MARON
AND MCKENNA et al., ACC/ESC Expert Consensus Document on Hypertrophic
Cardiomyopathy
JACC 2003; 42:
000-000
American
College of Cardiology/European Society of Cardiology Clinical
Expert Consensus Document on Hypertrophic Cardiomyopathy
A
Report of the American College of Cardiology Foundation Task
Force on Clinical Expert Consensus Documents and the European
Society of Cardiology Committee for Practice Guidelines
Genetics
and Molecular Diagnosis
Hypertrophic
cardiomyopathy is inherited as a Mendelian autosomal dominant
trait and is caused by mutations in any one of 10 genes, each
encoding protein components of the cardiac sarcomere composed
of thick or thin filaments with contractile, structural, or
regulatory functions 6,9,17-19,64,65,132-139.
It is possible to regard the diverse clinical spectrum as
a single, unified disease entity and primary disorder of the
sarcomere 18,63.
Three of the HCM-causing mutant genes predominate in frequency—i.e.,
beta-myosin heavy chain (the first identified), myosinbinding
protein C and cardiac troponin-T probably comprise more than
one-half of the genotyped patients to date. Seven other genes
each account for fewer cases: regulatory and essential myosin
light chains, titin, alpha-tropomyosin, alpha-actin, cardiac
troponin-I, and alpha-myosin heavy chain. This genetic diversity
is compounded by intragenic heterogeneity, with about 200
mutations now identified (see http://genetics.med.harvard.edu/_seidman/cg3),
most of which are missense, with a single amino acid residue
substituted with another 63.
Indeed, molecular defects responsible for HCM are usually
different in unrelated individuals, and many other mutations
in previously identified genes (and even in additional genes,
each probably accounting for a small proportion of familial
HCM) undoubtedly remain to be identified.
Phenotypic expression of HCM (i.e., LVH) is the product not
only of the causal mutation, but also of modifier genes and
environmental factors 140,141. The magnitude of effect that
modifier genes have on morphologic expression has not yet
been systematically explored, but it can be inferred from
the phenotypic variability of affected individuals in the
same family carrying identical disease-causing mutations.
As a result of the complexity of the molecular biology of
hypertrophy, a large number of genes may influence the expression
of the phenotype. There is also increasing recognition of
the role of genetics in the genesis of electrophysiological
abnormalities associated with LVH. For example, an increased
risk for atrial fibrillation (AF) in HCM has been identified
with a beta-myosin heavy chain Arg663 His mutation 136.
Missense mutations in the gene encoding the gamma-2-regulatory
subunit of the AMP-activated protein kinase (PRKAG2), a regulator
of cellular energy homeostasis, have been reported to cause
familial LVH associated with ventricular pre-excitation 134,142.
Absence of classical histopathology such as myocyte disarray,
a distinct molecular cause for LVH (in part, reflecting glycogen
accumulation in myocytes), and progressive conduction system
disease and heart block distinguish PRKAG2 from sarcomere
protein gene mutations typical of HCM 142. Indeed, this
syndrome is probably most appropriately regarded as a metabolic
storage disease distinct from true HCM. Therefore, it may
not be optimal to base management and clinical risk assessment
of patients with cardiac hypertrophy and Wolff-Parkinson-White
on the data derived from patients with HCM. Also, thickening
of the LV wall resembling HCM occurs in children (and some
adults) with other disease states—e.g., Noonan’s
syndrome, mitochondrial myopathies, Friedreich’s ataxia,
metabolic disorders, Anderson-Fabry disease (X-linked deficiency
of the lysosomal enzyme alpha-galactosidase) 143,144, LV
non-compaction 145, and cardiac amyloidosis 110.
Molecular genetic studies over the past decade have underscored
and provided important insights into the profound clinical
and genetic heterogeneity of HCM, including the power to achieve
preclinical diagnosis of individuals who are affected by a
mutant gene but who show no evidence of the disease phenotype
on a two-dimensional echocardiogram (or electrocardiogram
[ECG]) 6,17,57,64,65,146,147. Indeed, HCM may be even more
common in the general population than the cited prevalence
of 1:500 (based on recognition of the established phenotype
by echocardiography) 1 because of incomplete, time-dependent,
variable expression of the disease phenotype and because many
affected individuals have not been clinically recognized and
are not represented in general cardiologic practice, where
the disease is relatively uncommon 50. In the clinical assessment
of individual pedigrees, it is obligatory for the proband
to be informed of the familial nature and autosomal dominant
transmission of HCM.
