Circulation. 2006;113:e858-e862
doi: 10.1161/CIRCULATIONAHA.105.591982
(Circulation. 2006;113:e858-e862.)
© 2006 American Heart Association, Inc.
A Contemporary Approach to Hypertrophic Cardiomyopathy
Carolyn Y. Ho, MD;
Christine E. Seidman, MD
From the Cardiovascular Division, Brigham and Womens Hospital (C.Y.H., C.E.S.), and Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School (C.E.S.), Boston, Mass.
Correspondence to Carolyn Ho, Cardiovascular Division, Brigham and Womens Hospital, Boston, MA 02115. E-mail cho{at}partners.org
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Introduction
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A previously healthy 32-year-old female undergoes evaluation
after a syncopal episode. Physical examination reveals a systolic
ejection murmur. Echocardiography demonstrates a vigorous LV
with marked asymmetric septal hypertrophy, systolic anterior
motion of the mitral valve, and a 50mm Hg outflow tract
gradient. Family history is notable for unexpected death in
4 paternal family members. She has 2 children (
Figure 1A).

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Figure 1. A, HCM is a genetic cardiovascular disease. This family shows autosomal dominant inheritance with &50% of the family affected and equal numbers of affected male ( ) and female () family members. The case patient is indicated by an arrow. Deceased individuals are indicated by a diagonal slash (all died suddenly). B, DNA sequence analysis can identify sarcomere mutations that cause HCM. Top, The normal sequence of a portion of the cardiac troponin T gene is displayed with a triplet codon, TCC, encoding serine present. Bottom, DNA sequence obtained from a patient with HCM. The normal sequence is present on the allele inherited from the unaffected parent; the other allele shows a single base-pair substitution of a thymidine residue for the normal cytosine residue. This triplet codon, TTC, encodes phenylalanine and results in the substitution of a phenylalanine residue for the normal serine residue at amino acid position 179.
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The prevalence of unexplained left ventricular hypertrophy (LVH) in the general population is estimated to be 1 in 500.1,2 Hypertrophic cardiomyopathy (HCM) caused by sarcomere mutations may account for up to 60% of unexplained LVH, making HCM the most common genetic cardiovascular disorder.35 Accurate diagnosis of HCM is important for appropriate management of major HCM comorbidities, including atrial fibrillation, stroke, heart failure, and sudden cardiac death (SCD).6,7
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Clinical Aspects
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HCM typically is diagnosed by unexplained LVH on echocardiography.
Age of onset of LVH ranges from early childhood to late adulthood
and depends, in part, on the underlying genetic cause.
8,9 Histopathological
hallmarks of HCM are myocyte hypertrophy with disarray and increased
cardiac fibrosis (
Figure 2). Although small amounts of myocyte
disarray and fibrosis may be seen in other forms of cardiac
disease, the higher degree present in HCM is distinctive. In
their absence, the diagnosis of HCM should be questioned.

