The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Review Articles
Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M. D. , Editor
S IGNALING P ATHWAYS FOR C ARDIAC
H YPERTROPHY AND F AILURE
JOHN J. HUNTER, M.D.,
AND KENNETH R. CHIEN, M.D., PH.D.
H
EART failure is a leading cause of mortality
in the United States. As a result of advances
in genetic technology, a molecular basis of
heart failure is emerging.1,2 This review highlights the
ways in which these insights are leading to new ther-
apeutic targets in patients with acquired forms of
heart failure.
MORPHOLOGIC CLASSIFICATION
OF CARDIAC HYPERTROPHY
Myocardial hypertrophy is an early milestone dur-
ing the clinical course of heart failure and an impor-
tant risk factor for subsequent cardiac morbidity and
mortality. In response to a variety of mechanical, he-
modynamic, 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 initiat-
ing several different processes that lead to hypertro-
phy (Fig. 1). The so-called physiologic hypertrophy
that occurs in elite athletes is associated with pro-
portional increases in the length and width of car-
diac myocytes. By contrast, the assembly of contrac-
tile-protein units in series characterizes the eccentric
hypertrophy that occurs in patients with dilated car-
diomyopathy, with a relatively greater increase in the
length than in the width of myocytes. During pres-
sure overload, new contractile-protein units are as-
sembled in parallel, resulting in a relative increase in
From the University of California San Diego–Salk Institute Program in
Molecular Medicine, Department of Medicine and Center for Molecular
Genetics, University of California San Diego School of Medicine, La Jolla,
Calif. Address reprint requests to Dr. Chien at the Department of Medi-
cine, 0613-C, University of California San Diego, 9500 Gilman Dr., La
Jolla, CA 92093, or at kchien@ucsd.edu.
©1999, Massachusetts Medical Society.
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the width of individual cardiac myocytes and there-
fore in concentric hypertrophy. In hypertrophic car-
diomyopathy, 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 natriuret-
ic 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 my-
ocytes as a result of programmed cell death (apop-
tosis) has also been reported in both experimental
and clinical cardiac hypertrophy (Fig. 1).
GENETIC METHODS OF STUDYING
CARDIAC HYPERTROPHY AND FAILURE
Cardiac hypertrophy and failure are highly complex
disorders that arise as a result of a combination of
genetic, physiologic, and environmental factors. The
identification of mutations involving a single gene
that are responsible for inherited forms of hyper-
trophic cardiomyopathy, dilated cardiomyopathy, and
ventricular arrhythmogenesis (the long-QT syndrome)
has allowed us to pinpoint several of the initiating
events that can lead to features of heart failure in hu-
mans.4,5 There is still a broad gap, however, between
identifying the defective gene and understanding how
this defect leads to the cardiac abnormalities. In this
regard, in vitro assays of cardiac muscle cells and stud-
ies of genetically engineered animals are beginning
to identify the points in cardiac growth signaling that
cause these distinct forms of cardiac hypertrophy and
failure.
Assays of Cardiac-Muscle Cells
The ability to culture primary cardiac myocytes
has resulted in the availability of a well-characterized
in vitro system in which to study the hypertrophic
response. Although they are based on neonatal car-
diac-muscle cells, studies of these cultures have led
to the identification of signaling pathways that acti-
vate cellular responses known to occur during hy-
pertrophy in vivo, including an increase in cell size,
an increase in the expression of embryonic genes, and
the accumulation and assembly of contractile pro-
teins.6 By altering the expression of specific genes in
cultured cardiac myocytes, peptide hormones, growth
factors, and cytokines have been identified that can
activate specific features of the hypertrophic response
(Table 1).7 Among the most extensively characterized
of these substances are endothelin and angiotensin
II, insulin-like growth factor I, and other growth
 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

Figure 1. Morphology of Ventricular Muscle Cells in Cardiac Hypertrophy and Failure.

Phenotypically distinct changes in the morphology of myocytes occur in response to various growth stimuli. The expression of
embryonic genes such as natriuretic peptides is increased in both eccentric and concentric hypertrophy, but not in physiologic hy-
pertrophy, in response to exercise. Myofibrillar disarray (sarcomeric disorganization) is typical of hypertrophic cardiomyopathies;
this disorganization is focal and is accompanied by more widespread increases in the cross-sectional area of myocytes.

