Brief Review

Myocardial Remodeling in Hypertension

Toward a New View of Hypertensive Heart Disease
Arantxa González, Susana Ravassa, Begoña López, María U. Moreno, Javier Beaumont,
Gorka San José, Ramón Querejeta, Antoni Bayés-Genís, Javier Díez

A rterial hypertension has been related to multiple out-

comes, including cardiac, cerebral, and renal.1 The burden
of arterial hypertension remains high, despite the availability of
preventive interventions and low-cost, effective antihyperten-
sive medications.2 Therefore, to hypertension burden, beyond
new effective health strategies, novel pathophysiological and
clinical approaches are also required.
Hypertension can cause or is related to various cardiac
manifestations, including hypertensive heart disease (HHD)
and obstructive coronary heart disease. HHD is defined by
the presence of left ventricular (LV) hypertrophy (LVH) or
LV systolic and diastolic dysfunction and their clinical mani-
festations, such as arrhythmias and symptomatic heart failure
(HF), appearing in patients with hypertension.3 The classical
view of HHD sustains that in conditions of pressure overload
because of systemic hypertension and no other cardiac condi-
tions, the LV undergoes extensive growth, leading to LVH, in
an attempt to maintain cardiac output, despite the increased
afterload imposed by systemic hypertension.4 However, many
patients with high blood pressures do not present clinically
Downloaded from http://ahajournals.org by on September 8, 2021
Mechanisms and Consequences of MR in HHD
MR is a complex process driven by the responses of cardiomy-
ocytes, other resident cells of the myocardium (ie, fibroblasts,
endothelial cells, pericytes, and immune cells), and cells
recruited from the circulation (eg, immune and inflammatory
cells and progenitor cells) to a variety of dynamic stimuli,
including mechanical and nonmechanical stimuli, present in
conditions of cardiac injury (Figure 1).9 As a consequence,
the volume, composition, and biophysiology of cardiomyo-
cytes, the interstitial space, and the coronary microvascula-
ture develop a variety of interrelated alterations, which have a
detrimental impact on both cardiac function and clinical out-
comes of patients with HHD (Figure 1).9 Therefore, HHD is
not just a matter of LVH but the result of complex myocardial,
cellular, and tissue arrangements leading to changes in shape
or size and function of the LV and other cardiac chambers.10
Alterations of Cardiomyocytes
Hypertrophy

detectable LVH. Therefore, a new view of HHD is emerging,
sustaining that long-term exposure to the hemodynamic stress
imposed by hypertension, in combination with the influence
of other factors, including comorbidities (eg, obesity, diabetes
mellitus, and chronic kidney disease), sex, age, environmental
exposures, and genetic factors, eventually leads to LV dys-
function and HF, as well as disturbances of the cardiac rhythm
and the myocardial perfusion.5,6 This maladaptive change is
likely because of alterations in the structure and the function
of the myocardium that result in its remodeling (Figure 1).7,8
This article reviews the major pathological components
of myocardial remodeling (MR) in HHD, highlighting their
main mechanisms and their impact on cardiac function and the
patient’s clinical outcome. In addition, we discuss the poten-
tial of circulating and imaging biomarkers to recognize diverse
phenotypes of MR and track their evolution and review cur-
rent and future therapies that may allow personalized HHD
management targeting MR.
The hypertrophic growth of cardiomyocytes is the primary
response by which the heart reduces the stress on the LV wall
imposed by pressure overload. It entails stimulation of intra-
cellular signaling cascades that activate gene expression and
promotes protein synthesis, protein stability, or both, with
consequent increases in protein content and in the size and
organization of force-generating units (sarcomeres), which, in
turn, lead to increased size of individual cardiomyocytes. In
many cases, but not necessarily in all, the magnitude of the
cardiomyocyte growth will determine that LV mass increases
and, thus, LVH develops.11 Moreover, there are changes in sar-
comeric proteins that regulate passive cardiomyocyte stiffness
(eg, titin).12
The mechanisms whereby the mechanical stretch of
cardiomyocytes is transduced across the cell membrane are
unclear. They probably involve stretch-sensitive ion chan-
nels, a Na+/H+ exchanger, integrins and integrin-interacting
molecules, and other internal and membrane-bound stretch

From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M.,
J.B., G.S.J., J.D.); Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.); CIBERCV,
Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.); Division of Cardiology, Donostia University Hospital,
University of the Basque Country, San Sebastián, Spain (R.Q.); Heart Failure Unit and Cardiology Service, Hospital Universitari Germans Trias i Pujol,
Badalona, Spain (A.B.-G.); Department of Medicine, Universitat Autònoma de Barcelona, Spain (A.B.-G.); and Department of Cardiology and Cardiac
Surgery (J.D.) and Department of Nephrology (J.D.), University of Navarra Clinic, University of Navarra, Pamplona, Spain.
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.118.11125.
Correspondence to Javier Díez, Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Ave Pío XII, 55,
31008 Pamplona, Spain. Email jadimar@unav.es
(Hypertension. 2018;72:549-558. DOI: 10.1161/HYPERTENSIONAHA.118.11125.)
© 2018 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp DOI: 10.1161/HYPERTENSIONAHA.118.11125

