Controversies in

Cardiovascular Medicine
Is Inhibition of Hypertrophy a
Good Therapeutic Strategy in
Ventricular Pressure Overload?

Inhibition of Hypertrophy Is a Good Therapeutic Strategy in

Ventricular Pressure Overload
Gabriele G. Schiattarella, MD; Joseph A. Hill, MD, PhD

H ypertrophic growth of ventricular myocytes is a hallmark

feature of numerous forms of cardiovascular disease.1
The hypertrophic process is complex, involving a vast array
of structural, signaling, transcriptional, electrophysiological,
metabolic, and functional events within the growing cell.2,3
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to increases in workload demand, serving to minimize wall
stress and maintain contractile function. However, several
lines of evidence, preclinical and epidemiological, highlight
the maladaptive features of chronic ventricular hypertro-
phy. Indeed, in many instances, suppression of load-induced

Other cellular elements within the ventricle, fibroblasts, vas-
cular smooth muscle cells, and endothelium, also manifest
intricate stress responses, resulting in fibrosis, inflammatory
cell infiltration, endothelial dysfunction, and vascular stiff-
ness. Current thinking holds that these events, the reaction of
the heart to a host of pathological stresses, provide short-term
benefit. However, if disease-related stress remains unchecked,
these remodeling events become maladaptive and predispose
to cardiovascular morbidity and mortality.
Response by Crozatier and Ventura-Clapier
on p 1447
Among the risks conferred by disease-related ventricu-
lar hypertrophy are ventricular tachyarrhythmia, predispos-
ing to sudden cardiac death, and transition to heart failure.
Ultimately, these events derive from wholesale reprogram-
ming and relative dedifferentiation of the cardiac myocyte,
coupled with similar events in other cell types.
Conventional thinking holds that hypertrophic growth
of the myocardium is a compensatory response of the heart
growth is well tolerated.4 Furthermore, left ventricular hyper-
trophy is among the most robust markers of increased risk for
developing chronic heart failure.5 Therefore, we submit that
suppression of load-induced ventricular hypertrophy warrants
careful consideration as a therapeutic strategy.
Cardiomyocyte Hypertrophy: Comprehensive
Reprogramming of the Cell
Although evidence suggests that a small fraction of cells
within the ventricle are capable of re-entering the cell cycle,6–8
the majority of cardiomyocytes are postmitotic and, hence, do
not retain the ability to divide. Rather, they respond to stress
by growing, shrinking, or dying. In the context of many dis-
ease-related stresses, cardiac myocytes undergo hypertrophic
transformation, which entails significant cellular growth. In
the setting of uncontrolled hypertension, for example, cardio-
myocytes hypertrophy. Similarly, after myocardial infarction,
surviving cardiac myocytes in border and remote zones of tis-
sue increase in size in response to increases in hemodynamic

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From Departments of Internal Medicine (Cardiology) (G.G.S., J.A.H.) and Molecular Biology (J.A.H.), University of Texas Southwestern Medical
Center, Dallas, TX.
This article is Part I of a 2-part article. Part II appears on p 1448.
Correspondence to Joseph A. Hill, MD, PhD, Division of Cardiology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd,
NB11.200, Dallas, TX 75390–8573. E-mail joseph.hill@utsouthwestern.edu
(Circulation. 2015;131:1435-1447. DOI: 10.1161/CIRCULATIONAHA.115.013894.)
© 2015 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.115.013894

1435
 1436  Circulation  April 21, 2015
demand arising secondary to the loss of ventricular tissue. In
both cases, when the pressure overload state is persistent, the
hypertrophic phenotype of the myocardium inexorably pro-
gresses to a state of decompensation and clinical heart failure.
Mechanisms governing this transition from adaptive hypertro-
phy to maladaptive failure remain poorly understood.
Hypertrophic transformation of the cardiomyocyte involves
much more than simple cell growth. Rather, it entails a near-
comprehensive retooling of multiple aspects of cellular archi-
tecture and machinery. One element of this process is relative
dedifferentiation of the cell and reactivation of numerous
transcriptional, signaling, electrical, and metabolic events that
characterized the cell during development. As part of this, a
wide range of transcriptional and posttranslational events
occur, including activation of a pattern of gene expression
reminiscent of that observed during fetal development (fetal
gene program). Indeed, the fetal gene program, which was
extinguished shortly after birth, reignites rapidly in the setting
of disease.
Based on the pattern of sarcomere reorganization, it is pos-
sible to distinguish 2 broad patterns of ventricular hypertro-
phy.9 Pressure stress provokes concentric hypertrophy, which
is characterized by recruitment of sarcomeres laid down
in parallel; on the contrary, excess volume elicits eccen-
tric hypertrophy in which cardiomyocytes respond with the
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addition of sarcomeres in series.9 In both cases, increases in
wall thickness occur. (Concentric hypertrophy is marked by
increases in wall thickness with relatively little change in ven-
tricular volume; eccentric hypertrophy is marked by increases
in both wall thickness and ventricular cavity size.) According
to the pioneering stress-adaptation hypothesis by Grossman et
al,10 these increases in wall thickness are an adaptive response;
based on the law of Laplace, ventricular wall stress is pro-
portional to both ventricular pressure and cavity radius and
inversely proportional to ventricular wall thickness.11 Thus,
increases in wall thickness tend to lessen wall stress and
thereby diminish oxygen demand.
