Hypertrophic cardiomyopathy (HCM) is the most common and most commonly misunderstood genetic cardiac disease.   It was once thought to occur in about 1:500 of the general population. Based on echocardiographic analyses in unrelated young adults, genetic testing, detailed familial screening and advanced imaging, a prevalence that could be as high as 1:200.   At the same time, most people with HCM are unaware of their disease.

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Data from the late 20th century showed annual HCM mortality as high as 6%, leaving too many patients and clinicians believing that HCM is an ominous diagnosis associated with an unfavorable prognosis, unrelenting progression and no effective treatment strategies.   The reality is that current treatment approaches have reduced HCM-related mortality to 0.5% per year, comparable to the general population.   Despite the improvements in mortality, recent studies have shown that ≈8% of patients with HCM will develop left ventricular systolic dysfunction, also known as “end stage” HCM.

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HCM is often a monogenic, autosomal dominant disorder associated with at least 26 genes, most encoding thick and thin filament proteins of the cardiac sarcomere.      These mutations occur without regard to race, ethnicity, sex or global geography.   First-degree relatives of individuals with HCM who carry pathogenic variants are at 50% risk of inheriting the pathogenic variant, being genotype-positive. Many individuals who are genotype-positive may never develop or recognize cardiovascular symptoms, experience any adverse HCM-related events
or be identified with other clinical markers such as abnormal electrocardiogram or family history.

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Up to 60% of patients with HCM have an identifiable pathogenic or likely pathogenic variant. The remainder have no currently identified genetic etiology associated with their disease, including individuals with no other affected family members. More than 1,500 variants of the most common causal genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3 and ACTC1) have been identified, most unique to individual families. The age of onset of HCM, if symptoms ever appear, is highly variable and genotypes do not accurately predict individual outcomes.

 

HCM is a heterogeneous disorder characterized by left ventricular hypertrophy (LVH) in the absence of other cardiac, systemic or metabolic disease capable of producing similar LVH. Systemic and metabolic confounders (also known as phenocopies) include RASopathies, mitochondrial myopathies and glycogen/lysosomal storage diseases in children as well as Fabry, amyloid, sarcoid, hemochromatosis and Danon cardiomyopathy in adults. Conditions that can produce secondary LVH such as cardiac remodeling secondary to intensive athletic training (athlete’s heart) as well as morphologic changes related to chronic systemic hypertension (hypertensive cardiomyopathy), hemodynamic obstructions caused by left-sided obstructive lesions (valvular or subvalvular stenosis), obstruction after antero-apical infarction and stress cardiomyopathy can also confound diagnosis.

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Potential outcomes from HCM are quite varied, ranging from sudden cardiac death, myocardial infarction, AFib, other arrhythmias and heart failure to asymptomatic survival with normal life expectancy.   Most patients with HCM develop left ventricular outflow tract obstruction (LVOTO) over time, but about one-third remain unobstructive.   Both obstructive and unobstructive patients can exhibit a range of symptoms.

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Clinical evaluation for HCM is often triggered by the occurrence of symptoms, a cardiac event, detection of a heart murmur, an abnormal 12-lead ECG seen on routine exam or cardiac imaging during family screening studies. In adults, imaging with 2D echocardiography or cardiovascular magnetic resonance (CMR) showing a maximal end-diastolic wall thickness of >15mm anywhere in the left ventricle without another cause for hypertrophy establishes a clinical diagnosis of HCM.  More limited hypertrophy, 13-14mm, may be diagnosed in individuals who have a known family history of HCM or are identified as carrying a pathogenic or likely pathogenic variant associated with HCM.

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Younger age at diagnosis and the presence of a sarcomere mutation are strong predictors of lifetime adverse events, although most events occur later in life. Between 30% and 40% of patients with HCM can expect to experience adverse events during their lifetimes, including sudden death, progressive limiting cardiac symptoms, heart failure, AFib, ventricular arrhythmia and stroke.

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The pathophysiology of HCM includes LVOTO, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias and autonomic dysfunction. Clinical outcomes may be dominated by a single component or the interplay of multiple components. Clinical evaluation should include a comprehensive cardiac history, a three-generation family history to identify relatives with HCM or unexpected/sudden death and a comprehensive physical exam, including physical exertion maneuvers such as Valsalva, squat-to-stand, passive leg raising or walking. Any suggestive findings should trigger ECG and cardiac imaging.