549
 550  Hypertension  September 2018
Figure 1.  Pathophysiological continuum of hypertensive heart disease, which describes the progressive process at cardiac and organ tissue levels that
manifest as clinical disease in hypertensive patients. BP indicates blood pressure; CFR, coronary flow reserve; CV, cardiovascular; and LVH, left ventricular
hypertrophy.
sensors in a complex network that links the extracellular
matrix (ECM), the cytoskeleton, the sarcomere, Ca2+-handling
proteins, and the nucleus.13 Local humoral mechanisms acti-
Downloaded from http://ahajournals.org by on September 8, 2021
vated in conditions of pressure overload, including neuro-
hormones as catecholamines14 and angiotensin II,15 as well
as growth factors and cytokines released by noncardiomyo-
cytes, such as fibroblasts, vascular cells, and blood cells,16
can also play a role in activating gene expression and pro-
moting hypertrophy of the cardiomyocyte through specific
membrane receptors, although their quantitative importance
has not been determined. Because of the inter-relationships
of the cardiomyocyte responses to hypertrophic stimuli, they
are likely to implicate common mediators. For instance, it has
been recently reported that MRTF (myocardin-related tran-
scription factor)-A mediates both mechanical stretch- and
neurohormonal stimulation-induced gene and hypertrophic
responses in cardiomyocytes.17
Experimental evidence supports the notion that the genetic
reprogramming associated with cardiomyocyte hypertrophy
may no longer be considered as an adaptive process.18 In fact,
the genetic changes that accompany cardiomyocyte hyper-
trophy translate into derangements in energy metabolism,
contractile cycle and excitation-contraction coupling, cyto-
skeleton and membrane properties. These changes determine
mechanical dysfunction, which, in turn, provides the basis for
the cardiomyocyte malfunction, which is associated with LVH
and predisposes the LV to diastolic or systolic dysfunction.
For instance, the analysis of experimental findings suggests
that the hypertrophic growth of the cardiomyocyte is associ-
ated with metabolic changes that result in reduced fatty acid
oxidation and increased glucose use, the dysfunction of the
mitochondrial electron transport chain, and the subsequent
diminution in ATP production.19–21
Death
The hypertrophic response of the cardiomyocyte may be linked
to its death. The dysregulation of protein synthesis/processing
during the hypertrophic process occurs within the endoplasmic
reticulum and, when persistent, causes the accumulation of
unfolded proteins, thereby leading to endoplasmic reticulum
stress and activation of the unfolded protein response, which,
in turn, may induce cardiomyocyte apoptosis.22 For instance,
in cardiomyocytes isolated from spontaneously hypertensive
rats, which present LVH and dysfunction, an association was
found between the activation of unfolded protein response and
stimulation of apoptosis.23 Additionally, clinical evidence sug-
gests that in the hypertensive myocardium, there is a deficient
activity of the factors that prevent cardiomyocyte apoptosis
(eg, gp130/leukemia inhibitory factor receptor survival path-
way).24 Therefore, cardiomyocyte apoptosis is abnormally
stimulated in patients with HHD, namely in those with HF
with reduced ejection fraction (Figure 2).25
The apoptosis of cardiomyocytes may contribute to the
development of LV dysfunction or failure of the hypertensive
myocardium through 3 different pathways. First, it has been
reported that the loss of cardiomyocytes caused by apoptosis
increases in parallel with the deterioration of systolic function
in spontaneously hypertensive rats,26 suggesting that apoptosis
may serve as one mechanism involved in the loss of contrac-
tile mass and function in patients with HHD. Second, some
mechanisms that are activated during the apoptotic process
may also interfere with the function of viable cardiomyo-
cytes before death.27 Caspase-3 cleaves cardiac myofibrillar
proteins, resulting in an impaired force/Ca2+ relationship and
myofibrillar ATPase activity. In addition, the release of cyto-
chrome C from mitochondria during apoptosis may impair
oxidative phosphorylation and ATP production, thus leading
 González et al   Myocardial Remodeling in Hypertension   551
to energetic compromise and functional impairment. Third,
in addition to contributing to histological remodeling of the
myocardium, cardiomyocyte apoptosis may also contribute
to geometric remodeling of the LV chamber. In fact, severe
cardiomyocyte apoptosis may lead to side-to-side slippage
of cells, mural thinning, and chamber dilatation. Thus, wall
restructuring secondary to severe cardiomyocyte apoptosis
Downloaded from http://ahajournals.org by on September 8, 2021
may create an irreversible state of the myocardium, condition-
ing progressive dilatation and the continuous deterioration of
LV hemodynamics and performance with time.28
Although apoptosis is characteristic of HHD, it is impor-
tant to point out that in the response to any given cardiac injury,
various modalities of cell death, including apoptosis, necrosis,
and autophagy, are stimulated because they are interconnected
by common cellular pathways at multiple points.29 In fact,
autophagy is activated during hypertensive LVH, serving to
maintain cellular homeostasis.30 Excessive autophagy, how-
ever, eliminates essential cellular elements and possibly pro-
vokes cardiomyocyte death, which further contributes to MR.
Alterations of the Interstitial Space
Inflammation
Recent advances clearly show that inflammation and activa-
tion of immunity are central drivers in the pathogenesis of
hypertension-induced target organ damage.31–33 For instance,
experimental evidence supports a substantial involvement of
the inflammatory component in hypertensive animal model-
dependent cardiac damage, particularly in response to admin-
istration of exogenous angiotensin II,34 aldosterone35 and other
mineralocorticoids,36 stimulation of the sympathetic nervous
system,37 and induction of pressure overload.38 These models
are associated in a variable degree with increased permeability
of the capillary wall, induction of cytokines and chemokines,
and recruitment of inflammatory cells that will infiltrate the
myocardium. More recently, cardiomyocytes have emerged
as additional key players in orchestrating the inflammatory
response in experimental HHD.39 Injured cardiomyocytes
Figure 2.  Distribution of the cardiomyocyte
apoptotic index in normotensive subjects and
in hypertensive patients classified according
to stages of heart failure (HF). Box plots show
the 5th and 95th (vertical lines), 25th and 75th
(boxes), and 50th (horizontal line) percentile
values. Adapted from Ravassa et al25 with
permission. Copyright © 2007, The Author.
release damage-associated molecular pattern molecules, DNA
fragments, heat shock proteins, and matricellular proteins,
instructing surrounding healthy cardiomyocytes to produce
inflammatory mediators (eg, IL [interleukin]-1β, IL-6, macro-
phage chemoattractant protein-1, and TNF-α [tumor necrosis
factor α]), which in turn activate versatile signaling networks
within surviving cardiomyocytes and trigger leukocyte activa-
tion and recruitment.
Recently published studies suggested that the myocardial
proinflammatory cytokine milieu, as well as changes in the
composition of the ECM, are crucial in the differentiation of
resident cardiac fibroblasts to activated myofibroblasts, which
initiate the process leading to myocardial fibrosis and its
detrimental consequences.40 Accordingly, experimental find-
ings support a substantial role of inflammation in myocardial
fibrosis and diastolic dysfunction in hypertensive hearts.41,42
Additionally, a positive correlation between myocardial fibro-
sis, as well as the amount of myocardial inflammatory cells,
and passive myocardial stiffness and diastolic dysfunction
was reported in patients (mostly hypertensive) with HF with
preserved ejection fraction (HFpEF).43
The role of systemic inflammation in MR in hypertension
also deserves to be considered. Evidence from experimental
models of hypertension and hypertensive patients suggests an
imbalance of T effector and regulatory subsets of lymphocytes
in hypertension, causing low-grade inflammation and contrib-
uting to blood pressure elevation and progression of end-organ
damage.44 It has been demonstrated in numerous clinical trials
that hypertensive patients commonly have increased plasma
concentrations of C-reactive protein45 and proinflammatory
cytokines, such as IL-6, IL-1β, and TNF-α.46,47 In addition,
circulating levels of CXCR3 (C-X-C chemokine receptor
type 3) chemokines, which induce T-cell tissue homing, have
been reported to be elevated in hypertensive patients.48 On the
other hand, inverse correlations have been reported between
regulatory T-cell and C-reactive protein levels in hypertensive
patients.49
 552  Hypertension  September 2018
Recent findings in patients and rats with HFpEF support
that systemic inflammation induces oxidative stress in the
coronary microvascular endothelium that results in reduced
myocardial NO availability, leading to reduced protein kinase
G in cardiomyocytes, which, therefore, become stiff and
hypertrophied.50 A high cardiomyocyte stiffness has been
related to a diminished distensibility of the giant cytoskeletal
protein titin, whose elastic properties are dynamically modu-
lated by isoform shifts, phosphorylation, and oxidation.51 Of
interest, it has been reported that hypertensive patients with
HFpEF have markedly increased passive myocardial stiffness
because of increases in the contribution of both titin and col-
lagen (Figure 3).12
Fibrosis
Myocardial fibrosis, secondary to the diffuse accumulation
of collagen type I and type III fibers within the interstitium
and surrounding intramural coronary arteries and arterioles,
is one of the key features of hypertensive MR.52 The excess
of collagen relative to the mass of cardiomyocytes within the
myocardium in HHD is suggested to be the result of a process
with several consecutive steps:53 (1) the differentiation of resi-
dent fibroblasts and other cell types into myofibroblasts; (2)
an increased synthesis and secretion of procollagen, procol-
lagen processing enzymes, and profibrotic growth factors and
cytokines by myofibroblasts; (3) an increased extracellular
conversion of procollagen into microfibril-forming collagen
by the action of specific proteinases; (4) an increased spon-
taneous microfibril assembly to form fibrils; (5) an enhanced