Myocyte growth is dictated by a delicate balance between
protein synthesis and protein degradation. In the setting of
elevated afterload, protein synthesis predominates, culminat-
ing in hypertrophic growth. However, it is important to recog-
nize that hypertrophic remodeling is not a simple process of
the addition of new sarcomeres. Rather, this highly dynamic
cellular response involves intricate coordination of de novo
protein synthesis and organelle biogenesis, sarcomere remod-
eling, protein degradation, organelle breakdown, transcrip-
tional reprogramming, and metabolic shifts. In many ways,
the entire cellular architecture of the myocyte–frame, chassis,
drive train, and engine–is retooled.
In contrast to disease-related triggers, physiological stresses,
such as endurance exercise and pregnancy, induce a hypertro-
phic response characterized by normal or enhanced contractile
function coupled with normal architecture and organization
of cardiac structure.12 Beyond differences in growth triggers,
biological phenotypes, and clinical outcomes, pathological
and physiological hypertrophy differ in the signaling cascades
that drive the process. Some evidence suggests that the dis-
tinct phenotypes do not derive simply from differences in the
duration of the stimulus, highlighting significant gaps in our
understanding of these 2 remodeling responses.13 Other data
suggest that cell size is regulated by shared signaling path-
ways, but cell shape and sarcomeric organization are regu-
lated by distinct pathways.14 Current understanding does not
allow us to parse the effects of the myriad genes and pathways
involved, but it is thought that some confer benefit, whereas
others are maladaptive.
Substantial evidence points to alterations in transmembrane
Ca2+ fluxes, another central feature of pathological remodel-
ing, as a proximal trigger contributing to the pathogenesis
of hypertrophy and failure.15 These alterations perturb exci-
tation-contraction coupling, alter mitochondrial metabolism,
and abnormally activate Ca2+-responsive signaling pathways.
Recent evidence indicates that β-myosin heavy chain is
induced by pressure overload in rodents in only a minor sub-
population of smaller cardiac myocytes.16 The myocytes that
hypertrophied after surgical constriction of the thoracic aorta
express α-myosin heavy chain only. Thus, hypertrophic trans-
formation may involve yet another layer of complexity in that
it manifests significant heterogeneity among myocytes.
Cardiac Myocyte Death
Cell death within the myocardium is characteristic of a num-
ber of cardiac diseases, and it can occur to some extent in car-
diac hypertrophy. The major types of cardiomyocyte death are
necrosis and apoptosis, with the former occurring to a greater
extent. An emerging literature has demonstrated that necro-
sis can occur as a result of a series of programmed events,
not just as simple catastrophic dismantling of the cell. Indeed,
programmed necrosis and apoptosis share a number of fea-
tures and may represent different manifestations of a common
mechanism termed necroptosis.17,18
Both dying and hypertrophying cells often harbor signs
of activated autophagy, an evolutionarily ancient process of
ordered recycling of intracellular contents.19 Whether activa-
tion of the autophagic cascade reflects a cellular response to
stress, serving to promote cell survival, or is a process con-
tributing to cell death and disease progression, is context
dependent.20
Fibrosis
Another hallmark feature of pathological hypertrophic remod-
eling is accumulation and deposition of excessive extracellular
matrix.21 This surplus extracellular matrix, which constitutes
tissue scar or fibrosis, perturbs electrical conduction, thereby
predisposing to rhythm disturbances. It also promotes dys-
function of both mechanical contraction and relaxation. As
a result, cardiac fibrosis contributes importantly to morbidity
and mortality in cardiac hypertrophy. Indeed, the amount of
fibrotic scar in the myocardium correlates directly with the
incidence of arrhythmias and sudden cardiac death.22–24
 Schiattarella and Hill   Targeting Maladaptive Hypertrophy   1437
Extracellular matrix deposition and fibrosis arise through
the action of cardiac fibroblasts. These cells, the most abun-
dant cell type in the myocardium, proliferate in response
to pathological stress. Furthermore, they differentiate into
myofibroblasts, thereby gaining the capacity to contract and
secrete collagen I, collagen III, and fibronectin.25 Fibrosis
can be categorized as reactive (perivascular or interstitial) or
replacement, occurring at the site of an eliminated myocyte.
Myofibroblasts derive from activated, resident fibroblasts, but
may also originate from adult epicardial cells26 and circulat-
ing, collagen-secreting, bone marrow–derived cells.27,28 Both
individual myofibroblasts and collagenous septa within the
tissue facilitate and propagate the arrhythmic phenotype of
the hypertrophied heart.29–31
Cardiac fibrosis is an independent and predictive risk factor
for heart failure development in the setting of ischemic or non-
ischemic cardiomyopathy.32–34 Importantly, strong evidence
indicates that cardiac fibrosis, long held to be irreversible,
may regress under certain conditions.21,35 However, although
several signaling pathways have been implicated in fibrogen-
esis, tailored therapeutic approaches targeting cardiac fibrosis
remain elusive.21
Electrical Remodeling
Patients with left ventricular hypertrophy are at increased risk
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of malignant arrhythmia, which contributes significantly to
morbidity and mortality. Indeed, arrhythmia, especially ven-
tricular tachyarrhythmia, is a major cause of death in patients
with cardiac hypertrophy or failure. Underlying mechanisms,
collectively termed electrical remodeling, encompass altera-
tions in multiple electrogenic transport and signaling processes
within the cardiac myocyte. Although numerous insights have
emerged in elucidating the molecular pathogenesis of cardiac
hypertrophy,3,36 our understanding of mechanisms underlying
the myriad facets of electrical remodeling remains limited. As
a result, pharmacological treatment of hypertrophy-associated
arrhythmias lacks efficacy, and device-based therapy has
emerged as a widely used surrogate.
