# Hypertrophic Cardiomyopathy

## Definition and Genetics

### Diagnostic Criteria

Hypertrophic cardiomyopathy is defined by a left ventricular wall thickness of 15 mm or greater in any myocardial segment, or 13 mm or greater when accompanied by a positive family history or genetic test result, that cannot be explained by abnormal loading conditions such as hypertension, aortic stenosis, or the physiologic hypertrophy of the athlete's heart. It is the most common inherited cardiomyopathy, with a prevalence estimated at 1 in 200 to 500 individuals. The inheritance pattern is autosomal dominant with variable expressivity and age-related penetrance, meaning that phenotypic expression may not develop until adolescence or young adulthood. This necessitates serial screening of gene-positive but phenotype-negative family members throughout the period of greatest risk.

### Sarcomeric Gene Mutations

The genetic basis of HCM is dominated by sarcomeric protein gene mutations. Beta-myosin heavy chain mutations account for 30 to 40% of genotype-positive cases and are often associated with early-onset disease and severe hypertrophy. Myosin-binding protein C mutations similarly represent 30 to 40% of cases but typically manifest later in life with incomplete penetrance, frequently presenting in adulthood. Troponin T mutations deserve special attention because they may produce minimal hypertrophy yet carry a high arrhythmia risk, constituting a "malignant" phenotype with relatively thin walls. Less common mutations involve troponin I, alpha-tropomyosin, myosin light chains, and actin.

Individuals who carry a pathogenic genotype but have not yet developed the phenotype demonstrate approximately a 5 to 10% annual conversion rate during the growth period of first-degree relatives. Screening with echocardiography and electrocardiography is recommended every 1 to 3 years beginning at age 10 to 12, or earlier if the individual is a competitive athlete. Genetic testing is recommended for all probands, with cascade screening of first-degree relatives.

### Phenocopies to Exclude

Several conditions can mimic HCM and must be systematically excluded because they have distinct treatment implications. Fabry disease, caused by alpha-galactosidase A deficiency and inherited in an X-linked pattern, produces concentric left ventricular hypertrophy with characteristically reduced global longitudinal strain in the basal inferolateral wall, renal insufficiency, and angiokeratomas. Diagnosis relies on enzyme assay and genetic testing, with treatment involving enzyme replacement or chaperone therapy with migalastat. Danon disease, resulting from LAMP2 mutation and also X-linked, causes massive LVH in young males along with Wolff-Parkinson-White pattern, intellectual disability, and skeletal myopathy. PRKAG2 syndrome involves glycogen storage with progressive conduction disease, WPW, and LVH. Cardiac amyloidosis, whether TTR or AL type, presents with concentric LVH, diastolic dysfunction, and reduced GLS with apical sparing, and can be screened with a Tc-99m PYP scan for ATTR. Noonan syndrome presents with short stature, dysmorphic facies, pulmonic stenosis, and biventricular hypertrophy.

| Phenocopy | Inheritance | Key Features | Diagnostic Clue | Treatment |
|---|---|---|---|---|
| Fabry Disease | X-linked | Concentric LVH, renal failure, angiokeratomas | Reduced GLS basal inferolateral; low T1 on CMR | Enzyme replacement, migalastat |
| Danon Disease | X-linked (LAMP2) | Massive LVH, WPW, intellectual disability | Young males, skeletal myopathy | Transplant consideration |
| PRKAG2 Syndrome | AD | LVH, WPW, progressive conduction disease | Glycogen storage | Pacemaker if needed |
| Cardiac Amyloidosis | Varies | Concentric LVH, diastolic dysfunction | GLS apical sparing; Tc-99m PYP for ATTR | Tafamidis (ATTR), chemotherapy (AL) |
| Noonan Syndrome | AD | Biventricular hypertrophy, pulmonic stenosis | Short stature, dysmorphic facies | Supportive |

## Pathophysiology

### Left Ventricular Outflow Tract Obstruction

Dynamic left ventricular outflow tract obstruction is present at rest or with provocation in approximately 70% of HCM patients, with a resting gradient of 30 mmHg or greater found in roughly 30%. The mechanism involves systolic anterior motion of the mitral valve anterior leaflet toward the hypertrophied septum, driven by Venturi effect and drag forces. This SAM simultaneously creates LVOT obstruction and mitral regurgitation, with the regurgitant jet directed posteriorly.

