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Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M. D. , Editor
Myocardial hypertrophy is an early milestone during the clinical course of heart failure and an important risk factor for subsequent cardiac morbidity and
mortality. In response to a variety of mechanical, hemodynamic, hormonal, and pathologic stimuli, the
heart adapts to increased demands for cardiac work
by increasing muscle mass through the initiation of
a hypertrophic response. At the cellular level, cardiac
myocytes respond to biomechanical stress by initiating several different processes that lead to hypertrophy (Fig. 1). The so-called physiologic hypertrophy
that occurs in elite athletes is associated with proportional increases in the length and width of cardiac myocytes. By contrast, the assembly of contractile-protein units in series characterizes the eccentric
hypertrophy that occurs in patients with dilated cardiomyopathy, with a relatively greater increase in the
length than in the width of myocytes. During pressure overload, new contractile-protein units are assembled in parallel, resulting in a relative increase in
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the width of individual cardiac myocytes and therefore in concentric hypertrophy. In hypertrophic cardiomyopathy, mutant contractile proteins lead to
myofibrillar disarray and secondary hypertrophy of
myocytes. In most forms of cardiac hypertrophy, there
is an increase in the expression of embryonic genes,
including the genes for natriuretic peptides and fetal
contractile proteins.3 The induction of the natriuretic peptide genes is a feature of hypertrophy in all
mammalian species and is a prognostic indicator of
clinical severity. Recently, evidence of the loss of myocytes as a result of programmed cell death (apoptosis) has also been reported in both experimental
and clinical cardiac hypertrophy (Fig. 1).
GENETIC METHODS OF STUDYING
CARDIAC HYPERTROPHY AND FAILURE
Octo b er 2 1 , 19 9 9
The New England Journal of Medicine
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Copyright 1999 Massachusetts Medical Society. All rights reserved.
M EC H A NIS MS OF D IS EASE
Apoptosis
Physiologic hypertrophy
Growth7
stimuli
Normal muscle cell
Concentric hypertrophy
Increased expression7
of embryonic genes
Eccentric hypertrophy
Sarcomeric disorganization
GOAL
AND
MOLECULAR TARGETS
IN HEART FAILURE.*
TYPE
OF
IN THE
DRUGS
Growth hormone
Insulin-like growth factor I
Beta-blockers
MOLECULAR TARGET
Angiotensin II receptor
Endothelin-1 receptor
? Novel receptors
Antagonists of ras, p38, and c-jun
N-terminal kinase (JNK)
? Novel kinases
Growth-hormone receptor
Insulin-like growth factor I receptor
b1-Adrenergic receptor
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Pressure overload
Interleukin-6 family of cytokines
gp130
LIF receptor
Cardiac myocyte
Hypertrophic signals.
(ras, Gqa, p38b)
Organization of sarcomeres .
Increased expression of.
embryonic genes
Compensatory hypertrophy
Apoptotic signals.
(Gqa, p38a)
Apoptosis
Heart failure
Figure 2. Pathways Involved in Hypertrophy, Apoptosis, and Survival of Myocytes during the Transition between Cardiac
Hypertrophy and Heart Failure in Response to Biomechanical Stress.
Biomechanical stress, such as chronic hypertension and pressure overload, activates multiple parallel and converging
signals for hypertrophy and apoptosis, which represent two distinct outcomes. At the same time, biomechanical stress
also leads to the induction of gp130-dependent ligands, such as cardiotrophin 1. This cytokine binds to its receptor,
which consists of gp130LIF (leukemia inhibitory factor) receptor heterodimers, resulting in the activation of downstream gp130 pathways that block the actions of apoptotic pathways. In the absence of gp130, the response of cardiac
myocytes to biomechanical stress is shifted toward apoptosis, resulting in the loss of functional myocytes and the onset
of heart failure. Thus, the outcome of biomechanical stress is dependent on the balance between these two contradictory signal-transduction pathways.
factors that activate either heteromeric (Gq) or lowmolecular-weight guanosine triphosphate (GTP)
binding protein (ras) signaling pathways, as well as
cardiotrophin 1 and other members of the interleukin-6 cytokine family that activate cellular responses
by means of the transmembrane signal transducer
gp130. A relatively distinct pattern of cardiac cellular
responses has been associated with each of these
substances, implying that their actions are specific.
