BP was commonly measured on a back- cular risk, the relative risk reductions do not differ across
ground of antihypertensive treatment. Therefore, these the various risk strata; not surprisingly, the absolute risk
studies do not provide evidence to support treatment reduction is greater with increasing baseline cardiovascular
initiation in patients without hypertension [8]. risk. These data have been taken as support for the hypoth-
2. The HOPE-3 trial [212], in which only 22% of the esis that BP-lowering treatment should be based on car-
patients at intermediate cardiovascular risk had diovascular risk and target those at greatest cardiovascular
background antihypertensive treatment, showed risk, irrespective of their BP [218]. However, it has recently
that BP-lowering treatment did not reduce the risk of been made that whereas patients at high or very high car-
major cardiovascular events in patients with baseline diovascular risk exhibit the greatest absolute reduction in
SBP values in the high–normal range. cardiovascular outcomes with BP-lowering treatment, they
3. A meta-analysis of 13 RCTs or RCT subgroups (involv- also have the highest residual risk, which means failure of
ing 21 128 individuals) in patients at low–moderate treatment to exert full protection [8]. It is the opinion of
cardiovascular risk and untreated baseline BP in the this Task Force that these data support earlier treatment of
high–normal and normal range, showed no effect of patients with SBP or DBP values more than 140/90 mmHg
BP-lowering treatment on any cardiovascular out- when their cardiovascular risk is still low–moderate, to pre-
comes [217]. vent the accumulation of HMOD and a high incidence of
4. Another recent analysis, including patients with high– late treatment failure (residual risk), which would otherwise
normal BP, concluded that primary preventive BP occur if treatment was delayed by a purely cardiovascular
lowering was associated with reduced risk for death risk-based approach. The most effective strategy to reduce
and incident CVD if baseline SBP was 140 mmHg or risk is to prevent the development of high cardiovascular-
higher, but at lower BP levels [i.e. high–normal BP risk situations with earlier intervention. The assessment
(<140/90 mmHg)], treatment was not associated with of cardiovascular risk is at the core of the treatment strat-
any benefit in primary prevention [201]. egy recommended by these Guidelines because of the fre-
5. The situation may be different in very high-risk quent coexistence of multiple cardiovascular risk factors in
patients with a high–normal BP and established hypertensive patients, and to inform the use of concomitant
CVD. In a meta-analysis of 10 RCTs or RCT subgroups medications (e.g. statins, antiplatelet therapies, etc., see sec-
that also included individuals at high or very high tion ‘Managing concomitant cardiovascular disease risk’)
cardiovascular risk, mostly with previous CVD and to reduce cardiovascular risk. We conclude that, in gen-
untreated high–normal and normal BP (n 26 863), eral, the decision to use BP-lowering treatment should not
BP-lowering drug treatment, achieving an SBP reduc- be based solely on the level of cardiovascular risk because
tion of 4 mmHg, reduced the risk of stroke but not even in patients at the highest risk (with established CVD),
any other cardiovascular events [217]. In another when baseline BP is below 140/90 mmHg, the benefits of
analysis of trials including people with previous BP-lowering treatment are at best marginal and most evi-
CAD and a mean baseline SBP of 138 mmHg, treat- dent in patients with CAD at the upper end of the high–nor-
ment was associated with reduced risk for major mal BP range [201].
566 Manual of Hypertension of the European Society of Hypertension
Drug treatment in
low moderate risk patients Aim for BP control Aim for BP control
without CVD, renal disease within 3 months within 3 months
or HMOD after
3-6 months of lifestyle
intervention if BP not
controlled
Figure 65.3 Initiation of blood pressure-lowering treatment (lifestyle changes and medication) at different initial office
blood pressure levels. Abbreviations: BP, blood pressure; CAD, coronary artery disease; CVD, cardiovascular disease; HMOD,
hypertension-mediated organ damage.
INITIATION OF BLOOD PRESSURE-LOWERING DRUG also be initiated simultaneously with lifestyle interventions.
TREATMENT In lower-risk patients with grade 1 hypertension, BP-lowering
In patients with grade 2 or 3 hypertension, it is recommended drug treatment should be initiated after 3–6 months if BP is
that BP-lowering drug treatment should be initiated along- not controlled by lifestyle interventions alone (Figure 65.3).
side lifestyle interventions. In patients with grade 1 hyper- Recommended BP thresholds for the initiation of antihyper-
tension at high risk or with HMOD, drug treatment should tensive drug treatment are shown in Table 65.19.
Prompt initiation of BP-lowering drug treatment is recommended in patients with grade 2 or 3 hypertension at any level of CV I A
risk, simultaneous with the initiation of lifestyle changes [2,8].
In fit older patients with hypertension (even if aged >80 years), BP-lowering drug treatment and lifestyle intervention are I A
recommended when SBP is ≥160 mmHg [210,220,221].
BP-lowering drug treatment and lifestyle intervention are recommended for fit older patients (>65 years but not >80 years) when I A
SBP is in the grade 1 range (140–159 mmHg), provided that treatment is well tolerated [212].
Antihypertensive treatment may also be considered in frail older patients if tolerated [215]. IIb B
Withdrawal of BP-lowering drug treatment on the basis of age, even when patients attain an age of ≥80 years, is not recom- III A
mended, provided that treatment is well tolerated [213].
Abbreviations: BP, blood pressure; CAD, coronary artery disease; CVD, cardiovascular disease; HMOD, hypertension-mediated organ damage.
a Class of recommendation.
b Level of evidence.
c In patients with grade 1 hypertension and at low–moderate-risk, drug treatment may be preceded by a prolonged period of lifestyle intervention to determine if
this approach will normalize BP. The duration of the lifestyle intervention alone will depend on the level of BP within the grade 1 range, that is the likelihood of
achieving BP control with lifestyle intervention alone, and the opportunities for significant lifestyle change in individual patients.
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 567
Abbreviations: BP, blood pressure; CAD, coronary artery disease; CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure; TIA,
transient ischaemic attack.
a Treatment may be considered in these very high-risk patients with high–normal SBP (i.e. SBP 130–140 mmHg).
some groups the evidence is less compelling. In older reduction in cardiovascular events with intensive SBP
patients (>65 years), SBP should be targeted to between lowering to less than 130 mmHg [236].
130 and 140 mmHg, and DPB to less than 80 mmHg. 6. Further recent analysis of the ACCORD trial has
Treated SBP should not be targeted to less than 120 mmHg. shown that reducing SBP to less than 120 mmHg was
Importantly, we specify a target range because the associated with increased risk of major cardiovascular
lower safety boundary assumes greater importance when events [236].
BP is targeted to lower levels. Furthermore, in general, 7. With regard to DBP, earlier evidence suggested a
when SBP is lowered to less than 120 mmHg in patients benefit on major cardiovascular events when DBP
included in RCTs (i.e. older and higher-risk patients, often was lowered to less than 85 mmHg [237,238]. More
with comorbidities and CVD), the risk of harm appears to recently, in the Action in Diabetes and Vascular
increase and outweigh the benefits [222]. Disease: Preterax and Diamicron – MR Controlled
Evaluation (ADVANCE) trial [229], the benefits on
cardiovascular outcomes were observed at diastolic
BLOOD PRESSURE TARGETS IN SPECIFIC
pressures of 75 mmHg. This is consistent with evi-
SUBGROUPS OF HYPERTENSIVE PATIENTS
dence from the meta-analyses cited above, that it is
DIABETES MELLITUS safe and effective to lower DBP to less than 80 mmHg
RCTs in type 1 diabetes mellitus demonstrate that in patients with type 2 diabetes.
BP-lowering treatment has a renoprotective effect [228],
but because these patients tend to be younger, previous In summary, in patients with diabetes receiving
RCTs have had inadequate power to study cardiovascular BP-lowering drugs, it is recommended that office BP should
outcomes and to establish optimal BP targets. be targeted to an SBP of 130 mmHg [229], and lower if toler-
In contrast, there have been many BP-lowering treat- ated. In older patients (aged ≥65 years) the SBP target range
ment RCTs, either exclusively dedicated to patients with should be 130–140 mmHg [213] if tolerated. SBP should
type 2 diabetes or hypertension trials that have included not be lowered to less than 120 mmHg and DBP should be
a large cohort of patients with type 2 diabetes [2]. Most lowered to less than 80 mmHg. Attention should also be
of these RCTs have shown that BP lowering to less than given to the consistency of BP control, because visit-to-visit
140/85 mmHg is beneficial in patients with type 2 diabetes BP variability is associated with increased cardiovascular
and hypertension. However, the results have been less clear and renal disease risk. Furthermore, cardiovascular protec-
about whether a lower BP target is associated with further tion has been found to be greater when BP control is accom-
benefits. The evidence can be summarized as follows: panied by fewer visit-to-visit BP variations [239–241].
in part due to poor dietary persistence. The BP-lowering OTHER DIETARY CHANGES
effect of sodium restriction is greater in black people, in Hypertensive patients should be advised to eat a healthy
older patients, and in patients with diabetes, metabolic balanced diet containing vegetables, legumes, fresh
syndrome, or CKD [249]. In people with treated hyperten- fruits, low-fat dairy products, whole grains, fish, and
sion, effective sodium restriction may reduce the number unsaturated fatty acids (especially olive oil), and to have
or dose of BP-lowering drugs that are necessary to control a low consumption of red meat and saturated fatty acids
BP [250,251]. [262–264]. The Mediterranean diet includes many of
The effect of reduced dietary sodium on cardiovascu- these nutrients and foods, with a moderate consumption
lar events remains unclear [252–255]. Prospective cohort of alcohol (mostly wine with meals). A number of
studies have reported an overall increased risk of mor- studies and meta-analyses [262–265] have shown that
tality and cardiovascular events on high sodium intake. the Mediterranean diet is associated with a reduction in
However, they also reported that reducing sodium intake cardiovascular events and all-cause mortality. An RCT
below a certain level (about 3 g of sodium per day) fur- in high-risk individuals on the Mediterranean diet over
ther reduced BP, but paradoxically was associated with 5 years showed a 29% cardiovascular risk reduction
an increased risk of allcause and cardiovascular mortali- compared with a low-fat control diet, and a 39% reduction
ties in both the general population and in hypertensive in stroke [265]. The Mediterranean diet also significantly
people, suggesting a J-curve phenomenon [256]. The reduced ambulatory BP, blood glucose, and lipid levels
mechanism of this apparent increased risk at low sodium [266]. The diet should be accompanied by other lifestyle
intake is not well understood and might be confounded by changes such as physical exercise and weight loss [35].
reverse causality. There is no evidence from epidemiologi- With regard to coffee consumption, caffeine has been
cal studies that very low sodium intake may cause harm shown to have an acute pressor effect [267]. Nevertheless,
[257]. Although a few trials and meta-analyses suggest that coffee consumption is associated with cardiovascular
reducing salt intake from high to moderate is accompanied benefits, as highlighted by a recent systematic review of
by a lower risk of cardiovascular events [254,255,258], to prospective cohort studies including more than 1 mil-
date, no prospective RCT has provided definitive evidence lion participants and 36–352 cardiovascular events [267].
about the optimal sodium intake to minimize cardiovas- Moreover, green or black tea consumption may also have a
cular events and mortality. Increased potassium intake is small but significant BP-lowering effect [268,269].
associated with BP reduction and may have a protective Regular consumption of sugar-sweetened soft drinks
effect, thereby modifying the association between sodium has been associated with overweight, metabolic syndrome,
intake, BP and CVD [259]. type 2 diabetes, and higher cardiovascular risk. The con-
Globally, usual sodium intake is between 3.5 and sumption of these drinks should be discouraged [35].
5.5 g/day (which corresponds to 9–12 g of salt per day), Thus, adopting a healthy and balanced diet may assist in
with marked differences between countries and even BP reduction and also reduce cardiovascular risk.
between regions within countries. We recommend sodium
intake to be limited to approximately 2.0 g/day (equiva-
lent to approximately 5.0 g salt per day) in the general WEIGHT REDUCTION
population and to try to achieve this goal in all hyper- Excessive weight gain is associated with hypertension, and
tensive patients. Effective salt reduction is not easy and reducing weight towards an ideal body weight decreases
there is often poor appreciation of which foods contain BP [270]. In a meta-analysis, the mean SBP and DBP reduc-
high salt levels. Advice should be given to avoid added salt tions associated with an average weight loss of 5.1 kg were
and high-salt foods. A reduction in population salt intake 4.4 and 3.6 mmHg, respectively [271]. Both overweight
remains a public health priority but requires a combined and obesity are associated with an increased risk of cardio-
effort between the food industry, governments, and the vascular death and all-cause mortality. Weight reduction
public in general, as 80% of salt consumption involves is recommended in overweight and obese hypertensive
hidden salt in processed foods. patients for control of metabolic risk factors, but weight
stabilization may be a reasonable goal for many. The
Prospective Studies Collaboration [272] concluded that
MODERATION OF ALCOHOL CONSUMPTION mortality was lowest at a BMI of approximately 22.5–
There is a long-established positive linear association 25 kg/m2, whereas a more recent meta-analysis concluded
between alcohol consumption, BP, the prevalence of that mortality was lowest in subjects with overweight
hypertension and CVD risk. Binge drinking can have a [273,274]. Although the optimal BMI is unclear, main-
strong pressor effect [17]. The Prevention and Treatment tenance of a healthy body weight (BMI of approximately
of Hypertension Study (PATHS) investigated the effects 20–25 kg/m2 in people <60 years of age; higher in older
of alcohol reduction on BP; the intervention group had a patients) and waist circumference (<94 cm for men and
modest 1.2/0.7 mmHg lower BP than the control group at <80 cm for women) is recommended for nonhypertensive
the end of the 6-month period [260]. A Mendelian ran- individuals to prevent hypertension, and for hypertensive
domization meta-analysis of 56 epidemiological studies patients to reduce BP [35]. Weight loss can also improve
suggested that reduction of alcohol consumption, even the efficacy of antihypertensive medications and the
for light–moderate drinkers, might be beneficial for car- cardiovascular risk profile. Weight loss should employ a
diovascular health [261]. Hypertensive men who drink multidisciplinary approach that includes dietary advice,
alcohol should be advised to limit their consumption regular exercise, and motivational counselling [35,275].
to 14 and women to 8 units per week (1 unit is equal to Furthermore, short-term results are often not maintained
125 mL of wine or 250 mL of beer). Alcohol-free days dur- over the long-term. Weight loss can also be promoted by
ing the week and avoidance of binge drinking [35] are also antiobesity drugs and, to a greater degree, bariatric sur-
advised. gery, which appears to decrease cardiovascular risk in
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 571
severely obese patients. Further details are available in a with pharmacotherapy increases the chance of success by
recent document of the ESH and the European Association 70–100% compared with brief advice alone [289].
for the Study of Obesity [276].
Lifestyle interventions for patients with hypertension
REGULAR PHYSICAL ACTIVITY or high-normal BP
Physical activity induces an acute rise in BP, especially Recommendations Classa Levelb
SBP, followed by a short-lived decline in BP below base-
line. Epidemiological studies suggest that regular aerobic Salt restriction to <5 g per day is recommended I A
physical activity may be beneficial for both the prevention [248,250,255,258].
and treatment of hypertension, and to lower cardiovascu-
It is recommended to restrict alcohol consump- I A
lar risk and mortality. A meta-analysis of RCTs, which rely
tion to:
on self-reported exercise and are by necessity unblinded,
■■ Less than 14 units per week for men.
has shown that aerobic endurance training, dynamic resis- ■■ Less than 8 units per week for women [35].
tance training and isometric training reduce resting SBP
and DBP by 3.5/2.5, 1.8/3.2 and 10.9/6.2 mmHg, respec- It is recommended to avoid binge drinking. III C
tively, in general populations [277]. Endurance training,
but not other types of training, reduces BP more in hyper- Increased consumption of vegetables, fresh I A
tensive participants (8.3/5.2 mmHg). Regular physical fruits, fish, nuts, and unsaturated fatty acids
activity of lower intensity and duration lowers BP less than (olive oil); low consumption of red meat; and
moderate-intensity or high-intensity training, but is asso- consumption of low-fat dairy products are
ciated with at least a 15% decrease in mortality in cohort recommended [262,265].
studies [278,279]. This evidence suggests that hypertensive Body-weight control is indicated to avoid obesity I A
patients should be advised to participate in at least 30 min (BMI >30 kg/m2 or waist circumference
of moderate intensity dynamic aerobic exercise (walk- >102 cm in men and >88 cm in women), as is
ing, jogging, cycling or swimming) on 5–7 days/week. aiming at healthy BMI (about 20–25 kg/m)2
Performance of resistance exercises on 2–3 days/week can and waist circumference values (<94 cm in
also be advised. For additional benefit in healthy adults, men and <80 cm in women) to reduce BP and
a gradual increase in aerobic physical activity to 300 min cardiovascular risk [262,271,273,290].
a week of moderate intensity or 150 min a week of vig-
orous-intensity aerobic physical activity, or an equivalent Regular aerobic exercise (e.g. at least 30 min of I A
combination thereof, is recommended [35]. The impact of moderate dynamic exercise on 5–7 days per
isometric exercises on BP and cardiovascular risk is less week) is recommended [262,278,279].
well established [280].
Smoking cessation, supportive care, and referral I B
to smoking cessation programs are recom-
mended [286,288,291].
SMOKING CESSATION
Smoking is a major risk factor for CVD and cancer. Abbreviations: BMI, body mass index; BP, blood pressure.
Although the rate of smoking is declining in most a Class of recommendation.
European countries, especially in men, it is still common b Level of evidence mostly based on the effect on BP and/or cardiovascular
in many regions and age groups, and overall the preva- risk profile.
lence remains high at 20–35% in Europe [281]. There is
also evidence suggesting ill-health effects of passive smok-
ing [282]. Studies using ABPM have shown that both nor- PHARMACOLOGICAL THERAPY FOR
motensive subjects and untreated hypertensive smokers HYPERTENSION
present higher daily BP values than nonsmokers [283]. No
chronic effect of smoking has been reported for office BP DRUGS FOR THE TREATMENT OF HYPERTENSION
[284], which is not lowered by smoking cessation. Smoking Most patients will require drug therapy in addition to
is second only to BP in contributing risk to the global bur- lifestyle measures to achieve optimal BP control. In the
den of disease, and smoking cessation is probably the previous Guidelines, five major drug classes were recom-
single most effective lifestyle measure for the prevention mended for the treatment of hypertension: ACE inhibi-
of CVD, including stroke, myocardial infarction, and PAD tors, ARBs, beta-blockers, CCBs, and diuretics (thiazides
[285,286]. Therefore, the history of tobacco use should be and thiazide-like diuretics such as chlorthalidone and
established at each patient visit and hypertensive smokers indapamide), based on: proven ability to reduce BP; evi-
should be counselled regarding smoking cessation. Brief dence from placebo-controlled studies that they reduce
advice from a physician has a small but significant effect cardiovascular events; and evidence of broad equivalence
of 1–3% over and above the unassisted 12-month quit rate on overall cardiovascular morbidity and mortality, with
[287]. This can be improved by the use of pharmacologi- the conclusion that benefit from their use predominantly
cal measures, with varenicline and combination nicotine derives from BP lowering. These conclusions have since
replacement therapy being superior to bupropion or single been confirmed by recent meta-analyses [1,2,217,292].
nicotine replacement therapy [288]. In comparison with These meta-analyses have reported cause-specific differ-
placebo, nicotine replacement therapy or treatment with ences on outcomes between some drugs (e.g. less stroke
buproprion doubles the chance of quitting, while vareni- prevention with beta-blockers, and less heart failure pre-
cline or combination nicotine replacement therapy triples vention with CCBs); however, overall, major cardiovascu-
the chance of quitting. Combining behavioural support lar outcomes and mortality were similar with treatment
572 Manual of Hypertension of the European Society of Hypertension
Table 65.20 Compelling and possible contraindications to the use of specific antihypertensive drugs
Contraindications
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; HFrEF, heart failure with reduced ejection fraction.
based on initial therapy with all five major classes of treat- of RAS blockers also led to the premature cessation of
ment. These Guidelines thus recommend that the same another trial due to adverse events [291], when a renin
five major classes of drugs should form the basis of anti- inhibitor, aliskiren, was combined with either an ACE
hypertensive therapy. There are compelling or possible inhibitor or an ARB in people with diabetes. This result
contraindications for each class of drug (Table 65.20) and halted further research into the clinical utility of aliskiren
preferential use of some drugs for some conditions, as dis- for BP treatment.
cussed below. There is also evidence that there are differ- Both ACE inhibitors and ARBs reduce albuminuria more
ences in the persistence and discontinuation rates of the than other BP-lowering drugs and are effective at delaying
major drug classes [293,294]. the progression of diabetic and nondiabetic CKD [217]. A
Other classes of drugs have been less widely studied in recent meta-analysis shows that RAS blockers are the only
event-based RCTs or are known to be associated with a antihypertensive agents for which evidence is available of
higher risk of adverse effects [e.g. alpha-blockers, centrally a reduced risk of end-stage renal disease [217].
acting agents, and mineralocorticoid receptor antagonists ACE inhibitors and ARBs also appear effective in pre-
(MRAs)]. These are useful additions to the antihyperten- venting or regressing HMOD, such as LVH and small artery
sive armamentarium in patients whose BP cannot be con- remodelling, for an equivalent reduction in BP [292].
trolled by proven combinations of the aforementioned Both drugs reduce incident AF, which may be related to
major drug classes. improved left ventricular function and more effective left
ventricular structural regression [292]. ACE inhibitors and
BLOCKERS OF THE RENIN-ANGIOTENSIN SYSTEM ARBs are also indicated postmyocardial infarction and in
(ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND patients with chronic HFrEF, which are frequent complica-
ANGIOTENSIN RECEPTOR BLOCKERS) tions of hypertension.
