Hypertrophic Obstructive Cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) is hypertrophic cardiomyopathy with dynamic left ventricular outflow tract (LVOT) obstruction, defined by a gradient of 30 mmHg or more at rest or on provocation. LV wall thickness is 15 mm or more (13 mm or more with a family history or positive genotype) without another cause.

Hypertrophic cardiomyopathy affects about 1 in 500 people, and about two thirds have obstruction at rest or with provocation. It is the commonest cause of sudden cardiac death in young athletes.

Inheritance is autosomal dominant. Pathogenic variants in sarcomere genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3) are found in about 30 to 60% of cases.

Heart failure, atrial fibrillation, ventricular arrhythmia, sudden death, stroke and, rarely, end stage (burnt out) disease are the main complications.

Pathophysiology.

Septal hypertrophy narrows the LVOT. High velocity flow draws the anterior mitral leaflet (and chordae) toward the septum (systolic anterior motion), worsening obstruction and causing posteriorly directed mitral regurgitation.

Obstruction increases with reduced preload, reduced afterload and increased contractility, which explains triggers such as dehydration, vasodilators, exercise, and the post-ectopic beat.

Diastolic dysfunction, microvascular ischaemia, myocardial disarray and fibrosis (late gadolinium enhancement) cause symptoms and arrhythmia. Increasing LGE extent is associated with sudden death risk.

Symptoms include exertional dyspnoea, chest pain, fatigue, palpitations, presyncope and exertional syncope. Many patients are asymptomatic.

Signs: a harsh crescendo decrescendo systolic murmur at the left sternal edge and apex that increases with Valsalva and on standing and decreases with squatting and handgrip; jerky carotid pulse (pulsus bisferiens); double apical impulse; fourth heart sound; mitral regurgitation murmur.

• ECG: LVH with strain, deep lateral and inferior Q waves, giant T-wave inversion, left atrial enlargement.
• Echocardiography: wall thickness 15 mm or more, systolic anterior motion, a dagger shaped late peaking continuous wave Doppler profile.
• Measure the LVOT gradient at rest, with Valsalva, and after exercise. A peak gradient of 30 mmHg or more is obstruction; 50 mmHg or more is the threshold for invasive therapy.
• Cardiac MRI: wall thickness, apical aneurysm, LGE extent (over 15% of LV mass is a risk marker).
• 24 to 48 hour ambulatory ECG (non-sustained ventricular tachycardia, atrial fibrillation), and exercise testing.
• NT-proBNP, troponin, genetic testing, and cascade screening.

Sudden death risk: use a points based 5-year score using age, maximum wall thickness, left atrial size, LVOT gradient, family history of sudden death, non-sustained ventricular tachycardia and unexplained syncope. A 5-year risk under 4% is low (ICD not usually), 4 to under 6% intermediate (consider ICD), and 6% or more high (consider ICD).

An alternative approach considers an ICD for one or more of: sudden death in a relative, massive LVH (30 mm or more), unexplained syncope, apical aneurysm, or ejection fraction under 50%.

Differential diagnosis.

• Hypertensive heart disease and athlete's heart.
• Aortic stenosis (including subvalvular and supravalvular).
• Infiltrative and storage disease: cardiac amyloidosis, Fabry disease, Danon disease, Noonan syndrome.
• Mitochondrial disease and Friedreich ataxia.

General. Avoid dehydration, excess alcohol and drugs that worsen obstruction (vasodilators such as nitrates and dihydropyridine calcium channel blockers, high dose diuretics, digoxin, inotropes). Avoid competitive high intensity sport unless after specialist shared decision making. Moderate regular exercise is encouraged.

Drug therapy for obstruction.

