Biventricular Arrhythmogenic Cardiomyopathy

Biventricular arrhythmogenic cardiomyopathy is an inherited cardiomyopathy in which fibrofatty replacement involves both ventricles. It causes ventricular arrhythmia, progressive biventricular dysfunction and sudden death. It is a phenotype within the arrhythmogenic cardiomyopathy spectrum, not a separate gene disease.

Arrhythmogenic cardiomyopathy affects about 1 in 2,000 to 1 in 5,000 people. Presentation is usually between 20 and 50 years, earlier and more severe in men, and exercise is a recognised trigger.

Left ventricular involvement is present at diagnosis in a substantial minority and develops in many more over time. Genes include PKP2 (most frequent), DSP, DSG2, DSC2, JUP, TMEM43, PLN, FLNC, DES and LMNA. Inheritance is mostly autosomal dominant with variable penetrance. Rare recessive forms combine the cardiomyopathy with palmoplantar keratoderma and woolly hair. Carriers of more than one variant present earlier and more severely.

Competitive and endurance exercise, male sex, and a high ventricular ectopic burden predict worse outcome.

Pathophysiology.

Defective desmosomal and related proteins weaken cell adhesion and signalling. Mechanical stress, especially during exercise, causes myocyte detachment and death, then inflammation and fibrofatty replacement.

The process usually starts in the subepicardium of the right ventricular inferior, apical and outflow regions (the triangle of dysplasia) and spreads transmurally. It may extend to the left ventricular free wall and septum.

Scar provides re-entry circuits for ventricular tachycardia. Right ventricular failure is followed by left ventricular dilatation and systolic dysfunction in advanced disease.

Inflammatory hot phases, with chest pain and troponin rise and normal coronary arteries, mark episodes of myocyte injury and often precede scar progression.

Presentation is with palpitations, presyncope, syncope, cardiac arrest during exertion, or hot phase chest pain. Heart failure appears late, with right sided features first (oedema, ascites, raised jugular venous pressure) followed by left sided congestion. Examination is often normal early. A wide fixed split second heart sound may be present.

Diagnosis rests on combining structural, electrical, arrhythmic, tissue and genetic or family features.

• ECG: T-wave inversion in V1 to V3 beyond age 14 without right bundle branch block, epsilon wave, terminal activation duration of the QRS of 55 ms or more in V1 to V3.
• ECG, further features: low limb lead voltage (under 0.5 mV), and T-wave inversion in V5 to V6 or inferolateral leads when the left ventricle is involved.
• Ventricular tachycardia: left bundle branch block morphology with superior axis points to a right ventricular origin, and right bundle branch block morphology points to a left ventricular origin.
• Ambulatory ECG: over 500 ventricular ectopic beats in 24 hours is a minor criterion.
• Echocardiography and cardiac MRI: right ventricular regional akinesia, dyskinesia or aneurysm with a right ventricular end diastolic volume index of 110 mL/m2 or more (men) or 100 mL/m2 or more (women), or right ventricular ejection fraction of 40% or less. MRI also shows left ventricular subepicardial or mid-wall late gadolinium enhancement and fat.
• Genetic testing and cascade screening. Endomyocardial biopsy is rarely needed.
• Coronary assessment to exclude ischaemia. Troponin during hot phases.

Revised criteria are applied across categories: two major, or one major and two minor, or four minor criteria from different categories is definite; one major and one minor, or three minor, is borderline; one major or two minor is possible.

Differential diagnosis.

• Cardiac sarcoidosis and myocarditis.
• Dilated cardiomyopathy and idiopathic right ventricular outflow tract tachycardia.
• Congenital shunts with right ventricular volume overload and Uhl anomaly.
• Athlete's heart, Brugada syndrome and Chagas cardiomyopathy (regional).

Exercise. Avoid competitive and endurance sport. Light to moderate recreational activity is allowed after specialist assessment. Exercise restriction is the most effective way to slow progression.

Antiarrhythmic therapy.