Provocative maneuvers that increase the gradient include the Valsalva maneuver, which reduces preload; standing, which also reduces preload; post-premature ventricular contraction beats, which increase contractility while reducing afterload; dehydration; exercise; and amyl nitrite inhalation. Maneuvers that decrease the gradient include squatting, which increases both preload and afterload; leg elevation; and phenylephrine administration, which increases afterload.

| Maneuver | Effect on Gradient | Mechanism |
|---|---|---|
| Valsalva | Increase | Reduced preload |
| Standing | Increase | Reduced preload |
| Post-PVC beat | Increase | Increased contractility, reduced afterload |
| Exercise | Increase | Increased contractility, reduced SVR |
| Amyl nitrite | Increase | Reduced afterload |
| Squatting | Decrease | Increased preload and afterload |
| Leg elevation | Decrease | Increased preload |
| Phenylephrine | Decrease | Increased afterload  |  A gradient of 30 mmHg or greater at rest or 50 mmHg or greater with provocation defines obstructive HCM and establishes the threshold for considering intervention. |

### Diastolic Dysfunction

Impaired relaxation resulting from myocardial disarray, fibrosis, and hypertrophy is a universal feature of HCM. Elevated left ventricular filling pressures produce exertional symptoms even in patients with non-obstructive HCM. Left atrial dilation and atrial fibrillation are common consequences, with a 25% lifetime risk of AF in this population.

### Myocardial Ischemia

Myocardial ischemia occurs in HCM despite normal epicardial coronary arteries, driven by several mechanisms. Small vessel disease with arteriolar medial hypertrophy reduces coronary flow reserve. Myocardial bridging, most commonly involving the mid-LAD and present in 30 to 80% of HCM patients, causes systolic compression. Increased oxygen demand from the hypertrophied myocardium and elevated left ventricular end-diastolic pressure further compromise the supply-demand relationship.

### Histopathology

The histopathologic hallmark of HCM is myocyte disarray involving more than 5% of the myocardium, compared with less than 1% in normal hearts. Interstitial and replacement fibrosis are present to varying degrees. Abnormal intramural coronary arteries with thickened walls and narrowed lumina contribute to the microvascular ischemic substrate.

<image>
A detailed anatomical illustration of HCM pathophysiology showing a long-axis cross-section of the heart. The septum should be markedly thickened (25 mm) compared to the posterior wall (11 mm), creating asymmetric septal hypertrophy. The anterior mitral leaflet is shown in systolic anterior motion (SAM), contacting the septum and creating LVOT obstruction. A turbulent jet (shown in blue/mosaic color) passes through the narrowed LVOT. Simultaneously, a posteriorly directed mitral regurgitation jet (shown in red) is emanating from the malcoaptation point of the mitral valve into the left atrium. The LVOT obstruction point should be clearly labeled with an arrow showing the gradient. Include a small inset M-mode showing SAM of the mitral valve with anterior leaflet-septal contact during systole. Label all structures: IVS (with measurement), LVOT, aortic valve, LA, LV, MV anterior and posterior leaflets, and the direction of the MR jet.
</image>

## Clinical Evaluation

### Echocardiography

Echocardiographic assessment in HCM requires systematic measurement of wall thickness in all segments with characterization of the hypertrophy pattern. Asymmetric septal hypertrophy is the most common distribution at approximately 70%, but concentric, apical (the Japanese variant with deep T-wave inversions in precordial leads and an "ace of spades" LV cavity morphology), and midventricular patterns also occur. LVOT gradient assessment uses continuous-wave Doppler through the LVOT, revealing a late-peaking "dagger-shaped" spectral profile characteristic of dynamic obstruction. This must be differentiated from the symmetric envelope of fixed obstruction seen in aortic stenosis. SAM assessment by M-mode and 2D imaging correlates with the degree of obstruction. The mitral regurgitation jet in HCM is typically posteriorly directed due to SAM; an anteriorly directed jet suggests intrinsic mitral valve pathology rather than SAM-related MR. Diastolic function evaluation includes E/e' ratio and left atrial volume index. Exercise stress echocardiography is essential when the resting gradient is below 50 mmHg in a symptomatic patient, as an exercise-provoked gradient of 50 mmHg or greater confirms labile obstruction.

### Cardiac MRI

Cardiac MRI serves as the gold standard for wall thickness measurement, particularly for the apical and anterolateral walls that represent echocardiographic blind spots. Late gadolinium enhancement reveals patchy mid-wall enhancement at RV insertion points and in areas of maximal hypertrophy, with the extent of LGE correlating with arrhythmia risk and sudden cardiac death. LGE involving 15% or more of LV mass is an independent risk factor for SCD. T1 mapping and extracellular volume fraction detect diffuse fibrosis even in LGE-negative segments, with elevated native T1 suggesting underlying myocardial disease. Feature tracking strain analysis identifies subclinical dysfunction through reduced GLS despite a normal ejection fraction.