TABLE 1. POTENTIAL THERAPEUTIC AND MOLECULAR TARGETS IN THE SIGNALING PATHWAYS INVOLVED
IN HEART FAILURE.*

GOAL TYPE OF DRUGS MOLECULAR TARGET

Inhibition of pathologic hyper- Antagonists of Gqa-dependent receptors Angiotensin II receptor

trophy
Promotion of physiologic hyper-
trophy
Inhibition of neurohumoral over-
stimulation
Enhancement of contractile and
relaxation responses
Relief of energy deprivation
Inhibition of pathways of apopto- Promoters of myocyte survival
sis of myocytes
Inhibitors of intracellular kinase
cascades
Growth hormone
Insulin-like growth factor I
Beta-blockers
Relief of inhibition of sarcoplasmic retic- Phospholamban inhibitors
ulum calcium ATPase
Agents that counteract the desensitiza- Inhibitors of b-adrenergic–receptor kinase
tion of G protein–coupled receptor
kinases
Angiogenic growth factors
Inhibitors of apoptosis
Inhibitors of cytokines
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
Vascular endothelial-derived growth factor
Fibroblast growth factor 5
Agents involved in angiogenesis
? Others
gp130 ligands (e.g., cardiotrophin 1)
Neuregulin
Caspase inhibitors
Tumor necrosis factor a, ? others

*A more complete description of each of these classes has been published.7

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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. Apoptotic signals.

(ras, Gqa, p38b) (Gqa, p38a)

Organization of sarcomeres . Apoptosis

Increased expression of.
embryonic genes

Compensatory hypertrophy 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 gp130–LIF (leukemia inhibitory factor) receptor heterodimers, resulting in the activation of down-
stream 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 contradic-
tory signal-transduction pathways.

factors that activate either heteromeric (Gq) or low-
molecular-weight guanosine triphosphate (GTP)–
binding protein (ras) signaling pathways, as well as
cardiotrophin 1 and other members of the interleu-
kin-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 acti-
vation of different downstream intracellular kinase
cascades that stimulate the appearance of specific fea-
tures of myocardial-cell hypertrophy (Fig. 2). Study
of these downstream signaling pathways has identi-
fied kinases that generate primarily hypertrophic, ap-
optotic, and anti-apoptotic signals,8-10 as well as ki-
nases 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
Cardiac Hypertrophy and Failure
in Genetically Altered Animals
Mice have a heart rate of over 500 beats per
minute and an aorta that is 1 mm in diameter, but
they are a valid model for studying both pressure-
overload hypertrophy and heart failure, because of
the similarities of these disorders in mice and hu-
mans.12-14 The ability to engineer precise mutations
in the heart, coupled with the ability to quantitate
the effects of these mutations on cardiac function
in vivo,15,16 has led to the recognition of a pre-
viously unsuspected set of signaling pathways and
molecules that stimulate specific aspects of cardiac
growth. The effects of both the overexpression and
the loss of individual cardiac genes in animals have
been studied, and we will describe examples of each.
These models are useful not simply because they
replicate human disease but also because they allow
the differentiation of the many different processes
that together cause such conditions as pressure-