• Beta blocker, first line: metoprolol succinate 50 to 200 mg orally once daily (maximum 400 mg daily; usual ceiling 200 mg) or nadolol 40 to 160 mg once daily (maximum 240 mg), long term.
• Monitor heart rate, blood pressure and conduction; reduce in severe hepatic impairment; reduce nadolol dose or extend the interval when eGFR is under 50 mL/min/1.73 m2.
• Sotalol: 80 to 160 mg orally twice daily, long term; maximum 320 mg daily.
• Sotalol monitoring: ECG for QTc at baseline and after each change, stop if QTc over 500 ms; keep potassium over 4.0 mmol/L and magnesium normal; extend the interval at eGFR 30 to 60 and avoid at eGFR under 30 mL/min/1.73 m2.
• Amiodarone: load 200 mg orally three times daily for 1 week, then twice daily for 1 week, then 200 mg once daily; thyroid and liver tests every 6 months, chest imaging and lung function if symptoms; reduces warfarin requirement by 30 to 50%.
• Flecainide 50 to 100 mg orally twice daily (maximum 300 mg daily) with a beta blocker is used only when the left ventricle is structurally normal with preserved function; avoid when left ventricular ejection fraction is under 50% or late gadolinium enhancement is extensive.
• Catheter ablation (endocardial and epicardial) for recurrent ventricular tachycardia or shocks despite drugs.

Heart failure (ejection fraction under 40%):

• Sacubitril/valsartan 24/26 mg orally twice daily, doubled every 2 to 4 weeks to 97/103 mg twice daily (maximum); potassium and creatinine at 1 to 2 weeks.
• Start at 24/26 mg with eGFR under 30; hold if systolic blood pressure under 100 mmHg or potassium over 5.5 mmol/L. Alternative: ramipril 2.5 mg daily titrated to 10 mg.
• Spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30; check at 1 week and 4 weeks) or eplerenone 25 to 50 mg daily.
• Dapagliflozin 10 mg daily (eGFR 25 or over) or empagliflozin 10 mg daily (eGFR 20 or over).
• Furosemide 20 to 80 mg orally daily for right sided congestion, titrated to weight; add metolazone 2.5 to 5 mg in resistant oedema with daily electrolytes.
• Beta blocker: continue metoprolol succinate 50 to 200 mg orally once daily as tolerated (maximum 400 mg daily; usual ceiling 200 mg), with heart rate and blood pressure monitoring; reduce in severe hepatic impairment.

ICD.

• Secondary prevention for cardiac arrest, sustained ventricular tachycardia, or poorly tolerated ventricular tachycardia.
• Primary prevention by risk estimate: a 5-year risk model using age, sex, recent syncope, non-sustained ventricular tachycardia, ectopic burden, number of leads with T-wave inversion, and right and left ventricular ejection fractions.
• A 5-year risk under 5% does not usually justify an ICD, 5 to under 10% allows consideration, and 10% or more favours an ICD. The model is less validated in left dominant disease.
• Left ventricular ejection fraction of 35% or under independently qualifies.
• Subcutaneous devices are an option when pacing is not needed and ventricular tachycardia is not pace terminable.

Anticoagulation. For atrial fibrillation or ventricular thrombus:

• Apixaban 5 mg 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 rivaroxaban 20 mg once daily with the evening meal (15 mg if creatinine clearance 15 to 49 mL/min).
• Check creatinine and haemoglobin at least annually.

Advanced disease. Heart transplantation for refractory heart failure or incessant ventricular arrhythmia.

Monitoring. ECG, echocardiography and ambulatory ECG every 6 to 12 months. Cardiac MRI every 2 to 3 years or with clinical change. Device interrogation every 3 to 6 months.

Referral and escalation. Refer every suspected case to an inherited cardiac condition service. Urgent referral for syncope, sustained ventricular tachycardia or cardiac arrest, hot phase chest pain with raised troponin and normal coronary arteries, heart failure, left ventricular ejection fraction under 45%, severe right ventricular dysfunction, or a family history of sudden death under 50 years.

Special groups.

• Pregnancy: preconception counselling; continue metoprolol and avoid atenolol; ARNI, ACE inhibitors, spironolactone and SGLT2 inhibitors are stopped; risk is higher with reduced ventricular function.
• Relatives: cascade genetic testing, with ECG, ambulatory ECG, echocardiography and MRI every 1 to 3 years from adolescence, earlier with a family history of early sudden death.
• Region specific: exclude Chagas cardiomyopathy in endemic areas.