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. Key Research Papers
13. Connections
14. Featured Videos

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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 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy (updated in 2024) 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.

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2. Epidemiology

• Prevalence: 1 in 200–500 globally (0.2–0.5%); affects all ethnicities equally
• US burden: Approximately 600,000–750,000 Americans affected; prevalence may be underestimated due to asymptomatic cases
• Leading cause of SCD in athletes: Most common cause of sudden cardiac death in competitive athletes under 35 years in the United States (accounts for approximately 36% of SCD in young competitive athletes)
• Normal life expectancy: More than 90% of patients have a normal or near-normal life expectancy with appropriate modern management, including ICD when indicated
• Sex differences: Male predominance for symptomatic obstructive disease; women are more commonly affected by non-obstructive HCM and tend to present later with more advanced symptoms despite similar structural disease
• Underdiagnosis: Many cases are identified incidentally on electrocardiogram (ECG) or echocardiography ordered for other reasons; family screening programs identify preclinical disease before symptoms develop
• Age of presentation: Can manifest at any age from infancy to elderly; peak clinical presentation in the third to fifth decades; MYBPC3 mutations often produce a later-onset, more attenuated phenotype

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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 adenosine triphosphate (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

• Myocyte hypertrophy: Enlarged cardiomyocytes with bizarre shapes
• Myofibrillar disarray: Loss of the normal parallel sarcomere arrangement; disorganized interlocking whorls of cardiomyocytes (hallmark histologic feature)
• Interstitial fibrosis: Collagen deposition impairing electrical conduction and creating substrate for ventricular arrhythmias

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:

• Further obstructs the LVOT (dynamic obstruction — worsens with tachycardia, dehydration, standing, Valsalva)
• Prevents normal mitral valve coaptation → posterior mitral regurgitation

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

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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

• MYBPC3 (myosin-binding protein C): 40–50% of cases; the single most common gene; variants often produce a late-onset, milder phenotype with incomplete penetrance before age 50
• MYH7 (beta-myosin heavy chain): 35–40% of cases; typically causes earlier-onset, more severe hypertrophy; higher penetrance
• Other sarcomere genes: TNNI3 (troponin I), TNNT2 (troponin T), TPM1 (tropomyosin), MYL2 and MYL3 (myosin light chains), ACTC1 (cardiac actin), PLN (phospholamban) — together account for ~5–10%
• Double/compound variants: Two sarcomere mutations in the same patient → more severe phenotype, earlier onset, higher SCD risk

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

• Noonan syndrome (PTPN11, RAF1, KRAS mutations): Most common RASopathy causing HCM phenotype; childhood onset; associated with pulmonary stenosis, short stature, facial dysmorphia
• LEOPARD syndrome (PTPN11): Similar to Noonan with lentigines + hypertrophic cardiomyopathy
• Danon disease (LAMP2 — X-linked): Massive LVH (often wall thickness >30–40 mm), Wolff-Parkinson-White, skeletal myopathy, intellectual disability; devastating prognosis without transplantation
• Pompe disease (GAA — glycogen storage disease type II): Infantile form causes extreme LVH; enzyme replacement therapy available
• Fabry disease (GLA — X-linked): Alpha-galactosidase A deficiency; mimics non-obstructive HCM; treatable with enzyme replacement; screen with alpha-Gal A activity in suspected cases
• Friedrich's ataxia (FXN — frataxin): Progressive spinocerebellar degeneration + HCM; anticipation of neurological decline

Genetic Counseling and Family Screening

The 2020 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.

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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 electrocardiogram or echocardiography without ever having symptoms.