The action potential phenotype of ventricular myocyte
hypertrophy is characterized by delayed repolarization lead-
ing to prolongation of action potential duration (APD). This
derives, at least in part, from distorted transmembrane electric
currents.2,15,37 Indeed, a wide range of alterations in myocyte
ion channels and electrogenic ion transporters contribute to
APD prolongation.2,15,37 Delayed recovery of excitability,
in turn, predisposes to early and late afterdepolarizations.
Hypertrophy is also associated with myocardial fibrosis (vide
supra), altered electrotonic coupling among cells, slowed con-
duction, and dispersion of refractoriness, which together pro-
mote re-entrant arrhythmias.
This electrical remodeling response is heterogeneous within
the ventricle. In the setting of excessive afterload, such as in
severe transverse aortic constriction-induced heart failure,
APD is prolonged more in subepicardial ventricular myo-
cytes than in subendocardial myocytes.38 Additional evidence
for heterogeneity of APD prolongation has been reported in
a model of pacing-induced heart failure in dogs where APD
prolongation in midmyocardial cells was substantially greater
than in subepicardial cells.39
Alterations in Ca2+ handling contribute to both hypertrophic
signaling and electrical remodeling. For example, L-type Ca2+
current (ICa,L) is a major mechanism of Ca2+ influx in cardiac
myocytes. As a general rule, ICa,L density correlates inversely
with disease progression; in models of mild-to-moderate
hypertrophy, ICa,L is often increased, whereas in severe hyper-
trophy and failure, ICa,L often manifests significant declines.
Importantly, because membrane impedance is relatively high
during phase 2 of the action potential, small changes in ICa,L
can have significant effects on action potential morphology
and duration. Furthermore, entry of small amounts of extra-
cellular Ca2+ triggers release of much larger amounts of Ca2+
from intracellular stores. As a consequence, modest increases
in inward Ca2+ flux are amplified within the cell.
Electrical activity within the myocardium hinges critically
on electrotonic cell-cell coupling, such that depolarization in
one cell is transmitted seamlessly to neighboring cells. This
coupling is mediated through gap junctions, such as connexin
43, which can become disorganized in the hypertrophied or
failing heart, disrupting normal impulse conduction.40
It is worth remembering that the atria are also touched by
remodeling events in cardiac hypertrophy and failure. Reduced
contractility, development of fibrosis, and chamber enlarge-
ment can occur, leading to heterogeneity of conduction veloc-
ity41 and propensity to atrial fibrillation.42 This arrhythmia, in
turn, eliminates the component of ventricular filling provided
by atrial contraction. Furthermore, it promotes decreases in
the atrial myocyte effective refractory period and shortened
APD, which together promote sustained atrial fibrillation.43
Metabolic Remodeling
The metabolic demands of the myocardium are exceptionally
high. As a continuously working pump, the heart consumes
robust quantities of ATP, more than any other organ in the
body, and myocardial energy reserves are remarkably low,
sufficient for less than 10 contractions. The cardiomyocyte
derives ATP largely from fatty acid oxidation. That being said,
the heart is a metabolic omnivore that can flexibly burn fuel
derived from a wide range of sources. In the end, cardiomyo-
cytes must generate energy continuously, consuming nutrients
constantly and without interruption.44
Among the characteristic changes occurring with cardiac
hypertrophy is a shift in energy substrate use.45–47 This meta-
bolic remodeling response entails upregulation of glucose
uptake and glycolysis, whereas β-oxidation of fatty acids is
reduced. Approximate numbers are that glycolysis accounts
for 10% of ATP production in the normal heart and 20% in the
hypertrophied heart. Conversely, ATP production from fatty
acid metabolism drops from 70% to 50%. These shifts are
consistent with the overarching process of cellular dediffer-
entiation in the pathologically stressed myocardium, because
 1438  Circulation  April 21, 2015
the shift in metabolism mimics the metabolic program in fetal
myocardium.
The impact of the partial switch to a fetal program of glu-
cose metabolism from preferential use of lipid remains uncer-
tain. Arguably the greatest impact derives from improvements
in oxygen efficiency.48 However, concerns have been raised
because of evidence that cardiomyocytes cultured in high-
glucose media are dysfunctional.49
To accomplish the synthesis of macromolecules and
organelles required for cardiomyocyte hypertrophic growth,
exogenous nutrients, such as glucose, cannot be metabolized
exclusively for ATP production. Rather, metabolic intermedi-
ates must be channeled to support anabolic pathways. Here,
interplay between the plasticity of metabolic pathways and
protein quality control is critical to providing intermediate
metabolites that feed into the tricarboxylic acid cycle for ATP
production, as well as serving to promote macromolecule syn-
thesis.50 Overall, currently available information implicates
metabolic reprogramming in the hypertrophied heart as an
ultimately maladaptive response.51
Inflammation
Activation of immune mechanisms participates in ventricu-
lar remodeling, contributing to long-term cardiac injury in
certain contexts. In the case of heart failure, a variety of
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inflammatory molecules and pathways are activated.52–55 In
preclinical models, pressure overload triggers myocardial
inflammation, as demonstrated by increased expression of
several proinflammatory cytokines and leukocyte infiltration
within the myocardium.56–58 This and other evidence, both in
animals and patients, highlights the role of inflammation as
an important component of pathological hypertrophy and
points to the relationship between a proinflammatory state
and load-induced ventricular remodeling.59–62 Interestingly,
myocardial cytokine levels, a surrogate marker of inflam-
mation, are often higher in patients with elevated afterload
and preserved left ventricular function compared with those
patients with reduced ejection fraction.63 These data chal-
lenge the concept that cytokine activity and an inflammatory
response are necessarily detrimental in chronic pressure
overload.