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 MEC H A NIS MS OF D IS EASE
overload hypertrophy and congestive heart failure in
humans.
In the tissue-restricted approach to overexpression,
the regulatory region from a cardiac-specific gene is
fused to a candidate gene of interest and used to
produce transgenic mice that express the candidate
gene specifically in cardiac-muscle cells because of
the ability of the regulatory sequences to restrict ex-
pression to the heart.17 The availability of well-char-
acterized regulatory regions of cardiac-specific genes
has allowed the expression of candidate signaling mol-
ecules in the heart and even in the ventricles alone.
For example, transgenic mice have been produced
that express an active mutant of ras, a protein that
mediates many growth-related responses in cardiac
myocytes as well as in cancer cells.18 Since the regu-
latory sequences of a ventricle-specific gene control
the expression of this active form of ras, the heart is
the only tissue in the animals in which the ras path-
ways are activated.19,20 High levels of expression of
ras result in hypertrophic cardiomyopathy, including
massive cardiac hypertrophy, heart failure, and sud-
den death, but not the dilatation of any heart cham-
ber (unpublished data). Increased concentrations of
ras messenger RNA were recently described in en-
domyocardial-biopsy specimens from humans with
familial hypertrophic cardiomyopathy.21
It is possible to disrupt, or “target,” a gene of inter-
est in a mouse by replacing it with a mutated sequence
early in embryogenesis.22 Mice that are heterozygous
for the mutated allele can be mated to produce ho-
mozygous mice that do not have a functional copy
of the targeted gene. For example, mice with dele-
tions of a muscle-restricted cytoskeletal protein have
features of dilated cardiomyopathy,23 a finding that
supports a causative role for disrupted cytoskeleton
components in the pathogenesis of cardiomyopathy.
Since many structural and signaling components of
cardiac myocytes are common to other tissues, gene
targeting may be lethal; the animals may die from
defects in other tissues before the role of the gene
in the heart can be studied. This difficulty can now
be avoided by techniques to engineer heart-specific
gene deletions.24,25
PRESSURE OVERLOAD AND CONCENTRIC
HYPERTROPHY
The extent of ventricular hypertrophy in patients
is a powerful predictor of adverse events. According-
ly, identifying the signals that mediate the pathways
from mechanical stress to downstream cellular events
has been a major area of interest. Both myocytes and
nonmyocytes are direct biomechanical sensors of he-
modynamic load. Growth signals are generated by
the release of growth factors and cytokines, which
lead to a regionally localized response. The factors
that have been implicated in this response include
peptides that stimulate G protein–coupled receptors
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(endothelin-126,27), angiotensin II,28,29 interleukin-6–
related cytokines (cardiotrophin 130,31), and growth
factors that activate receptor tyrosine kinases (insu-
lin-like growth factor I32,33).
One of the first genetically defined models of con-
centric ventricular hypertrophy resulted from cardiac-
directed overexpression of the a1b-adrenergic recep-
tor.34 This confirmed previous work in cultured
cardiac myocytes demonstrating that a-adrenergic
stimulation induced a hypertrophic response. a-Adre-
nergic receptors share common intracellular signal-
ing pathways with other hypertrophic growth fac-
tors, including angiotensin II and endothelin-1. In
each of these pathways, signaling that results in hy-
pertrophy proceeds by means of the Gqa subunit
of heteromeric G protein, which was found to be
both necessary and sufficient to cause hypertrophy
in cultured cardiac-muscle cells.35 Subsequently, over-
expression of Gqa itself was found to induce both
a hypertrophic and an apoptotic response.36,37 Fur-
thermore, a protein inhibitor of Gqa, whose expres-
sion was also targeted to the heart by transgenic
techniques, had no effect on cardiac structure or func-
tion in unstressed mice, but it prevented hypertro-
phy when pressure overload was induced by con-
stricting the ascending aorta.38 Taken together, these
results suggest that Gqa-dependent pathways have a
critical role in the development of myocardial hy-
pertrophy (Fig. 2).
The activation of cell-surface receptors and their
immediate signaling targets, such as ras and Gqa, by
cardiac growth factors is the first step in initiating the
growth of myocytes (Fig. 2). Increases in intracellu-
lar calcium concentrations in response to these growth
factors may also activate calmodulin-dependent path-
ways.39-41 According to in vitro and in vivo results,
the primary downstream effectors are the mitogen-
activated protein kinases, including c-jun N-terminal
kinase and p38.7,9,10,31 These kinases are particularly
important switches in the pathways between apop-
tosis and adaptive hypertrophy. For example, in mice
p38 mitogen-activated protein kinases are strongly
activated by pressure overload, and upstream kinases
that specifically activate p38 cause the growth of cul-
tured myocytes. However, the activation of p38 is
also accompanied by an increase in the rate of apop-
tosis.9 The two isoforms of p38, a and b, have oppo-
site effects on apoptosis when stimulated by upstream
activators: p38a increases apoptosis, whereas p38b
inhibits it (Fig. 2).9
CHAMBER DILATATION AND DILATED
CARDIOMYOPATHY
Dilated cardiomyopathy represents a final common
pathway of the myocardium in response to many dif-
ferent pathologic conditions. This has led to the ob-
vious conclusion that there are common pathways to
cardiac dilatation and failure. Local myocardial inju-
Vol ume 341 Numb e r 17 · 1279
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

