Physiol Rev
82: 945–980, 2002; 10.1152/physrev.00012.2002.
Molecular Mechanisms of Inherited Cardiomyopathies
DIANE FATKIN AND ROBERT M. GRAHAM
Molecular Cardiology Unit, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
945
946
946
948
949
949
951
953
958
961
961
962
968
970
971
971
972
973
973
974
974
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
I. Introduction
II. Cardiomyocyte Cellular Physiology
A. Cardiac myocyte structure
B. Mechanisms of contraction
III. Hypertrophic Cardiomyopathy
A. Clinical manifestations
B. Chromosomal loci and disease genes
C. Functional consequences of gene mutations
D. Triggers and effectors of left ventricular hypertrophy
IV. Dilated Cardiomyopathy
A. Clinical manifestations
B. Chromosomal loci and disease genes
C. Pathophysiological mechanisms
D. Pathophysiology of HCM and DCM: is there a unifying hypothesis?
V. Arrhythmogenic Right Ventricular Dysplasia
A. Clinical manifestations
B. Chromosomal loci and disease genes
VI. Restrictive Cardiomyopathy
A. Clinical manifestations
B. Chromosomal loci and disease genes
VII. Conclusion
Fatkin, Diane, and Robert M. Graham. Molecular Mechanisms of Inherited Cardiomyopathies. Physiol Rev 82:
945–980, 2002; 10.1152/physrev.00012.2002.—Cardiomyopathies are diseases of heart muscle that may result from a
diverse array of conditions that damage the heart and other organs and impair myocardial function, including
infection, ischemia, and toxins. However, they may also occur as primary diseases restricted to striated muscle. Over
the past decade, the importance of inherited gene defects in the pathogenesis of primary cardiomyopathies has been
recognized, with mutations in some 18 genes having been identified as causing hypertrophic cardiomyopathy (HCM)
and/or dilated cardiomyopathy (DCM). Defining the role of these genes in cardiac function and the mechanisms by
which mutations in these genes lead to hypertrophy, dilation, and contractile failure are major goals of ongoing
research. Pathophysiological mechanisms that have been implicated in HCM and DCM include the following:
defective force generation, due to mutations in sarcomeric protein genes; defective force transmission, due to
mutations in cytoskeletal protein genes; myocardial energy deficits, due to mutations in ATP regulatory protein
genes; and abnormal Ca2⫹ homeostasis, due to altered availability of Ca2⫹ and altered myofibrillar Ca2⫹ sensitivity.
Improved understanding that will result from these studies should ultimately lead to new approaches for the
diagnosis, prognostic stratification, and treatment of patients with heart failure.
I. INTRODUCTION
Cardiomyopathies are diseases of heart muscle that
are associated with cardiac dysfunction. Heart failure due
to cardiomyopathy represents a major health problem in
our society. Although increased emphasis on prevention
programs and new therapeutic agents have resulted in
improved survival from acute coronary artery disease,
www.prv.org
there has been a dramatic increase in morbidity and mortality from heart failure, which has been described as the
emerging health epidemic of the 21st century.
Cardiomyopathies are classified traditionally according to morphological and functional criteria into four
categories: hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia,
and restrictive cardiomyopathy (135). These cardiomyop-
0031-9333/02 $15.00 Copyright © 2002 the American Physiological Society
945
946
DIANE FATKIN AND ROBERT M. GRAHAM
II. CARDIOMYOCYTE CELLULAR PHYSIOLOGY
A. Cardiac Myocyte Structure
1. Cardiac muscle fibers
Cardiac muscle fibers are comprised of separate cellular units (myocytes) connected in series. In contrast to
skeletal muscle fibers, cardiac muscle fibers do not assemble in parallel arrays but bifurcate and recombine to
form a complex three-dimensional network and have centrally, rather than peripherally, positioned nuclei. Cardiac
myocytes are joined at each end to adjacent myocytes by
specialized areas of interdigitating cell membrane, the
Physiol Rev • VOL
intercalated discs. The intercalated discs are comprised
of adherens junctions (containing N-cadherin, catenins,
and vinculin), desmosomes (containing desmin, desmoplakin, desmocollin, desmoglein), and gap junctions (containing connexins).
2. Sarcomeres and the sarcomeric cytoskeleton
Cardiac myocytes are surrounded by a thin membrane, the sarcolemma. The interior of each myocyte
contains bundles of longitudinally arranged myofibrils
that have a characteristic striated appearance, similar to
that of skeletal muscle, formed by repeating sarcomeres.
The sarcomere is the fundamental structural and functional unit of cardiac muscle that is comprised of interdigitating thick and thin filaments (Fig. 1). The thick
filaments are composed predominantly of myosin and
also contain the myosin binding proteins C, H, and X. The
thin filaments are composed of cardiac actin, ␣-tropomyosin, and troponins C, I, and T. Each sarcomere contains
an A band (comprised of overlapping thick filaments and
thin filaments), with a central M line (comprised of thick
filaments only). At each side of the A band are I bands
(comprised of thin filaments only) bounded by Z lines.
The sarcomeric cytoskeleton, comprised of titin and
the myomesins, provides a scaffolding for the thick and
thin filaments. Titin is a giant protein that spans from the
Z line to the M line. As well as contributing to sarcomere
assembly and organization, titin is a major determinant of
the elastic properties of the cardiac myofibril. Myomesins
1 and 2 are titin-associated proteins. The Z disc (at the Z
line) is formed by a lattice of interdigitating proteins that
maintain myofilament organization by cross-linking antiparallel titin and thin filaments from adjacent sarcomeres.
The Z-disc proteins include ␣-actinin, filamin, nebulette,
telethonin, and myotilin.
3. Extrasarcomeric cytoskeleton
The extrasarcomeric cytoskeleton is a complex network of proteins linking the sarcomere with the sarcolemma and the extracellular matrix. It provides structural
support for subcellular structures and transmits mechanical and chemical signals within and between cells. The
extrasarcomeric cytoskeleton has intermyofibrillar and
subsarcolemmal components (Fig. 1).
The intermyofibrillar cytoskeleton is comprised of
intermediate filaments, microfilaments, and microtubules.
Desmin intermediate filaments form a three-dimensional
scaffold throughout the extrasarcomeric cytoskeleton.
Desmin filaments surround the Z discs and form longitudinal connections to adjacent Z discs and lateral connections to subsarcolemmal costameres. Microfilaments
composed of nonsarcomeric actin (mainly ␥-actin) also
form a complex network linking the sarcomere (via ␣-actinin) to various components of the costameres. Tubulin
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
athies can be primary myocardial disorders or develop as
a secondary consequence of a variety of conditions, including myocardial ischemia, inflammation, infection, increased myocardial pressure or volume load, and toxic
agents. The pathogenesis of primary cardiomyopathies
has been poorly understood. Over the last decade, the
importance of gene defects in the etiology of primary
cardiomyopathies has been recognized. Autosomal dominant, autosomal recessive, X-linked, and maternal patterns of inheritance have been observed. Families with
inherited cardiomyopathies have provided a unique resource for studies of the genetic basis of these disorders.
Molecular genetic studies performed to date have focused
largely on monogenic inherited cardiomyopathies, i.e.,
caused by mutations in a single gene. Although relatively
uncommon, these monogenic disorders enable pathophysiological processes applicable to a wide range of
more commonly occurring heart diseases to be evaluated.
The usefulness of studying monogenic disorders was first
demonstrated by Brown and Goldstein (19) in their pioneering work on the role of the low-density lipoprotein
receptor in atherosclerosis. In 1989, Christine and Jon
Seidman and co-workers (63) reported the first association between an inherited gene defect and a primary
cardiomyopathy. In a subsequent study, they showed that
mutations in the ␤-myosin heavy chain gene were responsible for familial hypertrophic cardiomyopathy (40). Since
then, substantial progress has been made in elucidating
further gene defects in hypertrophic cardiomyopathy.
More recently, disease-causing genes have been identified
in dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia, and restrictive cardiomyopathy. Although
these genetic studies have enabled molecular triggers of
cardiomyopathies to be identified, the functional consequences of gene mutations and precise details of the
signaling pathways that lead to hypertrophy, dilation, and
contractile failure remain to be elucidated. Current concepts of the molecular genetic basis of inherited cardiomyopathies are summarized in this review.
INHERITED CARDIOMYOPATHIES
947
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
FIG. 1. Schematic of the components of cardiac myocyte structure. The sarcomere, comprised of interdigitating thick
and thin filaments, is the fundamental structural and functional unit of cardiac muscle. Sarcomeres are linked by a
complex network of cytoskeletal proteins with the sarcolemma, extracellular matrix, and nucleus. The intermyofibrillar
cytoskeleton is comprised of desmin intermediate filaments, actin-containing microfilaments, and microtubules. The
subsarcolemmal cytoskeleton is comprised of costameres, sites of interconnection between the various pathways linking
sarcomeres to sarcolemmal transmembrane proteins. Muscle contraction is an energy-requiring process that utilizes ATP
supplied by mitochondria. The intracellular free Ca2⫹ concentration ([Ca2⫹]i) critically regulates muscle contraction and
relaxation. Muscle contraction is initiated by an increase in [Ca2⫹]i. This results from depolarization-induced influx of a
small amount of Ca2⫹ via voltage-gated dihydropyridine receptors (DHPR) in t tubules, which in turn triggers the release
of a large quantum of Ca2⫹ from the sarcoplasmic reticulum (SR), a process called Ca2⫹-induced Ca2⫹ release. Muscle
relaxation is initiated by the uptake of cytosolic Ca2⫹ into the SR via the high energy-dependent pump, the SR
Ca2⫹-ATPase (SERCA2a) and by extrusion through the sarcolemmal Na⫹/Ca2⫹ exchanger. Pathophysiological mechanisms that have been implicated in hypertrophic and dilated cardiomyopathies include the following: defective force
generation, due to mutations in sarcomeric protein genes; defective force transmission, due to mutations in cytoskeletal
protein genes; myocardial energy deficits, due to mutations in ATP regulatory protein genes; and abnormal Ca2⫹
homeostasis, due to altered availability of Ca2⫹ and altered myofibrillar Ca2⫹ sensitivity. RyR, ryanodine receptor.
Physiol Rev • VOL
82 • OCTOBER 2002 •
www.prv.org
948
DIANE FATKIN AND ROBERT M. GRAHAM
B. Mechanisms of Contraction
The rod contains an elastic element and also binds myosin
light chains (MLC). The “swinging cross-bridge” model
was a subsequent modification of the sliding filament
model, which hypothesized that a swinging motion of the
myosin head was a critical factor for progression along
the thin filament (60, 84). In the first step of this model,
myosin is bound strongly to actin, with the myosin head
orientated in a 45° position relative to its tail. ATP binding
at the ATPase site causes rapid dissociation of myosin
from actin and the formation of ADP and Pi. Actin recombines weakly with this myosin-ADP-Pi complex, with the
myosin head orientated at a 90° angle. Release of ADP and
Pi enables the strong actin binding position to be regained. The power stroke is achieved in this last step by a
rowing-like movement of the myosin head as it “walks”
down the actin filament. Each cross-bridge cycle is associated with hydrolysis of one ATP molecule. The “leverarm” hypothesis was a subsequent modification of the
swinging cross-bridge model, in which structural changes
in the catalytic domain of the myosin head are amplified
by rotation of the myosin tail, acting as a lever arm (57,
59, 131). In this model, the power stroke is produced
not by movement of the myosin head (at the point of
actin attachment) but by the pivoting movement of the
myosin tail (at the hinge region). The lever arm rotation
has been attributed to the transition between two conformations of the myosin head, open and closed, that
influence nucleotide affinity and hydrolysis and that are
determined by actin binding. It has subsequently been
proposed that altered orientation of both the myosin
head and the ␣-helical tail may contribute to the overall
displacement of actin. Conflicting data have been reported for the extent of actin displacement, with estimates ranging from 4 –5 nm to 15–20 nm (59, 178). The
number of attached states may be an important determinant of actin displacement. It is possible that a single
myosin head may attach at two points on an actin
molecule or that one or two myosin heads may be
attached at any time point. Differences in compliance
and load in the various model systems studied may also
contribute to this range of data.
1. Actin-myosin interaction
2. Regulation by the troponin-tropomyosin complex
Currently, the universally accepted concept for the
process of muscle contraction is the “sliding filament”
theory, proposed by Huxley in 1957 (58). In this model,
force generation is achieved by the sliding movement of
the thick filaments relative to thin filaments, which is
mediated by the cyclical attachment and detachment of
myosin “cross-bridges” to actin. These cross-bridges consist of myosin heavy chain (MHC) molecules that project
from the thick filament. Muscle myosin contains two
MHC. Each MHC contains a head, with an actin binding
site and ATPase site. The heads are linked at a “hinge”
region to a long rod; that is an ␣-helical coiled-coil dimer.
Physiol Rev • VOL
The troponin-tropomyosin complex is a Ca2⫹-sensitive switch that regulates actin-myosin interaction. The
backbone of the thin filament is formed by a double
helical array of globular actin molecules. Tropomyosin
proteins assemble as ␣-helical coiled-coil dimers that lie
in a head-to-tail orientation within the major groove of the
actin filaments, spanning seven actin monomers. The troponin complex (troponins T, I, and C) is anchored to
tropomyosin predominantly by troponin T, and to a lesser
extent, by troponin I. Troponin C interacts with both
troponins T and I. During diastole, actin-myosin interac-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
is a cytosolic protein that is present in a polymerized form
(as microtubules) and in an unpolymerized form. Changes
in the total amount of tubulin and the proportion of the
polymerized form are thought to influence cytoskeletal
stiffness and hence contractile function.
Costameres are subsarcolemmal domains that are
located in a periodic, gridlike pattern, flanking the level of
the Z lines and overlying the I bands, along the cytoplasmic side of the sarcolemma. The costameres are sites of
interconnection between various cytoskeletal networks
linking the sarcomere and the sarcolemma. They are
thought to function as anchor sites for stabilization of the
sarcolemma and for integration of pathways involved in
mechanical force transduction. Costameres contain three
principal components: the focal adhesion-type complex,
the spectrin-based complex, and the dystrophin/dystrophinassociated glycoprotein complex. The focal adhesion-type
complex is comprised of cytoplasmic proteins, including
vinculin, talin, tensin, paxillin, and zyxin, that connect with
cytoskeletal actin filaments and with the transmembrane
proteins ␣- and ␤-integrin. The extracellular domains of the
integrins interact with collagens, laminin, and fibronectin in
the extracellular matrix. The spectrin-based complex contains ankyrin, that cross-links actin and spectrin, and spectrin, a component of the sarcolemma that interacts with
actin, ankyrin, and desmin. The dystrophin/dystrophin-associated glycoprotein complex is made up of the cytoskeletal
protein dystrophin, which binds to actin filaments, and the
dystrophin-associated glycoprotein complex (␣- and ␤-dystroglycans; ␣-, ␤-, ␥-, ␦-sarcoglycans; dystrobrevin; and
syntrophin). The dystrophin-associated glycoprotein complex has cytoplasmic, transmembrane, and extracellular
components. The cytoplasmic domain binds to the COOHterminal region of dystrophin; the extracellular domain
binds to laminin. Several actin-associated proteins are
located at sites of attachment of cytoskeletal actin filaments with costameric complexes, including ␣-actinin
and the muscle LIM protein MLP.
INHERITED CARDIOMYOPATHIES
tion is inhibited by the binding of troponin I to actintropomyosin. Ca2⫹ binding to troponin C induces a conformational change that weakens the interaction between
troponin I and actin-tropomyosin and strengthens the
interaction between troponin I and troponin C. These
changes release the thin filament from its inhibitory state,
promoting actin-myosin interaction and force generation.
A reduction in the intracellular Ca2⫹ concentration
([Ca2⫹]i) causes dissociation of Ca2⫹ from troponin C and
restores the relaxed state (148).
3. Role of calcium
Physiol Rev • VOL
4. Other regulatory factors
MLC and cardiac myosin binding protein C (cMyBP-C)
have been implicated as regulatory factors in muscle contraction. Essential and regulatory MLC bind to the ␣-helical lever arm of the myosin cross-bridge and influence
force production by modulating cross-bridge kinetics
(125, 140). cMyBP-C is thought to participate in the adrenergic regulation of cardiac contractility (38). The
MyBP-C motif, a highly conserved 100-residue region in
the NH2-terminal region of cMyBP-C, binds to the S2
segment near the lever arm of the myosin head (48).
Ultrastructural studies have shown that phosphorylation
of the MyBP-C motif by cAMP-dependent protein kinase
extends myosin cross-bridges from the backbone of the
thick filament and changes their orientation (176). Functional studies indicate that the phosphorylation status of
cMyBP-C is a determinant of the stiffness and attachment
rates of cross-bridges and Ca2⫹ sensitivity of force production (74, 176). In addition to these intrinsic sarcomere
components, numerous extrinsic factors, including neurohumoral, endocrine, and hemodynamic factors, influence cardiac contractility in vivo.
III. HYPERTROPHIC CARDIOMYOPATHY
A. Clinical Manifestations
1. Disease characteristics
Hypertrophic cardiomyopathy (HCM) is a primary
myocardial disorder with an autosomal dominant pattern
of inheritance that is characterized by hypertrophy of the
left (⫾right) ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial
fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in
500 (91). Various names have been given to this disorder
including hypertrophic obstructive cardiomyopathy and
idiopathic subaortic stenosis. These names reflect “textbook” features of asymmetric septal hypertrophy and left
ventricular outflow tract obstruction. This description of
the disease is based primarily on patients with severe
symptoms seen in tertiary hospital referral centers. Epidemiological studies now suggest that a wide spectrum of
clinical manifestations of varying severity and prognosis
is present in community populations. The generic name
HCM is thus more appropriate and is used in this review.
The first clinical description of HCM was reported in 1869
(51). HCM was recognized to be a genetic disorder in the
late 1950s. Since then, numerous clinical and pathological
studies of HCM have been performed. During the last
decade, molecular genetic studies have given important
insights into the pathogenesis of HCM and provide a new
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
The importance of Ca2⫹ in regulation of contraction
in normal myocytes and in cardiomyopathies has increasingly been recognized (Fig. 1). During the cardiac action
potential, [Ca2⫹]i is increased initially by direct Ca2⫹ entry into cells, via voltage-gated L-type channels and to a
lesser extent via Na⫹/Ca2⫹ exchange. This influx of Ca2⫹
triggers Ca2⫹ release from stores in the sarcoplasmic
reticulum via ryanodine receptors and inositol 1,4,5trisphosphate receptors. Increases in [Ca2⫹]i promote
Ca2⫹ binding to multiple cytosolic buffers, including troponin C. The magnitude of the systolic rise in [Ca2⫹]i is
determined not only by Ca2⫹ entry from the extracellular
fluid and the sarcoplasmic reticulum, but also by the
buffering capacity of the cell. During relaxation, Ca2⫹ is
removed from the cytosol by the sarcoplasmic reticulum
Ca2⫹-ATPase (SERCA2a), sarcolemmal Na⫹/Ca2⫹ exchange, sarcolemmal Ca2⫹-ATPase, and mitochondrial
Ca2⫹ uniporter. A complex network of positive and negative feedback mechanisms maintains the [Ca2⫹]i (8).
The Ca2⫹ dependence of force is generally expressed
as a function of the free [Ca2⫹]i. This relationship does
not directly indicate the total amount of Ca2⫹ required to
activate myofilaments, since changes in the sensitivity to
Ca2⫹ may be present. For example, myofilament Ca2⫹
sensitivity is decreased by protein kinase A phosphorylation of troponin I, low pH, and reduced sarcomere length
(8). Ca2⫹ activation may not just exert an “on-off” action
on actin-myosin interaction. It has been proposed that the
thin filament exists in three activation states. In the
“blocked” (off) state, Ca2⫹ is not bound to troponin C, and
cross-bridge binding is unable to occur; in the “closed”
(off) state, Ca2⫹ is bound to troponin C but there are no
strong cross-bridges; in the “open” (on) state, Ca2⫹ is
bound to troponin C and cross-bridges are strongly
bound. According to the three-state model, Ca2⫹ may
determine both whether or not cross-bridges bind and the
strength of binding. It has also been proposed that
changes in Ca2⫹ activation may alter the number of crossbridges attached, as well as the kinetics of cross-bridge
attachment and detachment (97, 148, 171).
949
950
DIANE FATKIN AND ROBERT M. GRAHAM
perspective for the diagnosis and management of patients
with this disorder.
2. Diagnosis of HCM
3. Natural history of HCM
The natural history of HCM is variable; some individuals remain asymptomatic throughout life, and others
may develop progressive symptoms with or without heart
failure or experience sudden death. Longitudinal echocardiographic studies have documented left ventricular rePhysiol Rev • VOL
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
Affected individuals with HCM exhibit significant
variability in their clinical presentation. Genotype-positive individuals may be asymptomatic or present with
symptoms ranging from palpitations and dizziness to syncope and sudden death. Genotype-phenotype studies have
shown that the age of onset of symptoms varies between
different HCM disease genes. For example, individuals
with ␤-MHC mutations typically present in the first two
decades of life, whereas those with cMyBP-C mutations
may be asymptomatic until the fifth or sixth decades
(116).
The primary modality for the diagnosis of HCM is
transthoracic echocardiography. The hallmark diagnostic
feature of HCM is asymmetric hypertrophy of the interventricular septum, with or without left ventricular outflow tract obstruction and systolic anterior motion of the
mitral valve. It is now recognized that the obstructive
form of HCM occurs in ⬍25% of affected individuals.
Studies of kindreds with HCM have shown that the distribution and severity of left ventricular hypertrophy may
vary considerably and that asymmetric hypertrophy is no
longer an essential requirement for the diagnosis of this
disorder. The diagnosis of HCM generally requires exclusion of secondary causes of hypertrophy, such as hypertension or aortic stenosis; however, in some individuals,
particularly in older age groups, these conditions may
coexist. The differentiation of HCM from physiological
left ventricular hypertrophy may be difficult, particularly
in competitive athletes. The extent of left ventricular
hypertrophy varies between different genes. For example,
individuals with ␤-MHC gene mutations usually develop
moderate or severe hypertrophy with a high disease penetrance, whereas those with cardiac troponin T gene mutations generally have only mild or clinically undetectable
hypertrophy (106, 173). Unusual forms of hypertrophy
have been reported, localized to the left ventricular apex
(cardiac troponin I mutations) (71) or midcavity (cardiac
actin and MLC gene mutations) (119, 125). The extent of
left ventricular hypertrophy may also vary between members of a single family with the same gene mutation.
These observations may be explained by a modifying role
of additional genetic and environmental factors, such as
blood pressure, exercise, diet, and body mass.
modeling with age. Progressive increases in left ventricular wall thickness have been reported in ungenotyped
individuals during adolescence and early adult life. In
some individuals, including those with cMyBP-C mutations, left ventricular wall thickness may increase in later
life (116). Age-related reductions in left ventricular wall
thickness, associated with myocyte loss and fibrosis, have
also been described in individuals with long-standing disease (“burnt out” HCM). Ten to 20% of individuals with
HCM may develop dilated cardiomyopathy. Ten to 16% of
affected individuals develop atrial fibrillation. The risk of
atrial fibrillation is increased in those with left atrial enlargement.
HCM is a frequent cause of sudden death, particularly
in young individuals and competitive athletes. Estimates
of the prevalence of sudden death vary according to the
population studied, ranging from ⬍1% in the general community to 3– 6% in tertiary hospital referral centers. Various mechanisms for sudden death have been proposed,
including ventricular bradyarrhythmias due to sinus node
and atrioventricular conduction abnormalities and tachyarrhythmias triggered by reentrant depolarization pathways related to myofibrillar disarray and fibrosis, abnormal
Ca2⫹ homeostasis, myocardial ischemia, left ventricular
diastolic dysfunction, or left ventricular outflow tract obstruction. Various risk stratification algorithms based on
clinical parameters have been proposed to identify individuals with an increased propensity for sudden death.
Given the complexity of mechanisms that may precipitate
sudden death, it is not surprising that no single risk factor
has been identified. Conflicting results have been found
for the positive predictive value of young age at diagnosis,
history of syncope, severity of symptoms, left ventricular
wall thickness, left ventricular outflow tract gradient, left
atrial size, and atrial fibrillation. The majority of clinical
risk factor studies have been performed in ungenotyped
populations. In genotyped individuals, it has been demonstrated that prognosis varies considerably between different HCM genes and between different mutations in the
same gene. For example, the Arg403Gln and Arg453Cys
␤-MHC mutations, cardiac troponin T mutations, and
some ␣-tropomyosin mutations (Ala63Val, Lys70Thr) are
“high risk” mutations with reduced life expectancy and
high rates of sudden death, whereas the Val606Met
␤-MHC mutation and cMyBP-C mutations have a relatively benign course (106, 116, 173, 174). The mechanisms
whereby HCM gene mutations influence prognosis are
unknown. Although some HCM mutations that alter the
charge of the encoded amino acid have been associated
with a poor outcome, other mutations that alter charge
have a good prognosis (170, 174). Electrophysiological
studies in mouse models may provide important insights
into the differential propensity for sudden death between
different HCM gene mutations.
