Hypertrophic Cardiomyopathy

• Sarcomeric Protein Dysfunction and Abnormal Calcium Handling: Mutations in genes encoding thick filament proteins (β-myosin heavy chain, myosin-binding protein C, regulatory light chain) or thin filament proteins (cardiac troponin T and I, α-tropomyosin, α-actin) result in abnormal protein-protein interactions and impaired force generation. These mutations trigger several molecular consequences: (1) increased myofilament calcium sensitivity, causing enhanced contractility at normal intracellular calcium levels; (2) abnormal sarcomeric organization with disrupted Z-disc structure; (3) activation of fetal gene programs; and (4) altered metabolic function with increased oxygen consumption. The net effect is cardiomyocytes that are hypercontractile and prone to dysrhythmia generation. Abnormal calcium cycling between the sarcoplasmic reticulum and cytoplasm, combined with impaired calcium buffering capacity, creates a milieu favorable for triggered arrhythmias and afterdepolarizations.

• Progressive Hypertrophy and Diastolic Dysfunction: The genetic defect initiates a pathologic remodeling process. Increased myofilament calcium sensitivity and abnormal mechanical stress sensing by sarcomeric proteins activate intracellular signaling cascades (phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase pathways) that promote myocyte growth and proliferation. This results in concentric or asymmetric LVH that occurs independent of external hemodynamic load—distinguishing HCM from secondary hypertrophy. The hypertrophied myocardium exhibits markedly increased stiffness due to: (1) increased collagen deposition and myocardial fibrosis with abnormal collagen cross-linking; (2) enlarged cardiomyocytes with disorganized sarcomeric architecture (myofibrillar disarray); and (3) increased interstitial edema. These changes impair active relaxation and increase passive stiffness, leading to diastolic dysfunction that precedes systolic dysfunction. On the pressure-volume relationship, the left ventricle operates on a steep, leftward-shifted curve, meaning minimal volume changes produce large pressure increments—this explains the exertional dyspnea even with normal or hyperdynamic systolic function.

• **Left Ventricular Outflow Tract Obstruction (Dynamic): The anatomic substrate for obstruction is asymmetric hypertrophy preferentially involving the interventricular septum, often with septal bulging into the LVOT. During systole, the anterior mitral leaflet is pushed anteriorly against the septum by Bernoulli forces (the systolic flow jet creates negative pressure that draws the leaflet forward) and by the geometric distortion caused by septal hypertrophy. This dynamic obstruction is load-dependent: decreased preload (Valsalva maneuver, standing, diuretics) increases obstruction, while increased afterload (squatting, handgrip) decreases it. The obstruction results in: (1) elevated LV systolic pressures (LV-to-aortic pressure gradient can exceed 100 mmHg); (2) prolonged ejection time; (3) turbulent, high-velocity flow that creates a characteristic systolic murmur; and (4) systolic anterior motion (SAM) of the mitral valve. Chronic obstruction causes mitral regurgitation as the leaflet fails to coapt properly. The elevated LV pressures increase myocardial oxygen demand and impair coronary perfusion (reduced diastolic pressure gradient across the aortic valve), predisposing to myocardial ischemia even with normal epicardial coronary arteries. Importantly, ~30% of HCM patients do not have a significant resting LVOT gradient (non-obstructive HCM); some develop gradients only with provocation (latent obstruction).

• Arrhythmia Substrate and Electrophysiologic Abnormalities: The combination of myofibrillar disarray, increased fibrosis, calcium handling defects, and abnormal impulse propagation creates a highly arrhythmogenic substrate. Myofibrillar disarray—seen pathologically as chaotic, whorled arrangements of myocytes—causes conduction slowing and unidirectional block, facilitating reentry circuits. Increased intracellular calcium and enhanced automaticity of Purkinje fibers and myocytes promote triggered activity (early and delayed afterdepolarizations). Fibrosis creates anatomic obstacles to conduction and zones of slow conduction. The autonomic nervous system is also dysregulated in HCM, with evidence of sympathetic hyperactivity and parasympathetic withdrawal. Together, these abnormalities explain the high burden of supraventricular and ventricular arrhythmias in HCM, including atrial fibrillation and ventricular fibrillation.

• Microvascular Ischemia: Beyond obstruction, HCM patients experience microvascular ischemia due to: (1) increased myocardial mass and oxygen demand; (2) reduced capillary density (capillary-to-fiber ratio is decreased); (3) medial hypertrophy of intramural coronary arteries, reducing their capacity; and (4) increased LV diastolic pressures that compress vessels during diastole. Positron emission tomography studies demonstrate regional perfusion defects. Chronic ischemia promotes fibrosis and myocyte death, contributing to progressive dysfunction and arrhythmia risk.