ry can cause progressive and sometimes deleterious
dilatation and thinning of the ventricular wall.
In about 25 percent of patients with idiopathic di-
lated cardiomyopathy, the disorder is familial and ge-
netic, and it is likely to be genetic in some nonfamil-
ial cases as well.4 Indeed, the first example of familial
dilated cardiomyopathy for which the genetic basis
was defined was Duchenne’s muscular dystrophy. In
this and related muscular dystrophies, the molecular
defect is in the dystrophin–dystroglycan–laminin
transmembrane complex that connects the actin cy-
toskeleton of the muscle cells to structural proteins
that are synthesized by fibroblasts surrounding the
myocytes (Fig. 3). In these dystrophies, there is an
impairment of the normal linkage by which force
generated by individual myocytes is translated into
work done by the muscle tissue as a unit, and exces-
sive stresses on individual myocytes cannot be spread
across that muscle.
The recent demonstration that the molecular de-
fect in Syrian hamsters with cardiomyopathy lies in
the d-sarcoglycan component of this complex42 fur-
ther implicates the linkage between the myocyte cy-
toskeleton and the extracellular matrix in the patho-
genesis 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 dilat-
ed 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 compo-
nent of a biomechanical sensor pathway that trans-
duces hemodynamic force into specific signaling re-
sponses. 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 ex-
cessive stress on the chamber wall due to myocyte loss
or severe hemodynamic loading, generates a persist-
ent signal for ventricular growth and hypertrophy.2,44
By contrast, mutations in sarcomeric proteins cause

Extracellular matrix Laminin-2

Sarcoglycans a
Dystroglycans
d g a b
b

a-Actinin
Syntrophins
MLP Z-disk
Cytoskeletal7
? Dystrophin
a-actin7
7
Desmin7
7

Figure 3. Primary Structural Components of the Linkage between the Cytoskeleton and the Extracellular Matrix, Includ-
ing Actin, the Dystrophin–Glycoprotein 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) (as-
sociated with dilated cardiomyopathy in mice).23 The question mark indicates an unknown factor.

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 MECH A NIS MS OF D IS EASE

hypertrophic cardiomyopathy but do not affect ven-
tricular systolic function.
Apoptosis of Cardiac Myocytes
Apoptosis is a mechanism by which cells can be
eliminated without an inflammatory response. Evi-
dence of an increased rate of apoptosis has been de-
tected in failing hearts at the time of transplantation
in humans, as well as in hearts from animals with ex-
perimentally induced hypertrophy and cardiomyop-
athy. Unlike necrosis, apoptosis leaves little or no
histologic trace of the lost cells. Accordingly, docu-
menting its occurrence and estimating the extent of
the loss of myocytes as a result of apoptosis have
been problematic; therefore, the importance of ap-
optosis in the transition from compensatory hyper-
trophy to heart failure has been unclear.
At the cellular level, there is normally a balance be-
tween apoptotic and anti-apoptotic signals, and cell
death occurs in response to a persistent shift in this
balance. The cytokine tumor necrosis factor a, act-
ing through its receptor, activates both apoptotic
and anti-apoptotic signals, with a tendency toward
promoting apoptosis. Similarly, p21 ras induces both
apoptotic c-jun N-terminal kinase and anti-apoptotic
1-phosphatidylinositol 3-kinase signals. Among mito-
gen-activated protein kinases, the extracellular signal–
regulated kinases tend to be anti-apoptotic, c-jun
N-terminal kinase promotes apoptosis,8 and as men-
tioned, the a and b isoforms of p38 have opposing
effects (Fig. 2).9 Cell death may occur when the ap-
optotic forces exceed a certain threshold. The acti-
vation 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-func-
tion mutation in the cytokine receptor gp130 of the
ventricular chamber have normal cardiac structure but
have massive cardiac apoptosis accompanied by rap-
idly progressive dilated cardiomyopathy when sub-
jected to pressure overload.25 These studies indicate
that the inhibition of apoptosis by gp130-dependent
pathways in myocytes has a critical role in the tran-
sition between compensatory hypertrophy and overt
heart failure and suggest that the balance between ap-
optotic and hypertrophic pathways determines wheth-
er chamber dilatation will occur (Fig. 2).25
Cardiac Function and Contractility
The b-adrenergic–receptor pathway is a critical
point of control for cardiac contractility in both nor-
mal and failing hearts (Fig. 4). The primary func-
tional disturbance in dilated cardiomyopathy is im-
paired contractility, yet when contractility is decreased
in mice by overexpression of the calcium-regulatory
protein phospholamban, the mass and volume of the
cardiac chamber are no different from those in nor-
mal mice.46 Moreover, when contractility is decreased,
as in mice with mutations in the myosin heavy chain,
the result is hypertrophic cardiomyopathy, without

