Hypertension : why pandemic ?

Atma Gunawan (con

Top 10 causes of death

WHO media center, May 2014

Top 10 causes of death
Hypertension !

WHO media center, May 2014

World Health Day 2013
(WHO press release, April 2013)
Factors associated with causes of hypertension
and lack of responsiveness
 Patient factors : obesity , stress , high salt diet, non adherence
 Misdiagnosis : white coat hypertension, mask hypertension, non dipping
hypertension, pseudohypertension
 Secondary hypertension : sleep disturbances, renal parenchymal
disease,primary aldosteronism, renal artery stenosis, cushing disease,
pheochromocytoma.
 Drug-related causes : late to start a combination, inappropriate
combinations, doses too low, Rapid inactivation , Drug interactions
(Glucocorticoids, NSAIDs, phenothiazines, oral contraceptives,
Sympathomimetics, nasal decongestans, cyclosporine, erythropoetin)
Obesity
Pandemic obesity

May 29th 2014, 8:15 am

Correlation of hypertension and obesity

Dolls, Bovet P et al, 2002

Obesity and hypertension
 Framingham Heart Study suggest that 78% of new cases of
hypertension in men and 65% in women are related to excess
body weight
 Every 10-pound weight gain is associated with an estimated
4.5-mm Hg increase in systolic blood pressure

Curr Opin Cardiol. 1996;11:490–495.

Prev Med. 1987;16:234–251
Correlates of prevalent hypertension among the study subjects: results
of multiple logistic regression analyses(a)

a Age, sex, marital status, religion, past history of smoking were not statistically significant
b BMI = body mass index.
c Figures in parentheses are standard errors.
d Figures in italics are 95% confidence intervals.
e By self-report.
Bulletin of the World Health Organization, 2001, 79 (6)
 Hemodynamic, neurohumoral, and renal changes in
experimental obesity caused by a high fat diet and in
human obesity
Model Arterial SNS PRA Na+reabsorb- GFR Insulin
pressure activity activity tion resistance
Obese ↑ ↑ ↑ ↑ ↑ ↑
rabbits
(high fat
diet)
Obese ↑ ↑ ↑ ↑ ↑ ↑
dogs
(high fat
diet)
Obese ↑ ↑ ↑ ↑ ↑ ↑
humans

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO.

23, pp. 17271–17276, June 4, 2010
Leptin-melanocortin
activation distinct areas of the
brain : Chronic Activation of the CNS
POMC-MC3/4R Pathway Causes SNS
Activation and Hypertension

POMC, pro-opiomelanocortin;
MC3/4R, melanocortin 3 and
melanocortin 4 receptor; ARC,
arcuate nucleus ; LH,lateral
hypothalamus; PVN,
paraventricular nucleus
DMV, dorsal motor nucleus of
the vagus; -MSH,-melanocyte-
stimulating hormone.;; RSNA,
renal sympathetic nerve activity,
MAPK, mitogenactivated
protein kinase; NTS, nucleus
solitary tract;; Jak2 (Janus
tyrosine kinase 2)

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 23, pp.

17271–17276, June 4, 2010
Resistant hypertension in visceral obesity

Methods
 The survey was performed on 5065 hypertensive patients with visceral
obesity. BP control was analyzed on the basis of office and home BP
measurements
Results
 The percentage of RH was 13.9%. RH was more frequent only in obese with
BMI≥35 and < 40  kg/m 2 (16.2%) and in morbidly obese individuals
(26.5%).
Patients with BMI≥35 and <40 kg/m2 and with morbid obesity were receiving
three-drug therapy more frequently than patients with visceral obesity and
BMI<30 kg/m2. A multiple regression analysis revealed that obesity was
associated with RH independent from longer than 5-year period of
antihypertensive therapy, diabetes, smoking cigarettes, cardiovascular
disease and heart failure. The analysis of home BP measurement revealed
that in 11.1% of patients RH was in fact “white coat” hypertension.

