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Hypertrophic Cardiomyopathy Overview

, MS, CGC and , MD.

Author Information
, MS, CGC
Genetic Counselor, Cardiovascular Genetics Center
Brigham and Women’s Hospital
Boston, Massachusetts
, MD
Medical Director,
Cardiovascular Genetics Center
Brigham and Women’s Hospital
Boston, Massachusetts

Initial Posting: ; Last Update: January 16, 2014.

Summary

Disease characteristics. Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH). Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload (e.g., long-standing hypertension, aortic stenosis) or storage/infiltrative disorders (e.g., Fabry disease, amyloidosis). The clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD), 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. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood.

Diagnosis/testing. The diagnosis of HCM is most often established with noninvasive cardiac imaging, including echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI). HCM can also be diagnosed by pathognomonic histopathologic findings in cardiac tissue, including myocyte disarray and fibrosis. Familial HCM without multisystem involvement can also be identified through family history and molecular genetic testing, focusing on genes that encode different components of the sarcomere.

Genetic counseling. Familial HCM caused by sarcomere gene mutations is inherited in an autosomal dominant manner.

Management. Treatment of manifestations: Treatment by physicians experienced in diagnosis and management of persons with HCM improves survival and quality of life. Treatment modalities include pharmacologic therapy, invasive septal reduction therapy, and pacemakers or implantable cardiac defibrillators. Cardiac transplantation may be necessary for patients who progress to advanced heart failure refractory to medical or device therapy.

Prevention of secondary complications: Anticoagulation should be initiated for affected individuals with persistent or paroxysmal atrial fibrillation to reduce the risk of thromboembolism; antibiotic prophylaxis for bacterial endocarditis should be considered on an individual basis.

Surveillance: Assessment of risk for sudden cardiac death is an important component of clinical management. In individuals with HCM without risk factors for SCD, surveillance should be repeated at regular intervals to assess for change and guide decisions regarding the appropriateness of implantable cardioverter defibrillator (ICD) therapy.

Agents/circumstances to avoid: Competitive endurance training, burst activities (e.g., sprinting), intense isometric exercise (e.g., heavy weight lifting), dehydration (i.e., use diuretics with caution), and medications that decrease afterload (e.g., ACE-inhibitors, angiotensin receptor blockers, and other direct vasodilators).

Evaluation of relatives at risk: If the disease-causing mutation has been identified in an affected family member, clarification of the genetic status of at-risk family members allows longitudinal evaluation for HCM to be focused on those who have inherited the disease-causing mutation. If no disease-causing mutation has been identified in an affected family member, longitudinal clinical evaluation for HCM is recommended for asymptomatic at-risk first degree relatives.

Pregnancy management: Women with HCM require care by an experienced cardiologist and obstetrician trained in high-risk OB.

Definition

This GeneReview intends to provide an overview of hypertrophic cardiomyopathy to help the reader understand the role of genetic testing in diagnosis and in the management of family members at risk.

Definition of hypertrophic cardiomyopathy (HCM). Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH). Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload (e.g., long-standing hypertension, aortic stenosis) or storage/infiltrative disorders (e.g., Fabry disease, amyloidosis).

The penetrance of LVH is age dependent. LVH often becomes apparent during adolescence or young adulthood, around the onset of puberty. However, LVH can develop late in life [Niimura et al 2002], in infancy, and in early childhood.

Diagnosis

The diagnosis of HCM is most often established with noninvasive cardiac imaging, including echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI). Histopathologic features include myocardial fibrosis and myocyte disarray.

  • Although asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy vary. LVH can be concentric, or confined to other walls or the LV apex.
  • Findings on transthoracic echocardiography may also include:
    • Systolic anterior motion (SAM) of the mitral valve with associated left ventricular outflow tract obstruction and mitral regurgitation
    • Mid-ventricular obstruction as a result of systolic cavity obliteration
    • Diastolic dysfunction, including restrictive physiology. Of note, impaired LV relaxation can be detected in individuals with a mutation in a gene that encodes a component of the sarcomere who have normal LV wall thickness [Nagueh et al 2001, Ho et al 2002], suggesting that diastolic dysfunction is an early phenotype of HCM, rather than a secondary consequence of LVH.

Clinical Manifestations of Hypertrophic Cardiomyopathy

The clinical manifestations of HCM are highly variable, ranging from asymptomatic LVH to arrhythmias (atrial fibrillation as well as malignant ventricular arrhythmias), to refractory heart failure. Moreover, phenotypic expression can vary even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope.