INHERITED CARDIOMYOPATHIES
B. Chromosomal Loci and Disease Genes
1. Chromosomal loci
TABLE
1. HCM chromosomal loci and disease genes
Chromosomal
Locus
Gene
Protein
1q32
2q31
3p21
3p21-p14
7q36
TNNT2
TTN
MYL3
TNNC1
PRKAG2*
11p11
11p15
12q23-q24
14q12
15q14
15q22
19q13
MYBPC3
CLP
MYL2
MYH7
ACTC
TPM1
TNNI3
Cardiac troponin T
Titin
Essential myosin light chain
Cardiac troponin C
AMP-activated protein kinase
(␥2-regulatory subunit)
Cardiac myosin binding protein C
Cardiac muscle LIM protein
Regulatory myosin light chain
␤-Myosin heavy chain
Cardiac actin
␣-Tropomyosin
Cardiac troponin I
* Recent data suggest that families with PRKAG2 mutations may
have a novel myocardial metabolic storage disease rather than hypertrophic cardiomyopathy (HCM) (see sect. IIID).
Physiol Rev • VOL
Mutations in the 12 known disease genes account for
⬃50 –70% of all cases of HCM. It is possible that families
in which mutations have not been found have undiscovered abnormalities in one of the known disease-causing
genes. Alternatively, a significant number of novel genes
may remain to be identified. Generally, individuals with
HCM-causing mutations are heterozygous at the disease
locus, i.e., one copy (allele) of the gene is mutated and the
other allele has the normal DNA sequence. Two cases of
homozygous HCM mutations have recently been reported;
one of these was an Arg869Gly point mutation in the
␤-MHC gene (55), and the other was a Ser179Phe mutation in the cardiac troponin T gene (136). Both mutations
caused a particularly severe phenotype with onset in
childhood and premature death.
2. ␤-Myosin heavy chain gene (MYH7)
Myosin exists as a hexameric protein with two heavy
chains and two sets of light chains. Cardiac MHC exists as
two isoforms: ␤- and ␣-MHC. In humans, ␤-MHC is
present in the embryonic heart and the adult atrium and is
the predominant isoform expressed in the adult ventricle.
␤-MHC is also expressed in slow skeletal muscles, such as
the soleus. In rodents, ␤-MHC is the principal isoform
expressed in the embryonic ventricle with a switch to
predominance of ␣-MHC in the adult ventricle. The MYH7
gene (encoding ␤-MHC) and the MYH6 gene (encoding
␣-MHC) are located in tandem on chromosome 14, ⬃4 kb
apart. MYH7 is comprised of 23 kb of genomic DNA, with
41 exons, 38 of which encode a protein of 1,935 amino
acids. Seventy-three mutations in the MYH7 gene have
been reported, accounting for ⬃30 –35% of cases of HCM
(32, 40). The majority of mutations are missense mutations. Deletions and premature termination codons have
also been identified. MYH7 mutations appear to be distributed throughout the gene-coding sequence. Three-dimensional structural studies of the MHC molecule have
demonstrated, however, that these mutations cluster predominantly in four domains in the MHC head: 1) the actin
binding surface, 2) the nucleotide binding pocket, 3) adjacent to two reactive cysteines in the hinge region, and 4)
in the ␣-helical tail near the essential MLC binding site
(130). A small number of mutations occur in the MHC rod.
Although the functional consequences have not been defined precisely, it has been proposed that rod mutations
may result in altered transmission of force from the head
to the body of the thick filament (170).
3. cMyBP-C gene (MYPBC3)
Myosin binding protein C has three isoforms: slow
skeletal, fast skeletal, and cardiac. The cardiac MyBP-C
isoform is expressed exclusively in cardiac tissue. It is
located in the sarcomere A bands and forms a series of
seven to nine transverse bands spaced at 43-nm intervals.
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
HCM is a genetically heterogeneous disorder, with 12
distinct chromosomal loci mapped to date. Disease-causing genes have now been identified in all 12 loci: the first
10 of these genes encoded protein components of the
cardiac sarcomere. Mutations have been found in four
genes that encode components of the thick filament:
␤-MHC (40), essential MLC (125), regulatory MLC (125),
and cMyBP-C (14, 172); in five genes that encode thin
filament proteins: cardiac actin (119), cardiac troponin T
(165), cardiac troponin I (71), cardiac troponin C (56), and
␣-tropomyosin (165); and in the sarcomeric cytoskeletal
protein titin (143) (Table 1). Recently, mutations in two
genes encoding nonsarcomeric proteins have been reported to cause HCM. Mutations in the ␥2-regulatory subunit of an AMP-activated protein kinase (AMPK) were
found to be responsible for a variant of HCM associated
with ventricular preexcitation (Wolff-Parkinson-White
syndrome) at the chromosome 7q36 locus (11). Mutations
in the gene encoding the cytoskeletal muscle LIM protein
have also been identified (39).
For each disease gene, a variety of different mutations have been reported. Single nucleotide substitutions
(“missense” mutations) and deletion or insertion of nucleotides have been identified. In some cases, the encoded
protein is of normal size. In other cases, the mutation may
result in a premature termination codon or cause a shift of
the reading frame with truncation of the encoded protein.
Mutations located at intron-exon boundaries can result in
abnormal splicing. In general, each affected family has a
unique mutation, although several mutation “hot spots”
have been found. Methylated CpG dinucleotides within
the genome are particularly prone to point mutations (26).
951
952
DIANE FATKIN AND ROBERT M. GRAHAM
4. Cardiac troponin T gene (TNNT2)
Cardiac troponin T is expressed in embryonic and
adult heart and in developing skeletal muscle. TNNT2 is
comprised of 17 kb of genomic DNA and has 17 exons. A
number of different cardiac troponin T isoforms are produced by alternate splicing. The principal isoform in the
adult heart consists of 288 amino acids and has two major
domains: an NH2-terminal domain that interacts with tropomyosin and a COOH-terminal domain that binds to
tropomyosin, troponin C, and troponin I. TNNT2 mutations account for ⬃5–10% of cases of HCM. Fourteen
mutations have been reported: 12 missense mutations
located in both the NH2-terminal and COOH-terminal domains, 1 splice site mutation, and 1 single codon deletion
(32, 165).
5. Cardiac troponin I gene (TNNI3)
Cardiac troponin I is expressed solely in cardiac
tissue. TNNI3 is comprised of 6.2 kb of genomic DNA and
has 8 exons that encode a protein of 210 amino acids.
Cardiac troponin I has an inhibitory region (residues 129 –
149) that, at low Ca2⫹ concentrations, depresses contraction by inhibition of actomyosin ATPase (mediated by
protein kinase C phosphorylation). Increased binding of
cardiac troponin I to the thin filament (mediated by protein kinase A) also contributes to inhibition of contraction. Under activating conditions, the inhibitory region of
cardiac troponin I binds to troponin C-Ca2⫹, permitting
actin-myosin interaction. Two binding sites for actin-tropomyosin and a second troponin C site are located more
proximal to the COOH terminus. Troponin I forms an
antiparallel dimer with troponin C. Eight TNNI3 mutations have been reported (⬍5% cases of HCM): seven
missense mutations and one single codon deletion (32,
71). Two mutations are located in the inhibitory region,
with one mutation found in each of the second troponin C
and actin-tropomyosin sites, respectively.
Physiol Rev • VOL
6. Cardiac troponin C gene (TNNC1)
Troponin C has two isoforms that are expressed in
cardiac and skeletal muscle. The TNNC1 gene encodes
the isoform that is present in the heart and in slow skeletal muscle. TNNC1 consists of 3 kb of genomic DNA with
6 exons that encode a protein of 161 amino acids. Ca2⫹
binding to cardiac troponin C induces conformational
changes in the troponin-tropomyosin complex that initiate muscle contraction. Cardiac troponin C has two Ca2⫹
binding sites, only one of which is functional. Recently,
one missense mutation in the TNNC1 gene was reported
in an individual with HCM (56).
7. ␣-Tropomyosin gene (TPM1)
␣-Tropomyosin is expressed in ventricular myocardium and in fast skeletal muscle. TPM1 consists of 15
exons, with multiple isoforms resulting from alternate
splicing. Five exons are present in all ␣-tropomyosin transcripts with the remaining 10 exons variably present in
different tissues. The cardiac ␣-tropomyosin isoform is
comprised of 10 exons and 284 amino acids. ␣-Tropomyosin has two binding sites for troponin T, one of which is
Ca2⫹ sensitive and the other Ca2⫹ insensitive. Six TPM1
missense mutations have been reported; three of these
are located in the Ca2⫹-sensitive troponin T site (32, 165).
8. Regulatory MLC gene (MYL2)
The MLC belong to a superfamily of Ca2⫹-binding
proteins, which is characterized by helix-loop-helix of
Ca2⫹-binding sites (EF hands). Other members of this
family included troponin C and calmodulin. Cardiac muscle has two regulatory (or phosphorylatable) MLC isoforms. The MLC-2 slow isoform is expressed in the ventricle and in slow skeletal muscle; the MLC-2 atrial
isoform is expressed in atrial myocardium. MYL2 encodes
the MLC2 slow isoform. It has seven exons that encode a
protein of 166 amino acids. Eight MYL2 missense mutations have been reported (32, 125).
9. Essential MLC gene (MYL3)
Two of the five essential (or alkali) MLC isoforms are
present in cardiac muscle. The MLC-1 slow/ventricular
isoform is expressed in the ventricle and slow skeletal
muscle. MYL3 is comprised of 7 exons, 6 of which encode
a protein of 195 amino acids. Two MYL3 missense mutations have been reported (32, 125).
10. Cardiac actin gene (ACTC)
Twenty actin genes are present in the human genome, four of which are found in cardiac, skeletal, and
smooth muscle. The cardiac and skeletal actin isoforms
are both expressed in the heart and skeletal muscle.
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
MYBPC3 is comprised of 24 kb of genomic DNA with 37
exons that encode a protein of 1,274 amino acids. The
protein has multiple immunoglobulin C2-like and fibronectin type 3 domains, as well as a cardiac-specific
region, a phosphorylation region, and overlapping myosin
and titin binding sites. MYPBC3 mutations are found in
⬃15–20% individuals with HCM. Thirty mutations have
been reported (14, 32, 172). The majority of mutations are
insertions, deletions, or splice site mutations that result in
truncation of the cMyBP-C protein with loss of the myosin
and titin binding sites. Missense mutations that preserve
the myosin and titin binding sites have also been found.
None of these mutations has been located in the cardiacspecific region.
INHERITED CARDIOMYOPATHIES
␣-Skeletal actin is the predominant actin isoform in the
embryonic heart but is downregulated in the adult heart.
ACTC has 6 exons that encode 375 amino acids. The
NH2-terminal domain of cardiac actin is the site of myosin
cross-bridge attachment; the COOH-terminal domain has
binding sites for ␣-actinin and dystrophin. Five ACTC
mutations have been identified; two of these were missense mutations located close to the myosin binding region (32, 119).
953
addition to its protein kinase activity, AMPK is postulated
to have a transcriptional regulatory role, since it is homologous to the SNF1 transcription factor complex that regulates glucose metabolism in yeast. Five PRKAG2 mutations have recently been reported in families with HCM
associated with preexcitation (Wolff-Parkinson-White
syndrome); four missense mutations and one in-frame
single codon insertion (2, 11, 47).
13. Cardiac muscle LIM protein gene (CLP)
11. Titin gene (TTN)
12. ␥2-Regulatory subunit of AMPK gene (PRKAG2)
AMPK is a heterotrimeric protein comprised of a
catalytic subunit (␣) and two regulatory subunits (␤ and
␥). The ␥-subunit has three isoforms (␥1, ␥2, ␥3) that vary
in length and tissue expression. The PRKAG2 gene encodes the ␥2-subunit, which is the predominant ␥-isoform
present in the heart. PRKAG2 is comprised of ⬎280 kb of
genomic DNA. Two isoforms have been identified: a
longer transcript (PRKAG2b) with 16 exons that encodes
569 amino acids, and a shorter transcript (PRKAG2a)
with 12 exons that encodes tissue-specific proteins of 352
and 328 amino acids, respectively. The shorter transcript
results from an alternate transcription initiation site in
intron 4. The ␥2-AMPK protein consists primarily of four
consecutive cystathionine-␤-synthase (CBS) domains.
AMPK acts as a “metabolic sensor” in cells, responding to
ATP depletion by regulating diverse intracellular pathways that utilize and generate ATP. In the absence of
metabolic stress, AMPK activity is suppressed by an autoinhibitory region on the ␣-subunit that blocks the catalytic site. During periods of hypoxic or metabolic stress,
consumption of ATP results in an increase in the AMP/
ATP ratio. Rising levels of AMP activate AMPK by interactions with both the autoinhibitory region and the ␥-subunit, as well as activating an upstream kinase, AMPKK. In
Physiol Rev • VOL
Cardiac muscle LIM protein is expressed in cardiac
and slow-twitch skeletal muscle. CLP has 4 exons that
encode a protein of 194 amino acids. Cardiac muscle LIM
protein consists of 2 LIM domains, linked by a spacer of
50 residues. LIM domains are highly conserved cysteinerich structures that contain two zinc fingers. Cardiac muscle LIM protein is present in embryonic muscle and has
been shown to be an important regulator of myogenic
differentiation. Cardiac muscle LIM protein is also
thought to act as a scaffold for protein assembly in the
actin-based cytoskeleton. The first of the two LIM domains interacts with ␣-actinin, a component of the Z
discs, whereas the second LIM domain interacts with
actin filaments and spectrin. Four CLP missense mutations have been reported in individuals with HCM (39).
C. Functional Consequences of Gene Mutations
Since the majority of HCM disease genes encode
protein components of the sarcomere, it has been widely
proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction. Characterization of the
fundamental deficit resulting from HCM-causing gene mutations has been a major focus of research over the last
decade. A variety of techniques have been used to examine the effects of mutations on sarcomere structure and
function, ranging from in vivo studies of myocardial performance in genetically engineered mouse models to in
vitro studies of interactions between single actin and
myosin molecules. It is clear, as detailed below, that the
type of strategy employed to investigate the effects of
sarcomere protein mutations greatly influences the outcome, with conflicting results found for the same mutation in many cases. Investigators have sought to answer
questions such as whether the various sarcomere protein
mutations cause similar or diverse effects on sarcomere
structure and function and whether sarcomere protein
mutations act by a dominant negative mechanism or alter
function by causing haploinsufficiency. In the dominant
negative model, both wild-type and mutant proteins are
present in equivalent proportions; the mutant peptide is
stably incorporated into the sarcomere but acts as a “poison polypeptide” and perturbs wild-type protein function.
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
Titin is a giant (3 kDa) protein that is the largest
known polypeptide. It comprises 10% of vertebrate striated muscle. Titin spans half sarcomeres, with an extensible portion within the I band and a stiffer portion within
the A band. Ninety percent of titin’s mass is comprised of
up to 298 repeating immunoglobulin and fibronectin 3
domains. The I-band region contains tandemly arranged
immunoglobulin domains, as well as a PEVK segment,
composed of a sequence rich in proline, glutamine, valine,
and lysine residues, and a cardiac-specific N2B region.
Titin contributes to the maintenance of sarcomere organization and myofibrillar elasticity. Titin may also participate in myofibrillar cell signaling. Tissue-specific expression of various titin isoforms results in differential tissue
elasticity. One HCM-causing TTN missense mutation has
been identified in a single individual (143). This mutation
was located in the Z-disc binding region of titin.
954
DIANE FATKIN AND ROBERT M. GRAHAM
Alternatively, mutations may result in null alleles or cause
a reduction in the amount of wild-type protein, leading to
an imbalance of sarcomere protein stoichiometry. Mutations that truncate the encoded protein are thought to act
by haploinsufficiency. Understanding the consequences
of sarcomere protein mutations is an essential prerequisite for determining the stimulus for hypertrophy in HCM.
For example, if HCM-causing mutant proteins merely induced an imbalance in the stoichiometry of the protein
components involved in sarcomere assembly, in vitro
analysis of the mutant proteins per se would have little
merit.
A) ARG403GLN ␤-MHC STUDIES. Based on their structural
location in the myosin head (see sect. IIIB2), the majority
of MYH7 gene mutations can be predicted to disrupt both
mechanical and catalytic components of actin-myosin interaction leading to a reduction of force generation. The
Arg403Gln missense mutation in ␤-MHC has been studied
the most extensively. The Arg-403 residue is located in the
myosin head at the base of a loop that interacts with actin.
A Glu substitution at this residue results in a loss of
charge. Studies of the structural and functional consequences of the Arg403Gln mutation in ␤-MHC have been
performed. Sarcomere assembly was disrupted when human Arg403Gln ␤-MHC was transfected into adult feline
cardiomyocytes (87) but was unchanged when this mutation was introduced into neonatal rat cardiomyocytes (7).
Functional studies of the Arg403Gln ␤-MHC mutation using soleus muscle biopsy specimens from patients with
HCM have shown that mutant muscle fibers have depressed velocity of shortening, reduced force/stiffness
ratio, and reduced power output when compared with
control muscle (77). A number of in vitro motility assays
performed with human and recombinant mutant ␤-MHC
have shown reduced velocity of actin translocation (23,
142, 155).
B) ARG403GLN ␣-MHC MOUSE MODEL. Geisterfer-Lowrance
et al. (41) generated a mouse model of HCM in which an
Arg403Gln point mutation was introduced into the murine
␣-MHC gene using the “hit-and-run” technique. In contrast
to transgenic models in which the location and level of
expression of a mutant transgene can be highly variable,
the hit-and-run technique results in precise targeting of a
single allele at a specific locus, analogous to human heterozygous HCM mutations. Heterozygous Arg403Gln
␣-MHC (designated ␣-MHC403/⫹) mutant mice demonstrated progressive left ventricular hypertrophy on transthoracic echocardiography, together with histological
evidence of myocyte hypertrophy, myofibrillar disarray,
and fibrosis (35, 41). Left ventricular sections from
␣-MHC403/⫹ mice showed normal sarcomere structure on
electron microscopy (12).
Physiol Rev • VOL
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
1. ␤-Myosin heavy chain gene mutations
Systolic function in ␣-MHC403/⫹ mouse hearts has
been evaluated in detail using several techniques. Serial in
vivo hemodynamic studies demonstrated that young (6
wk) ␣-MHC403/⫹ mice had normal myocardial histology
but altered contraction kinetics with accelerated systolic
pressure rise. By 20 wk of age, ␣-MHC403/⫹ mice had
developed myocardial histopathology as well as hyperdynamic left ventricular contraction, increased end-systolic
chamber stiffness, increased left ventricular outflow tract
pressure gradient, and lower cardiac index (43). It was
proposed that the fast systolic kinetics in young mice
represented primary effects of the Arg403Gln mutation
with later exacerbation of left ventricular dysfunction
attributable to altered left ventricular wall composition
and chamber geometry. Two groups of investigators have
studied isolated papillary muscles from ␣-MHC403/⫹ mice.
In one study, ␣-MHC403/⫹ and control left ventricular trabeculae and papillary muscles were able to generate similar peak force during twitch contractions, but mutant
muscle required higher intracellular Ca2⫹ concentrations
to achieve equivalent force. Increased Ca2⫹ mobilization
in mutant muscle was insufficient to maintain force, however, at high stimulation rates (37). In a second study,
sinusoidal length perturbation analysis was used to generate oscillatory work and evaluate cross-bridge function
in ␣-MHC403/⫹ papillary muscle strips. Ca2⫹ dependence
of ␣-MHC403/⫹ muscle was demonstrated. At maximal or
near-maximal Ca2⫹ activation, peak isometric tension and
oscillatory power were reduced in mutant muscle strips;
at submaximal Ca2⫹ concentrations, tension and power
output were shown to have increased Ca2⫹ sensitivity.
Compared with wild-type muscle strips, ␣-MHC403/⫹ muscle strips had depressed cross-bridge kinetics (12).
␣-MHC403/⫹ myocytes have been shown to have depressed velocity of contraction but equivalent sarcomere
length, fractional shortening, and peak amplitude of Ca2⫹
transients when compared with wild-type myocytes (70).
Finally, elegant single molecule studies of MHC isolated
from ␣-MHC403/⫹ mouse hearts have shown dose-related
increases in actin-activated ATPase activity, force generation, and actin filament sliding velocity (169).
Does the Arg403Gln MHC mutation cause hypo- or
hypercontractile function? Although several studies have
suggested that Arg403Gln MHC augments cross-bridge
kinetics and force generation, a large body of data derived
from in vitro studies has suggested that Arg403Gln MHC
perturbs actin-myosin interaction and depresses motor
function. Several pathophysiological mechanisms for
these findings have been proposed, including altered myosin binding affinity for actin, reductions in cross-bridge
cycling rates, reduction in the extent of actin displacement per cross-bridge cycle, a drag effect on normal
cross-bridges by mutant cross-bridges, or abnormal interactions between heterodimeric myosin heads. Observations of depressed contractile function, at the cellular
INHERITED CARDIOMYOPATHIES
2. cMyBP-C gene mutations
cMyBP-C is thought to have structural and regulatory
roles in the sarcomere. Experimental studies have focused on the effects of cMyBP-C mutations, in particular,
those that result in truncated proteins, on sarcomere
assembly. Transfection of a range of COOH-terminal truncation mutants into skeletal myoblasts demonstrated a
minimal region of 372 amino acids was required for correct localization into the sarcomere A band; one construct, which lacked the major myosin binding domain,
strongly inhibited myofibril assembly. It was proposed
that truncated protein might compete with endogenous
Physiol Rev • VOL
cMyBP-C at the myosin binding site. The truncated proteins were all detected by Western blot (45). In another
study, truncated cMyBP-C protein in cardiac tissue from a
patient with a splice donor site mutation was unable to be
detected by Western blot, despite the presence of a mRNA
transcript. It was suggested that the truncated protein
may have undergone rapid proteolysis and that a reduction in cMyBP-C protein might alter the stoichiometry of
sarcomere proteins with consequent impairment of sarcomere assembly (138).
Western blot analyses of myocardium from a transgenic mouse expressing a truncated cMyBP-C lacking
myosin and titin binding domains demonstrated endogenous regulation of total cMyBP-C levels with overexpression of the mutant protein compensated by a reduction in
wild-type protein (180). Histological analyses of myocardial sections from 25-wk-old mice showed foci of degenerate myocytes and sarcomeric disorganization. The mutant protein was incorporated into the sarcomere but was
also present diffusely throughout the cytoplasm. A second
mouse model with a similar cMyBP-C truncation was
generated using homologous recombination techniques
(95). In contrast to ␣-MHC403/⫹ mice, heterozygous mice
(MyBP-Ct/⫹) did not develop left ventricular hypertrophy
until after 125 wk of age. This late onset of hypertrophy is
analogous to that observed in patients with HCM caused
by cMyBP-C mutations. Total cMyBP-C protein expression in the left ventricle of MyBP-Ct/⫹ mice was slightly
reduced (90% wild-type levels). In contrast to the transgenic mouse studies, myocardial histology of MyBP-Ct/⫹
mice aged 125 wk was indistinguishable from agematched wild-type mice. In particular, sarcomere assembly was normal. Differences between these in vitro and in
vivo studies in the effects of truncated cMyBP-C on sarcomere organization and protein localization may result
from differences in the relative proportions of mutant and
wild-type protein, with abnormalities detected only with
overexpression models. Endogenous regulation of protein
levels or posttranslational modification may reduce the
levels of wild-type protein below a threshold level required for maintenance of normal sarcomere relationships. Alternatively, truncated protein may competitively
inhibit wild-type protein function. Dose-related effects are
suggested by the findings of normal myocardial histology
in heterozygous MyBP-Ct/⫹ mice but prominent left ventricular hypertrophy, disarray, and fibrosis in homozygous
MyBP-Ct/t mice (95, 96).