A crucial element within the inflammatory response
observed in models of pressure overload involves macro-
phages that infiltrate ventricular tissue, triggering myocardial
expression of nuclear factor-кB and inflammatory cytokines.64
One of the mechanisms whereby macrophages are involved
includes actions of macrophage-derived microRNA-155,
which functions as a modulator of cardiomyocyte hypertrophy
via paracrine mechanisms.65
These observations, coupled with the effects of anti-
inflammatory therapies in animals, have prompted efforts
to translate these insights into patients through clinical tri-
als.56,66 However, to date, anti-inflammatory therapies for
heart failure in humans have disappointed.67–69 Looking
to the future, the possible role of novel anti-inflammatory
therapies using selective approaches targeting specific cellu-
lar and molecular elements of pathological cardiac remodel-
ing and heart failure could be elucidated. Recently, a novel
connection among autophagy, afterload stress, and inflam-
mation was reported, where a lack of autophagy-mediated
removal of mitochondrial DNA promoted an inflamma-
tory response contributing to depressed cardiac contractile
performance.70
Vascular Remodeling
The vasculature that supplies the ventricle itself remod-
els in both physiological and pathological hypertrophy.
Hypertrophic growth of the heart involves parallel increases
in myocardial mass and vascular supply, the latter occurring
through proliferation of endothelium, smooth muscle cells,
and blood vessels.71,72 Indeed, it is possible to distinguish 2
interdependent phenomena involving heart vessels. The first is
remodeling of pre-existing vasculature with modifications of
endothelium, smooth muscle cells, and interstitial matrix, and
the second is de novo myocardial angiogenesis involving an
intricate network of molecules secreted from cardiomyocytes,
leukocytes, and fibroblasts (reviewed in References 73 and 74).
Paracrine signaling through mediators released by endothelial
cells may modify vascular smooth muscle cell function and
extracellular matrix components.75,76 Also, in the setting of
hypertension, vascular smooth muscle proliferates and hyper-
trophies, culminating in vascular wall thickening. In some set-
tings, flow reserve is compromised.
Dysfunction of vascular endothelial cells occurring in
pressure overload–induced heart failure may represent a
crucial node in vascular remodeling occurring in pathologi-
cal hypertrophy.77,78 Indeed, one model holds that capillary
growth in pathological hypertrophy does not keep up with
myocyte growth, leading to inadequate oxygen diffusion
capacity. Along those lines, it has also been postulated that
an imbalance in the capillary:cardiomyocyte ratio contrib-
utes to the transition from compensatory hypertrophy to
decompensated heart failure.74 Consistent with this notion,
enhancing angiogenesis in a model of afterload stress can
be protective.79 In fact, therapeutic strategies aimed to
restore the capillary network in heart failure have been
evaluated in both preclinical models and in humans.80–83
Despite some favorable findings, therapeutic myocardial
angiogenesis has failed to achieve clinical significance, at
least partly because these approaches typically involve the
delivery of genetic material or growth factors with atten-
dant complications.
Functional Role of Pathological Hypertrophy
Three stages of hypertrophic transformation of the heart were
initially proposed by Meerson.84 This model emphasizes that
the duration of pressure overload dictates the progression of
events, including hypertrophic growth and ultimately ven-
tricular systolic function. In this model, short-term hypertro-
phy represents a beneficial event that serves to normalize wall
 Schiattarella and Hill   Targeting Maladaptive Hypertrophy   1439
Figure 1. Canonical 3-stage model of hypertrophic transforma-
tion of the heart. This model posits short-term hypertrophy as a
beneficial event and long-term hypertrophy as detrimental. LVH
indicates left ventricular hypertrophy.
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stress, whereas prolonged hypertrophy is detrimental, provok-
ing increased oxygen consumption and cardiomyocyte death
(Figure 1).
Considerable evidence, from both preclinical and clini-
cal contexts, indicates that chronic, unremitting stress, as
occurs in hypertension or valvular heart disease, leads inevi-
tably to systolic dysfunction.85–89 Moreover, the Framingham
Heart Study established an association between ventricular
hypertrophy and increased cardiac mortality.5 However, the
inevitability of the transition from hypertrophy to failure
has been questioned. Drazner and colleagues90,91 have iden-
tified 3 challenges to this point of view: 1) in animal models
of pressure overload, hypertrophy can be blocked without
development of heart failure92–94; 2) in humans, concentric
hypertrophy does not uniformly progress to failure in the
absence of myocardial infarction95–97; and 3) some hyper-
tensive subjects develop dilated cardiomyopathy apparently
without antecedent concentric hypertrophy and without
clinical evidence of myocardial infarction.98 These impor-
tant caveats are based on the notion that the time course of
transition to heart failure in patients, if it occurs, is rela-
tively uniform and can be captured within the time span of
epidemiological studies.