Downloaded from http://ahajournals.org by on September 8, 2021
cross-linking of fibrils to form fibers through chemical reac-
tions catalyzed by lysyl oxidases and other enzymes; and (6)
an unchanged or decreased fiber degradation by matrix metal-
loproteinases and other enzymes. This process can be trig-
gered either to replace small foci of dead cardiomyocytes or as
a reaction to a diversity of mechanical (eg, stretch), humoral
(eg, aldosterone), and chemical (eg, advanced glycation end
Figure 3.  Collagen-dependent and titin-dependent myocardial stress at a
sarcomere length (SL) of 2.6 μm for referent control patients (green bars),
patients with hypertension but without heart failure (HF; orange bars), and
patients with hypertension and HF with preserved ejection fraction (red
bars). Total stress is the numeric sum of collagen- and titin-specific data.
LV indicates left ventricular. *P<0.01 vs referent control patients, †P<0.01
vs patients with hypertension but without HF. Adapted from Zile et al12 with
permission. Copyright © 2015, American Heart Association, Inc.
products and reactive oxygen species) stimuli acting on any
of these steps.
Fibrosis may contribute to the pathophysiological changes
of HHD through diverse pathways. First, a linkage between
fibrosis and LV dysfunction may be established.54 Initially, the
accumulation of collagen fibers compromises the rate of relax-
ation, diastolic suction, and passive stiffness, thereby contrib-
uting to impaired diastolic function. Continued accumulation
of collagen fibers, accompanied by changes in their spatial
orientation, further impairs diastolic filling. In particular, an
association of myocardial fibrosis with LV stiffness has been
described in patients with HHD without HF55 and in patients
with HFpEF (mostly hypertensives)56 and also that collagen
contributes to increased myocardial passive stiffness in these
patients.12 Additionally, these changes compromise cardio-
myocyte contraction and myocardial force development,
thus impairing systolic performance. Of interest, it has been
reported that acute chamber stiffening is the main mechanism
responsible for rising late-diastolic pressures when patients
with HFpEF undergo hypertension transients.57 This stiffening
is related to impaired dynamic systolic-diastolic interactions
and correlates with the quantity and degree of cross-linking
of collagen deposits. Second, perivascular fibrosis may con-
tribute to impaired coronary flow reserve (CFR) through
the external compression of intramural coronary arteries.58
Because the amount of perivascular collagen has been cor-
related inversely with CFR in hypertensive animals59 and
patients60 with LVH. Third, interstitial fibrosis may also con-
tribute to ventricular arrhythmias in hypertension.61 Patients
with HHD and arrhythmias exhibit higher values of myocar-
dial collagen than patients without arrhythmias, despite the
finding that ejection fraction and the frequency of coronary
vessels with significant stenosis may be similar in the 2 groups
of patients. Fibrosis induces conduction abnormalities thereby
promoting local reentry arrhythmias. Additionally, the myofi-
broblasts may alter the electric activity of the cardiomyocyte
through either direct intercellular interactions or secretion of
paracrine factors.62
Of interest, myocardial fibrosis may also adversely influ-
ence the clinical outcome in patients with HHD, namely in
those with HF. For instance, it has been shown that whereas
increased collagen type I cross-linking is associated per se
with HF hospitalization in patients with HHD and HF,63 the
coincidence of increased collagen type I cross-linking with
extensive collagen type I deposition is associated with HF
hospitalization and cardiovascular and all-cause death.64
Alterations of the Coronary Microvasculature
Together with alterations in the coronary macrocirculation
(eg, obstructive disease of the epicardial coronary arteries),
several structural alterations develop in the coronary micro-
vasculature (ie, prearterioles 100–500 μm in diameter and
arterioles <100 μm in diameter that make up the coronary
microcirculation, capillaries, and venules) as part of MR. In
combination with reduced diastolic myocardial perfusion
pressure because of increased arterial stiffness, they render
the hypertensive heart an ischemic organ.65.66 On one hand,
hyperplasia or hypertrophy and altered vascular smooth
muscle cellular alignment may promote encroachment of the
 González et al   Myocardial Remodeling in Hypertension   553
tunica media into the lumen, thereby causing both increased
medial thickness/lumen ratio or reduced maximal cross-sec-
tional area of prearterioles and arterioles. On the other hand,
vascular density in LVH becomes relatively decreased. This
seems to result from capillary rarefaction or inadequate vas-
cular growth in response to the increasing muscle mass. These
alterations may depend, in part, on the abnormal transmission
of highly pulsatile blood pressure into microvascular net-
works, especially in highly perfused organs with low vascular
resistance, such as the heart. Additionally, alterations in peri-
cytes (ie, smooth muscle-like cells of mesenchymal origin that
surround capillary endothelial cells) may be involved in the
paucity of microvessels in HHD as it has been demonstrated
in other cardiac diseases.67 Finally, deposition of fibrotic tissue
around prearterioles and arterioles (ie, perivascular fibrosis)
increases oxygen diffusion distance leading to impairment of
oxygen supply to cardiomyocytes.68
These structural alterations, namely those of the coro-
nary microcirculation, together with endothelial dysfunc-
tion,69 contribute to reduction of CFR in patients with HHD.70
Interestingly, associations between decreased CFR and LV
systolic and diastolic dysfunction71,72 and mortality73 have been
found in patients with HHD (Figure 4). In addition, it has been
proposed that the combination of microvascular ischemia and
myocardial fibrosis may be involved in the facilitation of ven-
tricular tachyarrythmias and sudden cardiac death in patients
with HHD.74,75 Of interest, it has been recently reported that
the proportion of sudden cardiac deaths attributable to HHD
in the absence of coronary artery disease has increased during
Downloaded from http://ahajournals.org by on September 8, 2021
the last years.76
Diagnosis and Treatment of MR in HHD
As MR negatively influences the clinical evolution of
patients with HHD, integrating its assessment into the eval-
uation and management of these patients may be warranted.
Therefore, it has been proposed that beyond the current
clinical protocols based on detecting LVH and LV dysfunc-
tion and LVH regression,77 the time has come for additional
strategies, aimed at both the noninvasive biochemical or
imaging diagnosis78,79 and therapeutic repair80,81 of hyper-
tensive MR, to be considered.
Figure 4.  Survival curves of hypertensive patients with heart failure
classified according to coronary flow reserve (CFR) threshold values
recorded in healthy controls. Adapted from Pereira et al73 with permission.
Copyright © 2010, American Society of Hypertension.
Phenotyping MR
Whereas cardiovascular magnetic resonance (CMR) is the
gold standard for the diagnosis of LVH, echocardiography is
the most frequently used in clinical practice because of its low
cost and availability. However, a recent analysis of 39 studies
focusing on LVH in hypertension reveals that LVH was vari-
ably defined according to as many as 19 different echocardio-
graphic criteria,82 thus making the assessment of this entity
highly imprecise and, more importantly, limiting the possibil-
ity to discriminate phenotypes truly representative of the diver-
sity of mechanistic pathways and alterations underlying HHD.
As regards the phenotyping of MR, although the endo-
myocardial biopsy is relatively safe and might serve to this
purpose taking advantage of the use of both histopathologic
and molecular methodologies,83 alternative noninvasive meth-
ods are needed for routine practice. In this regard, it is desir-
able that circulating or imaging biomarkers of MR are useful
for classifying and staging HHD (Table 1).
Circulating Biomarkers
The investigation of circulating biomarkers for MR detectable
in blood by immunochemical methods has been accelerating
at a remarkable pace. These investigations have deluged the
clinical and research communities with numerous candidates,
few of which are, however, likely to survive as useful clinical
tools in terms of diagnosis, prognosis, and therapy monitor-
ing. One possible explanation for this failure is that most of
the proposed biomarkers lack proof that they actually reflect
the structural, functional, or molecular alterations associated
with MR in patients with HHD. As shown in Table 1, several
circulating parameters have been proposed as biomarkers of
MR in HHD. However, a strong evidence of association with
MR alterations has not been demonstrated for all of them.
The clinical usefulness of circulating biomarkers of HHD
can be inferred from considering some examples. Recent find-
ings demonstrate that the presence of echocardiographic LVH
in conjunction with elevated circulating biomarkers for cardio-
myocyte injury/stress (high‐sensitivity cardiac troponin T and
amino-terminal pro‐B‐type natriuretic peptide) can identify a
malignant phenotype of LVH more likely to progress to LV
dysfunction, HF with reduced ejection fraction, or cardiovas-
cular death.84–86 In another study, it was found that the combi-
nation of 2 circulating biomarkers associated with a phenotype
of complex myocardial fibrosis characterized by both high
collagen type I deposition (ie, high serum PICP [C-terminal
propeptide of procollagen type I] levels)87,88 and high collagen
type I cross-linking (ie, low serum CITP [C-terminal telopep-
tide of collagen type I]:MMP-1 [matrix metalloproteinase-1
ratio])63 identifies a subgroup of ≈30% of patients with HHD
and HF with higher independent risk of HF hospitalization
and cardiovascular mortality than the remaining patients.64
Therefore, the combination of circulating biomarkers–based
phenotyping of HHD defines subpopulations of patients who
may benefit from enhanced surveillance and intervention to
prevent progression of the disease.
Imaging Biomarkers
CMR is currently the imaging method of choice to assess myo-
cardial fibrosis (Table 1). In fact, CMR-assessed myocardial
extracellular volume fraction (ECV) quantifies the interstitial
 554  Hypertension  September 2018

