Clinical Manifestations of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) caused by mutation in one of the genes currently known to encode different components of the sarcomere is characterized by unexplained left ventricular hypertrophy (LVH) that develops in the absence of predisposing cardiac conditions (e.g., aortic stenosis) or cardiovascular conditions (e.g., long-standing hypertension). The clinical manifestations of HCM range from asymptomatic to progressive heart failure and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion) chest pain, palpitations, orthostasis, presyncope, and syncope.

LVH most often becomes apparent during adolescence or young adulthood, possibly related to the onset of puberty; however, LVH caused by HCM can develop late in life [Niimura et al 2002], in infancy, and in childhood.

Diastolic dysfunction, as measured by tissue Doppler echocardiographic imaging, is a common finding in overt disease [Elliott & McKenna 2004] and also precedes both the development of LVH and symptoms in individuals who have a mutation in any one of the genes known to encode sarcomere proteins (i.e., “mutations in sarcomere genes”) [Nagueh et al 2001, Ho et al 2002]. This early diastolic dysfunction suggests that it may be a fundamental manifestation of HCM rather than a secondary consequence of LVH and altered myocardial compliance observed in established disease.

Approximately 25% of persons with HCM have detectable intracavitary obstruction at rest, but a much higher proportion may develop obstructive physiology with provocation [Maron et al 2003c, Elliott et al 2006, Maron et al 2006]. While individuals with significant outflow obstruction may be more symptomatic than those without outflow obstruction, the degree of outflow obstruction does not strictly correlate with the severity of symptoms. Furthermore, LV outflow tract and intracavitary gradients are dynamic, highly labile, and dependent on other physiologic variables, such as blood pressure and heart rate. Although evidence suggests that persons with outflow tract obstruction may have a higher risk of HCM-related death and symptom progression than those without outflow tract obstruction [Maron et al 2003c], high gradients may also be well tolerated over long periods of time.

Individuals with HCM are at an increased risk for atrial fibrillation (AF), which can be a significant cause of morbidity in adults:

• Olivotto et al [2001] found a 22% prevalence of AF over nine years and found AF to be associated with increased risk for heart failure-related mortality, stroke, and functional limitations.
• Kitaoka et al [2006] reported paroxysmal or persistent atrial fibrillation in 37% (51/137) of their older rural Japanese study population. From the time of initial diagnosis of AF, the one-year, three-year, and five-year survival rates were 92%, 86%, and 72%, respectively. In this study, 6/137 persons died of embolic stroke as a consequence of atrial fibrillation.

Approximately 10%-20% of individuals with HCM have a lifetime-increased risk for sudden cardiac death (SCD), most likely resulting from ventricular tachycardia/ ventricular fibrillation:

• HCM is the leading single cause of SCD in competitive athletes in the US [Maron 2003], accounting for approximately one third of such deaths.
• Although sudden death occurs most often in adolescents or young adults, it may occur at any age. However, SCD is uncommon in young children.
• SCD may be the first manifestation of disease [Maron et al 2000a]. Individuals with HCM who are at the highest risk for SCD may have at least 3%-5% annual risk for SCD [Maron 2002, Elliott & McKenna 2004], whereas individuals in the general HCM population have a 1% annual risk for SCD.

Early studies based on tertiary referral-based populations with HCM suggested a poor prognosis with estimated annual mortality rates of 4%-6%; however, subsequent studies on broader-based populations suggest that prognosis is typically more favorable with estimated annual mortality rates of 1%-3% and a normal life expectancy of 75+ years in an estimated 25% of individuals, the majority of whom have little functional disability [Maron et al 2003a, Maron et al 2003b, Elliott et al 2006].

Evaluation of prognosis and mortality in children with HCM revealed that the length of survival after establishing the diagnosis is shorter in those diagnosed before age one year than in those diagnosed after age one year; however, persons surviving until age one year have a 1% annual mortality rate regardless of the age at initial diagnosis [Colan et al 2007].