Although HCM was initially thought to be associated with high mortality, it is now recognized that the majority of persons with HCM will have a relatively mild course with normal life expectancy and manageable symptoms [Maron et al 2003a, Maron et al 2003b, Elliott et al 2006].

Approximately 25% of persons with HCM have detectable intracavitary obstruction at rest, and the majority of persons with HCM can develop outflow tract obstruction with provocation (e.g., reduction of preload or afterload) [Maron et al 2003c, Elliott et al 2006, Maron et al 2006]. The degree of obstruction does not strictly correlate with the severity of symptoms or risk for sudden cardiac death (SCD). Observational studies have reported that persons with HCM with outflow tract obstruction may be at higher risk for symptom progression and death than those without outflow tract obstruction [Maron et al 2003c, Sorajja et al 2009]; 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 have significant morbidity due to increased risk of thromboembolism and symptomatic deterioration. The prevalence of AF increases with age.

Approximately 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. The annual mortality rate in individuals with end-stage disease is estimated at 11% [Harris et al 2006] and cardiac transplantation may be required.

An important minority of persons with HCM are at increased risk for sudden cardiac death (SCD), most likely related to ventricular tachycardia/ventricular fibrillation.

  • SCD may be the first manifestation of disease [Maron et al 2000].
  • HCM is a well-described cause of SCD in competitive athletes in the US [Maron 2003].
  • Although sudden death occurs most often in adolescents or young adults, it may occur at any age and the risk persists throughout life.
  • Risk factors for sudden death are discussed in Management.

Prevalence of Hypertrophic Cardiomyopathy (HCM)

The prevalence of unexplained LVH in the general population is estimated at 1:500, predicting approximately 600,000 persons with HCM in the US. As such, HCM is one of the most common monogenic cardiovascular disorders.

Differential Diagnosis of HCM

Other cardiac conditions may result in cardiac hypertrophy and need to be distinguished from HCM. These include the following.

Acquired left ventricular hypertrophy (LVH). Secondary LVH can be pathologic, occurring in response to pressure overload (e.g., systemic hypertension, aortic stenosis). This type of adverse remodeling can lead to diastolic abnormalities and heart failure. Physiologic hypertrophy (athlete’s heart) may result from rigorous athletic training. Such training may result in increased left ventricular wall thickness accompanied by increased LV cavity size. This type of remodeling is thought to be adaptive and not associated with adverse consequences. Both pathologic and physiologic forms of secondary hypertrophy can regress if the underlying stimulus is removed. This may involve adequate treatment of high blood pressure, or a period of de-training for an athlete.

Syndromes with LVH (i.e., LVH associated with an underlying metabolic disorder or muscle disease)

  • Mutations in PRKAG2, encoding the γ-subunit of AMP kinase, result in unexplained cardiac hypertrophy secondary to the accumulation of glycogen-filled vacuoles. A high prevalence of conduction system disease [Konno et al 2010] and ventricular preexcitation help to differentiate this condition from HCM. Inheritance is autosomal dominant.
  • Danon disease, caused by mutation of LAMP2, encoding lysosome-associated membrane protein, is associated with striking LVH related to accumulation of autophagic vacuoles, ventricular preexcitation, and rapid disease progression with a nearly universally grave prognosis from life-threatening ventricular arrhythmias and/or progression to end-stage heart failure. Extracardiac features include skeletal myopathy and neurologic and ophthalmologic manifestations including retinal dystrophy. Inheritance is X linked; heterozygous females may manifest the cardiac phenotype.
  • Fabry disease results from deficient activity of the enzyme α-galactosidase (α-Gal) and progressive lysosomal deposition in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal enzyme activity, usually begins in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in the third to fifth decade. In middle age, most affected males develop cardiovascular and/or cerebrovascular disease.

    In contrast, males with greater than 1% α-Gal enzyme activity have a cardiac or renal variant phenotype. The cardiac variant phenotype usually presents in the sixth to eighth decade with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and proteinuria without ESRD. Studies suggest that approximately 3%-10% of unexplained LVH in adult males may be caused by underlying Fabry disease [Sachdev et al 2002].