Table 1.  Proposed Biomarkers for the Phenotyping of Myocardial Remodeling

Cardiomyocyte Alterations Interstitial Alterations Microvascular Alterations

Injury Endothelial Activation Coronary Flow
Type of Biomarker Hypertrophy Death Inflammation Fibrosis Dysfunction Dysregulation
Circulating CT-1 hs-TnT Gal-3 PICP VCAM-1
Annexin A5 sST-2 PIIINP P-selectin
CRP CITP:MMP-1 E-selectin
IL-6 Gal-3
GDF-15 sST-2
Imaging LV mass: 99 m Tc-annexin A5 VEGF receptors ECV (assessed by αvβ3 integrins Coronary flow reserve
(1.05×[1−ECV]) (assessed by SPECT) (assessed by PET) CMR) (assessed by PET and
(assessed by CMR) SPECT)
LV mass: (1.05×ECV)
(assessed by CMR)
Late gadolinium
enhancement
(assessed by CMR)
Backscatter amplitude
(assessed by
ultrasound)
Perfusable tissue index
(assessed by PET)
See references for each proposed biomarker in Table S1 in the online-only Data Supplement. CITP indicates carboxy-terminal telopeptide of collagen type I; CMR,
cardiac magnetic resonance; CRP, C-reactive protein; CT-1, cardiotrophin-1; ECV, extracellular volume; Gal-3, galectin-3; GDF-15, growth/differentiation factor 15;
hs-TnT, high-sensitivity troponin T; IL, interleukin; LV, left ventricular; MMP-1, matrix metalloproteinase-1; PET, positron emission tomography; PICP, carboxy-terminal
propeptide of procollagen type I; PIIINP, amino-terminal propeptide of procollagen type III; SPECT, single photon emission computed tomography; sST-2, soluble
suppressor of tumorigenicity-2; VCAM-1, vascular cell adhesion molecule-1; and VEGF, vascular endothelial growth factor.
Downloaded from http://ahajournals.org by on September 8, 2021

space, and if there is no myocardial edema or amyloidosis,
then ECV is an adequate measurement of diffuse myocardial
fibrosis.89 CMR-quantified myocardial ECV has been shown
to be increased in hypertension and associated with LVH and
dysfunction.90 But beyond the assessment of myocardial fibro-
sis, recent advances suggest that CMR may have a role in a
more global assessment of MR. As proposed by Treibel et al,91
using T1 mapping CMR can split LV mass into cellular and
ECM components by measuring ECV and then calculating the
cell volume as LV mass 1.05×(1−ECV) and the ECM volume
as LV mass 1.05×ECV (1.05 being the specific gravity of the
myocardium). With this approach, the authors demonstrated
that cell and ECM volumes increase proportionally in physi-
ological and pathological LVH, but the ratio of proportional
increase differs depending on the pathogenesis of the LVH.
Because no patients with hypertensive LVH were included in
this study, further studies are required to histopathologically
validate the method and ascertain its usefulness in phenotyp-
ing MR in HHD. Furthermore, it can be anticipated that the
combination of these measurements with circulating biomark-
ers of cardiomyocyte hypertrophy and myocardial fibrosis
would enhance the sensitivity for phenotyping the diversity of
MR patterns in HHD.
Currently, no technique allows for the direct visualization
of the coronary microvasculature in vivo in humans. Coronary
microcirculation function can be indirectly assessed using
several techniques that enable the measurement of param-
eters that are strongly dependent on the functional integrity
of the coronary microcirculation (eg, the ratio of hyperemic
to baseline coronary blood flow or CFR in response to vari-
ous vasoactive stimuli).69,92 CFR is an integrated measure of
flow through both the large epicardial arteries and the coro-
nary microcirculation. In the absence of obstructive steno-
sis of the epicardial arteries, reduced CFR is a biomarker of
coronary microvascular dysfunction, but because obstructive
disease of the epicardial arteries and coronary microvascu-
lar dysfunction often coexist in the hypertensive patient,65,66
discrimination of these 2 conditions on CFR is challenging.
Targeting MR
Recent findings show that regression of electrocardiographic93
and echocardiographic94 LVH is associated with lower inci-
dence of cardiovascular morbidity and mortality in patients
with HHD independently of blood pressure reduction.
However, the residual risk is still unacceptably high. In addi-
tion, the reduction in LV mass is not always achieved, and even
de novo LVH may develop in treated patients, despite a good
control of blood pressure.95 Additionally, although in small
and short-duration clinical studies, some conventional thera-
pies, such as renin-angiotensin-aldosterone system inhibitors,
reduce MR in patients with HHD,96,97 the alterations persist,
indicating a need to develop novel and effective anti-MR thera-
peutic strategies. In this conceptual framework, 2 approaches
are proposed: one relies on the biomarker-oriented use of drugs
currently used to treat hypertension that have proven ability to
repair MR, and another strategy is based on the development
of new pharmacological agents capable of targeting the mecha-
nisms underlying the alterations constitutive of MR.
 González et al   Myocardial Remodeling in Hypertension   555

Biomarker-Oriented Therapy Table 2.  Proposed Novel Strategies With Antiremodeling Therapeutic Potential
The use of panels combining circulating and imaging bio- Proposed Aims Molecular Targets Candidate Agents
markers of MR in translational research studies may integrate
At the cardiomyocyte level
diverse levels of information, overcome methodological limi-
tations, and contribute to a precise phenotyping of patients,   Prevent injury and death Drp1 Mdivi-1
with a view to personalizing HHD therapy. From this perspec- Cardiolipin MTP, SS-31
tive, and as an example, it can be hypothesized that patients
  Prevent hypertrophy Socs1 Anti-miR 155
presenting with the biomarker-based phenotype of complex
myocardial fibrosis, characterized by the combination of low CXCL1 Antibody
serum CITP:MMP-1 ratio (an index of increased myocardial CXCR2 SB265610
collagen type I cross-linking) and high serum PICP (an index   Preserve function Cardiolipin MTP
of increased myocardial collagen type I deposition), should be
At the interstitial level
treated with therapies with proven capacity to correct or atten-
uate both alterations of extracellular collagen processing and   Inhibit inflammation Rho-kinase Fasudil
consequently to reduce LV stiffness and improve LV function. P38 MAPK FR167653
In this context, recent data show that patients with HFpEF,
Socs1 Anti-miR 155
because of HHD among other etiologies, with a high degree of
collagen cross-linking (ie, low CITP:MMP-1) escape the ben- α7nAChR PNU282987
eficial effects of spironolactone, which is not able to reduce TLR2 Antibody
collagen type I deposition (ie, PICP levels) and to improve CXCL1 Antibody
diastolic function in this subgroup of patients.98 Interestingly,
CXCR2 SB265610
in a small pilot study, it has been shown that chronic treatment
with torasemide is able to reduce collagen cross-linking and   Reverse fibrosis Rho-kinase Fasudil
myocardial fibrosis in patients with HF with HHD.99 P38 MAPK FR167653

New Antiremodeling Strategies CXCL1 Antibody

During the last years, several new molecular targets and drugs CXCR2 SB265610
have been developed with therapeutic potential on MR act-
TLR2 Antibody
ing at 3 levels80,81: preventing cardiomyocyte hypertrophy and
TGF-β1 Receptor
Downloaded from http://ahajournals.org by on September 8, 2021