In an effort to address these issues, magnetic resonance
imaging data from the Dallas Heart Study have been used
to propose a 4-tiered classification of left ventricular hyper-
trophy.99 This scheme seeks to overcome the limitations of
the concentric versus eccentric hypertrophy model by incor-
porating left ventricle end-diastolic volume as a categorical
variable. Future work will determine whether this 4-tiered
classification conveys independent information regarding
prognosis or therapy.
Despite these caveats, the presence of left ventricular
hypertrophy, per se, is unequivocally associated with adverse
cardiovascular outcomes independent of the underlying dis-
ease-related cause.5 As noted earlier, whereas ventricular
hypertrophy may be beneficial in the short term to mini-
mize wall stress, in the long term it promotes progression to
heart failure and other cardiovascular disorders. Numerous
epidemiological studies have clearly demonstrated that left
ventricular hypertrophy is not benign but rather represents
a major risk factor for cardiovascular morbidity and mortal-
ity, more robust than other conventional risk factors.5,100–103
Substudies from the Framingham Heart Study have dem-
onstrated marked increases in coronary heart disease, heart
failure, and sudden cardiac death associated with left ven-
tricular hypertrophy, revealed by electrocardiographic and
echocardiographic approaches.104–106
Together these data clearly identify left ventricular
hypertrophy as an important risk factor of cardiovascular
disease. However, it is important to highlight that these
observations are strictly correlative, and no mechanism(s)
of hypertrophy-dependent increase in risk can be inferred.
Our knowledge of potential mechanism(s) by which ven-
tricular hypertrophy confers increased cardiovascular risk
is limited by the fact that transition from the early, com-
pensatory stage of hypertrophy to the maladaptive phase is
poorly characterized.
Is Load-Induced Hypertrophy
Ever Truly Compensatory?
Traditionally, ventricular hypertrophy has been viewed as
an obligatory initial response to pathological stress; only
with time does it transition to a disease-promoting event.
Consistent with this view, the term compensatory connotes
an adaptive role of hypertrophy as a consequence of pressure
stress based on the premise that it helps normalize ventricu-
lar wall stress and myocardial oxygen demand. However,
evidence from genetic and pharmacological studies in
mouse models of pressure overload have demonstrated that
hypertrophic growth is not universally required to preserve
cardiac function.92,94
Shortly after the report107 that calcineurin is capable of
triggering a robust cardiac growth response, we set out to
determine whether calcineurin signaling is required for
afterload-induced growth of the heart. Mice were exposed
to thoracic aortic constriction and injected daily with cyclo-
sporine or vehicle, delivered in an investigator-blinded
manner. After 3 weeks, hearts were evaluated by echocar-
diography and by postmortem gravimetric analyses. In the
animals exposed to cyclosporine, the load-induced growth
response was abolished, leading us to conclude that cal-
cineurin activation was, in fact, required for load-induced
cardiac hypertrophy in this context. Very surprising to us,
 1440  Circulation  April 21, 2015
however, was the fact that ventricular size and function by
echo were normal in the cyclosporine-treated animals. This
was true despite the imposition of 70 to 80 mm Hg of after-
load stress, which was persistently present until the end of
the entire study; ventricular volumes and contractile param-
eters were normal, and the animals behaved normally. This
astonishing finding was published,92 and we estimate that
this observation, which often goes unnoticed in the report-
ing of studies, has been replicated independently at least
100 times since then.
These findings, demonstrating that load-induced hyper-
trophy is not always required to maintain ventricular size
and performance, raise the prospect that the hypertrophic
growth response may be a relevant target for therapeutic
targeting.4 It is important, however, to recognize that these
observations derive largely from genetically engineered
mice and, therefore, are based on models with important
limitations. Heart rate in humans is substantially slower
than that in mice, and left ventricular ejection fraction is
lower. In addition, surgical banding of the aorta triggers an
acute increase in pressure stress on the left ventricle and
therefore does not mimic conditions of chronic, progres-
sively increasing hemodynamic load as occurs in humans.
Most preclinical studies in mice were conducted over a 3-
to 4-week period, which amounts to ≈3 years in humans;
perhaps blocking hypertrophy for a longer period of time
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would be harmful. Unfortunately, the critical study in large
animals has not been performed to date.
How Can All This Be?
Increases in afterload elicit early changes in myocyte biology
across a wide range of mechanisms. Frank-Starling–related
adaptations ensue, triggered by stretch. In addition, contractil-
ity continues to increase for >10 to 15 minutes after the ini-
tial stretch, a response initially described more than 100 years
ago by Gleb von Anrep and now termed the Anrep effect.108
Initially attributed to increases in circulating catecholamines
released by the adrenal gland, the Anrep effect was later dem-
onstrated in isolated ventricular myofilaments and was attrib-
uted to increases in myofilament calcium sensitivity.109 Thus,
the Anrep effect, a response that remains poorly characterized,
is a rapid, procontractile response that occurs in the setting of
abrupt increases in afterload. It is possible that this response,
coupled with hypertrophic growth, represents a load adapta-
tion intrinsic to cardiac muscle.
Initial, rapid mechanisms whereby cardiac muscle responds
to increased load are, however, insufficient to maintain car-
diac contractility for an extended period if the inciting stress
is not eliminated. Therefore, increases in cardiac mass ensue
but ultimately lead to untoward consequences. Indeed, with
persistent pressure stress, the heart undergoes apparently
irreversible decompensation, resulting in chamber dilatation
and reduced systolic function. This maladaptive hypertro-
phy, as emerges when the inciting stress is not abated, repre-
sents a common feature in virtually all forms of heart failure.