Both ACE inhibitors and ARBs are among the most widely ACE inhibitors are associated with a small increased
used classes of antihypertensive drugs. They have similar risk of angioneurotic oedema, especially in people of black
effectiveness [295,296] as each other and other major African origin and, in such patients, when RAS blockers
drug classes on major cardiovascular events and mortality are used, an ARB may be preferred.
outcomes [2,292]. ARBs are associated with significantly
lower treatment discontinuation rates for adverse events CALCIUM CHANNEL BLOCKERS
than those of all other antihypertensive therapies [297], CCBs are widely used for the treatment of hypertension
and similar rates to placebo [294]. ACE inhibitors and ARBs and have similar effectiveness as other major drug classes
should not be combined for the treatment of hypertension on BP, major cardiovascular events, and mortality out-
because there is no added benefit on outcomes and an comes [2,292]. CCBs have a greater effect on stroke reduc-
excess of renal adverse events [298,299]. Dual combination tion than expected for the BP reduction achieved, but
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 573
may also be less effective at preventing HFrEF [2,292]. on glucose metabolism may be reduced by the addition of
However, in antihypertensive treatment trials, emergent a potassium-sparing diuretic [305]. Both thiazides and thi-
heart failure is the event considered. Though clinically a azide-like agents are less effective antihypertensive agents
very relevant event, it is a difficult endpoint to quantify in patients with a reduced GFR (eGFR <45 mL/min) and
precisely, either because symptoms and signs are relatively become ineffective when the eGFR is less than 30 mL/min.
nonspecific or because oedema due to CCBs may result in In such circumstances, loop diuretics such as furosemide
misdiagnosis. Comparison with diuretics may also be dif- (or torasemide) should replace thiazides and thiazide-like
ficult because fluid loss may mask signs and symptoms of diuretics to achieve an antihypertensive effect.
incipient heart failure rather than preventing it. CCBs have
also been compared with other antihypertensive agents in BETA-BLOCKERS
HMOD-based trials, and are reported to be more effective RCTs and meta-analyses demonstrate that when compared
than betablockers in slowing the progression of carotid with placebo, beta-blockers significantly reduce the risk of
atherosclerosis, and in reducing LVH and proteinuria [17]. stroke, heart failure, and major cardiovascular events in
CCBs are a heterogeneous class of agents. Most RCTs hypertensive patients [300]. When compared with other
demonstrating the benefits of CCBs on outcomes have BP-lowering drugs, beta-blockers are usually equivalent
used dihydropyridines (especially amlodipine). A smaller in preventing major cardiovascular events, except for less
number of RCTs have compared non-dihydropyridines effective prevention of stroke, which has been a consistent
(verapamil and diltiazem) with other drugs, and meta- finding [1,2,217]. It is possible that the difference origi-
analyses evaluating the two subclasses (vs. other drugs) nated from small differences in achieved BP (including
have not shown substantial differences in effectiveness central SBP [108] between different drug treatments), to
[292]. which cerebrovascular events may be especially sensi-
tive. RCTs based on HMOD have also indicated that beta-
THIAZIDE/THIAZIDE-LIKE DIURETICS, EXAMPLE blockers are somewhat less effective than RAS blockers
CHLORTHALIDONE AND INDAPAMIDE and CCBs in preventing or regressing LVH, carotid IMT,
Diuretics have remained the cornerstone of antihyper- aortic stiffness, and small artery remodelling [17]. In addi-
tensive treatment since their introduction in the 1960s. tion, a mortality benefit in postmyocardial infarction is
Their effectiveness in preventing all types of cardiovascu- uncertain in patients without left ventricular dysfunction
lar morbidities and mortality has been confirmed in RCTs [306]. Beta-blockers, as well as diuretics, and particularly
and meta-analyses [300]. Diuretics also appear to be more their combination, are also associated with increased risk
effective than other drug classes in preventing heart failure of new-onset diabetes in predisposed subjects (mostly
[292]. There has been debate about whether thiazide-like those with the metabolic syndrome). They also exhibit a
diuretics such as chlorthalidone and indapamide should somewhat less favourable side effect profile than that of
be given preference over classical thiazide diuretics (e.g. RAS blockers, with a higher rate of treatment discontinua-
hydrochlorothiazide and bendrofluazide), but their supe- tion when assessed in real-life conditions [293].
riority on outcomes has never been tested in head-to-head Beta-blockers have been shown to be particularly use-
RCTs. Chlorthalidone and indapamide have been used in ful for the treatment of hypertension in specific situations
a number of RCTs showing cardiovascular benefits, and such as symptomatic angina, for heart rate control, post-
these agents are more potent per milligram than hydro- myocardial infarction, HFrEF, and as an alternative to ACE
chlorothiazide in lowering BP, with a longer duration of inhibitors or ARBs in younger hypertensive women plan-
action compared with hydrochlorothiazide and no evi- ning pregnancy or of child-bearing potential.
dence of a greater incidence of side effects [301]. Lower Finally, beta-blockers are not a homogeneous class. In
dose thiazide-like diuretics (typical of modern antihyper- recent years, the use of vasodilating beta-blockers – such
tensive treatment regimens) also have more evidence from as labetalol, nebivolol, celiprolol, and carvedilol – has
RCTs demonstrating reductions in cardiovascular events increased. Studies on nebivolol have shown that it has
and mortality, when compared with lower dose thiazide more favourable effects on central BP, aortic stiffness,
diuretics [302]. That said, hydrochlorothiazide, alone or endothelial dysfunction, and so on. It has no adverse effect
in combination with a potassium-sparing agent, has also on the risk of new-onset diabetes and a more favourable
been used in BP-lowering RCTs, with positive results [303]. side effect profile than classical beta-blockers [307,308],
A recent meta-analysis of placebo-controlled studies based including less adverse effects on sexual function.
on thiazides, chlorthalidone and indapamide reported Bisoprolol, carvedilol and nebivolol have been shown to
similar effects on cardiovascular outcomes of the three improve outcomes in RCTs in heart failure [136]; however,
types of diuretics [300]. Therefore, in the absence of evi- there are no RCTs reporting patient outcomes with these
dence from direct comparator trials and recognizing that beta-blockers in hypertensive patients.
many of the approved single-pill combinations (SPCs) are
based on hydrochlorothiazide (see below), we recommend OTHER ANTIHYPERTENSIVE DRUGS
that thiazides, chlorthalidone, and indapamide can all be Centrally active drugs were widely used in the earliest
considered suitable antihypertensive agents. Both thia- decades of antihypertensive treatment when other
zide and thiazide-like diuretics can reduce serum potas- treatments were not available, but are less frequently
sium and have a side effect profile that is less favourable used now, principally because of their poorer tolerability
than RAS blockers, which may account for their asso- relative to the newer major classes of drugs. The alpha-
ciation with a higher rate of treatment discontinuation blocker doxazosin was effective in the Anglo-Scandinavian
[293,300]. They also exhibit dysmetabolic effects that Cardiac Outcomes Trial (ASCOT) as third-line therapy
increase insulin resistance and the risk of new-onset dia- (with no increase in the risk of heart failure) [309], and
betes. Potassium may attenuate these effects [304], and a was more effective than placebo but less effective than
recent study has shown that the adverse effect of thiazides spironolactone at lowering BP in resistant hypertension
574 Manual of Hypertension of the European Society of Hypertension
in the Prevention And Treatment of Hypertension With factor than previously recognized. Studies using
Algorithm-based therapY-2 (PATHWAY-2) study [310]. urine or blood assays for the presence or absence of
Alpha-blockers may also be required in specific indications medication have shown that adherence to treatment
(e.g. the treatment of symptomatic prostatic hypertrophy). is low. This is supported by studies in the general
Antihypertensive drugs, other than the major classes population in which adherence to treatment, based
already discussed above, are no longer recommended for on prescription refilling, was <50% of the treatment
the routine treatment of hypertension, and are primarily in half of the patients [312]. Poor adherence has also
reserved for add-on therapy in rare cases of drug-resistant been shown to be associated with increased cardio-
hypertension where all other treatment options have vascular risk in various studies [313] (see section
failed. ‘Patient follow-up’).
4. Insufficient use of combination treatment. BP is a multi-
regulated variable depending on many compensat-
DRUG TREATMENT STRATEGY FOR HYPERTENSION ing pathways. Consequently, combinations of drugs,
Guidelines have generated a variety of different strategies working through different mechanisms, are required
to initiate and escalate BP-lowering medication to improve to reduce BP in most people with hypertension. Thus,
BP control rates. In previous Guidelines, the emphasis was monotherapy is likely to be inadequate therapy in
on initial use of different monotherapies, increasing their most patients. Indeed, almost all patients in RCTs
dose, or substituting for another monotherapy. However, have required combinations of drugs to control their
increasing the dose of monotherapy produces little addi- BP [314].
tional BP lowering and may increase the risk of adverse 5. Complexity of current treatment strategies. There is also
effects, while switching from one monotherapy to another evidence that adherence to treatment is adversely
is frustrating, time consuming, and often ineffective. For affected by the complexity of the prescribed treatment
these reasons, more recent Guidelines have increasingly regimen. In a recent study, adherence to treatment
focused on the stepped-care approach, initiating treat- was strongly influenced by the number of pills
ment with different monotherapies and then sequentially that a patient was prescribed for the treatment of
adding other drugs until BP control is achieved. Despite hypertension [315]. Nonadherence was usually
this, BP control rates have remained poor worldwide. As less than 10% with a single pill, rising to 20% with
shown by recent observations, irrespective of the world two pills, 40% with three pills, and very high rates
region, whether high-income or low-income economies, of partial or complete nonadherence in patients
or the level of sophistication of healthcare provision, only receiving five or more pills [315].
40% of patients with hypertension are treated; of these,
only 35% are controlled to a BP of less than 140/90 mmHg The above considerations suggest that the most effec-
[12]. This failure to achieve BP control in most hyper- tive evidence-based treatment strategy to improve BP
tensive patients, despite numerous iterations of previous control is one that: encourages the use of combination
Guidelines, suggests that these treatment strategies are treatment in most patients, especially in the context of
not working and that a different approach is needed. This lower BP targets; enables the use of SPC therapy for most
Task Force believes that one of the most important issues patients, to improve adherence to treatment; and fol-
to address in these Guidelines is ‘how do we improve BP lows a treatment algorithm that is simple, applies to all
control in treated patients?’. This has become an even more patients, and is pragmatic, with the use of SPC therapy
pressing matter because, based on new evidence, current as initial therapy for most patients, except those with BP
Guidelines are recommending more stringent BP targets in the high–normal range and in frail older patients (see
(on-treatment values of ≤130/80 mmHg in the general below).
population and ≤140/90 mmHg in older hypertensive
people), which will make the achievement of BP control DRUG COMBINATIONS FOR HYPERTENSION TREATMENT
even more challenging. Among the large number of RCTs of antihyperten-
Several reasons need to be considered to identify why sive therapy, only a few have directly compared differ-
the current treatment strategy has failed to achieve better ent two-drug combinations, with systematic use of the
BP control rates: two combinations in both arms. In other trials, treat-
ment was initiated using monotherapy in either arm and
1. Efficacy of pharmacological therapies. Are the best another drug (and sometimes more than one drug) was
available treatments, in whatever combination, added, usually in a nonrandomized fashion, according
incapable of controlling BP in most patients? The to a prespecified treatment algorithm. In a few trials,
evidence from RCTs demonstrating that BP control the design precluded the use of what might be consid-
can be achieved in most recruited patients, and that ered optimal combinations because multiple monothera-
no more than 5–10% of these patients exhibit resis- pies were being evaluated [e.g. the Antihypertensive and
tance to the selected treatment regimen, suggests Lipid-Lowering Treatment to Prevent Heart Attack Trial
that ineffective drug therapy is not the source of the (ALLHAT), where the add-on therapy to either a diuretic,
problem. CCB, ACE inhibitor, or alpha-blocker was a beta-blocker,
2. Physician or treatment inertia. (i.e. failure to adequately clonidine, or reserpine] [316].
uptitrate treatment). Evidence suggests that inertia With this caveat, Table 65.21 shows that a variety of
[311] contributes to suboptimal BP control, with drug combinations have been used in at least one active
many patients remaining on monotherapy and/or arm of placebo-controlled trials and have been associ-
suboptimal doses, despite inadequate BP control [12]. ated with significant benefit on major cardiovascular
3. Patient adherence to treatment. Evidence is accu- events. In trials comparing different regimens (Table
mulating that adherence is a much more important 65.22), all combinations have been used in a larger or
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 575
Table 65.21 Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a randomized
combination (combinations vs. placebo or monotherapy)
Combination of two RAS blockers/ACE inhibitor + ARB or RAS blocker + renin inhibitor)
ONTARGET [299] ACE inhibitor or ARB High-risk patients More renal events
ALTITUDE [291] ACE inhibitor or ARB High-risk diabetic More renal events
patients
Abbreviations: ACE, angiotensin-converting enzyme; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron – MR Controlled Evaluation;
ALTITUDE, Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints; ARB, angiotensin receptor blocker; CCB, calcium channel blocker;
FEVER, Felodipine Event Reduction; HYVET, Hypertension in the Very Elderly Trial; ISH, isolated systolic hypertension; NS, non-significant; ONTARGET, Ongoing
Telmisartan Alone and in combination with Ramipril Global Endpoint trial; PROGRESS, perindopril protection against recurrent stroke study; RAS, renin-angiotensin
system; SBP, systolic blood pressure; SCOPE, Study on Cognition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; STOP-H, Swedish
Trial in Old Patients with Hypertension; Syst-China, Systolic Hypertension in China; Syst-Eur, Systolic Hypertension in Europe; TIA, transient ischaemic attack.
smaller proportion of patients, without major differ- Three outcome trials directly compared two different
ences in benefits. The only exceptions are two trials in combinations, each involving a combination of a RAS
which a large proportion of the patients received either blocker (ACE inhibitor or ARB) and a CCB with other
an ARB–diuretic combination [317] or CCB– ACE inhibi- combinations. In the Avoiding Cardiovascular Events
tor combination [318], with both regimens being supe- Through Combination Therapy in Patients Living With
rior to a beta-blocker– diuretic combination in reducing Systolic Hypertension (ACCOMPLISH) trial, the ACE
cardiovascular outcomes. However, in six other trials (with inhibitor–CCB combination was superior to the same
seven comparisons), beta-blockers followed by diuretics ACE inhibitor in combination with a thiazide diuretic
or diuretics followed by beta-blockers were not associated at preventing major cardiovascular outcomes, despite
with a significantly different risk of any cardiovascular out- no apparent BP difference between the two arms [327].
come [233,234,316,319–321], and the beta-blocker-diuretic This finding was not confirmed in the Combination of
combination was significantly more effective than pla- OLMesartan and a CCB or diuretic in Japanese older
cebo in three trials [322–324]. It should be mentioned hypertensive patients (COLM) [328] and Combination
that the beta-blocker–diuretic combination may result in Therapy of Hypertension to Prevent Cardiovascular
more cases of new-onset diabetes in susceptible individ- Events (COPE) trials [329], which reported no significant
uals compared with other combinations [325]. A rarely differences in cardiovascular events when a RAS blocker-
used combination of thiazide and potassium-sparing CCB combination was compared with a RAS blocker–thi-
diuretic (amiloride) has also been shown to be equiva- azide diuretic combination, but both of these trials had
lent to CCB-based treatment [310,326], and was recently insufficient statistical power.
reported to be associated with fewer metabolic adverse Based on the results of outcome RCTs and recent meta-
effects compared with thiazide alone (less hypokalaemia analyses, and evidence of BP-lowering effectiveness, all
and glucose intolerance) [305]. five major drug classes can, in principle, be combined
576 Manual of Hypertension of the European Society of Hypertension
Table 65.22 Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a randomized combination
(combinations vs. other combinations)
SBP difference
Trial Comparator Type of patients (mmHg) Outcomes [change in relative risk (%)]
Abbreviations: ACCOMPLISH, Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension; ACE, angiotensin-
converting enzyme; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ARB, angiotensin receptor blocker; ASCOT, Anglo-
Scandinavian Cardiac Outcomes Trial; BB, beta-blocker; CAD, coronary artery disease; CAPPP, Captopril Prevention Project; CCB, calcium channel blocker; COLM,
Combination of OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients; CONVINCE, Controlled Onset Verapamil Investiga-
tion of Cardiovascular Endpoints; COPE, Combination Therapy of Hypertension to Prevent Cardiovascular Events; ELSA, European Lacidipine Study on Atherosclero-
sis; INVEST, International Verapamil-Trandolapril Study; LIFE, Losartan Intervention For Endpoint reduction in hypertension; LVH, left ventricular hypertrophy; NORDIL,
Nordic Diltiazem; NS, non-significant; SBP, systolic blood pressure; VALUE, Valsartan Antihypertensive Long-term Use Evaluation.
with one another, except for ACE inhibitors and ARBs, thiazide/thiazide-like diuretic are complementary because
whose concomitant use may lead to no additional benefit both CCBs or diuretics activate the RAS, which will be
but increased adverse effects and is thus discouraged. We counteracted by their combination with an ACE inhibi-
recommend that the treatment of hypertension should be tor or ARB. These combinations will also limit potential
preferentially based on combinations of an ACE inhibi- adverse effects associated with diuretic or CCB mono-
tor or ARB with a CCB and/or a thiazide/thiazide-like therapy, reducing the risk of hypokalaemia due to diuret-
diuretic. These combinations are now widely available in ics and reducing the prevalence of peripheral oedema due
a single pill and in a range of doses, facilitating simplifi- to CCBs. These combinations also ensure that the RAS
cation of treatment, flexible prescribing, and uptitration is inhibited as part of the treatment strategy, which is an
from lower to higher doses. Combination therapy that important consideration for many patient groups (e.g. dia-
includes an ACE inhibitor or ARB with either a CCB or betes, LVH, proteinuria).
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 577
Other combinations, such as CCB + diuretic, also have control, and cardiovascular outcomes may be especially
evidence from RCTs supporting their use [233,329]. These relevant [348].
are much less widely available as SPCs and do not include A consideration in the current Guidelines was to persist
blockade of the RAS, which may be desirable in many with the current stepped-care approach to BP treatment,
patient groups. which has been interpreted as recommending monother-
Beta-blockers in combination should be preferen- apy as initial therapy for most patients, reflecting current
tially used when there is a specific clinical indication practice. In fact, the previous Guidelines did acknowledge
for their use (e.g. in patients with symptomatic angina, the possibility of initial combination therapy for patients
for patients requiring heart rate control, postmyocardial with grade 2 or 3 hypertension, or patients at high or very
infarction, chronic HFrEF, and as an alternative to ACE high risk. In other words, initial monotherapy was only
inhibitors or ARBs in younger hypertensive women plan- recommended for grade 1 hypertension and low-risk or
ning pregnancy or of child-bearing potential). SPCs of moderate-risk patients. Thus, in reality, the shift in empha-
beta-blockers with an ACE inhibitor, CCB, or diuretic are sis in this new guidance is subtle. However, normalizing
available. the concept of initiating therapy with a two-drug com-
bination for most patients with hypertension is likely to
RATIONALE FOR INITIAL TWO-DRUG COMBINATION have a major effect on clinical practice and the speed
THERAPY FOR MOST PATIENTS and quality of BP control. We acknowledge that some
As discussed above and with the emphasis in these low-risk or moderate-risk patients with grade 1 hyper-
Guidelines on achieving a BP target in most patients of tension may achieve their BP target with monotherapy,
less than 130/80 mmHg, the majority of patients will but this is unlikely in patients with an initial SBP more
require combination therapy. Initial combination therapy than 150 mmHg who would require a BP reduction of at
is invariably more effective at BP lowering than mono- least 20 mmHg. Moreover, the possibility of starting with
therapy, indeed even low-dose combination therapy is a low-dose combination of two antihypertensive drugs,
usually more effective than maximal dose monotherapy even in grade 1 hypertensive patients with low–moder-
[341]. Furthermore, the combination of medications tar- ate-risk, is supported by the reduction of cardiovascular
geting multiple mechanisms, such as blocking the RAS as events obtained by combination therapy in the upper ter-
well as inducing vasodilatation and/or diuresis, reduces tile (grade 1 hypertension) in the HOPE-3 trial [212]. In
the heterogeneity of the BP response to initial treatment patients with high–normal BP and a high cardiovascular
and provides a steeper dose response than is observed risk or in frail older patients, treatment initiation with
with escalating doses of monotherapy [342]. Finally, two- monotherapy may be appropriate in the former because
drug combinations as initial therapy have been shown to only a small BP reduction may be required to achieve the
be safe and well tolerated, with no or only a small increase BP target, and in the latter because in older patients baro-
in the risk of hypotensive episodes [341], even when given reflex sensitivity is frequently impaired and the risk of
to patients with grade 1 hypertension [343], in which hypotension is greater.
adverse events leading to treatment discontinuation are
infrequent [294]. UPTITRATION OF TREATMENT TO THREE-DRUG
Although no RCT has compared major cardiovascular COMBINATION THERAPY
outcomes between initial combination therapy and mono- Studies suggest that two-drug combination therapy will
therapy, observational evidence suggests that the time control BP in approximately two-thirds of patients [341].
taken to achieve BP control is an important determinant For patients whose BP is not controlled by two-drug
of clinical outcomes, especially in higher risk patients, combination therapy, the logical option is to increase
with a shorter time to control associated with lower risk treatment to three-drug combination therapy: usually a
[344]. Furthermore, there is evidence from the more gen- RAS blocker, a CCB, and a diuretic. Studies suggest that a
eral hypertensive population that, compared with patients three-drug combination should control BP in more than
on initial monotherapy, those who start treatment with a 80% of patients [349,350]. This rate of BP control is much
two-drug combination exhibit more frequent BP control greater than the current rate of BP control across Europe
after 1 year [341,345]. This is probably because initial com- in treated hypertensive patients. We do not recommend
bination treatment is associated with a better long-term three-drug combinations as initial therapy.
adherence to the prescribed treatment regimen [346] and
because initial two-drug administration prevents thera- RATIONALE FOR SINGLE-PILL COMBINATION THERAPY AS
peutic inertia (i.e. reluctance or failure to upgrade treat- USUAL THERAPY FOR HYPERTENSION
ment from one to more drugs when BP is uncontrolled) The 2013 ESH/ESC Guidelines [17] favoured the use of
[347]. Studies from very large hypertension cohorts in combinations of two antihypertensive drugs in a single
usual care have shown that initial combination treatment pill, because reducing the number of pills to be taken daily
results in reduced treatment discontinuation and a lower improves adherence and increases the rate of BP control
risk of cardiovascular events than initial monotherapy fol- [346,351]. This recommendation is endorsed by the cur-
lowed by the traditional stepped-care approach [312,346]. rent Guidelines. It is further supported by data from recent
The usual-care settings for these studies may be especially studies using various methods to assess adherence to treat-
relevant to study the true impact of treatment strategies ment, including the quantification of antihypertensive
on adherence and therapeutic inertia, because this can be drugs in urine and blood [352,353], and estimates such as
difficult to replicate in a conventional RCT in which the pill counting or prescription refills, which, although indi-
motivation of the clinical staff and patients, and the moni- rect, allow the measurement of adherence on a prolonged
toring of treatment, are very different from usual care. In basis, thereby accounting for its time-variable nature
this regard, the outcome of these real-life studies of the [347,354]. These studies have unequivocally shown a direct
impact of initial combination therapy on adherence, BP inverse relationship between the number of pills and the
578 Manual of Hypertension of the European Society of Hypertension
likelihood of adherence. This approach is now facilitated control of BP in treated hypertensive patients (see section
by the availability of several SPCs with a range of dos- ‘Drugs for the treatment of hypertension’), this drug treat-
ages, which eliminates the often-stated disadvantage of ment algorithm has been developed to provide a simple and
SPC therapy (i.e. the inability to increase the dose of one pragmatic treatment recommendation for the treatment of
drug independently of the other). It is also convenient hypertension, based on a few key recommendations:
that the most widely available SPCs mirror the major drug
class combinations recommended by these Guidelines. 1. The initiation of treatment in most patients with an
The major advantage of an SPC as the usual therapeutic SPC comprising two drugs, to improve the speed,
approach for hypertension is that patients can progress efficiency, and predictability of BP control.
from 1, 2, or 3 drug treatments while remaining on a simple 2. Preferred two-drug combinations are a RAS blocker
treatment regimen with a single pill throughout, increasing with a CCB or a diuretic. A beta-blocker in combi-
the likelihood of adherence to therapy and achieving BP nation with a diuretic or any drug from the other
control. Such an approach has the potential to double BP major classes is an alternative when there is a specific
control rates in treated patients from the present low level indication for a beta-blocker, for example angina,
of 40%. Although, at present, the availability of two-drug postmyocardial infarction, heart failure, or heart rate
SPCs is largely limited to a RAS blocker with either a CCB control.
or diuretic, it would be desirable to see the development of 3. Use monotherapy for low-risk patients with stage
an expanded range of low-cost SPCs in different drug for- 1 hypertension whose SBP is <150 mmHg, very
mulations, tailored to different clinical requirements. high-risk patients with high–normal BP, or frail older
Polypills have also emerged as SPCs (i.e. a fixed-dose patients.
combination of one or more antihypertensive agents with a 4. The use of a three-drug SPC comprising a RAS
statin and low-dose aspirin), with the rationale that hyper- blocker, a CCB, and a diuretic if BP is not controlled
tensive patients are often at sufficient cardiovascular risk by a two-drug SPC.
to benefit from statin therapy. Studies of bioequivalence 5. The addition of spironolactone for the treatment of
suggest that when combined in the polypill, different resistant hypertension, unless contraindicated (see
agents maintain all or most of their expected effect [355]. section ‘Treatment of resistant hypertension’).
Furthermore, studies performed in the setting of secondary 6. The use of other classes of antihypertensive drugs in
prevention, particularly in patients with a previous myo- the rare circumstances in which BP is not controlled
cardial infarction, have shown that use of the polypill is by the above treatments.
accompanied by a better adherence to treatment compared 7. Information on availability and recommended doses
with separate medications [356]. The ESC Guidelines for of individual drugs, as well as SPCs and free combina-
the management of myocardial infarction suggest that the tions, can be found in national formularies.
use of the polypill may be considered to improve long-term
adherence to prescribed therapy (class IIb, level B) [353]. This treatment algorithm focuses on the five major
No data are available for primary prevention in patients classes of drugs: ACE inhibitors, ARBs, CCBs, thiazide or
with hypertension. Nevertheless, the advantage of treat- thiazide-like diuretics, and beta-blockers. The algorithm
ment simplification and adherence suggests that use of the recommends initial therapy for most patients with a two
polypill may be considered in patients with hypertension drug-combination, ideally as an SPC. Variations from the
as substitution therapy, when the need and effectiveness of core drug treatment algorithm for uncomplicated hyper-
each polypill component has been previously established tension shown in Figure 65.4 are specified in Figures
by their administration in separate tablets [355]. 65.5–65.8. Recommended BP target ranges for treated
hypertension are shown in Table 65.23.