death to preserve its function, reversing interstitial alterations

antagonists
to reduce stiffness, and boosting angiogenesis to increase
oxygen and nutrition supply (Table 2). The selection of the PCP/PCPE Torasemide
candidates should be oriented to target common mechanisms LOX Torasemide,
affecting simultaneously multiple pathways involved in MR. EXP3179
As an example, novel, growing evidence identifies new poten- ADAM-17 A9B8 antibody
tial targets within the immune system for therapeutic interven-
miR Let-7i miR mimic
tions (eg, promoting immunosuppressive T-regulatory activity
and reducing proinflammatory T effector lymphocytes or miR-133a miR mimic
the products or targets thereof) that could contribute to limit LOXL2 Antibody
hypertensive MR in terms of avoiding cardiomyocyte hyper- Lnc Wisper ASO
trophy,100 suppressing myocardial inflammation101 and fibro-
sis,102 and protecting coronary microcirculation.103 At the microvascular level
Although many emerging therapies targeting MR are   Stimulate angiogenesis AMPKα2/VEGF Anti-miR-195a-3p
promising in preclinical models, many clinical trials of novel CD151 Anti-miR-124
antiremodeling drugs have failed. Therefore, it is important
  Restore endothelial function Cardiolipin MTP
to rationalize drug discovery by using meaningful in vivo and
in vitro models to discard irrelevant molecules in terms of PDE5 Sildenafil
efficacy and pharmacokinetic and toxicological profiles at an   Reverse vascular remodeling ADAM-17 A9B8 antibody
early stage. In this regard, an algorithm for selection of new See references for each molecular target and candidate agent in Table S2.
antifibrotic agents to be further tested as potential therapeutic α7nAChR indicates α7 nicotinic acetylcholine receptor; ADAM, disintegrin
targets has recently been proposed.104 and metalloproteinase; AMPK, AMP-activated protein kinase; ASO, antisense
oligonucleotides; CD151, Cluster of Differentiation 151; CXCL1, chemokine
Conclusions and Perspectives (C-X-C motif) ligand 1; CXCR2, chemokine (C-X-C motif) receptor 2; Drp1,
dynamin-related protein-1; Lnc, long noncoding; LOX, lysyl oxidase; LOXL2, lysyl
The alterations that develop in the myocardium of the oxidase-like 2; MAPK, p38 mitogen-activated protein kinase; Mdivi-1, chemical
hypertensive LV leading to its remodeling provide struc- compound mitochondrial division inhibitor-1; MTP, mitochondrial-targeted
tural and functional support for the alterations of cardiac peptide; PCP, procollagen type I carboxy-terminal proteinase; PCPE, procollagen
function and electric activity that adversely influence the type I carboxy-terminal proteinase enhancer; PDE5, phosphodiesterase type 5;
clinical evolution of patients with HHD. Therefore, a major Socs1, suppressor of cytokine signaling 1; TGF-β, transforming growth factor-β;
unmet need in HHD management is the ability to identify TLR2, toll-like receptor 2; and VEGF, vascular endothelial growth factor.
 556  Hypertension  September 2018
homogeneous subsets of patients whose underlying myo-
cardial lesions are driven by specific mechanisms that can
be solely targeted using personalized treatment. From this
perspective, the noninvasive detection and effective repair
of MR must be considered as part of the overall clinical
care in patients with HHD. In doing so, adverse outcomes
associated with this cardiac disease could be prevented
more effectively. Clearly, further research is needed both in
the experimental and clinical settings to reach these aims.
Sources of Funding
This study was supported by the Ministry of Economy and
Competitiveness, Spain (Instituto de Salud Carlos III grants
CB16/11/00483 and PI15/01909 cofinanced by FEDER [Fondo
Europeo de DEsarrollo Regional] funds), the European Commission
FP7 Programme (HOMAGE [Heart Omics in Ageing] project 2012–
305507), the European Research Area Network on Cardiovascular
Diseases Joint Transnational Call 2016 LYMIT-DIS (Targeted
Lymphatic and Microvessel Treatment in Metabolic Disease HFpEF;
AC16/00020), and LIPCAR-HF (Long Intergenei Noncoding RNA
Predicting Cardiac Remodeling; AC16/00016).
Disclosures
None.
References
1. Lawes CM, Vander Hoorn S, Rodgers A; International Society of
Hypertension. Global burden of blood-pressure-related disease, 2001.
Lancet. 2008;371:1513–1518. doi: 10.1016/S0140-6736(08)60655-8.
2. Forouzanfar MH, Liu P, Roth GA, et al. Global burden of hypertension
and systolic blood pressure of at least 110 to 115 mm Hg, 1990-2015.
JAMA. 2017;317:165–182. doi: 10.1001/jama.2016.19043.
Downloaded from http://ahajournals.org by on September 8, 2021
3. Frohlich ED, Apstein C, Chobanian AV, Devereux RB, Dustan HP, Dzau
V, Fauad-Tarazi F, Horan MJ, Marcus M, Massie B, Pfeffer MA, Re RN,
Roccella EJ, Savage D, Shub C. The heart in hypertension. N Engl J Med.
1992;327:998–1008.
4. Izzo JL Jr, Gradman AH. Mechanisms and management of hypertensive
heart disease: from left ventricular hypertrophy to heart failure. Med Clin
North Am. 2004;88:1257–1271. doi: 10.1016/j.mcna.2004.06.002.
5. Lazzeroni D, Rimoldi O, Camici PG. From left ventricular hyper-
trophy to dysfunction and failure. Circ J. 2016;80:555–564. doi:
10.1253/circj.CJ-16-0062.
6. Drazner MH. The progression of hypertensive heart disease. Circulation.
2011;123:327–334. doi: 10.1161/CIRCULATIONAHA.108.845792.
7. Díez J, González A, López B, Querejeta R. Mechanisms of disease: patho-
logic structural remodeling is more than adaptive hypertrophy in hyper-
tensive heart disease. Nat Clin Pract Cardiovasc Med. 2005;2:209–216.
doi: 10.1038/ncpcardio0158.
8. Shimizu I, Minamino T. Physiological and pathological car-
diac hypertrophy. J Mol Cell Cardiol. 2016;97:245–262. doi:
10.1016/j.yjmcc.2016.06.001.
9. Swynghedauw B. Molecular mechanisms of myocardial remodeling.
Physiol Rev. 1999;79:215–262. doi: 10.1152/physrev.1999.79.1.215.
10. Knöll R, Iaccarino G, Tarone G, Hilfiker-Kleiner D, Bauersachs J, Leite-
Moreira AF, Sugden PH, Balligand JL; European Society of Cardiology.
Towards a re-definition of ‘cardiac hypertrophy’ through a rational charac-
terization of left ventricular phenotypes: a position paper of the Working
Group ‘Myocardial Function’ of the ESC. Eur J Heart Fail. 2011;13:811–
819. doi: 10.1093/eurjhf/hfr071.
11. Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. J Mol
Med (Berl). 1998;76:725–746.
12. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw
AD, Slater R, Palmer BM, Van Buren P, Meyer M, Redfield MM,
Bull DA, Granzier HL, LeWinter MM. Myocardial stiffness in
patients with heart failure and a preserved ejection fraction: contribu-
tions of collagen and titin. Circulation. 2015;131:1247–1259. doi:
10.1161/CIRCULATIONAHA.114.013215.
13. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S,
Sugden PH. Signaling pathways mediating cardiac myocyte gene expres-
sion in physiological and stress responses. J Cell Physiol. 2007;212:311–
322. doi: 10.1002/jcp.21094.
14. Scheuer J. Catecholamines in cardiac hypertrophy. Am J Cardiol.
1999;83:70H–74H.
15. Lijnen P, Petrov V. Renin-angiotensin system, hypertrophy and gene
expression in cardiac myocytes. J Mol Cell Cardiol. 1999;31:949–970.
doi: 10.1006/jmcc.1999.0934.
16. Kamo T, Akazawa H, Komuro I. Cardiac nonmyocytes in the
hub of cardiac hypertrophy. Circ Res. 2015;117:89–98. doi:
10.1161/CIRCRESAHA.117.305349.