b-Adrenergic receptor

GSa Adenylyl cyclase

Sarcoplasmic.
reticulum

Cyclic AMP. PKA P

Phospho-7
b-Adrenergic–. lamban
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 in-
hibition of the calcium pump. b-Adrenergic receptors are desensitized in both heart failure and maladaptive hypertro-
phy; a substantial component in this desensitization is up-regulation of the b-adrenergic–receptor kinase (bARK). A de-
ficiency 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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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
chamber dilatation.47 These observations, as well as
clinical and experimental studies of b-adrenergic–
blocking drugs in patients with heart failure, suggest
that impaired contractility in certain forms of dilated
cardiomyopathy may be a secondary phenomenon,
perhaps resulting from alterations in energy metab-
olism or intracellular calcium handling.
Animals have been developed that have increased
ventricular contractile function as a primary feature.
These include mice that overexpress b1- and b 2-adre-
nergic receptors48,49 or the Gsa protein to which it is
coupled50; mice that overexpress a peptide inhibitor
of the b-adrenergic–receptor kinase, the principal
desensitizer of b-adrenergic receptors51; and mice in
which the phospholamban gene has been disrupted.52
The increased risk of death among patients with heart
failure that is associated with chronic stimulation of
b-adrenergic agonists can be replicated in mice with
dilated cardiomyopathy due to a cytoskeletal gene
mutation.23 The offspring of genetic crosses between
these mice 23 and those overexpressing b 2-adrenergic
receptors49 have a very high mortality rate.53 How-
ever, a genetic cross between the cardiomyopathic
mice 23 and those overexpressing the peptide inhibi-
tor of the b-adrenergic–receptor kinase results in a
mouse with decreased chamber dimensions and im-
proved contractile function.53 This suggests that the
deleterious effect of long-term exposure to inotropic
drugs, such as phosphodiesterase inhibitors, in pa-
tients with heart failure may not be due to changes
in contractility alone.53 The different effects of over-
expression of the b 2-adrenergic receptor and overex-
pression of the inhibitor of the b-adrenergic–recep-
tor kinase might also reflect differing downstream
effects on cardiac relaxation,54 or pathologic effects
of chronic b-adrenergic overstimulation48 as compared
with those resulting from relief of desensitization.53
In this regard, phospholamban negatively regulates
the uptake of calcium by the sarcoplasmic reticulum
(Fig. 4), and a deficiency of phospholamban can halt
progression of dilated cardiomyopathy and heart fail-
ure.54 b-Adrenergic pathways lead to the phospho-
rylation of phospholamban, which reduces its activ-
ity and increases ATPase activity in the sarcoplasmic
reticulum.
CONCLUSIONS
The decrease in cardiac performance in the failing
heart may be a consequence of alterations in specific
signaling molecules and their downstream pathways
in individual myocytes (Table 1). By analogy to car-
cinogenesis, heart failure may be viewed as a pro-
gressive, multistep process involving physiologic and
molecular initiators, promoters, suppressors, and ef-
fectors of the chronic course to heart-muscle failure.7
Further unraveling of the signals that cause specific
features of heart failure, coupled with the growing
human genome data base, should ultimately lead to
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the identification of targets whose actions could be