Establishing the Diagnosis of HCM

The diagnosis of HCM caused by mutation in one of the genes currently known to encode different components of the sarcomere is established by the presence of the following (see Figure 1, Figure 2):

Figure

Figure 1
A. Normal heart histology
B. Heart with HCM showing disarray and increased fibrosis
C. Fibrosis can be better visualized with Masson trichrome staining in which fibrosis stains blue.
Images courtesy of Robert (more...)

Figure

Figure 2. Gross pathologic specimen from a patient with HCM, recovered at the time of cardiac transplantation
A. Note hypertrophy of the interventricular septum.
B. A friction plaque (arrow) is present in the LV outflow tract, anterior (more...)

• Left ventricular hypertrophy (LVH) in a nondilated ventricle, most often established with two-dimensional echocardiography.
  Note: (1) LVH should occur in the absence of other potential causes of cardiac hypertrophy (e.g., long-standing hypertension, aortic stenosis). (2) Although asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy varies and can include concentric and apical hypertrophy. (3) Findings on echocardiography may also include: (a) systolic anterior motion (SAM) of the mitral valve with associated left ventricular outflow tract obstruction and mitral regurgitation, (b) midventricular obstruction as a result of systolic cavity obliteration, and (c) diastolic dysfunction including restrictive physiology. (4) Cardiac MRI may be helpful when visualization of the left ventricle by echocardiography is suboptimal. (5) Although systolic function is typically preserved in HCM, 5%-10% of individuals with HCM progress to end-stage disease with impaired systolic function and, in some cases, left ventricular dilatation and regression of LVH. Without cardiac transplantation the annual mortality rate in this subset of individuals with HCM is estimated to be 11% [Harris et al 2006].
• Pathognomonic histopathologic features of HCM caused by mutation in one of the genes currently known to encode different components of the sarcomere in cardiac tissue, typically obtained as surgical specimens or at autopsy, include myocyte disarray, hypertrophy, and increased myocardial fibrosis (Figure 1). Although scant amounts of disarray may be present in other cardiac diseases, the greater extent seen in HCM is distinctive. At the level of the whole organ, LVH is found (Figure 2). LVH commonly affects the interventricular septum (IVS) more prominently, although many different patterns of hypertrophy have been noted.

Other findings that may suggest HCM but are not sufficiently sensitive to establish the diagnosis:

• Physical examination, which may reveal:
  • A fourth heart sound (S₄)
  • Prominent left ventricular apical impulse or lift
  • Brisk carotid upstroke that may be bifid
    
    Note: (1) Left ventricular outflow tract or intracavitary obstruction is common, but can be variable and dynamic, requiring provocative maneuvers such as Valsalva, standing from squatting, and exercise for detection. (2) An apical holosystolic murmur of mitral regurgitation may be the result of SAM of the mitral valve or primary mitral valve disease.
• Electrocardiogram (ECG). Most people with HCM have an abnormal ECG that can include the following:
  • A pattern consistent with LVH
  • A pattern consistent with left atrial enlargement
  • Prominent Q waves in inferior and lateral leads
  • Diffuse T-wave inversions
    Note: (1) No one consistent ECG pattern is observed [Maron 2002]. (2) ECG abnormalities may precede echocardiographic evidence of LVH.

Differential Diagnosis of Familial Hypertrophic Cardiomyopathy

Prevalence of HCM

Unexplained LVH occurs in approximately one in 500 individuals, with roughly 55%-70% attributable to HCM caused by mutation in one of the genes currently known to encode different components of the sarcomere.

Familial Hypertrophic Cardiomyopathy

To date, familial hypertrophic cardiomyopathy (HCM) is known to be caused by mutation in one of the 14 genes (see Table 1) encoding different components of the sarcomere (see Figure 3). More than 900 individual mutations have been identified [Genomics of Cardiovascular Development, Adaptation, and Remodeling].

