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: Mendelian in about half of patients, then autosomal dominant with age-related, often incomplete penetrance and variable expressivity; apparently sporadic cases can still be monogenic (incomplete penetrance in a parent, de novo variants), while genotype-negative patients without a family history are more often older, male and hypertensive, with a likely complex aetiology^[1]. Reported penetrance estimates vary substantially with variant class, ascertainment and cohort

Genetic yield: ~30–60% diagnostic rate with genetic testing (highest in early-onset, familial, or sarcomeric phenotypes)^[1]

In the prospective NHLBI HCM Registry (HCMR, 2,755 patients at 44 centres), 29.5% carried a pathogenic or likely pathogenic sarcomere variant (MYBPC3 18.5%, MYH7 8%; 36% when selected variants of uncertain significance were counted), and genotype tracked with morphology: sarcomere-positive patients more often had reverse septal curvature, more late gadolinium enhancement and less resting outflow obstruction, while sarcomere-negative patients more often had isolated basal septal hypertrophy with obstruction and less fibrosis.^[18]

Major genes (sarcomeric):

% column: MYBPC3 and MYH7 ranges run from a UK specialist-clinic cohort (874 consecutive unrelated patients, 383 (43.8%) with a rare sarcomere variant; 10% of these had variants in more than one gene and are not counted in the gene rows)^[23] to HCMR (MYBPC3 18.5% and MYH7 8% of 2,755 patients, of the 29.5% with a pathogenic or likely pathogenic sarcomere variant)^[18]; other genes are from the UK cohort only. Penetrance column: pooled penetrance in relatives found through cascade screening; penetrance in carriers identified incidentally in population studies is far lower (~11%)^[22]. 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 and genocopies to exclude: amyloidosis (including hereditary ATTR), Anderson-Fabry disease, glycogen storage disease (PRKAG2, Danon), mitochondrial disorders; a genocopy variant is found in under 5% of adults with HCM^[1]

1 in 500 individuals in the general population on echocardiographic screening^[1]

Up to 1 in 200 when genotype-positive relatives without hypertrophy and disease detectable only on CMR are included; most affected people in the population are undiagnosed^[21]

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

Morphological patterns:^[1][15]

• Asymmetric septal hypertrophy: the commonest pattern, with reverse-curvature (more often sarcomere variant-positive) and sigmoid (more often variant-negative, typically older patients) septal morphologies as distinct subtypes^[18]
• Apical HCM: spade-shaped LV cavity at end-diastole with giant precordial T-wave inversion; easily missed on echocardiography without contrast or CMR
• Mid-cavity obstruction: associated with apical aneurysm formation
• Concentric LVH: less typical of sarcomeric disease and should raise suspicion of a phenocopy
• Segmental hypertrophy confined to the anterolateral wall, the apex or the RV, which echocardiography may not detect

Red flags for a non-sarcomeric cause:^[1]

• ECG: short PR or pre-excitation (Danon disease, PRKAG2, Pompe disease); low QRS voltage despite thick walls (amyloidosis); AV block (amyloidosis, Fabry disease, sarcoidosis, mitochondrial disease)
• Echo and CMR: concentric LVH, RV hypertrophy, thickened valves or interatrial septum and pericardial effusion (amyloidosis); low native T1 (Fabry disease); diffuse subendocardial LGE or very high ECV (amyloidosis); LV free-wall LGE with septal sparing (Danon disease)
• Clinical and biochemical: age at onset, learning difficulty, skeletal myopathy or raised CK, renal impairment, neuropathic pain, carpal tunnel syndrome, deafness or visual loss
• Family pattern: X-linked or maternal inheritance

Other differential diagnoses: athletic remodelling (wall thickness rarely above 16 mm, with a dilated LV cavity, normal diastolic function and regression with detraining) and hypertensive heart disease (usually concentric and modest in degree).^[1]

1. General measures:

• Avoid dehydration and excessive diuresis, and avoid vasodilators/vasodilating beta-blockers, all of which can worsen LVOT obstruction
• Treat and control precipitants that worsen symptoms or obstruction (e.g. hypertension, AF, anaemia)
• Individualised exercise and driving advice, see the Exercise and Driving (DVLA) tabs
• Genetic counselling and family cascade testing, see the Genetic Testing page

2. Medical therapy:

• LVOT obstruction:
  • Beta-blockers (first-line, 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)^[7]
    • Titrate to symptom relief and resting HR 55–65 bpm; avoid vasodilating beta-blockers (carvedilol, nebivolol)
  • Verapamil (if beta-blockers contraindicated or not tolerated, Class IIa^[1]):
    • Start 40mg tds → titrate to 80–120mg tds (max 480mg/day)
    • Avoid routine combination with a beta-blocker (specialist use only, with ECG and BP monitoring): risk of bradycardia, 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, 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], Class IIa^[1] for oHCM, and a stronger Class 1 second-line option in adults^[15]; efficacy shown in EXPLORER-HCM^[9] and, for reducing the need for septal reduction therapy, VALOR-HCM^[10]): dosing, genotyping and monitoring detail