Symptoms

• Exertional dyspnea (most common): Results from diastolic dysfunction (stiff, non-compliant ventricle), elevated filling pressures, and reduced cardiac output during exercise — especially with LVOTO
• Chest pain: Demand ischemia from a combination of increased myocardial oxygen demand (hypertrophied muscle), microvascular dysfunction, and reduced coronary flow reserve (from abnormal intramural coronary arteries with medial hypertrophy) — even without epicardial coronary artery disease
• Syncope and presyncope: Exertional syncope is a particularly high-risk warning sign for SCD; caused by sudden drop in cardiac output with exercise (fixed or dynamic LVOTO) or exercise-triggered ventricular arrhythmias. Non-exertional syncope can also occur (vasovagal, arrhythmic)
• Palpitations: Atrial fibrillation (20–25% lifetime prevalence in HCM), premature ventricular contractions, non-sustained VT
• Fatigue: From reduced exercise capacity and diastolic impairment

Physical Examination with LVOTO

• Bisferiens carotid pulse ("spike-and-dome" or double-peaked pulse): Reflects the initial rapid ejection through the LVOT followed by the sudden obstruction when SAM occurs during mid-systole — a distinctive finding essentially pathognomonic for HCM with LVOTO
• Systolic ejection murmur: Harsh crescendo-decrescendo murmur heard best at the left lower sternal border and apex; caused by LVOTO turbulence
• Dynamic maneuver responses — the key bedside differentiator from aortic stenosis (AS):
  • Valsalva maneuver (straining phase) and standing from squatting: ↓preload → ↑LVOTO gradient → murmur gets LOUDER (HCM murmur increases with Valsalva; AS murmur decreases)
  • Squatting, passive leg raise, handgrip: ↑preload → ↓LVOTO gradient → murmur gets SOFTER (opposite to AS)
• Holosystolic apical murmur: From SAM-related posterior mitral regurgitation; distinct from the outflow murmur
• Sustained and displaced PMI: Reflects massive LV hypertrophy
• Double apical impulse: The forceful atrial kick into the stiff LV produces a palpable presystolic impulse (equivalent to an audible S4 gallop on auscultation)
• S4 gallop: Reflects vigorous atrial contraction against a stiff, non-compliant ventricle

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6. Diagnosis

Electrocardiography

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

• LVH voltage criteria (Sokolow-Lyon, Cornell): Reflect massive wall thickness
• Deep, narrow (septal) Q waves in leads I, aVL, V5, V6: From the abnormally thickened septum depolarizing first; can mimic old lateral or inferior myocardial infarction (MI) (pseudo-infarction pattern)
• Diffuse ST-T wave changes and deep T-wave inversions throughout
• Apical HCM (Yamaguchi variant): Giant negative T waves (≥10 mm depth) in precordial leads V3–V5; characteristic pattern; often normal or mild overall QRS voltage
• Left atrial enlargement (P-wave changes in lead II and V1)
• Wolff-Parkinson-White pattern (delta waves, short PR): Suggests Danon disease or PRKAG2 mutation — important to identify

Echocardiography (Primary Diagnostic Modality)

• LV wall thickness ≥15 mm (or ≥13 mm with first-degree family history of HCM or confirmed sarcomere gene variant) in any segment — asymmetric pattern, typically maximal at the basal interventricular septum
• LVOTO gradient: ≥30 mmHg at rest (obstructive HCM resting); ≥50 mmHg with provocation (Valsalva, exercise, amyl nitrite) in provokable HCM; dynamic character (gradient changes with loading conditions)
• Systolic anterior motion (SAM) of the anterior mitral valve leaflet on M-mode and 2D echo
• Mitral regurgitation: Posterior/eccentric jet from SAM-caused incomplete coaptation
• Diastolic dysfunction: Impaired relaxation (Grade I–III), elevated E/e' ratio, LA enlargement
• Apical HCM: Near-obliteration of the LV apex at end-systole; "ace of spades" or "spade-shaped" LV cavity on LV contrast ventriculography

Cardiac MRI (CMR)

CMR is the gold standard for:

