What is hypertrophic cardiomyopathy?

Hypertrophic Cardiomyopathy: Overview

Definition and Pathophysiology

Hypertrophic cardiomyopathy (HCM) is an inherited genetic heart disease characterized by left ventricular hypertrophy (≥15 mm wall thickness in adults, or >2 standard deviations in children) that occurs in the absence of abnormal loading conditions such as hypertension or aortic stenosis. 1

• HCM is caused by mutations in genes encoding cardiac sarcomeric proteins, most commonly β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3), which together account for approximately 50% of cases 1, 2
• The disease is inherited in an autosomal dominant pattern with equal distribution by sex, though women are diagnosed less commonly than men 1
• The characteristic pathology includes myocyte hypertrophy, myocyte disarray, and interstitial fibrosis, which contribute to the clinical manifestations 1, 2

Prevalence and Epidemiology

• The prevalence of unexplained asymptomatic hypertrophy in young adults ranges from 1:200 to 1:500 in the United States 1
• Symptomatic cases based on medical claims data occur in less than 1:3,000 adults, though the true burden is much higher when unrecognized disease is considered 1
• HCM affects all races and countries globally, though it appears under-diagnosed in women, minorities, and underserved populations 1

Clinical Manifestations

The clinical presentation of HCM is highly heterogeneous, ranging from completely asymptomatic individuals to those with severe symptoms, heart failure, and sudden cardiac death. 1

Functional Abnormalities

• Myocardial ischemia occurs despite normal coronary arteries due to small vessel disease, microvascular spasm, and inadequate capillary density relative to myocardial mass 1
• Diastolic dysfunction with impaired relaxation and inadequate filling is present in both obstructive and non-obstructive forms 1, 2
• Left ventricular outflow tract obstruction (LVOTO) develops in approximately two-thirds of patients, either at rest or with provocation, caused primarily by systolic anterior motion (SAM) of the mitral valve 3, 2

Symptom Patterns

• Common symptoms include exertional dyspnea, chest pain (typical angina or atypical), syncope, near-syncope, presyncope (dizziness/lightheadedness), and palpitations 1
• Atrial fibrillation occurs in a significant proportion of patients and is often poorly tolerated 1, 2
• Many patients, particularly younger individuals, remain asymptomatic or mildly symptomatic despite significant hypertrophy 1

Natural History and Prognosis

The natural history of HCM is diverse but relatively benign for most patients, with contemporary disease-related mortality as low as 0.5% per year and up to 25% of patients achieving normal longevity (≥75 years). 1

Important Prognostic Considerations

• Sudden cardiac death (SCD) is most common in young individuals (<30 years of age) but can occur throughout life, with an estimated annual frequency of 2-4% in community-based populations 1
• HCM is the most common cause of sudden cardiac death in young athletes 1, 2
• Deaths from non-HCM-related diseases (cancer, coronary artery disease, age-related comorbidities) are up to 2.6 times more likely than HCM-related deaths, with only 25% of HCM patients ultimately dying from their disease 1
• A small subset (5-10%) experience progressive decline in left ventricular function with development of end-stage heart failure 1

Critical Caveat About Mortality Data

Historical mortality rates of 3-6% per year from tertiary referral centers significantly overestimate the risk for most HCM patients and have led to an exaggerated perception that HCM is invariably unfavorable. 1 More recent data from community-based, non-tertiary center cohorts demonstrate much lower mortality rates, reflecting the true spectrum of disease severity 1.

Diagnosis

Diagnostic Criteria

• In adults: Left ventricular wall thickness ≥15 mm in one or more myocardial segments not explained by loading conditions 1, 4
• In children: Left ventricular wall thickness >2 standard deviations from the predicted mean (z-score >2) 1
• The hypertrophy is typically asymmetric, most commonly involving the basal interventricular septum, though it can involve the apex, free wall, or be concentric 1, 2

Diagnostic Evaluation

• Transthoracic echocardiography (TTE) with Doppler is essential for establishing diagnosis, defining the extent and distribution of hypertrophy, assessing for LVOTO, and guiding management 1
• 12-lead ECG is abnormal in most patients and useful for screening, though it lacks specificity 1
• Cardiac magnetic resonance (CMR) imaging is valuable for detecting myocardial fibrosis via late gadolinium enhancement (LGE), which has prognostic implications 1
• Genetic testing allows identification of specific mutations in probands and efficient cascade screening of family members once a mutation is defined 1

Differential Diagnosis

It is critical to distinguish HCM from other conditions that cause left ventricular hypertrophy (HCM mimics), as pathophysiology, natural history, and treatment differ substantially. 1