interrupted, thereby halting or perhaps reversing clin-
ical deterioration.
REFERENCES
1. Chien KR, Grace AA. Principles of cardiovascular molecular and cellu-
lar biology. In: Braunwald E, ed. Heart disease: a textbook of cardiovascu-
lar medicine. 5th ed. Vol. 2. Philadelphia: W.B. Saunders, 1997:1626-49.
2. Chien KR. Stress pathways and heart failure. Cell 1999;98:555-8.
3. Chien KR, Zhu H, Knowlton KU, et al. Transcriptional regulation dur-
ing cardiac growth and development. Annu Rev Physiol 1993;55:77-95.
4. Seidman CE, Seidman JG. Molecular genetics of inherited cardiomyop-
athies. In: Chien KR, ed. Molecular basis of cardiovascular disease: a com-
panion to Braunwald’s Heart Disease. Philadelphia: W.B. Saunders, 1999:
251-63.
5. Curran ME, Sanguinetti MC, Keating MT. Molecular basis of inherited
cardiac arrhythmias. In: Chien KR, ed. Molecular basis of cardiovascular
disease: a companion to Braunwald’s Heart Disease. Philadelphia: W.B.
Saunders, 1999:302-12.
6. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene
expression during myocardial growth and hypertrophy: molecular studies
of an adaptive physiologic response. FASEB J 1991;5:3037-46.
7. Hunter JJ, Grace AA, Chien KR. Molecular and cellular biology of car-
diac hypertrophy and failure. In: Chien KR, ed. Molecular basis of heart
disease: a companion to Braunwald’s Heart Disease. Philadelphia: W.B.
Saunders, 1999:211-50.
8. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing
effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;
270:1326-31.
9. Wang Y, Huang S, Sah VP, et al. Cardiac muscle cell hypertrophy and
apoptosis induced by distinct members of the p38 mitogen-activated pro-
tein kinase family. J Biol Chem 1998;273:2161-8.
10. Wang Y, Su B, Sah VP, Brown JH, Han J, Chien KR. Cardiac hyper-
trophy induced by mitogen-activated protein kinase kinase 7, a specific ac-
tivator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol
Chem 1998;273:5423-6.
11. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for Gal-
phaq and alpha1-adrenergic receptor signaling in cardiomyocytes: dissoci-
ation of Ras and Rho pathways. J Biol Chem 1996;271:31185-90.
12. Chien KR. Genes and physiology: molecular physiology in genetically
engineered animals. J Clin Invest 1996;97:901-9.
13. Rockman HA, Ross RS, Harris AN, et al. Segregation of atrial-specific
and inducible expression of an atrial natriuretic factor transgene in an
in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci U S A
1991;88:8277-81. [Erratum, Proc Natl Acad Sci U S A 1991;88:9907.]
14. Rockman HA, Ono S, Ross RS, et al. Molecular and physiological al-
terations in murine ventricular dysfunction. Proc Natl Acad Sci U S A
1994;91:2694-8.
15. Lin MC, Rockman HA, Chien KR. Heart and lung disease in engi-
neered mice: technological miniaturization combined with the power of
molecular genetics makes the mouse a model animal for understanding hu-
man cardiovascular and pulmonary disease. Nat Med 1995;1:749-51.
16. Christensen G, Wang Y, Chien KR. Physiological assessment of com-
plex cardiac phenotypes in genetically engineered mice. Am J Physiol 1997;
272:H2513-H2524.
17. Hunter JJ, Zhu H, Lee KJ, Kubalak S, Chien KR. Targeting gene ex-
pression to specific cardiovascular cell types in transgenic mice. Hyperten-
sion 1993;22:608-17.
18. Thorburn A, Thorburn J, Chen SY, et al. HRas-dependent pathways
can activate morphological and genetic markers of cardiac muscle cell hy-
pertrophy. J Biol Chem 1993;268:2244-9. [Erratum, J Biol Chem 1993;
268:16082.]
19. Hunter JJ, Tanaka N, Rockman HA, Ross J Jr, Chien KR. Ventricular
expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and
selective diastolic dysfunction in transgenic mice. J Biol Chem 1995;270:
23173-8.
20. Gottshall KR, Hunter JJ, Tanaka N, et al. Ras-dependent pathways in-
duce obstructive hypertrophy in echo-selected transgenic mice. Proc Natl
Acad Sci U S A 1997;94:4710-5.
21. Kai H, Muraishi A, Sugiu Y, et al. Expression of proto-oncogenes and
gene mutation of sarcomeric proteins in patients with hypertrophic cardio-
myopathy. Circ Res 1998;83:594-601.
22. Young SG, Lusis AJ, Hammer RE. Genetically modified animal mod-
els in cardiovascular research. In: Chien KR, ed. Molecular basis of cardio-
vascular disease: a companion to Braunwald’s Heart Disease. Philadelphia:
W.B. Saunders, 1999:37-85.
23. Arber S, Hunter JJ, Ross J Jr, et al. MLP-deficient mice exhibit a dis-
 MEC H A NIS MS OF D IS EASE
ruption of cardiac cytoarchitectural organization, dilated cardiomyopathy,
and heart failure. Cell 1997;88:393-403.
24. Chen J, Kubalak SW, Chien KR. Ventricular muscle-restricted target-
ing of the RXRalpha gene reveals a non-cell-autonomous requirement in
cardiac chamber morphogenesis. Development 1998;125:1943-9.
25. Hirota H, Chen J, Betz UAK, et al. Loss of a gp130 cardiac muscle
cell survival pathway is a critical event in the onset of heart failure during
biomechanical stress. Cell 1999;97:189-98.
26. Shubeita HE, McDonough PM, Harris AN, et al. Endothelin induc-
tion of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac
gene expression in ventricular myocytes: a paracrine mechanism for myo-
cardial cell hypertrophy. J Biol Chem 1990;265:20555-62.
27. Yamazaki T, Komuro I, Kudoh S, et al. Endothelin-1 is involved in me-
chanical stress-induced cardiomyocyte hypertrophy. J Biol Chem 1996;
271:3221-8.
28. Sadoshima J, Izumo S. Molecular characterization of angiotensin
II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fi-
broblasts: critical role of the AT1 receptor subtype. Circ Res 1993;73:413-
23.
29. Idem. The heterotrimeric G q protein-coupled angiotensin II receptor
activates p21 ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac
myocytes. EMBO J 1996;15:775-87.
30. Wollert KC, Taga T, Saito M, et al. Cardiotrophin-1 activates a distinct
form of cardiac muscle cell hypertrophy: assembly of sarcomeric units in
series VIA gp130/leukemia inhibitory factor receptor-dependent pathways.
J Biol Chem 1996;271:9535-45.
31. Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR.
Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mi-
togen-activated protein kinase-dependent pathway: divergence from down-
stream CT-1 signals for myocardial cell hypertrophy. J Biol Chem 1997;
272:5783-91.
32. Ito H, Hiroe M, Hirata Y, et al. Insulin-like growth factor-I induces
hypertrophy with enhanced expression of muscle specific genes in cultured
rat cardiomyocytes. Circulation 1993;87:1715-21.
33. Duerr RL, Huang S, Miraliakbar HR, Clark R, Chien KR, Ross J Jr.
Insulin-like growth factor-1 enhances ventricular hypertrophy and function
during the onset of experimental cardiac failure. J Clin Invest 1995;95:
619-27.
34. Milano CA, Dolber PC, Rockman HA, et al. Myocardial expression
of a constitutively active alpha 1B-adrenergic receptor in transgenic mice
induces cardiac hypertrophy. Proc Natl Acad Sci U S A 1994;91:10109-13.
35. LaMorte VJ, Thorburn J, Absher D, et al. Gq- and ras-dependent
pathways mediate hypertrophy of neonatal rat ventricular myocytes follow-
ing alpha 1-adrenergic stimulation. J Biol Chem 1994;269:13490-6.
36. D’Angelo DD, Sakata Y, Lorenz JN, et al. Transgenic Galphaq over-
expression induces cardiac contractile failure in mice. Proc Natl Acad Sci