FURTHER UPTITRATION OF ANTIHYPERTENSIVE THERAPY The drug treatment strategy for patients with hyperten-
When BP remains uncontrolled with three-drug combi- sion should be based on the algorithm shown (Figures
nation therapy, the patient is classified as having resis- 4–8), unless there are contraindications to these drugs
tant hypertension, assuming that secondary causes of (Table 65.20), or concomitant conditions or diseases are
hypertension and poor adherence to treatment have been present that require specific modification of the drugs, as
excluded, and that the elevation in BP has been confirmed outlined in the recommendations below.
by repeated office BP measurement, ABPM, or HBPM (see
section ‘Resistant hypertension’). Such patients should
be considered for specialist evaluation. Additional treat- DEVICE-BASED HYPERTENSION TREATMENT
ment options include the addition of low-dose spirono-
lactone (25–50 mg daily) [310] or another additional Various device-based therapies have emerged, principally
diuretic therapy [higher-dose amiloride 10–20 mg daily targeted at the treatment of resistant hypertension. These
[357], higher dose thiazide or thiazidelike diuretics, loop are discussed below.
diuretics in patients with significant renal impairment
(eGFR <45 mL/min/m 2), beta-blockers, alpha-blockers,
centrally acting agents (e.g. clonidine), or, rarely, minoxi- CAROTID BARORECEPTOR STIMULATION
dil] (see section ‘Resistant hypertension’). (PACEMAKER AND STENT)
Carotid baroreceptor stimulation or baroreflex amplification
therapy – externally via an implantable pulse generator or
THE DRUG TREATMENT ALGORITHM FOR internally via an implantable device designed to increase
HYPERTENSION the strain on the carotid bulb – can lower BP in patients
Reflecting on the evidence above, and recognizing the with resistant hypertension. An RCT with the first genera-
urgent need to address the factors contributing to the poor tion of an implantable pulse generator showed sustained
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 579
Consider monotherapy in
1 Pill Initial therapy low risk grade 1 hypertension
ACEi or ARB + CCB or diuretic (systolic BP <150 mmHg), or in
Dual combination
very old ( 80 years) or frailer patients
Step 2
1 Pill Triple combination ACEi or ARB + CCB + diuretic
Step 3
Triple combination + Resistant hypertension
Consider referral to a specialist centre
2 Pills spironolactone or Add spironolactone (25–50 mg o.d.) for further investigation
other drug or other diuretic, alpha-blocker or beta-blocker
Beta-blockers
Consider beta-blockers at any treatment step, when there is a specific
indication for their use, e.g. heart failure, angina, post-MI, atrial fibrillation,
or younger women with, or planning, pregnancy
Figure 65.4 Core drug treatment strategy for uncomplicated hypertension. The core algorithm is also appropriate for
most patients with HMOD, cerebrovascular disease, diabetes, or PAD. Abbreviations: ACEi, angiotensin-converting enzyme
inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; HMOD, hypertension-mediated organ dam-
age; MI, myocardial infarction; o.d., once daily; PAD, peripheral artery disease.
BP-lowering efficacy (and sympathetic nervous system better safety profile for the second-generation device [359].
inhibition), but with some concerns about procedural and However, no RCT is currently available with this second-
longer-term safety [358]. A second-generation unilateral generation device. Another consideration is that implanta-
device has been developed to improve safety and sustained tion is costly and requires a complex surgical intervention.
efficacy. A propensity score-matched comparison of the This has led to the development of an endovascular carotid
first-generation and second-generation systems revealed baroreflex amplification device using a dedicated stent-like
that BP at 12 months post-implantation was similar, with a device designed to stretch the carotid bulb and increase
Figure 65.5 Drug treatment strategy for hypertension and coronary artery disease. Abbreviations: ACEi, angiotensin-
converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CVD,
cardiovascular disease; o.d., once daily.
580 Manual of Hypertension of the European Society of Hypertension
Beta-blockers
ACEi or ARB + CCB Consider beta-blockers at any
1 PiII Initial therapy treatment step, when there is a
Dual combination or ACEi or ARB + diuretic (or loop
diuretic)b specific indication for their use,
e.g. heart failure, angina,
post-Ml, atrial fibrillation, or
younger women with, or
planning, pregnancy
Step 3
Triple combination + Resistant hypertension
2 PiIIs spironolactonec or Add spironolactone (25–50 mg o.d.)
other drug or other diuretic, alpha-blocker or beta-blocker
A reduction in eGFR and rise in serum creatinine is expected in patients with CKD' who receive BP-lowering therapy, especially in those
treated with an ACEi or ARB but a rise in serum creatinine of >30% should prompt evaluation of the patient for possible renovascular disease.
Figure 65.6 Drug treatment strategy for hypertension and chronic kidney disease. Abbreviations: ACEi, angiotensin-
converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CKD,
chronic kidney disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; o.d., once daily. aCKD is
defined as an eGFR <60 mL/min/1.72 m 2 with or without proteinuria. bUse loop diuretics when eGFR is <30 mL/min/1.72 m 2,
because thiazide/thiazide-like diuretics are much less effective/ineffective when eGFR is reduced to this level. cCaution: risk
of hyperkalaemia with spironolactone, especially when eGFR is <45 mL/min/1.72 m 2 or baseline K+ ≥4.5 mmol/L.
When antihypertensive therapy is not required in HFrEF, treatment should be precribed according to the ESC Heart Failure Guidelines.136
Figure 65.7 Drug treatment strategy for hypertension and heart failure with reduced ejection fraction. Do not use
non-dihydropyridine CCBs (e.g. verapamil or diltiazem). Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker; CCB, calcium channel blocker; ESC, European Society of Cardiology; HFrEF, heart failure
with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist. aConsider an angiotensin receptor/neprilysin
inhibitor instead of ACEi or ARB per ESC Heart Failure Guidelines [136]. bDiuretic refers to thiazide/thiazide-like diuretic.
Consider a loop diuretic as an alternative in patients with oedema. c MRA (spironolactone or eplerenone). (Ponikowski P
et al. Eur Heart J 2016; 37: 2129–2200.)[136]
Add oral anticoagulation when indicated according to the CHA2DS2-VASc score, unless contraindicated.
aRoutine combination of beta-blockers with non-dihydropyridine CCBs (e.g. verapamil or
diltiazem) is not recommended due to a potential marked reduction in heart rate.
Figure 65.8 Drug treatment strategy for hypertension and atrial fibrillation. Abbreviations: ACEi, angiotensin-convert-
ing enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CHA 2DS2-
VASc, Cardiac failure, Hypertension, Age ≥75 (Doubled), Diabetes, Stroke (Doubled) – Vascular disease, Age 65–74 and Sex
category (Female); DHP, dihydropyridine.
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 581
18–65 years Target to 130 Target to 130 Target to Target to 130 Target to 130 70–79
or lower if tolerated or lower if tolerated <140 to 130 or lower if tolerated or lower if
Not <120 Not <120 if tolerated Not <120 tolerated
Not <120
Abbreviations: AD, coronary artery disease; CKD, chronic kidney disease (includes diabetic and nondiabetic CKD); DBP, diastolic blood pressure; SBP, systolic
blood pressure; TIA, transient ischaemic attack.
a Refers to patients with previous stroke and does not refer to blood pressure targets immediately after acute stroke.
b Treatment decisions and blood pressure targets may need to be modified in older patients who are frail and independent.
BP-lowering technique is conflicting. Several observational There were no reports of right heart failure or high-output
studies and national and international registries [364] sup- cardiac failure after device implantation over the short-
port the BP-lowering efficacy of renal denervation origi- term, but longer follow-up is clearly needed [377,378].
nally reported in the Symplicity HTN-1 and HTN-2 trials
[365]. A reduction in sympathetic activity following renal
denervation has also been observed [366]. However, two OTHER DEVICES
RCTs with a sham procedure control [367,368] failed to The carotid body is located at the bifurcation of the
document the superiority of renal denervation compared common carotid. It is innervated by nerve fibres from
with the sham procedure in reducing BP, but did con- the vagus nerve through the cervical ganglion and the
firm the safety of the procedure. Another RCT, the Renal carotid sinus nerve [379]. Stimulation of the carotid
Denervation for Hypertension (DENERHTN) trial [369], body drives sympathetic tone, resulting in an increase
showed the superiority of renal denervation in combination in BP and minute ventilation. Surgical resection of the
with optimized pharmacotherapy compared with pharma- carotid body is associated with reductions in BP [380]
cotherapy alone. The PRAGUE-15 study [370] documented and sympathetic overactivity in patients with heart failure
similar effects between renal denervation and optimized [381]. Devices for endovascular carotid body modification
pharmacotherapy (mainly by adding spironolactone) with by ultrasoundguided ablation have been developed and
respect to BP-lowering efficacy; however, the latter was asso- are currently under investigation.
ciated with more side effects and high discontinuation rates.
Beyond resistant hypertension, interim data in the first 80 Device-based therapies for hypertension
patients treated with renal denervation but with no back-
ground antihypertensive therapy showed a modest effect of Recommendation Classa Levelb
renal denervation vs. sham control on 24 h ambulatory BP
Use of device-based therapies is not recom- III B
after 3 months [366]. This study is ongoing.
mended for the routine treatment of hyperten-
Evaluating the efficacy of renal denervation has been
sion, unless in the context of clinical studies
challenging because the procedure needs to be applied to a and RCTs, until further evidence regarding their
population with a high probability of BP response. This is safety and efficacy becomes available
complicated by the complex pathophysiology of hyperten- [367,368].
sion, the lack of clinically applicable measures of sympa-
thetic activity, the absence of predictors of the long-term BP Abbrevation: RCT, randomized controlled trial.
response following renal denervation, and the absence of aClass of recommendation.
bLevel of evidence.
reliable markers of procedural success to immediately estab-
lish whether denervation has been achieved [371]. There
is evidence indicating that isolated systolic hypertension, In summary, device-based therapy for hypertension
characterized by increased aortic stiffness, is associated is a fast-moving field. Further sham-controlled studies
with a limited response to renal denervation [372,373] and are needed before device-based therapies can be recom-
baroreceptor stimulation (see above). Except for rare prob- mended for the routine treatment of hypertension outside
lems related to the catheterization procedure (access site of the framework of clinical trials.
complications, vessel dissection, etc.), no major complica-
tions or deterioration of renal function have been reported.
Major uncertainties remain as to the clinical role of
renal denervation outside of clinical studies, which should HYPERTENSION IN SPECIFIC
be performed in carefully selected patients at specialist CIRCUMSTANCES
hypertension centres and by experienced operators.
RESISTANT HYPERTENSION
CREATION OF AN ARTERIOVENOUS FISTULA
The central iliac arteriovenous anastomosis creates a fixed- DEFINITION OF RESISTANT HYPERTENSION
calibre (4 mm) conduit between the external iliac artery Hypertension is defined as resistant to treatment when the
and vein using a stent-like nitinol device (ROX arteriove- recommended treatment strategy fails to lower office SBP
nous coupler) [374,375]. Device deployment can be veri- and DBP values to less than 140 mmHg and/or less than
fied and is reversible, resulting in the diversion of arterial 90 mmHg, respectively, and the inadequate control of BP
blood (0.8–1 L/min) into the venous circuit with immedi- is confirmed by ABPM or HBPM in patients whose adher-
ate, verifiable reductions in BP [374,375]. The BP-lowering ence to therapy has been confirmed. The recommended
effect of arteriovenous anastomosis was first observed in a treatment strategy should include appropriate lifestyle mea-
study of patients with chronic obstructive pulmonary dis- sures and treatment with optimal or best tolerated doses
ease (COPD), in whom a moderate improvement in the of three or more drugs, which should include a diuretic,
6 min walking test was shown [376]. In the ROX CONTROL typically an ACE inhibitor or an ARB, and a CCB. Pseudo-
HTN trial, patients with resistant hypertension were ran- resistant hypertension (see below) and secondary causes of
domized to receive either standard care or insertion of hypertension should also have been excluded (see section
an arteriovenous coupler in combination with standard ‘Secondary hypertension’).
care [377]. At 6 months, office and ambulatory BP were Prevalence studies of resistant hypertension have been
significantly reduced in the coupler group compared with limited by variation in the definition used, and reported
the control group. Some important safety aspects need to prevalence rates range from 5 to 30% in patients with
be considered. Ipsilateral venous stenosis, which needed treated hypertension. After applying a strict definition (see
venoplasty and/or stenting, occurred in 29% of patients. above) and having excluded causes of pseudo-resistant
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 583
hypertension (see section ‘Pseudo-resistant hyperten- 3. Obstructive sleep apnoea (usually, but not invariably,
sion’), the true prevalence of resistant hypertension is associated with obesity).
likely to be less than 10% of treated patients. Patients with 4. Undetected secondary forms of hypertension (see
resistant hypertension are at higher risk of HMOD, CKD section ‘Secondary hypertension’).
and premature cardiovascular events [382]. 5. Advanced HMOD, particularly CKD or large-artery
stiffening.
Table 65.24 Resistant hypertension characteristics, secondary causes, and contributing factors
Characteristics of patients with resistant Causes of secondary resistant Drugs and substances that may cause
hypertension hypertension raised BP
be challenging in routine clinical practice [387]. Some of resistant hypertension when spironolactone is contra-
methods are easy to use but of limited value (e.g. stan- indicated or not tolerated. Direct vasodilators, such as
dardized questionnaires), whereas others, such as drug hydralazine or minoxidil, are infrequently used because
screening of urine or blood, show considerable promise they may cause severe fluid retention and tachycardia.
but are not yet widely available [388]. Other methods New BP-lowering drugs (nitric oxide donors, vasopres-
include the measurement of BP after directly observed sin antagonists, aldosterone synthase inhibitors, neutral
treatment intake [389], which has been used in clinical endopeptidase inhibitors, and endothelin antagonists) are
trials [390] but may be more difficult to implement in all under investigation [388].
routine clinical practice.
Resistant hypertension
TREATMENT OF RESISTANT HYPERTENSION Recommendations Classa Levelb
Effective treatment combines lifestyle changes (espe-
cially the reduction of sodium intake), discontinuation It is recommended that hypertension be defined I C
of interfering substances, and the sequential addition as resistant to treatment (i.e. resistant
of antihypertensive drugs to the initial triple therapy. hypertension) when:
Ultimately, replacing all current drugs by a simpler treat- ■■ Optimal doses (or best-tolerated doses) of an
ment regimen using SPC treatment is recommended to appropriate therapeutic strategy, which
reduce pill burden and improve adherence to treatment. should include a diuretic (typically an ACE
The optimal drug treatment of resistant hypertension has inhibitor or an ARB with a CCB and a
thiazide/thiazide-type diuretic), fails to lower
been poorly studied. The most effective strategy seems
clinic SBP and DBP values to <140 mmHg
to be additional diuretic treatment to decrease volume
and/or <90 mmHg, respectively; and
overload, together with the restriction of salt intake,
■■ The inadequate control of BP has been
particularly in patients with CKD. BP control may be confirmed by ABPM or HBPM; and
improved by increasing the dose of the existing diuretic ■■ After exclusion of various causes of
or by switching to a more potent thiazide-like diuretic pseudo-resistant hypertension (especially
(chlorthalidone or indapamide). A loop diuretic should poor medication adherence) and secondary
replace thiazides/thiazide-like diuretics if the eGFR is hypertension.
less than 30 mL/min. Although resistant hypertension
may show a BP reduction if the existing diuretic dose is Recommended treatment of resistant hyperten- I B
further increased, most patients require the administra- sion is:
tion of additional drugs. There is growing evidence to ■■ Reinforcement of lifestyle measures,
suggest that the fourth-line treatment should involve a especially sodium restriction [395].
blockade of the biological effects of aldosterone through ■■ Addition of low-dose spironolactonec to
none (50–100 mg/day). Amiloride (10–20 mg/day) has mated glomerular filtration rate is <30 mL/min.
recently been shown to be as effective as spironolactone
25–50 mg daily) in reducing BP in the PATHWAY2 study
[357]. It is emphasized that the same cautions about
the use of these agents should be considered in patients SECONDARY HYPERTENSION
with reduced eGFR and baseline potassium levels more
than 4.5 mmol/L. The PATHWAY-2 study also evaluated Secondary hypertension is hypertension due to an
bisoprolol (5–10 mg/day) or doxazosin modified release identifiable cause, which may be treatable with an
(4–8 mg/day) as alternatives to spironolactone. Neither intervention specific to the cause. A high index of
was as effective as spironolactone, but they did reduce suspicion and early detection of secondary causes of
BP significantly vs. placebo when added to background hypertension are important because interventions may
treatment in resistant hypertension [310]. Thus, bisopro- be curative, especially in younger patients [e.g. corrective
lol and doxazosin have an evidence base for the treatment surgery for aortic coarctation, renal angioplasty in younger
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 585
patients with renal artery fibromuscular dysplasia, history is important when considering a diagnosis of sec-
reversal of an endocrine cause of hypertension (e.g. by ondary hypertension. Moreover, other commonly used
removal of an adrenal adenoma), or drug treatment of a drugs such as nonsteroidal anti-inflammatory drugs or
monogenic disorder affecting a specific drug-sensitive glucocorticoids can antagonize the BP-lowering effect
ion channel (e.g. selective use of amiloride in Liddle’s of antihypertensive medications in patients treated for
syndrome)]. Interventions that treat the cause of secondary hypertension and may contribute to a loss of BP control.
hypertension later in life are less likely to be curative
(i.e. remove the need for antihypertensive medication)
because longstanding hypertension results in vascular GENETIC CAUSES OF SECONDARY HYPERTENSION
and other organ damage that sustains the elevated BP, but Genetic causes of secondary hypertension are usually due
intervention is still important because it will often result to single-gene disorders (see section ‘Genetics and hyper-
in much better BP control with less medication. tension’) [194,195]. They are rare but important causes
The prevalence of secondary hypertension is reported of secondary hypertension because identifying the cause
to be 5–15% [396] of people with hypertension. Screening can point to a specific drug treatment (Table 65.29)
all hypertensive patients for secondary hypertension is [194,195]. Common features of these genetic disorders
not feasible or cost-effective; however, there are some gen- are that they usually present with hypertension in chil-
eral patient characteristics that suggest those more likely dren, adolescents, or young adults, and most monogenic
to have secondary hypertension and in whom screening disorders induce hypertension by increasing the renal
should be considered after confirming that BP is elevated tubular reabsorption of sodium. Thus, they are usually
with ABPM (Table 65.25). associated with a suppressed plasma renin concentration
It is beyond the scope of these Guidelines to describe (PRC) or plasma renin activity (PRA), which is unusual
the detailed clinical management of specific causes in younger patients and especially those treated with
of secondary hypertension. However, the commoner antihypertensive medications (e.g. RAS blockers, CCBs,
causes of secondary hypertension, clinical history, and or diuretics), that would be expected to increase PRC or
screening tests are described in Table 65.26, and the typi- PRA. Thus, the finding of a suppressed PRC or PRA, espe-
cal age distribution of these causes of secondary hyper- cially while taking these drugs, should raise the suspi-
tension is shown in Table 65.27. Review of these tables cion of secondary hypertension due a salt-retaining state.
demonstrates that most screening can be undertaken Importantly, beta-blockers in particular, but also nonste-
with blood and urine tests, abdominal ultrasound, and roidal anti-inflammatory drugs, alpha-methyl dopa, or
echocardiography. Referral to a specialist centre is rec- clonidine, suppress PRC and PRA. These drugs should be
ommended for additional investigations to confirm a discontinued (if clinically feasible) for at least 2 weeks
suspected diagnosis of secondary hypertension and for before measuring PRC or PRA.
clinical management. Other causes of secondary hyper-
tension due to drugs and substances, and rarer mono-
genic causes, are described below and are summarized
in Tables 65.28 and 65.29. HYPERTENSION URGENCIES AND
EMERGENCIES
DRUGS AND OTHER SUBSTANCES THAT MAY CAUSE Hypertension emergencies are situations in which severe
SECONDARY HYPERTENSION hypertension (grade 3) is associated with acute HMOD,
Medications and other substances may cause a sufficient which is often life-threatening and requires immediate
increase in BP to raise the suspicion of secondary hyper- but careful intervention to lower BP, usually with intra-
tension [397] (Table 65.28). Consequently, a careful drug venous (i.v.) therapy [398]. The rate and magnitude of
an increase in BP may be at least as important as the
absolute level of BP in determining the magnitude of
Table 65.25 Patient characteristics that should raise the organ injury [399]. Typical presentations of a hyperten-
suspicion of secondary hypertension sion emergency are:
Prevalence in
Cause hypertensive patients Suggestive symptoms and signs Screening investigations
Obstructive sleep apnoea 5–10% Snoring; obesity (can be present in non obese); Epworth score and ambulatory
morning headache; daytime somnolence polygraphy
Renal parenchymal 2–10% Mostly asymptomatic; diabetes; haematuria, Plasma creatinine and electrolytes,
disease proteinuria, nocturia; anaemia, renal mass in eGFR; urine dipstick for blood and
adult polycystic CKD protein, urinary albumin:creatinine
ratio; renal ultrasound
Renovascular disease
Atherosclerotic renovascu- 1–10% Older; widespread atherosclerosis (especially Duplex renal artery Doppler or CT
lar disease PAD); diabetes; smoking; recurrent flash angiography or MR angiography
Fibromuscular dysplasia pulmonary oedema; abdominal bruit
Younger; more common in women; abdominal
bruit
Endocrine causes
Primary Aldosteronism 5–15% Mostly asymptomatic; muscle weakness (rare) Plasma aldosterone and renin, and
aldosterone: renin ratio; hypokalae-
mia (in a minority): note hypokalae-
mia can depress aldosterone levels
Phaeochromocytoma <1% Episodic symptoms (the 5 ‘Ps’): paroxysmal Plasma or 24 h urinary fractionated
hypertension, pounding headache, perspira- metanephrines
tion, palpitations, and pallor; labile BP; BP
surges precipitated by drugs (e.g. beta-
blockers, metoclopramide, sympathomimetics,
opioids, and tricyclic antidepressants)
Cushing’s syndrome <1% Moon face, central obesity, skin atrophy, striae 24 h urinary-free cortisol
and bruising; diabetes; chronic steroid use
Thyroid disease 1–2% Signs and symptoms of hyperthyroidism or Thyroid function tests
(hyperthyroidism or hypothyroidism
hypothyroidism)
Other causes
Coarctation of the aorta <1% Usually detected in children or adolescence; Echocardiogram
different BP (≥20/10 mmHg) between
upper–lower extremities and/or between
right–left arm and delayed radial-femoral
femoral pulsation; low ABI interscapular
ejection murmur; rib notching on chest X-ray
Abbreviations: ABI, ankle-brachial index; BP, blood pressure; CKD, chronic kidney disease; CT, computed tomography; eGFR, estimated glomerular filtration rate;
MR, magnetic resonance; PAD, peripheral artery disease.
3. Patients with sudden severe hypertension due to Acute stroke, especially intracerebral haemorrhage,
phaeochromocytoma, associated with organ damage. when associated with severe hypertension has often
4. Pregnant women with severe hypertension or been termed a hypertension emergency, but a more cau-
pre-eclampsia (see section ‘Hypertension and tious approach is now recommended for acute BP lower-
pregnancy’). ing in the emergency setting of acute stroke (see section
‘Cerebrovascular disease and cognition’).