• Wall thickness quantification: Superior to echo for apical HCM, anterolateral wall, and areas difficult to image with ultrasound
• Late gadolinium enhancement (LGE): Identifies myocardial fibrosis; patchy LGE at sites of maximal hypertrophy predicts SCD risk. LGE >15% of LV mass is a major SCD risk factor. Apical aneurysm identification is critical (missed by echo in ~25% of cases)
• LV apical aneurysm detection: Associated with high risk of VT, thromboembolism, and SCD
• Phenotype characterization: Distinguishes HCM from HCM phenocopies (e.g., cardiac amyloid, Fabry disease, athlete's heart)

Genetic Testing

Recommended for all patients with HCM (Class IIa recommendation, 2020 AHA/ACC). Identifies the causative variant in 40–60% of patients. A positive result:

• Enables cascade genetic testing of first-degree relatives (can identify disease before echocardiographic expression)
• Identifies high-risk mutations (double variants, Danon/LAMP2, PLN) and syndromic causes requiring different management
• Guides prognosis counseling

Additional Testing

• 48-hour Holter monitor: Documents non-sustained VT (NSVT — an SCD risk factor); identifies paroxysmal atrial fibrillation (AF)
• Exercise stress echocardiography: Unmasks provokable LVOTO; assesses blood pressure response (blunted or hypotensive blood pressure (BP) response = SCD risk factor); evaluates functional capacity; guides exercise restriction counseling
• Implantable loop recorder: For unexplained syncope without documented arrhythmia on short-term monitoring
• Serum NT-proBNP: Correlates with LVOTO gradient and symptom severity; useful for monitoring treatment response

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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 (2020 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 blood pressure 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

• Secondary prevention (Class I): Prior cardiac arrest or documented sustained VT/VF
• Primary prevention (Class IIa): One or more major SCD risk factors (shared decision-making discussion incorporating patient age, comorbidities, values, and impact on quality of life)
• Subcutaneous ICD (S-ICD): Preferred in younger patients when pacing is not needed; avoids transvenous leads, preserving venous access for decades; appropriate if no LVOTO requiring pacing therapy
• Transvenous ICD: Required when ATP (anti-tachycardia pacing), CRT, or dual-chamber pacing (septal myectomy, permanent pacing for septal ablation-related heart block) is needed
• Annual reassessment: SCD risk factors and ICD indication should be formally reassessed at least annually

Activity Restriction

Patients with HCM should avoid competitive, high-intensity endurance sports. The 2020 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.

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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)

• Beta-blockers (first-line): Metoprolol succinate (target 100–200 mg/day), atenolol, or propranolol. Mechanism: reduce heart rate → prolong diastolic filling time → reduce LV contractility → lower LVOTO gradient. Start low and titrate to symptom relief and heart rate 55–65 bpm. Avoid abrupt discontinuation (rebound tachycardia and gradient worsening).
• Non-dihydropyridine calcium channel blockers (second-line): Verapamil (360–480 mg/day in divided doses). Negative inotropic and chronotropic effects reduce gradient. Important caution: avoid verapamil in severe LVOTO (gradient >100 mmHg) with low blood pressure — vasodilatory effect can cause acute hemodynamic collapse. Diltiazem is an alternative.
• Disopyramide (Class IA antiarrhythmic): A powerful negative inotrope uniquely useful in HCM; reduces LVOTO gradient by 50% or more. Dosing: 100–300 mg extended-release twice daily. Always combine with a beta-blocker or verapamil (disopyramide increases AV nodal conduction, which beta-blockers/verapamil counteract to prevent rapid ventricular response if atrial fibrillation develops). Side effects: Anticholinergic effects — dry mouth, urinary retention (particularly in men with prostatic hypertrophy), constipation, blurred vision, cognitive effects; QT prolongation (monitor QTc — hold if QTc >500 ms). The extended-release formulation (Norpace CR) improves tolerability.
• Mavacamten (first-in-class cardiac myosin inhibitor): See Section 10 for detailed discussion.