Few studies have examined the functional consequences of cMyBP-C truncations. Hemodynamic analyses
in isolated heart preparations from transgenic cMyBP-C
mice aged 25 wk showed no differences in contraction or
relaxation parameters between mutant and wild-type
hearts (180). Similarly, in vivo hemodynamic studies
showed no differences in systolic or diastolic parameters
between MyBP-Ct/⫹ and wild-type mice (95). Studies of
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
level, however, cannot be readily reconciled with the
clinical finding of preserved, or enhanced, systolic function in patients with HCM. These apparently conflicting
findings highlight the importance of the methods used to
evaluate contractile performance. Studies of the interaction between single myosin and actin molecules might
intuitively appear to be the optimal technique for determining the fundamental consequences of a mutant protein. However, these studies do not take into account the
effects of loading or the regulatory influences of other
protein components of the sarcomere. In the intact heart,
the presence of hypertrophy, myofibrillar disarray, fibrosis, and hemodynamic changes will further influence left
ventricular systolic and diastolic performance. Differences in contractile “environment” may explain the seemingly paradoxical findings related to effects of mutant
protein “dose”: in single molecule studies, increasing
amounts of mutant myosin cause progressive increases in
systolic function, whereas in vivo studies in homozygous
Arg403Gln ␣-MHC mice demonstrate reduced systolic
function with a rapidly progressive dilated cardiomyopathy (33).
Studies of left ventricular diastolic function in
␣-MHC403/⫹ mouse hearts have uniformly shown prolongation of relaxation, analogous to that observed in patients with HCM (41, 43, 149). It has been proposed that
diastolic dysfunction may be a direct mechanical consequence of slowed cross-bridge cycling rates and thus a
fundamental consequence of HCM mutations. The detection of prolonged decay of Ca2⫹ transients in ␣-MHC403/⫹
myocytes raises the additional possibility that Ca2⫹ dysregulation or altered Ca2⫹ sensitivity may contribute to
impaired relaxation (70). Myocardial energetic studies
suggest that an energy-requiring process may also prolong
diastolic relaxation (149). The development with age of
left ventricular structural changes may increase diastolic
stiffness and further exacerbate left ventricular diastolic
filling abnormalities. Further studies are required to determine the molecular and cellular consequences of diastolic dysfunction and its relationship with the development of hypertrophy.
955
956
DIANE FATKIN AND ROBERT M. GRAHAM
ventricular fibers from transgenic mice demonstrated a
leftward shift in the pCa-force relationship and a reduction of maximum power (180). It is not clear whether
these changes represent primary effects of the mutant
protein on sarcomere function or are a consequence of
the deranged sarcomere structure present in this model.
3. Cardiac troponin T gene mutations
Physiol Rev • VOL
4. Cardiac troponin I gene mutations:
Arg145Gly mutation
The Arg-145 residue is located in the inhibitory region of cardiac troponin I that is required for inhibition of
actin-tropomyosin-activated myosin ATPase and Ca2⫹-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
A) ARG92GLN, ILE79ASN MUTATIONS. The Arg-92 and Ile-79
residues are located in the NH2-terminal domain of cardiac troponin T. The functional consequences of the
Arg92Gln and Ile79Asn missense mutations have varied
according to the techniques employed. In one study,
transfection of Arg92Gln and Ile79Asn cardiac troponin T
into quail myotubes resulted in increased myotube shortening velocity. The Ile79Asn mutation, but not Arg92Gln,
reduced maximum force (154). In a second study, in vitro
motility assays performed using recombinant embryonic
rat cardiac troponin T bearing an Ile79Asn substitution
demonstrated a 50% increase in velocity of translocation
of thin filaments over myosin (83). In contrast, transfection of Arg92Gln cardiac troponin T in adult feline cardiac
myocytes showed reductions in fractional shortening and
peak velocity of shortening (88). Ca2⫹ sensitivity of force
production was increased in Arg92Gln and Ile79Asn cardiac troponin T in skinned cardiac muscle preparations
(108, 157) but was decreased in transfected rat adult
cardiac myocytes (139) and quail myotubes (154). Ca2⫹
sensitivity of myofibrillar ATPase was increased in transfected rabbit cardiac myofibrils (177). No abnormalities of
sarcomere structure have been reported in any of these
studies.
An Arg92Gln cardiac troponin T transgenic mouse
model with transgene expression levels ranged from 1 to
10% has been characterized. Adult mice exhibited systolic
and diastolic left ventricular dysfunction with variable
myocyte degeneration, necrosis, myofibril disarray, and
fibrosis (82, 117). Another group of investigators have
found that Arg92Gln cardiac troponin T transgenic mice
with 30, 67, and 92% transgene expression levels exhibited
dose-related myocardial disarray and fibrosis (162). Surprisingly, mutant hearts in the latter study were smaller
than control hearts, with a reduction in both the number
and size of myocytes. Isolated working hearts from the
mice with 67% transgene expression were hypercontractile with stepwise increases in cardiac work load. Single
myocytes from these mice had reduced shortening and
prolonged contraction times. Both isolated heart and
myocyte studies showed impaired diastolic relaxation.
Skinned papillary muscle fibers from transgenic mice expressing Ile79Asn cardiac troponin T showed increased
Ca2⫹ sensitivity of ATPase activity and force development
with accelerated kinetics of force activation and relaxation. A computer simulation of intracellular Ca2⫹ and
force generation predicted that the Ile79Asn cardiac troponin T mutation altered cross-bridge kinetics and increased cardiac troponin T Ca2⫹ affinity (103).
B) INT15G TO A SUBSTITUTION. The Int15G to A substitution results in truncation of the COOH terminus of the
cardiac troponin T protein. Transfection of a truncated
cardiac troponin T in quail myotubes resulted in decreased Ca2⫹ sensitivity of force production, similar to
the findings in the Arg92Gln experiments (175). In recombinant cardiac muscle preparations, this truncation mutant reduced Ca2⫹ activation and inhibition of force and
reduced activation and inhibition of actin-tropomyosinactivated myosin ATPase activity (157). In in vitro motility
assays, truncated cardiac troponin T increased the velocity of actin-tropomyosin filaments to a greater extent than
wild-type cardiac troponin T at low pCa (activating conditions) but failed to decrease the velocity of filaments
and had negligible inhibition of actin-tropomyosin-activated myosin ATPase at high pCa (relaxing conditions).
Varying proportions of wild-type and mutant cardiac troponin T significantly influenced the results: at pCa 5, the
inhibitory effect of wild-type protein on thin filament
velocity was enhanced at lower protein levels (10 –50%)
(132). A transgenic mouse with a truncated cardiac troponin T exhibited similar findings to the Arg92Gln cardiac
troponin T transgenic mouse, with myocyte disarray, fibrosis, and a reduction in the number and size of myocytes. Echocardiographic studies in the truncated cardiac
troponin T mouse showed a mild reduction in systolic
contraction and a relatively greater extent of impaired
diastolic relaxation (161).
Cardiac troponin T mutations would be predicted to
influence the inhibitory regulatory effect of the tropomyosin-troponin complex. In vitro studies showing increased
contraction kinetics and increased Ca2⫹ sensitivity of
force generation are consistent with this concept. The
observation of hypocontractility in some studies has also
been attributed to increased Ca2⫹ sensitivity, with higher
basal levels of sarcomeric activation resulting in initiation
of contraction at shorter, less optimal sarcomere lengths
against a stronger passive restoring force (162). This may
also partly explain the small size of myocytes. Myocyte
degeneration and loss may further depress contractile
performance. Despite myocardial histopathology and
functional changes, none of the cardiac troponin T mouse
models has exhibited left ventricular hypertrophy. Individuals with HCM caused by cardiac troponin T mutations
typically have minimal left ventricular hypertrophy.
INHERITED CARDIOMYOPATHIES
5. ␣-Tropomyosin gene mutations:
Asp175Asn mutation
Asp175 is located in the Ca2⫹-sensitive troponin T
binding domain of ␣-tropomyosin. The substitution of Asp
to Asn at this residue causes the loss of one negative
charge, which alters the mobility of ␣-tropomyosin on gel
electrophoresis (16) and results in local unfolding of the
encoded protein. In in vitro motility assays, Asp175Asn
␣-tropomyosin had a relatively greater increase in velocity than wild-type ␣-tropomyosin, following addition of
troponin. All other parameters were unchanged, suggesting that the effects of the mutation were due predominantly to altered interaction with troponin T (9). Addition
of N-ethylmaleimide-conjugated myosin subfragment-1
(NEM-S1), a strongly binding myosin analog that cooperatively enhances thin filament activation, failed to further
increase thin filament velocity, indicating that the
Asp175Asn substitution switched ␣-tropomyosin to a fully
on state (133).
Mechanical properties of skeletal muscle fibers from
patients with HCM due to Asp175Asn ␣-tropomyosin have
been studied (16). The levels of mutant and wild-type
␣-tropomyosin protein were similar (⬃50%), and other
␣-tropomyosin isoforms were not upregulated. The muPhysiol Rev • VOL
tant fibers demonstrated no differences in shortening velocity or maximal force generation but did have increased
Ca2⫹ sensitivity of force production, compared with controls. Transgenic mice expressing Asp175Asn ␣-tropomyosin exhibited varying extent of myocyte hypertrophy,
disarray, and fibrosis by 20 wk of age. Both endogenous
and mutant ␣-tropomyosin protein incorporated into
myofibrils. Normal ␣-tropomyosin stoichiometry was
maintained with overexpression of the mutant protein
compensated by a reciprocal reduction in the level of
endogenous protein. Transthoracic echocardiography
showed no significant differences between transgenic and
control mice in left ventricular diameters, fractional
shortening, or wall thickness. After an 8-wk swimming
program, left ventricular fractional shortening increased
in control mice but was unchanged in transgenic mice. In
isolated heart preparations from mice expressing 60%
Asp175Asn protein, both the rates of contraction and
relaxation were reduced. These functional changes were
not observed in mice expressing ⬍40% mutant protein.
Skinned fiber preparations from transgenic mouse hearts
showed a leftward shift in the pCa2⫹-force relationship
(112).
These in vitro and in vivo data indicate that the
Asp175Asn mutation increases the basal level of activation of ␣-tropomyosin. This may result from structural
changes, such as altered protein conformation, or functional changes mediated by changes in binding of the
troponin complex or altered Ca2⫹ affinity. Variability in
functional assays has been observed, as found with cardiac troponins T and I. Downregulation of endogenous
␣-tropomyosin suggests that mutations may act by haploinsufficiency. However, similar (50%) levels of mutant and
endogenous protein have been found in human HCM,
consistent with a dominant negative mechanism.
6. Myosin essential and regulatory light chain gene
mutations: Met149Val essential MLC, Glu22Lys
regulatory MLC mutations
MLC are thought to influence the mechanical efficiency of cross-bridge cycling and the speed of contraction. No specific functional domains in the MLC have been
recognized. In vitro motility assays have shown that actin
sliding velocities were increased by the Met149Val essential MLC substitution but were unchanged by the
Glu22Lys regulatory MLC substitution (125). These two
missense mutations have also been evaluated in transgenic mouse models (141). Mice with Met158Val essential
MLC (analogous to human Met149Val essential MLC) exhibited dose-related myofibril disarray and fibrosis. While
this mutation is associated with the development of papillary muscle hypertrophy in humans, transgenic mice had
lower left ventricular mass and smaller myocytes than
observed in control mice. Functional analyses in isolated
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
mediated binding to troponin C. In vitro functional analyses have shown that the Arg145Gly cardiac troponin I
mutation results in reduced inhibition of actin-tropomyosin-activated myosin ATPase and increased Ca2⫹ sensitivity of ATPase regulation (30, 158). A transgenic mouse
overexpressing Arg145Gly cardiac troponin I (1.2-fold)
had normal life expectancy and no overt phenotype, with
the exception that females stressed by pregnancy developed histological evidence of cardiomyocyte hypertrophy
and patchy myocardial fibrosis. Isolated working heart
preparations from unstressed mutant mice showed significantly enhanced contractility (⫹dP/dt) and prolonged
relaxation (⫺dP/dt). Mice with 3.5-fold transgene overexpression died by 17 days. At 10 days after birth, the
ventricles of these mice showed myocyte disarray, nuclear degeneration, and interstitial fibrosis. Skinned papillary muscle strips from 10-day-old mutant mice showed
no differences in unloaded shortening velocity, maximum
shortening velocity, or maximum relative power but increased Ca2⫹ sensitivity and reduced maximum tension
(61). It has been proposed that mutations in the inhibitory
region of cardiac troponin I disrupt the Ca2⫹-sensitive
switch and cause the thin filament to remain in an “on”
position analogous to the changes observed with cardiac
troponin T gene mutations. The differences in contractile
performance between mice with 1.2- and 3.5-fold transgene expression may reflect dose-related differences in
basal sarcomere length or more severe myocardial histopathology.
957
958
DIANE FATKIN AND ROBERT M. GRAHAM
D. Triggers and Effectors of Left
Ventricular Hypertrophy
1. Triggers of left ventricular hypertrophy
The development of left ventricular hypertrophy has
been generally considered to be an adaptive response to
biomechanical stress that enables cardiac work to be
maintained. Despite these generally accepted principles
of hypertrophy development and its consequences, it is of
note that a recent study using genetically engineered mice
with a markedly blunted growth response to pressure
overload questions the adaptive value of load-induced
hypertrophy (31). Surprisingly, despite failing to correct
wall stress after acute partial transthoracic aortic constriction, cardiac function in these animals with either
inhibition of Gq signaling or disruption of catecholamine
synthesis was well maintained. Indeed, function was even
better maintained than in wild-type mice whose wall
stress was normalized as a result of hypertrophy development. This study also highlights the primacy, not only
of the Gq signaling pathway in load-induced hypertrophy,
but somewhat more surprisingly, that of the sympathetic
nervous system.
Left ventricular hypertrophy may be “physiological”
in elite athletes or occur in pathological states, such as
hypertension, myocardial infarction, cardiomyopathies,
valvular heart disease, and a variety of systemic disorders.
The hypertrophic process is thought to be initiated by
factors extrinsic and intrinsic to the cardiac myocyte.
Extrinsic stimuli include vasoactive peptides (e.g., angiotensin II, endothelin-1), ␣1-adrenergic agonists (e.g., norepinephrine, epinephrine, phenylephrine), activators of
protein kinase C (e.g., tumor-producing phorbol esters),
peptide growth factors (e.g., insulin-like growth factor,
fibroblast growth factor), cytokines (e.g., cardiotrophin1), arachidonate metabolites (e.g., prostaglandin F2␣), mechanical stretch, and cell contact. Intrinsic stimuli include
Physiol Rev • VOL
elevated [Ca2⫹]i, the heterotrimeric G protein Gq, as well
as activated small G proteins, kinases, phosphatases, and
transcriptional factors (151). These extrinsic and intrinsic
factors trigger a complex cascade of intracellular pathways, termed the “hypertrophic response,” which results
in increased myocardial mass, altered spatial relationships between myocytes and other cellular and extracellular components of the myocardium, reprogramming of
myocardial gene expression, and apoptosis. A rapidly
growing list of genes has been found to elicit cardiac
hypertrophy when overexpressed in transgenic mice. Determination of which of these genes are clinically relevant
in human hypertrophy will be important.
A) HCM. Despite a decade of research, the stimulus for
hypertrophy in HCM has not been definitively identified.
Collectively, data from in vitro and in vivo studies demonstrate that sarcomere protein gene mutations perturb
sarcomere structure and/or function and thus are likely to
be disease causing. The precise consequences of sarcomere protein gene mutations differ according to the type
of model studied with both reduced and augmented motor
function described for individual HCM disease genes. Mutations in the various sarcomere protein genes also have
diverse effects on motor function. It appears, however,
that mechanical dysfunction of the sarcomere is a common feature and, hence, a potential stimulus for hypertrophy (Fig. 2). Whether a threshold level of sarcomere
dysfunction is required before the hypertrophic response
is triggered is unknown. Observations of hypo- and hypercontractility in different studies of a single gene highlight
the importance of the model used and the effects of the
contractile “milieu,” i.e., the presence or absence of thin
filament regulatory elements, myocyte loading, myocardial histopathology, etc. What is the most physiologically
relevant method for studying contractile function of mutant sarcomere proteins? This will remain unanswered
until we understand the origin (i.e., in the intact organ or
at the cellular or molecular level) and the nature of the
signaling processes that initiate the hypertrophic response.
B) INTRACELLULAR CALCIUM. Several years ago, the observation that transgenic mice expressing constitutively activated calcineurin developed left ventricular hypertrophy
that was prevented by administration of the calcineurin
inhibitors cyclosporin and FK506 initiated intense interest
in the role of elevated [Ca2⫹]i and the calcineurin signaling pathway in the pathogenesis of left ventricular hypertrophy (105). Calcineurin is a cytoplasmic protein phosphatase that is activated by sustained [Ca2⫹]i. Activated
calcineurin dephosphorylates NFAT3 (nuclear factor of
activated T cells) transcription factors, which causes their
translocation to the nucleus where they combine with the
cardiac-restricted zinc finger transcription factor GATA4,
resulting in synergistic activation of embryonic cardiac
genes and a hypertrophic response. Although the trans-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
working heart preparations showed hypercontractility
and impaired relaxation in the mutant mice. Studies of
skinned ventricular fibers and in vitro motility assays
showed no differences in shortening velocity or actin
translocation, respectively, between mutant and wild-type
mice. Met158Val essential MLC fibers did demonstrate
leftward shifts in the ATPase activity and pCa-force
curves and reduced power output. Histological, cellular,
and molecular analyses of transgenic mice with the
Glu22Lys RLC mutation were indistinguishable from wildtype mice. Skeletal muscle fibers from an individual with
a Glu22Lys regulatory MLC mutation were found to have
a leftward shift in the pCa-force relationship (78). These
data suggest that the essential MLC and regulatory MLC
may regulate power output through a Ca2⫹-dependent
mechanism.
INHERITED CARDIOMYOPATHIES
959
genic mouse studies suggested that the calcineurin pathway might be critical in the development of myocardial
hypertrophy, studies in a variety of different models have
suggested that multiple signaling pathways are likely to be
involved (118, 151). Recently, the effects of calcineurin
Physiol Rev • VOL
inhibition in HCM were examined in ␣-MHC403/⫹ mice
(35). Paradoxically, cyclosporin and FK506 administration both dramatically increased the severity of left ventricular hypertrophy and accelerated sudden death in the
mutant mice. Cyclosporin-induced hypertrophy was pre-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
FIG. 2. Potential pathophysiological
mechanisms underlying hypertrophic
cardiomyopathy (A) and dilated cardiomyopathy (B). LV, left ventricular;
SERCA2a, sarcoendoplasmic reticulum
Ca2⫹-ATPase; SNSA, sympathetic nervous system activity.
960
DIANE FATKIN AND ROBERT M. GRAHAM
Physiol Rev • VOL
cardial ischemia due to increased oxygen demands of the
hypertrophic myocardium, it is also possible that alterations of myocardial metabolism may occur as primary
effects of mutant proteins (Fig. 2). For example, if sarcomere dysfunction due to contractile protein mutations
created a mechanically unfavorable and energy-requiring
state, a relative myocardial energy deficit may then provide a stimulus for hypertrophy. Although defective myocardial energetics remain an attractive hypothesis, the
clinical diagnosis of families with PRKAG2 gene mutations has very recently been questioned. The demonstration of vacuoles containing glycogen-associated granules
within the myocardium of affected individuals, together
with in vitro experiments indicating constitutive activation of AMPK, suggested that PRKAG2 gene mutations
might not cause familial HCM, but rather a novel myocardial metabolic storage disease (2).
2. Effectors of left ventricular hypertrophy
To date, research interest in HCM has been directed
toward characterization of the consequences of gene mutations on sarcomere structure and function and identification of factors that might trigger the hypertrophic response. The cascade of signaling pathways that constitute
the effectors of hypertrophy in HCM is largely unexplored. It has not been established whether the various
HCM gene mutations stimulate the same or different hypertrophic pathways. It is also not known to what extent
hypertrophic response pathways in HCM might differ
from those in other pathological states.
The severity of left ventricular hypertrophy varies
considerably between individuals with different sarcomere protein gene mutations and also between individuals in a family with the same gene mutations. Are these
differences due to varying severity of the stimulus for
hypertrophy or do other factors influence the expression
of the hypertrophic phenotype? Observations in mouse
models do not support a direct correlation between the
extent of sarcomere dysfunction and left ventricular hypertrophy. For example, although cardiac function is impaired in ␣-MHC403/⫹ mice and normal in mice with truncated cMyBP-C, both mouse models develop similar
severity of left ventricular hypertrophy (95). In both of
these mouse models, heterozygous mice have left ventricular hypertrophy but homozygous mice exhibit dilated
cardiomyopathy rather than severe hypertrophy (33, 95,
96). These findings suggest that the extent to which left
ventricular hypertrophy can compensate for a cardiac
motor deficit is dose related and that severe dysfunction
is less likely to be “rescued.” Further studies are required
to determine the effects of additional genetic factors and
environmental factors as modifiers of the hypertrophic
phenotype. In the ␣-MHC403/⫹ mice, left ventricular hypertrophy is observed in 100% of mice with a 129SvEv back-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
vented by coadministration of the L-type Ca2⫹ channel
blocker diltiazem. Studies of ␣-MHC403/⫹ and wild-type
myocytes showed no differences in Ca2⫹ transients at
baseline. Diastolic Ca2⫹ levels increased in wild-type
myocytes but were unchanged in ␣-MHC403/⫹ myocytes
after acute administration of cyclosporin, and after
chronic oral treatment with cyclosporin. Similar results
were also found in response to acute administration of
minoxidil, a K⫹ channel agonist that has been shown to
cause left ventricular hypertrophy in humans and rodents.
These data suggest first that abnormal Ca2⫹ regulation
may play an important role in the hypertrophic response
in HCM, and second, that administration of calcineurin
inhibitors such as cyclosporin may actually be harmful to
patients with HCM.
What is the basis for the abnormalities of Ca2⫹ regulation observed in HCM? The inability to elevate diastolic Ca2⫹ in response to cyclosporin in ␣-MHC403/⫹ myocytes might be indicative of a relative depletion of
intracellular Ca2⫹ reserves that might result from sequestration of Ca2⫹ by the contractile apparatus due to reciprocal feedback of cross-bridge formation on troponin
C/Ca2⫹ binding affinity. This might also explain the increased Ca2⫹ sensitivity observed in mutant myofibrils
and contribute to delayed diastolic relaxation (Fig. 2).
These data raise intriguing questions about the mechanisms by which intracellular Ca2⫹ might influence hypertrophic signaling pathways. In contrast to the traditional
concept, cytoplasmic free [Ca2⫹] did not appear to be the
stimulus for left ventricular hypertrophy in ␣-MHC403/⫹
mice. It is possible that the [Ca2⫹] in another intracellular
compartment or total cellular Ca2⫹ might be the critical
Ca2⫹ sensor. Calcium may provide a critical link between
mechanical dysfunction of the sarcomere and induction
of the hypertrophic gene program. Despite these considerations, it should be noted that recent studies of mice in
which calcineurin was inhibited not by drugs, which can
affect unrelated pathways as well as being toxic, but by
genetic engineering, provide compelling evidence for an
important role of the calcineurin/NFAT3/GATA4 pathway
in load-induced hypertrophy (28, 137, 182). It will be of
interest to see if inhibition of this pathway also prevents
the hypertrophy observed in the various genetically induced HCM models, which should be evident when they
are crossed with the calcineurin-inhibited animals.
C) MYOCARDIAL ENERGETICS. The recent finding of mutations in the PRKAG2 gene (see sect. IIIB12) was somewhat unexpected, given the traditional dogma that sarcomere dysfunction was the fundamental defect in HCM.
These PRKAG2 mutations raise the intriguing possibility
that defective myocardial energetics may be a common
feature of HCM mutations. Alterations of myocardial metabolism had been observed previously in patients with
HCM (66) and in ␣-MHC403/⫹ mice (149). Although these
energetic changes might result from factors such as myo-
INHERITED CARDIOMYOPATHIES
ground but only in 50% of mice with a Black Swiss background (95). These observations are best explained by the
presence of modifier gene(s) in these mouse strains. Exacerbation of left ventricular hypertrophy in ␣-MHC403/⫹
mice by calcineurin inhibitors and the subsequent prevention of hypertrophy with Ca2⫹ blockade demonstrated,
for the first time, that environmental factors (i.e., pharmacological agents) could also modify the hypertrophic
phenotype in HCM.
IV. DILATED CARDIOMYOPATHY
1. Disease characteristics
Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by cardiac dilatation and contractile
dysfunction of the left and/or right ventricles. DCM may
result from a diverse variety of etiologic agents that cause
cardiomyocyte dysfunction or injury. In ⬃50% of cases, a
specific precipitating cause is unable to be identified (“idiopathic” DCM). The incidence of idiopathic DCM has
been estimated to be 5– 8 cases per 100,000 per year (27).
Although DCM has traditionally been regarded as a sporadic nongenetic disorder, recent studies of large families
with DCM suggest that inherited gene defects are an
important cause of idiopathic DCM (“familial” DCM).