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Figure 2. A, Histological section of normal myocardium stained with hematoxylin and eosin. Note the orderly arrangement of myocytes and scant interstitial fibrosis. B, In contrast, the histology from a patient with HCM stained with Massons trichrome shows characteristic myocyte disarray, hypertrophy, and increased interstitial fibrosis (stained blue). C, Patients with mutations in PRKAG2 show nonmembrane-bound vacuoles in myocytes (arrows) that stain for glycogen and amylopectin. There is only mild fibrosis and no myocyte disarray. D, Mutations in LAMP2 show vacuoles with large periodic acid-Schiffpositive (PAS+) inclusions. As with PRKAG2 mutations, myocyte size is increased, not because of classic hypertrophy but rather because of the presence of glycogen-filled vacuoles.
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The spectrum of HCM is broad. Diagnosis of some individuals occurs incidentally during the investigation of asymptomatic murmurs or with family screening; others present with dyspnea, chest pain, or exercise intolerance. Clinical progression can be indolent or more rapidly result in refractory symptoms and heart failure. Medical treatment is first-line therapy, traditionally with either ß-blockers or nondihydropyridine calcium channel blockers to facilitate diastolic filling and to reduce intracavitary gradients. The negative inotropic effect of disopyramide also may be beneficial in reducing obstructive physiology.10 Intracavitary obstruction that is significant (>50 mm Hg at rest or >100 mm Hg with provocation) and associated with refractory symptoms can be addressed by ethanol septal ablation or surgical myectomy to mechanically reduce outflow tract obstruction. An end-stage phenotype with impaired systolic function and, in some, LVH regression occurs in a small subset of HCM patients. These patients require standard therapy for advanced heart failure, including consideration for cardiac transplantation.
SCD risk is increased in a small subset of patients. In the United States, HCM is the leading cause of SCD in competitive athletes.7 Assessment of an individuals risk for SCD, although imprecise and controversial, is a critical component of management. The presence of clinical predictors (SCD in first-degree family members, identification of a malignant genotype, unexplained syncope, abnormal blood pressure response to exercise, significant ventricular ectopy on Holter monitoring, and massive [>30 mm] LVH) is associated with increased risk and should prompt consideration of implantable cardioverter-defibrillator placement in appropriate individuals.11 The positive predictive value of these risk factors individually is low, but with >2 risk factors, the annual SCD incidence approximates 3% to 5%.12,13 In contrast, in the absence of any risk factors, individuals are at low risk (annual incidence <1%) and require regular reassessment of risk profile but not intervention.12,13
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Genetic Aspects
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HCM is caused by dominant mutations in genes that encode constituents
of the sarcomere (
Figure 1). More than 400 individual mutations
have been identified in 11 sarcomere genes summarized in
Table 1 (and at http://cardiogenomics.med.harvard.edu/mutation-db.tcl),
4,14,15 including cardiac ß- and

-myosin heavy chains; cardiac
troponins T, I, and C; cardiac myosin binding protein C;

-tropomyosin;
actin; the essential and regulatory myosin light chains; and
titin. HCM mutations do not show specific racial predilections
and are typically "private," ie, unique from family to family.
Sarcomere mutations also account for sporadic cases of HCM.
Select mutations identified in family studies have yielded some
phenotypic correlates. A few families have demonstrated a high
incidence of premature death or end-stage heart failure, defining
their mutations as potentially "malignant." Others are associated
with distinctive HCM morphology; eg, familial inheritance of
apical pattern hypertrophy has been associated with mutations
in cardiac actin.
16 However, there are numerous exceptions,
indicating the importance of genetic modifiers and environment
on ultimate phenotypic development. Integration of genotype
information with comprehensive clinical evaluation and risk
assessment is appropriate and necessary for optimal patient
management.
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Beyond LVH: Redefining the Phenotype of HCM
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Although an HCM gene mutation is present at birth, it may be
decades before LVH becomes clinically detectable. With gene-based
diagnosis and newer imaging techniques, there is increased recognition
that LVH is not the most specific nor sensitive manifestation
of HCM. Studies of preclinical individuals with sarcomere gene
mutations demonstrate that diastolic abnormalities, detected
by Doppler tissue imaging, develop in advance of LVH.
17,18 These
results indicate that altered diastolic function is not, as
previously considered, a secondary consequence of increased
fibrosis and hypertrophy but rather a primary and early manifestation
of sarcomere dysfunction resulting from an underlying genetic
mutation.
Ongoing research in animal models of HCM has illuminated disease mechanisms. Promising results have been seen with therapeutic strategies to manipulate intracellular calcium handling in prehypertrophic mice,19 as well as with treatment targeted against myocardial fibrosis (with angiotensin II receptor blockers, aldosterone antagonists, and HMG-CoA reductase inhibitors) in animals with overt HCM.2022 Translation into human clinical protocols may be beneficial and presents an exciting new treatment paradigm with a goal of altering phenotype rather than merely palliating symptoms.
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New Causes of Inherited Cardiac Hypertrophy
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Metabolic Cardiomyopathies: Deficits of Myocardial Energetics
Genetic studies of familial and sporadic unexplained LVH accompanied
by conduction abnormalities (progressive AV block, atrial fibrillation,
ventricular pre-excitation/Wolff-Parkinson-White syndrome) have
identified metabolic cardiomyopathies. These genetic forms of
hypertrophy reflect mutations in the

