Hypertrophic Cardiomyopathy (HCM)

Monogenic (Mendelian): ~40–60%, pathogenic sarcomeric variant (e.g. MYH7, MYBPC3)^[1]

Acquired: not a cause of true HCM; exclude hypertensive/athletic LVH and infiltrative phenocopies (amyloidosis, Fabry)

Complex (likely polygenic): ~40–60% genotype-negative, increasingly attributed to a polygenic background^[1]

Inheritance: Autosomal dominant with age-related, often incomplete penetrance and variable expressivity; reported penetrance estimates vary substantially with variant class, ascertainment and cohort

Genetic yield: ~60% diagnostic rate with genetic testing^[1]

Major genes (sarcomeric):

Gene-level penetrance and phenotype figures derive largely from referral cohorts and vary widely with variant class, ascertainment and family screening; treat them as indicative rather than fixed.

Pathophysiology: Sarcomeric protein mutations → myofibrillar disarray, increased myocardial stiffness, diastolic dysfunction, myocardial ischemia (microvascular dysfunction), and arrhythmogenic substrate

Phenocopies to exclude: Amyloidosis, Anderson-Fabry disease, mitochondrial disorders

1 in 500 individuals in the general population^[1]

Most common genetic cardiovascular disease

An important cause of sudden cardiac death in young people and athletes (the reported proportion varies by registry and population)

Clinical Presentation:

• Often asymptomatic, diagnosed on family screening or incidental finding
• Dyspnea on exertion (most common symptom)
• Angina (even with normal coronaries due to microvascular dysfunction)
• Palpitations, presyncope, syncope
• Sudden cardiac death (may be first presentation)

Physical Examination:

• Systolic ejection murmur at left sternal edge (if LVOT obstruction present)
• Murmur increases with Valsalva, standing (decreased preload)
• Double apical impulse, prominent 'a' wave on JVP

ECG Findings (>90% abnormal):

• LV hypertrophy criteria
• Deep T-wave inversion (especially lateral and inferior leads)
• Pathological Q waves
• Atrial fibrillation

First-line:

• 12-lead ECG
• Transthoracic echocardiography (measure wall thickness, SAM, LVOTO gradient)
• Ambulatory ECG monitoring (24-48 hours)
• Exercise stress test (symptom assessment, LVOTO, BP response, arrhythmias)

Advanced imaging:

• Cardiac MRI - LV mass, late gadolinium enhancement (fibrosis), apical aneurysm

Genetic testing:

• Recommended in all patients with confirmed HCM
• Enables cascade family screening

Medical therapy for symptoms/LVOTO:

• Beta-blockers (first-line, ESC 2023 Class I^[1]):
  • Bisoprolol: start 2.5mg od → titrate to 5–10mg od
  • Metoprolol succinate: start 25mg od → titrate to 100–200mg od
  • Atenolol: 25mg od → 50–100mg od (less preferred; caution in renal impairment)
  • Titrate to symptom relief and resting HR 55–65 bpm; avoid vasodilating beta-blockers (carvedilol, nebivolol)
• Verapamil (if beta-blockers contraindicated or not tolerated, ESC 2023 Class IIa^[1]):
  • Start 40mg tds → titrate to 80–120mg tds (max 480mg/day)
  • Never combine with beta-blocker: risk of complete AV block and haemodynamic collapse
  • Caution in severe LVOTO or significant sinus node disease
• Disopyramide (add-on to beta-blocker for persistent obstructive symptoms, ESC 2023 Class IIa^[1]):
  • Start 100mg tds → maintenance 100–150mg tds (total 300–600mg/day)
  • Always combine with beta-blocker or verapamil: disopyramide has vagolytic properties that can accelerate AV conduction → risk of rapid ventricular response if AF develops
  • Monitor QTc (withdraw if QTc >500ms), anticholinergic side effects (urinary retention, dry mouth, blurred vision)
  • Reduce dose in renal impairment (renally excreted)
• Mavacamten (cardiac myosin inhibitor, NICE TA913^[6], ESC 2023 Class IIa^[1] for oHCM; efficacy shown in EXPLORER-HCM^[9] and, for reducing the need for septal reduction therapy, VALOR-HCM^[10]):

  The dosing, genotyping and monitoring details below combine the product SmPC with a local ICC-service SOP^[8]; exact protocols vary between centres and should be checked against your local pathway and the current SmPC.

