Hypertrophic Cardiomyopathy

Table of Contents

  1. Overview
  2. Epidemiology
  3. Pathophysiology
  4. Genetics and Etiology
  5. Clinical Presentation
  6. Diagnosis
  7. Risk Stratification and SCD Prevention
  8. Medical Treatment
  9. Septal Reduction Therapy
  10. Mavacamten and Novel Therapies
  11. Complications and Prognosis
  12. Research Papers
  13. Connections
  14. Featured Videos

Back to Table of Contents

1. Overview

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, affecting approximately 1 in 200–500 people — roughly 600,000–750,000 Americans. It is caused by autosomal dominant mutations in sarcomeric protein genes, producing inappropriate myocardial hypertrophy (thickening of the heart muscle wall) that is not explained by pressure overload conditions such as hypertension or aortic stenosis.

Most patients with HCM live normal or near-normal lives with modern care. However, HCM is the leading cause of sudden cardiac death (SCD) in young competitive athletes under age 35 in the United States, making early recognition, genetic screening, and individualized risk stratification critically important.

The 2022 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy provides the current management framework and introduced major updates including the formal role of mavacamten (the first cardiac myosin inhibitor) as a medical alternative to invasive septal reduction therapy.

Back to Table of Contents

2. Epidemiology

Back to Table of Contents

3. Pathophysiology

HCM begins at the sarcomere — the basic contractile unit of the heart muscle. Mutations in sarcomeric protein genes (most commonly MYH7 encoding beta-myosin heavy chain and MYBPC3 encoding myosin-binding protein C) cause two fundamental defects: increased myosin ATPase activity and calcium hypersensitivity of the thin filament. The result is a hypercontractile state that exhausts myocyte energy supply, impairs relaxation (diastolic dysfunction), and triggers secondary remodeling.

Molecular Cascade

Hypercontractility depletes ATP → activates calcineurin-NFAT, PI3K-Akt-mTOR, and MAPK signaling cascades → pathological hypertrophy. Simultaneously, impaired calcium reuptake (reduced SERCA2a activity) prolongs myocyte contraction and contributes to diastolic stiffness.

Histologic Triad

Left Ventricular Outflow Tract Obstruction (LVOTO)

Asymmetric septal hypertrophy (ASH) — typically most severe at the basal interventricular septum — narrows the left ventricular outflow tract (LVOT). During systole, the abnormally positioned anterior mitral valve leaflet is drawn toward the hypertrophied septum by the Venturi effect of high-velocity blood flowing through the narrowed LVOT. This systolic anterior motion (SAM) of the mitral valve:

Resting LVOTO gradient ≥30 mmHg is present in approximately 25% of patients; provokable gradient ≥50 mmHg during exercise or Valsalva in approximately 70%.

Back to Table of Contents

4. Genetics and Etiology

HCM is an autosomal dominant condition with 50–75% penetrance and highly variable expressivity — meaning family members who carry the same mutation can have very different degrees of wall thickening and symptoms. This variability is influenced by modifier genes, environment, and lifestyle factors.

Major Sarcomere Genes

Sarcomere-Negative HCM

Approximately 5–10% of patients with a classic HCM phenotype have no identifiable mutation in known sarcomere genes ("sarcomere-negative HCM"). These cases likely represent undiscovered genes or phenocopies — other conditions that mimic HCM structurally.

Syndromic HCM and Phenocopies

Genetic Counseling and Family Screening

The 2022 AHA/ACC guideline gives a Class I recommendation for genetic counseling and cascade testing of all first-degree relatives of patients with HCM. Relatives who carry the pathogenic variant but have no echocardiographic evidence of disease (genotype-positive, phenotype-negative) should receive serial clinical and echocardiographic follow-up every 1–3 years, since penetrance can be delayed decades.

Back to Table of Contents

5. Clinical Presentation

The classic symptomatic triad of HCM is exertional dyspnea, chest pain, and syncope or presyncope. However, many patients — perhaps the majority — are diagnosed incidentally on ECG or echocardiography without ever having symptoms.