Drugs to Avoid in Obstructive HCM

• Vasodilators (nitrates, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), dihydropyridine CCBs such as amlodipine, nifedipine): Reduce afterload and preload → exacerbate LVOTO → can cause acute hemodynamic deterioration
• Digoxin: Positive inotrope → increases LV contractility → worsens LVOTO; also proarrhythmic; avoid in obstructive HCM
• High-dose diuretics: Excessive diuresis reduces preload → worsens LVOTO
• Dehydration, alcohol excess, extreme heat: Environmental triggers that acutely worsen LVOTO by reducing preload

Atrial Fibrillation Management in HCM

Atrial fibrillation 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.

• Anticoagulation for ALL HCM patients with atrial fibrillation — regardless of CHA₂DS₂-VASc score (Class I recommendation). The inherent risk of stroke in HCM with atrial fibrillation is high enough to mandate anticoagulation regardless of other factors.
• Rhythm control preferred over rate control: Given poor tolerance of atrial fibrillation. Beta-blockers and verapamil for rate control; antiarrhythmics (amiodarone, sotalol) for rhythm maintenance.
• Catheter ablation: For symptomatic refractory atrial fibrillation; moderate success rates (60–70% freedom from atrial fibrillation at 1 year); LA fibrosis in HCM reduces success compared to non-HCM atrial fibrillation ablation.

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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.

• Outcomes: 90–95% relief of resting LVOTO; operative mortality <0.5–1% at high-volume centers (comparable to routine cardiac surgery); durable results lasting decades
• Concomitant procedures: Papillary muscle mobilization for anomalous insertion, mitral valve repair or replacement for intrinsic MV disease contributing to obstruction, atrial fibrillation ablation/Maze procedure for coexisting atrial fibrillation
• Preferred for: Younger patients (decades of benefit), complex anatomy (anomalous papillary muscles, mid-cavity obstruction), concomitant atrial fibrillation ablation, failure of prior ASA, intrinsic mitral valve pathology
• Post-myectomy: New LBBB (common, usually benign); occasional complete heart block requiring permanent pacemaker (2–5%)

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.

• Outcomes: 85–90% gradient reduction at 3–6 months; requires repeat echo follow-up to confirm effect; repeat ablation needed in ~15% of cases
• Periprocedural complications:
  • Complete heart block requiring permanent pacemaker: 10–20% (most significant complication; occurs because septal branches supply the AV node and His bundle in many patients)
  • New LBBB: ~50% of cases
  • Small procedural myocardial infarction: intentional, but affects myocardial scar burden
  • VT from infarct scar: theoretical late risk; not confirmed in long-term studies but theoretically higher than myectomy scar
• Preferred for: Elderly patients or those with significant surgical comorbidities; suitable coronary anatomy (accessible first septal perforator supplying the target area, confirmed by echo contrast opacification)
• Not suitable for: Complex anatomy, anomalous papillary muscles, intrinsic MV disease, very young patients (decades of scar ahead), failed echo contrast guidance

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 2020 AHA/ACC guideline recommends referral to centers with multidisciplinary HCM expertise before SRT.

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10. Mavacamten and Novel Therapies

Mavacamten (Camzyos) — First Cardiac Myosin Inhibitor

U.S. Food and Drug Administration-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 (Lancet 2020, PMID 32871100 — 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 (J Am Coll Cardiol 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 (N Engl J Med 2024, PMID 38739079): 24-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. U.S. Food and Drug Administration (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.

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11. Complications and Prognosis