  • CYP2C19 genotyping required before prescribing: metabolised 74% by CYP2C19, 18% CYP3A4. Poor metabolisers (2–4% Caucasian, up to 18% Asian): maximum dose 5mg od; start at 2.5mg. Intermediate/normal/rapid metabolisers: start at 5mg (or 2.5mg if on strong CYP2C19 inhibitor)
  • Discontinue disopyramide and/or rate-limiting calcium channel blockers at least 5 days before initiating mavacamten
  • Echo at weeks 4, 8 and 12 after initiation; every 6 months on maintenance if stable
  • Escalate: 2.5mg → 5mg → 10mg → 15mg od based on Valsalva LVOTO gradient and LVEF (max 5mg if poor metaboliser or on strong CYP2C19 inhibitor)
  • Stop/interrupt if LVEF <50% (negative inotropic effect); restart at 2.5mg once LVEF recovers
  • Pause if Valsalva LVOTO gradient <20mmHg at any assessment (risk of LVEF depression)
  • CYP2C19 inhibitors (omeprazole, fluoxetine, fluvoxamine): cap dose at 5mg. Avoid mavacamten with combined strong CYP2C19 + strong CYP3A4 inhibitors (absolute contraindication)
  • Contraindicated in pregnancy; confirmed negative pregnancy test required before initiation in women of reproductive age
  • NICE TA913: recommended for symptomatic (NYHA II-III) obstructive HCM with LVOT gradient ≥50mmHg uncontrolled on standard therapy, LVEF ≥55%
  • Obstructive vs non-obstructive: the benefit of myosin inhibitors is established in obstructive HCM. In non-obstructive HCM the evidence is weaker, MAVERICK-HCM^[11] was a small phase 2 study and the phase 3 ODYSSEY-HCM^[13] trial did not meet its primary endpoints for exercise capacity or symptoms
  • Emerging: aficamten, a next-generation cardiac myosin inhibitor, improved exercise capacity in symptomatic obstructive HCM in the phase 3 SEQUOIA-HCM^[12] trial (not yet routine UK practice; evidence evolving)

Septal reduction therapy (for severe obstructive HCM, LVOT gradient ≥50mmHg on max medical therapy with NYHA III-IV):

• Surgical myectomy (the preferred septal reduction therapy at experienced centres, particularly in younger patients and those with complex anatomy)
• Alcohol septal ablation (for those unsuitable for surgery or patient preference; avoid in young patients if possible)

ICD for primary prevention: Based on HCM Risk-SCD calculator score^[2]; see Risk section

Atrial fibrillation management: Anticoagulation mandatory regardless of CHA₂DS₂-VASc score; rhythm or rate control; amiodarone most effective antiarrhythmic

• Sudden cardiac death (VT/VF): the most feared complication and may be the first presentation. It is an important cause of death in younger patients, but with contemporary management overall mortality is low and heart failure and AF-related stroke account for more deaths in older cohorts^[1]
• Atrial fibrillation: common and poorly tolerated, carrying a disproportionately high stroke and thromboembolic risk relative to general-population AF^[1]
• Heart failure: via two routes, diastolic heart failure with preserved ejection fraction, and end-stage "burnt-out" HCM with systolic impairment and LV remodelling (a minority, poor prognosis, transplant pathway)
• Dynamic LVOT obstruction: drives exertional dyspnoea, angina and presyncope or syncope, with accompanying systolic anterior motion (SAM) mediated mitral regurgitation
• Apical aneurysm: a feature of apical or mid-cavity HCM that harbours thrombus (an embolic source) and forms a re-entrant arrhythmic focus. Empirical anticoagulation is generally advised once the aneurysm reaches roughly 2 cm, independent of AF status (expert consensus, no randomised trial)^[15]

Additional risk modifiers (outside calculator):

• Extensive LGE (>15% LV mass) on CMR, independent predictor of SCD (Class IIb modifier)
• LVEF <50%, Class IIb modifier
• LV apical aneurysm, high-risk feature; ICD strongly recommended
• End-stage/burnt-out HCM, separate management pathway

Based on ESC 2023 Cardiomyopathy guidelines^[1].

Advanced / complicated = significant LVOTO, NYHA III–IV symptoms, falling LVEF or end-stage progression, sustained arrhythmia (AF, NSVT/VT), prior aborted SCD, or an implanted device.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Avoid vasodilators and high-dose diuretics in obstructive HCM (can worsen LVOT gradient)^[1]
• Screen first-degree relatives with ECG and echo (start age 10-12 or earlier if symptomatic)^[1]
• Anticoagulation required for all AF (CHA2DS2-VASc not applicable)^[1]
• Exercise and competitive sport: ESC 2020/2023 favour an individualised, shared decision-making approach based on risk assessment rather than blanket disqualification^[3]; recreational exercise is encouraged, and competitive/vigorous sport may be reasonable for many lower-risk individuals. The prospective LIVE-HCM study found no increase in serious arrhythmic events in HCM patients who exercised vigorously^[14]
• Ensure preconception counselling for all women of childbearing age^[5]
• Annual follow-up minimum; more frequent if symptomatic or high-risk
• Offer genetic testing to patients with a confirmed clinical diagnosis of HCM, primarily to enable cascade screening of relatives; yield is highest with a sarcomeric phenotype or a positive family history, and the result rarely alters the proband's own management^[1]