17. Kuwahara K, Kinoshita H, Kuwabara Y, Nakagawa Y, Usami S, Minami T,
Yamada Y, Fujiwara M, Nakao K. Myocardin-related transcription factor
A is a common mediator of mechanical stress- and neurohumoral stimula-
tion-induced cardiac hypertrophic signaling leading to activation of brain
natriuretic peptide gene expression. Mol Cell Biol. 2010;30:4134–4148.
doi: 10.1128/MCB.00154-10.
18. Kong SW, Bodyak N, Yue P, Liu Z, Brown J, Izumo S, Kang PM. Genetic
expression profiles during physiological and pathological cardiac hyper-
trophy and heart failure in rats. Physiol Genomics. 2005;21:34–42. doi:
10.1152/physiolgenomics.00226.2004.
19. Facundo HDTF, Brainard RE, Caldas FRL, Lucas AMB. Mitochondria
and cardiac hypertrophy. Adv Exp Med Biol. 2017;982:203–226. doi:
10.1007/978-3-319-55330-6_11.
20. Tuomainen T, Tavi P. The role of cardiac energy metabolism in car-
diac hypertrophy and failure. Exp Cell Res. 2017;360:12–18. doi:
10.1016/j.yexcr.2017.03.052.
21. Neubauer S. The failing heart–an engine out of fuel. N Engl J Med.
2007;356:1140–1151. doi: 10.1056/NEJMra063052.
22. Dickhout JG, Carlisle RE, Austin RC. Interrelationship between cardiac
hypertrophy, heart failure, and chronic kidney disease: endoplasmic retic-
ulum stress as a mediator of pathogenesis. Circ Res. 2011;108:629–642.
doi: 10.1161/CIRCRESAHA.110.226803.
23. Sun Y, Liu G, Song T, Liu F, Kang W, Zhang Y, Ge Z. Upregulation
of GRP78 and caspase-12 in diastolic failing heart. Acta Biochim Pol.
2008;55:511–516.
24. González A, Ravassa S, Loperena I, López B, Beaumont J, Querejeta R,
Larman M, Díez J. Association of depressed cardiac gp130-mediated anti-
apoptotic pathways with stimulated cardiomyocyte apoptosis in hyperten-
sive patients with heart failure. J Hypertens. 2007;25:2148–2157. doi:
10.1097/HJH.0b013e32828626e2.
25. Ravassa S, González A, López B, Beaumont J, Querejeta R, Larman M,
Díez J. Upregulation of myocardial Annexin A5 in hypertensive heart dis-
ease: association with systolic dysfunction. Eur Heart J. 2007;28:2785–
2791. doi: 10.1093/eurheartj/ehm370.
26. Li Z, Bing OH, Long X, Robinson KG, Lakatta EG. Increased cardio-
myocyte apoptosis during the transition to heart failure in the spontane-
ously hypertensive rat. Am J Physiol. 1997;272(5 pt 2):H2313–H2319.
doi: 10.1152/ajpheart.1997.272.5.H2313.
27. Narula J, Arbustini E, Chandrashekhar Y, Schwaiger M. Apoptosis and the
systolic dysfunction in congestive heart failure. Story of apoptosis inter-
ruptus and zombie myocytes. Cardiol Clin. 2001;19:113–126.
28. Chandrashekhar Y. Role of apoptosis in ventricular remodeling. Curr
Heart Fail Rep. 2005;2:18–22.
29. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogen-
esis of heart disease: mechanisms and significance. Annu Rev Physiol.
2010;72:19–44. doi: 10.1146/annurev.physiol.010908.163111.
30. Wang ZV, Rothermel BA, Hill JA. Autophagy in hypertensive heart dis-
ease. J Biol Chem. 2010;285:8509–8514. doi: 10.1074/jbc.R109.025023.
31. Kvakan H, Luft FC, Muller DN. Role of the immune system in hyperten-
sive target organ damage. Trends Cardiovasc Med. 2009;19:242–246. doi:
10.1016/j.tcm.2010.02.004.
32. McMaster WG, Kirabo A, Madhur MS, Harrison DG. Inflammation,
immunity, and hypertensive end-organ damage. Circ Res. 2015;116:1022–
1033. doi: 10.1161/CIRCRESAHA.116.303697.
33. Altara R, Mallat Z, Booz GW, Zouein FA. The CXCL10/CXCR3 axis
and cardiac inflammation: implications for immunotherapy to treat
infectious and noninfectious diseases of the heart. J Immunol Res.
2016;2016:4396368. doi: 10.1155/2016/4396368.
34. Behr TM, Willette RN, Coatney RW, Berova M, Angermann CE, Anderson
K, Sackner-Bernstein JD, Barone FC. Eprosartan improves cardiac per-
formance, reduces cardiac hypertrophy and mortality and downregulates
myocardial monocyte chemoattractant protein-1 and inflammation in
hypertensive heart disease. J Hypertens. 2004;22:583–592.
35. Yoshida K, Kim-Mitsuyama S, Wake R, Izumiya Y, Izumi Y, Yukimura
T, Ueda M, Yoshiyama M, Iwao H. Excess aldosterone under normal
salt diet induces cardiac hypertrophy and infiltration via oxidative stress.
Hypertens Res. 2005;28:447–455. doi: 10.1291/hypres.28.447.
 González et al   Myocardial Remodeling in Hypertension   557
36. Ogata T, Miyauchi T, Sakai S, Takanashi M, Irukayama-Tomobe Y,
Yamaguchi I. Myocardial fibrosis and diastolic dysfunction in deoxycor-
ticosterone acetate-salt hypertensive rats is ameliorated by the peroxi-
some proliferator-activated receptor-alpha activator fenofibrate, partly
by suppressing inflammatory responses associated with the nuclear
factor-kappa-B pathway. J Am Coll Cardiol. 2004;43:1481–1488. doi:
10.1016/j.jacc.2003.11.043.
37. Levick SP, Murray DB, Janicki JS, Brower GL. Sympathetic ner-
vous system modulation of inflammation and remodeling in
the hypertensive heart. Hypertension. 2010;55:270–276. doi:
10.1161/HYPERTENSIONAHA.109.142042.
38. Deckx S, Heggermont W, Carai P, Rienks M, Dresselaers T, Himmelreich
U, van Leeuwen R, Lommen W, van der Velden J, Gonzalez A, Diez J,
Papageorgiou AP, Heymans S. Osteoglycin prevents the development of
age-related diastolic dysfunction during pressure overload by reducing
cardiac fibrosis and inflammation. Matrix Biol. 2018;66:110–124. doi:
10.1016/j.matbio.2017.09.002.
39. Ghigo A, Franco I, Morello F, Hirsch E. Myocyte signalling in leuco-
cyte recruitment to the heart. Cardiovasc Res. 2014;102:270–280. doi:
10.1093/cvr/cvu030.
40. Shinde AV, Frangogiannis NG. Mechanisms of fibroblast activation in
the remodeling myocardium. Curr Pathobiol Rep. 2017;5:145–152. doi:
10.1007/s40139-017-0132-z.
41. Kuwahara F, Kai H, Tokuda K, Takeya M, Takeshita A, Egashira K,
Imaizumi T. Hypertensive myocardial fibrosis and diastolic dysfunction:
another model of inflammation? Hypertension. 2004;43:739–745. doi:
10.1161/01.HYP.0000118584.33350.7d.
42. Kai H, Kuwahara F, Tokuda K, Imaizumi T. Diastolic dysfunction in hyper-
tensive hearts: roles of perivascular inflammation and reactive myocardial
fibrosis. Hypertens Res. 2005;28:483–490. doi: 10.1291/hypres.28.483.
43. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher
F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W,
Schultheiss HP, Tschöpe C. Cardiac inflammation contributes to
changes in the extracellular matrix in patients with heart failure
and normal ejection fraction. Circ Heart Fail. 2011;4:44–52. doi:
10.1161/CIRCHEARTFAILURE.109.931451.
44. Idris-Khodja N, Mian MO, Paradis P, Schiffrin EL. Dual opposing roles
Downloaded from http://ahajournals.org by on September 8, 2021
of adaptive immunity in hypertension. Eur Heart J. 2014;35:1238–1244.
doi: 10.1093/eurheartj/ehu119.
45. Blake GJ, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive pro-
tein, and risk of future cardiovascular events. Circulation. 2003;108:2993–
2999. doi: 10.1161/01.CIR.0000104566.10178.AF.
46. Bautista LE, Vera LM, Arenas IA, Gamarra G. Independent association
between inflammatory markers (C-reactive protein, interleukin-6, and
TNF-alpha) and essential hypertension. J Hum Hypertens. 2005;19:149–
154. doi: 10.1038/sj.jhh.1001785.
47. Dalekos GN, Elisaf M, Bairaktari E, Tsolas O, Siamopoulos KC.
Increased serum levels of interleukin-1beta in the systemic circulation of
patients with essential hypertension: additional risk factor for atherogen-
esis in hypertensive patients? J Lab Clin Med. 1997;129:300–308.