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Diagnosis can be more difficult in children due to adjustments for body size and growth. While a body surface area adjusted z-score of ≥2 standard deviations above the mean is the traditional diagnostic HCM cut-off for children, more recent data suggest z ≥2.5 standard deviations is more useful in children who are asymptomatic and have no family history of HCM. For children with a positive genetic test or definitive family history, z ≥2 may be diagnostic.

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CMR provides high spatial resolution and assessment of myocardial fibrosis with the use of late gadolinium enhancement (LGE) contrast. Because CMR shows sharp contrast between the blood pool and myocardium, it can provide more accurate measurements of LV wall thickness and identify areas of LVH not well-visualized by echocardiography, including the anterolateral wall, posterior septum and apex.

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Discussion of genetic testing is standard in patients with identified HCM. First-line genetic testing consists of targeted gene panels that include known disease-causing HCM variants. Exome sequencing and whole genome sequencing may be considered as second tier testing if no causal variant is identified on initial targeted testing. Current technology can identify a pathogenic variant in about 30% of sporadic cases and 60% of familial cases by searching for the eight most common genes, MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3 and ACTC1.

All first-degree relatives of those diagnosed with HCM should be advised to undergo clinical screening for HCM. If a pathogenic or likely pathogenic variant is identified in the proband, this is a clinically actionable finding which can be utilized by first degree relatives for more predictive risk stratification. Family members who do not carry the familial disease-causing variant do not need continued clinical surveillance.   Family members who carry the pathogenic or likely pathogenic variant should undergo clinical screening with ECG and echocardiography at the time they receive their genotype-positive status followed by regular interval screening. Children and adolescents should be screened every 1-2 years, and adults every 3-5 years.   This would also be true when there is no pathogenic variant identified in the family member with HCM or if genetic information is not available.

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Identifying a variant of uncertain significance (VUS) is not clinically actionable but may be useful for research purposes.   Classification of a VUS can change over time, so re-reviewing these variants periodically may prove meaningful over time.

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Individuals who carry a pathogenic or likely pathogenic HCM-causing gene variant but are both asymptomatic and show no signs of LVH on cardiac imaging are genotype-positive, phenotype-negative. They may also be described as having preclinical HCM. All need ongoing cardiac surveillance for progression to clinical HCM. Up to 15% of patients develop clinical HCM before the age of 18, and a third of patients who develop clinical HCM need medical, surgical or device therapy before age 18.

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HCM can lead to sudden cardiac death (SCD) in younger individuals, but is rare in genotype-positive, phenotype-negative patients. Established clinical risk factors for SCD include family history of SCD from HCM, massive LVH (≥ 3cm), unexplained syncope, HCM with LV systolic dysfunction, LV apical aneurysm, extensive LGE on CMR imaging and non-sustained ventricular tachycardia (NSVT). Patients at high risk for SCD may be good candidates for ICD placement for primary prevention. Because the risk of SCD extends over many decades of life, patients need periodic reassessment and discussion of SCD risk.

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Conventional pharmacologic therapy does not appear to alter the natural history of HCM but may provide symptom relief for patients with LVOTO. Maximum tolerable doses of nonvasodilating beta blockers are first-line therapy, with calcium channel blockers verapamil or diltiazem reasonable alternatives. Disopyramide can be also be utilized given its anti-inotropic effects, although tolerance is often limited by significant anti-cholinergic side effects such as dry mouth and eyes, constipation and urinary retention. These side effects can often be reduced with the use of pyridostigmine. Disopyramide can prolong QT interval and be pro-arrhythmic, so is often initiated inpatient. It is vital to eliminate medications that may provoke outflow tract obstruction, including pure vasodilators (dihydropyridine class calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) and high dose diuretics.

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Patients who remain symptomatic on standard pharmacologic therapy may consider mavacamten, a cardiac myosin inhibitor approved by the Food and Drug Administration in April 2022 to improve functional capacity and symptoms in adults with symptomatic NYHA class II-III obstructive HCM.    Compared to placebo in the pivotal EXPLORER-HCM trial, patients taking mavacamten showed improved peak oxygen consumption and/or improvement in NYHA status. Individuals taking mavacamten also showed greater improvement in quality-of-life as measured by Kansas City Cardiomyopathy Questionnaire versus placebo.

 

Mavacamten was generally well-tolerated in clinical trials, although 88% of patients in EXPLORER-HCM reported treatment-emergent adverse events, primarily dizziness and syncope. The most frequent serious adverse events included AFib, syncope and stress cardiomyopathy (all 2%).