The most common emergency symptoms will depend The term ‘hypertension urgency’ has also been used
on the organs affected but may include headache, visual to describe severe hypertension in patients presenting
disturbances, chest pain, dyspnoea, dizziness, and other to the emergency department in whom there is no clini-
neurological deficits. In patients with hypertensive cal evidence of acute HMOD [405]. Whilst these patients
encephalopathy, the presence of somnolence, lethargy, require BP reduction, they do not usually require admis-
tonic clonic seizures and cortical blindness may precede a sion to hospital, and BP reduction is best achieved with
loss of consciousness; however, focal neurological lesions oral medication according to the drug treatment algo-
are rare and should raise the suspicion of stroke. rithm presented in Figure 65.4. However, these patients
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 587
Table 65.28 Medications and other substances that may increase blood pressure
Medication/Substance
Oral contraceptive pill Especially oestrogen containing; cause hypertension in 5% of women, usually mild but can be severe
Diet pills For example, phenylpropanolamine and sibutramine
Nasal decongestants For example, phenylephrine hydrochloride and naphazoline hydrochloride
Stimulant drugs Amphetamine, cocaine, and ecstasy; these substances usually cause acute rather than chronic hypertension
Liquorice Chronic excessive liquorice use mimics hyperaldosteronism by stimulating the mineralocorticoid receptor and inhibiting
cortisol metabolism
Immunosuppressive For example, cyclosporin A (tacrolimus has less effect on BP and rapamycin has almost no effect on BP) and steroids
medications (e.g. corticosteroids and hydrocortisone)
Antiangiogenic cancer Antiangiogenic drugs such as VEGF inhibitors (e.g. bevacizumab), tyrosine kinase inhibitors (e.g. sunitinib), and
therapies sorafenib have been reported to increase BP
Other drugs and substances Anabolic steroids, erythropoietin, nonsteroidal anti-inflammatory drugs, and herbal remedies (e.g. ephedra and ma
that may raise BP huang)
Table 65.31 Hypertensive emergencies requiring immediate blood pressure lowering with intravenous drug therapy
Clinical presentation Timeline and target for BP reduction First-line treatment Alternative
Acute coronary event Immediately reduce SBP to <140 mmHg Nitroglycerine, labetalol Urapidil
Acute cardiogenic pulmonary Immediately reduce SBP to <140 mmHg Nitroprusside or nitroglycerine Urapidil (with loop
oedema (with loop diuretic) diuretic)
Acute aortic dissection Immediately reduce SBP to <120 mmHg Esmolol and nitroprusside or Labetalol OR metoprolol
AND heart rate to <60 bpm nitroglycerine or nicardipine
Eclampsia and severe pre Immediately reduce SBP to <160 mmHg Labetalol or nicardipine and Consider delivery
eclampsia/HELLP AND DBP to <105 mmHg magnesium sulfate
Abbreviations: BP, blood pressure; bpm, beats/min; DBP, diastolic blood pressure; HELLP, haemolysis, elevated liver enzymes, and low platelets; i.v., intravenous;
MAP, mean arterial pressure; SBP, systolic blood pressure.
Table 65.32 Drug types, doses, and characteristics for treatment of hypertension emergencies
Onset of Duration
Drug action of action Dose Contraindications Adverse effects
Esmolol 1–2 min 10–30 min 0.5–1 mg/kg i.v. bolus; 50–300 µg/kg/min Second or third-degree AV Bradycardia
i.v. infusion block, systolic heart failure,
asthma, bradycardia
Metoprolol 1–2 min 5–8 h 2.5–5 mg i.v. bolus over 2 minutes; may Second or third-degree AV Bradycardia
repeat every 5 minutes to a maximum dose block, systolic heart failure,
of 15 mg asthma, bradycardia
Labetalol 5–10 min 3–6 h 0.25–0.5 mg/kg i.v. bolus; 2–4 mg/min i.v. Second or third-degree AV Bronchoconstriction,
infusion until goal BP is reached, thereafter block; systolic heart failure, foetal bradycardia
5–20 mg/h asthma, bradycardia
Fenoldopam 5–15 min 30–60 min 0.1 mg/kg/min i.v. infusion, increase every Caution in glaucoma
15 min with 0.05 to 0.1 µg/kg/min
increments until goal BP is reached
Clevidipine 2–3 min 5–15 min 2 mg/h i.v. infusion, increase every 2 min Headache, reflex
with 2 mg/h until goal BP tachycardia
Nicardipine 5–15 min 30–40 min 5–15 mg/h i.v. infusion, starting dose Liver failure Headache, reflex
5 mg/h, increase every 15–30 min with tachycardia
2.5 mg until goal BP, thereafter decrease to
3 mg/h
Clonidine 30 min 4–6 h 150 –300 µg i.v. bolus over 5–10 min Sedation, rebound
hypertension
be prescribed, and longer-term follow-up is essential as BP the patient’s clinical condition, concomitant treatments,
will invariably rise. In younger patients with hypertension and frailty. That said, age alone must never be a barrier to
treated with BP-lowering medication, office BP should be treatment because high BP is an important risk factor even
reduced to at least 130/80 mmHg if treatment is well tol- at the most advanced ages. Furthermore, a recent study of a
erated. Other interventions, for example statins or anti- cohort of older patients from the general population (thus
platelet therapy, should also be considered for higher-risk including those with frailty) has shown that better adher-
patients (see section ‘Should blood pressure-lowering drug ence to antihypertensive treatment was associated with a
treatment be initiated on the basis of blood pressure values reduced risk of cardiovascular events and mortality, even
or the level of total cardiovascular risk?’). when age was more than 85 years (mean 90 years) [432].
It is recommended that older patients are treated according
to the treatment algorithm outlined in section ‘Treatment of
ISOLATED SYSTOLIC HYPERTENSION IN THE YOUNG hypertension’. In very old patients, it may be appropriate to
Some young, healthy people, and men in particular, may initiate treatment with monotherapy. In all older patients,
present with isolated grade 1 systolic hypertension (i.e. when combination therapy is used, it is recommended that
brachial SBP at least 140–159 mmHg and a normal DBP this is initiated at the lowest available doses. In all older
<90 mmHg), and this may be associated with a normal cen- patients, and especially very old or frail patients, the pos-
tral aortic SBP due to excessive peripheral systolic pressure sible occurrence of postural BP should be closely monitored
amplification [428]. It is unclear whether isolated systolic and symptoms of possible hypotensive episodes checked
hypertension in the context of a normal aortic pressure is by ABPM. Unless required for concomitant diseases, loop
benign. A recent examination of prospective data from the diuretics and alpha-blockers should be avoided because of
Chicago Heart Association Detection Project found that their association with injurious falls [433,434]. Renal func-
young men with isolated systolic hypertension had a cardio- tion should be frequently assessed to detect possible increases
vascular risk similar to that of individuals with high–normal in serum creatinine and reductions in eGFR as a result of
BP and that isolated systolic hypertension in the young was BP-related reductions in renal perfusion. When treated, BP
closely associated with smoking [429]. On the basis of cur- should be lowered to a systolic value of 130–139 mmHg and
rent evidence, these young individuals should receive recom- a diastolic value of less than 80 mmHg if tolerated. Treated
mendations on lifestyle modification (particularly cessation SBP values of less than 130 mmHg should be avoided. A key
of smoking); whether they should receive drug treatment is emphasis in treating older patients, and especially the very
unclear, but they do require longer-term follow-up as many old, is to carefully monitor for any adverse effects or toler-
will develop sustained hypertension [430]. ability problems associated with BP-lowering treatment,
keeping in mind that adverse effects can be more frequent
than reported in RCTs, in which specific medical expertise
HYPERTENSION IN OLDER PATIENTS and close patient supervision may minimize adverse effects
(AGE 65 YEARS) and tolerability problems.
An important consideration is frail, dependent older
The prevalence of hypertension increases with age, with a patients, including those with orthostatic hypotension.
prevalence of 60% over the age of 60 years and 75% over These have been excluded from RCTs. The SPRINT trial
the age of 75 years. For the purposes of these Guidelines, showed the benefits of BP-lowering treatment being
older is defined as at least 65 years and the very old as at extended to recruited patients who were at the frailer end
least 80 years. of the spectrum, including those with reduced gait speed
For many years, advanced age has been a barrier to the [215]. This suggests that the benefit of treatment is not lim-
treatment of hypertension because of concerns about ited to fit and independent older patients; however, to what
potentially poor tolerability, and even harmful effects of extent BP-lowering treatment benefits the very frail [214]
BP-lowering interventions in people in whom mechanisms and institutionalized patients remains to be determined.
preserving BP homeostasis and vital organ perfusion may In some patients, the best achievable BP may be higher
be more frequently impaired. This approach is not appro- than the recommended target, but it should be recognized
priate, because evidence from RCTs has shown that in old that any amount of BP lowering is likely to be worthwhile
and very old patients, antihypertensive treatment substan- and associated with a reduced risk of major cardiovascular
tially reduces cardiovascular morbidity and cardiovascular events (especially stroke and heart failure) and mortality.
and all-cause mortality [220,431] (see section ‘Treatment of
hypertension’). Moreover, treatment has been found to be
generally well tolerated. However, older patients are more
likely to have comorbidities such as renal impairment, WOMEN, PREGNANCY, ORAL
atherosclerotic vascular disease, and postural hypoten- CONTRACEPTION AND HORMONE-
sion, which may be worsened by BP-lowering drugs. Older REPLACEMENT THERAPY
patients also frequently take other medications, which may
negatively interact with those used to achieve BP control. A HYPERTENSION AND PREGNANCY
further important caveat is that RCTs have not included very Hypertensive disorders in pregnancy affect 5–10% of preg-
frail patients, dependent patients, and patients with pos- nancies worldwide and remain a major cause of maternal,
tural hypotension. It is thus uncertain whether, and to what foetal, and neonatal morbidity and mortality. Maternal risks
extent, such patients would benefit from BP-lowering treat- include placental abruption, stroke, multiple organ failure,
ment in the context of their comorbidities and reduced life and disseminated intravascular coagulation. The fetus is at
expectancy. Thus, in older hypertensive patients, treatment high risk of intrauterine growth retardation (25% of cases of
presents more difficulties than in younger people, because pre-eclampsia), prematurity (27% of cases of pre-eclampsia),
the decision to treat hypertension must take into account and intrauterine death (4% of cases of pre-eclampsia) [435].
592 Manual of Hypertension of the European Society of Hypertension
DEFINITION AND CLASSIFICATION OF HYPERTENSION IN All pregnant women should be assessed for proteinuria
PREGNANCY in early pregnancy to detect pre-existing renal disease and,
The definition of hypertension in pregnancy is based on in the second half of pregnancy, to screen for pre-eclampsia.
office BP values, SBP at least 140 mmHg and/or DBP at A dipstick test of at least 1+ should prompt evaluation of
least 90mmHg [436,437], and is classified as mild (140– ACR in a single spot urine sample and a value less than
159/90–109 mmHg) or severe (≥160/110 mmHg), in con- 30 mg/mmol can reliably rule out proteinuria in preg-
trast to the conventional hypertension grading. nancy [442].
Hypertension in pregnancy is not a single entity but In addition to basic laboratory tests, the following inves-
comprises: tigations may be considered:
1. Pre-existing hypertension: precedes pregnancy or 1. Ultrasound investigation of the kidneys and adrenals,
develops before 20 weeks of gestation, and usually and plasma or urinary fractionated metanephrine
persists for more than 6 weeks postpartum and may assays in pregnant women with a history suggestive of
be associated with proteinuria. phaeochromocytoma.
2. Gestational hypertension: develops after 20 weeks 2. Doppler ultrasound of uterine arteries (performed
of gestation and usually resolves within 6 weeks after 20 weeks of gestation) to detect those at higher
postpartum. risk of gestational hypertension, pre-eclampsia, and
3. Pre-existing hypertension plus superimposed ges- intrauterine growth retardation [443].
tational hypertension with proteinuria. 3. A soluble fms-like tyrosine kinase 1:placental growth
4. Pre-eclampsia: gestational hypertension with signifi- factor ratio of at least 38 can be used to exclude the
cant proteinuria (>0.3 g/24 h or ≥30 mg/mmol ACR). development of pre-eclampsia in the next week when
It occurs more frequently during the first pregnancy, in suspected clinically [444].
multiple pregnancy, in hydatidiform mole, in antiphos-
pholipid syndrome, or with pre-existing hypertension, PREVENTION OF HYPERTENSION AND PRE-ECLAMPSIA
renal disease, or diabetes. It is often associated with Women at high or moderate-risk of pre-eclampsia should
foetal growth restriction due to placental insufficiency be advised to take 100–150 mg of aspirin daily from weeks
and is a common cause of prematurity [438]. The only 12–36 [445]. High risk of pre-eclampsia includes any of
cure for pre-eclampsia is delivery. As proteinuria may the following:
be a late manifestation of pre-eclampsia, it should be
suspected when denovo hypertension is accompanied 1. Hypertensive disease during a previous pregnancy
by headache, visual disturbances, abdominal pain, or 2. CKD
abnormal laboratory tests, specifically low platelets 3. Autoimmune disease such as systemic lupus erythe-
and/or abnormal liver function. matosus or antiphospholipid syndrome
5. Antenatally unclassifiable hypertension: this term is 4. Type 1 or type 2 diabetes
used when BP is first recorded after 20 weeks of gesta- 5. Chronic hypertension
tion and it is unclear if hypertension was pre-existing. Moderate-risk of pre-eclampsia includes one or more of
Reassessment 6 weeks postpartum will help distin- the following risk factors:
guish pre-existing from gestational hypertension.
1. First pregnancy
BLOOD PRESSURE MEASUREMENT IN PREGNANCY 2. Age of at least 40 years
BP in pregnancy should be measured in the sitting posi- 3. Pregnancy interval of more than 10 years
tion (or the left lateral recumbent during labour) with 4. BMI of at least 35 kg/m2 at first visit
an appropriately sized arm cuff at heart level and using 5. Family history of pre-eclampsia
Korotkoff V for DBP. Manual auscultation remains the 6. Multiple pregnancy
gold standard for BP measurement in pregnancy, because
automated devices tend to under-record the BP and are CLINICAL MANAGEMENT OF HYPERTENSION IN
unreliable in severe pre-eclampsia. Only validated devices PREGNANCY
should be used in pregnancy [439]. ABPM is superior to Mild hypertension of pregnancy (BP 140–159/90–
office BP measurement for the prediction of pregnancy 109 mmHg) The goal of drug treatment of hypertension in
outcome [440]. ABPM devices recommended for use in pregnancy is to reduce maternal risk; however, the agents
pregnancy are more accurate than those used for office selected must be safe for the fetus. The benefits of drug treat-
measurement or HBPM. ABPM helps avoid unnecessary ment for mother and fetus in hypertension in pregnancy
treatment of white-coat hypertension, and is useful in the have not been extensively studied, with the best data from
management of high-risk pregnant women with hyperten- a single trial using alpha-methyldopa, performed 40 years
sion and those with diabetic or hypertensive nephropathy. ago [446–448]. A further study suggested that tighter vs. less
tight control of BP in pregnancy showed no difference in the
INVESTIGATION OF HYPERTENSION IN PREGNANCY risk of adverse perinatal outcomes and overall serious mater-
Basic laboratory investigations recommended for monitor- nal complications. However, secondary analysis suggested
ing pregnant hypertensive women include urine analysis, that tighter control of BP may reduce the risk of developing
blood count, haematocrit, liver enzymes, serum creati- more severe hypertension and pre-eclampsia [446].
nine and serum uric acid (increased in clinically evident Most women with pre-existing hypertension and nor-
pre-eclampsia). Hyperuricaemia in hypertensive pregnan- mal renal function will not have severe hypertension
cies identifies women at increased risk of adverse maternal and are a low risk for developing complications during
and foetal outcomes [441]. pregnancy. Indeed, some of these women may be able to
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 593
withdraw their medication in the first half of pregnancy consensus is to lower BP to less than 160/105 mmHg to pre-
because of the physiological fall in BP. Despite the paucity vent acute hypertensive complications in the mother. Both
of evidence, European Guidelines [17,449,450] have rec- labetalol and nicardipine have shown to be safe and effective
ommended initiating drug treatment: for the treatment of severe pre-eclampsia if i.v. BP-lowering
therapy is necessary [452]. In both cases, monitoring of foe-
1. In all women with persistent elevation of BP at least tal heart rate is necessary. To prevent foetal bradycardia, the
150/95 mmHg; cumulative dose of labetalol should not exceed 800 mg/24 h.
2. In women with gestational hypertension (with or Intravenous sodium nitroprusside is contraindicated in preg-
without proteinuria), pre-existing hypertension with nancy because of an increased risk of foetal cyanide poison-
the superimposition of gestational hypertension, or ing. The drug of choice when pre-eclampsia is associated
hypertension with subclinical HMOD, when BP is with pulmonary oedema is nitroglycerin (glyceryl trinitrate),
more than 140/90 mmHg. given as an i.v. infusion of 5 µg/min, and gradually increased
every 3–5 min to a maximum dose of 100 µg/min.
Women with pre-existing hypertension may continue their Delivery is indicated urgently in pre-eclampsia with
current antihypertensive medication, but ACE inhibitors, visual disturbances or haemostatic disorders, and at 37
ARBs, and direct renin inhibitors are contraindicated due to weeks in asymptomatic women [453].
adverse foetal and neonatal outcomes. Methyldopa, labetalol, Blood pressure postpartum. Postpartum hypertension is
and CCBs are the drugs of choice. Beta-blockers may induce common in the first week. Any drug recommended can be
foetal bradycardia; consequently, if used, their type and dose used according to the hypertension treatment algorithm
should be carefully selected, with atenolol best avoided. shown in Figure 65.4, with the caveats: methyldopa should
Diuretic therapy is generally avoided because plasma volume be avoided because of the risk of postpartum depres-
is reduced in women who develop pre-eclampsia. sion and consideration should be given to drug choice in
There are no data to define the optimal BP treatment breastfeeding women.
target in pregnant women. Nevertheless, for pragmatic
reasons, if treatment is initiated it is important to suggest a HYPERTENSION AND BREASTFEEDING
treatment target to calibrate how much treatment to give. All antihypertensive drugs taken by the nursing mother
A BP target of less than 140/90 is suggested for pregnant are excreted into breast milk. Most are present at very low
women receiving antihypertensive therapy. concentrations except for propranolol and nifedipine, with
Severe hypertension of pregnancy (160/110 mmHg). breast milk concentrations similar to those in maternal
There is no agreed definition of severe hypertension, with plasma. Reference to prescribing information in breast-
values ranging between 160 and 180 mmHg/more than feeding women is important.
110 mmHg. The 2018 ESC Task Force on CVD during
pregnancy [435] considers an SBP of at least 170 mmHg RISK OF RECURRENCE OF HYPERTENSIVE DISORDERS IN A
or DBP of at least 110 mmHg an emergency in a pregnant SUBSEQUENT PREGNANCY
woman, who should be immediately admitted to hospital Women experiencing hypertension in their first pregnancy
for treatment. The selection of the antihypertensive drug are at increased risk in a subsequent pregnancy. The earlier
and its route of administration depends on the expected the onset of hypertension in the first pregnancy, the higher
time of delivery. Pharmacological treatment with i.v. the risk of recurrence in a subsequent pregnancy.
labetalol, oral methyldopa, or CCB should be initiated.
Intravenous hydralazine is no longer the drug of choice LONG-TERM CARDIOVASCULAR CONSEQUENCES OF
as it is associated with more perinatal adverse effects than GESTATIONAL HYPERTENSION
other drugs [451]. However, hydralazine is still used when Women who develop gestational hypertension or
other treatment regimens fail to achieve adequate BP con- pre-eclampsia are at increased risk of hypertension, stroke,
trol. Intravenous urapidil can also be considered. and ischaemic heart disease in later adult life [454,455].
In hypertensive crises, that is in patients with eclampsia or Lifestyle modifications are indicated to avoid complica-
severe pre-eclampsia (with or without haemolysis, elevated tions in subsequent pregnancies and to reduce maternal
liver enzymes, and low platelets syndrome), hospitalization cardiovascular risk in the future. Therefore, annual visits
and BP-lowering therapy is essential, and delivery needs to to a primary care physician to check BP and metabolic fac-
be considered after the maternal condition has stabilized tors are recommended for these patients.
[435]. Intravenous magnesium sulfate is recommended for Further detail on the management of hypertension and
the prevention of eclampsia and treatment of seizures. The other cardiovascular disorders in pregnancy is available [435].
In all other cases, initiation of drug treatment is recommended when SBP is ≥150 mmHg or DBP is ≥95 mmHg. I C
Methyldopa, labetalol, and CCBs are recommended as the drugs of choice for the treatment of hypertension in I B (methyldopa)
pregnancy [447,448].
I C (labetalol or CCBs)
Continued
594 Manual of Hypertension of the European Society of Hypertension
ACE inhibitors, ARBs, or direct renin inhibitors are not recommended during pregnancy. III C
SBP ≥170 mmHg or DBP ≥110 mmHg in a pregnant woman is an emergency, and admission to hospital is I C
recommended.
In severe hypertension, drug treatment with i.v. labetalol, oral methyldopa, or nifedipine is recommended. I C
The recommended treatment for hypertensive crisis is i.v. labetalol or nicardipine and magnesium. I C
In pre-eclampsia associated with pulmonary oedema, nitroglycerin given as an i.v. infusion is recommended. I C
In women with gestational hypertension or mild pre-eclampsia, delivery is recommended at 37 weeks [453]. I B
It is recommended to expedite delivery in pre-eclampsia with adverse conditions, such as visual disturbances or I C
haemostatic disorders.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; DBP, diastolic blood pressure; i.v., intrave-
nous; SBP, systolic blood pressure.
a Class of recommendation.
b Level of evidence.
b Level of evidence.
which can be marked in people with diabetes due to auto-
c When eGFR <30 mL/min/1.73 m2, avoid thiazide/thiazide-like diuretics
nomic neuropathy [235]. Initiation of antihypertensive drug
therapy is recommended when the office BP is more than and consider using a loop diuretic when a diuretic is required.
140/90 mmHg. Alongside lifestyle interventions, treatment
should usually be initiated with a twodrug combination of
an ACE inhibitor or ARB with a CCB or thiazide/thiazide- HYPERTENSION AND CHRONIC KIDNEY
like diuretic, and treatment escalated according to the rec- DISEASE
ommended treatment algorithm (see section ‘Treatment of
hypertension’). This approach ensures that the treatment Hypertension is a major risk factor for the development
strategy includes an ACE inhibitor or ARB, which has been and progression of CKD, irrespective of the cause of CKD.
shown to reduce albuminuria and the appearance or pro- In patients with CKD, resistant hypertension, masked
gression of diabetic nephropathy more effectively than hypertension, and elevated nighttime BP are common,
other drug classes [235]. Combination of an ACE inhibitor and are associated with a lower eGFR, higher levels of
with an ARB is contraindicated because it is accompanied albuminuria, and HMOD [483,484].
by an excess of renal adverse events [298,473,474]. The effects of lowering BP in patients with CKD have been
Recent RCTs have shown that some antidiabetic agents the subject of many meta-analyses. A recent meta-analysis has
(the selective inhibitors of sodium glucose cotransporter shown that BP lowering significantly reduced end-stage renal
2 in the kidney) can reduce office and ambulatory BP by disease in patients with CKD, but only in those with albu-
several mmHg [475,476], and that this occurs even when minuria and without any beneficial effect on cardiovascular
people are treated with antihypertensive drugs. This may events [203]. However, a more recent and larger meta-anal-
help improve BP control (see below), which is especially ysis has shown a significant reduction in all-cause mortality
difficult in diabetes [477], and may reduce the progression following BP reduction in patients with CKD [485].
596 Manual of Hypertension of the European Society of Hypertension
teinuria less than 1 g/day, the lowest risk of developing diuretics and consider using a loop diuretic if required.