48. Youn JC, Yu HT, Lim BJ, Koh MJ, Lee J, Chang DY, Choi YS, Lee
SH, Kang SM, Jang Y, Yoo OJ, Shin EC, Park S. Immunosenescent
CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are
increased in human hypertension. Hypertension. 2013;62:126–133. doi:
10.1161/HYPERTENSIONAHA.113.00689.
49. De Ciuceis C, Agabiti-Rosei C, Rossini C, et al. Relationship between
different subpopulations of circulating CD4+ T lymphocytes and
microvascular or systemic oxidative stress in humans. Blood Press.
2017;26:237–245. doi: 10.1080/08037051.2017.1292395.
50. Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschöpe
C, Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ,
Hamdani N. Myocardial microvascular inflammatory endothelial activa-
tion in heart failure with preserved ejection fraction. JACC Heart Fail.
2016;4:312–324. doi: 10.1016/j.jchf.2015.10.007.
51. Linke WA, Hamdani N. Gigantic business: titin properties and func-
tion through thick and thin. Circ Res. 2014;114:1052–1068. doi:
10.1161/CIRCRESAHA.114.301286.
52. Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart
disease. J Clin Invest. 2007;117:568–575. doi: 10.1172/JCI31044.
53. González A, Schelbert EB, Díez J, Butler J. Myocardial interstitial fibro-
sis in heart failure: biological and translational perspectives. J Am Coll
Cardiol. 2018;71:1696–1706. doi: 10.1016/j.jacc.2018.02.021.
54. Brower GL, Gardner JD, Forman MF, Murray DB, Voloshenyuk T,
Levick SP, Janicki JS. The relationship between myocardial extracellu-
lar matrix remodeling and ventricular function. Eur J Cardiothorac Surg.
2006;30:604–610. doi: 10.1016/j.ejcts.2006.07.006.
55. Díez J, Querejeta R, López B, González A, Larman M, Martínez Ubago
JL. Losartan-dependent regression of myocardial fibrosis is associ-
ated with reduction of left ventricular chamber stiffness in hypertensive
patients. Circulation. 2002;105:2512–2517.
56. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kühl U,
Schultheiss HP, Tschöpe C. Diastolic tissue Doppler indexes correlate
with the degree of collagen expression and cross-linking in heart failure
and normal ejection fraction. J Am Coll Cardiol. 2011;57:977–985. doi:
10.1016/j.jacc.2010.10.024.
57. Pérez Del Villar C, Savvatis K, López B, Kasner M, Martinez-Legazpi P,
Yotti R, González A, Díez J, Fernández-Avilés F, Tschöpe C, Bermejo J.
Impact of acute hypertension transients on diastolic function in patients
with heart failure with preserved ejection fraction. Cardiovasc Res.
2017;113:906–914. doi: 10.1093/cvr/cvx047.
58. Schwartzkopff B, Motz W, Frenzel H, Vogt M, Knauer S, Strauer BE.
Structural and functional alterations of the intramyocardial coro-
nary arterioles in patients with arterial hypertension. Circulation.
1993;88:993–1003.
59. Brilla CG, Janicki JS, Weber KT. Impaired diastolic function and coro-
nary reserve in genetic hypertension. Role of interstitial fibrosis and
medial thickening of intramyocardial coronary arteries. Circ Res.
1991;69:107–115.
60. Dai Z, Aoki T, Fukumoto Y, Shimokawa H. Coronary perivascular fibro-
sis is associated with impairment of coronary blood flow in patients
with non-ischemic heart failure. J Cardiol. 2012;60:416–421. doi:
10.1016/j.jjcc.2012.06.009.
61. McLenachan JM, Dargie HJ. Ventricular arrhythmias in hypertensive
left ventricular hypertrophy. Relationship to coronary artery disease,
left ventricular dysfunction, and myocardial fibrosis. Am J Hypertens.
1990;3:735–740.
62. Rohr S. Arrhythmogenic implications of fibroblast-myocyte inter-
actions. Circ Arrhythm Electrophysiol. 2012;5:442–452. doi:
10.1161/CIRCEP.110.957647.
63. López B, Ravassa S, González A, Zubillaga E, Bonavila C, Bergés
M, Echegaray K, Beaumont J, Moreno MU, San José G, Larman M,
Querejeta R, Díez J. Myocardial collagen cross-linking is associated with
heart failure hospitalization in patients with hypertensive heart failure. J
Am Coll Cardiol. 2016;67:251–260. doi: 10.1016/j.jacc.2015.10.063.
64. Ravassa S, López B, Querejeta R, Echegaray K, San José G, Moreno MU,
Beaumont FJ, González A, Díez J. Phenotyping of myocardial fibrosis in
hypertensive patients with heart failure. Influence on clinical outcome. J
Hypertens. 2017;35:853–861. doi: 10.1097/HJH.0000000000001258.
65. Feihl F, Liaudet L, Levy BI, Waeber B. Hypertension and micro-
vascular remodelling. Cardiovasc Res. 2008;78:274–285. doi:
10.1093/cvr/cvn022.
66. Feihl F, Liaudet L, Waeber B. The macrocirculation and microcirculation
of hypertension. Curr Hypertens Rep. 2009;11:182–189.
67. Avolio E, Madeddu P. Discovering cardiac pericyte biology: from
physiopathological mechanisms to potential therapeutic applications
in ischemic heart disease. Vascul Pharmacol. 2016;86:53–63. doi:
10.1016/j.vph.2016.05.009.
68. Frohlich ED. Fibrosis and ischemia: the real risks in hypertensive heart
disease. Am J Hypertens. 2001;14:194S–199S.
69. Treasure CB, Klein JL, Vita JA, Manoukian SV, Renwick GH, Selwyn
AP, Ganz P, Alexander RW. Hypertension and left ventricular hypertrophy
are associated with impaired endothelium-mediated relaxation in human
coronary resistance vessels. Circulation. 1993;87:86–93.
70. Kelm M, Strauer BE. Coronary flow reserve measurements in hyperten-
sion. Med Clin North Am. 2004;88:99–113.
71. Galderisi M, Cicala S, Caso P, De Simone L, D’Errico A, Petrocelli A, de
Divitiis O. Coronary flow reserve and myocardial diastolic dysfunction in
arterial hypertension. Am J Cardiol. 2002;90:860–864.
72. Ikonomidis I, Tzortzis S, Paraskevaidis I, Triantafyllidi H, Papadopoulos
C, Papadakis I, Trivilou P, Parissis J, Anastasiou-Nana M, Lekakis
J. Association of abnormal coronary microcirculatory function with
impaired response of longitudinal left ventricular function during adenos-
ine stress echocardiography in untreated hypertensive patients. Eur Heart
J Cardiovasc Imaging. 2012;13:1030–1040. doi: 10.1093/ehjci/jes071.
73. Pereira VF, de Carvalho Frimm C, Rodrigues AC, Cúri M. Coronary
reserve impairment prevents the improvement of left ventricular dysfunc-
tion and adversely affects the long-term outcome of patients with hyper-
tensive dilated cardiomyopathy. J Am Soc Hypertens. 2010;4:14–21. doi:
10.1016/j.jash.2009.12.002.
74. Zehender M, Faber T, Koscheck U, Meinertz T, Just H. Ventricular
tachyarrhythmias, myocardial ischemia, and sudden cardiac death in
patients with hypertensive heart disease. Clin Cardiol. 1995;18:377–383.
 558  Hypertension  September 2018
75. Shenasa M, Shenasa H. Hypertension, left ventricular hypertro-
phy, and sudden cardiac death. Int J Cardiol. 2017;237:60–63. doi:
10.1016/j.ijcard.2017.03.002.
76. Junttila MJ, Hookana E, Kaikkonen KS, Kortelainen ML, Myerburg RJ,
Huikuri HV. Temporal trends in the clinical and pathological characteris-
tics of victims of sudden cardiac death in the absence of previously identi-
fied heart disease. Circ Arrhythm Electrophysiol. 2016;9:e003723.
77. Schiattarella GG, Hill JA. Inhibition of hypertrophy is a good therapeutic
strategy in ventricular pressure overload. Circulation. 2015;131:1435–
1447. doi: 10.1161/CIRCULATIONAHA.115.013894.
78. González A, López B, Ravassa S, Beaumont J, Arias T, Hermida N,
Zudaire A, Díez J. Biochemical markers of myocardial remodelling
in hypertensive heart disease. Cardiovasc Res. 2009;81:509–518. doi:
10.1093/cvr/cvn235.
79. Hoey ET, Pakala V, Teoh JK, Simpson H. The role of imaging
