(Circulation. 1995;92:700-704.)
© 1995 American Heart Association, Inc.
Articles |
Prevalence of Hypertrophic Cardiomyopathy and Limitations of Screening Methods
From the Inherited Cardiac Diseases Section, Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Lameh Fananapazir, MD, FRCP, Co-Chief, Inherited Cardiac Diseases Section, Director, Clinical Electrophysiology Laboratory, Building 10, Room 7B-14, Cardiology Branch, NHLBI, National Institutes of Health, 10 Center Dr MSC 1650, Bethesda, MD 20892-1650.
Key Words: Editorials • hypertrophy • cardiomyopathy
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Introduction |
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 Top Introduction Limitations of Epidemiological...Insights From Genetic Studies...References |
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Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease with an autosomal dominant pattern of inheritance that has traditionally been characterized by left ventricular hypertrophy (LVH) in the absence of another cause for the increased cardiac mass.1 It may be associated with severe symptoms and occasionally masquerades as "heart attacks," valvular heart disease, or arrhythmias of uncertain origin. HCM is the most common cause of sudden cardiac death in otherwise healthy young individuals, such as athletes. Since the diagnosis is frequently made postmortem, there is a pressing need to investigate the prevalence of HCM and the methods by which it is detected. Recent advances in the molecular genetics of HCM have increased our understanding of its pathophysiology and heightened our awareness of the variable expression of the disease. The use of molecular markers (the genetic defects) has demonstrated the marked phenotypic variability of HCM even within the same family. Features associated with HCM, such as arrhythmias, myocardial ischemia, and/or diastolic dysfunction, may be present in patients in the absence of LVH as determined by echocardiography.2 3 4 Hence, epidemiological studies that rely solely on echocardiographic parameters provide a restricted view of the prevalence and impact of HCM in the general population.
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Limitations of Epidemiological Studies of HCM |
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TopIntroductionLimitations of Epidemiological...Insights From Genetic Studies...References |
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Several echocardiographic studies have estimated the prevalence of HCM in the general population to be 0.2%.5 6 The Coronary Artery Risk Development in Adults (CARDIA) study investigators report an almost identical prevalence of HCM.7 The CARDIA study was initially designed to investigate the longitudinal influence of lifestyle and other factors on the risk of coronary heart disease in a biracial cohort population of adults 18 to 30 years old.8 Recruitment to the study was from four urban areas. In a subset of this population, the CARDIA investigators identified 7 patients with HCM out of 4111 study subjects. HCM was estimated to be 2.9 times more common in men than women and 2.4 times more common in blacks than whites. HCM was mild in almost every case. Only 1 patient had significant LV outflow tract obstruction. Two of the 7 patients had normal 12-lead ECGs. An additional 5 subjects with LV wall thickness of 15 to 21 mm were not thought to have HCM because of coexisting hypertension.
Although the CARDIA population undoubtedly provides valuable information about the risks of coronary artery disease in young adults, it is questionable whether it or similar epidemiological populations are appropriate for the determination of the prevalence and characteristics of a relatively uncommon genetic cardiac disease such as HCM. In particular, the number of patients who were diagnosed with HCM in the CARDIA study is too small to be certain about the precision of the calculated prevalence of HCM or the apparent sex and racial predispositions to HCM. We estimate that equal sample sizes of approximately 9470 men and 9470 women may be needed to detect the difference reported in the CARDIA study of 0.17% (0.26% in men versus 0.09% in women) between the two groups with an 80% statistical power at a P=.05 (two-sided) significance level.
Although no claims of statistical significance are made, the findings
of the CARDIA study suggest that HCM is almost three times more
frequent in men than women. However, a population recruited for
epidemiological study may be deemed to be sufficiently large only if
the identified patients reflect what is known about the genetics of the
disease. The genetics of HCM (autosomal dominant) dictate an equal
inheritance of the disease gene in men and women, and although it is
possible that men with an HCM gene more frequently express LVH, the use
of molecular markers allows a definitive comparison of LV wall
thickness in men and women with HCM caused by a ß-myosin heavy chain
(ß-MHC) disease gene. Fig 1
depicts the maximum LV
wall thickness in adult men and women who have inherited distinct
ß-MHC gene mutations and demonstrates that the LV wall dimensions are
not significantly different in men and women with the identical disease
genes. Hence, a valid population should have an equal prevalence of men
and women with HCM as detected by echocardiography.
The CARDIA study also suggests more than two times greater frequency of
HCM in blacks versus whites. However, we estimate that equal sample
sizes of 
13 750 blacks and 13 750 whites would be needed to detect
a difference of 0.14% (0.24% in blacks versus 0.1% in whites)
between the two groups with an 80% statistical power at a
P=.05 (two-sided) significance level.