• Systemic disorders to exclude include RASopathies, mitochondrial myopathies, glycogen/lysosomal storage diseases, Fabry disease, amyloidosis, sarcoidosis, hemochromatosis, and Danon cardiomyopathy 1
• Secondary causes include athlete's heart (physiologic remodeling from training), hypertensive cardiomyopathy, and left-sided obstructive lesions (valvular or subvalvular stenosis) 1

Left Ventricular Outflow Tract Obstruction

Classification of LVOT Gradients

LVOT gradients are classified as follows: obstructive (≥30 mmHg at rest), labile/provocable (≥30 mmHg only with provocation), and non-obstructive (<30 mmHg both at rest and with provocation). 3

• A peak instantaneous LVOT gradient ≥50 mmHg represents the conventional threshold for considering surgical or percutaneous septal reduction therapy in symptomatic patients 3
• LVOT obstruction is dynamic and varies considerably with loading conditions, contractility, and daily activities 3
• Factors that increase obstruction include increased myocardial contractility, decreased ventricular volume, and decreased afterload 3

Clinical Significance

• The presence of LVOT obstruction (gradient ≥30 mmHg) is associated with symptomatic status and development of atrial fibrillation, embolic complications, and death 1, 3
• Provocable gradients can be assessed using exercise testing with Doppler echocardiography, Valsalva maneuver, or amyl nitrite inhalation 1

Sudden Cardiac Death Risk Stratification

Major risk factors for sudden cardiac death in HCM include: family history of sudden death from HCM in first-degree relatives ≤50 years old, massive left ventricular hypertrophy (wall thickness ≥30 mm), unexplained syncope, left ventricular systolic dysfunction (EF <50%), left ventricular apical aneurysm, extensive late gadolinium enhancement on CMR (≥15% of LV mass), and nonsustained ventricular tachycardia on ambulatory monitoring. 4

ICD Recommendations

• For patients with HCM and unexplained syncope within the preceding 6 months, an ICD is reasonable if meaningful survival greater than 1 year is expected (Class IIa recommendation). 4
• ICD therapy should be considered for secondary prevention in survivors of sustained ventricular arrhythmias 1
• The inheritable nature of HCM and ease of clinical identification mandate cardiac evaluation of first-degree relatives of probands 1

Management Strategies

Medical Therapy

Beta-adrenergic blocking agents are most useful in patients with obstructive HCM as they decrease myocardial contractility and oxygen demands while increasing ventricular volume. 5

• Calcium channel antagonists (particularly verapamil) are the agents of choice for patients with diastolic dysfunction, as they enhance left ventricular relaxation, relieve microvascular spasm, and improve coronary filling 5
• Avoid arterial vasodilators, diuretics, nitrates, and positive inotropic agents as they can increase the intraventricular gradient 5
• Recently developed myosin inhibitors represent novel targeted therapies studied in randomized controlled trials 6

Septal Reduction Therapy

Surgical myomectomy or alcohol septal ablation should be considered for patients with LVOT gradients ≥50 mmHg whose symptoms are refractory to medical therapy. 3

• Management strategies are largely dependent on the presence or absence of symptoms caused by obstruction 3
• For patients with LVOT gradients <30 mmHg and symptoms, focus on treating other potential causes rather than targeting the mild gradient 3

Lifestyle Modifications

Current guidelines recommend that patients with HCM avoid high-intensity competitive sports due to increased risk of sudden cardiac death. 1

• Moderate-intensity exercise may be safe in selected patients, though the increase in cardiorespiratory fitness achieved is modest 1
• The RESET-HCM trial demonstrated that moderate-intensity exercise training can be performed safely in HCM patients 1
• Given that inactivity is common in HCM patients (likely due to fear of exercise-induced adverse events) and that individuals with genetic cardiomyopathies are not immune from cardiometabolic diseases, appropriate exercise counseling is important 1

Advanced Heart Failure

• A small subset of patients progress to end-stage heart failure with left ventricular remodeling and systolic dysfunction, which may require heart transplantation or left ventricular assist device therapy 1, 6

Family Screening

Serial transthoracic echocardiography is reasonable for clinically unaffected first-degree relatives when genetic status is unknown: every 12-18 months for children or adolescents from high-risk families and every 5 years for adult family members. 1

• Once a mutation is identified in a proband, genetic testing of family members is efficient and inexpensive for determining genetic status 1
• Genetic diagnosis allows identification of asymptomatic affected patients prior to clinical disease onset 7