2. Prevalence of familial DCM
The reported prevalence of familial DCM has varied
according to the methods of detection and diagnostic
criteria employed. Studies based solely on a positive clinical history of DCM in relatives of probands have yielded
a relatively low prevalence (⬍10%) of familial disease. In
contrast, studies in which first degree relatives of probands have been evaluated systematically, irrespective of
the presence of symptoms, with physical examination,
12-lead electrocardiography, and transthoracic echocardiography, suggest a prevalence of up to 35% (49, 69, 102).
These data may underestimate the true prevalence of
familial DCM. In the majority of studies, the diagnosis of
DCM has been based on the World Health Organization
criteria, i.e., the presence of both ventricular dilation and
contractile dysfunction (135). Abnormalities of either ventricular dimensions or contractile function have been observed commonly, however, in asymptomatic relatives of
probands with DCM. It is not yet clear whether these
findings represent early disease or a more benign form of
disease. Age-related penetrance (i.e., absence of disease
manifestations in genotype-positive individuals until after
a particular age) and nonpenetrance (i.e., genotype-positive but phenotype-negative throughout life) may contribute to underestimation of the prevalence of familial disPhysiol Rev • VOL
ease. The diagnosis of familial DCM may also be
confounded by the concurrent presence of conditions
known to promote DCM, such as myocardial ischemia,
viral infection, or alcohol excess. The extent to which
genetic factors may increase susceptibility to the recognized DCM precipitating factors has not been evaluated.
3. Diagnosis of familial DCM
Studies of families with DCM have revealed autosomal dominant, autosomal recessive, X-linked, and maternal modes of inheritance, with the autosomal dominant
pattern observed most frequently. Familial DCM exhibits
marked clinical variability, with several distinct phenotypic groups: DCM alone, DCM with conduction-system
disease (sinus bradycardia, atrioventricular conduction
block, atrial tachyarrhythmias), DCM with skeletal myopathy with or without conduction-system disease, or DCM
with sensorineural deafness. In some families, DCM may
occur as part of a multisystem inherited disorder. The
relative prevalence of each of these phenotypic groups
has not been determined.
Apart from family history, no single clinical parameters have been found to reliably distinguish familial from
nonfamilial DCM. In some cases, genetically affected individuals may be asymptomatic, with an incidental finding
of cardiomegaly on a routine chest X-ray. The majority of
individuals present with symptoms attributable to left
ventricular failure or cardiac arrhythmias, including
weakness, fatigue, dyspnea, orthopnea, palpitations, or
exercise intolerance. Symptoms of right heart failure,
such as peripheral edema and abdominal distension due
to hepatic congestion and ascites, are likely to occur with
disease progression.
It has been suggested that individuals with familial
DCM are diagnosed at an earlier age than individuals with
nonfamilial DCM (101). This may reflect the presence of a
relatively malignant phenotype in some families, or more
intensive screening of individuals deemed to be at high
risk due to their family history.
The principal modality for the diagnosis of familial
and nonfamilial DCM is transthoracic echocardiography.
Two-dimensional echocardiographic imaging is used to
quantitatively assess ventricular structure and systolic
function and to evaluate valvular pathology and atrial
size. Doppler echocardiographic studies are used to assess ventricular diastolic function as well as the severity
of mitral and tricuspid valve regurgitation. Gated radionuclide scans may be used to quantitate ventricular volumes and contractile performance, particularly in individuals in whom echocardiography is technically difficult.
Cardiac catheterization may also be used for assessment
of ventricular function, particularly in individuals concurrently at risk for coronary artery disease. Endomyocardial
biopsy generally shows nonspecific findings such as myo-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
A. Clinical Manifestations
961
962
DIANE FATKIN AND ROBERT M. GRAHAM
4. Natural history of familial DCM
The natural history of familial DCM is variable both
between and within families. Affected individuals may
have a relatively benign course, develop progressive heart
failure (that may necessitate cardiac transplantation), or
experience sudden death. Premature death may result
from severe heart failure or ventricular arrhythmias. In
familial DCM, sudden death may occur at any age irrespective of ventricular function. In general, the 5-yr survival after a diagnosis of congestive cardiac failure is only
50% (27). In the subgroup of families with DCM and
conduction-system disease, affected individuals generally
experience progressive atrioventricular conduction disturbances in the second to fourth decades with the subsequent development of DCM. Implantation of permanent
pacemakers may be required for high-grade atrioventricular conduction block. Thromboembolic complications in
familial DCM may result from marked blood stasis in the
ventricle or coincide with the onset of atrial arrhythmias.
Genotype-phenotype correlations in familial DCM have
not as yet been determined. Although multiple clinical
parameters have been proposed as predictors or mortality
in DCM, it is likely that family genotype may be the
strongest determinant of outcome.
B. Chromosomal Loci and Disease Genes
1. Chromosomal loci
Molecular genetic studies performed in families with
DCM indicate that this disorder is genetically heterogeneous. Adult-onset autosomal dominant DCM without accompanying conduction system disease has been associated with 12 loci (Table 2). Seven of these loci were
identified using genome-wide linkage analyses in large
families [chromosomes 1q32 (29), 2q31 (147), 6q12-q16
(156), 9q13-q22 (73), 9q22-q31 (64), 10q22-q23 (17), 14q12
(67)]. The remaining five loci were identified using a
Physiol Rev • VOL
TABLE
2. DCM chromosomal loci and disease genes
Chromosomal Locus
Gene
Protein
Autosomal dominant inheritance
DCM only
1q32
2q31
2q35
5q33
6q12-q16
9q13-q22
9q22-q31
10q22-q23
11p11
MYH7
ACTC
TPM1
Cardiac troponin T
Titin
Desmin
␦-Sarcoglycan
?
?
?
Metavinculin
Cardiac myosin
binding protein C
␤-Myosin heavy chain
Cardiac actin
␣-Tropomyosin
LMNA
?
?
Lamins A and C
?
?
LMNA
?
Lamins A and C
?
?
?
TNNT2
TTN
DES
SGCD
?
?
?
VCL
MYBPC3
14q12
15q14
15q22
DCM ⫹ conduction-system disease
1p1-q21
2q14-q22
3p22-p25
DCM ⫹ skeletal myopathy
⫾ conduction-system disease
1p1-q21
6q23
DCM ⫹ sensorineural deafness
6q23-q24
X-linked inheritance
Xp21 (X-linked DCM)
Xq28 (X-linked infantile DCM)
DMD
G4.5
Dystrophin
Tafazzin
DCM, dilated cardiomyopathy.
candidate gene approach in small families. The first disease gene identified was cardiac actin (chromosome
15q14) (123). Five further sarcomere protein genes that
have been associated with HCM have now been shown to
also cause DCM: ␤-MHC (chromosome 14q12) (67),
cMyBP-C (chromosome 11p11) (134), cardiac troponin T
(chromosome 1q32) (67), ␣-tropomyosin (chromosome
15q22) (122), and titin (chromosome 2q31) (44). DCMonly mutations have also been found in the cytoskeletal
proteins desmin (chromosome 2q35) (80), ␦-sarcoglycan
(chromosome 5q33) (168), and metavinculin (chromosome 10q22-q23) (120).
Linkage studies performed in families with autosomal dominant DCM with conduction system disease have
identified three loci: on chromosomes 1p1-q21 (68), 2q14q22 (65), and 3p22-p25 (121); the disease-causing gene has
been found in one of these loci (lamin A/C gene at chromosome 1p1-q21) (34). Autosomal dominant DCM with
conduction-system disease and skeletal myopathy has
been mapped to two loci [chromosomes 1p1-q21 (15, 109)
and 6q23 (100)]; mutations in the lamin A/C gene have
been associated with two skeletal myopathies with cardiac involvement, Emery-Dreifuss muscular dystrophy
(15), and autosomal dominant limb girdle muscular dystrophy 1B (109). Autosomal dominant DCM with sensori-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
cyte hypertrophy, necrosis, nuclear abnormalities, and
interstitial fibrosis.
Electrocardiography in individuals with DCM may
reveal sinus tachycardia, poor R-wave progression in the
praecordial leads, intraventricular conduction delays, or
nonspecific S-T segment and T-wave changes. Individuals
with familial DCM accompanied by conduction-system
disease may exhibit sinus bradycardia; first-, second-, or
third-degree atrioventricular conduction block; and atrial
fibrillation or flutter. Conduction abnormalities and atrial
tachyarrhythmias may also result from advanced heart
failure. Ambulatory electrocardiographic monitoring in
individuals with DCM commonly reveals frequent ventricular ectopic beats or nonsustained ventricular tachycardia.
INHERITED CARDIOMYOPATHIES
2. Cardiac actin gene (ACTC)
The ACTC gene encodes the sarcomere thin filament
protein cardiac actin. Characteristics of the ACTC gene
have been described in section IIIB10. ACTC was the first
gene associated with adult-onset autosomal dominant
DCM. Because cardiac actin has an integral role in cardiac
muscle contraction, it was considered to be a promising
candidate for DCM. Olson et al. (123) described two missense mutations in the ACTC gene in two small unrelated
families with DCM. Subsequently, ACTC mutations were
found in several families with HCM (119). The pathophysiological basis for differences in phenotypic expression of
ACTC mutations has not been established. It has been
proposed that the location of mutations in distinct functional domains of the ACTC molecule might account for
these differences: HCM-causing mutations identified to
date have been located in regions that are involved in
actin-myosin interaction and force generation, whereas
DCM-causing mutations have been located in the immobilized end of the actin molecule at the Z line that is
thought to be involved in transmission of force from the
sarcomere to the extrasarcomeric cytoskeleton.
3. ␤-Myosin heavy chain gene (MYH7)
The MYH7 gene encodes the sarcomere thick filament protein ␤-MHC. Characteristics of the MYH7 gene
have been described in section IIIB2. The chromosome
14q12 DCM locus was identified by Kamisago et al. (67) in
linkage analysis performed in a multigeneration family
characterized by early-onset (⬍25 years age) DCM in
⬃50% of affected members. The MYH7 gene, associated
previously with HCM, was located within the genetically
determined disease interval. Subsequent screening of
MYH7 in probands from the index family and from 20
additional families with DCM revealed 2 missense mutations: one mutation in the large linked family and a second mutation in a small unlinked family (67). The phenotype of the second family was also characterized by an
early onset of ventricular dilation and dysfunction, includPhysiol Rev • VOL
ing the sudden death of an infant aged 2 mo. HCM-causing
MYH7 mutations have been clustered predominantly in
four regions of the molecule and are thought to perturb
actin-myosin interaction and force generation. One of the
two DCM-causing MYH7 mutations (Ser532Pro), located
in a conserved ␣-helical structure of the lower 50-kDa
myosin domain, is predicted to disrupt actin-myosin binding. The other mutation (Phe764Leu), located in a “hinge”
region between the myosin head and neck, is predicted to
alter the magnitude or polarity of cross-bridge movement
and hence the efficiency of contraction.
4. cMyBP-C gene (MYBPC3)
The MYBPC3 gene encodes the sarcomere thick filament protein cMyBP-C. Characteristics of the MYBPC3
gene have been described in section IIIB3. The MYBPC3
gene was selected as a potential candidate gene for DCM
subsequent to the finding that a number of HCM-causing
genes could also cause DCM. One missense MYBPC3
mutation has recently been reported in an individual with
DCM (134).
5. Cardiac troponin T gene (TNNT2)
The TNNT2 gene encodes the sarcomere thin filament protein cardiac troponin T. Characteristics of the
TNNT2 gene have been described in section IIIB4. The
TNNT2 gene was selected as a potential candidate gene
for DCM due to its previous association as a disease gene
for HCM. The TNNT2 gene was screened by Kamisago et
al. (67) in 19 probands from families with DCM in whom
MYH7 mutations had not been identified. A deletion in
cardiac troponin T (⌬Lys210) was identified in two unrelated families in this cohort. No mutations in the genes
encoding cardiac troponin I or ␣-tropomyosin were
found. HCM-causing TNNT2 mutations have been located
in both the NH2- and COOH-terminal domains of cardiac
troponin T. The DCM-causing TNNT2 deletion was located in a COOH-terminal region (residues 207–234) implicated in Ca2⫹-sensitive troponin C binding. Because
none of the HCM-causing mutations identified has been
found in this region, it has been suggested that the pathophysiological mechanisms responsible for HCM and DCM
may differ.
6. ␣-Tropomyosin gene (TPM1)
The TPM1 gene encodes the sarcomere thin filament
protein cMyBP-C. Characteristics of the TPM1 gene have
been described in section IIIB7. The TPM1 gene was selected as a potential candidate gene for DCM due to its
previous association as a disease gene for HCM. The
TPM1 gene was screened in 350 individuals with familial
and sporadic DCM. Two missense mutations were identified in probands with familial disease (122). HCM-causing
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
neural hearing loss has been mapped to chromosome
6q23-q24 (144).
Autosomal recessive inheritance has been associated
with infantile forms of DCM. No chromosomal loci or
disease genes for autosomal dominant infantile DCM have
been reported. Two disease genes have been found to
cause X-linked DCM. Mutations in the gene encoding
dystrophin have been found in Duchenne and Becker
muscular dystrophy but have also been shown to cause an
adult-onset X-linked DCM without skeletal myopathy
(167). Mutations in G4.5, encoding tafazzin, cause Barth’s
syndrome as well as a childhood-onset X-linked DCM
(24). Mutations in mitochondrial DNA have been found in
maternally inherited mitochondrial myopathies (153).
963
964
DIANE FATKIN AND ROBERT M. GRAHAM
TPM1 mutations have been found to occur in regions of
the molecule that would be expected to impair troponin T
binding and Ca2⫹ sensitivity and, hence, force generation.
In contrast, the two DCM-causing TPM1 mutations could
be predicted to alter the surface charge of ␣-tropomyosin,
which might be expected to influence the structural integrity of the ␣-tropomyosin filament or impair its interaction with actin.
7. Titin gene (TTN)
8. Desmin gene (DES)
The DES gene encodes desmin, a cytoskeletal protein
that belongs to the intermediate filament family. Desmin
is a muscle-specific protein that is expressed in all muscle
tissues. Desmin is one of the earliest known myogenic
markers to be expressed in cardiac and skeletal muscle,
suggesting that it might play a modulating role in myogenic commitment and differentiation. In mature muscle,
the desmin intermediate filament network is thought to
contribute to force transmission from the sarcomere and
resistance to mechanical stress. The DES gene is a singlecopy gene comprised of 8.4 kb of genomic DNA with 9
exons that encode a protein of 470 amino acids. The
structure of the desmin protein resembles other intermediate filaments, with a central ␣-helical coiled-coil rod
domain flanked by nonhelical NH2-terminal head and
COOH-terminal tail domains.
Missense mutations in the DES gene have been found
to cause desmin-related myopathy, a familial disorder
characterized by skeletal myopathy, cardiac conductionsystem abnormalities, restrictive cardiomyopathy, and intracytoplasmic accumulation of desmin-reactive deposits.
These DES mutations have been clustered in a highly
conserved COOH-terminal rod region. On the basis of its
expression pattern and the identification of mutations in
desmin-related myopathy, the DES gene was considered
to be a possible candidate gene for DCM. A missense
mutation (Ile451Met) in the DES gene was recently reported in one family with autosomal dominant DCM without conduction-system disease or skeletal myopathy. This
mutation was located in the desmin tail domain (80).
Mice completely lacking desmin exhibit marked disPhysiol Rev • VOL
9. ␦-Sarcoglycan gene (SGCD)
The SGCD gene encodes the sarcolemmal transmembrane glycoprotein, ␦-sarcoglycan, one of four proteins
(␣, ␤, ␥, ␦) that associate in stoichiometrically equal proportions to form the sarcoglycan complex, a component
of the dystrophin-associated glycoprotein transmembrane
complex. ␦-Sarcoglycan is expressed in striated and
smooth muscles, with the highest levels of expression
found in skeletal and cardiac muscle. The SGCD gene is
comprised of at least 100 kb of genomic DNA with 8 exons
encoding a protein of 290 amino acids. ␦-Sarcoglycan
has a small intracellular domain, a single transmembrane
hydrophobic domain, and a large extracellular COOH terminus.
Mutations in the SGCD gene were first reported in
families with autosomal recessive limb girdle muscular
dystrophy (LGMD2F) (114). With the exception of electrocardiographic evidence of left ventricular hypertrophy
in one individual, no cardiac abnormalities have been
reported in this disorder. A deletion of the first exon of
the SGCD gene, resulting in the complete absence of
␦-sarcoglycan protein, was found to be the cause of autosomal recessive cardiomyopathy observed in the Syrian
hamster (115). These animals exhibit histological features
of muscular dystrophy with progressive myocardial necrosis, ventricular hypertrophy and dilation, and premature death due to heart failure. On the basis of these
findings, SGCD gene mutations in human DCM were
sought. In a series of individuals with familial and sporadic DCM, one missense mutation in the SGCD gene was
found in a family with autosomal dominant DCM and a
high prevalence of sudden death at an early age, and 2
different mutations that both resulted in a deletion of the
Lys238 codon were identified in 2 of 50 individuals with
sporadic DCM who had presented with heart failure at
⬍20 yr of age. None of these individuals had clinical
evidence of skeletal myopathy (168).
10. Metavinculin gene (VCL)
The VCL gene encodes the cytoskeletal proteins vinculin and its splice variant, metavinculin. Vinculin is ubiq-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
The TTN gene encodes the giant sarcomeric cytoskeletal protein titin. Characteristics of the TTN gene
have been described in section IIIB11. The 2q31 locus had
been identified by linkage analysis in a multigeneration
family with DCM (147). Screening of more than 340 exons
of the TTN gene in 2 large families that mapped to this
locus resulted in the finding of a two novel mutations: a
2-bp insertion that caused a frameshift and premature
stop codon predicted to truncate the titin protein and a
missense mutation in an immunoglobulin sequence at the
Z-disc/I-band transition zone (44).
ruption of myofibril organization and myocyte degeneration with progressive ventricular dilation and impaired
systolic contraction (104). Observations in an affected
family (80) and in desmin knockout mice suggest that a
reduction or absence of normal desmin function can result in DCM. The significance of cytoplasmic desmin deposits in desmin-related myopathies is not clear, since
these may occur in the absence of DES mutations and
accumulations of other myofibrillar proteins may concurrently be present. The mechanism by which some DES
mutations cause restrictive cardiomyopathy and others
cause DCM is unknown.
INHERITED CARDIOMYOPATHIES
11. Lamin A/C gene (LMNA)
The LMNA gene encodes the intermediate filament
proteins lamins A and C. The lamins are located in the
nuclear lamina, at the nucleoplasmic side of the inner
nuclear membrane. Lamins are classified broadly as A
type and B type. The A-type lamins include four transcripts produced by alternate splicing of the LMNA gene:
lamins A, C, A␦10, and C2. The B-type lamins include
lamins B1 and B2, transcribed from the LMNB1 and
LMNB2 genes, respectively. B-type lamins are expressed
Physiol Rev • VOL
throughout development and are the only lamins present
in the embryo. A-type lamins are expressed in differentiated cells in a wide range of tissues. Lamins A, C, and B2
are expressed in heart and skeletal muscle. The functions
of lamins A and C have not been determined precisely.
The lamins are presumed to have a structural role in
maintaining the integrity of the nuclear membrane. In
dividing cells, the binding of lamins to M-phase chromatin
is important for reassembly of nuclear membranes in
daughter cells during mitosis. Lamin binding to interphase
chromatin may maintain chromatin architecture and contribute to regulation of the cell cycle and gene transcription (150). The coding sequence of the LMNA gene spans
24 kb of genomic DNA with 12 exons. The principal
transcripts, lamins A and C, have identical sequence for
the first 566 amino acids (exons 1–10) but differ in their
COOH-terminal regions, which contain 98 and 6 unique
amino acids, respectively. Lamins A and C consist of a
central rod domain flanked by globular head (NH2-terminal) and tail (COOH-terminal) domains. The rod domain is
formed by an ␣-helical coiled-coil dimer.
Nineteen LMNA mutations have been found in families with autosomal dominant DCM with conduction-system disease (34, 42). These include missense mutations,
deletions, and frameshift mutations that result in premature termination codons. These LMNA mutations have
been located predominantly in the central rod domain
common to lamins A and C. Families with autosomal
dominant DCM with conduction-system disease caused
by mutations in the lamin A/C rod typically have no
clinical evidence of skeletal myopathy and normal creatine kinase levels. In one family with a mutation in the
lamin C-specific region of the tail domain, there were no
clinical features of skeletal myopathy, but creatine kinase
levels were mildly elevated in some family members (34).
Over 30 LMNA mutations have also been found to
cause two forms of autosomal dominant skeletal myopathy (Emery-Dreifuss muscular dystrophy and limb girdle
muscular dystrophy type 1B) (15, 42, 109) and familial
partial lipodystrophy (20, 146). Emery-Dreifuss muscular
dystrophy is characterized by a childhood onset of contractures of the elbows, Achilles tendons, and postcervical muscles, together with slowly progressive wasting and
weakness of humeroperoneal muscles. In later life, affected individuals may develop conduction-system disease, most commonly, heart block. Left ventricular dilation and contractile dysfunction occur infrequently.
Creatine kinase levels are typically elevated. The clinical
manifestations of the autosomal dominant form of EmeryDreifuss muscular dystrophy are similar to those of the
X-linked form, which results from mutations in the gene
encoding emerin, a protein in the inner nuclear membrane. Mutations causing autosomal dominant EmeryDreifuss muscular dystrophy were first identified in the
globular head and tail domains of lamins A and C (15).
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
uitously expressed, while metavinculin is coexpressed
with vinculin exclusively in cardiac, skeletal, and smooth
muscle. In the heart, vinculin and metavinculin are localized to subsarcolemmal costameres where they interact
with ␣-actinin, talin, and ␥-actin to form a microfilamentous network linking the cytoskeleton to the sarcolemma.
Vinculin and metavinculin are also present in adherens
junctions in intercalated discs, where they participate in
cell-cell adhesion. The specific function of metavinculin in
the heart is unknown. The VCL gene is comprised of ⬎75
kb of genomic DNA and has 22 exons that encode the 2
isoforms vinculin (1,066 amino acids) and metavinculin
(1,134 amino acids). The larger isoform, metavinculin, is
generated by alternate splicing of exon 19 and has an
additional 68 amino acids in the COOH-terminal region.
Cross-species analyses have shown that the first half of
the inserted sequence is variable, whereas the second half
is highly conserved. Vinculin and metavinculin are comprised of a globular head and a rod-shaped tail. Four to six
single molecules assemble into multimers by head-to-tail
and tail-to-tail interactions. The head region contains
talin-binding domains, while the tail region interacts with
␥-actin and paxillin.
Because vinculin is an “immediate early response
gene,” increased levels of expression may be induced by a
variety of growth-inducing factors. In one study, vinculin
levels were increased 1.2-fold in heart tissue explanted
from 19 patients with end-stage heart failure due to nonischemic DCM (53). In contrast, absent metavinculin protein and disorganized intercalated discs were found in 1 of
23 individuals with idiopathic DCM (85). Vinculin but not
metavinculin mRNA was detected in the diseased heart
tissue. These observations suggest that altered vinculin
and metavinculin expression might be a consequence of,
or contribute to, heart failure. Very recently, 2 VCL mutations were identified in a cohort of 350 individuals with
familial and sporadic DCM: 1 missense mutation and 1
3-bp deletion. Heart tissue from the individual with an
Arg975Trp VCL mutation showed disruption of intercalated discs. In vitro assays demonstrated that both the
Arg975Trp substitution and the Leu-95 deletion significantly altered metavinculin-mediated cross-linking of actin filaments (120).
965
966
DIANE FATKIN AND ROBERT M. GRAHAM
12. Dystrophin gene (DMD)
The DMD gene encodes dystrophin, a large cytoskeletal protein that is expressed predominantly in skeletal,
cardiac, and smooth muscle, and to a lesser extent, the
brain. Dystrophin interacts with both cytoskeletal actin
and the dystrophin-associated glycoprotein complex in
the sarcolemma. Dystrophin is thought to contribute to
intracellular organization, force transduction, and membrane stability. The DMD gene is the largest known gene
(2.4 Mb). It contains 79 exons that encode a protein of
3,685 amino acids. Transcription regulation of the DMD
gene is complex, with at least eight independent, tissuespecific promoters. Alternate splicing gives rise to a range
of different transcripts and protein isoforms. Four domains in the dystrophin protein have been identified: a
240-amino acid NH2-terminal domain that is homologous
to the actin-binding domain of ␣-actinin, a large rodshaped domain comprised of 25 triple-helical segments
similar to the repeat domains of spectrin, a cysteine-rich
segment similar to the COOH-terminal domain of Dictyostelium ␣-actinin, and a 420-amino acid COOH-terminal
domain with no homology to known proteins. The dystrophin protein forms a rod shape and is ⬃150 nm in length.
Mutations in the DMD gene were first identified in
Duchenne and Becker muscular dystrophies (52, 72).