    Inheritance is X-linked but heterozygous females may have significantly reduced α-Gal enzyme activity and manifest clinical disease.
  • Cardiac amyloidosis can be associated with LVH from accumulation of the amyloid protein, often resulting in a restrictive cardiomyopathy [Shah et al 2006, Dubrey et al 2011]. The type of amyloidosis (primary, familial, or senile) is determined by the underlying amyloidogenic protein and strongly influences prognosis.
    • Primary amyloidosis results from a plasma cell dyscrasia (commonly multiple myeloma) with abnormal monoclonal immunoglobulin light chains. Often, there is associated renal involvement and a poor overall prognosis.
    • Transthyretin (TTR) amyloidosis, caused by mutation of TTR, is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy, cardiomyopathy, vitreous opacities, and CNS amyloidosis. Onset is usually in the third or fourth decade but may be later. Cardiac amyloidosis is mainly characterized by progressive restrictive cardiomyopathy. Inheritance is autosomal dominant.

Childhood-onset conditions with LVH. In their study of “isolated” and syndromic HCM in children in the pediatric cardiomyopathy registry, Colan et al [2007] identified one disease in each of three major categories that accounted for a significant proportion of affected children [Colan et al 2007 (full text)] (see Table 1).

  • Inborn errors of metabolism. Glycogen storage disease type II (GSD II; Pompe disease) was seen 25 (34%) of 74 individuals with an inborn error of metabolism associated with cardiac hypertrophy.
  • Malformation syndromes. Noonan syndrome was seen in 60 (78%) of 77 individuals with a malformation syndrome.
  • Neuromuscular disorders. Friedreich ataxia (FRDA) was seen in 56 (88%) of 64 individuals with neuromuscular disorders and cardiac hypertrophy.

Genetics of Hypertrophic Cardiomyopathy

In this review, the authors consider hypertrophic cardiomyopathy (HCM) as a primary cardiomyopathy that occurs in the absence of acquired or syndromic causes of cardiac hypertrophy. HCM is most commonly caused by mutations in one of the genes (listed in Table 1) that encode different components of the sarcomere. Mutation of one of the genes that encodes a component of the sarcomere are found in approximately 50%-60% of probands (adult and children) with a family history of HCM, and approximately 20%-30% of probands without a family history of HCM [Gersh et al 2011]. Approximately 6% of affected individuals have more than one sarcomere gene DNA variant (either biallelic variants in one gene or heterozygous variants in more than one gene), but a much smaller number will have more than one pathogenic variant [Ingles et al 2013].

More than 1500 individual mutations have been identified.

Evaluation Strategy

A general approach to identify the specific genetic cause in individuals with hypertrophic cardiomyopathy (HCM) is summarized in Figure 1. Genetic testing for HCM is best viewed as a family test rather than a test of an individual since results are most accurately interpreted after integrating genetic and medical test (echo, ECG) results from multiple family members. In this manner, a cohesive understanding of the family’s phenotype can be determined and appropriate segregation of genotypic data can be confirmed.

Figure 1

Figure

Figure 1. Familial hypertrophic cardiomyopathy: Algorithm for genetic testing and clinical cardiac screening

Notes:

1. Consider re-testing the person who best meets diagnostic criteria when new genes/tests are available.
2. (more...)

It is appropriate to consider the potential benefits to the patient/family and limitations of genetic testing for HCM before proceeding.

Benefits

  • Testing provides confirmation of clinical diagnosis of HCM and differentiation from other causes of cardiac hypertrophy
  • More definitive identification of at-risk family members is possible.
  • Testing provides insight into the underlying disease biology.

Limitations

  • Results may be ambiguous. It may not be possible to determine if a DNA variant is pathogenic, disease-modifying, or not clinically relevant. Moreover, the interpretation of the pathogenicity of a variant may change over time.
  • Testing cannot detect all disease-causing variants; not all individuals with a clinical diagnosis of HCM will have a DNA variant identified with current testing strategies.
  • Test results are unlikely to directly affect the management of a person with HCM.
  • Due to reduced penetrance and variable expressivity, results cannot be used predict age of onset or clinical outcomes.

Genetic Testing Strategy

Family History

A detailed three- to four-generation family history should be obtained. Attention should be directed to identifying in relatives a history of any of the following: heart failure, HCM, cardiac transplantation, unexplained or sudden death (particularly in relatives age <40 years), cardiac conduction system disease and/or arrhythmia, or unexplained stroke or other thromboembolic disease. Note: The family member who will be undergoing molecular genetic testing should have an unequivocal diagnosis of HCM and is, ideally, the most severely affected person in the family.