Therefore, the concept of transition from a short-term com-
pensatory response to maladaptation points to cardiac hyper-
trophy as a novel therapeutic target.
Translational Studies in Large Animals
Our understanding of mechanisms that govern the transi-
tion between compensated ventricular hypertrophy and heart
failure remains incomplete. This stems partly from a lack of
longitudinal analyses of ventricular structure and function
in patients with increased afterload (eg, aortic stenosis and
arterial hypertension). To date, most evidence that provides
insight into the effects of suppressing cardiac hypertrophy on
cardiac function derives from studies in rodents.110 However,
because of intrinsic differences in contractile performance,
Ca2+ handling, myosin isoform distributions, heart rate, and
life span between rodents and humans, these models do not
faithfully recapitulate human disease. In this regard, large ani-
mal models could be more informative.
Pressure overload–induced cardiac hypertrophy has been
studied in nonhuman primates, where left ventricular hyper-
trophy and myocardial fibrosis comparable to that seen in
patients with aortic stenosis are found.111 Studies to evaluate
molecular mechanisms and pathophysiological adaptations in
pressure overload–induced heart failure have been conducted
primarily in dogs.112–114 In view of the considerable remaining
gaps in our understanding of this biology, additional explora-
tion of the role of compensatory hypertrophy in large animal
models is warranted.
How Might Hypertrophy Be Targeted?
Clinical management of pathological left ventricular hyper-
trophy currently focuses on the underlying growth cues (eg,
hypertension and valve disease) and typically involves a
wide spectrum of pharmacological agents that have shown
safety and efficacy in reducing hypertrophy. These pharma-
cological agents are mostly directed against the crucial neu-
rohormonal axes activated in response to stress. Adrenergic
and renin-angiotensin-aldosterone system (RAAS) path-
ways represent 2 mechanisms recruited to increase con-
tractility in the early phases of stress, becoming deleterious
in the chronic context. β-Adrenergic receptor blockers,
angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers are effective in reducing left ventricular
mass and are associated with a favorable clinical outcome
in clinical settings.115,116
Pharmacotherapy to reduce blood pressure can lead to
regression of ventricular hypertrophy.36 Although all antihy-
pertensive drugs promote hypertrophy regression to some
extent, current evidence suggests that the RAAS-targeting
drugs are the most efficacious at regressing ventricular
hypertrophy. Based on robust evidence that regression of
hypertrophy is independently associated with improved cardio-
vascular outcome, numerous clinical trials have documented
the favorable impact of antihypertensive drug therapy. For
 Schiattarella and Hill   Targeting Maladaptive Hypertrophy   1441

Table. Novel Compounds and Targets With Confirmed or example, the Losartan Intervention for Endpoint Reduction in
Potential Antihypertrophic Activity a Hypertension study reported a greater reduction in left ven-
Target(s)/Mechanism(s) of tricular mass index in the losartan-treated cohort compared
Variable Action References (PMID) with an atenolol-based regimen.117 Several other trials reached
HDAC inhibitors a similar conclusion, pointing to a class effect of RAAS-
Apicidin Class I HDACs 18697792 targeting antihypertensive agents at promoting hypertrophy
Vorinostat Class I, II HDACs 20139990-17211407 regression.118–121 Together, these data highlight the role of cur-
Romidepsin Class I, II HDACs 20139990-21699444 rent therapies targeting chronic neurohormonal activation in
Trichostatin A Pan-HDACs 16380549-16735673- the prevention of heart failure and limiting progression of ven-
12975471 tricular hypertrophy, lending further support to the notion that
Valproic acid Class I HDACs (weak) 16380549 inhibiting ventricular hypertrophy is an attractive therapeutic
Scriptaid Pan-HDACs 16735673 option in patients.
SK-7041 Pan-HDACs 16380549 All of these trials were conducted using compounds tar-
Prohypertrophic microRNAs as therapeutic targets geting cardiomyocyte cell-surface receptors. More recently,
miR-199a Hif1α/sirtuin 1 20458739
efforts have focused on antihypertrophic effects of molecules
that act inside the cardiomyocyte, targeting crucial signal-
miR-199b Dyrk1a 21102440
ing cascades that alter gene expression and protein function.
miR-208a THRAP1 and myostatin 19726871-21900086
These agents include histone deacetylase (HDAC) inhibitors,
miR-23a MuRF1 19574461
a wide spectrum of prohypertrophic microRNAs (reviewed in
miR-499 DRP1 22752967
Reference 122), and several other small molecules (reviewed in
miR-21 Sprouty2 and spry1 17234972-19043405
Reference 123; Table).