2 regulatory subunit (
PRKAG2)
of AMP-activated protein kinase, an enzyme involved with glucose
metabolism, or in the X-linked lysosome-associated membrane
protein (
LAMP2) gene.
5,23,24
These clinical entities are distinct from HCM caused by sarcomere protein mutations, despite the shared feature of LVH. A high prevalence of conduction system disease (with the requirement of permanent pacing in 30% of patients in 1 series) characterizes PRKAG2 mutations.24 LAMP2 mutations are X-linked, resulting in male predominance. LAMP2 mutations are further distinguished by profound LVH seen on the ECG and echocardiogram (typically concentric) (Movie) and ventricular pre-excitation. In addition, LAMP2 mutations are associated with early-onset LVH (often in childhood) with rapid progression of heart failure and a poor prognosis.5 The histopathology of PRKAG2 and LAMP2 mutations shows prominent nonmembrane-bound vacuoles containing glycogen and amylopectin rather than the myocardial disarray or interstitial fibrosis characteristic of HCM (Figure 2). Although incompletely defined, the molecular signaling pathways triggered by PRKAG2 and LAMP2 mutations are almost certainly different from those produced by sarcomere gene mutations, suggesting that clinical approaches should not be predicated on HCM management tenets.
Contemporary Diagnosis of HCM
Genetic testing allows accurate diagnosis and precise identification of mutations in sarcomere proteins, PRKAG2 and LAMP2, independently of age, family history, or clinical manifestations. As such, incorporating genotype assessment can importantly enhance the contemporary evaluation of unexplained LVH. This is currently accomplished by bidirectional DNA sequence analysis of sarcomere genes to identify potential disease-associated sequence variants (Figure 1B).
The identification of a sarcomere gene mutation provides a definitive diagnosis of HCM and establishes the precise genetic cause. Mutation confirmation in family members can be accomplished simply and identify family members at risk for disease development. Mutation carriers without clinical manifestations are at risk for developing HCM and require longitudinal clinical follow-up, as summarized in Table 2. All mutation carriers should be counseled about the 50% chance of transmission of the mutation to offspring. Family members who do not carry a mutation are not at risk for developing HCM or transmitting HCM to offspring. Longitudinal clinical follow-up is not required.
Despite the power and specificity of genetic diagnosis, there are important current limitations. Mutations in sarcomere genes account for &60% of cases of inherited LVH; expanding the screen to include PRKAG2 and LAMP2 will slightly increase diagnostic yield. Nonetheless, mutations will not be detected in all individuals with unexplained LVH, and a negative analysis does not exclude a genetic origin. Discovery of other genes that cause LVH will continue to improve gene-based diagnosis. Increasingly, efforts to determine the molecular mechanisms by which gene mutations produce HCM will inspire clinical trials of new strategies for disease prevention and rational treatment. Through its ability to identify preclinical individuals with gene mutations, genetic diagnosis will play a crucial role in these endeavors by targeting preventive therapy to patients at high risk for disease development.
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Case Conclusion
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Genetic testing was performed on this patient, and an
Arg92Trp mutation was identified in the cardiac troponin T gene. She
received an implantable cardioverter-defibrillator on the basis
of her syncopal episode, her family history, and the identification
of this mutation (associated with SCD in other families
25).
Family mutation confirmation testing revealed that her father
(previously diagnosed with atrial fibrillation and mild LVH)
and 1 of her 2 children (clinically unaffected at 14 years of
age) carry the mutation.
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Acknowledgments
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Sources of Funding
Drs Ho and Seidman received research grants from the National Institutes of Health. Dr Seidman also received a research grant from Howard Hughes Medical Institute.
Disclosures
None.
Additional Resources
CardioGenomics Home Page for sarcomere gene mutations. Available at: http://cardiogenomics.med.harvard.edu. Accessed May 31, 2006.
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Footnotes
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The online-only Data Supplement, which contains a movie, can be found at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.591982/DC1.
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