### Cardiopulmonary Exercise Testing

Peak VO2 provides important prognostic and functional information, with values below 16 mL/kg/min or less than 50% of predicted associated with worse prognosis. An abnormal blood pressure response to exercise, defined as failure to augment systolic blood pressure by 20 mmHg or greater, or frank hypotension during exercise, constitutes a risk factor for sudden cardiac death, particularly in patients under 40 years of age.

## Sudden Cardiac Death Risk Stratification

### Major Risk Factors (2020 AHA/ACC, 2024 ESC)

The highest-risk individuals are those with prior cardiac arrest or sustained ventricular tachycardia, for whom ICD implantation is indicated for secondary prevention. Additional major risk factors include a family history of sudden cardiac death from HCM, especially in a first-degree relative or when multiple relatives are affected or death occurred at a young age; unexplained syncope, particularly if exertional or recurrent; maximum left ventricular wall thickness of 30 mm or greater; left ventricular apical aneurysm, which provides a substrate for monomorphic ventricular tachycardia; extensive LGE on CMR involving 15% or more of LV mass; reduced LVEF below 50%, representing end-stage HCM; nonsustained ventricular tachycardia on ambulatory monitoring, especially in patients under 30 or with multiple runs; and an abnormal exercise blood pressure response.

### ESC HCM Risk-SCD Calculator

The ESC HCM Risk-SCD calculator estimates 5-year SCD risk using age, maximal wall thickness, LVOT gradient, left atrial size, family history of SCD, NSVT, and unexplained syncope. A calculated risk of 6% or greater supports ICD recommendation, a risk of 4 to 6% suggests ICD should be considered, and a risk below 4% generally does not support ICD implantation unless additional risk modifiers are present. Important limitations include the absence of CMR LGE data, apical aneurysm, LVEF below 50%, and extensive exercise-induced ischemia from the calculation.

### ICD Recommendations

For secondary prevention following prior cardiac arrest or sustained VT, ICD implantation is a Class I indication. For primary prevention, ICD should be considered when one or more major risk factors are present, incorporating shared decision-making that weighs the individual risk profile, patient preferences, and potential ICD complications. The subcutaneous ICD is preferred in HCM patients when pacing and antitachycardia pacing are not needed, as it avoids the long-term transvenous lead complications that are particularly relevant in young patients who will require the device for decades.

## Management of Obstruction

### Pharmacological

Beta-blockers are first-line therapy for symptomatic obstructive HCM, reducing obstruction through negative inotropic and chronotropic effects. Agents such as metoprolol, propranolol, and nadolol are titrated to a resting heart rate of 55 to 60 bpm. Non-dihydropyridine calcium channel blockers, with verapamil preferred over diltiazem, serve as second-line options when beta-blockers are not tolerated. Verapamil should be started cautiously and avoided when the resting gradient exceeds 100 mmHg or when signs of severe heart failure are present, as it can paradoxically worsen obstruction in these settings. Disopyramide, a Class IA antiarrhythmic with potent negative inotropic properties, is added to a beta-blocker when the gradient persists. Dosing ranges from 400 to 800 mg daily in divided doses, and it must be combined with an AV nodal blocking agent because its vagolytic properties can cause 1:1 conduction of atrial flutter. Anticholinergic side effects including dry mouth, urinary retention, and constipation are common.

Mavacamten represents a paradigm shift as the first-in-class cardiac myosin inhibitor. The EXPLORER-HCM trial demonstrated that 37% of patients achieved the primary endpoint of improved peak VO2 and NYHA class compared with 17% on placebo, with average LVOT gradient reductions of approximately 50 mmHg and reduced MR severity. The VALOR-HCM trial showed that mavacamten reduced the need for septal reduction therapy from 77% to 18%. Dosing begins at 5 mg daily and is titrated based on LVOT gradient and LVEF, with mandatory echocardiographic monitoring of ejection fraction at weeks 4, 8, and 12. Dose reduction is required if EF falls below 50%, and the drug requires enrollment in a Risk Evaluation and Mitigation Strategy program. CYP2C19 drug interactions must be monitored, as poor metabolizers are at risk of excessive EF reduction. Aficamten is a next-generation cardiac myosin inhibitor with positive results from the SEQUOIA-HCM trial and more predictable pharmacokinetics that may eliminate the need for CYP2C19 genotyping.

### Septal Reduction Therapy

Surgical myectomy, the Morrow procedure, remains the gold standard for drug-refractory obstructive HCM with an LVOT gradient of 50 mmHg or greater and NYHA Class III to IV symptoms. The procedure involves transaortic resection of basal septal muscle, with operative mortality below 1% at experienced centers performing more than 50 procedures per year. It eliminates the gradient in more than 95% of cases and resolves SAM-related mitral regurgitation.