miR-24 E2F2 23307820-19748357
Our group has focused on reversible protein acetylation as
miR-27b PPAR-γ 21844895 a tractable means of governing cardiomyocyte growth,124–127
miR-350 MAPK11/14 and MAPK8/9 23000971 autophagy,126 and disease responsiveness.128 Among those
miR-195 HMGA1 17108080-25100012 studies, we have noted that inhibition of HDACs is capable
miR-221 p27 22275134 of blunting load-induced growth.127 Beyond that, HDAC
Downloaded from http://ahajournals.org by on February 27, 2024

miR-212/132 FoxO3 23011132 inhibitors can promote regression of ventricular hypertro-

miR-25 SERCA2a 24670661 phy despite the persistent presence of afterload stress126 (and
miR-155 Socs1 23956210 with preservation–even improvement–in contractile perfor-
Other compounds mance.) HDAC inhibitors, 4 of which are US Food and Drug
CPG-ODN c274 TLR9 agonist 23638055 Administration approved as third-line therapy for Sézary syn-
Curcumin P300 inhibitor 18292809 drome, may emerge as a novel means of targeting ventricu-
FTY720 Sphingolipid/NFAT inhibitor 23753531 lar hypertrophy. Indeed, we have speculated that it might be
BAY94-8862 MR antagonist 22791416 possible to use HDAC inhibitors to sculpt the hypertrophied
Cinaciguat sGC stimulator 22778174 ventricle in patients with heart failure with preserved ejection
LCl699 Aldosterone synthase inhibitor 21986283 fraction, trimming left ventricular wall thickness progres-
Resveratrol Antioxidant 23784505 sively, to afford clinical benefit.
MTP-131 Antioxidant 21620606
Comprehensive understanding of molecular events
involved in maladaptive cardiac hypertrophy and the
TRV120027 AT1 receptor 22891045
remodeling that culminates in decompensated heart fail-
LCZ696 Angiotensin/neprilysin 23731190
inhibitor ure is the first step toward developing novel treatments
 HA-1077 ROCK 14500337-15840407-
with clinical potential. This is especially true for patients
(Fasudil) 15096457 with heart failure with preserved ejection fraction, most of
Y-27632 ROCK 12623300-12176125 whom harbor ventricular hypertrophy, which contributes
Sildenafil PDE5 25139994 to symptoms and clinical outcomes,129 and for which evi-
Ruboxistaurin PKCβ 15878171
dence-based therapy is lacking. Although these pathways
manifest redundancy in their effects, hypertrophy often
AT1 indicates angiotensin II receptor type 1; DRP1, dynamin-related protein
1; Dyrk1A, dual specificity tyrosine-phosphorylation-regulated 1A; E2F2, E2F remains present in models in which 1 pathway is sup-
transcription factor 2; FoxO3, forkhead box O3; HDAC, histone deacetylase; Hif1α, pressed, suggesting that serial pharmacological brakes may
hypoxia inducible factor1α; HMGA1, high mobility group A1; MAPK, mitogen- be required for clinical gain.
activated protein kinase; MR, mineralocorticoid receptor; MuRF1, muscle RING-finger
protein-1; NFAT, nuclear factor of activated T cells; PDE5, phosphodiesterase type 5;
PKCβ, protein kinase Cβ; PPAR, peroxisome proliferator–activated receptor; ROCK, A Note of Caution
rho-associated protein kinase; SERCA2a, sarcoplasmic reticulum Ca2+ ATPase; Considerable evidence points to a progression of remodel-
Socs1, suppressor of cytokine signaling 1; THRAP1, thyroid hormone receptor– ing events in which stress elicits the following: 1) a hyper-
associated protein 1; TLR9, toll-like receptor 9 ; and sGC, soluble guanylyl cyclase. trophic growth response which has beneficial features; 2)
 1442  Circulation  April 21, 2015
maladaptive hypertrophy, which is a clear-cut marker for
untoward events; and 3) the clinical syndrome of heart fail-
ure. However, assuming this model has validity, little is
known regarding specific markers of these different phases
of disease pathogenesis or transition points separating
them.
A large number of preclinical studies have demonstrated that
it is possible to blunt load-induced hypertrophy, even in the set-
ting of persistent afterload stress, without affecting contractile
function.4,92,94 These studies, then, have delineated a strategy
wherein one might target maladaptive hypertrophy and thus
obviate the untoward consequences of continued progression
of this process. Consistently, in both preclinical studies and
clinical trials, inhibition of cardiac hypertrophic growth usually
results in the amelioration of left ventricular dysfunction.5,9,130
Caution is warranted. Not all forms of pathological car-
diac hypertrophy can be blocked without provoking ven-
tricular dysfunction.131–134 Although the great majority of
studies (again, exclusively in rodents to date) demonstrate
that the load-induced growth response can be inhibited
without untoward effects, there are examples where hyper-
trophy elicited by a specific signaling cascade appears to be
required.135–137 Also, ventricular mass alone may not provide
the full picture of the myriad remodeling events involved in
heart growth.138 Therefore, further work is required to deter-
mine whether accompanying alterations (eg, contractile func-
Downloaded from http://ahajournals.org by on February 27, 2024
tion and coronary hemodynamics) associated with ventricular
hypertrophy can be reversed by treatment and in which cat-
egory of patients.
We wish to highlight that, whereas cardiac hypertrophy in
response to pathological stimuli manifests common charac-
teristics irrespective of the triggering stress, it is likely that
several subtypes of pathological hypertrophy exist. Thus,
whereas efforts to block the inciting stimuli are warranted, we
do not know whether all forms of maladaptive hypertrophy
should be prevented.