    • Adults only. The 2024 AHA/ACC guideline restricts cardiac myosin inhibitors to adult patients, and rates adding one to a beta-blocker or non-dihydropyridine calcium channel blocker as Class 1 in symptomatic obstructive HCM, alongside disopyramide and septal reduction therapy. Roughly 5.7% of patients develop an LVEF below 50% attributable to the drug alone, rising to 7–10% once other clinical factors are included, which is what the echo schedule below is for^[15]
    • CYP2C19 genotyping recommended 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 before starting mavacamten; published clinical experience favours a gradual taper of disopyramide during mavacamten initiation over an abrupt washout beforehand, since abrupt discontinuation has been associated with heart failure decompensation^[17]
    • Echo at weeks 4, 8 and 12 after initiation; on maintenance, every 6 months if LVEF ≥55% and every 3 months if LVEF 50–<55% (UK SmPC)
    • Escalate: 2.5mg → 5mg → 10mg → 15mg od based on Valsalva LVOTO gradient and LVEF (maximum 5mg in CYP2C19 poor metabolisers, 15mg otherwise; interacting drugs per SmPC Table 1)
    • Stop/interrupt if LVEF <50% (negative inotropic effect); interrupt for at least 4 weeks and until LVEF ≥50%, then restart following the SmPC interruption algorithm
    • Interrupt or down-titrate if LVEF falls or the Valsalva LVOTO gradient drops below threshold (e.g. <20 mmHg), to avoid LVEF depression
    • CYP2C19/CYP3A4 inhibitors and inducers (including over-the-counter omeprazole/esomeprazole): the dose change depends on CYP2C19 phenotype and inhibitor strength, so follow UK SmPC Table 1 and recheck LVEF 4 weeks after any change; intermittent omeprazole/esomeprazole is not recommended. Contraindicated: combined strong CYP2C19 + strong CYP3A4 inhibitors, and strong CYP3A4 inhibitors in CYP2C19 poor metabolisers or when phenotype is undetermined
    • 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)
    • General advice: follow the current UK SmPC (medicines.org.uk/emc/product/15030/smpc) for dosing, monitoring and interactions; a local ICC-service SOP can add service-level detail^[8]
• Microvascular dysfunction / angina:
  • Beta-blockers and verapamil (as above for LVOT obstruction) are also first-line for angina in HCM, including angina attributable to microvascular dysfunction rather than epicardial coronary disease or LVOTO
  • Ranolazine was tested in the RESTYLE-HCM randomised, double-blind, placebo-controlled trial in patients with non-obstructive HCM and did not meet its primary endpoint, no significant difference from placebo in exercise capacity (peak VO₂), NT-proBNP, diastolic function or quality of life; it showed a secondary reduction in 24-hour premature ventricular complex burden. It is not an established therapy for HCM-related microvascular symptoms^[16]
  • Coronary angiography is recommended for anginal symptoms to exclude concomitant epicardial coronary disease, which is associated with a poorer prognosis when present alongside microvascular dysfunction^[1]
• Atrial fibrillation management:
  • For clinical AF, oral anticoagulation is recommended irrespective of CHA₂DS₂-VASc unless contraindicated; device-detected/subclinical AF should be individualised by episode duration, bleeding risk and specialist judgement; rhythm or rate control; amiodarone most effective antiarrhythmic

3. Device therapy / surgery:

• Septal reduction therapy (for severe obstructive HCM, LVOT gradient ≥50mmHg on max medical therapy with NYHA III-IV): surgical myectomy is the preferred option at experienced centres, particularly in younger patients and those with complex anatomy; alcohol septal ablation (percutaneous) is an option for those unsuitable for surgery or by patient preference, generally avoided in young patients if possible
• ICD for primary prevention: based on HCM Risk-SCD calculator score^[2]; see Risk section

4. Advanced heart failure and/or transplant referral:

• End-stage ("burnt-out") HCM with severe systolic impairment and refractory heart failure warrants advanced-heart-failure/transplant service referral, as for any advanced cardiomyopathy

• 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. Anticoagulation is commonly considered independent of AF status, particularly for larger aneurysms (a threshold of roughly 2 cm is often cited), demonstrated thrombus, prior embolism, severe systolic dysfunction or additional risk markers. Decisions should be individualised, as the evidence is observational and consensus-based with no randomised trial^[15]

The 2024 AHA/ACC guideline takes a different approach^[15]