Note: (1) Confirming the absence of other affected relatives can be complicated by various medical issues (e.g., failure to undergo appropriate cardiac screening; reduced penetrance; early death from other causes before onset of HCM) and/or social issues (e.g., isolation from family members, undisclosed adoption, and alternate paternity or maternity). Thus, it may not be possible to distinguish whether the proband with HCM is truly a simplex case (i.e., a single occurrence in the family). (2) Clinical evaluation of family members can provide valuable information about the family history (e.g., diagnosis of a family member with previously unrecognized HCM). (3) Family history should be reviewed and updated periodically.

Selection of a Multi-Gene Panel and Consideration of Possible Outcomes of Testing

Multi-gene panels comprising genes known to be associated with HCM or genes associated with a variety of genetic cardiomyopathies are available (see Table 1 for a list of genes). Of note, the genes included in any multi-gene panel and the corresponding detection rate will vary between laboratories and over time within the same laboratory.

Laboratories have their own classification systems for variants. No standardized criteria define pathogenicity of a variant.

The general categories of possible results include:

  • Positive: the laboratory has identified a variant they believe has strong data to support that it is disease-causing (i.e., pathogenic)
  • Variant of unknown significance: the laboratory has identified a variant that could be disease-causing or benign. Additional information is necessary to understand the significance.
  • Negative: the laboratory did not identify any potentially disease-causing variants. Importantly, this result is non-diagnostic and inconclusive. It does not eliminate a genetic cause. Retesting in the future should be considered if new genes are identified in which mutations cause HCM.

Assessment of the pathogenicity of any variant identified should include scrutiny of the information provided by the laboratory which forms the basis for their classification, as well as consideration of the personal medical history and family medical history information for the proband/family. Often, this latter assessment may be aided by the genetic testing of family members for cosegregation analysis (see Genetic Testing of At-Risk Family Members).

Table 1. Molecular Genetics of Hypertrophic Cardiomyopathy (HCM) in Descending Order of Frequency

% of FHCM Caused by Mutations in This GeneGene 1Protein Name 1OMIM 1
40%MYH7Myosin-7160760
192600
40%MYBPC3Myosin-binding protein C, cardiac type115197
600958
5%TNNT2Troponin T, cardiac muscle115195
191045
5%TNNI3Troponin I, cardiac muscle191044
613690
2%TPM1Tropomyosin alpha-1 chain115196
191010
UnknownMYL2Myosin regulatory light chain 2, ventricular/cardiac muscle isoform160781
608758
1%MYL3Myosin light chain 3160790
608751
UnknownACTC1Actin, alpha cardiac muscle 1102540
612098
UnknownCSRP3Cysteine and glycine-rich protein 3 600824
612124
UnknownACTN2Alpha-actinin-2102573
UnknownMYH6Myosin-6160710
613251
UnknownTCAPTelethonin604488
UnknownTNNC1Troponin C, slow skeletal and cardiac muscles191040
613243
UnknownPLNCardiac phospholamban172405
613874
UnknownMYOZ2Myozenin-2605602
613838
UnknownNEXNNexilin613121
613876

1. Data are compiled from the following standard references: gene symbol from HGNC; OMIM numbers from OMIM; protein name from UniProt.

Genetic Testing of At-Risk Family Members

If a definitive pathogenic mutation is identified in the family member who was tested, testing can be performed in at-risk relatives to identify those who are heterozygous for the disease-causing mutation (and thus at high risk for developing HCM).

If the pathogenicity of the variant identified in the family is uncertain (i.e., likely pathogenic or of unknown significance), testing other affected family members as part of a segregation analysis can help in variant interpretation: Observation that the variant segregates with HCM in other affected family members (and does not segregate with the normal phenotype) provides further support for pathogenicity.

The number of relatives tested is an important consideration, as the a priori chance that first-degree relatives will inherit the variant is 50%. In contrast, the absence of the variant in a single affected individual provides strong evidence that the variant is not pathogenic.

  • It is appropriate to combine genetic testing with clinical evaluation in at-risk relatives to provide more comprehensive information about the disease and variant transmission in the family.
  • When pathogenicity of a variant is refuted by segregation analysis, this information should be communicated back to the genetic testing laboratory.

If the variant identified in the tested family member is of uncertain significance, testing unaffected at-risk family members for the variant is not helpful, as this information will not aid in interpretation of the variant and will not reliably modify the a priori risk to that relative of developing HCM.