Duchenne muscular dystrophy is an X-linked recessive
disorder, affecting 1 in 3,500 live-born males. Affected
males present in childhood with gait disturbances; develop progressive weakness of pelvifemoral, shoulder girdle, neck flexor, and trunk muscles; and may be wheelchair-bound by adolescence. Pseudohypertrophy of the
calf muscles and markedly raised creatine kinase levels
are characteristic features. Cardiomyopathy and conduction abnormalities may occur late in the disease. The
severity of cardiac disease is unrelated to the severity of
the skeletal muscle disease. Becker muscular dystrophy is
a milder, allelic form. Affected males present later in life
and have a milder course. Cardiac involvement is less
Physiol Rev • VOL
frequent than in Duchenne muscular dystrophy. In general, individuals with Duchenne muscular dystrophy have
frameshift or nonsense DMD mutations that result in
premature termination of translation and a reduction or
absence of dystrophin protein. Individuals with Becker
muscular dystrophy usually have DMD deletions that result in truncation or reduced levels of expression of dystrophin.
DMD mutations have also been found to cause Xlinked DCM, a disorder in which affected males present
with congestive cardiac failure in adolescence or early
twenties with rapid progression to death within 1–2 yr
(167). Although creatine kinase levels may be elevated,
clinical evidence of skeletal myopathy is absent. Female
carriers may develop a slowly progressive late-onset
DCM. DMD gene defects associated with X-linked DCM
have been clustered in two regions: at the NH2-terminal
end (including the promoter, first exon, and a “hinge”
region between NH2-terminal actin-binding domain and
the central rod domain) and mid-rod domain exons. Point
mutations, deletions, insertions, and inversions have been
reported. A nonsense mutation subsequently deleted by
alternate splicing has been described (36). These DMD
mutations have resulted in quantitative and qualitative
abnormalities of dystrophin protein (36, 111). In one
study, deletions in NH2-terminal exons were associated
with a more severe clinical course than deletions in exons
in the rod domain (5).
13. Tafazzin gene (G4.5)
The G4.5 gene encodes the tafazzins, a group of
proteins of unknown function with no similarities to other
proteins. They are expressed ubiquitously with high levels
present in cardiac and skeletal muscle. G4.5 is a singlecopy gene comprised of ⬃11 kb of genomic DNA with 11
exons. Up to 10 different mRNAs can be produced by
alternate splicing, resulting in tafazzin proteins ranging
from 129 to 292 amino acids in length, that differ at the
NH2-terminal and central regions (exons 5–7). Two putative functional domains have been identified: a highly
hydrophobic segment of 30 residues at the NH2 terminus
that might act as a membrane anchor and a hydrophilic
segment in the central region that might form an exposed
loop interacting with other proteins.
Mutations in G4.5 were first associated with Barth’s
syndrome, an X-linked disorder characterized by infantileonset DCM, skeletal myopathy, short stature, neutropenia, and abnormal mitochondria (10). Histopathological
studies of the ventricular myocardium variably show hypertrophy, dilation, and/or endocardial fibroelastosis. On
electron microscopic examination, mitochondria typically
have concentric, tightly packed cristae with occasional
inclusion bodies. Increased urinary levels of 3-methylglutaconic acid and 2-ethylhydracrylic acid may be
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
Recent studies have found that Emery-Dreifuss muscular
dystrophy-causing mutations may also be located in the
rod domain of lamins A and C. Autosomal dominant limb
girdle muscular dystrophy type 1B is a slowly progressive
skeletal myopathy without contractures and with agerelated conduction disturbances. Mutations causing this
disorder have been located in the rod and tail domains of
lamins A and C (109). Familial partial lipodystrophy is an
autosomal dominant disorder characterized by regional
fat loss in the peripubertal period as well as insulin resistance. Mutations causing partial lipodystrophy have all
been located in the tail domain of lamins A and C with
mutation hot spots at codons 482 and 486 (20, 146).
Cardiac and skeletal muscle involvement have not been
reported in any of the families with this disorder.
INHERITED CARDIOMYOPATHIES
14. Mitochondrial DNA
Cardiac myocytes contain numerous mitochondria,
scattered throughout the cytoplasm between myofibrils,
that have an essential role in energy generation and contractile function. Mitochondria contain their own DNA,
transcription, and translation systems. The mitochondrial
genome covers 16.6 kb and contains 13 structural genes
encoding proteins involved in oxidative phosphorylation,
22 transfer RNAs, and 2 ribosomal RNAs. Mitochondrial
DNA is maternally inherited. A large number of mitochondrial proteins are not encoded by mitochondrial DNA but
by nuclear DNA. These include proteins involved in enzyme complexes, mitochondrial DNA replication and
transcription, as well as structural proteins and transport
proteins in the mitochondrial membranes. These nuclear
genes may have autosomal dominant, autosomal recessive, or sex-linked patterns of inheritance.
Point mutations and deletions in mitochondrial DNA
have been found in a number of multisystem disorders
that may have associated cardiac abnormalities, such as
adult-onset hypertrophy and childhood-onset DCM (89).
In particular, mitochondrial abnormalities have been implicated in a fatal infantile form of DCM (153). The role of
mitochondrial DNA mutations in the pathogenesis of
adult-onset DCM is not entirely clear. Although several
studies have shown that point mutations and deletions in
mitochondrial DNA occur more frequently in individuals
with DCM than in control subjects, it is not clear whether
Physiol Rev • VOL
these abnormalities exert a primary effect or occur as a
secondary consequence of established DCM (4, 81, 90).
Primary mitochondrial DNA mutations might directly
cause DCM or increase susceptibility to myocardial damage or stress. It is notable that mitochondrial DNA has a
high rate of spontaneous mutation and that deletions
occur with normal aging and with alcohol and ischemic
injury. It is feasible that the presence of congestive heart
failure might accelerate these processes. Progressive mitochondrial impairment would be expected to significantly impair myocardial energy generation and further
exacerbate contractile dysfunction.
15. Additional disease genes
Further additions to this growing list of DCM disease
genes can be expected. Of the 15 chromosomal loci
mapped for autosomal dominant DCM ⫾ conduction-system disease, 10 disease-causing genes have been identified. It is important to note that in 9 of these 10 genes, only
a very small number of mutations (1–3) in each gene have
been reported. Furthermore, current data suggest that
these known disease genes may only account for a relatively small proportion of all cases of DCM. For example,
Olson et al. (123) found only 2 mutations in the ACTC
gene in a cohort of 350 patients with familial and sporadic
DCM. Three studies in other populations with autosomal
dominant DCM have failed to identify further ACTC mutations: 136 Japanese patients, of whom 30 had familial
and 106 had sporadic disease (159); 86 European patients,
of whom 43 had familial and 43 had sporadic disease
(163); and 57 South African (56% black) patients (93). In
the cohort of 350 patients screened for ACTC mutations,
Olson and colleagues (120, 122) subsequently identified 2
mutations in each of the TPM1 and VCL genes, respectively. No mutations in the DES gene were found in 63
European patients with autosomal dominant DCM, of
whom 41 had familial and 22 had sporadic disease (163).
These observations suggest that either a large number of
different genes may cause DCM or that important diseasecausing genes remain to be discovered. Linkage studies in
large families with DCM will continue to be an invaluable
method for identification of DCM disease genes. A major
limitation of the candidate gene approach alone, without
linkage or functional analyses, is that apparent mutations
may in fact be rare polymorphisms.
In the past few years, there has been a proliferation
of mouse models generated by overexpression or deletion
of a variety of cardiac proteins, including sarcomeric,
cytoskeletal, and cell signaling proteins, that have exhibited a DCM phenotype. These studies demonstrate that
perturbation of the normal function of diverse proteins
contributing to cardiac structure and function may cause
DCM. Until disease-causing mutations are identified, how-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
present. G4.5 mutations reported to cause Barth’s syndrome include splice site mutations, insertions, deletions,
and nonsense and missense mutations. These mutations
have been located throughout the G4.5 gene. Mutations in
G4.5 have subsequently been associated with three other
myocardial disorders: X-linked endocardial fibroelastosis
(24), an X-linked form of noncompaction of the left ventricle (13), and X-linked infantile DCM (24). X-linked endocardial fibroelastosis is characterized by DCM with
infantile death, neutropenia, and mitochondrial abnormalities. The same missense mutation in a conserved region
of exon 10 of the G4.5 gene was found in two unrelated
families (24). X-linked noncompaction of the left ventricle
is a recessive disorder with infantile DCM, cardiac arrhythmias, and sudden death. Cardiac pathology typically
shows numerous prominent trabeculations and deep intertrabecular recesses in the ventricular myocardium as
well as ventricular hypertrophy, dilation, and endocardial
fibroelastosis. A missense mutation in a conserved region
of exon 8 of the G4.5 gene has been reported in one family
(13). X-linked DCM is a recessive disorder in which male
infants develop DCM and sudden death. A deletion in
exon 8 of the G4.5 gene was identified in one family,
resulting in the complete absence of all tafazzin proteins (24).
967
968
DIANE FATKIN AND ROBERT M. GRAHAM
ever, the relevance of these models to human DCM remains speculative.
C. Pathophysiological Mechanisms
1. “Defective force transmission” hypothesis
Physiol Rev • VOL
The identification of mutations in the genes encoding
the two sarcomere proteins ␤-MHC and cardiac troponin
T first raised the alternative hypothesis that defects in
force generation could be responsible for familial DCM
(67) (Fig. 2). The ␤-MHC gene mutations were predicted
to disrupt actin-myosin binding and cross-bridge function,
respectively, while the cardiac troponin T mutation was
located in the Ca2⫹-sensitive troponin C binding domain.
Although DCM can be a late complication of chronic
HCM, individuals with these ␤-MHC gene and cardiac
troponin T gene mutations appeared to have a primary
DCM with no clinical or histological evidence of antecedent HCM. Potential mechanism(s) by which sarcomere
protein gene mutations might cause either HCM or DCM
are discussed below.
3. Role of nuclear lamina proteins
The discovery that mutations in the LMNA gene
caused DCM raised intriguing questions about the role of
nuclear lamina proteins in the heart and in the pathogenesis of cardiac and skeletal myopathies. Currently, there
are no data to suggest that lamins A and C participate
directly in either force transmission or force generation in
cardiac myocytes. Although connections between lamin B
and the desmin intermediate filament network have been
proposed, no interactions between lamins A and C and
any of the cytoskeletal or sarcomeric proteins have been
described.
One possibility is that LMNA mutations might promote DCM by disruption of nuclear function. Mutations
that alter the charge or hydrophobicity of lamins A and C
might alter dimer formation, head-to-tail assembly of
dimers, or lateral assembly of complex filaments. Derangement of nuclear structure might result from impaired lamin filament assembly or from other altered
properties of mutant lamin proteins. Derangement of nuclear function might occur as a generalized consequence
of altered nuclear structure or specific lamin dysfunction.
Because lamins bind to chromatin and several transcription factors, LMNA mutations might result in altered transcription regulation. Potential downstream target genes
regulated by LMNA have not been identified. It is notable
that DCM, skeletal myopathies, and partial lipodystrophy
caused by LMNA mutations are not present at birth but
develop later in life. These observations would be consistent with the hypothesis that mutant lamins might confer
an increased susceptibility to degenerative processes
such as apoptosis or biomechanical stress (e.g., repetitive
contractions, high energy requirements). Dysregulated
apoptosis has been implicated in several cardiovascular
disorders, including heart failure (113), cardiac conduction defects (62), myocardial infarction (160), and arrhythmogenic right ventricular dysplasia (86). Whether
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
Subsequent to the finding that HCM was caused
predominantly by mutations in genes encoding sarcomere proteins, investigators sought to identify an equivalent unifying paradigm for the pathogenesis of DCM.
The “defective force transmission” hypothesis has been
widely promoted. This hypothesis is based on the
premise that the cytoskeleton provides an intracellular
scaffolding that is important for transmission of force
from the sarcomere to the extracellular matrix, and for
protection of the myocyte from external mechanical
stress. Hence, defects in cytoskeletal proteins are presumed to predispose to DCM by reducing force transmission and/or resistance to mechanical stress. Identification of mutations in the genes encoding cardiac
actin, desmin, metavinculin, the ␦-sarcoglycan subunit
of the dystrophin-associated glycoprotein complex, and
dystrophin have provided support for the defective
force transmission hypothesis for DCM (Fig. 2). Cardiac dysfunction may be related to effects of the protein itself or from abnormal interactions with other
proteins. For example, a dystrophin gene mutation has
been described that encodes a truncated protein with
an abnormal conformation that alters the assembly of
the sarcoglycan complex (36). It has also been demonstrated that the absence of the ␦-sarcoglycan component of the sarcoglycan complex results in loss of the
entire complex (21). Interestingly, in ␦-sarcoglycan-null
mice, it has been proposed that cardiac and skeletal
myopathy may not result directly from the loss of the
sarcoglycan complex in myocytes but may be mediated
by ischemic damage due to a sarcoglycan deficit in
vascular smooth muscle (21).
At least two other cytoskeletal proteins are potential
candidate genes for DCM. The muscle LIM protein MLP
promotes protein assembly along the actin cytoskeleton.
MLP deficiency has been associated with the onset and
progression of heart failure. In mice, the absence of MLP
results in severe DCM and heart failure (3). In individuals
with DCM, reduced levels of MLP expression in myocardial tissue have been demonstrated (181). In the latter
case, it is not known, however, whether MLP deficiency is
the cause of, or a consequence of, heart failure. Recently,
MLP gene mutations have been found in individuals with
HCM (39). ␣-Actinin and various other constituents of the
dystrophin-associated glycoprotein complex have been
implicated in limb girdle muscular dystrophies but have
not as yet been shown to cause DCM.
2. “Defective force generation” hypothesis
INHERITED CARDIOMYOPATHIES
4. Role of altered gene expression
in progression of DCM
RNA microarray analyses of myocardial tissue from
patients with DCM have shown that expression of a large
number of genes may be upregulated or downregulated as
a secondary response to cardiac failure. This molecular
response is comprised of factors that may exacerbate
progression of heart failure and as well as factors that
form part of compensatory mechanisms. In one study,
genes with altered expression profiles were clustered into
several groups: 1) cytoskeletal and myofibrillar genes
(e.g., striated muscle LIM protein-1, myomesin, nonsarcomeric regulatory MLC-2, ␤-actin), 2) genes responsible for
degradation and disassembly of myocardial proteins (e.g.,
␣1-antichymotrypsin, ubiquitin, gelsolin), 3) genes involved in metabolism (e.g., ATP synthase ␣-subunit, succinate dehydrogenase flavoprotein subunit, aldose reductase), 4) genes responsible for protein synthesis
(elongation factor-2, eukaryotic initiation factor-4AII),
and 5) genes encoding stress proteins (␣␤-crystallin and
␮-crystallin) (179). Cumulative mutations in mitochondrial genes with a progressive myocardial energy deficit
may also contribute significantly to cardiac decompensation (4, 81, 90).
5. Variable phenotypic expression of sarcomere
protein gene mutations
It is notable that mutations in six genes encoding
sarcomere proteins have now been shown to result in
either HCM or DCM. The factors that determine the phenotypic expression of sarcomere protein gene mutations
have not as yet been identified. One possibility is that the
HCM-causing and DCM-causing mutations may occur in
distinct functional domains of the encoded proteins. In
Physiol Rev • VOL
support of this proposal, it has been noted that HCMcausing mutations in cardiac actin occur in regions involved in force generation, whereas DCM-causing mutations have been identified in regions putatively involved in
force transmission (123). A DCM-causing mutation, but
not HCM-causing mutations, was found in the troponin
C-binding domain of cardiac troponin T, suggesting that
these two disease phenotypes might arise by different
pathophysiological mechanisms (67). In contrast, both
HCM- and DCM-causing mutations in the ␤-MHC gene
occurred in regions involved in actin-myosin interaction
and force generation (67). These latter observations suggest a second possibility, that is, whether a mutation
results in HCM or DCM is determined by the extent of
contractile deficit incurred. If myocardial hypertrophy is a
compensatory response to a certain degree of contractile
dysfunction, it is feasible that this compensatory response
might be inadequate to rescue more severe dysfunction
and DCM may ensue. A “dose effect” of mutant protein
has been observed in mouse models. For example, heterozygous mice expressing Arg403Gln ␣-MHC develop
HCM, whereas homozygous mice develop rapidly progressive DCM and neonatal death (33, 35, 41). Similarly, heterozygous mice expressing a truncated cMyBP-C exhibit
HCM; homozygous mice have a normal life span but develop DCM (95, 96). Further studies are required to determine the correlation between the “dose” of mutant
protein and quantitative differences in sarcomere function. Although these observations in mice suggest that
there might be a continuum between the extent of sarcomere dysfunction and the presence of hypertrophy or
dilation, a contrasting hypothesis is that independent
pathways are triggered that lead either to HCM or DCM. If
this is the case, then determining the components of each
pathway and determining which of these pathways is
activated may have important implications for the therapeutic management of individuals with sarcomere protein
gene mutations.
6. Mechanisms of tissue specificity
Mutations in the genes encoding desmin, lamins A
and C, ␦-sarcoglycan, and dystrophin have been found to
cause DCM without skeletal myopathy, as well as skeletal
myopathy with or without cardiac disease. Various possible explanations for these tissue differences in phenotypic expression have been proposed. First, if different
domains within the protein have distinct functions in
different tissues, then the location of the mutation within
the peptide might be important. Observations supporting
this proposal include the finding of a DCM-causing mutation in the DES gene in the desmin tail region (80) with a
skeletal myopathy-causing mutation located in the rod
(25, 46). In the LMNA gene, initial observations suggested
that DCM-causing mutations occurred predominantly in
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
apoptosis has a primary or secondary role in these disorders has not been established.
Sullivan et al. (152) recently characterized homozygous null LMNA mice. By 3– 4 wk of age, these mice
exhibited clinical and histological features of skeletal myopathy, similar to Emery-Dreifuss muscular dystrophy.
Myocardial tissue specimens showed patchy myocyte degeneration and atrophy. Histological analyses also
showed thymic atrophy, a reduction of spleen size, and
absent white fat. Heterozygous LMNA knockout mice
were phenotypically normal. These mice will provide a
useful model to further evaluate the role of lamins A and
C in the heart. Although the majority of reported LMNA
mutations have been missense mutations, if the major
consequence of mutant peptide is absence of normal
lamin filament assembly, then missense alleles may be
functionally equivalent to null alleles. Hence, observations in LMNA null mice may be directly relevant to
studies of the pathogenesis of DCM.
969
970
DIANE FATKIN AND ROBERT M. GRAHAM
7. Conclusions
Collectively, current data suggest that mutations in a
number of individual genes can cause DCM by multiple
distinct pathophysiological mechanisms. In adult-onset
forms of familial DCM, affected individuals appear phenotypically normal at birth and subsequently acquire disease manifestations in later life. These observations suggest that the mutant proteins do not prevent normal
cardiac development. The progressive onset of disease
may result from increased susceptibility to factors such as
biomechanical stress, apoptosis, or other degenerative
processes. Given the clinical variability of autosomal
dominant DCM both between and within families, it is
likely that phenotypic expression of DCM disease genes
can be modified by other genetic factors and/or environmental factors. In determining the role of genetic factors
in the pathogenesis of DCM, it will be important to establish whether genetic variants (polymorphisms) in various
genes increase susceptibility to other genetic and/or environmental factors. Finally, multiple changes in gene
expression have been found to occur in response to heart
Physiol Rev • VOL
failure. Identification and characterization of all the genes
responsible for the onset and progression of DCM will be
an important goal of future studies.
D. Pathophysiology of HCM and DCM:
Is There a Unifying Hypothesis?
Despite more than a decade of research, as indicated
above, the mechanisms by which disease-causing mutations impair cardiac function and result in either left
ventricular hypertrophy or chamber dilation remain elusive. Functionally, the chief defect in DCM is impaired
systolic performance, whereas in HCM it is diastolic dysfunction. That HCM is caused by mutations in genes that
encode sarcomeric proteins (␤-MHC; regulatory and essential MLC; cMyBP-C; troponins T, I, and C; ␣-tropomyosin; and actin) or intrasarcomeric cytoskeletal proteins
(titin) has led to the hypothesis that the left venticular
hypertrophy in this disorder develops as a compensatory
response to impaired force generation. However, this hypothesis requires further consideration, given that impaired force generation cannot be readily reconciled with
the clinical finding of preserved or enhanced systolic
function. Along the same lines, the finding that single gene
defects that cause DCM involve extrasarcomeric cytoskeletal proteins (desmin, ␦-sarcoglycan, metavinculin,
and dystrophin) has led to the suggestion that this disorder results from defective force transmission. This follows given that efficient myocyte contraction necessitates
cell shortening, i.e., efficient mechanical coupling, and
that the sarcomere is anchored to the cell wall by cytoskeletal proteins. Again, however, no experimental evidence has been generated to support this hypothesis,
and, as yet, the functional consequences of DCM-causing
cytoskeletal protein mutations have not been investigated. Furthermore, it is now known that DCM can also
be caused by mutations of sarcomeric and intrasarcomeric proteins (actin, ␤-MHC, MyBP-C, cardiac troponin T, ␣-tropomyosin, and titin) and even nuclear proteins
(lamins A and C). Involvement of the former has been
suggested to indicate that some proteins, such as cardiac
actin, may not only function as important components of
the sarcomere, critical to force generation, but may also
function as intrasarcomeric cytoskeletal proteins that
contribute to force transmission. Whether involvement of
all DCM-causing sarcomeric proteins, let alone the nuclear lamins, can be reconciled on this basis remains
unclear.
Very recent findings from studies of both HCM- and
DCM-causing troponin mutations do, however, provide
novel insights into their pathophysiology. Despite some
conflicting observations, detailed above, there is generally
good agreement that the functional defect associated with
HCM-linked mutations in cardiac troponin T (Ile79Asn,
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
the lamin A/C rod (34), while mutations associated with
Emery-Dreifuss muscular dystrophy were localized in the
globular head and tail regions (15). Subsequent studies
have shown, however, that mutations causing EmeryDreifuss muscular dystrophy may also occur throughout
the rod region (42). The importance of location per se is
challenged by observations of marked phenotypic variability within family members bearing the same mutation.
For example, a Leu-320 deletion in the LMNA gene in one
family resulted in DCM with conduction defects; some
family members had clinical features of skeletal myopathy, whereas others did not (18). A second possibility is
that tissue-specific differences in gene regulation might
be present. This may result from factors such as differing
effects of a mutation on tissue-specific promoter sequences or tissue differences in promoter activity. In one
family with X-linked DCM associated with a deletion in
the muscle-specific promoter, differences between cardiac and skeletal muscle dystrophin expression were attributed to upregulation of nonmuscle isoforms in the
skeletal muscle but not cardiac tissue (110). A third possibility is that other genetic factors may modify the phenotypic expression of a mutant protein. Finally, it is possible that susceptibility to environmental factors may
differ between tissues. For example, it has been proposed
that muscle tissues bearing mutant desmin may have
increased susceptibility to biomechanical stress (25). Further studies are required in affected individuals and in
mouse models to determine whether quantitive or qualitative differences in mutant protein are present in cardiac
and skeletal muscle. These studies might provide a clue
for subsequent mechanistic analyses.
INHERITED CARDIOMYOPATHIES
Physiol Rev • VOL
trophy development as a result of calcineurin/NFAT/
GATA4 and/or calmodulin kinase II activation.
Studies of animal models of HCM, as well as clinical
disorders that mimic the HCM phenotype (e.g., Friedreich’s ataxia, mitochondrial mutations, and very-longchain acyl-CoA dehydrogenase deficiency) have been
found to cause disordered cardiac energetics (either inefficient ATP utilization or generation) (11, 149). Moreover, it is likely that the resulting relative or absolute ATP
depletion contributes to diastolic dysfunction, as well as
to impaired Ca2⫹ uptake via the high energy-dependent
pump of the sarcoplasmic reticulum (SERCA2a). Although the latter would also deplete sarcoplasmic reticulum Ca2⫹ stores and, thus, availability of Ca2⫹ for cardiac
contraction, this may be offset, and systolic function
maintained, by the increased Ca2⫹ sensitivity of the HCMlinked mutations.
Taken together, these recent findings suggest the
exciting possibility that energy compromise and mutation-induced alterations in myofibrillar Ca2⫹ sensitivity,
acting either separately or in concert, may underlie a
unifying pathophysiology for both HCM and DCM (Fig. 2).