Alcohol septal ablation provides a percutaneous alternative, involving injection of 1 to 3 mL of absolute ethanol into the first septal perforator branch of the LAD to create a controlled septal infarction. Gradient reduction of 70 to 80% is typical, but there is a higher rate of complete heart block at 10 to 20% requiring permanent pacemaker implantation. Alcohol septal ablation is best suited for patients with high surgical risk, elderly patients, or those with unfavorable anatomy for myectomy. Myectomy is preferred over ablation in young patients, those with massive hypertrophy of 30 mm or greater, and when concomitant mitral valve or papillary muscle abnormalities require surgical correction.

## Atrial Fibrillation in HCM

### Epidemiology and Impact

Atrial fibrillation has a lifetime prevalence of 20 to 25% in HCM and is typically paroxysmal initially, often progressing to persistent AF. It is poorly tolerated because loss of atrial kick in a stiff left ventricle and rapid ventricular rates worsen LVOT obstruction. The thromboembolism risk is substantial at 4 to 6% per year, exceeding that of the general AF population regardless of CHA2DS2-VASc score.

### Management

Anticoagulation is recommended for all HCM patients with atrial fibrillation regardless of CHA2DS2-VASc score, with direct oral anticoagulants preferred over warfarin per 2024 guidelines. For rate control, beta-blockers are preferred, with verapamil or diltiazem as second-line agents. Digoxin should be avoided because it may worsen obstruction. For rhythm control, amiodarone is the most effective agent despite its long-term toxicity profile. Sotalol or dronedarone serve as alternatives, while flecainide or propafenone should only be used with an AV nodal blocker and in the absence of significant obstruction. Catheter ablation for AF in HCM has a higher recurrence rate than in the general AF population at approximately 40 to 50% at 5 years due to left atrial dilation and fibrosis, but remains reasonable for drug-refractory symptomatic atrial fibrillation.

<image>
A clinical decision-making flowchart for the management of symptomatic HCM. Start with "Symptomatic HCM" at top with two main branches: "Obstructive (LVOT gradient >= 30 mmHg rest or >= 50 mmHg provoked)" and "Non-Obstructive (gradient < 30 mmHg)." Obstructive branch: Step 1 "Beta-blocker (titrate to HR 55-60)" → if inadequate: Step 2 "Add disopyramide or switch to verapamil" → if inadequate: Step 3 "Consider mavacamten (cardiac myosin inhibitor)" → if still refractory with gradient >= 50 mmHg: Step 4 "Septal reduction therapy" with two sub-options "Surgical myectomy (preferred if <65, concomitant MV disease, massive hypertrophy)" and "Alcohol septal ablation (if high surgical risk, favorable anatomy)." Non-Obstructive branch: "Beta-blocker or verapamil for symptoms; if HF develops (EF decline), treat as dilated CM; transplant evaluation if refractory." Side panel: SCD risk assessment with ICD decision pathway. Use blue for pharmacological steps, red for interventional steps, green for medical therapy in non-obstructive.
</image>

## Key Clinical Pearls

- Always perform provocative maneuvers (Valsalva, standing, post-exercise) during echo when HCM is suspected -- a resting gradient of zero does not exclude obstructive physiology
- Mavacamten represents a paradigm shift in HCM therapy but requires mandatory echocardiographic monitoring of LVEF due to risk of excessive myocardial suppression -- never prescribe without REMS enrollment and scheduled follow-up
- Dehydration, hypovolemia, and vasodilators (nitrates, PDE5 inhibitors, dihydropyridine CCBs) are poorly tolerated in obstructive HCM and may precipitate acute obstruction and syncope -- educate patients on hydration and medication avoidance
- HCM is the most common cause of SCD in young athletes; pre-participation screening with ECG (European model) or history/physical (American model) remains debated
- Genotype-positive/phenotype-negative individuals should avoid high-intensity competitive athletics (controversial, shared decision-making); serial imaging every 1-3 years through adolescence and young adulthood
- End-stage (burned-out) HCM with progressive LV dilation and EF decline (< 50%) occurs in 5-10% of patients; manage as dilated cardiomyopathy with standard HFrEF GDMT and transplant evaluation

## References

- Ommen SR, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy. Circulation. 2020;142:e558-e631.
- Arbelo E, et al. 2023 ESC Guidelines for the Management of Cardiomyopathies. Eur Heart J. 2023;44:3503-3626.
- Olivotto I, et al. Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM). Lancet. 2020;396:759-769.
- Desai MY, et al. Mavacamten in Patients with Hypertrophic Cardiomyopathy Referred for Septal Reduction (VALOR-HCM). JAMA. 2022;330:1467-1477.
- Maron BJ, et al. Hypertrophic Cardiomyopathy: Present and Future, with Translation into Contemporary Cardiovascular Medicine. JACC. 2014;64:83-99.