• Sarcomeric Gene Mutations (Primary HCM): Autosomal dominant inheritance accounts for ~50% of familial disease; de novo mutations account for ~25% of cases. β-myosin heavy chain (MYH7) mutations are found in ~40% of genotyped HCM patients and are associated with variable severity; some variants correlate with early-onset, malignant disease. Cardiac myosin-binding protein C (MYBPC3) mutations account for ~40% of cases and often present later in life with better overall prognosis but can still cause SCD. Cardiac troponin T (TNNT2) mutations (~10%) and α-tropomyosin (TPM1) mutations are rare but often associated with severe phenotypes and high arrhythmia risk. Other genes implicated include regulatory and essential light chain genes (MYL2, MYL3), α-actin (ACTC1), and titin (TTN). Gene mutations can be identified in 50-60% of HCM patients using contemporary genetic testing, though the clinical significance of variants of uncertain significance remains to be determined.

• Age and Penetrance: HCM exhibits age-dependent penetrance and expressivity; hypertrophy may not manifest until late childhood, adolescence, or early adulthood in genotype-positive individuals. Penetrance by adulthood is ~95% but varies by specific mutation. Younger patients and those with certain mutations (particularly β-myosin heavy chain variants p.Arg403Gln and p.Arg719Trp) tend to have more severe phenotypes with earlier symptom onset.

• Secondary Causes (Phenocopy HCM): Storage and infiltrative diseases can mimic HCM: (1) Friedreich's ataxia causes LVH with a characteristic restrictive physiology; (2) Amyloidosis (particularly transthyretin variants) produces LVH with restrictive filling and conduction abnormalities; (3) Fabry disease (α-galactosidase A deficiency) results in LVH and can present with chest pain and arrhythmias; (4) Anderson-Fabry disease specifically causes a distinctive HCM phenotype with diastolic dysfunction. These conditions are distinguished by additional systemic manifestations, specific imaging features, and genetic/biochemical testing.

• Metabolic and Endocrine Risk Factors: While HCM is primarily genetic, metabolic stress may unmask latent disease or modify expression. Thyroid disease, acromegaly, and pheochromocytoma can transiently increase LVH or precipitate symptoms; however, these conditions present with other clinical features distinguishing them from primary HCM.

• Dyspnea and Exercise Limitation (Most Common Symptom): Exertional dyspnea is the hallmark symptom, occurring in 50-90% of symptomatic patients. The mechanism is multifactorial: (1) diastolic dysfunction with elevated LV end-diastolic pressures elevates pulmonary venous pressure; (2) dynamic LVOT obstruction increases afterload and reduces cardiac output response to exercise; (3) myocardial ischemia triggers reflex sympathetic activation and peripheral vasoconstriction; and (4) atrial fibrillation (present in 5-10% of HCM patients) further impairs diastolic filling. Patients often report they can exercise briefly but experience rapid onset of breathlessness with continued exertion. Orthopnea and paroxysmal nocturnal dyspnea indicate advanced diastolic dysfunction.

• Chest Pain: Typical or atypical chest pain occurs in 15-30% of patients, often exertional and substernal but without the classic pattern of angina. The mechanism is demand ischemia due to (1) increased myocardial oxygen consumption from hypertrophy and hypercontractility; (2) microvascular ischemia; and (3) possible epicardial coronary artery disease superimposed on HCM. Importantly, coronary angiography is typically normal or shows only minimal atherosclerosis, distinguishing HCM-related chest pain from atherosclerotic coronary disease. Chest pain in HCM is a marker of worse prognosis and higher arrhythmia risk.

• Syncope and Presyncope: Syncope occurs in 15-25% of symptomatic HCM patients and is a critical red flag for sudden cardiac death risk. The mechanisms include: (1) dynamic LVOT obstruction with exercise-induced hemodynamic collapse; (2) sudden-onset atrial fibrillation with rapid ventricular response reducing cardiac output; (3) ventricular arrhythmias (nonsustained ventricular tachycardia [NSVT] or ventricular fibrillation); (4) inadequate blood pressure response to exercise due to blunted vasodilation in the setting of fixed cardiac output; and (5) abnormal baroreceptor reflex (paradoxical vasodilation and bradycardia with LV pressure elevation). Exertional syncope is particularly concerning and warrants aggressive risk stratification and therapeutic intervention.

• Palpitations: Palpitations may represent sinus tachycardia during exertion, frequent premature atrial or ventricular contractions, or sustained arrhythmias (atrial fibrillation or ventricular tachycardia). The prevalence of atrial fibrillation increases with age and disease severity, and its development significantly worsens outcomes due to loss of atrial contribution to LV filling and thromboembolic risk.

• Fatigue: Some patients report generalized fatigue disproportionate to symptoms, likely reflecting chronically elevated catecholamine levels and poor exercise capacity.