Figure

Figure 3. The sarcomere is the basic contractile unit of the cardiac myocyte. Cardiac contraction occurs when calcium binds the troponin complex (subunits I, C, and T) and α-tropomyosin and releases the inhibition of myosin-actin interactions (more...)

Table 1. Molecular Genetics of Hypertrophic Cardiomyopathy (HCM)

View in own window

Locus Name	Gene Symbol	Protein Name	OMIM	% of HCM Caused by Mutations in This Gene	Molecular Genetic Test Availability for HMC 1	Allelic Disorders 2
CMH1	MYH7	Myosin heavy chain, cardiac muscle beta isoform	160760 192600	40%	Clinical	DCM 3, Laing distal myopathy
CMH4	MYBPC3	Myosin-binding protein C, cardiac-type	600958	40%	Clinical	DCM
CMH2	TNNT2	Troponin T, cardiac muscle	115195	5%	Clinical	DCM
CMH7	TNNI3	Troponin I, cardiac muscle	191044	5%	Clinical	DCM, restrictive cardiomyopathy
CMH3	TPM1	Tropomyosin 1 alpha chain	115196 191010	2%	Clinical	DCM
CMH10	MYL2	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	160781 608758	Unknown	Clinical
CMH8	MYL3	Myosin light polypeptide 3	160790 608751	1%	Clinical
	ACTC1	Actin, alpha cardiac muscle 1	102540	Unknown	Clinical	DCM
	CSRP3	Cysteine and glycine-rich protein 3, muscle LIM protein	600824	Unknown	Clinical
CMH9	TTN	Titin	188840		Clinical	DCM, Udd distal myopathy
	ACTN2	Alpha-actinin-2	102573	Unknown	Clinical	DCM
	MYH6	Myosin heavy chain, cardiac muscle alpha isoform	160710		Research	DCM
	TCAP	Telothonin	604488		Research	LGMD2G 4, DCM
Other genes implicated in HCM 5
	TNNC1	Troponin C, slow skeletal and cardiac muscles	191040	Unknown	Clinical	DCM

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Per the GeneTests Laboratory Directory

2. Allelic disorders = other phenotypes caused by mutation in the same gene

3. DCM = dilated cardiomyopathy

4. LGMD = limb-girdle muscular dystrophy

5. The consensus of the GeneReview authors is that additional confirmatory data supporting pathogenicity for this gene is necessary.

Hypertrophic Cardiomyopathy (HCM)

When the diagnosis of LVH is established in an individual without other systemic involvement, the following approach can help determine if HCM was inherited or was caused by a de novo mutation in the proband. This approach is particularly relevant because a person with HCM may remain asymptomatic for years.

Family history. A detailed three- to four-generation family history should be obtained from relatives to assess the possibility of familial HCM. Attention should be directed to a history of any of the following in relatives: heart failure, HCM, cardiac transplantation, unexplained sudden death, unexplained cardiac conduction system disease and/or arrhythmia, or unexplained stroke or other thromboembolic disease.

Screening of first-degree relatives for HCM. A medical history, physical examination, echocardiogram, and ECG may reveal asymptomatic HCM, thus supporting the diagnosis of familial HCM in the proband. However, because the age of onset is variable and penetrance is often reduced early in life, a normal baseline echocardiogram and ECG in a first-degree relative does not rule out HCM in that individual, particularly in children or young adults. Also, the onset of clinical features may be delayed to middle age or later in life. Therefore, it is recommended that first-degree relatives with a normal echocardiogram and ECG be rescreened and longitudinally followed throughout life, according to the screening guidelines in Table 2.

Any abnormal cardiovascular test results in a relative of a proband should be followed with a full cardiovascular assessment by a cardiologist familiar with HCM, as subtle changes in the context of familial disease may indicate a mild disease phenotype [McKenna et al 1997].