CKD (not cardiovascular risk) was obtained with an
SBP of less than 140 mmHg [487]. Another systematic
review failed to demonstrate that a BP target of less than HYPERTENSION AND CHRONIC OBSTRUCTIVE
130/80 mmHg improved clinical outcomes more than PULMONARY DISEASE
a target of less than 140/90 mmHg in nondiabetic CKD
[488]. In a large retrospective cohort containing 398 419 Hypertension is the most frequent comorbidity in patients
treated hypertensive patients (30% with diabetes), the with COPD, and coincidence of the two diseases may affect
nadir SBP and DBP for the lowest risk of end-stage renal 2.5% of the adult population [490]. Patients with hyper-
disease and mortality were 137 and 71 mmHg, respec- tension and COPD are at particularly high cardiovascular
tively, with a clear increase in mortality risk at SBP less risk [490,491]. Both conditions share similar environmen-
than 120 mmHg [489]. tal risks and, in addition, hypoxia may exacerbate the
Current evidence suggests that in patients with CKD, BP risk [490,491]. Treatment of COPD with anticholinergic
should be lowered to less than 140/90 mmHg and towards agents and long-acting beta-2 adrenoceptor agonists may
130/80 mmHg. Lifestyle advice, especially sodium restric- adversely affect the cardiovascular system (increase heart
tion, may be especially effective at aiding BP lowering in rate and BP). The presence of COPD also has an impact on
patients with CKD. Because BP lowering reduces renal per- the selection of antihypertensive drugs, which should con-
fusion pressure, it is expected and not unusual for eGFR sider their effects on pulmonary function. Concern has
to be reduced by 10–20% in patients treated for hyperten- been predominantly directed to the use of beta-blockers,
sion. Thus, careful monitoring of blood electrolytes and although there is evidence that in COPD these drugs
eGFR is essential, but clinicians should not be alarmed maintain their cardiovascular-protective effects [492,493].
by the anticipated decline in GFR when treatment is ini- Beta-blockers may negatively affect the reduced basal lung
tiated. This decline usually occurs within the first few function in patients with COPD, diminish the effective-
weeks of treatment and stabilizes thereafter. If the decline ness of emergency beta-agonist administration, reduce the
in GFR continues or is more severe, the treatment should benefit of long-acting beta-agonist treatment, and make the
be stopped, and the patient investigated to determine the discrimination of asthma and COPD more difficult. That
presence of renovascular disease. said, when tolerated, the use of cardiac beta 1-selective beta-
blockers in patients with COPD has proven to be safe in
different settings, including hypertension [494]. It should
also be noted that diuretics may decrease the plasma level
Therapeutic strategies for treatment of hypertension of potassium (in addition to the hypokalaemic effects of
in CKD glucocorticoids and beta 2-adrenoceptor agonists), worsen
carbon dioxide retention (including metabolic alkalosis-
Recommendations Classa Levelb
related hypoxia in hypoventilated patients), increase
In patients with diabetic or non-diabetic CKD, I A haematocrit, and deteriorate mucus secretion in bron-
it is recommended that an office BP of chi. Therefore, in general, diuretics are not recommended
≥140/90 mmHg be treated with lifestyle advice for widespread use in hypertensive patients with COPD
and BP-lowering medication [9,203,485]. [490,495].
In conclusion, management of hypertensive patients
Continued with COPD should include lifestyle changes, among
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 597
which cessation of smoking is essential. CCBs, ARBs or ■■ To target SBP to ≤130 mmHg if tolerated, but I A
ACEIs, or the CCB/RAS blocker combination are recom- not <120 mmHg [2,496].
mended as the initial drugs of choice. If the BP response I A
■■ In older patients (aged ≥65 years), to target
is poor, or depending on other comorbidities, thiazides or to an SBP range of 130–140 mmHg [2,496]. I C
thiazide-like diuretics and beta1-selective beta-blockers ■■ To target DBP to <80 mmHg, but not
can be considered. <70 mmHg.
In hypertensive patients with a history of I A
myocardial infarction, beta-blockers and RAS
HYPERTENSION AND HEART DISEASE blockers are recommended as part of treatment
[503].
CORONARY ARTERY DISEASE
In patients with symptomatic angina, beta- I A
There are strong epidemiological relationships between blockers and/or CCBs are recommended [503].
CAD and hypertension. The INTERHEART study showed
that 50% of the population-attributable risk of a myo- Abbreviations: BP, blood pressure; CAD, coronary artery disease; CCB, cal-
cardial infarction can be accounted for by lipids, with cium channel blocker; DBP, diastolic blood pressure; RAS, renin–angiotensin
hypertension accounting for 25% [10]. Another registry- system; SBP, systolic blood pressure.
a Class of recommendation.
based study of over 1 million patients showed that isch-
b Level of evidence.
aemic heart disease (angina and myocardial infarction)
accounted for most (43%) of the CVD-free years of life lost
due to hypertension from the age of 30 years [7]. In hypertensive patients with CAD, beta-blockers and
More compelling is the beneficial effect of BP treat- RAS blockers may improve outcomes in postmyocardial
ment on reducing the risk of myocardial infarction. A infarction [503]. In patients with symptomatic angina,
recent meta-analysis of RCTs of antihypertensive ther- beta-blockers and calcium antagonists are the preferred
apy showed that for every 10 mmHg reduction in SBP, components of the drug treatment strategy.
CAD was reduced by 17% [2]. A similar risk reduction
has been reported by others with more intensive BP con- LEFT VENTRICULAR HYPERTROPHY AND HEART
trol [496]. The benefits of reducing cardiac events are FAILURE
also evident in high-risk groups, such as those with dia- Hypertension is the leading risk factor for the development
betes [231,425]. of heart failure [7], and most patients with heart failure will
There remains some inconsistency over the optimal have a history of hypertension. This may be a consequence of
BP target in less than patients with overt CAD, and espe- CAD, which results in HFrEF. Hypertension also causes LVH,
cially whether there is a J-curve relationship between which impairs left ventricular relaxation (so-called diastolic
achieved BP and cardiovascular outcomes in CAD [497– dysfunction) and is a potent predictor of heart failure, even
500]. A recent analysis [501] of 22–672 patients with sta- when left ventricular systolic function is normal and there is
ble CAD who were treated for hypertension found that, no preceding myocardial infarction (HFpEF). Hypertension-
after a median follow-up of 5.0 years, an SBP of at least dependent fibrosis and structural alteration of large and
140 mmHg and a DBP of at least 80 mmHg were each small arteries (microvascular disease) also contribute.
associated with increased risk of cardiovascular events. Treating hypertension has a major impact on reducing
An SBP of less than 120 mmHg was also associated with the risk of incident heart failure and heart failure hospital-
increased risk, as was a DBP of less than 70 mmHg. ization, especially in old and very old patients [51,213,316].
Similar findings were also reported from another anal- This has been observed using diuretics, beta-blockers, ACE
ysis of RCT data evaluating the relationships between inhibitors, or ARBs, with CCBs being less effective in com-
achieved BP and risks of cardiovascular outcomes [222]. parative trials [504].
Whether a J-curve phenomenon exists in patients with Reducing BP can also lead to the regression of LVH,
CAD who have been revascularized remains uncer- which has been shown to be accompanied by a reduction
tain. Other analyses do not support the existence of a of cardiovascular events and mortality [125]. The mag-
J-curve, even in hypertensive patients at increased car- nitude of LVH regression is associated with baseline left
diovascular risk [239]. For example, in patients with ventricular mass, duration of therapy, the SBP reduction
CAD and initially free from congestive heart failure [505,506], and the drugs used, with ARBs, ACE inhibi-
enrolled in ONTARGET, a BP reduction from baseline tors, and CBBs causing more effective LVH regression than
over the examined BP range had little effect on the risk beta-blockers [173] or diuretics.
of myocardial infarction and predicted a lower risk of In patients with HFrEF, antihypertensive drug treatment
stroke [502]. Thus, a target BP of approximately less should start (if not already initiated) when BP is more than
than 130/80 mmHg in patients with CAD appears safe 140/90 mmHg. It is unclear how low BP should be lowered
and can be recommended, but achieving a BP less than in patients with heart failure. Outcomes for patients with
120/80 mmHg is not recommended. heart failure have repeatedly been shown to be poor if BP
values are low, which suggests (although data interpreta-
Therapeutic strategies in hypertensive patients with tion is made difficult by the possibility of reversed causal-
CAD ity) that it may be wise to avoid actively lowering BP to less
than 120/70 mmHg. However, some patients may achieve
Recommendations Classa Levelb even lower BP levels than this because of the desirability
to remain on treatment with guideline-directed heart fail-
In patients with CAD receiving BP-lowering drugs, it is recommended:
ure medications, which, if tolerated, should be continued
Continued because of their protective effect [136].
598 Manual of Hypertension of the European Society of Hypertension
PREVIOUS STROKE OR TRANSIENT ISCHAEMIC with hypertension, for prevention of both recurrent stroke
ATTACK and other cardiovascular events.
RCTs of antihypertensive treatment (placebo controlled) The appropriate BP targets to prevent recurrent stroke
in patients with a previous stroke or TIA, in a stable clini- are uncertain, but should be considered in the context of
cal condition, and with BP more than 140/90 mmHg, a consistent finding in many meta-analyses that stroke is
have shown that BP lowering reduces the risk of recurrent the one major cardiovascular event that is reduced at lower
stroke [338,523]. No evidence is yet available that recur- achieved BP levels. This is supported by the results from
rent stroke is prevented by initiating therapy when BP is the recent Secondary Prevention of Small Subcortical
in the high–normal range. We recommend resumption of Strokes 3 study [244,524] in patients with a recent lacu-
BP-lowering therapy several days after stroke, or immedi- nar stroke, which suggested an SBP target of less than
ately after TIA, for previously treated or untreated patients 130 mmHg [525], and other studies [526].
Therapeutic strategies in hypertensive patients with acute stroke and cerebrovascular disease
In acute ischaemic stroke, routine BP lowering with antihypertensive therapy is not recommended [516,517], with the excep- III A
tions:
■■ In patients with acute ischaemic stroke who are eligible for i.v. thrombolysis, BP should be carefully lowered and maintained IIa B
at <180/105 mmHg for at least the first 24 h after thrombolysis [514,515].
■■ In patients with markedly elevated BP who do not receive fibrinolysis, drug therapy may be considered, based on clinical
IIb C
judgement, to reduce BP by 15% during the first 24 h after the stroke onset.
In all hypertensive patients with ischaemic stroke or TIA, an SBP target range of 120–130 mmHg should be considered IIa B
[244,524,526].
The recommended antihypertensive drug treatment strategy for stroke prevention is a RAS blocker plus a CCB or a thiazide-like I A
diuretic [338].
Abbreviations: BP, blood pressure; CCB, calcium channel blocker; i.v., intravenous; RAS, renin–angiotensin system; SBP, systolic blood pressure; TIA, transient
ischaemic attack.
a Class of recommendation.
b Level of evidence.
Prevention of stroke is a consistent benefit of antihyper- BP lowering reduced the incidence and risk of cognitive
tensive therapy and has been observed in all large RCTs impairment and dementia by 9%. One study showed that
using different drug regimens. However, individual RCTs achieving better BP control over 4 years reduced the pro-
comparing modern treatment regimens [317,527] and gression of cerebral white matter lesions and the decrease
meta-analyses suggest that beta-blockers are less effective in global cognitive performance [535].
at stroke prevention than other classes of antihypertensive Trials are urgently needed to better define the potential
agents [2,528]. Although the beta-blocker in these studies impact of BP lowering on preventing cognitive decline
was atenolol, there are no data with more modern beta- or in delaying dementia when cognitive dysfunction is
blockers with regards to stroke prevention in hyperten- already present.
sion. Thus, optimal antihypertensive treatment for stroke
prevention should not include beta-blockers unless there
is a compelling indication for their use, mindful of the fact
that the most common recurrent event after stroke is a fur- HYPERTENSION, ATRIAL FIBRILLATION, AND
ther stroke rather than myocardial infarction [529]. OTHER ARRHYTHMIAS
Hypertension predisposes to cardiac arrhythmias, includ-
COGNITIVE DYSFUNCTION AND DEMENTIA ing ventricular arrhythmias, but most commonly AF
Several epidemiological and clinical studies have shown [536–538], which should be considered a manifestation
that hypertension in midlife predicts cognitive decline and of hypertensive heart disease [539]. Even high–normal
dementia (both Alzheimer’s disease and vascular demen- BP is associated with incident AF [540,541], and hyper-
tia) in older patients [530–533]. However, evidence on tension is the most prevalent concomitant condition in AF
the beneficial effects of BP lowering on cognitive decline patients. AF adds to the risk of stroke and heart failure. AF
is scant and conflicting. A meta-analysis [534] of 12 stud- necessitates stroke prevention with oral anticoagulation,
ies investigating the impact of different antihypertensive with monitoring of the associated risks and prevention of
drugs on dementia and cognitive function concluded that bleeding [542].
600 Manual of Hypertension of the European Society of Hypertension
Most patients show a high ventricular rate with AF [542] ORAL ANTICOAGULANTS AND HYPERTENSION
and, in such patients, beta-blockers or non-dihydropyridine Many patients requiring oral anticoagulants (e.g. with AF)
calcium antagonists (e.g. diltiazem and verapamil) are recom- will be hypertensive. Hypertension is not a contraindication
mended as antihypertensive agents. Non-dihydropyridine to oral anticoagulant use. However, although its role has
CCBs should be avoided in patients with reduced left ven- been unappreciated in most old and more recent RCTs on
tricular systolic function and may precipitate heart failure anticoagulant treatment [537], hypertension does substan-
in some patients. Beta-blockers are often indicated in these tially increase the risk of intracerebral haemorrhage when
patients, and may need to be combined with digoxin to gain oral anticoagulants are used, and efforts should be directed
rate control [542]. towards achieving a BP goal of less than 130/80 mmHg in
In RCTs of hypertensive patients with LVH and/or high patients receiving oral anticoagulants. Detailed informa-
cardiovascular risk [543,544], RAS blockers have been tion on hypertension and oral anticoagulants has been pub-
shown to reduce first occurrence of AF, compared with lished recently [526,536]. Anticoagulants should be used to
beta-blockers or CCBs, consistent with similar effects of reduce the risk of stroke in most AF patients with hyperten-
RAS blockers in patients with heart failure [545–547]. RAS sion, including those with AF in whom hypertension is the
blockers do not prevent recurrence of paroxysmal or per- single additional stroke risk factor [554,555]. BP control is
sistent AF [548–550]. In patients with heart failure, beta- important to minimize the risks of AF-related stroke and
blockers [551] and MRAs [552] may also prevent AF. The oral anticoagulant-related bleeding. Until more data are
preventive effect of RAS blockers against the development available, BP values in AF patients taking oral anticoagu-
of AF is indirectly supported by a general practice database lants should be at least less than 140 mmHg for SBP and
in the UK, with approximately 5 million patient records, less than 90 mmHg for DBP. Oral anticoagulants should be
which has reported that ACE inhibitors, ARBs, and beta- used with caution in patients with persistent uncontrolled
blockers are associated with a lower risk of AF compared hypertension (SBP ≥180 mmHg and/or DBP ≥100 mmHg),
with CCBs [553]. Hence, RAS blockers should be consid- and urgent efforts to control BP should be made.
ered as part of the antihypertensive treatment strategy in
hypertensive patients with a high risk of AF (e.g. LVH), to
prevent incident AF.
HYPERTENSION AND VASCULAR DISEASE
CAROTID ATHEROSCLEROSIS
Therapeutic strategies in hypertensive patients with AF A small number of studies have reported the effects of
Recommendation Class a Level b
the various pharmacological classes of antihypertensive
drugs on carotid IMT, and very few on carotid plaques.
In patients with AF, screening for hypertension is I C Reducing BP regresses carotid IMT and may delay the inti-
recommended [536]. mal atherosclerotic process. There appear to be differential
drug effects on IMT regression, with CCBs having greater
A beta-blocker or non-dihydropyridine CCB IIa B efficacy than diuretics and beta-blockers [146], and ACE
should be considered as part of the treatment inhibitors more than diuretics [557]. However, the rel-
of hypertension if rate control is needed [536]. evance of these findings is unclear because most patients
Stroke prevention with oral anticoagulation is I A
receive combinations of treatment and the progression or
recommended in patients with AF and
treatment-induced changes in carotid IMT are poorly pre-
hypertension, and a CHA2DS2-VASc score of dictive of future cardiovascular events [184,558]. Patients
≥2 in men and ≥3 in women [536, 556]. with carotid plaques are at high risk of atheroembolic
stroke and cardiovascular events, and BP lowering should
Stroke prevention with oral anticoagulants IIa B be complemented by lifestyle advice and treatment with
should be considered in AF patients with statins and antiplatelet therapy. A common conundrum
hypertension, even when hypertension is the faced by clinicians is the hypertensive patient with a tight
single additional risk factor (CHA2DS2-VASc carotid stenosis, especially when bilateral. No study has
score of 1) [536, 556]. addressed this scenario and therefore advice is necessarily
pragmatic, and we recommend a more cautious approach
Oral anticoagulants should be used with caution IIa B
to BP lowering, initiating with monotherapy and carefully
in patients with marked BP elevation
(SBP ≥180 mmHg and/or DBP ≥100 mmHg);
monitoring for adverse effects.
the aim should be to lower SBP to at least
<140 mmHg, and SBP lowering to <130
ARTERIOSCLEROSIS AND INCREASED ARTERIAL
should be considered. If this is not possible,
STIFFNESS
then patients should make an informed decision
that they accept that the stroke protection Large artery stiffening is a major factor contributing to the
provided by the anticoagulant will be rise in SBP and fall in DBP with ageing. Arterial stiffness
associated with higher bleeding risk [536]. is usually measured in studies as PWV. Arterial stiffening
results from arteriosclerotic structural changes in large
Abbreviations: AF, atrial fibrillation; BP, blood pressure; CCB, calcium channel conduit arteries, leading to a loss of arterial elasticity, and
blocker; CHA2DS2-VASc, Congestive heart failure, Hypertension, Age ≥75 the distending force resulting from the pressure exerted
years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex cat- on the arterial wall. Thus, all antihypertensive drugs, by
egory (female); DBP, diastolic blood pressure; SBP, systolic blood pressure.
a Class of recommendation.
reducing BP, reduce arterial stiffness, as the reduction in
b Level of evidence.
BP unloads the stiff components of the arterial wall, lead-
ing to a passive decrease in PWV. Pharmacodynamic RCTs
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 601
[559] and meta-analyses [560,561] suggest that ACE inhib- PREVENTION OF AORTIC DILATION AND
itors and ARBs may reduce PWV beyond the effect of BP DISSECTION IN HIGH-RISK SUBJECTS
lowering on a long-term basis. Whether RAS blockers are Chronic hypertension can be associated with modest
more effective than other antihypertensive drugs in this aortic root dilatation. When more extensive aortic root
regard has not been demonstrated. Moreover, whether any dilatation is present or the dilatation extends beyond the
long-term reduction in aortic stiffness [562] translates into aortic root, an additional cause for aortopathy should be
a reduction in cardiovascular events beyond the impact of sought. All hypertensive patients with aortic dilatation,
BP lowering alone [563] has not been demonstrated. whether associated with Marfan syndrome, bicuspid aor-
tic valve disease, or not, should have their BP controlled
≤130/80 mmHg [568]. In patients with Marfan syndrome,
LOWER EXTREMITY ARTERIAL DISEASE prophylactic use of ACE inhibitors, ARBs, or beta-blockers
seems to be able to reduce either the progression of the
LEAD is often a manifestation of more widespread athero- aortic dilation or the occurrence of complications [568–
sclerosis and especially atherosclerotic renal artery disease 570]. However, there is no evidence for the specific efficacy
[564], and these patients are at very high cardiovascular risk of these treatments in aortic disease of other aetiologies.
[190]. BP control is an important part of the cardiovascular
risk-reduction strategy in these patients. Beta-blockers have HYPERTENSION BICUSPID AORTIC VALVE-RELATED
not been shown to worsen the symptoms of claudication in AORTOPATHY
two meta-analyses [565,566]. Thus, beta-blockers remain
Bicuspid aortic valve disease occurs in 1 in 100 people,
a treatment option in hypertensive patients with LEAD
more often men, and is associated with coexistent aortic
when there is a specific indication for their use. When
coarctation, which should be excluded in patients with
critical limb ischaemia is present, BP reduction should be
bicuspid aortic valve disease. Bicuspid aortic valve disease
instituted slowly as it may worsen ischaemia. In patients
is associated with an aortopathy, and the risk of develop-
with LEAD, antihypertensive treatment should be comple-
ment of aortic dilation is higher in patients with bicuspid
mented by lifestyle changes and especially smoking cessa-
aortic valve disease than in the normal population [571]
tion, as well as statin and antiplatelet therapy [190].
and is probably exacerbated by hypertension. Beyond aor-
tic dilation and aneurysm formation, bicuspid aortic valve
Therapeutic strategies in hypertensive patients with disease is also a risk factor for dissection and rupture [572].
LEAD Thus, BP should be tightly controlled in patients with bicus-
pid aortic valve disease and targeted ≤130/80 mmHg if tol-
Recommendations Classa Levelb erated. There is popular misconception that BP-lowering
BP-lowering treatment is recommended to reduce I A treatment has deleterious effects in patients with aortic
CV risk [2,190,503]. stenosis and hypertension, when in fact it is well tolerated
even in patients with severe aortic stenosis. Moreover, vaso-
A combination of a RAS blocker, CCB, or diuretic IIa B dilating drugs (including RAS blockers) also appear to be
should be considered as initial therapy [2]. well tolerated. Thus, treatment of hypertension should be
considered in these patients [573].
Beta-blockers may also be considered [566]. IIb C
Abbreviations: BP, blood pressure; CCB, calcium channel blocker; CV, car-
diovascular; LEAD, lower extremity arterial disease; RAS, renin–angiotensin HYPERTENSION AND SEXUAL DYSFUNCTION
system.
a Class of recommendation.
Sexual dysfunction may have an important negative effect
b Level of evidence.
on the quality of life of both men and women. Compared
with the normotensive population, the prevalence of sex-
ual dysfunction is greater in hypertensive individuals, in
whom it presents an important cause of low adherence to
HYPERTENSION IN VALVULAR DISEASE AND or discontinuation of antihypertensive treatment [574].