If no variant is identified in the tested family member no further genetic testing can be pursued (at this time) to clarify the genetic status of at-risk family members.

Clinical Cardiovascular Screening

Clinical cardiovascular screening by ECG and echocardiography in relatives at risk for HCM should be performed in accordance with published recommendations (see Surveillance, For relatives at risk for HCM [Gersh et al 2011]. This includes relatives known to have inherited the family’s disease-causing mutation, as well as at-risk relatives in whom testing has not been done or has not been informative.

  • Family members diagnosed with HCM during the course of family screening should proceed with additional testing for risk stratification of sudden death (see Evaluations Following Initial Diagnosis [Gersh et al 2011].
  • The follow-up of a family member who does not have the family-specific variant should be determined based on the evidence supporting the pathogenicity of the variant.
    • If evidence for pathogenicity is strong, the family member can be dismissed from routine cardiovascular screening but should be evaluated if symptoms develop.
    • Without strong evidence to support pathogenicity, it is appropriate to consider periodic cardiovascular screening and evaluate sooner if symptoms develop.

Note: As our understanding about human DNA variation evolves, it is possible that the classification of a variant will change, potentially affecting the recommendations made to a person/family.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hypertrophic cardiomyopathy (HCM) is most commonly caused by mutation in one of the genes currently known to encode different components of the sarcomere and is inherited in an autosomal dominant manner. Genetic counseling and risk assessment depend on determination of the inheritance of HCM in an individual and results of molecular genetic testing.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed as having HCM have an affected parent.
  • A proband with HCM may also have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown but estimated at 30%.
  • 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 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 has the 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.
  • If the disease-causing mutation identified 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. Genetic testing can be performed directly on an at-risk sib to clarify the at-risk sib’s genetic status. Furthermore, genetic testing should be pursued in clinically affected siblings, regardless of whether the familial mutation was found in a parent.

When the parents are clinically unaffected and the family’s disease-causing mutation has not been identified, there is still the potential for genetic disease. As such, the risk to the sibs of an affected proband may be increased over the general population risk, but cannot be accurately estimated.

Offspring of a proband. Each child of an individual with familial HCM has a 50% chance of inheriting the mutation and therefore being at risk for developing HCM. However, penetrance may be incomplete and disease severity and age of onset cannot be predicted.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Practice guidelines recommend construction of a three- (or more) generation family history in all persons with HCM to help identify at-risk family members [Hershberger et al 2009]. At-risk family members should seek clinical evaluation according to the guidelines listed in Table 2 and may consider genetic testing if there is a known pathogenic mutation in the family.

Because HCM is associated with variable expressivity and age-dependent penetrance, family history should be updated periodically.

Determining the mode of inheritance. Because more than one mutation in a gene encoding a sarcomere protein has been identified in a single individual (i.e., double heterozygosity), determining the mode of inheritance is critical for accurate risk assessment of other family members [Richard et al 2006, Girolami et al 2010].

Genetic testing of at-risk asymptomatic relatives is possible when the disease-causing mutation has been identified in an affected family member.

Testing of at-risk adult relatives should be performed in the context of formal genetic counseling. Test results are 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 (rather than diagnostic) testing that will identify family members requiring surveillance for emergence of findings of HCM over time and will allow reassurance of family members who are not at increased risk.

Testing of at-risk relatives younger than age 18 years requires consideration of the potential risks and benefits.

  • Potential risks. The principal arguments against such testing are that it removes the individual’s 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.
  • Potential benefits. Early detection of the family-specific disease-causing mutation: (1) may provide helpful insight to guide management of minors, particularly in the setting of known early-onset and/or aggressive disease; (2) allows for stringent surveillance for the onset of asymptomatic (but clinically detectable) HCM and earlier risk assessment for sudden death, an important consideration for asymptomatic at-risk young people interested in or involved in competitive sports.

    Absence of the family-specific disease-causing mutation can provide reassurance that the person is unlikely to develop HCM, thus obviating unnecessary surveillance.

Note: The use of predictive genetic testing in family management requires a high degree of confidence that the mutation identified in the probands is definitively the cause of disease in the family.