Molecular genetic testing. The presence of a family history increases the likelihood that a mutation in a sarcomere gene will be identified. The frequency of genetic causation in simplex cases of HCM (i.e., a single occurrence in a family) remains largely unknown. Molecular genetic testing for HCM typically includes all genes encoding different components of the sarcomere for which testing is available on a clinical basis (see Table 1).

Note: No definitive genotype-phenotype correlations can be used to direct the approach to genetic testing.

Broader genotype-phenotype correlations have been attempted. Although in some cases the age of onset of hypertrophy may be associated with the underlying gene mutation, caution must be used in applying these generalizations to specific individuals and families as numerous exceptions have been noted.

Examples of broad genotype-phenotype correlations include the following:

• MYH7 mutations have been associated with onset on the second decade of life
• MYH7 mutation NP_000248.2:p.Arg403Gln (also known as NM_000257.2:c.1208G>A.) has been associated with an increased risk of sudden death.
• MYBPC mutations have been associated with later onset in the fourth or fifth decade of life [Niimura et al 2002, Richard et al 2006].
• TNNT2 mutations have been associated with mild LVH and increased risk of sudden death in some families [Richard et al 2006].

In children with LVH without systemic disease, a mutation in one of the genes encoding different components of the sarcomere was identified in 55% of the total: 49% of simplex cases (i.e., a single occurrence in a family) and 64% of familial cases. This prevalence of mutations in genes encoding different components of the sarcomere is essentially identical to that found in individuals with adult/adolescent HCM [Morita et al 2008]. Although most mutations were identified in MYH7 and MYBPC3, the proportion of MYBPC3 missense mutations was higher in those with childhood-onset than in those with adult-onset disease, in which most MYBPC3 mutations result in frameshifts. However, given the similarity in the prevalence and distribution of causal gene mutations, it remains unclear what underlies early-onset versus late-onset disease.

Mode of Inheritance

Familial hypertrophic cardiomyopathy (HCM) caused by mutation in one of the genes currently known to encode different components of the sarcomere is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed as having familial HCM have an affected parent.
• A proband with familial HCM may also have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include echocardiogram, ECG, and physical examination by a cardiologist familiar with familial HCM. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of the possibility of incomplete penetrance and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate diagnostic evaluations have been performed.

Note: Although some individuals diagnosed with familial HCM have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's parents.
• If a parent of the proband is affected the risk to the sibs of inheriting the disorder is approximately 50%.
• If a parent of the proband is shown to have a disease-causing mutation, the risk to the sibs of inheriting the allele is 50%. However, the clinical severity and age of onset cannot be predicted from the mutation.
• When the parents are clinically unaffected and the disease-causing mutation is not known in the family, the risk to the sibs of a proband may be increased over the general population risk, but cannot be accurately estimated.
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is extremely low but may be greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

• Each child of an individual with familial HCM has a 50% chance of inheriting the mutation.
• If a child inherits a disease-causing mutation there is a greater than 90% chance that the child will develop clinically evident HCM, although the severity and age of onset cannot be predicted.

Related Genetic Counseling Issues

Determining the mode of inheritance. Because cases have been reported where more than one mutation in a gene encoding a sarcomere protein has been identified in a single individual, determining the mode of inheritance is critical for accurate risk assessment of other family members [Richard et al 2006].

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic adult relatives of individuals with familial HCM is possible after molecular genetic testing has identified the disease-causing mutation in the proband. Such testing should be performed in the context of formal genetic counseling, and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing, but will identify family members who require serial clinical follow-up to assess for phenotypic conversion and allow reassurance of family members who are not at risk.

Testing of asymptomatic individuals younger than age 18 years requires careful consideration of the potential risks and benefits. The principal arguments against testing asymptomatic individuals younger than age 18 years are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have educational and career implications. However, early detection of familial HCM may provide helpful insight to guide management of minors, particularly in the setting of known early-onset and/or aggressive disease. A positive molecular genetic test may guide more stringent clinical screening for the onset of asymptomatic but clinically detectable HCM and earlier risk assessment for sudden death. The latter is an important consideration for young people participating in competitive sports. Currently, there is no evidence to indicate that physical activity should be strictly restricted in individuals who have a mutation in one of the genes encoding different components of the sarcomere, but no clinical evidence of HCM (i.e., no LVH); however, parents may wish to encourage development of interests other than serious competitive athletics. Furthermore, a negative test result in the context of known mutation in the family can provide reassurance that the person is not at risk of developing HCM and thus obviate unnecessary screening.