AORTOPATHY A large meta-analysis of prospective cohort studies has
provided strong evidence that in men, erectile dysfunction
COARCTATION OF THE AORTA (i.e. inadequate penile erection) is a significant indepen-
When feasible, treatment of aortic coarctation is predomi- dent risk factor for cardiovascular events and mortality
nantly surgical and usually done in childhood. Even after [575], which means that it may be viewed as an early marker
surgical correction, these patients may develop systolic of vascular damage [576]. Sexual dysfunction may be trig-
hypertension at a young age and require long-term follow- gered or aggravated by treatment with thiazide or thiazide-
up. Few patients with aortic coarctation remain undetected like diuretics, conventional beta-blockers, or centrally
until adult life, and by then often have severe hypertension, acting agents (e.g. clonidine), while ACE inhibitors, ARBs,
HMOD (especially LVH and left ventricular dysfunction), CCBs, or vasodilating beta-blockers may have neutral or
and an extensive collateral circulation below the coarcta- even beneficial effects [574,577]. Phosphodiesterase-5
tion. Such patients should be evaluated in a specialist cen- inhibitors are effective against erectile dysfunction in
tre. The medical therapy for hypertension in patients with patients with hypertension. They should be given only in
aortic coarctation should follow the treatment algorithm the absence of nitrate administration, but prescription also
outlined in section ‘Treatment of hypertension’, as there appears to be safe in patients with multidrug BP-lowering
have been no formal RCTs to define optimal treatment treatment [578], with some caution if treatment includes
strategies [567]. alpha-blockers [577]. However, it seems prudent for
602 Manual of Hypertension of the European Society of Hypertension
b Level of evidence.
is nevertheless advisable to assess risk factors and asymp-
tomatic organ damage at least every 2 years.
plify the treatment strategy to try and improve adherence ■■ Feedback on behavioural and clinical improvements
to treatment and BP control, by prescribing a single pill to ■■ Assessment and resolution of individual barriers to adherence
■■ Collaboration with other healthcare providers, especially nurses
most patients with hypertension. This is a response to the
fact that despite the clear-cut benefits of BP treatment in and pharmacists
trials, most treated patients do not achieve recommended Patient level
BP targets in real life. The lower BP targets recommended ■■ Self-monitoring of BP (including telemonitoring)
in these Guidelines will mean that BP control rates will be ■■ Group sessions
even worse unless action is taken to ensure that patients are ■■ Instruction combined with motivational strategies
more likely to adhere to logical combinations of treatment. ■■ Self-management with simple patient-guided systems
Several methods are available to detect poor adherence, but ■■ Use of reminders
most are indirect, poorly reliable, and provide little infor- ■■ Obtain family, social, or nurse support
mation on the most important issue: dosing history. Today, ■■ Provision of drugs at worksite
the most accurate methods that can be recommended,
despite their limitations, are the detection of prescribed Drug treatment level
drugs in blood or urine samples. Directly observed treat- ■■ Simplification of the drug regimen favouring the use of SPC therapy
■■ Reminder packaging
ment, followed by BP measurement over subsequent hours
via HBPM or ABPM, can also be very useful to determine Health system level
if BP really is poorly controlled despite witnessed con- ■■ Supporting the development of monitoring systems (telephone
sumption of medication in patients with apparent resis- follow-up, home visits, and telemonitoring of home BP)
tant hypertension. In contrast, questionnaires frequently ■■ Financially supporting the collaboration between healthcare
overestimate drug adherence. The assessment of adherence providers (e.g. pharmacists and nurses)
should be improved with the development of cheaper and ■■ Reimbursement of SPC pills
more reliable methods of detection that are easily applica- ■■ Development of national databases, including prescription data,
ble in daily practice [354,626]. available for physicians and pharmacists
Barriers to optimal adherence may be linked with phy- ■■ Accessibility to drugs
sician attitudes, patient beliefs and behaviour, the com-
plexity and tolerability of drug therapies, the healthcare Abbreviations: BP, blood pressure; SPC, single-pill combination.
system, and several other factors. Therefore, the assess-
ment of adherence should always be conducted in a no-
blame approach, and should favour an open discussion to of rigorous trials on adherence interventions. Thus, the
identify the specific barriers limiting the patient’s ability to level of evidence indicating that a sustained improve-
follow the therapeutic recommendations. Individualized ment in medication adherence can be achieved within the
solutions should be found. Patients should be encouraged resources available today in clinical practice is low. This is
to take responsibility for their own cardiovascular health. essentially due to the short duration of most studies, their
Patient adherence to therapy can be improved by several heterogeneity, and their questionable designs. Whether
interventions. The most useful interventions are those linking available interventions ameliorate treatment outcomes
drug intake with habits [347], those giving adherence feed- remains to be demonstrated in adequate trials.
back to patients, self-monitoring of BP [64] using pill boxes A list of the interventions associated with improved
and other special packaging, and motivational interviewing. patient adherence to treatment is shown in Table 65.33.
Increasing the integration among healthcare providers with
the involvement of pharmacists and nurses increases drug
adherence. Using multiple components has a greater effect CONTINUED SEARCH FOR ASYMPTOMATIC
on adherence, as the effect size of each intervention is gener- HYPERTENSION-MEDIATED ORGAN DAMAGE
ally modest. Recent data suggest that adherence to treatment
may also be improved with the use of telemetry for transmis- The importance and need to detect HMOD at initial
sion of recorded home values, maintaining contact between assessment to help risk stratify the patient, and to review
patients and physicians, and studies are ongoing [627]. the progression or regression of HMOD during follow-up,
Prescription of an appropriate therapeutic regimen is cru- have been described in section ‘Blood pressure measure-
cial [389]. This might be achieved through: possible dru- ment’. The presence of HMOD demonstrates that BP is ele-
grelated adverse events, using long-acting drugs that require vated and that the patient would benefit from treatment.
once daily dosage [628,629], avoiding complex dosing The regression of asymptomatic organ damage occurring
schedules, using SPCs whenever possible, and taking into during treatment can often indicate an improved prog-
consideration the effect of treatment on a patient’s budget. nosis (see section ‘Clinical evaluation and assessment of
Compared with the large number of trials for individual hypertension-mediated organ damage in patients with
drugs and treatments, there are only a limited number hypertension’).
606 Manual of Hypertension of the European Society of Hypertension
CAN ANTIHYPERTENSIVE MEDICATIONS BE What is the optimal salt intake to reduce cardiovascular and mortality risk?
REDUCED OR STOPPED? What are the long-term outcome benefits resulting from the recom-
mended lifestyle changes?
In some patients in whom treatment is accompanied by
effective BP control for an extended period, it may be pos- Outcome-based comparison between treatments based on thiazide vs.
sible to reduce the number and/or dosage of drugs. This thiazide-like diuretics
may particularly be the case if BP control is accompanied
by healthy lifestyle changes such as weight loss, exercise Incremental value of central vs. peripheral BP in risk estimation and
habit, and a low-fat and low-salt diet, which remove envi- risk reduction by treatment
ronmental pressor influences. A reduction of medications Outcome-based comparison of BP treatment with classical vs.
should be made gradually, and the patient should be vasodilator beta-blockers
checked frequently because reappearance of hyperten-
sion can occur quickly, within weeks, or may take many Optimal BP treatment targets in specific clinical conditions (e.g.
months. Patients with prior HMOD or previous accelerated diabetes, CKD, and post-stroke)
hypertension should not have their treatment withdrawn.
Protective effect of antihypertensive treatment in patients with cognitive
dysfunction or dementia
What are the appropriate BP thresholds and targets for drug treatment 1. BP, epidemiology, and risk. Globally, over 1 billion peo-
in younger hypertensive patients? ple have hypertension. As populations age and adopt
more sedentary lifestyles, the worldwide prevalence of
What are the optimal BP treatment targets according to HBPM and hypertension will continue to rise towards 1.5 billion
ABPM? by 2025. Elevated BP is the leading global contributor
What are the outcome benefits associated with antihypertensive
to premature death, accounting for almost 10 million
treatment in patients with resistant hypertension?
deaths in 2015, 4.9 million due to ischaemic heart
disease and 3.5 million due to stroke. Hypertension
What are the benefits of BP treatment for patients with BP in the is also a major risk factor for heart failure, AF, CKD,
high–normal range? PAD, and cognitive decline.
2. Definition of hypertension. The classification of BP and
What baseline level of cardiovascular risk predicts treatment benefit? the definition of hypertension is unchanged from
previous European Guidelines, and is defined as an
More data on the benefits of BP treatment in the very elderly and the
office SBP at least 140 and/or DBP at least 90 mmHg,
influence of frailty
which is equivalent to a 24 h ABPM average of at
Outcome-based comparison between office BP and out-of-office least 130/80 mmHg, or a HBPM average at least
BP-guided treatment 135/85 mmHg.
3. Screening and diagnosis of hypertension. Hypertension is
Outcome-based comparison between treatments guided by BP control usually asymptomatic (hence the term ‘silent killer’).
and by HMOD reductions, especially in younger patients Because of its high prevalence, screening programmes
should be established to ensure that BP is mea-
More outcome studies of the optimal SBP treatment target for patients
sured in all adults at least every 5 years, and more
at different levels of baseline cardiovascular risk and with different
frequently in people with a high–normal BP. When
comorbidities, including diabetes and CKD
hypertension is suspected because of an elevated
More outcome studies of the optimal DBP treatment target screening BP, the diagnosis of hypertension should be
confirmed either by repeated office BP measurements
Impact of single-pill vs. multidrug treatment strategies on adherence to over a number of visits or by out-of-office BP mea-
treatment, BP control, and clinical outcomes surement using 24 h ABPM or HBPM.
4. The importance of cardiovascular risk assessment and detec-
Outcome-based comparison between treatment strategies based on tion of HMOD. Other cardiovascular risk factors such
initial monotherapy vs. initial combination therapy
as dyslipidaemia and metabolic syndrome frequently
Continued cluster with hypertension. Thus, unless the patient
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 607
is already at high or very high risk due to established suggests that lowering office SBP to <140 mmHg is
CVD, formal cardiovascular risk assessment is rec- beneficial for all patient groups, including indepen-
ommended using the SCORE system. However, it is dent older patients. There is also evidence to support
important to recognize that the presence of HMOD, targeting SBP to 130 mmHg for most patients, if
especially LVH, CKD, or advanced retinopathy, further tolerated. Even lower SBP levels (<130 mmHg) will be
increases the risk of cardiovascular morbidity and mor- tolerated and potentially beneficial for some patients,
tality, and should be screened for as part of risk assess- especially to further reduce the risk of stroke. SBP
ment in hypertensive patients because the SCORE should not be targeted to less than 120 mmHg
system alone may underestimate their risk. because the balance of benefit vs. harm becomes con-
5. Think: could this patient have secondary hypertension? For cerning at these levels of treated SBP.
most people with hypertension, no underlying cause 10. BP targets in old and very old patients. As discussed above,
will be detected. Secondary (and potentially remedi- independence, frailty, and comorbidities will all influ-
able) causes of hypertension are more likely to be ence treatment decisions, especially in older (≥65 years)
present in people with young onset of hypertension and very old (>80 years) patients. The desired SBP target
(<40 years), people with severe or treatment-resistant range for all patients aged more than 65 years is 130–
hypertension, or people who suddenly develop 139 mmHg. This is lower than in previous Guidelines
significant hypertension in midlife on a background and may not be achievable in all older patients, but any
of previously normal BP. Such patients should be BP lowering towards this target is likely to be beneficial
referred for specialist evaluation. provided that the treatment is well tolerated.
6. Treatment of hypertension: importance of lifestyle interven- 11. BP targets in patients with diabetes and/or CKD. The
tions. The treatment of hypertension involves lifestyle BP treatment targets for patients with diabetes or
interventions and drug therapy. Many patients with kidney disease have been a moving target in previous
hypertension will require drug therapy, but life- Guidelines because of seemingly contradictory results
style interventions are important because they can from major outcome trials and meta-analyses. For
delay the need for drug treatment or complement diabetes, targeting the SBP to less than 140 mmHg
the BP-lowering effect of drug treatment. Moreover, and towards 130 mmHg, as recommended for all
lifestyle interventions such as sodium restriction, other patient groups, is beneficial on major outcomes.
alcohol moderation, healthy eating, regular exercise, Moreover, targeting SBP to less than 130 mmHg, for
weight control, and smoking cessation all have health those who will tolerate it, may further reduce the risk
benefits beyond their impact on BP. of stroke but not other major outcomes. SBP should
7. When to consider drug treatment of hypertension. The not be less than 120 mmHg. For patients with CKD,
treatment thresholds for hypertension are now less the evidence suggests that the target BP range should
conservative than they were in previous Guidelines. be 130–139 mmHg.
We now recommend that patients with low-moderate- 12. How low should DBP be lowered? The optimal DBP target
risk grade 1 hypertension (office BP 140–159/90– 99), has been less well defined, but a DBP target of less than
even if they do not have HMOD, should now receive 80 mmHg is recommended. Some patients with stiff
drug treatment if their BP is not controlled after a arteries and isolated systolic hypertension will already
period of lifestyle intervention alone. For higher-risk have DBP levels below this target. These are high-risk
patients with grade 1 hypertension, including those patients and the low DBP should not discourage treat-
with HMOD, or patients with higher grades of hyper- ment of their elevated SBP to the recommended target,
tension (e.g. grade 2 hypertension, ≥160/100 mmHg), provided that treatment is well tolerated.
we recommend initiating drug treatment alongside 13. The need to do better on BP control. A key message in
lifestyle interventions. These recommendations apply these Guidelines is the need to do better at improv-
to all adults aged <80 years. ing BP control rates. Despite the overwhelming
8. Special considerations in frail and older patients. It is evidence of treatment benefit, on average, less than
increasingly recognized that biological rather than 50% of patients with treated hypertension achieve an
chronological age, as well as consideration of frailty SBP target of less than 140 mmHg. Physician inertia
and independence, are important determinants of (inadequate uptitration of treatment, especially from
the tolerability of and likely benefit from BP-lowering monotherapy) and poor patient adherence to treat-
medications. It is important to note that even in ment (especially when based on multiple pills) are
the very old (i.e. >80 years), BP-lowering therapy now recognized as the major factors contributing to
reduces mortality, stroke, and heart failure. Thus, poor BP control.
these patients should not be denied treatment or have 14. Start treatment in most patients with two drugs, not one.
treatment withdrawn simply on the basis of age. For Monotherapy is usually inadequate therapy for most
people more than 80 years who have not yet received people with hypertension; this will be especially
treatment for their BP, treatment is recommended true now that the BP treatment targets for many
when their office SBP is at least 160 mmHg, provided patients are lower than in previous Guidelines. These
that the treatment is well tolerated. Guidelines have set out to normalize the concept
9. How low should SBP be lowered? This has been a hotly that initial therapy for the majority of patients with
debated topic. A key discussion point is the balance hypertension should be with a combination of two
of potential benefits vs. potential harm or adverse drugs, not a single drug. The only exception would be
effects. This is especially important whenever BP in a limited number of patients with a lower baseline
targets are lowered, as there is a greater potential for BP close to their recommended target, who might
harm to exceed benefit. Thus, in these Guidelines, achieve that target with a single drug, or in some
we recommend a target range. The evidence strongly frailer old or very old patients in whom more gentle
608 Manual of Hypertension of the European Society of Hypertension
reduction of BP may be desirable. Evidence suggests include alpha-methyl dopa, labetalol, or CCBs. The
that this approach will improve the speed, efficiency, same drugs are suitable if BP lowering is required in
and consistency of initial BP lowering and BP control, pregnant women. ACE inhibitors or ARBs should not
and is well tolerated by patients. be used in pregnant women.
15. A single-pill strategy to treat hypertension. Poor adher- 18. Is there a role for device-based therapy for the treatment of
ence to longer-term BP-lowering medication is now hypertension? A number of device-based interventions
recognized as a major factor contributing to poor BP have been developed and studied for the treatment of
control rates. Research has shown a direct correlation hypertension. To date, the results from these studies
between the number of BP-lowering pills and poor have not provided sufficient evidence to recommend
adherence to medications. Moreover, SPC therapy has their routine use. Consequently, the use of device-
been shown to improve adherence to treatment. SPC based therapies is not recommended for the routine
therapy is now the preferred strategy for initial two- treatment of hypertension, unless in the context of
drug combination treatment of hypertension and for clinical studies and RCTs, until further evidence
three-drug combination therapy when required. This regarding their safety and efficacy becomes available.
will control the BP of most patients with a single pill 9. Managing cardiovascular disease risk in hypertensive
1
and could transform BP control rates. patients beyond BP: statins. For hypertensive patients at
6. A simplified drug treatment algorithm. We have sim-
1 moderate CVD risk or higher, or those with estab-
plified the treatment strategy so that patients with lished CVD, BP lowering alone will not optimally
uncomplicated hypertension and many patients reduce their risk. These patients would also benefit
with a variety of comorbidities (e.g. HMOD, diabe- from statin therapy, which further reduces the risk of
tes, PAD, or cerebrovascular disease) receive similar a myocardial infarction by approximately one-third
medication. We recommend a combination of an ACE and stroke by approximately one-quarter, even when
inhibitor or ARB with a CCB or thiazide/ thiazide-like BP is controlled. Similar benefits have been seen in
diuretic as initial therapy for most patients. For those hypertensive patients at the border between low and
requiring three drugs, we recommend a combination moderaterisk. Thus, many more hypertensive patients
of an ACE inhibitor or ARB with a CCB and a thia- would benefit from statin therapy than are currently
zide/thiazide-like diuretic. We recommend that beta- receiving this treatment.
blockers be used when there is a specific indication 20. Managing cardiovascular disease risk in hypertensive
for their use (e.g. angina, postmyocardial infarction, patients beyond BP: antiplatelet therapy. Antiplatelet
HFrEF, or when heart rate control is required). therapy, especially low-dose aspirin, is recommended
17. Hypertension in women and in pregnancy. In women for secondary prevention in hypertensive patients, but
with hypertension who are planning pregnancy, ACE is not recommended for primary prevention (i.e. in
inhibitors or ARBs and diuretics should be avoided, patients without CVD).
and the preferred medications to lower BP, if required,
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 609
Classification of BP
It is recommended that BP be classified as optimal, normal, or high–normal, or grades 1–3 hypertension, according to office BP. I C
Screening programmes for hypertension are recommended. All adults (≥18 years) should have their office BP measured and I B
recorded in their medical file, and be aware of their BP.
Diagnosis of hypertension
Prompt initiation of BP-lowering drug treatment is recommended in patients with grade 2 or 3 hypertension at any level of CV I A
risk, simultaneously with the initiation of lifestyle changes.
In fit older patients with hypertension (even if aged >80 years), BP-lowering drug treatment and lifestyle intervention are I A
recommended when SBP is ≥160 mmHg.
BP-lowering drug treatment and lifestyle intervention are recommended in fit older patients (>65 years but not >80 years) when I A
SBP is in the grade 1 range (140–159 mmHg), provided that treatment is well tolerated.
Withdrawal of BP-lowering drug treatment on the basis of age, even when patients attain an age of ≥80 years, is not recom- III A
mended, provided that treatment is well tolerated.
It is recommended that the first objective of treatment should be to lower BP to <140/90 mmHg in all patients, and provided that I A
the treatment is well tolerated, treated BP values should be targeted to 130/80 mmHg or lower in most patients.
In patients <65 years receiving BP-lowering drugs, it is recommended that SBP should be lowered to a BP range of 120– I A
129 mmHg in most patients.d
In older patients (aged ≥65 years) receiving BP-lowering drugs, it is recommended that SBP should be targeted to a BP range of I A
130–139 mmHg.
It is recommended to restrict alcohol consumption to <14 units per week for men and <8 units per week for women. I A
Increased consumption of vegetables, fresh fruits, fish, nuts, unsaturated fatty acids (olive oil); low consumption of red meat; and I A
consumption of low-fat dairy products are recommended.
Body weight control is indicated to avoid obesity (BMI >30 kg/m2, or waist circumference >102 cm in men and >88 cm in I A
women) and aim for healthy BMI (about 20–25 kg/m2) and waist circumference values (<94 cm in men and <80 cm in
women) to reduce BP and cardiovascular risk.
Continued
610 Manual of Hypertension of the European Society of Hypertension
Regular aerobic exercise (e.g. ≥30 min of moderate dynamic exercise on 5–7 days per week) is recommended. I A
Smoking cessation and supportive care and referral to smoking cessation programmes are recommended. I B
Combination treatment is recommended for most hypertensive patients as initial therapy. Preferred combinations should comprise I A
a RAS blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic. Other combinations of the five major classes can be
used.It is recommended that beta-blockers are combined with any of the other major drug classes when there are specific I A
clinical situations (e.g. angina, post-myocardial infarction, heart failure, or heart rate control).
It is recommended to initiate antihypertensive treatment with a two-drug combination, preferably in an SPC. Exceptions are frail I B
older patients and those at low risk and with grade 1 hypertension (particularly if SBP is <150 mmHg) [342,346,351].
It is recommended that if BP is not controllede with a two-drug combination, treatment should be increased to a three-drug I A
combination, usually a RAS blocker with a CCB and thiazide/thiazide-like diuretics, preferably as an SPC.
It is recommended that if BP is not controllede with a three-drug combination, treatment should be increased by the addition of I B
spironolactone or, if not tolerated, other diuretics such as amiloride or higher doses of other diuretics, a beta-blocker, or an
alpha-blocker.
Use of device-based therapies is not recommended for the routine treatment of hypertension, unless in the context of clinical III B
studies and RCTs, until further evidence regarding their safety and efficacy becomes available.
Cardiovascular risk assessment with the SCORE system is recommended for hypertensive patients who are not already at high or I B
very high risk due to established CVD, renal disease, or diabetes.
For patients at high or very high cardiovascular risk, statins are recommended. I B
Antiplatelet therapy, in particular low-dose aspirin, is recommended for secondary prevention in hypertensive patients. I A
Aspirin is not recommended for primary prevention in hypertensive patients without CVD. III A
Abbreviations: ABPM, ambulatory blood pressure monitoring; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; BP,
blood pressure; CCB, calcium channel blocker; CVD, cardiovascular disease; HBPM, home blood pressure monitoring; HMOD, hypertension-mediated organ dam-
age; RAS, renin–angiotensin system; RCT, randomized controlled trial; SBP, systolic blood pressure; SCORE, Systematic COronary Risk Evaluation; SPC, single-pill
combination.
a Class of recommendation.
b Level of evidence.
c In patients with grade 1 hypertension and low-moderate-risk, drug treatment may be preceded by a prolonged period of lifestyle intervention to determine if this
will normalize BP. The duration of the lifestyle intervention alone will depend on the level of BP within the grade 1 range (i.e. the likelihood of achieving BP
control with lifestyle intervention alone) and the opportunities for significant lifestyle change in individual patients.
d Less evidence is available for this target in low-moderate-risk patients.
management of arterial hypertension: Algeria: Algerian Jelakovic; Czech Republic: Czech Society of Hypertension,
Society of Cardiology, Salim Benkhedda; Armenia: Jiri Widimsky; Estonia: Estonian Society of Hypertension,
Armenian Cardiologists Association, Parounak Zelveian; Margus Viigimaa; Finland: Finnish Hypertension Society,
Austria: Austrian Society of Cardiology, Peter Siostrzonek; Ilkka Pörsti; France: French Society of Hypertension,
Azerbaijan: Azerbaijan Society of Cardiology, Ruslan Thierry Denolle; Germany: German Hypertension
Najafov; Belarus: Belorussian Scientific Society of Society, Bernhard K. Krämer; Greece: Hellenic Society of
Cardiologists, Olga Pavlova; Belgium: Belgian Society of Hypertension, George S. Stergiou; Italy: Italian Society of
Cardiology, Michel De Pauw; Bosnia and Herzegovina: Hypertension, Gianfranco Parati; Latvia: Latvian Society
Association of Cardiologists of Bosnia and Herzegovina, of Hypertension and Atherosclerosis, Karlis Trusinskis;
Larisa Dizdarevic-Hudic; Bulgaria: Bulgarian Society of Lithuania: Lithuanian Hypertension Society, Marius
Cardiology, Dimitar Raev; Cyprus: Cyprus Society of Miglinas; Norway: Norwegian Society of Hypertension,
Cardiology, Nikos Karpettas; Czech Republic: Czech Eva Gerdts; Poland: Polish Society of Hypertension,
Society of Cardiology, Ales Linhart; Denmark: Danish Andrzej Tykarski; Portugal: Portuguese Society of
Society of Cardiology, Michael Hecht Olsen; Egypt: Hypertension, Manuel de Carvalho Rodrigues; Romania:
Egyptian Society of Cardiology, Amin Fouad Shaker; Romanian Society of Hypertension, Maria Dorobantu;
Estonia: Estonian Society of Cardiology, Margus Viigimaa; Russian Federation: Russian Society of Hypertension,
Finland: Finnish Cardiac Society, Kaj Metsärinne; The Irina Chazova; Serbia: Serbian Society of Hypertension,
Former Yugoslav Republic of Macedonian: Macedonian Dragan Lovic; Slovakia: Slovak Society of Hypertension,
FYR Society of Cardiology, Marija Vavlukis; France: French Slavomira Filipova; Slovenia: Slovenian Hypertension
Society of Cardiology, Jean-Michel Halimi; Georgia: Society, Jana Brguljan; Spain: Spanish Society of
Georgian Society of Cardiology, Zurab Pagava; Germany: Hypertension, Julian Segura; Sweden: Swedish Society
German Cardiac Society, Heribert Schunkert; Greece: of Hypertension, Stroke and Vascular Medicine, Anders
Hellenic Society of Cardiology, Costas Thomopoulos; Gottsäter; Switzerland: Swiss Society of Hypertension,
Hungary: Hungarian Society of Cardiology, Dénes Pall; Antoinette Pechère-Bertschi; Turkey: Turkish Society of
Iceland: Icelandic Society of Cardiology, Karl Andersen; Hypertension and Atherosclerosis, Serap Erdine; Ukraine:
Israel: Israel Heart Society, Michael Shechter; Italy: Ukrainian Antihypertensive Society, Yuriy Sirenko; United
Italian Federation of Cardiology, Giuseppe Mercuro; Kingdom: British and Irish Hypertension Society, Adrian
Kosovo: Kosovo Society of Cardiology, Gani Bajraktari; Brady.