Major Complications

• Sudden cardiac death (SCD): The most feared complication; underlying mechanism is ventricular fibrillation or polymorphic VT; most common in young athletes and young adults; ICD implantation has dramatically reduced SCD rates in high-risk HCM
• Heart failure (burnt-out HCM): Approximately 5% of HCM patients over a lifetime transition to an end-stage dilated phenotype with LV dilation and EF <50%; managed as HFrEF with GDMT; may require transplantation
• Atrial fibrillation: 20–25% lifetime risk; often the precipitant of symptomatic decompensation in HCM; increases stroke risk substantially (Class I anticoagulation indication regardless of CHA₂DS₂-VASc)
• Stroke and systemic embolism: atrial fibrillation-related LA thrombus or in situ LA stasis in enlarged, poorly contracting LA; anticoagulation is essential
• Progressive mitral regurgitation: SAM-related MR can worsen over time; severe MR may require MV repair at time of myectomy
• Acute LVOTO exacerbation: Triggered by dehydration, hemorrhage, vasodilators, tachycardia; can cause acute hemodynamic collapse — treat with intravenous (IV) fluids, phenylephrine (vasopressor), beta-blockers; avoid nitrates/dobutamine
• Infective endocarditis: Rare but recognized complication; predominantly affects the anterior mitral leaflet (point of SAM contact with septum) or the LVOT endocardium

Prognosis

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

• Annual mortality: Approximately 0.5–1% in contemporary cohorts (down from the historical 2–4% from older referral-center series that over-represented severe cases)
• Most patients: Normal or near-normal life expectancy; the majority never require SRT or ICD
• SCD reduction: ICD implantation in high-risk patients has reduced SCD as a cause of HCM-related death by approximately 60–70%
• Predictors of worse prognosis: Extensive CMR LGE (>15% LV mass), LVEF <50%, LV apical aneurysm, NSVT, severe symptoms (NYHA III–IV), massive hypertrophy (≥30 mm), double sarcomere mutations, syndromic HCM (Danon, Noonan)
• Sex disparity: Women with HCM have more symptoms and worse functional status despite similar wall thickness; often present later and are less frequently referred for advanced therapies — an important equity issue in HCM care
• Pregnancy: Most women with HCM tolerate pregnancy well; avoid vasodilators; continue beta-blockers (safe in pregnancy); obstructive HCM with severe symptoms is high-risk — cardiology co-management throughout

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Key Research Papers

1. Ommen SR, Ho CY, Asif IM, et al. (2024). 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation — PubMed PMID: 38718139
2. Semsarian C, Ingles J, Maron MS, et al. (2015). New perspectives on the prevalence of hypertrophic cardiomyopathy. Journal of the American College of Cardiology — PubMed PMID: 25814232
3. Maron BJ, Doerer JJ, Haas TS, et al. (2009). Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation — PubMed PMID: 19221222
4. Maron MS, Olivotto I, Betocchi S, et al. (2003). Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. The New England Journal of Medicine — PubMed PMID: 12540642
5. O'Mahony C, Jichi F, Pavlou M, et al. (2014). A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). European Heart Journal — PubMed PMID: 24126876
6. Olivotto I, Oreziak A, Barriales-Villa R, et al. (2020). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) — PubMed PMID: 32871100
7. Desai MY, Owens A, Geske JB, et al. (2022). Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. Journal of the American College of Cardiology — PubMed PMID: 35798455
8. Maron MS, Masri A, Nassif ME, et al. (2024). Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. The New England Journal of Medicine — PubMed PMID: 38739079

PubMed Topic Searches

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

1. PubMed: Hypertrophic cardiomyopathy
2. PubMed: HCM SCD risk stratification
3. PubMed: Mavacamten EXPLORER-HCM
4. PubMed: HCM septal myectomy
5. PubMed: Alcohol septal ablation
6. PubMed: Hypertrophic cardiomyopathy genetics
7. PubMed: MYBPC3 MYH7 mutations
8. PubMed: HCM atrial fibrillation
9. PubMed: HCM ICD prevention
10. PubMed: HCM cardiac MRI
11. PubMed: HCM guidelines 2022
12. PubMed: HCM treatment outcomes

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Connections

• Cardiology
• Cardiomyopathy
• Valvular Heart Disease
• Aortic Stenosis
• Arrhythmia
• Heart Failure
• Atrial Fibrillation
• Long QT Syndrome
• Myocarditis
• Hypertension
• Chest Pain
• Shortness of Breath
• Heart Palpitations
• Magnesium
• Omega-3 Fatty Acids

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