• Asymptomatic Presentation: 25-50% of HCM patients are asymptomatic at diagnosis, discovered through screening (family screening, incidental imaging, or evaluation for murmur). Asymptomatic patients have a better initial prognosis than symptomatic ones, though long-term outcomes depend on risk stratification findings.

Physical Examination Findings

• Systolic Murmur: The classic finding is a mid-to-late systolic ejection murmur at the left lower sternal border that increases with Valsalva maneuver, standing, and amyl nitrite (decreased preload/increased obstruction) and decreases with squatting and handgrip exercise (increased afterload/decreased obstruction). This dynamic nature distinguishes it from the fixed systolic murmur of aortic stenosis. The murmur is absent in non-obstructive HCM. The intensity and timing correlate with the severity of the gradient.

• Carotid Upstroke: A brisk, bifid (double-peaked) carotid pulse may be present, reflecting the rapid early ejection before obstruction develops in mid-systole.

• Fourth Heart Sound (S₄): An audible S₄ is common, reflecting atrial contraction against a stiff LV during late diastole.

• Systolic Anterior Motion (SAM): While not palpable, SAM of the anterior mitral leaflet can sometimes produce a midsystolic click that precedes the murmur.

• Other Findings: Hyperdynamic precordium, displaced apex beat (if significant LVH), signs of heart failure or atrial fibrillation if advanced disease present.

Important Clinical Variants

• Apical HCM: Hypertrophy predominantly involving the LV apex; may present with giant negative T waves on ECG and apical aneurysm formation; associated with better prognosis than septal HCM.

• Restrictive Phenotype: Severe diastolic dysfunction mimicking restrictive cardiomyopathy; associated with worse outcomes.

• End-Stage HCM: 5-10% of patients progress to an end-stage, dilated phenotype with LV dilation, systolic dysfunction, and poor prognosis; may clinically resemble dilated cardiomyopathy.

• 12-Lead Electrocardiography: Nearly 90% of HCM patients have abnormal ECGs, though findings are nonspecific. Classic patterns include: (1) deep, symmetric T-wave inversions in the precordial leads (especially V2-V4 or in apical HCM, V4-V6); (2) left ventricular hypertrophy with increased voltage (Sokolow-Lyon criteria, Cornell voltage); (3) left axis deviation; (4) prolonged PR interval (up to 50% of patients); (5) pathologic Q waves that mimic myocardial infarction, particularly in apical or lateral forms; (6) atrial fibrillation or signs of atrial enlargement (broad, bifid P waves); and (7) ventricular preexcitation in a minority of HCM patients with associated Wolf-Parkinson-White syndrome. The ECG pattern often correlates with the location of hypertrophy; apical HCM produces characteristic deep T-wave inversions in V4-V6. A completely normal ECG is rare in HCM (<5% of cases) and should prompt consideration of alternate diagnoses.

• Transthoracic Echocardiography: The gold-standard diagnostic test demonstrating the following characteristic findings: (1) left ventricular wall thickness ≥15 mm in the absence of hemodynamic burden (≥13 mm in women, relatives of affected individuals, or athletes) satisfies the diagnostic criterion for HCM; (2) asymmetric septal hypertrophy is most common; (3) systolic anterior motion (SAM) of the anterior mitral leaflet with septal contact during systole is a hallmark of obstructive HCM; (4) left ventricular outflow tract gradient measured by continuous-wave Doppler: gradients are classified as obstructive (≥30 mmHg at rest or with provocation) or non-obstructive (<30 mmHg); (5) diastolic dysfunction with reduced early (E wave

• IV volume expansion: normal saline restores LV cavity size and mechanically widens the LVOT.
• Pure alpha-1 agonist: phenylephrine raises afterload and reduces the Venturi effect on the mitral leaflet. Avoid norepinephrine's beta activity if a pure vasoconstrictor is available.
• Avoid: inotropes (dobutamine, digoxin), nitrates, dihydropyridine calcium channel blockers, ACEI/ARB, and aggressive diuresis — all worsen the gradient.

First-line pharmacotherapy (symptomatic obstructive HCM), per the 2024 AHA/ACC multisociety HCM guideline

• Non-vasodilating beta blockers: metoprolol. Negative inotropy blunts the systolic jet, and prolonged diastole improves filling of a stiff ventricle.
• Non-dihydropyridine calcium channel blockers: verapamil, if beta blockers fail or are not tolerated. Use cautiously — its vasodilatory effect can precipitate collapse in patients with very high gradients or resting hypotension.

Escalation

• Disopyramide: class IA antiarrhythmic used for its potent negative inotropy; added to a beta blocker. Watch QT prolongation and anticholinergic effects (dry mouth, urinary retention).
• Cardiac myosin inhibitors: mavacamten reduces actin–myosin cross-bridge formation and lowers gradients in symptomatic obstructive disease; requires REMS-mandated serial echocardiographic monitoring of LVEF and attention to CYP2C19 interactions.