Clinical testing is always indicated in symptomatic individuals regardless of age. Individuals who are symptomatic during childhood usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for familial HCM is possible by analyzing fetal DNA extracted from cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation for disease-causing mutations. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for (typically) adult-onset diseases are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Evaluations Following Initial Diagnosis

Risk assessment for SCD is essential to management of individuals diagnosed with familial hypertrophic cardiomyopathy (HCM).

The clinical parameters analyzed to assess an individual’s risk for SCD include the following:

• Personal history of aborted/resuscitated sudden death or cardiac arrest
• Family history of SCD
• Extreme LVH (>30mm)
• Hypotensive blood pressure response to exercise
• Significant ventricular ectopy on Holter monitoring
• Unexplained syncope

In addition to a detailed personal medical and family history, a thorough risk assessment should include the following:

• Echocardiogram to measure the degree of LVH
• Exercise testing to assess blood pressure response to exercise
• Holter monitoring for significant ventricular ectopy

Accurate risk assessment is difficult because the positive and negative predictive value of any single parameter is low. However, the presence of two or more risk factors has been associated with an increased risk for sudden cardiac death [Elliott et al 2000] and, conversely, the absence of any risk features places an individual in a low-risk category. However, controversy remains as to the appropriate interpretation of risk factors and risk stratification for an individual requires detailed and thoughtful evaluation.

Note: (1) All individuals who have survived prior cardiac arrest or had resuscitated sudden death should have an implantable cardioverter-defibrillatory (ICD) implanted for secondary prevention. (2) Individuals without prior events who are deemed to be at increased risk based on the above criteria should also be considered for ICD implantation for primary prevention of SCD.

Treatment of Manifestations

No treatments to prevent or decrease disease development or to reverse established manifestations currently exist.

Medical management used for symptom palliation typically relies on the following:

• Beta blockers
• Calcium channel blockers
• Antiarrhythmics
• Disopyramide (its negative inotropic effects can reduce obstructive physiology)

Diastolic dysfunction is a common feature of familial HCM that may contribute significantly to symptoms of exertional dyspnea and volume overload, independent of obstruction. Diastolic dysfunction is typically challenging to treat:

• β-blockers and calcium channel blockers can be used to slow heart rate and increase diastolic filling time.
• Diuretics may be considered judiciously to relieve symptomatic volume overload with the caveat that patients may be preload-dependent to maintain adequate cardiac output, particularly if obstructive physiology is present.

When symptomatic obstruction is refractory to medical therapy, either of the following may be considered to alleviate symptoms:

• Ethanol septal ablation is a recently developed catheter-based procedure in which ethanol is injected through a septal perforator vessel in the IVS muscle bed to induce focal myocardial infarction targeting the thickest portion of the proximal septum, which is primarily responsible for obstructive physiology.
• Surgical myectomy (removal of a section of muscle from the IVS) can reduce or eliminate symptoms and can potentially increase longevity.

For atrial fibrillation the goal is to restore and maintain sinus rhythm. Anticoagulation is also required because of the high risk for thromboembolic complications. Treatment options:

• Beta blockers or calcium channel blockers
• Antiarrhythmic drug therapy
• Cardioversion
• Catheter-based ablation

For the small subset of individuals who progress to heart failure, appropriate medical treatment for heart failure is necessary, including consideration for cardiac transplantation in some cases.