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Thus, there is a danger that the echocardiographic
findings in the CARDIA population will reinforce a mistaken impression
that HCM is more common in black than white athletes. This impression
has arisen because far more black than white athletes participate in
certain competitive sports. For example, at present, a large
percentage of the NBA basketball players are black. At the NIH, the
racial mix of 600 HCM families that are followed is similar to that
of the general population.
A far greater sample size than the one available to the CARDIA investigators would also have been necessary to determine the prevalence of the diverse clinical presentations and morphologies characteristic of HCM. Individuals with many of these morphologies may not have been recruited because the study specifically excluded subjects with long-term disease or disability.
It is also possible to either underestimate or overestimate the prevalence of HCM through the choice of the locality from which subjects are recruited. For example, we have observed from our family/genetic studies that it is not uncommon for many members of an extended HCM family to reside in rural areas around a small town.3 4 It is therefore possible that the disease is underrepresented in the four urban areas that were part of the CARDIA study. Conversely, if by chance an epidemiological study includes one of these large local families, a false impression would be created that HCM is very prevalent among young and otherwise healthy adults.
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Insights From Genetic Studies |
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TopIntroductionLimitations of Epidemiological...Insights From Genetic Studies...References |
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Limitations of Echocardiographic Definitions
Echocardiography has played an indispensable role in describing the diverse morphological features of HCM and in defining the mechanisms of LV outflow tract obstruction in patients with the obstructive form of the disease. The many names that the disease has acquired, such as idiopathic hypertrophic subaortic stenosis, asymmetrical septal hypertrophy, midcavity obstructive HCM, and apical or Japanese HCM, attest to its phenotypic heterogeneity.
In recognition of this, and to differentiate
the disease from other
causes of LVH, it has become customary to use a broad
echocardiographic definition of HCM: LV wall thickness
of 
15 mm without LV dilatation in the absence of another cardiac or
systemic cause for the increased LV mass.1 This
definition, however, has serious limitations: (1) It fails, even in
adults, to identify many patients with HCM who have inherited a disease
gene but who have not developed LVH; (2) it excludes patients who do
have HCM but who have another coexisting disease that may contribute to
the LVH, such as hypertension or valvular heart disease; and
(3) the clinical outcome of HCM patients correlates poorly with the
severity of the LVH. Notably, it is now recognized that
arrhythmias and sudden cardiac death can occur in the absence
of significant LVH (Fig 2).9 10
Furthermore, an LV wall thickness of 16 mm in a patient who has
inherited a genetic defect that is associated with a high incidence of
sudden death may be a more significant prognostic finding than an LV
wall thickness of 32 mm in an HCM patient in whom the disease is caused
by a mutation associated with a benign prognosis.3 4
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The same concerns also apply to population studies that use echocardiography to differentiate between LVH due to athletic training and the milder forms of HCM.11 Since many patients who have mild LVH may carry an HCM disease gene, exclusion of the disease in these subjects may not be possible until genetic testing becomes feasible for all patients in question.
Genetic Heterogeneity
It is now clear that HCM is not a
single genetic disease. To date,
three genes, ß-MHC on chromosome 14q, an 
-tropomyosin on
chromosome 15, and cardiac troponin-T on chromosome 1, and two loci on
chromosomes 11 and 7 have been linked to
HCM.12 13 14 15 HCM
also displays allelic heterogeneity; ie, one of
multiple distinct mutations of a particular gene can cause the disease.
For example, more than 30 missense mutations of the ß-MHC gene have
been described.3 4 16 Hence, it is likely
that eventually
>100 genetically distinct diseases may be shown to cause LVH and
similar echocardiographic appearances. The natural
histories of the various genetic abnormalities, however, may be
significantly different.3 4 17
Increasingly, therefore,
the starting point of diagnosis and management of the disease in an HCM
family will be the definition of the particular genetic abnormality,
followed by the description of its specific features and clinical
course. Although the initial identification of a genetic defect may be
laborious, once the genetic abnormality has been detected in a patient,
determination of which of his or her relatives has inherited the
disease gene is straightforward. For example, to date, at the NIH we
have identified 26 distinct ß-MHC gene mutations in 48 unrelated
kindreds with HCM. The natural history and clinical features of each
mutation are being characterized in extended kindreds.
Sporadic Versus Inherited HCM and Disease Penetrance
HCM
occurs sporadically or is inherited. A problem that has arisen
from the echocardiographic definition of HCM is that
previously 40% of the cases of HCM were believed to be
sporadic.18 19 This estimation of sporadic cases was
probably because of the small size of families that were studied and
the lack of appreciation that the LVH associated with HCM can skip one
or more generations.3 4 20 True instances
of sporadic HCM,
ie, those in which a genetic mutation demonstrated in an
offspring is not present in either biological parent, are
probably rare.21 Even in such de novo examples of HCM, the
pattern of inheritance of the disease in the progeny of the sporadic
case is autosomal dominant (Fig 3).