European Journal of Internal Medicine

Volume 23, Issue 7, Pages 643–648, October 2012
Sleep disturbances
Short sleep
 National surveys in USA have shown a decline in self-reported sleep
duration over the past 50 years by 1.5 to 2 hours.
 >30% of Americans report sleeping less than 6 h/night
 Short sleep : <5-6 h/day or per night
 In children the definition of “short sleep” was <10 h/day or < 10 h
per night
 Effect of short sleep :
- longer exposures to elevated SNS activity
- raise blood pressure and heart rate (non-dipping HT)
- increase aldosterone levels
 ABPM on a sleep-insufficient day and a normal workday
recorded by portable multibiomedical (PMB)
Means of ambulatory blood pressure on a Effects of Insufficient Sleep on
sleep-insufficient day and a normal workday Autonomic Nervous System Activity

Urinary excretion Normal Sleep- P

norepinephrine Workday Insufficient
nmol/g Day

Sleep period 124±39 168±78 <.05

Waking hours 230±49 270 ±68 <.05

24 Hours 194±46 223±58 <.05

Tochikubo et al. [16]. Hypertension 1996; 27: 1318-1324

Sleep duration to risk of hypertension incidence: a meta-
analysis of prospective cohort studies .
(a) Short sleep duration. (b) Long sleep duration

Hypertension Research (2013) 36, 985–995

Baseline polysomnographic data of the subject
with normotension, controlled hypertension and resistant
hypertension

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 23 NUMBER 2 | FEBRUARY 2010

Meta-Analysis of Short Sleep Duration and Obesity in
Adults

SLEEP, Vol. 31, No. 5, 2008

Obstructive sleep apnea
• At least 10 apneic and hypopneic episodes (min 10
seconds) per sleep hour
• 10% of 30-60 years of age (5% of woman and 15% of men)
 Superimposed recordings of the electrooculogram (EOG),
electroencephalogram (EEG), electromyogram (EMG), ECG (EKG),
sympathetic nerve activity (SNA), respiration (RESP), and blood
pressure (BP) during REM sleep in a patient with OSA
 All Htn CAD
Drug Stroke or CHF
Resistant TIA Nieto Shafer
Javaheri
Htn
Basetti JAMA Card 1999
Circ 1999
Logan 2000
Sleep,
J Htn 2001 1999
Treatment of sleep apnea

Behavioral factors :
- weight loss
- no alcohol and smoking,
and no sedatives before
sleep
- avoidance of supine sleep
- sleep position :lateral
decubitus
Spironolactone 25-50 mg/d
Nasal CPAP Continuous
positive airway pressure
Oral dental devices
Surgical procedures :
UPP, nasal
surgery,,tonsilectony,LAUP
Maxiofacial
surgery,tracheostomy
Stress
 Stress : anxiety and depression
• Anxiety and depressionare two of the most
common type of stress.
• Anxiety and depression are not the same, but
they often occur together. There is also overlap in
some of the treatments
• Depression is a common disorder, affecting over
350 million people worldwide
• Anxiety is the most common mental disorder in
the United States. One out of five people suffer
from an anxiety disorder.
Depression
• Depression is typically characterized by low energy and
mood, low self-esteem, and loss of interest or pleasure
in normally enjoyable activities
• Women tend to experience sadness and guilt, men often
feel restless or angry and are more likely to turn to
alcohol and drugs to cope.
• Depressed mood, such as feeling sad, empty or tearful
(in children and teens, depressed mood can appear as
constant irritability)
• Significantly reduced interest or feeling no pleasure in all
or most activities
• Significant weight loss when not dieting, weight gain, or
decrease or increase in appetite (in children, failure to
gain weight as expected)
• Insomnia or increased desire to sleep
• Either restlessness or slowed behavior that can be
observed by others
Fatigue or loss of energy
• racing thoughts, and a feeling of
• Feelings of worthlessness, or excessive or inappropriate
guilt
• Trouble making decisions, or trouble thinking or
concentrating
Recurrent thoughts of death or suicide, or a suicide
•
attempt
Anxiety
• Anxiety disorder is characterized by
emotional, physical, and behavioral
symptoms that create an unpleasant
feeling that is typically described as
• uneasiness, fear, or worry.
The worry is frequently accompanied by
physical symptoms, especially
fatigue,headaches, muscle tension,
muscle aches, difficulty swallowing,
• trembling, twitching, irritability,
sweating, and hot flashes.
Emotional symptoms include fear,
•
impending doom.
People suffering from anxiety often
withdraw and seek to avoid people or
certain places.
 Are symptoms of anxiety and depression
risk factors for hypertension?
OBJECTIVE:
• To test the hypothesis that symptoms of anxiety and depression increase the risk of experiencing hypertension, using the
National Health and Nutrition Examination I Epidemiologic Follow-up Study.
DESIGN:
• A cohort of men and women without evidence of hypertension at baseline were followed up for 7 to 16 years. The
association between 2 outcome measures (hypertension and treated hypertension) and baseline anxiety and depression was
analyzed .
PARTICIPANTS: A population-based sample of 2992 initially normotensive persons.
MAIN OUTCOME MEASURES:
• Incident hypertension was defined as blood pressure of 160/95 mm Hg or more, or prescription of antihypertensive
medications. Treated hypertension was defined as prescription of antihypertensive medications.
RESULTS:
• In the multivariate models for whites aged 45 to 64 years, high anxiety (relative risk [RR], 1.82; 95% confidence interval [CI],
1.30-2.53) and high depression (RR, 1.80; 95% CI, 1.16-2.78) remained independent predictors of incident hypertension. The
risks associated with treated hypertension were also increased for high anxiety (RR, 2.36; 95% CI, 1.73-3.23) and high
depression (RR, 1.89; 95% CI, 1.25-2.85). For blacks aged 25 to 64 years, high anxiety (RR, 2.74; 95% CI, 1.35-5.53) and high
depression (RR, 2.99; 95% CI, 1.41-6.33) remained independent predictors of incident hypertension. The risks associated
with treated hypertension were also increased for high anxiety (RR, 3.24; 95% CI, 1.59-6.61) and high depression (RR, 2.92;
95% CI, 1.37-6.22). For whites aged 25 to 44 years, intermediate anxiety (RR, 1.62; 95% CI, 1.18-2.22) and intermediate
depression (RR, 1.60; 95% CI, 1.17-2.17) remained independent predictors of treated hypertension only.