in hypertensive heart disease. Int J Angiol. 2014;23:85–92. doi:
10.1055/s-0034-1370885.
80. Tarone G, Balligand JL, Bauersachs J, Clerk A, De Windt L, Heymans
S, Hilfiker-Kleiner D, Hirsch E, Iaccarino G, Knöll R, Leite-Moreira
AF, Lourenço AP, Mayr M, Thum T, Tocchetti CG. Targeting myocar-
dial remodelling to develop novel therapies for heart failure: a posi-
tion paper from the Working Group on Myocardial Function of the
European Society of Cardiology. Eur J Heart Fail. 2014;16:494–508.
doi: 10.1002/ejhf.62.
81. González A, Ravassa S, Beaumont J, López B, Díez J. New targets to
treat the structural remodeling of the myocardium. J Am Coll Cardiol.
2011;58:1833–1843. doi: 10.1016/j.jacc.2011.06.058.
82. Cuspidi C, Esposito A, Negri F, Sala C, Masaidi M, Giudici V, Zanchetti
A, Mancia G. Studies on left ventricular hypertrophy regression in arte-
rial hypertension: a clear message for the clinician? Am J Hypertens.
2008;21:458–463. doi: 10.1038/ajh.2007.85.
83. Chimenti C, Frustaci A. Contribution and risks of left ventricular endo-
myocardial biopsy in patients with cardiomyopathies: a retrospective
study over a 28-year period. Circulation. 2013;128:1531–1541. doi:
10.1161/CIRCULATIONAHA.13.001414.
84. Neeland IJ, Drazner MH, Berry JD, Ayers CR, deFilippi C, Seliger SL,
Nambi V, McGuire DK, Omland T, de Lemos JA. Biomarkers of chronic
Downloaded from http://ahajournals.org by on September 8, 2021
cardiac injury and hemodynamic stress identify a malignant phenotype of
left ventricular hypertrophy in the general population. J Am Coll Cardiol.
2013;61:187–195. doi: 10.1016/j.jacc.2012.10.012.
85. Seliger SL, de Lemos J, Neeland IJ, Christenson R, Gottdiener J,
Drazner MH, Berry J, Sorkin J, deFilippi C. Older adults, “Malignant”
left ventricular hypertrophy, and associated cardiac-specific bio-
marker phenotypes to identify the differential risk of new-onset
reduced versus preserved ejection fraction heart failure: CHS
(Cardiovascular Health Study). JACC Heart Fail. 2015;3:445–455. doi:
10.1016/j.jchf.2014.12.018.
86. Peters MN, Seliger SL, Christenson RH, Hong-Zohlman SN, Daniels
LB, Lima JAC, de Lemos JA, Neeland IJ, deFilippi CR. “Malignant” left
ventricular hypertrophy identifies subjects at high risk for progression
to asymptomatic left ventricular dysfunction, heart failure, and death:
MESA (Multi-Ethnic Study of Atherosclerosis). J Am Heart Assoc.
2018;7:e006619.
87. Querejeta R, López B, González A, Sánchez E, Larman M,
Martínez Ubago JL, Díez J. Increased collagen type I synthe-
sis in patients with heart failure of hypertensive origin: relation
to myocardial fibrosis. Circulation. 2004;110:1263–1268. doi:
10.1161/01.CIR.0000140973.60992.9A.
88. López B, Querejeta R, González A, Sánchez E, Larman M, Díez J. Effects
of loop diuretics on myocardial fibrosis and collagen type I turnover
in chronic heart failure. J Am Coll Cardiol. 2004;43:2028–2035. doi:
10.1016/j.jacc.2003.12.052.
89. Diao KY, Yang ZG, Xu HY, Liu X, Zhang Q, Shi K, Jiang L, Xie LJ, Wen
LY, Guo YK. Histologic validation of myocardial fibrosis measured by
T1 mapping: a systematic review and meta-analysis. J Cardiovasc Magn
Reson. 2016;18:92. doi: 10.1186/s12968-016-0313-7.
90. Wang S, Hu H, Lu M, et al. Myocardial extracellular volume fraction
quantified by cardiovascular magnetic resonance is increased in hyper-
tension and associated with left ventricular remodeling. Eur Radiol.
2017;27:4620–4630. doi: 10.1007/s00330-017-4841-9.
91. Treibel TA, Kozor R, Menacho K, Castelletti S, Bulluck H, Rosmini
S, Nordin S, Maestrini V, Fontana M, Moon JC. Left ventricu-
lar hypertrophy revisited: cell and matrix expansion have disease-
specific relationships. Circulation. 2017;136:2519–2521. doi:
10.1161/CIRCULATIONAHA.117.029895.
92. Camici PG, d’Amati G, Rimoldi O. Coronary microvascular dysfunction:
mechanisms and functional assessment. Nat Rev Cardiol. 2015;12:48–
62. doi: 10.1038/nrcardio.2014.160.
93. Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic
left ventricular hypertrophy or strain is associated with lower incidence
of cardiovascular morbidity and mortality in hypertensive patients inde-
pendent of blood pressure reduction - A LIFE review. J Electrocardiol.
2014;47:630–635. doi: 10.1016/j.jelectrocard.2014.07.003.
94. de Simone G, Devereux RB, Izzo R, Girfoglio D, Lee ET, Howard BV,
Roman MJ. Lack of reduction of left ventricular mass in treated hyper-
tension: the strong heart study. J Am Heart Assoc. 2013;2:e000144. doi:
10.1161/JAHA.113.000144.
95. Pierdomenico SD, Cuccurullo F. Risk reduction after regression of echo-
cardiographic left ventricular hypertrophy in hypertension: a meta-anal-
ysis. Am J Hypertens. 2010;23:876–881. doi: 10.1038/ajh.2010.80.
96. López B, Querejeta R, Varo N, González A, Larman M, Martínez Ubago
JL, Díez J. Usefulness of serum carboxy-terminal propeptide of procol-
lagen type I in assessment of the cardioreparative ability of antihyperten-
sive treatment in hypertensive patients. Circulation. 2001;104:286–291.
97. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myo-
cardial fibrosis in patients with hypertensive heart disease. Circulation.
2000;102:1388–1393.
98. Ravassa S, Trippel T, Bach D, Bachran D, González A, López B,
Wachter R, Hasenfuss G, Delles C, Dominiczak AF, Pieske B, Díez
J, Edelmann F. Biomarker-based phenotyping of myocardial fi-
brosis identifies patients with heart failure with preserved ejec-
tion fraction resistant to the beneficial effects of spironolactone:
results from the Aldo-DHF trial [published online April 30, 2018].
Eur J Heart Fail. doi: 10.1002/ejhf.1194. https://onlinelibrary.
wiley.com/doi/abs/10.1002/ejhf.1194.
99. López B, Querejeta R, González A, Beaumont J, Larman M, Díez J.
Impact of treatment on myocardial lysyl oxidase expression and collagen
cross-linking in patients with heart failure. Hypertension. 2009;53:236–
242. doi: 10.1161/HYPERTENSIONAHA.108.125278.
100. Fabbiano S, Menacho-Márquez M, Robles-Valero J, Pericacho M,
Matesanz-Marín A, García-Macías C, Sevilla MA, Montero MJ, Alarcón
B, López-Novoa JM, Martín P, Bustelo XR. Immunosuppression-
independent role of regulatory T cells against hypertension-driv-
en renal dysfunctions. Mol Cell Biol. 2015;35:3528–3546. doi:
10.1128/MCB.00518-15.
101. Kvakan H, Kleinewietfeld M, Qadri F, Park JK, Fischer R, Schwarz
I, Rahn HP, Plehm R, Wellner M, Elitok S, Gratze P, Dechend R,
Luft FC, Muller DN. Regulatory T cells ameliorate angiotensin II-
induced cardiac damage. Circulation. 2009;119:2904–2912. doi:
10.1161/CIRCULATIONAHA.108.832782.
102. Kanellakis P, Dinh TN, Agrotis A, Bobik A. CD4⁺CD25⁺Foxp3⁺ regu-
latory T cells suppress cardiac fibrosis in the hypertensive heart. J
Hypertens. 2011;29:1820–1828. doi: 10.1097/HJH.0b013e328349c62d.
103. Matrougui K, Abd Elmageed Z, Zakaria AE, Kassan M, Choi S, Nair
D, Gonzalez-Villalobos RA, Chentoufi AA, Kadowitz P, Belmadani S,
Partyka M. Natural regulatory T cells control coronary arteriolar endo-
thelial dysfunction in hypertensive mice. Am J Pathol. 2011;178:434–
441. doi: 10.1016/j.ajpath.2010.11.034.
104. Gyöngyösi M, Winkler J, Ramos I, Do QT, Firat H, McDonald K,
González A, Thum T, Díez J, Jaisser F, Pizard A, Zannad F. Myocardial
fibrosis: biomedical research from bench to bedside. Eur J Heart Fail.
2017;19:177–191. doi: 10.1002/ejhf.696.