V. ARRHYTHMOGENIC RIGHT
VENTRICULAR DYSPLASIA
A. Clinical Manifestations
1. Disease characteristics
Arrhythmogenic right ventricular dysplasia (ARVD)
is a primary heart muscle disease characterized by myocyte loss due to necrosis and/or apoptosis, with fatty or
fibrofatty replacement. The pathological process predominantly affects the right ventricle and may be focal or
diffuse with progressive changes extending from the subepicardium to the endocardium, resulting in chamber dilation and wall thinning. Extensive wall thinning may give
rise to a parchment appearance (Uhl anomaly). Single or
multiple aneurysms of the right ventricular free wall have
been reported in 50% cases. Left ventricular involvement
has been found in up to 76% of cases (22). In advanced
disease, ARVD may be difficult to distinguish clinically
from DCM. The prevalence of ARVD has been estimated
to be 1/5,000, although higher rates (4.4/1,000) have been
reported in some areas of northern Italy (127, 164). ARVD
is thought to be familial in at least 30% cases, with autosomal dominant inheritance observed most commonly
(164). An autosomal recessive form of ARVD has been
reported in association with palmoplantar keratoderma
and woolly hair (Naxos disease).
2. Diagnosis of ARVD
A definitive diagnosis of ARVD may be difficult to
establish using clinical criteria. The age of onset, degree
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
Arg92Gln, Phe110Ile, Glu163Lys, Glu244Asp, Arg278Cys,
and Int15G13 A) (157, 177) and cardiac troponin I
(Arg145Gly, Arg162Trp) (30, 158) is a sensitization of the
cardiac contractile apparatus and myofibrillar ATPase activity to Ca2⫹. In contrast, a DCM-causing troponin T
mutation, ⌬Lys210, has now been shown to result in
desensitization of the Ca2⫹-force relationship, with no
change in either the slope of this relationship or in maximal force generation. In addition, sensitivity of myofibrillar ATPase to Ca2⫹ is also impaired, but the stoichiometry
of the three troponin components (troponin T, troponin I,
and troponin C) within the sarcomere is unaltered (107).
The structural basis for these alterations in Ca2⫹ sensitivity must await resolution of sarcomere assembly in
atomic detail, although it is of interest that Lys-210 is in a
domain of troponin T that interacts strongly and in a
Ca2⫹-sensitive manner with troponin C, but very weakly
with tropomyosin and troponin I. Whether the Ca2⫹ insensitivity of this troponin T mutation is due to a decrease
in Ca2⫹ avidity or to a decrease in the conformational
changes following Ca2⫹ binding remains unclear. Nevertheless, although maximal force generation is unaltered,
given that in intact cardiac muscle the contractile apparatus is never activated beyond the half-maximal level,
even small changes in Ca2⫹ sensitivity can be expected to
markedly alter force generation. In terms of the DCMcausing troponin T mutation, impaired Ca2⫹ sensitivity, as
with the impaired force transmission of cytoskeletal protein mutations, could well be expected to result in ventricular dilation as a compensatory response to the decrease in stroke volume. Moreover, impaired Ca2⫹
sensitivity is likely to enhance diastolic relaxation, although it is unclear if such a lusiotropic effect occurs in
the in vivo setting. Together, these altered responses at
the cellular level, if also applicable to other causes of
DCM, could explain the impaired systolic and preserved
diastolic function in this disorder. The recent finding of a
progressive increase in phospholamban-mediated inhibition of Ca2⫹ uptake via the Ca2⫹ pump, in an animal
model of DCM, potentially provides also a cogent explanation for progression of DCM to overt heart failure (50).
This defect would reduce sarcoplasmic reticulum Ca2⫹
stores and limit availability of Ca2⫹ during systole. Together with impaired myofibrillar Ca2⫹ sensitivity, this
would lead to systolic function being further depressed.
In contrast to the defects in DCM, the Ca2⫹ sensitization of HCM-linked mutations is likely to promote enhanced systolic contractility but impaired cardiac muscle
relaxation. The resulting diastolic dysfunction could contribute to the high incidence of sudden death, due either
to ventricular arrhythmia generation or to an increase in
cytostolic free Ca2⫹, the latter potentially being exacerbated by exercise- or stress-induced enhancement of cardiac sympathetic drive. Increased cytostolic free Ca2⫹,
particularly during diastole, would also promote hyper-
971
972
DIANE FATKIN AND ROBERT M. GRAHAM
B. Chromosomal Loci and Disease Genes
1. Chromosomal loci
Eight chromosomal loci have been identified in families with ARVD (Table 3). Seven of these loci have been
found in autosomal dominant ARVD, on chromosomes
14q23-q24 (ARVD1) (127), 1q42-q43 (ARVD2) (128), 14q12q22 (ARVD3) (145), 2q32 (ARVD4) (129), 3p23 (ARVD5)
(1), and 10p12-p14 (ARVD6) (79); the seventh locus (chromosome 10q22) (99) was mapped in a family with autosomal dominant myofibrillar myopathy characterized
mainly by skeletal muscle disease with ARVD occurring in
some family members. Muscle biopsy specimens showed
myopathic changes with accumulation of desmin, dystrophin, and ␥-sarcoglycan. A disease-causing gene (cardiac ryanodine receptor gene) has recently been identified at the ARVD2 locus (166). Autosomal recessive
ARVD (Naxos disease) has been mapped to chromosome
17q21, with mutations in the plakoglobin gene recently
identified (98).
TABLE
3. ARVD chromosomal loci and disease genes
Chromosomal Locus
Gene
Protein
Autosomal dominant inheritance
1q42-q43 (ARVD2)
2q32 (ARVD4)
3p23 (ARVD5)
10p12-p14 (ARVD6)
10q22 (myofibrillar myopathy)
14q12-q22 (ARVD3)
14q23-q24 (ARVD1)
RYR2
?
?
?
?
?
?
Cardiac ryanodine receptor
?
?
?
?
?
?
Autosomal recessive inheritance
17q21 (Naxos disease)
JUP
Plakoglobin
ARVD, arrhythmogenic right ventricular dysplasia.
Physiol Rev • VOL
2. Cardiac ryanodine receptor gene (RYR2)
The RYR2 gene encodes the cardiac ryanodine receptor, which is the major Ca2⫹ release channel in cardiac
muscle. The cardiac ryanodine receptor is one of three
ryanodine receptor isoforms, each of which is encoded by
a separate gene. RYR2 is expressed in the heart and, to a
lesser extent, in the brain and gestational myometrium.
RYR1 and RYR3 are expressed in skeletal muscle and in
brain, respectively. RYR2-encoded proteins associate
as homotetramers with four FK506-binding proteins
(FKBP12.6) to form a membrane-spanning complex in the
sarcoplasmic reticulum. Stimulation of voltage-sensitive
L-type Ca2⫹ channels on the outer myocardial cell membrane permits small amounts of Ca2⫹ to enter the cell.
This Ca2⫹ influx activates the ryanodine receptors in the
sarcoplasmic reticulum resulting in the release of large
quanta of Ca2⫹ that is responsible for initiating myocardial contraction. Phosphorylation of RYR2 by protein kinase A dissociates FKBP12.6 and regulates the channel
open probability (92). Administration of FK506 disinhibits
coordinated Ca2⫹ flux through the ryanodine receptor, an
effect due to its interaction with FKBP12.6. Ca2⫹ overload-induced cardiac failure has been reported in children
receiving FK506 as an immunosuppressive following
heart transplantation (6). RYR2 is comprised of 105 exons
that encode a protein of 4,967 amino acids. Several distinct transcripts of RYR2 arise by alternate splicing. The
cardiac ryanodine receptor has a large NH2-terminal cytoplasmic domain that contains interaction sites for
FKBP12.6, ATP, and calmodulin and a COOH-terminal
transmembrane domain that is anchored to the sarcoplasmic reticulum by 4 –10 hydrophobic motifs.
Four missense mutations in RYR2 have been identified in four unrelated families that map to the ARVD2
locus (166). These four mutations were located in two
clusters in the cytosolic portion of the cardiac ryanodine
receptor: one cluster at the NH2-terminal end and a second cluster in the central FKBP12.6 interacting domain.
RYR2 mutations have also recently been reported in
families and sporadic cases of catecholamine-sensitive
polymorphic ventricular tachycardia, indicating that this
disorder is allelic to ARVD (76, 126). Catecholamine-sensitive polymorphic ventricular tachycardia is characterized by exercise-induced, bidirectional polymorphic ventricular tachycardia that occurs in the absence of
structural heart disease. RYR2 mutations in this disorder
have been found in the two clusters: in the cytosolic
central FKBP12.6-interacting domain and in the COOHterminal transmembrane region, respectively. The three
clusters of mutations in the RYR2 gene (proximal NH2
terminal, central FKBP12.6 interacting domain, COOH terminal) correspond with the location of mutations in the
RYR1 gene, the skeletal muscle homolog of RYR2, that
have been reported to cause malignant hyperthermia and
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
of penetrance, and clinical features vary both between
and within families. Affected individuals present most
commonly with ventricular and supraventricular arrhythmias, which may be well-tolerated or result in syncope or
sudden death. Sudden death is frequently precipitated by
exercise. ARVD is a major cause of death in the young,
occurring at a rate of 2.5%/year (164). In Italy, ARVD has
a relatively high prevalence and accounts for 20% of sudden deaths in individuals aged less than 35 yr and over
20% deaths in competitive athletes (164). Electrocardiographic studies typically show T-wave inversion in the
precordial leads. Late potentials may be present on signalaveraged electrocardiography. Sick sinus syndrome and
complete atrioventricular conduction block are late complications observed in some older patients with severe
disease. Heart failure may occur with disease progression
in up to 20% cases.
INHERITED CARDIOMYOPATHIES
central core disease (94). Malignant hyperthermia is a
skeletal myopathy characterized by muscle rigidity and
contractures that is triggered by administration of anesthetics and depolarizing muscle relaxants; central core
disease is a nonprogressive skeletal myopathy, characterized by hypotonia and proximal muscle weakness, that is
associated with an increased risk of hyperthermia during
anesthetic administration.
3. Plakoglobin gene (JUP)
4. Pathophysiological mechanisms
Linkage studies have shown that ARVD is a genetically heterogeneous disorder. Although only two diseasecausing genes have been identified to date, it is clear that
diverse pathophysiological pathways may culminate in
the ARVD phenotype. Mutations in the cardiac ryanodine
receptor are presumed to alter Ca2⫹ channel properties
with either hyperactivation or hypersensitivity to activating levels of Ca2⫹. The subsequent imbalance of intracellular Ca2⫹ homeostasis would be expected to disrupt
normal excitation-contraction coupling, promote cardiac
arrhythmias, and potentially trigger apoptosis and/or necrosis. In contrast, it has been proposed that mutant
plakoglobin might render cells more susceptible to the
effects of mechanical stress, resulting in detachment of
intercalated discs and subsequent cellular necrosis. A
common feature of these two pathophysiological mechanisms is the end point of cell death. These putative mechanisms would both be consistent with the characteristic
Physiol Rev • VOL
myocardial histopathological findings in patients with
ARVD (22). Cumulative cell death in the heart, skin, and
hair might account for the progressive changes with age
in these tissues. The cause of right ventricular predominance in ARVD has not been established. One possible
explanation is that disease-causing genes might be expressed to a greater extent in the right rather than the left
ventricle. Alternatively, differences between the right and
left ventricular “environment,” such as pressure and loading conditions, may determine phenotypic expression.
Further insights into the pathogenesis of this disorder will
be gained with the identification and characterization of
additional disease genes.
VI. RESTRICTIVE CARDIOMYOPATHY
A. Clinical Manifestations
1. Disease characteristics
Restrictive cardiomyopathy (RCM) is a myocardial
disorder characterized by impaired diastolic filling of the
left ventricle, with rapid early filling and slow late filling.
RCM is the least common of the four categories of cardiomyopathies. It is most frequently caused by pathological conditions that stiffen the myocardium by infiltration
or fibrosis, such as eosinophilic endomyocardial disease,
hemochromatosis, amyloidosis, sarcoidosis, scleroderma,
carcinoid, Gaucher’s disease, Fabry disease, glycogen
storage disease, metastatic malignancy, anthracycline
toxicity, or radiation damage. These pathophysiological
processes may be confined to the heart or affect multiple
organs. Several of the infiltrative diseases that result in
RCM may be inherited, including familial amyloidosis,
hemochromatosis, Gaucher’s disease, and glycogen storage disease.
In some individuals, RCM may occur in the absence
of a precipitating condition (“idiopathic” RCM). Idiopathic RCM is not generally recognized to have a familial
predisposition; however, several small families have been
reported (75). The phenotypes in these families have been
variable: isolated RCM, RCM with atrioventricular conduction block and skeletal myopathy, and RCM with skeletal myopathy. Autosomal dominant and autosomal recessive patterns of inheritance have been observed.
2. Diagnosis of RCM
Individuals with RCM may present with dyspnea,
weakness, or exercise intolerance due to the inability to
increase cardiac output by tachycardia without further
reducing ventricular filling. In severe cases, there may be
signs of right heart failure, including hepatomegaly, ascites, and peripheral edema. The jugular venous pressure
may be elevated with an inspiratory increase in height
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
The JUP gene encodes the cytoplasmic protein plakoglobin. This protein is a key component of desmosomes
and adherens junctions in many tissues, including the
heart, skin, and hair. It belongs to the catenin family of
proteins. Plakoglobin associates with desmoglein, one of
the transmembrane desmosomal proteins, and is a component of the cadherin-catenin complex in fasciae adherens. It is thought to be important for tight adhesion and
signaling between cells (54). The JUP gene is comprised
of ⬃17 kb of genomic DNA with 13 exons that encode a
protein of 744 amino acids. The plakoglobin protein contains a distinct repeating amino acid repeat, the armadillo
repeat. Several protein isoforms may arise by alternate
splicing, not all of which have been fully characterized.
A homozygous two-base pair deletion in the JUP
gene was found in all affected members of a family with
autosomal recessive ARVD (Naxos disease) that mapped
to the chromosome 17q21 locus (98). Family members
that were heterozygous for this deletion were clinically
unaffected. The deletion caused a frameshift and premature stop codon, resulting in truncation of the encoded
protein. COOH-terminal truncations of plakoglobin have
been shown in vitro to produce marked alterations of
desmosome morphology (124).
973
974
DIANE FATKIN AND ROBERT M. GRAHAM
3. Natural history of RCM
The prognosis in RCM varies according to the underlying cause, but the majority of individuals experience
progressive deterioration due to congestive cardiac failure with a high incidence of premature mortality. Symptomatic improvement in RCM may be achieved with diuretic or vasodilator therapy. Specific therapies are
indicated in some cases; for example, iron chelation and
immunosuppressive drugs may benefit individuals with
Physiol Rev • VOL
hemochromatosis and primary amyloidosis, respectively.
Cardiac transplantation may be performed in individuals
with disease pathologies localized to the heart.
B. Chromosomal Loci and Disease Genes
1. Chromosomal loci
No genetic linkage studies of large families with idiopathic RCM have been described. Only one diseasecausing gene, DES, on chromosome 2q35, has been identified to date (46).
2. Desmin gene (DES)
Desmin-related myopathies are a heterogeneous
group of disorders characterized predominantly by skeletal myopathy and cardiac conduction disturbances with
accumulation of desmin deposits in skeletal and cardiac
muscle. RCM is a relatively infrequent manifestation of
desmin-related myopathy. Missense mutations in the DES
gene have been found in several families with desminrelated myopathy (with and without RCM) (25, 46).
Desmin accumulation in skeletal and cardiac muscle may
be a relatively nonspecific finding and has been observed
in the absence of DES gene mutations. As noted in section
IVB8, mutations in the DES gene may cause DCM. The
mechanism for these differences in cardiac phenotypic
expression has not been studied. Further studies of those
families with suspected familial RCM are required to explore the potential genetic basis of this disorder.
VII. CONCLUSION
Over the last decade, substantial progress has been
made in defining single gene mutations that can cause
inherited cardiomyopathies. Disease-causing genes have
yet to be identified for a number of mapped chromosomal
loci, and it is likely that additional loci remain to be
discovered. Further genetic studies of families with inherited myopathies are required to compile a comprehensive
list of disease genes and mutations. The availability of
data from the Human Genome Project should reduce the
need for time-consuming and laborious positional cloning
strategies and greatly facilitate identification of candidate
genes in mapped loci. Identification of all disease-causing
genes may be required to fully understand the pathogenesis of inherited cardiomyopathies.
Elucidating the normal function of these genes in the
heart and the mechanisms by which gene mutations initiate disease pathways are major goals of future research
studies. The generation of genetically engineered mouse
models with tissue-restricted gene expression will be an
invaluable resource for these studies. Dissecting out the
components of intracellular signaling cascades triggered
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
(Kussmaul sign). Transthoracic echocardiography may
show thickening of the left (⫾right) ventricular walls,
with variable effects on chamber diameter and contractility. A classic feature of cardiac amyloidosis is the presence of sparkling echodense spots in the myocardial walls
giving a speckled “ground-glass” appearance. The mitral
and aortic valve leaflets may also be thickened. Transmitral Doppler interrogation typically shows increased peak
E-wave velocity, producing an increase in the E/A wave
ratio, and shortened E-wave deceleration time. These
Doppler findings are not specific to RCM and may occur in
other disorders that increase left ventricular diastolic
stiffness, such as HCM and coronary artery disease. The
characteristic hemodynamic feature of RCM is the “dip
and plateau” or “square root” sign, consisting of a marked
rapid decline in ventricular pressure at the onset of diastole (dip), followed by a rapid rise to a plateau in early
diastole (plateau). These changes are reflected in atrial
pressure tracings as a prominent y-descent (rapid atrial
emptying in early diastole) followed by a rapid rise and
plateau (abrupt cessation of atrial filling due to restriction). Pulmonary venous and arterial pressures and systemic venous pressures are generally elevated.
The principal differential diagnosis of RCM is constrictive pericarditis. Although these conditions have similar clinical and hemodynamic features, differentiation
between them has important management implications,
since patients with constrictive pericarditis may benefit
from surgical intervention. Both conditions cause impairment of diastolic filling with elevation of left and right
ventricular pressures and reduced stroke volume and cardiac output. In RCM, the diastolic filling pressure in the
left ventricle usually exceeds that in the right ventricle by
at least 5 mmHg; in constrictive pericarditis, diastolic
filling pressures in the left and right ventricles are equivalent. Marked respiratory variations in left ventricular
isovolumic relaxation time and peak mitral valve velocity
in early diastole are observed in constrictive pericarditis,
but not in RCM. Endomyocardial biopsy can be useful to
detect myocardial histopathology in RCM; transthoracic
or transesophageal echocardiography, computed tomography scanning, and magnetic resonance imaging may
demonstrate pericardial thickening or calcification in constrictive pericarditis.
INHERITED CARDIOMYOPATHIES
Address for reprint requests and other correspondence: D.
Fatkin or R. M. Graham, Molecular Cardiology Unit, Victor
Chang Cardiac Research Institute, Level 6, 384 Victoria St.,
Darlinghurst, New South Wales 2010, Australia (E-mail:
[email protected] or b.graham@victorchang.
unsw.edu.au).
Physiol Rev • VOL
REFERENCES
1. AHMAD F, LI D, KARIBE A, GONZALEZ O, TAPSCOTT T, HILL R, WEILBAECHER D, BLACKIE P, FUREY M, GARDNER M, BACHINSKI LL, AND ROBERTS
R. Localization of a gene responsible for arrhythmogenic right
ventricular dysplasia to chromosome 3p23. Circulation 98: 2791–
2795, 1998.
2. ARAD M, BENSON DW, PEREZ-ATAYDE AR, MCKENNA WJ, SPARKS EA,
KANTOR RJ, MCGARRY K, SEIDMAN JG, AND SEIDMAN CE. Constitutively
active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 109: 357–362,
2002.
3. ARBER S, HUNTER JJ, ROSS J, HONGO M, SANSIG G, BORG J, PERRIARD
JC, CHIEN KR, AND CARONI P. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88: 393– 403, 1997.
4. ARBUSTINI E, DIEGOLI M, FASANI R, GRASSO M, MORBINI P, BANCHIERI N,
BELLINI O, DAL BELLO B, PILOTTO A, MAGRINI G, CAMPANA C, FORTINA
P, GAVAZZI A, NARULA J, AND VIGANO M. Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy.
Am J Pathol 153: 1501–1510, 1998.
5. ARBUSTINI E, DIEGOLI M, MORBINI P, DAL BELLO B, BANCHIERI N,
PILOTTO A, MAGANI F, GRASSO M, NARULA J, GAVAZZI A, VIGANO M, AND
TAVAZZI L. Prevalence and characteristics of dystrophin defects in
adult male patients with dilated cardiomyopathy. J Am Coll Cardiol 35: 1760 –1768, 2000.
6. ATKISON P, JOUBERT G, BARRON A, GRANT D, PARADIS K, SEIDMAN E,
WALL W, ROSENBERG H, HOWARD J, WILLIAMS S, AND STILLER C. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 34: 894 – 896, 1995.
7. BECKER KD, GOTTSHALL KR, HICKEY R, PERRIARD JC, AND CHIEN KR.
Point mutations in human ␤ cardiac myosin heavy chain have
differential effects on sarcomeric structure and assembly: an ATP
binding site change disrupts both thick and thin filaments, whereas
hypertrophic cardiomyopathy mutations display normal assembly.
J Cell Biol 137: 131–140, 1997.
8. BERS DM. Calcium fluxes involved in control of cardiac myocyte
contraction. Circ Res 87: 275–281, 2000.
9. BING W, REDWOOD CS, PURCELL IF, ESPOSITO G, WATKINS H, AND
MARSTON SB. Effects of two hypertrophic cardiomyopathy mutations in ␣-tropomyosin, Asp175Asn and Glu180Gly, on Ca2⫹ regulation of thin filament motility. Biochem Biophys Res Commun
236: 760 –764, 1997.
10. BIONE S, D’ADAMO P, MAESTRINI E, GEDEON AK, BOLHUIS PA, AND
TONIOLO D. A novel X-linked gene, G4.5, is responsible for Barth
syndrome. Nat Genet 12: 385–389, 1996.
11. BLAIR E, REDWOOD C, ASHRAFIAN H, OLIVEIRA M, BROXHOLME J, KERR B,
SALMON A, OSTMAN-SMITH I, AND WATKINS H. Mutations in the ␥2
subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 10: 1215–1220,
2001.
12. BLANCHARD E, SEIDMAN C, SEIDMAN JG, LEWINTER M, AND MAUGHAN D.
Altered crossbridge kinetics in the ␣MHC403⫹ mouse model of
familial hypertrophic cardiomyopathy. Circ Res 84: 475– 483, 1999.
13. BLEYL SB, MUMFORD BR, THOMPSON V, CAREY JC, PYSHER TJ, CHIN TK,
AND WARD K. Neonatal lethal noncompaction of the left ventricular
myocardium is allelic with Barth syndrome. Am J Hum Genet 61:
868 – 872, 1997.
14. BONNE G, CARRIER L, BERCOVICI J, CRUAUD C, RICHARD P, HAINQUE B,
GAUTEL M, LABEIT S, JAMES M, BECKMANN J, WEISSENBACH J, VOSBERG
HP, FISZMAN M, KOMAJDA M, AND SCHWARTZ K. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with
familial hypertrophic cardiomyopathy. Nat Genet 11: 438 – 440,
1995.
15. BONNE G, DI BARLETTA MR, VARNOUS S, BECANE HM, HAMMOUDA EH,
MERLINI L, MUNTONI F, GREENBERG CR, GARY F, URTIZBEREA JA,
DUBOC D, FARDEAU M, TONIOLO D, AND SCHWARTZ K. Mutations in the
gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 21: 285–288, 1999.
16. BOTTINELLI R, COVIELLO DA, REDWOOD CS, PELLEGRINO MA, MARON BJ,
SPIRITO P, WATKINS H, AND REGGIANI C. A mutant tropomyosin that
causes hypertrophic cardiomyopathy is expressed in vivo and as-
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
by a gene defect that ultimately results in cardiac hypertrophy, dilation, and contractile dysfunction is a further
research objective. The use of RNA microarray technology will facilitate identification of genes that participate in
these pathways. A detailed understanding of these molecular and cellular events may lead to the identification of
new targets for therapeutic intervention. In contrast to
current therapies directed predominantly toward alleviation of symptoms, targeted therapies should influence the
onset and progression of the disease process itself.
Disease manifestations in inherited cardiomyopathies are likely to be a complex interaction of both genetic
and environmental factors. The potential role of genetic
factors in modifying a disease phenotype, increasing susceptibility to secondary causes of disease and influencing
responses to therapy, needs to be evaluated. Determination of the role of various environmental factors, such as
exercise, alcohol, and pharmacological agents, will be
important for counseling and managing patients with
these disorders.