Symptoms

Physical Examination with LVOTO

Back to Table of Contents

6. Diagnosis

Electrocardiography

The ECG is abnormal in 75–95% of patients with HCM. Classic findings:

Echocardiography (Primary Diagnostic Modality)

Cardiac MRI (CMR)

CMR is the gold standard for:

Genetic Testing

Recommended for all patients with HCM (Class IIa recommendation, 2022 AHA/ACC). Identifies the causative variant in 40–60% of patients. A positive result:

Additional Testing

Back to Table of Contents

7. Risk Stratification and SCD Prevention

Identifying which patients with HCM are at highest risk for sudden cardiac death — and offering ICD protection to those who are — is the cornerstone of HCM management. The annual SCD rate in modern cohorts is approximately 0.5–1%, but it is much higher in specific high-risk subgroups.

Major SCD Risk Factors (2022 AHA/ACC HCM Guideline)

Any one of the following is considered a significant risk factor warranting ICD discussion:

  1. Prior cardiac arrest or documented sustained ventricular tachycardia (VT): Most powerful predictor; ICD indicated for secondary prevention (Class I)
  2. Family history of SCD attributed to HCM: Particularly in first-degree relatives under age 50
  3. Unexplained syncope: Especially exertional syncope (highly suspicious for arrhythmic mechanism); recent syncope carries higher weight than remote
  4. Massive LV hypertrophy (max wall thickness ≥30 mm): Associated with high arrhythmia burden; Danon disease and other syndromic HCM often reach this threshold
  5. Hypotensive blood pressure response to exercise: Failure of systolic BP to increase ≥20 mmHg above baseline during treadmill exercise stress test; reflects severely limited cardiac output reserve
  6. Non-sustained VT (NSVT) on ambulatory monitoring: ≥3 consecutive ventricular beats at ≥120 bpm; marker of arrhythmic substrate
  7. Extensive late gadolinium enhancement on CMR (>15% of LV mass): Quantifies fibrosis extent; now incorporated into formal risk models; Class IIa recommendation for ICD
  8. LV apical aneurysm: Even small apical aneurysms are associated with monomorphic VT circuits and SCD; Class IIa ICD indication
  9. Ejection fraction <50% (burnt-out/end-stage HCM): Transition to dilated phenotype with systolic dysfunction; managed similarly to DCM (ICD for EF ≤35%)

HCM Risk-SCD Calculator

The European HCM Risk-SCD calculator (Spirito, O'Mahony et al.) generates a 5-year SCD risk score using: age, max LV wall thickness, LA diameter, LVOTO gradient, family history of SCD, NSVT on Holter, and history of unexplained syncope. A 5-year risk score ≥6% supports ICD implantation in the European guidelines, though the 2022 US guideline uses a broader multifactorial assessment rather than a strict numerical cutoff.

ICD Implantation

Activity Restriction

Patients with HCM should avoid competitive, high-intensity endurance sports. The 2022 AHA/ACC guideline endorses shared decision-making for moderate recreational exercise (Class IIa), recognizing that some patients can safely exercise at moderate intensity. Dehydration and extreme exertion remain particularly dangerous.

Back to Table of Contents

8. Medical Treatment

Medical management targets symptom relief in obstructive HCM and arrhythmia prevention. Currently, no proven medication reduces SCD or halts disease progression in asymptomatic patients (except mavacamten for obstruction-related symptoms).

Symptomatic Non-Obstructive HCM

Beta-blockers (metoprolol succinate, atenolol) or verapamil for symptom control; no proven mortality benefit in this subset. Address diastolic dysfunction with adequate heart rate control and avoidance of tachycardia.

Symptomatic Obstructive HCM (LVOTO ≥30 mmHg resting or ≥50 mmHg provoked)

Drugs to Avoid in Obstructive HCM

Atrial Fibrillation Management in HCM

AF is particularly dangerous in HCM: loss of the atrial kick into a stiff ventricle sharply reduces cardiac output, tachycardia worsens LVOTO, and LA stasis markedly increases stroke risk.

Back to Table of Contents

9. Septal Reduction Therapy

Septal reduction therapy (SRT) is indicated for patients with drug-refractory obstructive HCM (LVOTO gradient ≥50 mmHg at rest or with provocation) who remain in NYHA Class III–IV or have recurrent exertional syncope despite maximally tolerated medical therapy (including mavacamten trials at experienced centers).

Surgical Septal Myectomy (Morrow Procedure)

The gold standard for septal reduction at experienced HCM centers (≥50–100 procedures/year). The operation involves direct surgical resection of the thickened basal interventricular septum through a transaortic incision — creating a wider LVOT and eliminating the Venturi mechanism driving SAM.

