Arrhythmogenic Left Ventricular Cardiomyopathy

Arrhythmogenic left ventricular cardiomyopathy (ALVC) is an inherited cardiomyopathy in which fibrofatty replacement of LV myocardium, typically subepicardial or mid-wall, produces ventricular arrhythmia and sudden death with little or no right ventricular involvement.

Arrhythmogenic cardiomyopathy overall affects about 1 in 2,000 to 1 in 5,000 people, and left ventricular involvement is common. Presentation is often in the second to fourth decades, and exercise is a trigger.

Common genes are DSP (the leading cause of ALVC), FLNC truncating variants, DES, PLN (R14del), LMNA, DSG2, DSC2 and TMEM43. Inheritance is mostly autosomal dominant with variable penetrance.

A "hot phase" of recurrent chest pain with troponin rise and normal coronary arteries in young people, mimicking myocarditis, is a typical presentation, especially with DSP variants.

Pathophysiology.

Defective desmosomal or related proteins impair cell adhesion and signalling. Mechanical stress, especially during exercise, leads to myocyte detachment and death, inflammation, then fibrofatty replacement.

Scar from the epicardium inward provides re-entry substrate, causing ventricular arrhythmia with right bundle branch block morphology. Systolic dysfunction develops later in some patients.

Palpitations, presyncope, syncope, and cardiac arrest, often during exertion. Chest pain with raised troponin (hot phase) occurs in a subset. Heart failure appears late. Examination is often normal.

• ECG: low QRS voltage in limb leads (under 0.5 mV), T-wave inversion in V4 to V6 or inferolateral leads, and ventricular ectopy or tachycardia with right bundle branch block morphology.
• Ambulatory ECG: often over 500 ventricular ectopic beats in 24 hours.
• Echocardiography: normal or mildly reduced ejection fraction, regional hypokinesia, or dyskinesia.
• Cardiac MRI: ring like or mid-wall to subepicardial LGE in the LV, with fat infiltration; the key test. Coronary angiography or CT to exclude ischaemia.
• Genetic testing (DSP, FLNC, DES, PLN, LMNA, DSG2, DSC2, TMEM43) and family screening.
• Troponin during hot phases, and exercise testing where safe.

Diagnosis rests on structural and arrhythmic features that fit with LV involvement, together with exclusion of myocarditis, sarcoidosis, ischaemic and dilated cardiomyopathy, supported by genotype and family history.

Differential diagnosis.

• Viral or autoimmune myocarditis (especially in hot phases).
• Dilated cardiomyopathy and cardiac sarcoidosis.
• Hypertrophic cardiomyopathy and ischaemic cardiomyopathy.
• Chagas disease (regional) and Lamin A/C cardiomyopathy.

Exercise. Avoid competitive and endurance exercise. Restriction is the most effective way to slow progression. Light to moderate activity can continue after specialist assessment.

Antiarrhythmic and symptomatic therapy.

• Beta blocker, first line: metoprolol succinate 50 to 200 mg orally once daily (maximum 400 mg daily; usual ceiling 200 mg) or bisoprolol 2.5 to 10 mg daily (maximum 20 mg); nadolol 40 to 160 mg daily (maximum 240 mg) is an alternative; long term.
• Monitor heart rate and blood pressure; reduce bisoprolol in eGFR under 20 mL/min/1.73 m2 and severe hepatic impairment.
• Sotalol (second line): 80 to 160 mg orally twice daily, long term; maximum 320 mg daily (higher doses only in life threatening arrhythmia); QTc and electrolytes at baseline and after changes, stop if QTc over 500 ms; extend interval in eGFR 30 to 60 mL/min/1.73 m2 and avoid under 30.
• Amiodarone (third line): load 200 mg orally three times daily for 1 week, then twice daily for 1 week, then 200 mg daily; thyroid and liver tests every 6 months, chest imaging and lung function if symptoms; reduce warfarin dose by 30 to 50%.
• Flecainide is avoided in structural heart disease.
• Catheter ablation (endocardial and epicardial) for recurrent ventricular tachycardia despite drugs.

Heart failure therapy for ejection fraction under 40%:

• Sacubitril/valsartan 24/26 mg twice daily titrated to 97/103 mg twice daily (maximum), potassium and creatinine at 1 to 2 weeks (alternative ramipril 2.5 mg daily to 10 mg).
• Spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L and eGFR over 30; monitor at 1 week and 4 weeks).
• Dapagliflozin 10 mg daily (eGFR 25 or over) or empagliflozin 10 mg daily.
• Evidence based beta blocker.

ICD. For survivors of cardiac arrest, sustained ventricular tachycardia or haemodynamically poorly tolerated ventricular tachycardia. Primary prevention is considered with ejection fraction 35% or under, or with unexplained syncope, non-sustained ventricular tachycardia, extensive LGE, or higher risk genotype (DSP, FLNC, PLN, LMNA, TMEM43) with ejection fraction under 45 to 50%.

Hot phase. Admit for monitoring, avoid exercise, beta blocker for arrhythmia; evidence for immunosuppression is lacking. Avoid anti-inflammatory drugs where the evidence for benefit is weak.

Anticoagulation for atrial fibrillation or 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 food, 15 mg if creatinine clearance 15 to 49 mL/min.

Monitoring. ECG, echocardiography, ambulatory ECG every 6 to 12 months in affected patients; cardiac MRI every 2 to 3 years; device checks every 3 to 6 months.

Referral and escalation. Refer all suspected cases to a specialist inherited cardiac condition service. Urgent assessment for syncope, aborted sudden death, sustained ventricular tachycardia, hot phase chest pain with raised troponin and normal coronary arteries, heart failure, ejection fraction under 50%, or a family history of sudden death.

Special groups.

• Pregnancy: continue metoprolol; avoid atenolol; assess ventricular function first. ARNI, ACE inhibitors, spironolactone and SGLT2 inhibitors are stopped before conception.
• Relatives: cascade genetic testing, then ECG, ambulatory ECG, echocardiography and MRI every 1 to 3 years; children from adolescence, earlier with high risk family history.
• Region specific: Chagas cardiomyopathy should be excluded in endemic areas.