U S A 1997;94:8121-6.
37. Adams JW, Sakata Y, Davis MG, et al. Enhanced Galphaq signaling: a
common pathway mediates cardiac hypertrophy and apoptotic heart failure.
Proc Natl Acad Sci U S A 1998;95:10140-5.
The New England Journal of Medicine
Downloaded from nejm.org at MIT LIBRARIES on October 10, 2013. For personal use only. No other uses without permission.
Copyright © 1999 Massachusetts Medical Society. All rights reserved.
38. Akhter SA, Luttrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ,
Koch WJ. Targeting the receptor-Gq interface to inhibit in vivo pressure
overload myocardial hypertrophy. Science 1998;280:574-7.
39. Gruver CL, DeMayo F, Goldstein MA, Means AR. Targeted develop-
mental overexpression of calmodulin induces proliferative and hypertrophic
growth of cardiomyocytes in transgenic mice. Endocrinology 1993;133:
376-88.
40. Molkentin JD, Lu JR, Antos CL, et al. A calcineurin-dependent tran-
scriptional pathway for cardiac hypertrophy. Cell 1998;93:215-28.
41. Mende U, Kagen A, Cohen A, Aramburu J, Schoen FJ, Neer EJ. Tran-
sient cardiac expression of constitutively active Galphaq leads to hypertro-
phy and dilated cardiomyopathy by calcineurin-dependent and independ-
ent pathways. Proc Natl Acad Sci U S A 1998;95:13893-8.
42. Nigro V, Okazaki Y, Belsito A, et al. Identification of the Syrian ham-
ster cardiomyopathy gene. Hum Mol Genet 1997;6:601-7.
43. Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT. Actin
mutations in dilated cardiomyopathy, a heritable form of heart failure. Sci-
ence 1998;280:750-2.
44. Chen J, Chien KR. Complexity in simplicity: monogenic disorders and
complex cardiomyopathies. J Clin Invest 1999;103:1483-5.
45. Minamisawa S, Hoshijima M, Ward CA, et al. Genetic complementa-
tion identifies phospholamban–sarcoplasmic reticulum Ca++ ATPase inter-
action as a critical Ca++ cycling defect that drives the progression of dilated
cardiomyopathy. Cell (in press).
46. Kadambi VJ, Ponniah S, Harrer JM, et al. Cardiac-specific overexpres-
sion of phospholamban alters calcium kinetics and resultant cardiomyocyte
mechanics in transgenic mice. J Clin Invest 1996;97:533-9.
47. Geisterfer-Lowrance AA, Christe M, Conner DA, et al. A mouse
model of familial hypertrophic cardiomyopathy. Science 1996;272:731-4.
48. Engelhardt S, Hein L, Wiesmann F, Lohse MJ. Progressive hypertro-
phy and heart failure in beta1-adrenergic receptor transgenic mice. Proc
Natl Acad Sci U S A 1999;96:7059-64.
49. Milano CA, Allen LF, Rockman HA, et al. Enhanced myocardial func-
tion in transgenic mice overexpressing the beta 2-adrenergic receptor. Sci-
ence 1994;264:582-6.
50. Iwase M, Bishop SP, Uechi M, et al. Adverse effects of chronic endog-
enous sympathetic drive induced by cardiac GS alpha overexpression. Circ
Res 1996;78:517-24.
51. Koch WJ, Rockman HA, Samama P, et al. Cardiac function in mice
overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor.
Science 1995;268:1350-3.
52. Luo W, Grupp IL, Harrer J, et al. Targeted ablation of the phospho-
lamban gene is associated with markedly enhanced myocardial contractility
and loss of beta-agonist stimulation. Circ Res 1994;75:401-9.
53. Rockman HA, Chien KR, Choi DJ, et al. Expression of a beta-adre-
nergic receptor kinase 1 inhibitor prevents the development of myocardial
failure in gene-targeted mice. Proc Natl Acad Sci U S A 1998;95:7000-5.
54. Xiao RP, Avdonin P, Zhou YY, et al. Coupling of beta2-adrenoceptor
to Gi proteins and its physiological relevance in murine cardiac myocytes.
Circ Res 1999;84:43-52.
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