Kyrgyzstan: Kyrgyz Society of Cardiology, Tatiana
Romanova; Latvia: Latvian Society of Cardiology, Karlis
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Index
risk reduction, 312, 313, 315 Arterial stiffness (AS), 75, 89; see also Early vascular ageing; Large
uptitration of, 578 artery damage
Antihypertensive Treatment in Acute Cerebral Haemorrhage 2 clinical importance, 250
(ATACH-2), 435 clinical measurements of, 248
Antihypertensive treatment, nephroprotective effect, 319 devices and methods to determine, 249
evidence with therapies and renal outcomes, 321 in ESRD patients, 470
kidney and BP, 319–320 genetics of, 91
role of antidiabetic drugs in BP control, 321–322 gradient, see Elastic taper
trials focused on renal outcomes, 320–321 increased, 600–601
trials not focused on renal outcomes, 321 as intermediate endpoint, 250–251
Antihypertensive Treatment of Acute Cerebral Haemorrhage local determination of, 250
(ATACH1), 482 molecular mechanisms behind, 91
Antioxidant, 69 partial pressure wave reflection, 185
Antioxidant response element (ARE), 69 pathophysiology of, 247
Antiplatelet therapy, 603–604; see also Cardiovascular disease pharmacology of, 251
Anxiety, 149–150; see also Psychosocial risk factors predictive value of, 250, 251
AOBP, see Automated office blood pressure regional measurements of, 248
Aortic dilation, 601 risk for total mortality and cardiovascular events, 90–91
Aortic pulse wave velocity (aPWV), 90 role on assuring continuous blood flow, 184
Aortic stiffening, 247; see also Large artery damage as surrogate endpoint, 251
APA, see Aldosterone-producing adenoma systemic, 250
APD, see Automated peritoneal dialysis threshold value, 251
Apnoea-hypopnea index (AHI), 128 Arteriograph® system, 248; see also Large artery damage
Apparent mineralocorticoid excess (AME), 60 Arteriosclerosis, 600–601
Appetite suppressants, 459 Arteriovenous (AV), 403; see also Central iliac arteriovenous
aPWV, see Aortic pulse wave velocity anastomosis; Device-based hypertension treatment
ARA, see Angiotensin receptor antagonist coupler, 403–404
ARAII, see Angiotensin II-AT1 receptor blockers fistula, 403, 582
ARAS, see Atherosclerotic RAS Artery damage, see Large artery damage
ARB, see Angiotensin receptor blocker ARV, see Average real variability
ARE, see Antioxidant response element AS, see Arterial stiffness
Area method, 250 ASA, see American Stroke Association
ARIC, see Atherosclerosis Risk in Communities ASCOT, see Anglo-Scandinavian Cardiac Outcomes Trial
ARISTOTLE (Apixaban for reduction in stroke and other ASCOT-BPLA, see Anglo-Scandinavian Cardiac Outcomes
ThromboemboLic events in AF), 412, 413 Trial–Blood Pressure-Lowering Arm
ARNI, see Angiotensin Receptor-Neprilysin Inhibitor ASCOT Lipid-Lowering Arm (ASCOT-LLA), 166
ARNIs, see Angiotensin-neprilysin inhibitors ASCOT-LLA, see ASCOT Lipid-Lowering Arm
ARR, see Aldosterone:renin ratio ASCVD, see Atherosclerotic CVD
Arrhythmias, 599 ASE, see American Society of Echocardiography
Arterial baroreceptors, 401; see also Baroreceptor activation Aspirin for Evidence-based Pre-eclampsia Prevention (ASPRA), 450
therapy ASPRA, see Aspirin for Evidence-based Pre-eclampsia Prevention
Arterial hypertension (AH), 275, 411, 435, 479, 543; see also Acute ASSERT, see Atrial Fibrillation Reduction Atrial Pacing Trial
stroke; Atrial fibrillation; Arterial hypertension guidelines, Assessments for hypertensive individuals, 10
2018 ESC/ESH ankle-brachial index, 11
atrial fibrillation and, 411–412 cardiac imaging techniques, 11
atrial fibrillation in patients with, 412–413 carotid arteries, 11
diagnosis in patients with atrial fibrillation, 412 echocardiography, 10–11
treatment in patients with atrial fibrillation, 413–414 electrocardiography, 10
Arterial hypertension guidelines, 2018 ESC/ESH, 543 pulse wave velocity, 12
BP classification, 547 Asymmetric dimethylarginine (ADMA), 470
BP measurement, 551–557 AT, see Atrial tachycardia
BP relationship with risk of CV and renal events, 548 AT-1R, see Angiotensin-1 receptors
challenges in CV risk assessment, 550–551 AT1-R, see Angiotensin II type 1 receptors
changes in, 545 ATACH1, see Antihypertensive Treatment of Acute Cerebral
changes in recommendations, 545–546 Haemorrhage
clinical evaluation and assessment of organ damage, 557–562 ATACH-2, see Antihypertensive Treatment in Acute Cerebral
ESC CPG, 543 Haemorrhage 2
gaps in evidence, 606 Atherosclerosis Risk in Communities (ARIC), 123, 346, 276
genetics and hypertension, 563 Atherosclerotic CVD (ASCVD), 8
hypertension and total cardiovascular risk assessment, 548 Atherosclerotic RAS (ARAS), 503, 504; see also Renovascular
hypertension definition, 547 hypertension
hypertension in specific circumstances, 582–603 ATl, see Type 1 angiotensin receptor
hypertension-mediated organ damage, 548–549 ATP III, see Adult Treatment Panel III report
hypertension prevalence, 547 Atrial fibrillation (AF), 140, 172, 198, 411, 548, 599; see also Arterial
hypertension treatment, 563 hypertension
key messages, 606–608 arterial hypertension and, 411–412
managing CV risk, 603 arterial hypertension diagnosis in patients with, 412
patient follow-up, 604 drug treatment strategy, 580
preamble, 543–544 LVH and, 234–235
recommendations, 546–547 in patients with arterial hypertension, 412–413
‘what to do’ and ’what not to do’ messages, 609–610 treatment of arterial hypertension in patients with, 413–414, 600
632 Index
Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT), 413 criteria to define BP categories, 425
Atrial tachycardia (AT), 413 -elevating substance, 101
Attention-deficit/hyperactivity disorder (ADHD), 459 evolutionary aspects of, 51–52
Augmentation index (AIx), 84, 184, 470 during exercise and at high altitude, 556
Automated BP measurement, 198; see also Home blood pressure future directions, 63
monitoring gene model, 51
Automated multiple BP readings, 552 genetic basis for common diseases, 52
Automated office blood pressure (AOBP), 173–174; see also Office genetic basis of monogenic HTN, 58–61
blood pressure genome-wide association study results, 53–57
Automated peritoneal dialysis (APD), 469 germ theory model, 51
Automatic full field perfusion image analyser (AFFPIA), 277 heritability of, 52
Automatic oscillometric devices, 412 inappropriate target BP values, 379–380
Autonomic dysfunction, 95 measurements, 284–285
adrenergic tone associated with hypertension, 96 medications and substances that increase, 587
effects of non-pharmacological and pharmacological monitors, 179
treatment, 98 Montreal Adoption Study, 52
in hypertension, 97 mutations altering BP, 59
and hypertension-related organ damage, 95–96 Na+ homeostasis, 58
and hypertensive state, 95 optimal target BP in stroke prevention, 488–490
mechanisms responsible for sympathetic activation in relationship with risk of cardiovascular and renal events, 548
hypertension, 97 salt-sensitivity, 76
muscle sympathetic nerve activity, 96 sodium and intravascular volume, 58
therapeutic approach, 98 targets for patients with kidney disease, 465
Autonomic nervous system, 61–62 values, 209
Autoregulatory mechanisms, 346 vascular mechanisms, 62–63
AV, see Arteriovenous Blood pressure, changes in; see also Day-night blood pressure
Average real variability (ARV), 211 change
AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent day-night, 203–204, 206–207
Strokes), 412 early morning, 204–206
Avon Longitudinal Study of Parents and Children study Blood pressure control, 25
(ALSPAC study), 121 factors related to shortness of control rates, 29
A/V ratio, 276 indirect assessment of, 29
methodology and BP control results, 26–28
rates and trends in Europe, 25, 29
B Blood pressure lowering, 311–312; see also Antihypertensive
treatment
baPWV, see Brachial-ankle PWV aggressive, 345
Bariatric surgery, 421; see also Diabetic/obese hypertensive drugs, 491
patient effects in grade 1 hypertension, 314
Baroreceptor activation therapy (BAT), 401; see also Interventional effects of, 316
therapies effects on stroke, 489
arterial baroreceptors, 401 meta-analysis of RCTs, 489
Barostim neo, 402 risk reduction of outcomes, 312
CALM-FIM_EUR study, 402 threshold for, 488–490
cuboid, 402 Blood pressure-lowering drug treatment, 564; see also Hypertension
CVRxRheos device, 402 treatment
MobiusHD, 402–403 beneficial effects of, 563–564
rationale, 401 and blood pressure values, 565
Rheos carotid pacemaker system, 401–402 combination therapies, 491
Bartter syndrome, 61 drugs, 491
BAT, see Baroreceptor activation therapy initiation in older people, 564–565
Benign nephrosclerosis, 21; see also Kidney initiation in patients with high-normal blood pressure, 565
Beta-adrenoceptor blockade, 529 initiation of, 566
Beta-blockers, 47, 328, 573; see also Renin-angiotensin system multiple drug intolerance in, 366
inhibitors Blood Pressure-Lowering Treatment Trialists’ Collaboration
action mechanism, 328 (BPLTTC), 312
adverse effects, 330 Blood pressure measurement, 551, 556–557; see also Acute stroke;
classification of, 328–329 Intracerebral haemorrhage; Ischaemic stroke; Arterial
hemodialysis patients, 473 hypertension guidelines, 2018 ESC/ESH
pharmacokinetics and dosing, 329, 330 in acute stroke, 479
Bevacizumab, 458 ambulatory blood pressure monitoring, 553
Biofeedback, 113–114; see also Stress central aortic pressure, 556
Biological ageing of humans, 89; see also Early vascular ageing in chronic post-stroke phase, 487
Blood-oxygen level–dependent (BOLD), 506 conventional office, 551–552
Blood pressure (BP), 7, 19, 37, 51, 75, 177, 241, 283, 319, 544; see also evidence from randomised trials, 487–488
Childhood blood pressure during exercise and in high altitude, 556
and airborne pollution, 151 home monitoring, 552–553
autonomic nervous system, 61–62 hypertension diagnosis, 555
blood pressure regulatory pathways and genetic basis, 52 indications for out-of-office, 555–556
classification of, 547 masked hypertension, 554
classification of hypertension stages, 551 office, 551, 552
common variant or rare variant, 52 optimal target blood pressure, 488–490
Index 633
Diastolic arterial pressure (DAP), 38 Drug treatment strategy, 574, 581; see also Hypertension
Diastolic blood pressure (DBP), 111, 171, 177, 312, 345, 395, treatment
425, 431 core, 579
Diastolic dysfunction, 597 drug combinations, 574–577
Dietary; see also Hypertension treatment; Non-pharmacological for hypertension and atrial fibrillation, 580
interventions for hypertension and chronic kidney disease, 580
calcium and magnesium intake, 305 for hypertension and coronary artery disease, 579
changes, 570 for hypertension and heart failure, 580
fibre, 306 rationale for initial two-drug combination therapy, 577
potassium intake, 305 rationale for single-pill combination therapy, 577–578
sodium restriction, 304–305, 569–570 uptitration of antihypertensive therapy, 578
Dietary Approaches to Stop Hypertension (DASH), 304, 306, 390 uptitration of treatment to three-drug combination
sodium trial, 75 therapy, 577
Digital intervention, 538; see also Patient follow-up Dry weight Reduction in Hypertensive Hemodialysis Patients
Digital subtraction angiography (DSA), 503 (DRIP), 471
Dihydropyridine (DHPCCB), 467 DSA, see Digital subtraction angiography
Dihydropyridine-type (DHP), 327 DTI, see Doppler tissue imaging
Dipper/non-dipper classification, 203; see also Day-night blood Dual (multiple)-action drugs, 44
pressure change Dyslipidaemia, 163
Direct active renin concentration (DRC), 512 clinical surveys on statin therapy, 165
Direct distance (DD), 248 clinical trials on statin therapy, 165–167
Directly observed treatment (DOT), 373 hypertension and atherosclerosis, 163–164
Distal convoluted tubule (DCT), 61 lipid-lowering therapies and hypertension, 164–165
Diuretics, 44–46, 330, 497; see also Antihypertensive drug prognostic relevance and management, 164
loop, 331, 333 total CV risk profile identification, 164
thiazide, 330–331
DJ-1 protein, 69; see also Reactive oxygen species
DM, see Diabetes mellitus E
DOHAS, see Dialysis Outcomes Heart Failure Aldactone study
Doppler tissue imaging (DTI), 230 EAE, see European Association of Echocardiography
DOT, see Directly observed treatment Early morning blood pressure surge, 204–206; see also Day-night
DRC, see Direct active renin concentration blood pressure change
DRIP, see Dry weight Reduction in Hypertensive Hemodialysis Early vascular ageing (EVA), 89
Patients arterial stiffness, 90–91
Drug adherence, 369 chronic inflammation, 91
advantages and limits of methods used to assess, 371 cognition, 91–92
aspects of, 369 determinants of, 90
changes in blood pressure in relation to changes in urinary emergence of concept, 91
adherence ratio, 372 historical notes on artery research, 89
components of, 370 human ageing in perspective, 89
definitions and taxonomy of, 369–370 interventions retarding vascular ageing, 92–93
in hypertension, 372–373 new research directions, 92
interventions improving, 605 role of glycaemia, 91
methods available to support, 374 vascular ageing process, 89
methods of measuring, 370–371 EBM, see Evidence-Based Medicine
persistence to therapy, 370 Eccentric LVH, 81
in resistant hypertension, 373–374 ECG, see Electrocardiogram
risk factors of poor adherence, 371–372 Echocardiography, 10–11
strategies to improve, 374–375 EchoNoRMAL, 228
Drug combinations, 574–577 ECM, see Extracellular matrix
Drug-induced hypertension, 455 ECs, see Endothelial cells
alcohol, 460 ECST, see European Carotid Surgery Trial
amphetamines, 459 ED, see Emergency department
anaesthetics, 459 EDCFs, see Endothelium-derived constricting factors
analgesics, 455 EDHF, see Endothelium-derived hyperpolarising factor
antidepressants, 459 EDRFs, see Endothelium-derived relaxing factors
anti-HIV treatments, 459 EDV, see End-diastolic volume
antihypertensive medication, 459 EETs, see Epoxyeicosatrienoic acids
based on pathophysiology, 456–457 EF, see Ejection fraction
caffeine, 460 Efficacy of Nitric Oxide in Stroke (ENOS), 481
chemotherapeutic agents, 458 EGF, see Epidermal growth factor
drugs and toxins, 460 eGFR, see Estimated glomerular filtration rate
herbal supplements, 460 EGIR, see European Group for the Study of Insulin
illicit drugs, 460 EH, see Essential hypertension
immunosuppressants, 458 eHealth technologies, 537; see also Patient follow-up
recombinant human erythropoietin, 458–459 Ejection fraction (EF), 11, 231
sex hormones, 457–458 EKG, see Electrocardiography
sympathomimetics, 459–460 Elastic taper, 183
systemic corticosteroids, 455 Electrocardiogram (ECG), 225, 289–290, 560; see also Integrated
Drug intolerance, 363; see also Adverse effects diagnostic approach
Drug treatment algorithm, 578; see also Hypertension Electrocardiography (EKG), 10, 139
treatment Electrolytes, 288–289; see also Integrated diagnostic approach
Index 637
ELSA, see European Lacidipine Study on Atherosclerosis Epicardial arteries, 265; see also Endothelial damage
Emergency department (ED), 431 Epidermal growth factor (EGF), 62
Empagliflozin Cadiovascular Outcomes and Mortality in Type 2 Epithelial Na+ channel (ENaC), 138
Diabetes (EMPA-REG), 322 Eplerenone, 396
EMPA-REG, see Empagliflozin Cadiovascular Outcomes and EPO, see Erythropoietin
Mortality in Type 2 Diabetes EPOGH, see European Project on Genes in Hypertension
EMPs, see Endothelial microparticles Epoxyeicosatrienoic acids (EETs), 142
ENaC, see Epithelial Na+ channel EPS, see Enlarged perivascular spaces
End-diastolic volume (EDV), 231 Epworth Sleepiness Scale (ESS), 127
Endocrine Society guidelines, 512 ERA-EDTA, see European Renal Association-European Dialysis and
EndoPAT, 266 Transplant Association
End-organ damage Erythropoietin (EPO), 458
and clinical complications, 390–391 ESC, see European Society of Cardiology
hemodynamic mechanisms leading to, 186 ESH, see European Society of Hypertension
Endothelial cells (ECs), 253; see also Endothelial damage ESO, see European Stroke Organization
dysfunction, 261 ESRD, see End-stage renal disease
function assessment techniques, 266–267 ESS, see Epworth Sleepiness Scale
Endothelial damage, 261 Essential hypertension (EH), 84, 345, 401; see also Interventional
CECs, 267 therapies
circulating markers, 267 Estimated glomerular filtration rate (eGFR), 12, 319, 396, 561
coronary epicardial and microvascular function, 265 ESV, see End-systolic volume
coronary microcirculation, 265 ET-1, see Endothelin-1
EMPs, 267 Ethnic factors in hypertension, 389, 594, 595
EndoPAT, 266 antihypertensive treatment, 391–392
endothelial activation, 261 end-organ damage and complications, 390–391
endothelial function assessment, 265 epidemiology of hypertension, 389–390
endothelial repair mechanisms, 264–265 lifestyle changes, 391
EPCs, 267 pathophysiologic considerations, 390
epicardial arteries, 265 pharmacotherapy, 391–392
evidence for, 267–269 EURIKA (European Study on Cardiovascular Risk Prevention and
flow-mediated dilation, 265–266 Management in Usual Daily Practice), 25
forearm plethysmography, 266–267 European Association of Echocardiography (EAE), 229
low-mediated dilation of brachial artery, 265–266 European Carotid Surgery Trial (ECST), 490
mechanisms of, 261–264 European Group for the Study of Insulin (EGIR), 141
methods for assessing, 265 European Lacidipine Study on Atherosclerosis (ELSA),
micromyography, 267 11, 214
molecular mechanisms in endothelial cell activation, 262 European Project on Genes in Hypertension (EPOGH), 390
progression of, 263 European Renal Association-European Dialysis and Transplant
soluble markers, 267 Association (ERA-EDTA), 468
vascular reactivity tests, 265 European Society of Cardiology (ESC), 164, 188, 228, 251, 278, 395,
Endothelial microparticles (EMPs), 264, 267; see also Endothelial 446, 535, 543; see also Arterial hypertension guidelines,
damage 2018 ESC/ESH
Endothelial nitric oxide synthase (eNOS), 68, 150, 261 classes of recommendations, 544
Endothelial progenitor cells (EPCs), 85, 264, 267; see also levels of evidence, 544
Endothelial damage European Society of Endocrinology Clinical Practice
Endothelin-1 (ET-1), 68, 110, 139, 263 Guideline, 530
Endothelium-derived constricting factors (EDCFs), 253 European Society of Hypertension (ESH), 3, 228, 251, 278, 296,
Endothelium-derived hyperpolarising factor (EDHF), 253, 261 395, 446, 468, 535, 543; see also Arterial hypertension
Endothelium-derived relaxing factors (EDRFs), 253 guidelines, 2018 ESC/ESH; Hypertension Specialist
End-stage renal disease (ESRD), 22, 250, 288, 319, 390, 419, 463; Programme
see also Chronic kidney disease, advanced activities and training, 3
arterial stiffness, 470 affiliated societies, 5
β-blockers, 473 annual meeting on hypertension, 3–4
blockers of renin−angiotensin−aldosterone system, books, 5
472–473 Centres of Excellence, 4–5
calcium channel blockers, 473 centres of excellence in hypertension, 297, 298
diagnosis of hypertension in dialysis patients, 469 guidelines, 5
endothelial dysfunction, 470 Hypertension Specialist Programme, 4
epidemiology, 468–470 journals, 5
hypertension in patients with, 468 Milan meetings, 3
hypertension management in dialysis, 471–472 publications, 5
hypertension treatment in patients on dialysis, 470 research projects, 5
outcome trials with major antihypertensive classes, 472 scientific documents, 5
pathogenesis, 470 structure of, 4
use of antihypertensive agents in patients on dialysis, 472 summer schools and courses, 4
End-systolic volume (ESV), 231 Web portal and applications, 4
Enlarged perivascular spaces (EPS), 241 working groups, 4
ENOS, see Efficacy of Nitric Oxide in Stroke European Stroke Organization (ESO), 483
eNOS, see Endothelial nitric oxide synthase Eutrophic remodelling, 255–256; see also Microcirculation
Environmental Protection Agency (EPA), 150 EVA, see Early vascular ageing
EPA, see Environmental Protection Agency Evidence-Based Medicine (EBM), 491
EPCs, see Endothelial progenitor cells Exercise, 307; see also Non-pharmacological interventions
638 Index
Exercise systolic blood pressure, 217 Glucose-lowering drugs and blood pressure, 604; see also
clinical aspects of exaggerated, 220–221 Cardiovascular disease
at different workloads and impact of physical fitness, 220 Gordon syndrome, 60
exaggerated blood pressure response to physical exercise, Grade 1 hypertension
217–219 blood pressure-lowering drug treatment, 564–565
exercise hypotension, 217 drug treatment for patients with, 564
Kaplan-Meier plot, 218, 219 Growth factors, 62
Oslo Ischemia Study cohort, 218 GRS, see Genetic risk score
physiology and pathophysiology related to, 219–220 GS, see Gitelman syndrome
prognostic impact of exercise blood pressure, 221 GTN, see Guanylate trinitrate
Extracellular matrix (ECM), 91, 247, 256 Guanylate trinitrate (GTN), 179
Guidelines, 543; see also Arterial hypertension guidelines, 2018
ESC/ESH
F Guyton’s ’pressure-natriuresis’ model, 58
GWAS, see Genome-wide association studies
FAK, see Focal adhesion kinase
Familial hyperaldosteronism type 2 (FH II), 60
Fasting plasma glucose (FPG), 285 H
Fatty kidney, 320
Fawn-hooded rat (FHR), 256 HAART, see Highly active antiretroviral therapy
18F-DOPA, see 6-(18F)-fluoro-l-3, 4-dihydroxyphenylalanine Haemorrhagic stroke, 435
Felodipine Event Reduction (FEVER), 488 H-AHF, see Hypertensive acute heart failure
FEVER, see Felodipine Event Reduction Hallmark of hypertension, 38
FFA, see Free fatty acid HARVEST study, 121, 122
18F-FDG, see 2-(18F)-fluoro-2-deoxy-D-glucose Hazard ratio (HR), 140, 464, 488
FH II, see Familial hyperaldosteronism type 2 HBP, see Home blood pressure
FHR, see Fawn-hooded rat HBPM, see Home blood pressure monitoring
Fibromuscular dysplasia (FMD), 62, 503 HCTZ, see Hydrochlorothiazide
Fibrosis, 82 HDFP, see Hypertension Detection and Follow-up Program
FLEMINGHO, see Flemish Study on Environment, Genes and Heat HDL, see High-density lipoprotein
Outcomes HDL-c, see High-density lipoprotein cholesterol
Flemish Study on Environment, Genes and Heat Outcomes HDPAL, see Hemodialysis Patients Treated with Atenolol or
(FLEMINGHO), 83 Lisinopril
Flow-mediated dilatation (FMD), 139, 265–266 Head and neck paragangliomas (HNPGLs), 525
2-(18F)-fluoro-2-deoxy-D-glucose (18F-FDG), 527 Health-related smartphone applications, 538; see also Patient