• Surgical septal myectomy (Morrow procedure) at an experienced HCM center is preferred, particularly in younger patients or when concomitant mitral/papillary muscle surgery is needed.
• Alcohol septal ablation: for poor surgical candidates; risk of complete heart block.

Arrhythmia and adjunct care

• ICD: Class I for secondary prevention after cardiac arrest or sustained VT; primary prevention considered with massive hypertrophy, family history of SCD, unexplained syncope, NSVT, apical aneurysm, LV systolic dysfunction, or extensive late gadolinium enhancement.
• Anticoagulation (DOAC preferred) for HCM with atrial fibrillation irrespective of CHA₂DS₂-VASc score.
• End-stage ("burnt-out") HCM with EF <50%: standard HFrEF quadruple therapy — ARNI (or ACEI/ARB), beta blocker, MRA, and SGLT2 inhibitor — plus transplant evaluation.

Emergencies

• Sudden cardiac death: myofibrillar disarray and fibrosis create reentry; the terminal rhythm is ventricular fibrillation or pulseless VT. Signalled by exertional syncope, documented NSVT, or aborted arrest. Immediate defibrillation and ACLS; ICD thereafter.
• Rapid atrial fibrillation: loss of atrial kick in a non-compliant ventricle causes abrupt pulmonary edema or syncope. Look for irregularly irregular pulse with acute decompensation; cardiovert if hemodynamically unstable.
• Cardioembolic stroke: atrial myopathy plus AF; HCM confers thromboembolic risk out of proportion to conventional scores.
• Hemodynamic collapse after a vasodilator or diuretic: escalating gradient with hypotension after nitroglycerin given for presumed angina — a classic iatrogenic emergency.

Disease-related

• Progressive heart failure: diastolic dysfunction and microvascular ischemia; signalled by orthopnea, rising natriuretic peptides.
• End-stage systolic dysfunction: fibrotic replacement causes wall thinning, cavity dilation, and EF decline — heralded by paradoxical resolution of the murmur and gradient.
• Mitral regurgitation: SAM-related failure of leaflet coaptation produces a posteriorly directed jet; a holosystolic apical murmur radiating to the axilla accompanies the LVOT murmur.
• Apical aneurysm with mural thrombus: mid-cavity obstruction raises apical wall stress; found on CMR, and a source of VT and embolism.
• Infective endocarditis: the SAM jet damages the anterior mitral leaflet and septal endocardium, creating a nidus.

Treatment-related

• Complete heart block: alcohol septal ablation infarcts the septal conduction system (right bundle branch block is typical); myectomy more often produces left bundle branch block. Permanent pacemaker may be required.
• Ventricular septal defect or excessive infarct: rare complications of septal reduction; new harsh murmur with shunt physiology.
• Mavacamten-induced systolic dysfunction: excessive myosin inhibition drops LVEF, hence mandated serial echocardiography.
• Disopyramide toxicity: QT prolongation with torsades, plus anticholinergic urinary retention.
• ICD complications: inappropriate shocks, lead fracture, device infection.

• The maneuver question: anything that decreases preload or afterload (Valsalva strain, abrupt standing, nitrates) makes the murmur louder; squatting, passive leg raise, and handgrip make it softer. Mitral valve prolapse behaves the same way — the distinguishing feature is the midsystolic click, not the maneuver response.
• HCM versus aortic stenosis: HCM gives a brisk, bifid (pulsus bisferiens) carotid upstroke; AS gives pulsus parvus et tardus and radiates to the carotids. This is the single most tested discriminator.
• Young athlete who collapses during exertion, or a sibling who died suddenly: think HCM. The single best next step is transthoracic echocardiography (with ECG) — not stress testing, not angiography.
• First-degree relatives require screening with ECG and echocardiography, with periodic repeat because penetrance is age-dependent; genetic testing of the proband guides cascade testing. Autosomal dominant inheritance is the association examiners return to.
• Do not give: nitroglycerin, digoxin, dihydropyridines, or aggressive diuresis to a hypotensive obstructive HCM patient. The stem often presents "chest pain" and tempts you toward nitrates — the correct answer is IV fluids and phenylephrine.
• Apical HCM (Yamaguchi syndrome): giant symmetric precordial T-wave inversions with a spade-shaped LV cavity on imaging; more common in patients of Japanese descent and often mistaken for anterior ischemia.
• Secondary prevention ICD after aborted cardiac arrest or sustained VT is a Class I recommendation in the AHA/ACC HCM guideline — reflexively correct when the stem mentions prior resuscitated arrest.
• Common distractor: athlete's heart. Physiologic hypertrophy shows symmetric, mild wall thickening with a dilated LV cavity and normal-to-supranormal diastolic function that regresses with deconditioning; HCM shows asymmetric thickening with a small cavity and abnormal filling.