To a certain extent, this specificity reflects the activation of different downstream intracellular kinase
cascades that stimulate the appearance of specific features of myocardial-cell hypertrophy (Fig. 2). Study
of these downstream signaling pathways has identified kinases that generate primarily hypertrophic, apoptotic, and anti-apoptotic signals,8-10 as well as kinases that regulate the assembly of myofilaments (rho
kinase).11 In addition, nuclear signaling proteins have
been found that activate and suppress various cardiac
genes during hypertrophy.7
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The New England Journal of Medicine
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Copyright 1999 Massachusetts Medical Society. All rights reserved.
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
toskeleton and the extracellular matrix in the pathogenesis of cardiomyopathy. Moreover, a molecular
defect involved in familial dilated cardiomyopathy in
humans has been mapped to the cytoskeletal region
of the cardiac actin gene.43 One of the first examples
of a genetic link between the cytoskeleton and dilated cardiomyopathy was provided by studies of mice
that have a deficiency in a muscle-specific LIM (lin-1,
ISL-1, and mec-3) domain protein23 and have many
features of the dilated cardiomyopathy that occurs in
humans. This cytoskeletal protein may be a component of a biomechanical sensor pathway that transduces hemodynamic force into specific signaling responses. Disruption of other cytoskeletal proteins,
such as desmin, plakoglobin, and N-cadherin, results
in cardiac dilatation and impaired cardiac function
during fetal development or after birth. In summary,
increased biomechanical stress on cardiac myocytes,
either through genetic abnormalities or through excessive stress on the chamber wall due to myocyte loss
or severe hemodynamic loading, generates a persistent signal for ventricular growth and hypertrophy.2,44
By contrast, mutations in sarcomeric proteins cause
Extracellular matrix
Laminin-2
Sarcoglycans
a
Dystroglycans
g a b
a-Actinin
Cytoskeletal7
a-actin7
7
MLP
?
Syntrophins
Z-disk
Dystrophin
Desmin7
7
Figure 3. Primary Structural Components of the Linkage between the Cytoskeleton and the Extracellular Matrix, Including Actin, the DystrophinGlycoprotein Complex, and Laminin-2 (Merosin).
Genetic defects in these components lead to dilated cardiomyopathy, with or without associated skeletal myopathy.
This complex is physically associated with the Z-disk of cardiac myocytes, the Z-disk components desmin (associated
with dilated cardiomyopathy in humans and mice) and a-actinin, and a muscle-specific cytoskeletal protein (MLP) (associated with dilated cardiomyopathy in mice).23 The question mark indicates an unknown factor.
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The New England Journal of Medicine
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effects (Fig. 2).9 Cell death may occur when the apoptotic forces exceed a certain threshold. The activation of apoptotic signals during the hypertrophic
response of myocytes may explain the risk of death
associated with ventricular hypertrophy in humans.
In support of this concept, mice with a loss-of-function mutation in the cytokine receptor gp130 of the
ventricular chamber have normal cardiac structure but
have massive cardiac apoptosis accompanied by rapidly progressive dilated cardiomyopathy when subjected to pressure overload.25 These studies indicate
that the inhibition of apoptosis by gp130-dependent
pathways in myocytes has a critical role in the transition between compensatory hypertrophy and overt
heart failure and suggest that the balance between apoptotic and hypertrophic pathways determines whether chamber dilatation will occur (Fig. 2).25
Cardiac Function and Contractility
b-Adrenergic receptor
Adenylyl cyclase
GSa
Cyclic AMP.
PKA
Sarcoplasmic.
reticulum
P
Phospho-7
lamban
b-Adrenergic.
receptor kinase
Calcium
Calcium pump
Figure 4. Regulation of the Contractile Function of Myocytes.
The contractile function of myocytes is regulated by changes in calcium flux into and out of the sarcoplasmic reticulum.
Activation of b-adrenergic receptors leads to increased uptake of calcium into the sarcoplasmic reticulum by the calcium
pump; the phosphorylation (P) of phospholamban by cyclic AMP-dependent protein kinase (PKA) removes its tonic inhibition of the calcium pump. b-Adrenergic receptors are desensitized in both heart failure and maladaptive hypertrophy; a substantial component in this desensitization is up-regulation of the b-adrenergicreceptor kinase (bARK). A deficiency of phospholamban has recently been shown to halt the progression of heart failure and dilated cardiomyopathy
in a genetically based animal model.45
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Octo b er 2 1 , 19 9 9
The New England Journal of Medicine
Downloaded from nejm.org on December 8, 2014. For personal use only. No other uses without permission.
Copyright 1999 Massachusetts Medical Society. All rights reserved.
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