Stress-Induced Cardiac Growth: A Model
How is it that hypertrophy can be both beneficial and del-
eterious? We propose a model in which hypertrophic
transformation of the heart under conditions of disease-related
stress is similar to many other processes in biology. There has
been significant evolutionary pressure to promote organismal
survival until procreation can occur and young can be fostered
to independence. However, our species did not evolve to live 9
decades! In the settings of life-threatening stress, activation of
both the β-adrenergic cascade and the RAAS axis occurs, and
the end result is enhanced cardiac performance and improved
survival. These pathways allow for survival in the setting of
sublethal injury, for example. However, chronic activation of
these processes, life saving in the short term, clearly conveys
markedly enhanced risk in the long term. Indeed, chronic
suppression of those evolutionarily ancient neurohumoral
responses is fundamental to present day, evidence-based ther-
apy for heart failure. Again, a large number of studies have
demonstrated robust benefits from therapeutic strategies in
which evolutionary adaptations to stress are blocked.
We suggest that ventricular hypertrophy is the same. It pro-
vides short-term benefit and long-term harm (Figure 2). If this
model holds true, then suppression of ventricular hypertrophy,
a therapeutic target currently not under widespread consider-
ation, emerges as a novel and potentially important target for
consideration of drug development going forward.
Summary and Perspective
Heart failure is defined as a syndrome in which cardiac out-
put is unable to meet the metabolic needs of peripheral tis-
sues. In this setting, when cardiac output is depressed, the
myocardium has a limited repertoire of responses, and, as a
result, so does the treating physician. The heart is capable of
responding in 4 ways: increases in 1) heart rate, 2) ventricu-
lar filling, 3) contractility, and 4) mass. Clinically, we have
a full spectrum of means to regulate heart rate and optimize
ventricular filling pressures. Contractility is a mechanism
that we target routinely in the acute setting, but no safe and
effective therapies are available that promote contractility
chronically. This leaves ventricular hypertrophy as the final
frontier of heart failure therapy, a target that has never been
developed and that, in fact, seems counterintuitive on initial
consideration.
Figure 2. Model of the hypertrophic response to
toxic stress. We propose that hypertrophic transfor-
mation of the heart under stress is similar to other
biological processes, which evolved to provide
short-term benefit. These include activation of the
β-adrenergic and renin-angiotensin-aldosterone
axes (RAAS). Cornerstone therapy for heart failure
(HF Rx) involves interruption of these responses,
and we suggest that judicious suppression of
hypertrophy may provide similar benefit.
 Schiattarella and Hill   Targeting Maladaptive Hypertrophy   1443
That said, it is critical to recognize that hypertrophic
transformation of the ventricle is just that, a transformation
involving cellular dedifferentiation and comprehensive repro-
gramming of the cardiac myocyte and other cellular elements
within the ventricle. Although increases in myocyte size and
consequent increases in ventricular mass are hallmark fea-
tures, a wide range of additional events occur in these stressed
cells. Here, we present an overview of the large body of robust
epidemiological and preclinical data pointing to the untoward
consequences of hypertrophic transformation of the myocar-
dium. These data, at the very least, raise the prospect of target-
ing hypertrophy therapeutically.
In recent years, significant strides have been achieved in
our understanding of, and therapeutic targeting of, patho-
logical hypertrophic remodeling. We view hypertrophic
transformation as a fundamental, potentially indispensable
step in the myocardial response to pressure overload, which
is coupled with significant detrimental consequences. This
response may be beneficial in the short term, but when main-
tained chronically it becomes significantly detrimental. It is
analogous to the responses of β-adrenergic and RAAS acti-
vation, which we now go to great lengths to block and for
which suppression seemed counterintuitive at first. We argue
that hypertrophy is comparable, and patients may benefit
from judicious attenuation of this chronic, long-term hyper-
trophic response.
Downloaded from http://ahajournals.org by on February 27, 2024
Acknowledgments
We thank members of the Hill laboratory for constructive comments.
Sources of Funding
This work was supported by grants from the National Institutes of
Health (HL-120732 and HL-100401), American Heart Association
(14SFRN20510023), Cancer Prevention & Research Institute of
Texas (RP110486P3), Leducq Foundation (11CVD04), and the
Sostegno Territoriale alle Attività di Ricerca program (University of
Naples Federico II).
Disclosures
None.
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Response to Schiattarella and Hill

Bertrand Crozatier, MD, PhD; Renée Ventura-Clapier, PhD
We agree with many points presented in the review of Sciattarella and Hill, particularly with their description of the abnor-
malities present in the hypertrophied myocardium. We also acknowledge that ventricular hypertrophy has been identified as a
cardiovascular risk factor. However, this does not imply that hypertrophy, per se, has to be blocked. This management of the
hypertrophy process has proved to be beneficial in a number of studies, but we also presented examples of detrimental effects
of this procedure. Sciattarella and Hill were cautious to say that it cannot be applied to all forms of hypertrophy. We could thus
agree with them, but we fully disagree when they state that chronically maintaining hypertrophy is analogous to an activation
of β-adrenergic and renin-angiotensin-aldosterone systems. We specifically believe the opposite. As shown in our review, an
increased contractility is present in the ventricle that is not allowed to increase its wall thickness. Hypercontractility is necessary
for maintaining a normal ventricular function when wall stress is increased. It is likely that, in patients with pre-existing patholo-
gies such as coronaropathies, a prolonged increased contractility will induce a myocardial ischemia and will be detrimental.
Alternative strategies directed toward the cause of hypertrophy, such as ventricular assistance devices or renin-angiotensin-
aldosterone system and β-adrenergic inhibition, indirectly lead to a regression of hypertrophy. New therapeutic approaches such
as those presented in our article that would reorchestrate the different constitutive elements of the ventricles could be promising
approaches. They would better protect cardiomyocytes than a direct blockade of hypertrophy.
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