• It declines to tie a management recommendation to a calculated risk threshold, stating that recommendations should not be assigned to prespecified risk estimates as the sole arbiter of the decision to implant. The 5-year estimate is used to inform the shared decision-making conversation (Class 2a) rather than to gate it^[15]
• Instead, an ICD is reasonable (Class 2a) for an adult with one or more major risk factors^[15]:
  • Sudden death judged definitely or likely attributable to HCM in one or more first-degree or close relatives aged 50 years or younger
  • Maximal LV wall thickness ≥30 mm in any segment
  • One or more recent episodes of syncope suspected to be arrhythmic
  • LV apical aneurysm with transmural scar or LGE
  • LV systolic dysfunction (LVEF <50%)
• Extensive LGE and NSVT sit one tier lower (Class 2b), for selected patients without a major risk factor or where the decision remains uncertain^[15]
• An ICD should not be implanted in a patient with no risk factors, nor for the sole purpose of enabling participation in competitive athletics (both Class 3: Harm)^[15]
• Risk should be reassessed at first evaluation and every 1 to 2 years thereafter, in both guidelines^[1][15]

Why this matters in practice: the two models can disagree for the same patient. Apical aneurysm and LVEF <50% are standalone Class 2a indications under the AHA approach, whereas ESC treats them as modifiers to a HCM Risk-SCD estimate that does not itself include them. A patient with an apical aneurysm and a calculated 5-year risk below 4% therefore sits at Class 2a in the American framework and Class IIb in the European one. UK practice follows the ESC model; the divergence is worth naming explicitly in shared decision-making rather than presenting either score as definitive^[1][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: important risk modifier; consider ICD through shared decision-making, particularly alongside other risk markers (NSVT, extensive LGE, unexplained syncope, LV systolic dysfunction, or family history of SCD)
• End-stage/burnt-out HCM, separate management pathway

Prospective registry evidence (NHLBI HCM Registry):

• HCMR enrolled 2,750 patients at 44 centres in North America and Europe, each with protocolised contrast CMR, biomarkers and genotyping, and followed them for a mean of 6.9 years^[19]
• Five variables were independently associated with the primary composite outcome (HCM-related death, non-fatal sustained ventricular arrhythmia requiring cardioversion or defibrillation, LV assist device or transplant): LV scar as a percentage of LV mass on LGE (HR 1.86 per 10% increase, 95% CI 1.58–2.20), LV mass index (HR 1.09 per 10 units), LV end-systolic volume index (HR 1.28 per 10 units), heart failure at enrolment (HR 2.89, 95% CI 1.75–4.77), and log NT-proBNP (HR 1.41 per log unit, 95% CI 1.17–1.70); C-index 0.77^[19]
• Scar of 9% or more of LV mass marked a substantial rise in the composite event rate; a secondary model for sudden cardiac death and ventricular arrhythmia alone retained LGE percentage, LV mass index, LVEF and log NT-proBNP (C-index 0.76)^[19]
• Read the endpoint before applying these figures: the primary HCMR model predicts a composite that includes heart-failure outcomes, so it is not interchangeable with HCM Risk-SCD, which estimates sudden cardiac death alone. The ESC >15% LGE modifier above and HCMR's 9% signal are derived for different endpoints and are not competing cut-offs
• The practical message is that quantified CMR scar and NT-proBNP add prognostic information beyond the conventional risk factors, and both now have prospective support^[19]

mWHO class II–III or above: refer to a Pregnancy Heart Team before conception (see Pregnancy).

Based on the 2023 ESC cardiomyopathy guideline^[1] and the 2024 AHA/ACC HCM guideline^[15]. The two differ on surveillance interval in genotype-positive, phenotype-negative individuals: ESC proposes every 1 to 3 years with ECG and echocardiography up to age 60 and every 3 to 5 years thereafter, while AHA specifies every 1 to 2 years in children and adolescents and every 3 to 5 years in adults. The intervals below follow the AHA schedule, which is the more commonly applied of the two in practice; either is defensible.

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.

• 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]
• Screen first-degree relatives with ECG and echo from childhood, not from a fixed age: at the time HCM is diagnosed in the family for children of genotype-positive or early-onset families, and no later than puberty for other children^[1]
• Avoid vasodilators and high-dose diuretics in obstructive HCM (can worsen LVOT gradient)^[1]
• Anticoagulation for clinical AF irrespective of CHA2DS2-VASc, unless contraindicated; individualise for device-detected subclinical AF^[1]
• Exercise and competitive sport: ESC 2020/2023 favour an individualised, shared decision-making approach based on risk assessment rather than blanket disqualification^[3][4]; 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]
• Clinically stable patients: review every 1–2 years; sooner if symptoms change or high-risk features develop