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The
echocardiographic definition of HCM requires that
all subjects who inherit the disease gene express the classic cardiac
phenotype. However, the disease penetrance, ie, the percentage
of individuals with the genetic mutation who manifest the LVH
phenotype, varies significantly in HCM. For example, the
403Arg
Gln ß-MHC gene mutation is associated with a
100% disease penetrance in adults,3 but the
908LeuVal and the 256GlyGlu ß-MHC gene
mutations are associated with a markedly reduced disease
penetrance.3 4 As shown in Fig 1
, if a
maximum LV wall
thickness of 15 mm is taken to be the cutoff point between normal and
LVH due to HCM, the calculated disease penetrances of the
908LeuVal and the 256GlyGlu ß-MHC gene
mutations are only 47% and 57%, respectively.
The determination of the
genotype also provides an opportunity
for reevaluation of the definition of LVH. An important finding of our
genetic studies in large HCM families is that LVH needs to be assessed
not by reference to an arbitrary value of LV wall thickness but in the
context of cardiac dimensions of family members who do not have the
disease allele. The upper limit of normal wall thickness in the
family with the 908LeuVal ß-MHC gene mutations was 12
mm,3 but the normal LV wall thickness in the family with
the 256GlyGlu ß-MHC gene mutation was 14
mm4. Genotyping also confirms that within a kindred,
clinical features of family members with the mutant allele may vary
considerably (Fig 3). Conversely, it is possible that the
similar
morphological appearances of the seven patients with HCM identified by
the CARDIA study were due to inheritance of seven distinct genetic
abnormalities. The prevalence and spectrum of these distinct genetic
abnormalities can only be known by study of all the blood relatives of
each patient.
A further consideration is that LVH may be only one of
several
phenotypic characteristics of the disease. Because the
myocardium can only respond to disease in a limited number
of ways, it is not surprising that examples of dilated and restrictive
cardiomyopathy are also occasionally noted in large
HCM families. Some children and adult patients may have an abnormal
12-lead ECG or be prone to arrhythmias in the absence of LVH
(Fig 2).3 4 Conversely, the ECG may be
normal despite
significant LVH.4 A more recent finding is that although
in most cases the disease predominantly affects the heart, other organs
may be involved. For example, we have demonstrated that ß-MHC
gene–associated HCM is a generalized disease of striated muscle: the
ß-MHC gene mutation is expressed in slow skeletal
muscle,22 isolated skinned slow skeletal muscle fibers
from patients with ß-MHC gene mutations have abnormal
mechanics,23 soleus muscle from these patients shows
abnormal energetics during exercise as demonstrated by magnetic
resonance spectroscopy,24 and many patients with ß-MHC
gene mutations show a muscle histology similar to that of central core
disease—a nonprogressive myopathy characterized by loss of
mitochondria from the center of many of the slow fibers.25
Consistent with the pleiotropy of HCM, central cores can be
present in skeletal muscle in some of the children and adults in
the absence of LVH.24
Genetic Screening
Genetic studies in HCM (1) lead to better
definition and diagnosis
of the disease; (2) increase our understanding of its pathophysiology
and are critical for the elucidation of the molecular basis of the
disease and of LVH in general; (3) permit preclinical diagnosis and
genetic counseling; (4) improve risk stratification; and (5) may lead
to development of therapies that may prevent progression of the disease
in children or cause regression of the disease in adults.
However, before there is a rush to commercialize this new development, it is worth considering that genetic testing also presents certain problems: (1) Genetic defects identified to date probably account for less than one third of the cases of HCM. (2) The clinical presentation of the disease varies significantly in affected patients within the same kindred. For example, the risk of sudden cardiac death differs within the family on the basis of whether individuals have one or a number of the following: ventricular arrhythmias, atrial tachycardia, bradyarrhythmias, myocardial ischemia, or severe LV outflow tract obstruction.2 (3) Genetic testing may increase the psychological burden in patients who have inherited a disease gene with incomplete penetrance who will never develop the clinical disease. (4) It may have other social consequences, such as adversely affecting employment or the ability to obtain medical insurance.
In conclusion, the molecular biology of HCM has considerably expanded the spectrum of the disease beyond its original morphological definitions, illustrating the limitations of traditional epidemiological studies. The knowledge that will accrue from the joining of molecular studies to the careful clinical and physiological evaluation of affected families will benefit many patients with diverse cardiac disease. However, in our effort to hasten these benefits, we should also be aware of the pitfalls of genetic testing and try to anticipate the problems that may undermine its promise.
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References |
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TopIntroductionLimitations of Epidemiological...Insights From Genetic Studies...References |
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