Prevention of Primary Manifestations

For individuals with familial HCM felt to be at increased risk for SCD, consideration of ICDs is warranted. ICDs are currently the best option for the prevention of SCD. Maron et al [2000b] reported an appropriate discharge rate of 7% per year in an entire cohort with ICDs, with an 11% and 5% per year appropriate discharge rate in persons who received ICDs for secondary prevention (after resuscitated sudden death or sustained ventricular tachycardia) and primary prevention, respectively.

Elliott et al [2006] found an appropriate ICD discharge rate in 15.4% (8/52) of their cohort who received ICD for primary (n=41) and secondary (n=11) prevention.

Prevention of Secondary Complications

Patients with familial HCM who develop atrial fibrillation are at an increased risk for thromboembolic complications. For patients with persistent or paroxysmal atrial fibrillation, anticoagulation should be considered.

The hemodynamic changes associated with pregnancy and delivery place women with familial HCM at increased risk for obstetric complications, particularly if significant obstructive physiology is present. Experienced cardiovascular and high-risk obstetrics care is required.

Patients with obstructive physiology have traditionally been considered at moderate risk for infective endocarditis and previous guidelines have recommended antibiotic prophylaxis for this subgroup. Official guidelines were recently revised and decision making should be considered on an individual basis [Wilson et al 2007].

Surveillance

Risk for SCD should be reassessed approximately annually (or sooner if any clinical parameters change) to assess for changes in the risk profile [Maron et al 2003b].

Agents/Circumstances to Avoid

Physical activity guidelines have been established to detail reasonable exercise restrictions for people with familial HCM:

• Patients are instructed to avoid competitive endurance training and to use moderation in all physical activities.
• Patients should avoid burst activities, like sprinting, as well as intense isometric exercise, such as heavy weight lifting [Maron et al 2004a].

To avoid exacerbation of obstructive physiology and worsening of symptoms, patients with outflow tract obstruction should be particularly careful to avoid the following:

• Dehydration
• Hypovolemia (therefore, diuretics must be used with caution)
• Medications that decrease afterload (e.g., ACE inhibitors; angiotensin receptor blockers and other direct vasodilators; medications for erectile dysfunction, e.g., sildenafil)

Testing of Relatives at Risk

Screening guidelines have been proposed for the longitudinal evaluation of clinically unaffected at-risk family members (see Table 2). Because penetrance of diagnostic features is age dependent, a single unremarkable evaluation does not exclude the possibility of future development of HCM and associated risk. Clinical manifestations, often not present in infancy/early childhood, commonly develop during adolescence and early adulthood, but may also develop late in life. As such, serial follow-up is required, with frequency based on the individual’s age, family history, and physician discretion.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Literature Cited