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The FDA approval of mavacamten included a black box warning for risk of heart failure due to systolic dysfunction, a risk of reduced ejection fraction, and contraindications for concomitant use of some CPY450 inhibitors and inducers due to an increased risk of heart failure. The drug is available only through a risk evaluation and mitigation strategy, CAMZYOS™ REMS. Prescribers, patients and pharmacies must all enroll in the CAMZYOS REMS program.​

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Results of the VALOR-HCM trial results suggest mavacamten may offer a viable alternative to septal reduction therapy (SRT) for carefully selected patients with more severe symptoms. Among patients with obstructive HCM with NYHA class III-IV symptoms (or class II with syncope) who met guideline criteria for SRT, just 17.9% met guideline criteria for SRT after 16 weeks of mavacamten treatment compared to 76.8% of patients on placebo. Long-term freedom from SRT has yet to be determined.

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SRT is considered for patients with severe outflow tract obstruction who remain symptomatic despite maximal tolerable medical therapy. Transaortic extended septal myectomy can treat a broad range of symptomatic patients with obstructive HCM. Experienced operators at high volume comprehensive HCM centers demonstrate clinical success >90-95% with mortality <1%. Long-term survival after surgical myectomy is similar to an age-matched general population. Myectomy via an apical approach can be utilized in combination with transaortic myectomy to treat septal hypertrophy not confined to the basilar septum and/or for patients with mid-cavitary obstruction.    Apical myectomy can also be useful for patients with apical predominant hypertrophy wherein the primary pathology is reduced LV cavity size and therefore low stroke volume, even in the absence of outflow obstruction.

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The mitral valve and subvalvar apparatus can also contribute significantly to the pathophysiology of LVOTO in HCM and are potential surgical targets. Many patient with LVOTO have a component of Systolic Anterior Motion (or “SAM”) of the mitral valve that contributes to the blockage of blood trying to leave the heart. In almost every patient with HCM and LVOTO, the posteromedial papillary muscle is apically displaced and abnormally bound to the ventricular septum and posterior wall of the ventricle. This can easily be mobilized during surgery and may place the anterior leaflet of the mitral valve in a more favorable position. Many patients will also have accessory chordae from the mitral valve or submitral apparatus that insert into the ventricular septum, thereby “tethering” the anterior leaflet in an unfavorable position and potentiating SAM. These can also be easily excised during surgery. Some patients have an abnormally long anterior mitral valve leaflet and be predisposed to SAM even following surgery. Edge-to-edge mitral valve repair, also known as an “Alfieri Stitch” can be performed for such patients to prevent persistent SAM.

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Alcohol septal ablation offers a noninvasive alternative for patients who are not surgical candidates. Appropriate coronary anatomy is necessary, and alcohol septal ablation should be completed by an experienced interventional cardiologist. This procedure may be less effective for high resting gradients or septal thickness ≥30 mm and may also carry a higher risk of complete heart block, necessitating implantation of a pacemaker.

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There is potential for increased risk of thromboembolism in the setting of HCM. If AFib is detected, anticoagulation is recommended regardless of CHA2DS2-VASc score. Direct acting oral anticoagulants (DOACs) are first line, with warfarin as a second-line option.

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HCM with associated heart failure can be challenging to manage. Diastolic dysfunction often results from chamber stiffness, altered ventricular load, nonuniform contraction and relaxation, and smaller ventricular size. Diuretics may be needed if there are signs/symptoms of congestion, but this must be done cautiously, especially if there is known dynamic obstruction.  Some with HCM will develop “burnout HCM” when LVEF is <50%. Aggressive management with traditional guideline-directed medical therapy for heart failure with reduced ejection fraction should then be initiated. An LVEF <50% is also a risk factor for SCD.   Patients with an LVEF <50% may have a higher symptom burden with an only mildly reduced LVEF and should be managed as advanced disease. Consider sending to a transplant center for consultation.

 

The success of ICD placement and SRT have shifted long-term management efforts to HCM patients with AFib, ventricular arrhythmias and heart failure. The presence of HCM has minimal impact on the clinical management of AFib, ventricular arrhythmias or heart failure.   For most patients with HCM, mild to moderate intensity physical activity is beneficial and leads to improved cardiorespiratory fitness, physical functioning, quality of life and overall health. Athletes with HCM may benefit from a comprehensive evaluation and discussion of the potential risks of sports participation. ICD placement for the sole purpose of participation in competitive sports should not be performed.