CONCLUSION:Anxiety and depression are predictive of later incidence of hypertension and

prescription treatment for hypertension.

Arch Fam Med. 1997 Jan-Feb;6(1):43-9.

 Correlation between blood pressure and depression

Correlation between systolic blood pressure Correlation between diastolic blood pressure
and Zung Self-rating Depression Scale score and Zung Self-rating Depression Scale score

Exp Clin Cardiol Vol 18 No 1 2013

 Depression is CAD risk factors, meta-analysis
(Framingham study and Rugulies)

Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med
2002;23:51– 61.
 Association between 12-month anxiety and hypertension
(n = 4351)

Hypertension variable(s) 12-month anxiety

disorders
OR (95% CI)
Hypertension diagnosis 1.55 (1.10–2.18)
Hypertension and another 2.25 (1.46–3.45)
chronic physical condition
Another chronic physical 1.74 (1.28–2.37)
condition

PLoS ONE May 2009 | Volume 4 | Issue 5 |

Adjusted for demographic variables (age, sex, race marriage, location), SES, lifetime
smoking and alcohol use, substance use disorders and traumatic life events.
Anxiety and Risk of Incident CHD

JACC Vol. 56, No. 1, 2010 Anxiety and Incident CHD June 29,
2010:38–46
 Stress and Hypertension
(sympathetic - adrenal medulla excite)
Emotion
Noises
Strressor
Exertion
Tension
Hyppootthhaallaamu
uss
SSyymmppaatthheettiicc RReenniinn Angiotensin Ⅱ Ald ↑
iimmppuullssee↑j ↑j ↑
Retention of water and sodium
AAddrreennaall
miinneess↑j
ccaatteecchhoollaam Hyppeerrtteennssiio Elevated artteriial
onn pt.rtessure
Vaassooccoonnssttrriiccttii
oonn
Pathophysiologic by which chronic stress
promote atherosclerosis

Catecholamine release
Stimuli NE Epinephrine
Cold,Hypoxia 10-20 fold 5 fold
Hemorrhagic 50 fold 10 fold
shock
Execution 45 fold 6 fold