• Beta blocker, first line. Metoprolol 25 to 50 mg orally twice daily (tartrate) or 50 to 200 mg once daily (succinate), long term.
• Titrate metoprolol to resting heart rate 50 to 60 beats/min; maximum 400 mg daily (usual ceiling 200 mg). Monitor heart rate, blood pressure and bronchospasm; reduce in severe hepatic impairment.
• Bisoprolol 2.5 to 10 mg orally once daily (maximum 20 mg, usual ceiling 10 mg); maximum 10 mg in eGFR under 20 mL/min/1.73 m2 or severe hepatic impairment.
• Verapamil (if a beta blocker is not tolerated; not combined with a beta blocker without monitoring): 120 to 240 mg orally (modified release) once daily, titrated to 480 mg daily (maximum 480 mg).
• Monitor heart rate, blood pressure, PR interval and constipation on verapamil. Avoid with resting gradient over 100 mmHg, severe symptoms, hypotension or systolic dysfunction. Reduce dose in hepatic impairment; it interacts with statins, digoxin and dabigatran.
• Disopyramide (add on, with a beta blocker or verapamil to control AV conduction): 100 to 150 mg orally three times daily or controlled release 250 mg twice daily; daily total 300 to 600 mg (maximum 600 mg in this indication).
• On disopyramide, record an ECG at baseline and after dose changes, and stop if QTc over 480 ms or rises over 25%. Anticholinergic effects occur (pyridostigmine 30 to 60 mg orally three times daily may help); avoid in glaucoma and prostatism. Reduce dose and extend interval if eGFR under 40, avoid under 15.
• Mavacamten (symptomatic obstructive disease, functional class II to III, ejection fraction 55% or more): start 5 mg orally once daily (2.5 mg if on a moderate CYP2C19 inhibitor or CYP2C19 poor metaboliser status).
• Titrate mavacamten by echocardiography at weeks 4, 8 and 12, then every 12 weeks, to a Valsalva gradient under 30 mmHg (aim under 20) without ejection fraction falling under 55%. Doses are 2.5, 5, 10 and 15 mg (maximum 15 mg).
• Interrupt mavacamten if ejection fraction falls under 50% (resume at a lower dose when 50% or more after 4 weeks) and during intercurrent illness or atrial fibrillation with rapid rate.
• Mavacamten is contraindicated with moderate or strong CYP2C19 inhibitors and strong CYP3A4 inducers and in pregnancy (effective contraception needed during and for 4 months after).
• Aficamten, a newer myosin inhibitor, is licensed in some regions with echocardiography directed titration from 5 mg daily; confirm product information before use.

Invasive septal reduction. For a gradient of 50 mmHg or more with refractory functional class III to IV symptoms (or recurrent exertional syncope) despite maximal therapy:

• Surgical septal myectomy (preferred in younger patients, septum over 30 mm, or associated mitral or papillary muscle abnormalities).
• Alcohol septal ablation: 1 to 3 mL absolute alcohol into the first septal perforator; septum 16 mm or more; complete heart block needing a pacemaker in about 10% of patients.

Sudden death prevention. ICD for survivors of cardiac arrest or sustained ventricular tachycardia. Primary prevention when the 5-year risk is 6% or more, or when one or more of these is present: sudden death in a relative, massive LVH (30 mm or more), unexplained syncope, apical aneurysm, or ejection fraction under 50%.

Arrhythmia. Atrial fibrillation: anticoagulate regardless of CHA2DS2-VASc score.

Give apixaban 5 mg orally twice daily (2.5 mg twice daily if two of: age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over). Or give rivaroxaban 20 mg once daily with the evening meal (15 mg if creatinine clearance 15 to 49 mL/min). Treat long term; review creatinine, haemoglobin and bleeding.

Early rhythm control with amiodarone (load 200 mg three times daily for 1 week, then twice daily for 1 week, then 200 mg daily; thyroid and liver tests every 6 months; reduces warfarin requirement by 30 to 50%) or ablation. Control rate with beta blocker or verapamil.

Acute hypotension or decompensation in obstruction. Intravenous fluid, stop vasodilators and inotropes, phenylephrine 100 to 200 microgram intravenous bolus (infusion titrated to blood pressure), and beta blocker.

Monitoring. Clinical review, ECG and echocardiography every 1 to 2 years in stable disease, annually if symptomatic or high risk. Ambulatory ECG every 1 to 2 years. Cardiac MRI every 3 to 5 years or with change. On mavacamten, echocardiography at weeks 4, 8 and 12 and then every 12 weeks.

Referral and escalation. Refer all patients to a cardiomyopathy service. Urgent referral for syncope, ventricular arrhythmia, heart failure, resting gradient over 50 mmHg with symptoms, wall thickness of 30 mm or more, apical aneurysm, ejection fraction under 50%, family history of sudden death, new atrial fibrillation, or planned pregnancy.

Special groups.

• Pregnancy: most tolerate pregnancy well. Continue metoprolol (avoid atenolol), avoid hypovolaemia, vaginal delivery is usual. Mavacamten is contraindicated.
• Relatives: screen first degree relatives with ECG and echocardiography at diagnosis and every 1 to 3 years (children from 10 to 12 years, earlier if competitive sport or severe family history).
• Older adults: lower starting doses of beta blocker, verapamil and disopyramide; hypertension commonly coexists.
• Kidney or liver impairment: reduce disopyramide when eGFR is under 40 and avoid it under 15; limit bisoprolol to 10 mg when eGFR is under 20; reduce verapamil in hepatic impairment.