Currently, a major rate-limiting step in translating the
results of molecular genetic discoveries to clinical practice is the inability to efficiently perform genotype analyses in large numbers of individuals. Since each family
tends to have a unique mutation, all the known disease
genes need to be evaluated in every new proband. With
the use of conventional techniques, this approach is both
time-consuming and expensive. The development of automated methods for performing large-scale genotyping is
urgently required. The ability to perform genotype analyses will enable young individuals genetically at risk to be
identified before the onset of symptoms and signs of
disease. These genotype-positive, phenotype-negative individuals will be an important group to target in clinical
trials of preventative pharmacological therapy. Genotype
analyses will also enable clinical surveillance of the offspring of affected individuals to be rationalized, i.e., serial
diagnostic investigations, counseling on life-style modifications, etc., need only be performed in genotype-positive
individuals. Genotype-phenotype correlations will enable
“high-risk” and “low-risk” mutations to be determined.
This prognostic information will assist physicians in selection of appropriate therapies, timing of follow-up visits, pregnancy counseling, etc. Molecular genetic studies
have provided a new framework for understanding the
pathogenesis of inherited cardiomyopathies. Ultimately, it
is hoped that this knowledge will lead to new approaches
to clinical management, including diagnosis, genetic
counseling, prognostic stratification, and treatment.
975
976
17.
18.
19.
20.
21.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
sociated with an increased calcium sensitivity. Circ Res 82: 106 –
115, 1998.
BOWLES KR, GAJARSKI R, PORTER P, GOYTIA V, BACHINSKI L, ROBERTS R,
PIGNATELLI R, AND TOWBIN JA. Gene mapping of familial autosomal
dominant dilated cardiomyopathy to chromosome 10q21– q23.
J Clin Invest 98: 1355–1360, 1996.
BRODSKY GL, MUNTONI F, MIOCIC S, SINAGRA G, SEWRY C, AND
MESTRONI L. Lamin A/C gene mutation associated with dilated
cardiomyopathy with variable skeletal muscle involvement. Circulation 101: 473– 476, 2000.
BROWN MS AND GOLDSTEIN JL. A receptor-mediated pathway for
cholesterol homeostasis. Science 232: 34 – 47, 1986.
CAO H AND HEGELE RA. Nuclear lamin A/C R482Q mutation in
Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 9: 109 –112, 2000.
CORAL-VAZQUEZ R, COHN RD, MOORE SA, HILL JA, WEISS RM, DAVISSON
RL, STRAUB V, BARRESI R, BANSAI D, HRSTKA RF, WILLIAMSON R, AND
CAMPBELL KP. Disruption of the sarcoglycan-sarcospan complex in
vascular smooth muscle: a novel mechanism for cardiomyopathy
and muscular dystrophy. Cell 98: 465– 474, 1999.
CORRADO D, BASSO C, THIENE G, MCKENNA WJ, DAVIES MJ, FONTALIRAN
F, NAVA A, SILVESTRI F, BLOMSTROM-LUNDQVIST C, WLODARSKA EK,
FONTAINE G, AND CAMERINI F. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 30: 1512–1520, 1997.
CUDA G, FANANAPAZIR L, EPSTEIN ND, AND SELLERS JR. The in vitro
motility activity of ␤-cardiac myosin depends on the nature of the
␤-myosin heavy chain gene mutation in hypertrophic cardiomyopathy. J Muscle Res Cell Motil 18: 275–283, 1997.
D’ADAMO P, FASSONE L, GEDEON A, JANSSEN EAM, BIONE S, BOLHUIS
PA, BARTH PG, WILSON M, HAAN E, ORSTAVIK KH, PATTON MA, GREEN
AJ, ZAMMARCHI E, DONATI MA, AND TONIOLO D. The X-linked gene
G4.5 is responsible for different infantile dilated cardiomyopathies.
Am J Hum Genet 61: 862– 867, 1997.
DALAKAS MC, PARK KY, SEMINO-MORA C, LEE HS, SIVAKUMAR K, AND
GOLDFARB LG. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med
342: 770 –780, 2000.
D’CRUZ LG, BABOONIAN C, PHILLIMORE HE, TAYLOR R, ELLIOTT PM,
VARNAVA A, DAVISON F, MCKENNA WJ, AND CARTER ND. Cytosine
methylation confers instability on the cardiac troponin T gene in
hypertrophic cardiomyopathy. J Med Genet 37: e18, 2000. (http://
jmedgenet.com/cgi/content/full/37/9/e18)
DEC GW AND FUSTER V. Idiopathic dilated cardiomyopathy. N Engl
J Med 331: 1564 –1575, 1994.
DE WINDT LJ, LIM HW, BUENO OF, LIANG Q, DELLING U, BRAZ JC,
GLASCOCK BJ, KIMBALL TF, DEL MONTE F, HAJJAR RJ, AND MOLKENTIN
JD. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98: 3322–3327, 2001.
DURAND JB, BACHINSKI LL, BIELING LC, CZERNUSZEWICZ GZ, ABCHEE
AB, YU QT, TAPSCOTT T, HILL R, IFEGWU J, MARIAN AJ, BRUGADA R,
DAIGER S, GREGORITCH JM, ANDERSON JL, QUINONES M, TOWBIN JA,
AND ROBERTS R. Localization of a gene responsible for familial
dilated cardiomyopathy to chromosome 1q32. Circulation 92:
3387–3389, 1995.
ELLIOTT K, WATKINS H, AND REDWOOD CS. Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic
cardiomyopathy. J Biol Chem 275: 22069 –22074, 2000.
ESPOSITO G, RAPACCIUOLO A, PRASAD SVN, TAKAOKA H, THOMAS SA,
KOCH WJ, AND ROCKMAN HA. Genetic alterations that inhibit in vivo
pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105: 85–92, 2002.
FAMILIAL HYPERTROPHIC CARDIOMYOPATHY MUTATION DATABASE. http://
www.angis.org.au/Databases/Heart/.
FATKIN D, CHRISTE ME, ARISTIZABAL O, MCCONNELL BK, SRINIVASAN S,
SCHOEN FJ, SEIDMAN CE, TURNBULL DH, AND SEIDMAN JG. Neonatal
cardiomyopathy in mice homozygous for the Arg403Gln mutation
in the ␣ cardiac myosin heavy chain gene. J Clin Invest 103:
147–153, 1999.
FATKIN D, MACRAE C, SASAKI T, WOLFF MR, PORCU M, FRENNEAUX M,
ATHERTON J, VIDAILLET HJ, SPUDICH S, DE GIROLAMI U, SEIDMAN JG,
AND SEIDMAN CE. Missense mutations in the rod domain of the lamin
Physiol Rev • VOL
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
A/C gene as causes of dilated cardiomyopathy and conductionsystem disease. N Engl J Med 341: 1715–1724, 1999.
FATKIN D, MCCONNELL BK, MUDD JO, SEMSARIAN C, MOSKOWITZ IGP,
SCHOEN FJ, GIEWAT M, SEIDMAN CE, AND SEIDMAN JG. An abnormal
Ca2⫹ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. J Clin Invest 106: 1351–1359, 2000.
FRANZ WM, MULLER M, MULLER OJ, HERRMANN R, ROTHMANN T, CREMER M, COHN RD, VOIT T, AND KATUS HA. Association of nonsense
mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy. Lancet 355: 1781–1785,
2000.
GAO WD, PEREZ NG, SEIDMAN CE, SEIDMAN JG, AND MARBAN E.
Altered cardiac excitation-contraction coupling in mutant mice
with familial hypertrophic cardiomyopathy. J Clin Invest 103: 661–
666, 1999.
GAUTEL M, ZUFFARDI O, FREIBURG A, AND LABEIT S. Phosphorylation
switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction? EMBO J 14: 1952–1960,
1995.
GEIER C, OEZCELIK C, PERROT A, BIT-AVRAGIM N, SCHEFFOLD T, AND
OSTERZIEL KJ. Muscle LIM protein: a novel disease gene for hypertrophic cardiomyopathy? Circulation 104 Suppl II: II-521, 2001.
GEISTERFER-LOWRANCE AAT, KASS S, TANIGAWA G, VOSBERG HP, MCKENNA W, SEIDMAN CE, AND SEIDMAN JG. A molecular basis for
familial hypertrophic cardiomyopathy: a ␤ cardiac myosin heavy
chain missense mutation. Cell 62: 999 –1006, 1990.
GEISTERFER-LOWRANCE AAT, CHRISTE M, CONNER DA, INGWALL JS,
SCHOEN FJ, SEIDMAN CE, AND SEIDMAN JG. A mouse model of familial
hypertrophic cardiomyopathy. Science 272: 731–734, 1996.
GENSCHEL J AND SCHMIDT HHJ. Mutations in the LMNA gene encoding lamin A/C. Hum Mutat 16: 451– 459, 2000.
GEORGAKOPOULOS D, CHRISTE ME, GIEWAT M, SEIDMAN CE, SEIDMAN
JG, AND KASS DA. The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an ␣-cardiac myosin
heavy chain missense mutation. Nat Med 5: 327–330, 1999.
GERULL B, GRAMLICH M, ATHERTON J, MCNABB M, TROMBITAS K, SASSEKLAASSEN S, SEIDMAN JG, SEIDMAN CE, GRANZIER H, LABEIT S, FRENNEAUX M, AND THIERFELDER L. Mutations of TTN, encoding the giant
muscle filament titin, cause familial dilated cardiomyopathy. Nat
Genet 30: 201–204, 2002.
GILBERT R, KELLY MG, MIKAWA T, AND FISCHMAN DA. The carboxyl
terminus of myosin binding protein C specifies incorporation into
the A-band of striated muscle. J Cell Sci 109: 101–111, 1996.
GOLDFARB LG, PARK KY, CERVENAKOVA L, GOROKHOVA S, LEE HS,
VASCONCELAS O, NAGLE JW, SEMINO-MORA C, SIVAKUMAR K, AND DALAKAS MC. Missense mutations in desmin associated with familial
cardiac and skeletal myopathy. Nat Genet 19: 402– 403, 1998.
GOLLOB MH, GREEN MS, TANG ASL, GOLLOB T, KARIBE A, HASSAN AS,
AHMAD F, LOZADO R, SHAH G, FANANAPAZIR L, BACHINSKI L, AND ROBERTS R. Identification of a gene responsible for familial WolffParkinson-White syndrome. N Engl J Med 344: 1823–1831, 2001.
GRUEN M AND GAUTEL M. Mutations in the ␤-myosin S2 that cause
familial hypertrophic cardiomyopathy abolish the interaction with
the regulatory domain of myosin binding protein-C. J Mol Biol 286:
933–949, 1999.
GRUNIG E, TASMAN JA, KUCHERER H, FRANZ W, KUBLER W, AND KATUS
HA. Frequency and phenotypes of familial dilated cardiomyopathy.
J Am Coll Cardiol 31: 186 –194, 1998.
HAGHIGHI K, SCHMIDT AG, HOIT BD, BRITTSAN AG, YATANI A, LESTER
JW, ZHAI J, KIMURA Y, DORN GW, MACLENNAN DH, AND KRANIAS EG.
Superinhibition of sarcoplasmic reticulum function by phospholamban induces cardiac contractile failure. J Biol Chem 276:
24145–24152, 2001.
HALLOPEAU M. Retrecissement ventriculoaortique. Gazette Medicale
Paris 24: 683– 684, 1869.
HART KA, HODGSON S, WALKER A, COLE CG, JOHNSON L, DUBOWITZ V,
AND BOBROW M. DNA deletions in mild and severe Becker muscular
dystrophy. Hum Genet 75: 281–285, 1987.
HELING A, ZIMMERMANN R, KOSTIN S, MAENO Y, HEIN S, DEVAUX B,
BAUER E, KLOVEKORN WP, SCHLEPPER M, SCHAPER W, AND SCHAPER J.
Increased expression of cytoskeletal, linkage and extracellular proteins in failing human myocardium. Circ Res 86: 846 – 853, 2000.
HERTIG CM, BUTZ S, KOCH S, EPPENBERGER-EBERHARDT M, KEMLER R,
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
22.
DIANE FATKIN AND ROBERT M. GRAHAM
INHERITED CARDIOMYOPATHIES
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
Physiol Rev • VOL
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
MILASIN J, FALASCHI A, CAMERINI F, GIACCA M, AND MESTRONI L.
Linkage of familial dilated cardiomyopathy to chromosome 9. Am J
Hum Genet 57: 846 – 852, 1995.
KUNST G, KRESS KR, GRUEN M, UTTENWEILER D, GAUTEL M, AND FINK
RHA. Myosin binding protein C, a phosphorylation-dependent force
regulator in muscle that controls the attachment of myosin heads
by its interaction with myosin S2. Circ Res 86: 51–58, 2000.
KUSHWAHA SS, FALLON JT, AND FUSTER V. Restrictive cardiomyopathy. N Engl J Med 336: 267–276, 1997.
LAITINEN PJ, BROWN KM, PIIPPO K, SWAN H, DEVANEY JM, BRAHMBHATT
B, DONARUM EA, MARINO M, TISO N, VIITASALO M, TOIVONEN L,
STEPHAN DA, AND KONTULA K. Mutations of the cardiac ryanodine
receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103: 485– 490, 2001.
LANKFORD EB, EPSTEIN ND, FANANAPAZIR L, AND SWEENEY HL. Abnormal contractile properties of muscle fibers expressing ␤-myosin
heavy chain gene mutations in patients with hypertrophic cardiomyopathy. J Clin Invest 95: 1409 –1414, 1995.
LEVINE RJC, YANG Z, EPSTEIN ND, FANANAPAZIR L, STULL JT, AND
SWEENEY HL. Structural and functional responses of mammalian
thick filaments to alterations in myosin regulatory light chains. J
Struct Biol 122; 149 –161, 1998.
LI D, AHMAD F, GARDNER MJ, WEILBAECHER D, HILL R, KARIBE A,
GONZALEZ O, TAPSCOTT T, SHARRATT GP, BACHINSKI LL, AND ROBERTS R.
The locus of a novel gene responsible for arrhythmogenic rightventricular dysplasia characterised by early onset and high penetrance maps to chromosome 10p12–p14. Am J Hum Genet 66:
148 –156, 2000.
LI D, TAPSCOFT T, GONZALEZ O, BURCH PE, QUINONES MA, ZOGHBI WA,
HILL R, BACHINSKI LL, MANN DL, AND ROBERTS R. Desmin mutation
responsible for idiopathic dilated cardiomyopathy. Circulation
100: 461– 464, 1999.
LI YY, MAISCH B, ROSE ML, AND HENGSTENBERG C. Point mutations in
mitochondrial DNA of patients with dilated cardiomyopathy. J Mol
Cell Cardiol 29: 2699 –2709, 1997.
LIM DS, OBERST L, MCCLUGGAGE M, YOUKER K, LACY J, DEMAYO F,
ENTMAN ML, ROBERTS R, MICHAEL LH, AND MARIAN AJ. Decreased left
ventricular ejection fraction in transgenic mice expressing mutant
cardiac troponin T-Q(92), responsible for human hypertrophic cardiomyopathy. J Mol Cell Cardiol 32: 365–374, 2000.
LIN D, BOBKOVA A, HOMSHER E, AND TOBACMAN LS. Altered cardiac
troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. J Clin Invest 97:
2842–2848, 1996.
LYMN RW AND TAYLOR EW. Mechanism of adenosine triphosphate
hydrolysis by actomyosin. Biochemistry 10: 4617– 4624, 1971.
MAEDA M, HOLDER E, LOWES B, VALENT S, AND BIES RD. Dilated
cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin. Circulation 95: 17–20, 1997.
MALLAT Z, TEDGUI A, FONTALIRAN F, FRANK R, DURIGON M, AND FONTAINE G. Evidence of apoptosis in arrhythmogenic right ventricular
dysplasia. N Engl J Med 335: 1190 –1196, 1996.
MARIAN AJ, YU QT, MANN DL, GRAHAM FL, AND ROBERTS R. Expression of a mutation causing hypertrophic cardiomyopathy disrupts
sarcomere assembly in adult feline cardiac myocytes. Circ Res 77:
98 –106, 1995.
MARIAN AJ, ZHAO G, SETA Y, ROBERTS R, AND YU Q. Expression of a
mutant (Arg92Gln) human cardiac troponin T, known to cause
hypertrophic cardiomyopathy, impairs adult cardiac myocyte contractility. Circ Res 81: 76 – 85, 1997.
MARIN-GARCIA J AND GOLDENTHAL MJ. Mitochondrial cardiomyopathy: molecular and biochemical analysis. Pediatr Cardiol 18: 251–
260, 1997.
MARIN-GARCIA J, GOLDENTHAL MJ, ANANTHAKRISHNAN R, PIERPONT
MEM, FRICKER FJ, LIPSHULTZ SE, AND PEREZ-ATAYDE A. Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy.
Cardiovasc Res 31: 306 –313, 1996.
MARON BJ, GARDIN JM, FLACK JM, GIDDING SS, KUROSAKI TT, AND BILD
DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Circulation 92: 785–789, 1995.
MARX SO, REIKEN S, HISAMATSU Y, JAYARAMAN T, BURKHOFF D, ROSEMBLIT N, AND MARKS AR. PKA phosphorylation dissociates FKBP12.6
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
EPPENBERGER HM. N-cadherin in adult rat cardiomyocytes in
culture. II. Spatio-temporal appearance of proteins involved in
cell-cell contact and communication. Formation of two distinct
N-cadherin/catenin complexes. J Cell Sci 109: 11–20, 1996.
HO CY, LEVER HM, DESANCTIS R, FARVER CF, SEIDMAN JG, AND SEIDMAN CE. Homozygous mutation in cardiac troponin T. Implications
for hypertrophic cardiomyopathy. Circulation 102: 1950 –1955,
2000.
HOFFMANN B, SCHMIDT-TRAUB H, PERROT A, OSTERZIEL KJ, AND GE〉NER
R. First mutation in cardiac troponin C, L29Q, in a patient with
hypertrophic cardiomyopathy. Hum Mutat 17: 524, 2001.
HOLMES KC AND GEEVES MA. The structural basis of muscle contraction. Philos Trans R Soc Lond 355: 419 – 431, 2000.
HUXLEY AF. Muscle structure and theories of contraction. Prog
Biophys Biophys Chem 7: 255–318, 1957.
HUXLEY AF. Mechanics and models of the myosin motor. Philos
Trans R Soc Lond 355: 433– 440, 2000.
HUXLEY HE. The mechanism of muscular contraction. Science 164:
1356 –1366, 1969.
JAMES J, ZHANG Y, OSINSKA H, SANBE A, KLEVITSKY R, HEWETT TE, AND
ROBBINS J. Transgenic modeling of a cardiac troponin I mutation
linked to familial hypertrophic cardiomyopathy. Circ Res 87: 805–
811, 2000.
JAMES TN, ST. MARTIN E, WILLIS PW, AND LOHR TO. Apoptosis as a
possible cause of gradual development of complete heart block and
fatal arrhythmias associated with absence of the AV node, sinus
node and internodal pathways. Circulation 93: 1424 –1438, 1996.
JARCHO JA, MCKENNA W, PARE JAP, SOLOMON SD, HOLCOMBE RF,
DICKIE S, LEVI T, DONIS-KELLER H, SEIDMAN JG, AND SEIDMAN CE.
Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 321: 1372–1378, 1989.
JHA S, KAO A, DESAI S, ST. JOHN SUTTON MG, JESSUP M, AND KEATING
MT. Identification of a new locus for autosomal dominant dilated
cardiomyopathy on chromosome 9q22– q31. Circulation 104 Suppl
II: II-135, 2001.
JUNG M, POEPPING I, PERROT A, ELLMER AE, WIENKER TF, DIETZ R, REIS
A, AND OSTERZIEL KJ. Investigation of a family with autosomal
dominant dilated cardiomyopathy defines a novel locus on chromosome 2q14 – q22. Am J Hum Genet 65: 1068 –1077, 1999.
JUNG WI, SIEVERDING L, BREUER J, HOESS T, WIDMAIER S, SCHMIDT O,
BUNSE M, VAN ERCKELENS F, APITZ J, LUTZ O, AND DIETZE GJ. 31P NMR
spectroscopy detects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy. Circulation 97: 2536 –
2542, 1998.
KAMISAGO M, SHARMA SD, DEPALMA SR, SOLOMON S, SHARMA P, MCDONOUGH B, SMOOT L, MULLEN MP, WOOLF PK, WIGLE ED, SEIDMAN
JG, AND SEIDMAN CE. Mutations in sarcomere protein genes as a
cause of dilated cardiomyopathy. N Engl J Med 343: 1688 –1696,
2000.
KASS S, MACRAE C, GRABER HL, SPARKS EA, MCNAMARA D, BOUDOULAS
H, BASSON CT, BAKER PB, CODY RJ, FISHMAN MC, COX N, KONG A,
WOOLEY CF, SEIDMAN JG, AND SEIDMAN CE. A gene defect that causes
conduction system disease and dilated cardiomyopathy maps to
chromosome 1p1–1q1. Nat Genet 7: 546 –551, 1994.
KEELING PJ, GANG Y, SMITH G, SEO H, BENT SE, MURDAY V, CAFORIO
ALP, AND MCKENNA WJ. Familial dilated cardiomyopathy in the
United Kingdom. Br Heart J 73: 417– 421, 1995.
KIM SJ, IIZUKA K, KELLY RA, GENG YJ, BISHOP SP, YANG G, KUDEJ A,
MCCONNELL BK, SEIDMAN CE, SEIDMAN JG, AND VATNER SF. An ␣-cardiac myosin heavy chain gene mutation impairs contraction and
relaxation function of cardiac myocytes. Am J Physiol Heart Circ
Physiol 276: H1780 –H1787, 1999.
KIMURA A, HARADA H, PARK JE, NISHI H, SATOH M, TAKAHASHI M, HIROI
S, SASAOKA T, OHBUCHI N, NAKAMURA T, KOYANAGI T, HWANG TH, CHOO
JA, CHUNG KS, HASEGAWA A, NAGAI R, OKAZAKI O, NAKAMURA H,
MATSUZAKI M, SAKAMOTO T, TOSHIMA H, KOGA Y, IMAIZUMI T, AND
SASAZUKI T. Mutations in the cardiac troponin I gene associated
with hypertrophic cardiomyopathy. Nat Genet 16: 379 –382, 1997.
KOENIG M, HOFFMAN EP, BERTELSON CJ, MONACO AP, FEENER C, AND
KUNKEL LM. Complete cloning of the Duchenne muscular dystrophy
(DMD) cDNA and preliminary genomic organization of the DMD
gene in normal and affected individuals. Cell 50: 509 –517, 1987.
KRAJINOVIC M, PINAMONTI B, SINAGRA G, VATTA M, SEVERINI GM,
AND
977
978
93.
94.
95.
96.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
from the calcium release channel (ryanodine receptor): defective
regulation in failing hearts. Cell 101: 365–376, 2000.
MAYOSI BM, KHOGALI S, ZHANG B, AND WATKINS H. Cardiac and
skeletal actin gene mutations are not a common cause of dilated
cardiomyopathy. J Med Genet 36: 796 –797, 1999.
MCCARTHY TV, QUANE KA, AND LYNCH PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum
Mutat 15: 410 – 417, 2000.
MCCONNELL BK, FATKIN D, SEMSARIAN C, JONES KA, GEORGAKOPOULOS
D, MAGUIRE CT, HEALEY MJ, MUDD JO, MOSKOWITZ IPG, CONNER DA,
GIEWAT M, WAKIMOTO H, BERUL CI, SCHOEN FJ, KASS DA, SEIDMAN CE,
AND SEIDMAN JG. Comparison of two murine models of familial
hypertrophic cardiomyopathy. Circ Res 88: 383–389, 2001.
MCCONNELL BK, JONES KA, FATKIN D, ARROYO LH, LEE RT, ARISTIZABAL O, TURNBULL DH, GEORGAKOPOULOS D, KASS D, BOND M, NIIMURA
H, SCHOEN FJ, CONNER D, FISCHMAN DH, SEIDMAN CE, AND SEIDMAN
JG. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. J Clin Invest 104: 1235–1244, 1999.
MCDONALD KS AND MOSS RL. Strongly binding myosin crossbridges
regulate loaded shortening and power output in cardiac myocytes.
Circ Res 87: 768 –773, 2000.
MCKOY G, PROTONOTARIOS N, CROSBY A, TSATSOPOULOU A, ANASTASAKIS
A, COONAR A, NORMAN M, BABOONIAN C, JEFFERY S, AND MCKENNA WJ.
Identification of a deletion in plakoglobin in arrhythmogenic right
ventricular cardiomyopathy with palmoplantar keratoderma and
woolly hair (Naxos disease). Lancet 355: 2119 –2124, 2000.
MELBERG A, OLDFORS A, BLOMSTROM-LUNDQVIST C, STALBERG E, CARLSSON B, LARSSON E, LIDELL C, EEG-OLOFSSON KE, WIKSTROM G, HENRIKSSON KG, AND DAHL N. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked
to chromosome 10q. Ann Neurol 46: 684 – 692, 1999.