Not all individuals harboring a genetic defect will express
the clinical features of HCM (e.g., LVH on echocardiogram,
abnormal ECG pattern or disease-related symptoms) at all times
during life, and 12-lead ECG abnormalities or evidence of
diastolic dysfunction assessed by Doppler tissue imaging may
even precede the appearance of the phenotype on echocardiogram
especially in the young 148-151. Indeed, clinical
and molecular genetic studies have demonstrated that there
is in fact no minimum LV wall thickness required to be consistent
with the presence of an HCMcausing mutant gene 17,65,146-148,152.
For example, it is common for children less than 13 years
old to be affected “silent” mutation carriers
without evidence of LVH on an echocardiogram. Most commonly,
substantial LV remodeling with the spontaneous appearance
of LVH occurs associated with accelerated body growth and
maturation during the adolescent years and with morphologic
expression usually completed at the time physical maturity
is achieved (about 17 to 18 years) 150,152,153.
Furthermore, novel diagnostic criteria for HCM have recently
emerged, based on genotype-phenotype studies showing that
incomplete penetrance and disease expression with absence
of (or minimal) LVH may occur in adult individuals (most commonly
due to cardiac myosin-binding protein-C or troponin-T mutations)
17,19,65,135,149,151. In both cross-sectional 17 and
serial echocardiographic studies 65, mutations in myosin-binding
protein C gene have demonstrated age-related penetrance and
late-onset of the phenotype in which delayed and de novo appearance
of LVH on echocardiogram occurs in mid-life and even later.
Therefore, the traditional tenet that held that a normal echocardiogram
(and ECG) obtained after full growth has been achieved defined
a genetically unaffected relative has been revised. Such late-onset
adult morphologic conversions dictate that it is no longer
possible, based solely on a normal echocardiogram and ECG,
to issue definitive reassurance to asymptomatic family members
at maturity (or even in middle-age) that they are free of
a disease-causing mutant HCM gene.
Clinical screening of first-degree relatives and other family
members should be encouraged. Therefore, when a DNA-based
diagnosis is not feasible, the recommended clinical strategies
for screening family members employ history and physical examination,
12-lead ECG, and two dimensional echocardiography at annual
evaluations during adolescence (12 to 18 years of age). Due
to the possibility of delayed adult-onset LVH, it is reasonable
and prudent to recommend that adult relatives with normal
echocardiograms at or beyond age 18 have subsequent clinical
studies performed about every five years. Screening in relatives
younger than age 12 is not usually pursued systematically
unless the child has a high-risk family history or is involved
in particularly intense competitive sports programs. Affected
patients identified through family screening (or otherwise)
are conventionally evaluated on approximately a 12- to 18-month
basis, as described under Risk Stratification and Sudden Cardiac
Death heading.
Laboratory DNA analysis for mutant genes is the most definitive
method for establishing the diagnosis of HCM. At present,
however, there are several obstacles to the translation of
genetic research into practical clinical applications and
routine clinical strategy. These include the substantial genetic
heterogeneity, the low frequency with which each causal mutation
occurs in the general HCM population, and the important methodologic
difficulties associated with identifying a single disease-causing
mutation among 10 different genes in view of the complex,
time-consuming, and expensive laboratory techniques involved.
Mutation analysis is presently confined to a few research-oriented
laboratories. The current development of better methodologies
for automated, direct DNA sequencing and indirect approaches
for sequence profiling now provides sensitive techniques that
can accurately define the molecular cause for HCM in a single
proband, without involving family members or complex linkage
analysis in large pedigrees. However, the large number and
size of the genes that may need to be examined in each proband
continue to limit the efficiency of a gene-based diagnosis.
However, once a mutation is defined in a proband, an accurate
definition of genetic status in all family members is both
efficient and inexpensive.
Although there is interest in the application of gene therapy
to a variety of inheritable human conditions, at this time
the clinical utilization of this technology in HCM is extremely
problematic. Hypertrophic cardiomyopathy is transmitted as
an autosomal dominant trait, and affected persons possess
one mutated and one normal allele. Because most mutations
in this disease cause substitution of a single amino acid
within the encoded protein, gene therapy would theoretically
have the daunting task of selectively targeting and inactivating
the mutated gene, the encoded protein, or both. Furthermore,
selection of patients for gene therapy would be particularly
complex given that some forms of the disease are compatible
with normal longevity and absence of symptoms. Also, such
therapeutic interventions would presumably be applicable only
to a small patient subset consisting of very young affected
members from high-risk families identified prior to the development
of LVH. Spontaneous animal models of HCM 154, or model organisms
including mice and rabbits, may foster the development of
pharmacologic therapies that reduce disease manifestations,
including hypertrophy and interstitial (matrix) fibrosis 155-158.
©
2003 by the American College of Cardiology and the European
Society of Cardiology |