1. Arad M, Maron BJ, Gorham JM, Johnson WH, Saul JP. Glycogen storage disease presenting as hypertrophic cardiomyopathy. N Eng J Med. 2005;352:362–72. [PubMed: 15673802]
2. Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and case-specific outcomes in Hypertrophic Cardiomyopathy in children: Findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773–81. [PubMed: 17261650]
3. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36:2212–8. [PubMed: 11127463]
4. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;363:1881–91. [PubMed: 15183628]
5. Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, Tome Esteban MT, McKenna WJ. Historical trends in reported survival rates in hypertrophic cardiomyopathy. Heart. 2006;92:785–91. [PMC free article: PMC1860645] [PubMed: 16216855]
6. Falk RH, Skinner M. The systemic amyloidoses: an overview. Adv Intern Med. 2000;45:107–37. [PubMed: 10635047]
7. Genomics of Cardiovascular Development, Adaptation, and Remodeling. NHLBI Program for Genomic Applications, Harvard Medical School. Available at www​.cardiogenomics.org. Accessed June 2007.
8. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation. 2006;114:216–25. [PubMed: 16831987]
9. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002;105:2992–7. [PubMed: 12081993]
10. Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, Seidman JG, Seidman CE. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000;343:1688–96. [PubMed: 11106718]
11. Kitaoka H, Kubo T, Okawa M, Hitomi N, Furuno T, Doi Y. Left ventricular remodeling of hypertrophic cardiomyopathy: longitudinal observation in a rural community. Circ J. 2006;70:1543–9. [PubMed: 17127796]
12. Maron BJ. Hypertrophic Cardiomyopathy: a systematic review. JAMA. 2002;287:1308–20. [PubMed: 11886323]
13. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349:1064–75. [PubMed: 12968091]
14. Maron BJ, Casey SA, Hauser RG, Aeppli DM. Clinical course of hypertrophic cardiomyopathy with survival to advanced age. J Am Coll Cardiol. 2003a;42:882–8. [PubMed: 12957437]
15. Maron BJ, Chaitman BR, Ackerman MJ, Bayes de Luna A, Corrado D, Crosson JE, Deal BJ, Driscoll DJ, Estes NA, Araujo CGS, Liang DH, Mitten MJ, Myerburg MJ, Pelliccia A, Thompson PD, Towbin JA, Van Camp SP. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004a;109:2807–16. [PubMed: 15184297]
16. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH, Spirito P, Ten Cate FJ, Wigle ED. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines (Committee to Develop an Expert Consensus Document on Hypertrophic Cardiomyopathy). J Am Coll Cardiol. 2003b;42:1–27. [PubMed: 12849651]
17. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ, Burton DA, Cecchi F. Epidemiology of Hypertrophic Cardiomyopathy-related death: Revisited in a large non-referral-based patient population. Circulation. 2000a;102:858–64. [PubMed: 10952953]
18. Maron BJ, Pelliccia A. The heart of trained athletes: Cardiac remodeling and the risks of sports, including sudden death. Circulation. 2006;114:1633–44. [PubMed: 17030703]
19. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004b;44:2125–32. [PubMed: 15582308]
20. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000b;342:365–73. [PubMed: 10666426]
21. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003c;348:295–303. [PubMed: 12540642]
22. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi S, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232–9. [PubMed: 17088454]
23. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komajda M. Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adult members of affected families. Heart. 1997;77:130–2. [PMC free article: PMC484661] [PubMed: 9068395]
24. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. NEJM. 2008;358:1899–908. [PMC free article: PMC2752150] [PubMed: 18403758]
25. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, Quinones MA, Roberts R, Marian AJ. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation. 2001;104:128–30. [PMC free article: PMC2900859] [PubMed: 11447072]
26. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002;105:446–51. [PubMed: 11815426]
27. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of Hypertrophic Cardiomyopathy. Circulation. 2001;104:2517–24. [PubMed: 11714644]
28. Richard P, Villard E, Charron P, Isnard R. The genetic bases of cardiomyopathies. J Am Coll Cardiol. 2006;48:A79–89.
29. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 2002;105:1407–11. [PubMed: 11914245]
30. Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart. Arch Intern Med. 2006;166:1805–13. [PubMed: 17000935]
31. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, Bolger A, Cabell CH, Takahashi M, Baltimore RS, Newburger JW, Strom BL, Tani LY, Gerber M, Bonow RO, Pallasch T, Shulman ST, Rowley AH, Burns JC, Ferrieri P, Gardner T, Goff D, Durack DT. Prevention of Infective Endocarditis. Guidelines from the American Heart Association. A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. J Am Dent Assoc. 2007;138:739–45. [PubMed: 17545263]

Suggested Reading

1. Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. J Mol Cell Cardiol. 2008;45:281–8. [PMC free article: PMC2627482] [PubMed: 18572189]

Author Notes

Brigham and Women’s Hospital Cardiovascular Genetics Center
Web: www.brighamandwomens.org

Revision History

• 17 May 2011 (cd) Revision: testing available on a clinical basis for ACTN2 and CSRP3
• 26 May 2009 (cd) Revision: sequence analysis and prenatal testing available clinically for TNNC1-related familial hypertrophic cardiomyopathy.
• 5 August 2008 (me) Review posted live
• 11 June 2007 (ac) Original submission