MESSINA DN, SPEER MC, PERICAK-VANCE MA, AND MCNALLY EM. Linkage of familial dilated cardiomyopathy with conduction defect and
muscular dystrophy to chromosome 6q23. Am J Hum Genet 61:
909 –917, 1997.
MESTRONI L, ROCCO C, GREGORI D, SINAGRA G, DI LENARDA A, MIOCIC
S, VATTA M, PINAMONTI B, MUNTONI F, CAFORIO ALP, MCKENNA WJ,
FALASCHI A, GIACCA M, AND CAMERINI F. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. J Am
Coll Cardiol 34: 181–190, 1999.
MICHELS VV, MOLL PP, MILLER FA, TAJIK AJ, CHU JS, DRISCOLL DJ,
BURNETT JC, RODEHEFFER RJ, CHESEBRO JH, AND TAZELAAR HD. The
frequency of familial dilated cardiomyopathy in a series of patients
with idiopathic dilated cardiomyopathy. N Engl J Med 326: 77– 82,
1992.
MILLER T, SZCZESNA D, HOUSMANS PR, ZHAO J, DE FREITAS F, GOMES
AV, CULBREATH L, MCCUE J, WANG Y, XU Y, KERRICK WG, AND POTTER
JD. Abnormal contractile function in transgenic mice expressing a
familial hypertrophic cardiomyopathy-linked troponin T (I180) mutation. J Biol Chem 276: 3743–3755, 2001.
MILNER DJ, WEITZER G, TRAN D, BRADLEY A, AND CAPETANAKI Y.
Disruption of muscle architecture and myocardial degeneration in
mice lacking desmin. J Cell Biol 134: 1255–1270, 1996.
MOLKENTIN JD, LU JR, ANTOS C, MARKHAM B, RICHARDSON J, ROBBINS
J, GRANT SR, AND OLSON EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93: 215–228, 1998.
MOOLMAN JC, CORFIELD VA, POSEN B, NGUMBELA K, SEIDMAN CE,
BRINK PA, AND WATKINS H. Sudden death due to troponin T mutations. J Am Coll Cardiol 29: 549 –555, 1997.
MORIMOTO S, LU QW, HARADA K, TAKAHASHI-YANAGA F, MINAKAMI R,
OHTA M, SASAGURI T, AND OHTSUKI I. Ca2⫹-desensitizing effect of a
deletion mutation ␦K210 in cardiac troponin T that causes familial
dilated cardiomyopathy. Proc Natl Acad Sci USA 99: 913–918, 2002.
MORIMOTO S, YANAGA F, MINAKAMI R, AND OHTZUKI I. Ca2⫹-sensitizing
effects of the mutations at Ile-79 and Arg-92 of troponin T in
hypertrophic cardiomyopathy. Am J Physiol Cell Physiol 275:
C200 –C207, 1998.
MUCHIR A, BONNE G, VAN DER KOOI AJ, VAN MEEGEN M, BAAS F,
BOLHUIS PA, DE VISSER M, AND SCHWARTZ K. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb
girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 9: 1453–1459, 2000.
MUNTONI F, MELIS MA, GANAU A, AND DUBOWITZ V. Transcription of
Physiol Rev • VOL
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
the dystrophin gene in normal tissues and in skeletal muscle of a
family with X-linked dilated cardiomyopathy. Am J Hum Genet 56:
151–157, 1995.
MUNTONI F, WILSON L, MARROSU G, MARROSU MG, CIANCHETTI C,
MESTRONI L, GANAU A, DUBOWITZ V, AND SEWRY C. A mutation in the
dystrophin gene selectively affecting dystrophin expression in the
heart. J Clin Invest 96: 693– 699, 1995.
MUTHUCHAMY M, PIEPLES K, RETHINASAMY P, HOIT B, GRUPP IL, BOIVIN
GP, WOLSKA B, EVANS C, SOLARO RJ, AND WIECZOREK DF. Mouse
model of a familial hypertrophic cardiomyopathy mutation in ␣-tropomyosin manifests cardiac dysfunction. Circ Res 85: 47–56, 1999.
NARULA J, HAIDER N, VIRMANI R, DISALVO TG, KOLODGIE FD, HAJJAR
RJ, SCHMIDT U, SEMIGRAN MJ, DEC GW, AND KHAW BA. Apoptosis in
myocytes in end-stage heart failure. N Engl J Med 335: 1182–1189,
1996.
NIGRO V, DE SA MOREIRA E, PILUSO G, VAINZOF M, BELSITO A, POLITANO
L, PUCA AA, PASSOS-BUENO MR, AND ZATZ M. Autosomal recessive
limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation
in the delta-sarcoglycan gene. Nat Genet 14: 195–198, 1996.
NIGRO V, OKAZAKI Y, BELSITO A, PILUSO G, MATSUDA Y, POLITANO L,
NIGRO G, VENTURA C, ABBONDANZA C, MOLINARI AM, ACAMPORA D,
NISHIMURA M, HAYASHIZAKI Y, AND PUCA GA. Identification of the
Syrian hamster cardiomyopathy gene. Hum Mol Genet 6: 601– 607,
1997.
NIIMURA H, BACHINSKI LL, SANGWATANAROJ S, WATKINS H, CHUDLEY AE,
MCKENNA W, KRISTINSSON A, ROBERTS R, SOLE M, MARON BJ, SEIDMAN
JG, AND SEIDMAN CE. Mutations in the gene for cardiac myosinbinding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 338: 1248 –1257, 1998.
OBERST L, ZHAO G, PARK JT, BRUGADA R, MICHAEL LH, ENTMAN ML,
ROBERTS R, AND MARIAN AJ. Dominant-negative effect of a mutant
cardiac troponin T on cardiac structure and function in transgenic
mice. J Clin Invest 102: 1498 –1505, 1998.
OLSON EN AND MOLKENTIN JD. Prevention of cardiac hypertrophy by
calcineurin inhibition. Hope or hype? Circ Res 84: 623– 632, 1999.
OLSON TM, DOAN TP, KISHIMOTO NY, WHITBY FG, ACKERMAN MJ, AND
FANANAPAZIR L. Inherited and de novo mutations in the cardiac actin
gene cause hypertrophic cardiomyopathy. J Mol Cell Cardiol 32:
1687–1694, 2000.
OLSON TM, ILLENBERGER S, KISHIMOTO NY, HUTTELMAIER S, KEATING
MT, AND JOCKUSCH BM. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 105: 431– 437, 2002.
OLSON TM AND KEATING MT. Mapping a cardiomyopathy locus to
chromosome 3p22–p25. J Clin Invest 97: 528 –532, 1996.
OLSON TM, KISHIMOTO NY, WHITBY FG, AND MICHELS VV. Mutations
that alter the surface charge of alpha-tropomyosin are associated
with dilated cardiomyopathy. J Mol Cell Cardiol 33: 723–732, 2001.
OLSON TM, MICHELS VV, THIBODEAU SN, TAI YS, AND KEATING MT.
Actin mutations in dilated cardiomyopathy, a heritable form of
heart failure. Science 280: 750 –752, 1998.
PALKA HL AND GREEN KJ. Roles of plakoglobin end domains in
desmosome assembly. J Cell Sci 110: 2359 –2371, 1997.
POETTER K, JIANG H, HASSANZADEH S, MASTER SR, CHANG A, DALAKAS
MC, RAYMENT I, SELLERS JR, FANANAPAZIR L, AND EPSTEIN ND. Mutations in either the essential or regulatory light chains of myosin are
associated with a rare myopathy in human heart and skeletal
muscle. Nat Genet 13: 63– 69, 1996.
PRIORI SG, NAPOLITANO C, TISO N, MEMMI M, VIGNATI G, BLOISE R,
SORRENTINO V, AND DANIELI GA. Mutations in the cardiac ryanodine
receptor gene (hRyR2) underlie catecholaminergic polymorphic
ventricular tachycardia. Circulation 103: 196 –200, 2001.
RAMPAZZO A, NAVA A, DANIELI GA, BUJA G, DALIENTO L, FASOLI G,
SCOGNAMIGLIO R, CORRADO D, AND THIENE G. The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome
14q23– q24. Hum Mol Genet 3: 959 –962, 1994.
RAMPAZZO A, NAVA A, ERNE P, EBERHARD M, VIAN E, SLOMP P, TISO N,
THIENE G, AND DANIELI GA. A new locus for arrhythmogenic right
ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42–
q43. Hum Mol Genet 4: 2151–2154, 1995.
RAMPAZZO A, NAVA A, MIORIN M, FONDERICO P, POPE B, TISO N, LIVOLSI
B, ZIMBELLO R, THIENE G, AND DANIELI GA. ARVD4, a new locus for
arrhythmogenic right ventricular cardiomyopathy, maps to chromosome 2 long arm. Genomics 45: 259 –263, 1997.
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
97.
DIANE FATKIN AND ROBERT M. GRAHAM
INHERITED CARDIOMYOPATHIES
Physiol Rev • VOL
148. SOLARO RJ AND VAN EYK J. Altered interactions among thin filament
proteins modulate cardiac function. J Mol Cell Cardiol 28: 217–230,
1996.
149. SPINDLER M, SAUPE KW, CHRISTE ME, SWEENEY HL, SEIDMAN CE,
SEIDMAN JG, AND INGWALL JS. Diastolic dysfunction and altered
energetics in the ␣MHC403/⫹ mouse model of familial hypertrophic
cardiomyopathy. J Clin Invest 101: 1775–1783, 1998.
150. STUURMAN N, HEINS S, AND AEBI U. Nuclear lamins: their structure,
assembly and interactions. J Struct Biol 122: 42– 66, 1998.
151. SUGDEN PH. Signaling in myocardial hypertrophy. Life after calcineurin? Circ Res 84: 633– 646, 1999.
152. SULLIVAN T, ESCALANTE-ALCALDE D, BHATT H, ANVER M, BHAT N,
NAGASHIMA K, STEWART CL, AND BURKE B. Loss of A-type lamin
expression compromises nuclear envelope integrity leading to
muscular dystrophy. J Cell Biol 147: 913–919, 1999.
153. SUOMALAINEN A, PAETAU A, LEINONEN H, MAJANDER A, PELTONEN L,
AND SOMER H. Inherited idiopathic dilated cardiomyopathy with
multiple deletions of mitochondrial DNA. Lancet 340: 1319 –1320,
1992.
154. SWEENEY HL, FENG HS, YANG Z, AND WATKINS H. Functional analyses
of troponin T mutations that cause hypertrophic cardiomyopathy:
insights into disease pathogenesis and troponin function. Proc Natl
Acad Sci USA 95: 14406 –14410, 1998.
155. SWEENEY HL, STRACESKI AJ, LEINWAND LA, TIKUNOV BA, AND FAUST L.
Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem 269: 1603–1605, 1994.
156. SYLVIUS N, TESSON F, GAYET C, CHARRON P, BENAICHE A, MANGIN L,
PEUCHMAURD M, DUBOSCQ-BIDOT L, FEINGOLD J, BECKMANN JS,
BOUCHIER C, AND KOMAJDA K. A new locus for autosomal dominant
dilated cardiomyopathy identified on chromosome 6q12– q16. Am J
Hum Genet 68: 241–246, 2001.
157. SZCZESNA D, ZHANG R, ZHAO J, JONES M, GUZMAN G, AND POTTER JD.
Altered regulation of cardiac muscle contraction by troponin T
mutations that cause familial hypertrophic cardiomyopathy. J Biol
Chem 275: 624 – 630, 2000.
158. TAKAHASHI-YANAGA F, MORIMOTO S, AND OHTZUKI I. Effect of
Arg145Gly mutation in human cardiac troponin I on the ATPase
activity of cardiac myofibrils. J Biochem 127: 355–357, 2000.
159. TAKAI E, AKITA H, SHIGA N, KANAZAWA K, YAMADA S, TERASHIMA M,
MATSUDA Y, IWAI C, KAWAI K, YOKOTA Y, AND YOKOYAMA M. Mutational
analysis of the cardiac actin gene in familial and sporadic dilated
cardiomyopathy. Am J Med Genet 86: 325–327, 1999.
160. TAKEMURA G, OHNO M, HAYAKAWA Y, MISAO J, KANOH M, OHNO A, UNO
Y, MINATOGUCHI S, FUJIWARA T, AND FUJIWARA H. Role of apoptosis in
the disappearance of infiltrated and proliferated interstitial cells
after myocardial infarction. Circ Res 82: 1130 –1138, 1998.
161. TARDIFF JC, FACTOR SM, TOMPKINS BD, HEWETT TE, PALMER BM,
MOORE RL, SCHWARTZ S, ROBBINS J, AND LEINWAND LA. A truncated
cardiac troponin T molecule in transgenic mice suggests multiple
cellular mechanisms for familial hypertrophic cardiomyopathy.
J Clin Invest 101: 2800 –2811, 1998.
162. TARDIFF JC, HEWETT TE, PALMER BM, OLSSON C, FACTOR SM, MOORE
RL, ROBBINS J, AND LEINWAND LA. Cardiac troponin T mutations
result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J Clin Invest 104: 469 – 481, 1999.
163. TESSON F, SYLVIUS N, PILOTTO A, DUBOSQ-BIDOT L, PEUCHMAURD M,
BOUCHIER C, BENAICHE A, MANGIN L, CHARRON P, GAVAZZI A, TAVAZZI L,
ARBUSTINI E, AND KOMAJDA M. Epidmiology of desmin and cardiac
actin gene mutations in a European population of dilated cardiomyopathy. Eur Heart J 21: 1872–1876, 2000.
164. THIENE G, BASSO C, DANIELI G, RAMPAZZO A, CORRADO D, AND NAVA A.
Arrhythmogenic right ventricular cardiomyopathy. Trends Cardiovasc Med 7: 84 –90, 1997.
165. THIERFELDER L, WATKINS H, MACRAE C, LAMAS R, MCKENNA W, VOSBERG HP, SEIDMAN JG, AND SEIDMAN CE. ␣-Tropomyosin and cardiac
troponin T mutations cause familial hypertrophic cardiomyopathy:
a disease of the sarcomere. Cell 77: 710 –712, 1994.
166. TISO N, STEPHAN DA, NAVA A, BAGATTIN A, DEVANEY JM, STANCHI F,
LARDERET G, BRAHMBHATT B, BROWN K, BAUCE B, MURIAGO M, BASSO
C, THIENE G, DANIELLI GA, AND RAMPAZZO A. Identification of mutations in the cardiac ryanodine receptor gene in families affected
with arrhythmogenic right ventricular cardiomyopathy type 2
(ARVD2). Hum Mol Genet 10: 189 –194, 2001.
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
130. RAYMENT I, HOLDEN HM, SELLERS JR, FANANAPAZIR L, AND EPSTEIN ND.
Structural interpretation of the mutations in the ␤-cardiac myosin
that have been implicated in familial hypertrophic cardiomyopathy.
Proc Natl Acad Sci USA 92: 3864 –3868, 1995.
131. RAYMENT I, HOLDEN HM, WHITTAKER M, YOHN CB, LORENZ M, HOLMES
KC, AND MILLIGAN RA. Structure of the actin-myosin complex and its
implications for muscle contraction. Science 261: 58 – 65, 1993.
132. REDWOOD C, LOHMANN K, BING W, ESPOSITO GM, ELLIOTT K, ABDULRAZZAK H, KNOTT A, PURCELL I, MARSTON S, AND WATKINS H. Investigation of a truncated cardiac troponin T that causes familial hypertrophic cardiomyopathy. Circ Res 86: 1146 –1152, 2000.
133. REDWOOD CS, PURCELL IF, ESPOSITO G, WATKINS H, MARSTON SB, AND
BING W. Functional effects of hypertrophic cardiomyopathy mutations in ␣-tropomyosin on Ca2⫹ regulation of thin filaments (Abstract). Biophys J 74: A354, 1998.
134. REGITZ-ZAGROSEK V, DAEHMLOW S, KNUEPPEL T, KOTSCH K, GILLE C,
FROEMMEL C, ELSNER A, HUMMEL M, AND HETZER R. Novel mutations
in the ␤ myosin heavy chain and myosin binding protein C gene are
associated with dilated cardiomyopathy. Circulation 104 Suppl II:
II-572, 2001.
135. REPORT OF THE 1995 WORLD HEALTH ORGANIZATION/INTERNATIONAL SOCIETY AND FEDERATION OF CARDIOLOGY TASK FORCE. The definition and
classification of cardiomyopathies. Circulation 93: 841– 842, 1996.
136. RICHARD P, CHARRON P, LECLERCQ C, LEDEUIL C, CARRIER L, DUBOURG
O, DESNOS M, BOUHOUR JB, SCHWARTZ K, DAUBERT JC, KOMAJDA M,
AND HAINQUE B. Homozygotes for a R869G mutation in the betamyosin heavy chain gene have a severe form of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 32: 1575–1583, 2000.
137. ROTHERMEL BA, MCKINSEY TA, VEGA RB, NICOL RL, MAMMEN P, YANG
J, ANTOS CL, SHELTON JM, BASSEL-DUBY R, OLSON EN, AND WILLIAMS
RS. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98:
3328 –3333, 2001.
138. ROTTBAUER W, GAUTEL M, ZEHELEIN J, LABEIT S, FRANZ WM, FISCHER
C, VOLLRATH B, MALL G, DIETZ R, KUBLER W, AND KATUS HA. Novel
splice donor site mutation in the cardiac myosin-binding protein-C
gene in familial hypertrophic cardiomyopathy. J Clin Invest 100:
475– 482, 1997.
139. RUST EM, ALBAYYA FP, AND METZGER JM. Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins. J Clin Invest
103: 1459 –1467, 1999.
140. SANBE A, GULICK J, HAYES E, WARSHAW D, OSINSKA H, CHAN CB,
KLEVITSKY R, AND ROBBINS J. Myosin light chain replacement in the
heart. Am J Physiol Heart Circ Physiol 279: H1355–H1364, 2000.
141. SANBE A, NELSON D, GULICK J, SETSER E, OSINSKA H, WANG X, HEWETT
TE, KLEVITSKY R, HAYES E, WARSHAW DM, AND ROBBINS J. In vivo
analysis of an essential myosin light chain mutation linked to
familial hypertrophic cardiomyopathy. Circ Res 87: 296 –302, 2000.
142. SATA M AND IKEBE M. Functional analysis of the mutations in the
human cardiac ␤-myosin that are responsible for familial hypertrophic cardiomyopathy. J Clin Invest 98: 2866 –2873, 1996.
143. SATOH M, TAKAHASHI M, SAKAMOTO T, HIROE M, MARUMO F, AND
KIMURA A. Structural analysis of the titin gene in hypertrophic
cardiomyopathy: identification of a novel disease gene. Biochem
Biophys Res Commun 262: 411– 417, 1999.
144. SCHONBERGER J, LEVY H, GRUNIG E, SANGWATANAROJ S, FATKIN D,
MACRAE C, STACKER H, HALPIN C, EAVEY R, PHILBIN EF, KATUS H,
SEIDMAN JG, AND SEIDMAN CE. Dilated cardiomyopathy and sensorineural hearing loss. A heritable syndrome that maps to chromosome 6q23– q24. Circulation 101: 1812–1818, 2000.
145. SEVERINI GM, KRAJINOVIC M, PINAMONTI B, SINAGRA G, FIORETTI P,
BRUNAZZI MC, FALASCHI A, CAMERINI F, GIACCA M, AND MESTRONI L. A
new locus for arrhythmogenic right ventricular dysplasia on the
long arm of chromosome 14. Genomics 31: 193–200, 1996.
146. SHACKLETON S, LLOYD DJ, JACKSON SNJ, EVANS R, NIERMEIJER MF,
SINGH BM, SCHMIDT H, BRABANT G, KUMAR S, DURRINGTON PN, GREGORY S, O’RAHILLY S, AND TREMBATH RC. LMNA, encoding lamin A/C is
mutated in partial lipodystrophy. Nat Genet 24: 153–156, 2000.
147. SIU BL, NIIMURA H, OSBORNE JA, FATKIN D, MACRAE C, SOLOMON S,
BENSON DW, SEIDMAN JG, AND SEIDMAN CE. Familial dilated cardiomyopathy locus maps to chromosome 2q31. Circulation 99: 1022–
1026, 1999.
979
980
DIANE FATKIN AND ROBERT M. GRAHAM
Physiol Rev • VOL
175.
176.
177.
178.
179.
180.
181.
182.
myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 326: 1108 –1114, 1992.
WATKINS H, SEIDMAN CE, SEIDMAN JG, FENG HS, AND SWEENEY HL.
Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. J Clin Invest 98:
2456 –2461, 1996.
WEISBERG A AND WINEGRAD S. Relation between crossbridge structure and actomyosin ATPase activity in rat heart. Circ Res 83:
60 –72, 1998.
YANAGA F, MORIMOTO S, AND OHTSUKI I. Ca2⫹ sensitization and potentiation of the maximum level of myofibrillar ATPase activity
caused by mutations of troponin T found in familial hypertrophic
cardiomyopathy. J Biol Chem 274: 8806 – 8812, 1999.
YANAGIDA T, ESAKI S, IWANE AH, INOUE Y, ISHIJIMA A, KITAMURA K,
TANAKA H, AND TOKUNAGA M. Single-motor mechanics and models of
the myosin motor. Philos Trans R Soc Lond 355: 441– 447, 2000.
YANG J, MORAVEC CS, SUSSMAN MA, DIPAOLA NR, FU D, HAWTHORN L,
MITCHELL CA, YOUNG JB, FRANCIS GS, MCCARTHY PM, AND BOND M.
Decreased SLIM1 expression and increased gelsolin expression in
failing human hearts measured by high-density oligonucleotide
arrays. Circulation 102: 3046 –3052, 2000.
YANG Q, SANBE A, OSINSKA H, HEWETT TE, KLEVITSKY R, AND ROBBINS
J. A mouse model of myosin binding protein C human familial
hypertrophic cardiomyopathy. J Clin Invest 102: 1292–1300, 1998.
ZOLK O, CARONI P, AND BOHM M. Decreased expression of the cardiac
LIM domain protein MLP in chronic human heart failure. Circulation 101: 2674 –2677, 2000.
ZOU Y, HIROI Y, UOZUMI H, TAKIMOTO E, TOKO H, ZHU W, KUDOH S,
MIZUKAMI M, SHIMOYAMA M, SHIBASAKI F, NAGAI R, YAZAKI Y, AND
KOMURO I. Calcineurin plays a critical role in the development of
pressure overload-induced cardiac hypertrophy. Circulation 104:
97–101, 2001.
82 • OCTOBER 2002 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
167. TOWBIN JA, HEJTMANCIK JF, BRINK P, GELB B, ZHU XM, CHAMBERLAIN
JS, MCCABE ERB, AND SWIFT M. X-linked dilated cardiomyopathy.
Molecular genetic evidence of linkage to the Duchenne muscular
dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87:
1854 –1865, 1993.
168. TSUBATA S, BOWLES KR, VATTA M, ZINTZ C, TITUS J, MUHONEN L,
BOWLES NE, AND TOWBIN JA. Mutations in the human ␦-sarcoglycan
gene in familial and sporadic dilated cardiomyopathy. J Clin Invest
106: 655– 662, 2000.
169. TYSKA MJ, HAYES E, GIEWAT M, SEIDMAN CE, SEIDMAN JG, AND WARSHAW DM. Single-molecule mechanics of R403Q cardiac myosin
isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res 86: 737–744, 2000.
170. VIKSTROM KL AND LEINWAND LA. Contractile protein mutations and
heart disease. Curr Opin Cell Biol 8: 97–105, 1996.
171. WANNENBURG T, HEIJNE GH, GEERDINK JH, VAN DEN DOOL HW, JANSSEN PML, AND DE TOMBE PP. Cross-bridge kinetics in rat myocardium: effect of sarcomere length and calcium activation. Am J
Physiol Heart Circ Physiol 279: H779 –H790, 2000.
172. WATKINS H, CONNER D, THIERFELDER L, JARCHO JA, MACRAE C, MCKENNA W, MARON BJ, SEIDMAN JG, AND SEIDMAN CE. Mutations in the
cardiac myosin binding protein-C gene on chromosome 11 cause
familial hypertrophic cardiomyopathy. Nat Genet 11: 434 – 437,
1995.
173. WATKINS H, MCKENNA WJ, THIERFELDER L, SUK HJ, ANAN R,
O’DONOGHUE A, SPIRITO P, MATSUMORI A, MORAVEC CS, SEIDMAN JG,
AND SEIDMAN CE. Mutations in the genes for cardiac troponin T and
␣-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 332:
1058 –1064, 1995.
174. WATKINS H, ROSENZWEIG A, HWANG DS, LEVI T, MCKENNA W, SEIDMAN
CE, AND SEIDMAN JG. Characteristics and prognostic implications of