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 position statement on genetic testing of minors for adult-onset conditions 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.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

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 an option for families in which a definitive disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's Cardiomyopathy Foundation (CCF)
    PO Box 547
    Tenafly NJ 07670
    Phone: 866-808-2873 (toll-free)
    Fax: 201-227-7016
    Email: info@childrenscardiomyopathy.org
  • Hypertrophic Cardiomyopathy Association (HCMA)
    328 Green Pond Road
    PO Box 306
    Hibernia NJ 07842
    Phone: 973-983-7429
    Fax: 973-983-7870
    Email: support@4hcm.org
  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
    Email: review.personal.info@heart.org
  • Cardiomyopathy Association (CMA)
    Chiltern Court
    Asheridge Road
    Unit 10
    Chesham Buckinghamshire HP5 2PX
    United Kingdom
    Phone: +44 01494 791224; 0800 018 1024 (UK only)
    Fax: +44 01494 797199
    Email: info@cardiomyopathy.org

Management

Evaluations Following Initial Diagnosis

An important subset of individuals with HCM are at increased risk for sudden cardiac death (SCD) and may benefit from an implantable cardioverter defibrillator (ICD). Further evaluation to assess for the presence or absence of risk predictors associated with SCD is a standard part of patient management.

SCD risk factors include:

  • Personal history of ventricular fibrillation (VF), aborted/resuscitated sudden death / cardiac arrest, or sustained ventricular tachycardia (VT)
  • Family history of SCD
  • Extreme LVH (>30mm)
  • Hypotensive blood pressure response to exercise
  • Nonsustained ventricular tachycardia (VT) on ambulatory monitoring
  • Unexplained syncope

Risk factor information, obtained from the medical history, family history, and cardiovascular testing, includes:

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

Accurate risk assessment is difficult because the positive predictive value of any single parameter – other than prior cardiac arrest or sustained VT – is relatively low. The presence of two or more risk factors has been associated with an increased risk for sudden cardiac death [Elliott et al 2000, Dimitrow et al 2010], although implantation of a primary prevention ICD may be appropriate in the presence of a single compelling risk factor. Conversely, the absence of any risk factors places an individual in a low-risk category [Maron et al 2003b], although 3%-5% of persons with SCD do not have a standard risk factor.

Guidelines [Garratt et al 2010, Gersh et al 2011]* recommend that implantable cardioverter defibrillator (ICD) therapy:

Currently ICD implantation is the only effective treatment to prevent SCD, but it is associated with cumulative morbidity.

* See Published Guidelines/Consensus Statements for full text of guidelines.

Treatment of Manifestations

Treatment by physicians experienced in diagnosis and management of persons with HCM improves survival and quality of life. Treatment modalities include pharmacologic therapy, invasive septal reduction therapy, and pacemakers or implantable cardiac defibrillators. Cardiac transplantation may be necessary for patients who progress to advanced heart failure refractory to medical or device therapy.

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

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

  • Beta blockers
  • L-type calcium channel blockers
  • Disopyramide (its negative inotropic effects can reduce obstructive physiology)
  • Antiarrhythmic drug therapy for treatment of atrial fibrillation and/or ventricular arrhythmias

Note: Direct vasodilators (e.g., ACE inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers) should be avoided in patients with obstructive physiology as they may exacerbate obstruction.

Diastolic dysfunction, a common feature of familial HCM that may contribute significantly to symptoms of exertional dyspnea and volume overload independent of obstruction, 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, invasive septal reduction therapy may be considered to alleviate symptoms:

  • Surgical myectomy (removal of a section of muscle from the interventricular septum) has a long and established track record for reducing or eliminating symptoms.
  • Alcohol septal ablation is a more recently developed catheter-based procedure in which ethanol is injected through a septal perforator vessel to induce focal myocardial infarction targeting the portion of the septum that is primarily responsible for obstructive physiology.

For atrial fibrillation (AF), rate control and medical or invasive attempts at rhythm control may be required, based on symptom burden [Gersh et al 2011]. Because of high thromboembolic risk from atrial fibrillation (AF) in HCM, anticoagulation is recommended, even with paroxysmal occurrences.

Prevention of Primary Manifestations

For individuals with familial HCM felt to be at increased risk for SCD, ICD therapy is an important consideration. ICDs are currently the best option for the prevention of SCD and have been shown to be effective in sensing and terminating ventricular tachycardia (VT) and ventricular fibrillation (VF).

The annual rate of appropriate ICD therapies has been estimated at 2%-4% in individuals with an ICD placed for primary prevention, and 4%-11% in individuals with an ICD placed for secondary prevention [Maron et al 2007, O’Mahony et al 2012].