JACC Vol. 45, No. 5, 2005. Psychosocial Factors and CAD

 Hormonal responses to stress

Hormone Secretion site Change

Β-endorphine Anterior pituitary Increase
ADH Hypothalamus Increase
Aldosteron Adrenal cortex Increase
Glucocorticoid Adrenal cortex Increase
Prolactin Anterior pituitary Increase
Growth hormone Anterior pituitary Acute ↑ ; chronic ↓
Insulin Pancreas Decrease
TRH Anterior pituitary Decrease
TSH Anterior pituitary Decrease
T3, T4 Thyroid Decrease

Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart
disease. Psychosom Med 2005. In press
Late to start a combination
 Inadequate Management of
Hypertension
• 40 % of patients had BP ≥ 160/90 mmHg
despite an average of more than 6
hypertension-related visits per year.
• Increases in therapy (combination)  only
in 6,7 % of visits.
Physicians are NOT
AGGRESSIVE ENOUGH in
treating hypertension.

Berlowitz DR, et al. N Engl J Med, 1998

 Guidelines Worldwide Acknowledge That Most Patients
Need Combination Therapy to Achieve BP Goals

 Most patients with hypertension will require two or more

JNC VII

antihypertensive medications to achieve their BP goals

 When BP is > 20/10 mmHg above goal, consideration should
be given to initiating therapy with two drugs
 Combination treatment should be considered as first choice when there
ESH/ESC

is high CV risk
 i.e., in individuals in whom BP is markedly above the
hypertension threshold (> 20/10 mmHg), or associated with
multiple risk factors sub-clinical organ damage, diabetes,
renal or CV disease

 Many patients will require more than one drug to achieve adequate
BP control
NICE

– Pathophysiological reasoning suggests that adding an ACE-I/ARB

to a CCB or a diuretic (or vice versa in the younger group) are
logical combinations

The Japanese Society of

Hypertension Committee for  The use of two or three drugs in combination is often necessary
JSH

Guidelines for the

Management of Hypertension
to achieve the target BP control
2009 – A low dose of a diuretic should be included in this combination

Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J. 2007;28:1462–1536; http://www.nice.org.uk/
download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3–107.
 Combination Therapy Versus Monotherapy in Reducing Blood
Pressure: Meta-analysis on 11,000 Participants from 42 Trials
Low-dose therapy has the advantage of reducing adverse effects that, with the exception of ACEI/ARB, are strongly dose related;
for 2 classes (thiazides and calcium channel blockers), for example, adverse effects are 80% lower at half-standard than standard
dose. The prevalence of adverse effects from combining 2 drugs at half-standard dose would therefore, for most
combinations, be lower than with 1 drug at standard dose.

The extra blood pressure reduction from combining drugs from 2 different classes is
approximately 5 times greater than doubling the dose of 1 drug

Wald et al. Am J Med 2009;122:290–300

CCBs and ARBs Interact Synergistically on Vascular and Renal Function,
Sympathetic Nervous System and Renin-Angiotensin System Activity

negative
Natriuresis sodium balance
reinforces the
effects of the
ARB

Vasodilation
Arterial Arterial +
Venous

CCB ARB
• ↑ SNS ↑ S • ↓ RAS  ↓ SNS
riod • Arterio- and venodilation
• Effective in low-renin patients • Effective in high-renin patients
• No renal or congestive heart failure benefits • Congestive heart failure and renal benefits
• Peripheral edema • Attenuates peripheral edema
• Reduces cardiac ischemia • No effect on cardiac ischemia

SNS = sympathetic nervous system; RAS = renin-angiotensin system

 Messages
 Obesitas, gangguan tidur, terlambat memulai kombinasi obat, adalah sebagian
dari penyebab mengapa hipertensi tidak terkontrol.
 Penyebab hipertensi pada obesitas berkaitan dengan tingginya prevalensi sleep
apnea, peningkatan rangsangan saraf simpatis, retensi sodium, aktivasi renin
angiotensin dan meningkatnya resistensi insulin

 Efek dari kurang tidur mengakibatkan aktivasi saraf simpatis berlebihan,

kenaikan kadar aldosteron, non-dipping hipertensi.

 Kebanyakan trial menunjukan bahwa setidaknya dibutuhkan dua kombinasi

obat untuk mencapai target.

 Kombinasi obat menciptakan efek sinergis, saling melengkapi dan menghasilkan

penurunan tekanan darah lebih besar dibandingkan monoterapi.