6-(18F)-fluoro-l-3, 4-dihydroxyphenylalanine (18F-DOPA), 527 follow-up
FMD, see Fibromuscular dysplasia; Flow-mediated dilatation Healthy vascular ageing (HVA), 90, 92; see also Early vascular ageing
Focal adhesion kinase (FAK), 256 Heart assessment, 10; see also Cardiovascular risk
Forearm plethysmography, 266–267 cardiac imaging techniques, 11
FOSIDIAL, see Fosinopril in Dialysis echocardiography, 10–11
Fosinopril in Dialysis (FOSIDIAL), 472 electrocardiography, 10
FPG, see Fasting plasma glucose organ damage in diabetes/obesity, 419
Fractional shortening (FS), 231 Heart disease, 597
Framingham Heart Study, 303, 412 Heart failure (HF), 81, 225, 319, 390, 597–598; see also Heart
Framingham Offspring Study, 140 disease; Ventricular hypertrophy
Framingham Risk Score (FRS), 141 clinical aspects of chronic, 227–228
Framingham Study, 123 consequences of, 232
Free fatty acid (FFA), 137, 417 left ventricular hypertrophy and, 597–598
FRS, see Framingham Risk Score from LVH to chronic, 225–226
FS, see Fractional shortening relative risk reduction of, 231
Fuster polypill, 357; see also Polypill risk factor, 225
therapeutic strategies, 598
Heart failure with preserved ejection fraction (HFpEF), 82,
G 225, 560
structural, functional and ultrastructural LV characteristics
68Ga-DOTA-peptides, 527 in, 230
GEMINI trial, 468 Heart failure with reduced ejection fraction (HFrEF), 82, 225, 560
Gene model, 51 drug treatment strategy, 580
Genetic basis for common diseases, 52 structural, functional and ultrastructural LV characteristics in, 230
Genetic risk score (GRS), 91 Heart in hypertension, 559
Genetics and hypertension, 563; see also Arterial hypertension electrocardiogram, 560
guidelines, 2018 ESC/ESH transthoracic echocardiography in hypertension, 560
Genome-wide association studies (GWAS), 52 Heart Outcomes Prevention Evaluation (HOPE), 165, 313, 442, 491
Geometric taper, 183 Heart rate (HR), 37, 121, 130
Germ theory model, 51 as cardiovascular risk factor, 121, 124–125
Gestational hypertension, 446–448 distribution of resting heart rate in HARVEST study, 122
long-term CV consequences of, 593 five-year risk of cardiovascular events, 124
GFR, see Glomerular filtration rate hazard ratios and 95% CIs for 10-bpm increment, 124
GISSI-AF study, 234 lowering in hypertension, 124
Gitelman syndrome (GS), 61 as predictor of hypertension and metabolic abnormalities,
Glomerular filtration rate (GFR), 12, 140, 186, 319, 395 121–122
prognosis of CKD by GFR and albuminuria category, 12 prognostic value of ambulatory heart rate, 123–124
Index 639
Hypertension in specific circumstances, 582; see also Arterial acute aortic dissection, 435–436
hypertension guidelines, 2018 ESC/ESH acute heart failure, 433–434
atrial fibrillation, and other arrhythmias, 599–600 acute management of, 587
cancer therapy, 602 acute stroke, 434
cerebrovascular disease and cognition, 598–599 choice of treatment, 433
chronic kidney disease, 595–596 diagnostic workup, 588
chronic obstructive pulmonary disease, 596–597 drug types, doses, and characteristics for treatment, 589
diabetes mellitus, 595 epidemiology, 432
ethnic groups, 594 haemorrhagic stroke, 435
heart disease, 597–598 hypertensive crisis, 431
hormone-replacement therapy and hypertension, 594 initial evaluation, 432
lower extremity arterial disease, 601 ischaemic stroke, 434–435
masked hypertension, 588, 590 management flowchart, 433
older patients, 591 prognosis and follow-up, 587–588
oral contraceptive pills, 594 requiring blood pressure lowering, 589
perioperative management, 602 treatment in, 432–433
pregnancy, 591–593 treatment of ischaemic and haemorrhagic stroke, 434
resistant hypertension, 582–584 Hypertensive retinopathy, 561
secondary hypertension, 584–585 Hypertensive urgency, 431, 585–587
sexual dysfunction, 601–602 acute aortic dissection, 435–436
valvular disease and aortopathy, 601 acute heart failure, 433–434
vascular disease, 600–601 acute stroke, 434
white-coat hypertension, 588 choice of treatment, 433
younger adults, 590–591 epidemiology, 432
Hypertension in the Very Elderly Trial (HYVET), 565 haemorrhagic stroke, 435
Hypertension-mediated organ damage (HMOD), 283, 548–549; see hypertensive crisis, 431
also Arterial hypertension guidelines, 2018 ESC/ESH initial evaluation, 432
antihypertensive treatment, 561–562 ischaemic stroke, 434–435
assessment of, 557–559 management flowchart, 433
blood vessels, 560–561 treatment in, 432
brain, 561 treatment of ischaemic and haemorrhagic stroke, 434
characteristics of, 559 Hypertrophy, 255
clinical evaluation of, 557, 562–563 Hyperuricaemia, 155; see also Serum uric acid
heart, 559–560 established hypertensive patients, 159
hospital-based care, 562 hypertension and CV disease, 158
hypertensive retinopathy, 561 in patients with hypertension, 158
kidney, 561 pre-hypertension, 158–159
medical history, 557, 558 prevention of CV events, 159
physical examination, 557, 558 randomized clinical trials, 159
risk stratification in hypertensive patients, 559 as risk factor for hypertension, 157–158
routine workup, 558 treatment of, 158
Hypertension Optimal Treatment (HOT), 347 Hypocretin system, 132; see also Obstructive sleep apnoea
Hypertension Prevention Trial, 304 Hypokalaemia, 289
Hypertension Specialist Programme, 294 Hyponatremia, 289
BP-VP clinic, 297–298 Hypothalamic−pituitary−adrenocortical (HPA), 111
European Society of Hypertension, 296, 297, 298 HYVET, see Hypertension in the Very Elderly Trial
Hypertension specialists, 294–297
credits needed to collect for recognition of status of, 296
eligibility criteria, 296 I
general practitioner hypertension specialist, 295
hospital hypertension specialist, 295 ICAM-1, see Intercellular adhesion molecule-1
role of, 294–295 ICH, see Intracerebral haemorrhage
Hypertension treatment, 293, 563, 564–566, 569–571; see also ICH-ADAPT, see Intracerebral Haemorrhage Acutely Decreasing
Arterial hypertension guidelines, 2018 ESC/ESH Arterial Pressure Trial
beneficial effects of BP-lowering therapy, 563–564 ID, see Inner lumen diameter
BP treatment targets, 567–569 IDACO (International Database on Ambulatory Blood Pressure in
device-based hypertension treatment, 578–582 Relation to Cardiovascular Outcomes), 31, 191, 214, 124
dietary changes, 570 IDF, see International Diabetes Federation
dietary sodium restriction, 569–570 IDHOCO (International Database of HOme blood pressure in
drug treatment algorithm, 578 relation to Cardiovascular Outcome), 197
drug treatment strategy, 574–578 IDNT, see Irbesartan Diabetic Nephropathy Trial
hypertensiology, 293–294 IL, see Interleukin
hypertension specialist programme, 294–298 IL-1, see Interleukin-1β
lifestyle changes, 569 IL-6, see Interleukin-6
moderation of alcohol consumption, 570 Illicit drugs, 460; see also Drug-induced hypertension
pharmacological therapy for hypertension, 571–574 Imaging software Integrative Vessel Analysis (IVAN), 276
to prevent CV disease, 294 123I-MIBG scintigraphy, 527
regular physical activity, 571 Immune system in hypertension, 70–72; see also Oxidative stress;
smoking cessation, 571 Reactive oxygen species
weight reduction, 570–571 interactions between ROS, immune system, kidneys and CV
Hypertensive acute heart failure (H-AHF), 431 system, 68
Hypertensive emergency, 431, 585–587 Immunosuppressants, 458; see also Drug-induced hypertension
Index 641
Normotension (NT), 84 Oslo Ischemia Study cohort, 218; see also Exercise systolic blood
North American Symptomatic Carotid Endarterectomy Trial pressure
(NASCET), 490 Outer arteriolar diameter (OD), 276
Novel oral anticoagulants (NOACs), 328, 412 Out-of-office blood pressure measurements, 285, 552, 555–556
Nox, see NADPH oxidases Oxidative stress, 67; see also Immune system in hypertension;
Nrf2, see Nuclear factor erythroid 2-related factor 2 Reactive oxygen species
NRI, see Net reclassification improvement Oxide-mediated vasodilation, 21
NSAIDs, see Nonsteroidal anti-inflammatory drugs
NT, see Normotension
Nuclear factor erythroid 2-related factor 2 (Nrf2), 69, 92 P
Nuclear factor-k B (NF-k B), 139
Nuclear medicine scanning techniques, 527 PA, see Primary aldosteronism
Nurses, 537–538; see also Patient follow-up PAC, see Plasma aldosterone concentration
PAD, see Peripheral artery disease
Paediatric HTN, see Childhood blood pressure
O PAMELA, see Pressioni Arteriose Monitorate E Loro Associazioni
Pan-African Society of Cardiology (PASCAR), 32
Obesity, 127, 417, 420, 421; see also Diabetic/obese hypertensive Papilledema, 432
patient PAPY, see Primary Aldosteronism Prevalence in HYpertension
adverse consequences of, 128 PAR, see Protease-activated receptor
attributable to OSA, 129 PARADIGM-HF, 348
epidemiology of, 127 Paragangliomas (PGLs), 62; see also Pheochromocytoma and
-induced hypertension, 417–418 Paragangliomas
interaction between OSA and, 129 PARTAGE (Predictive Values of Blood Pressure and Arterial Stiffness
-related hypertension, 417 in Institutionalized Very Aged Population), 348
OBP, see Office blood pressure Particulate matter (PM), 150
Obstructive sleep apnoea (OSA), 127, 278 PASCAR, see Pan-African Society of Cardiology
adverse consequences of, 128 PAST-BP, see Prevention After Stroke—Blood Pressure
definition, 127 PATHS, see Prevention and Treatment of Hypertension Study
diagnosis, 127–128 PATHWAY-2 (Prevention And Treatment of Hypertension With
mechanisms underlying, 129 Algorithm-based therapY-2), 574
metabolic disturbances, 130–131 double-blind crossover study, 396
obesity and, 129 Patient follow-up, 535, 604; see also Arterial hypertension
obesity attributable to, 129 guidelines, 2018 ESC/ESH
prevalence of, 128–129 alternative modes of hypertension care, 539
role of hypocretin in, 132 antihypertensive medications, 606
role of leptin and ghrelin in, 131 asymptomatic hypertension-mediated organ damage, 605
role of sympathetic nervous system, 129–130 BP control and CV risk, 536–537
symptoms, 127 digital intervention, 538
therapeutic interventions, 132–133 elevated blood pressure at control visits, 604
OCT, see Optical coherence tomography frequency of, 535
OD, see Organ damage; Outer arteriolar diameter healthcare professionals for, 537
Odds ratio (OR), 32 high–normal BP and white-coat hypertension, 604
Office blood pressure (OBP), 171, 197; see also Home blood pressure home blood pressure telemonitoring, 538–539
monitoring of hypertensive patients, 604
auscultatory method, 173 improvement in BP control, 604–605
automated, 173–174 initial evaluation and monitoring, 539
classification of, 547 mobile applications, 538
factors affecting measurements, 172 nurses, 537–538
failure to guide treatment by out-of-office BP, 380–381 pharmacists, 537
home vs. office and ambulatory blood pressure monitoring, recommended tests and investigations, 540
198–199 treatment of BP and CVr risk, 539–540
hypertension treatment initiation, 566 virtual clinics, 539
measurement, 171, 173, 551 impact of visit frequency on BP control, 536
noninvasive arterial BP measurement, 172 effect of visit frequency on CV outcomes, 536
sources of variability, 172 PATS, see Post-Stroke Antihypertensive Study
superiority of HBPM over, 197 PCC, see Plasma cortisol concentration
thresholds for treatment, 567 PCCs, see Pheochromocytomas
treatment target range, 569, 581 PCR, see Protein/creatinine ratio
Omics’ technologies, 63 PCSK9, see Proprotein convertase subtilisin-kexin type 9
ONTARGET (Ongoing Telmisartan Alone and in combination PDGF, see Platelet-derived growth factor
with Ramipril Global Endpoint Trial ACEinhibitors), Percutaneous transluminal renal angioplasty (PTRA), 507
234, 347, 442 Perioperative management, 602–603
Optical coherence tomography (OCT), 278, 507 Peripheral artery disease (PAD), 439, 442, 548
OR, see Odds ratio antihypertensive treatment, 441
Oral antithrombotic treatment, 441
anticoagulants, 600 clinical aspects, 439
contraceptive pills, 594 control of lipids, 441
glucose tolerance test, 285 drug treatment of intermittent claudication, 441
Orexin-A, 132 masked PAD, 439
Organ damage (OD), 451 prevalence, 439–440
OSA, see Obstructive sleep apnoea prognosis, 440
Index 645
Small artery function, 257; see also Microcirculation and altered function, 81–82
Small interfering RNA (siRNA), 267 cause-and-effect relationships, 85
Small vessel disease (SVD), 13, 244; see also Brain damage direct observation, 84–85
SMD, see Standardized mean difference ex vivo evidence, 84
Smoking cessation, 307, 571; see also Hypertension treatment; hemodynamic studies, 84
Non-pharmacological interventions large artery structure and function, 83
SNPs, see Single-nucleotide polymorphisms pathogenesis of LVH, 81
SNS, see Sympathetic nervous system structural changes in blood vessels, 82–83
Socioeconomic determinants, 31 structural changes in coronary vascular bed, 82
comparisons between countries, 31–32 structural changes in heart, 81
meta-analyses and current concepts, 32 structure and function of resistance arteries, 83–84
possible mechanisms, 32–33 treatment, 85
SOD, see Superoxide dismutase vascular tree and structural change, 82
Sodium, 75; see also Potassium; Resistant hypertension Study on Cognition and Prognosis in the Elderly (SCOPE), 491
BP salt-sensitivity, 76 SUA, see Serum uric acid
depletion intensification, 396 Subclinical organ damage, 8; see also Cardiovascular risk
homeostasis, 20 prognostic value of treatment-induced, 13
intake and cardiovascular disease, 76–77 SUCH, see Sustained uncontrolled hypertension
intake, blood pressure and organ damage, 75–76 SUPERNOVA (Supernormal vascular ageing), 90; see also Early
recommendations, 77 vascular ageing
Sodium-glucose cotransporter 2 (SGLT2), 420 determinants of, 92
Sodium-potassium-chloride cotransporter-2 (NKCC2), 61 Superoxide dismutase (SOD), 69
Sokolow-Lyons index, 10 Surrogate endpoint, 187
Soluble fms-like tyrosine kinase-1 (sFlt-1), 448 Sustained uncontrolled hypertension (SUCH), 554
Soluble markers, 267; see also Endothelial damage SV, see Stroke volume
SOS, see Swedish Obese Individuals SVD, see Small vessel disease
SPCs, see Single-pill combinations Swedish Obese Individuals (SOS), 304
Specific diets, 306–307; see also Non-pharmacological Sympathetic nervous system (SNS), 76, 81, 138, 227, 401,
interventions 417, 458
Speckle-tracking imaging (STI), 231 stress response, 109–110
SPECT, see Single-photon emission computed tomography Sympathomimetics, 459–460; see also Drug-induced hypertension
Sphygmomanometer types, 412 Symplicity HTN, 405–406; see also Renal denervation therapy
Spontaneously hypertensive rat (SHR), 256 Synthetic corticosteroids, 455
Spontaneously hypertensive stroke-prone rat (SHRSP), 256 Systematic COronary Risk Evaluation (SCORE), 548
SPRINT, see Systolic Blood Pressure Intervention Trial correction factors for CV risk estimates, 550
SPS3, see Secondary Prevention of Small Subcortical Strokes risk modifiers, 550
Spurious hypertension, 178 SCORE project, 8
SPYRAL multielectrode catheter, 407; see also Renal denervation Systemic corticosteroids, 455; see also Drug-induced hypertension
therapy Systemic embolic events (SEE), 413
Standard deviation (SD), 129, 204, 212 Systemic embolism (SE), 413
Standardized mean difference (SMD), 112 Systolic arterial pressure (SAP), 38
STAT (Studying the Treatment of Acute hyperTension), 431 Systolic blood pressure (SBP), 109, 140, 171, 177, 184, 312, 320, 395,
Statin, 603; see also Cardiovascular disease 425, 431, 479
therapy, 165–167 Systolic Blood Pressure Intervention Trial (SPRINT), 174, 228, 314,
Steno-2 study, 166 320, 465, 535
Stenotic carotid plaques, 560 Systolic Hypertension in the Elderly Program study (SHEP
STI, see Speckle-tracking imaging study), 347
STOP-Bang Questionnaire, 128
STOP questionnaire, 128
Stress, 109; see also Psychosocial risk factors T
biofeedback, 113–114
in daily life, 149 T2D, see Type 2 diabetes
and hypertension, 109, 110 Tablet feed, 373
mindfulness-based stress reduction, 112–113 Tachycardia, 123
reduction in hypertension, 111 TADs, see Tricyclic antidepressants
risk factors for hypertension, 109 TAIM, see Trial of Antihypertensive Interventions and
role of hypothalamic−pituitary−adrenal axis, 111 Management
role of immune system and endothelial dysfunction, 111 TAL, see Thick ascending limb
role of renin–angiotensin–aldosterone system, 110–111 Tandem mass spectrometry (LC-MS/MS), 526
role of sympathetic nervous system, 109–110 Target-organ damage (TOD), 432; see also Diabetic/obese
transcendental meditation technique, 111–112 hypertensive patient
yoga, 114 assessment of, 427–428
Stroke, 245, 487, 599; see also Acute stroke; Brain damage; in diabetes/obesity, 419
Cerebrovascular disease and cognition; Chronic post- Taurine, 457–458
stroke phase TC, see Total cholesterol
effects of blood pressure lowering, 489 TCD, see Transcranial Doppler
Stroke index (SI), 38 TDI, see Tissue Doppler imaging
Stroke in Hypertension Optimal Treatment (SHOT), 316, 490 Testosterone, 457
Stroke-prone spontaneously hypertensive rats (SHR-SP), 77 TG, see Triglycerides
Stroke volume (SV), 37 TGF-β, see Transforming growth factor-β
Stroke volume index (SI), 42 Th-1 cells, see T-helper-1 cells
Structural cardiovascular changes in hypertension, 81 T-helper-1 cells (Th-1 cells), 67
Index 649
Thiazide diuretics, 330; see also Diuretics Urine protein-to-creatinine ratio (UPCR), 464
adverse effects, 331 USPSTF, see United States Preventive Services Task Force
classification, 331
contraindications and precautions, 331
mechanism of action, 330–331 V
pharmacokinetics and dosing, 331, 332
thiazide/thiazide-like diuretics, 573 Vagal nerve stimulation, 405; see also Central iliac arteriovenous
Thick ascending limb (TAL), 61 anastomosis
3DE, see Three-dimensional echocardiography Valsartan Antihypertensive Long-term Use Evaluation (VALUE),
Three-dimensional echocardiography (3DE), 11 123, 491, 347
Three-drug combination therapy, 577 VALUE, see Valsartan Antihypertensive Long-term Use Evaluation
TIA, see Transient ischaemic attack Valvular disease and aortopathy, 601
TIMP-1, see Tissue inhibitor of metalloproteinases-1 coarctation of aorta, 601
TIPS-2 (The second Indian Polycap Study), 358 hypertension bicuspid aortic valve-related aortopathy, 601
Tissue Doppler imaging (TDI), 231 prevention of aortic dilation and dissection in high-risk
Tissue inhibitor of metalloproteinases-1 (TIMP-1), 226 subjects, 601
TM, see Transcendental Meditation VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes),
TNF, see Tumor necrosis factor 466, 467
TNT, see Treating to New Targets Variability independent of mean (VIM), 212
TOD, see Target-organ damage Vascular
TOHP, see Trials of Hypertension Prevention mechanisms, 62–63
TONE (Trial of Non-pharmacologic Interventions in the remodelling, 275
Elderly), 304 volume, 58
Total cholesterol (TC), 287 Vascular ageing process, 89; see also Early vascular ageing
Total peripheral resistance (TPR), 37, 255 Vascular brain injury (VBI), 13
index, 38 Vascular cell adhesion molecule-1 (VCAM-1), 267
Toxins, 460; see also Drug-induced hypertension Vascular cerebral damage, 241–243; see also Brain damage
TPR, see Total peripheral resistance role of genetic factors in, 244
TRANSCEND, 347 Vascular disease, 600
Transcendental Meditation (TM), 111–112; see also Stress arteriosclerosis and arterial stiffness, 600–601
Transcranial Doppler (TCD), 241 carotid atherosclerosis, 600
Transforming growth factor-β (TGF-β), 71 Vascular endothelial growth factor (VEGF), 418, 458
TGF-β1, 76 VEGFA, 63
Transient ischaemic attack (TIA), 487, 560, 599; see also VEGF-C, 20
Cerebrovascular disease and cognition Vascular smooth muscle cell (VSMC), 83, 91, 104, 247, 253; see also
Transplant renal artery stenosis, 495; see also Post-transplant patient Microcirculation
with hypertension contractile apparatus of, 253
Transthoracic echocardiography in hypertension, 560 Vasoconstrictor agents, 62
Treating to New Targets (TNT), 347 Vasodilating beta-blocker, 44
Tregs, see Regulatory T cells Vasodilators, 62, 397, 433
Trial of Antihypertensive Interventions and Management VBI, see Vascular brain injury
(TAIM), 303 VCAM-1, see Vascular cell adhesion molecule-1
Trials of Hypertension Prevention (TOHP), 76, 303 Vegetarian diets, 306
Tricyclic antidepressants (TADs), 459 VEGF, see Vascular endothelial growth factor
TRIDENT (Triple Therapy Prevention of Recurrent Intracerebral Ventricular hypertrophy, 225
Disease EveNts Trial), 490 cardiac structure, 228
Triglycerides (TG), 287 clinical aspects of chronic HF, 227–228
Triple therapy optimization, 396; see also Resistant hypertension consequences of LV mass change, 235
Tumor necrosis factor (TNF), 166 evaluation of LVH, 228
TNF-α, 137, 418 LV diastolic function assessment, 229–231
Turkish study, 140 LVH and atrial fibrillation, 234–235
2D and 3D speckle tracking echocardiography, 231 LVH and HF, 232
Two-dimensional transthoracic echocardiography (2D-TTE), LVH and ischemia, 232
10, 560 LVH and ventricular tachyarrhythmias, 232–234
Two-drug combination therapy, 577 LVH to chronic HF, 225–226
2D-TTE, see Two-dimensional transthoracic echocardiography LV systolic function assessment, 231–232
Two-site pulse wave velocity measurements, 248; see also Large pathogenesis of cardiac structure adaptation, 226–227
artery damage proposed treatment, 227
Type 1 angiotensin receptor (ATl), 257 Very-low-frequency (VLF), 213
Type 2 diabetes (T2D), 417–418; see also Diabetic/obese VHL, see von Hippel–Lindau disease
hypertensive patient Vicious circle hypothesis, 269
VIM, see Variability independent of mean
Virtual clinics, 539; see also Patient follow-up
U Vitamin K antagonists (VKAs), 412
Vitamin supplementation, 305–306; see also Non-pharmacological
UA, see Uric acid interventions
UAE, see Urinary albumin excretion VKAs, see Vitamin K antagonists
United States Preventive Services Task Force (USPSTF), 165, 206 VLF, see Very-low-frequency
UPCR, see Urine protein-to-creatinine ratio von Hippel–Lindau disease (VHL), 526
Urapidil, 435 von Willebrand factor (vWF), 267
Uric acid (UA), 289; see also Integrated diagnostic approach VSMC, see Vascular smooth muscle cell
Urinary albumin excretion (UAE), 9, 427, 464 vWF, see von Willebrand factor
650 Index