The potential for complications must be considered in the discussion of ICD placement. Although ICDs are generally safe, they are not benign and cumulative morbidity needs to take into account the age at implantation and duration of therapy. The rate of complications has been reported at 5% per year in persons with HCM. The rate of inappropriate shocks is roughly double the rate of appropriate therapies in persons who received ICDs for primary prevention [Maron et al 2007, Lin et al 2009, O’Mahony et al 2012].

In the absence of highly sensitive, patient-specific predictors, the decision to implant an ICD requires detailed and thoughtful evaluation, as well as the active input of well-informed patients.

Prevention of Secondary Complications

Because persons with HCM who develop atrial fibrillation are at increased risk for thromboembolic complications, anticoagulation should be strongly considered in those with persistent or paroxysmal atrial fibrillation.

Affected individuals 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 have been revised and decision making should be individualized [Wilson et al 2007].

Surveillance

For individuals with HCM who do not currently meet criteria for placement of an ICD for primary prevention, risk for SCD should be reassessed approximately every 12-24 months (or sooner if any clinical parameters change) [Gersh et al 2011].

For relatives at risk for HCM. Screening guidelines for HCM have been proposed for the longitudinal evaluation of clinically unaffected at-risk family members (see Table 2). Note that the following screening guidelines apply to both mutation-positive relatives and asymptomatic first-degree relatives (adults and children) of an individual with primary HCM in whom a disease-causing mutation has not been identified.

Because penetrance of diagnostic features (i.e., LVH) is age dependent, a single unremarkable evaluation does not exclude the possibility of future development of HCM. Diagnostic clinical manifestations are often not present in infancy/early childhood; they commonly develop during adolescence and early adulthood, but may also develop late in life. Therefore, longitudinal follow up is required at a frequency based on the individual’s age and family history, and physician discretion. Screening should be performed in response to any symptoms that develop or any change in clinical status.

Table 2. Guidelines for Clinical Screening of Healthy At-Risk Family Members with Physical Examination, Echocardiography, and Electrocardiogram (ECG)

AgeScreening Guideline
<12 yrsOptional unless any of the following are present:
  • Family history of early HCM-related death, early development of LVH, or other adverse complications
  • Competitive athlete in intense training program
  • Symptoms
  • Other clinical findings that suggest early LVH
12-18 yrsRepeat evaluation every 12-18 months
>18-21 yrsRepeat evaluation every ≤5 years or in response to any change in symptoms
More frequent evaluation if the family has late-onset LVH or HCM-related complications

Adapted from Gersh et al [2011]

Agents/Circumstances to Avoid

Affected individuals are advised to use moderation in all physical activities. Physical activity guidelines have been established to detail reasonable exercise restrictions for people with familial HCM [Maron et al 2004, Gersh et al 2011]:

  • Avoid competitive endurance training and participation in recreational activities that require an intensity level similar to competitive athletics.
  • Avoid burst activities, like sprinting, as well as intense isometric exercise, such as heavy weight lifting.
  • Avoid exercise in extreme environmental conditions and maintain adequate hydration.

To avoid exacerbation of obstructive physiology and worsening of symptoms, patients with outflow tract obstruction should be particularly careful in alcohol consumption; use Jacuzzis, steam rooms, saunas with caution; and 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 including dihydropyridine calcium channel blockers)
  • Medications for erectile dysfunction (e.g., sildenafil, tadalafil)

Cautious use of stimulant medications may be considered in children diagnosed with HCM only after other treatment methods have been explored. Children with HCM undergoing treatment with stimulants should be carefully monitored by a pediatric cardiologist [Vetter et al 2008].

Evaluation of Relatives at Risk

If the disease-causing mutation has been identified in an affected family member, clarification of the genetic status of at-risk family members (see Figure 1) allows appropriate longitudinal evaluation of those who have the disease-causing mutation (see Surveillance and Table 2).

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

Pregnancy Management

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. Perinatal care with specialists experienced in cardiovascular medicine and high-risk obstetrics is highly recommended.

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.

References

Published Guidelines/Consensus Statements

  1. Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA (2007) Epidemiology and case-specific outcomes in Hypertrophic Cardiomyopathy in children: Findings from the Pediatric Cardiomyopathy Registry. Available online. 2007. Accessed 1-7-14.
  2. Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O’Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndrome. Available online. 2010. Accessed 1-10-14. [PubMed: 20663787]
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Chapter Notes

Author Notes

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

Revision History

  • 16 January 2014 (me) Comprehensive update posted live
  • 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
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