Alcohol Septal Ablation (ASA)

A percutaneous catheterization-based alternative introduced by Sigwart in 1994. Under echo guidance, 1–3 mL of absolute alcohol is injected into the first (occasionally second) septal perforating branch of the left anterior descending artery. This creates a controlled myocardial infarction in the proximal septum — the scar contracts and thins over 3–6 months, widening the LVOT.

Myectomy vs. ASA

Both procedures achieve similar intermediate-term outcomes for gradient relief and symptom improvement in appropriately selected patients. Myectomy is generally preferred in younger patients and at high-volume HCM centers of excellence. The 2022 AHA/ACC guideline recommends referral to centers with multidisciplinary HCM expertise before SRT.

Back to Table of Contents

10. Mavacamten and Novel Therapies

Mavacamten (Camzyos) — First Cardiac Myosin Inhibitor

FDA-approved in April 2022, mavacamten represents the first disease-targeted pharmacological therapy for obstructive HCM and a paradigm shift in management.

Mechanism: Mavacamten selectively and reversibly inhibits cardiac myosin ATPase activity, shifting the equilibrium of myosin heads from the force-generating "disordered relaxed" state to the energy-conserving "super-relaxed" state. This directly reduces excessive actin-myosin cross-bridge formation → decreases LV contractility and stiffness → reduces LVOTO gradient and improves diastolic function — without the non-specific negative inotropic effects of beta-blockers or verapamil.

EXPLORER-HCM trial (N Engl J Med 2020, PMID 32706 — landmark phase III RCT): In 251 patients with symptomatic obstructive HCM, mavacamten vs. placebo at 30 weeks. Primary composite endpoint (≥1.5-step NYHA improvement OR ≥3.0 mL/kg/min increase in peak VO₂ + ≥1-step NYHA improvement): 37% mavacamten vs. 17% placebo (P<0.001). Post-exercise LVOTO gradient reduced by 47 mmHg vs. 10 mmHg.

VALOR-HCM trial (JAMA 2022): Patients who already met guideline criteria for SRT were randomized. After 16 weeks, only 17.9% of mavacamten patients still met SRT criteria vs. 76.8% on placebo (P<0.001). Mavacamten effectively deferred the need for invasive intervention in the majority of drug-refractory obstructive HCM patients.

Dosing and monitoring (REMS program required): Starting dose 2.5–5 mg/day; titrated to 10–15 mg based on LVOT gradient and LVEF. Echocardiographic LVEF monitoring is mandatory (weekly initially, then every 4–12 weeks): hold mavacamten if LVEF falls below 50% (risk of systolic dysfunction from excess negative inotropy). Half-life ~9 days — effects resolve over 4–6 weeks after discontinuation. Avoid strong CYP2C19 inhibitors (fluconazole, fluvoxamine) and inducers (rifampin) which alter drug levels significantly.

Aficamten — Next-Generation Cardiac Myosin Inhibitor

Aficamten has the same mechanism as mavacamten (cardiac myosin inhibitor) but a significantly shorter half-life (~3 days), enabling faster dose adjustment and more responsive LVEF monitoring — potentially a safer profile for clinical use.

SEQUOIA-HCM trial (2024, PMID 38739): 28-week phase III RCT in 282 patients with symptomatic obstructive HCM. Primary endpoint (change in peak VO₂): aficamten +1.8 mL/kg/min vs. placebo −0.0 mL/kg/min (P<0.001). LVOTO gradient reduced by 43 mmHg. NYHA class improvement and KCCQ scores significantly improved. FDA approval anticipated.

Gene Therapy (Investigational)

AAV-based gene therapy vectors delivering corrective or silencing constructs targeting MYBPC3 and MYH7 are in early preclinical stages. CRISPR base editing for specific point mutations (e.g., common founder mutations in MYBPC3) has shown efficacy in mouse models. Long-term safety and delivery efficiency to adult cardiomyocytes remain major hurdles. Clinical trials are years away for HCM specifically.

Back to Table of Contents

11. Complications and Prognosis

Major Complications

Prognosis

With modern management, the prognosis of HCM has improved dramatically:

Back to Table of Contents

12. Research Papers

The following PubMed topic searches return current peer-reviewed literature relevant to hypertrophic cardiomyopathy. Each link opens a live PubMed query.

Back to Table of Contents

Connections

Back to Table of Contents