Left Dominant Arrhythmogenic Cardiomyopathy

Left dominant arrhythmogenic cardiomyopathy (LDAC) is the arrhythmogenic cardiomyopathy phenotype in which the LV is predominantly affected and RV structure and function are relatively preserved. It is characterised by fibrofatty replacement, ventricular arrhythmia and risk of sudden death, often with only mild or no LV dilatation.

LDAC is a genotype driven classification within the broader arrhythmogenic cardiomyopathy spectrum, which affects about 1 in 2,000 to 1 in 5,000 people. It is now recognised as at least as common as the classic right ventricular form in genotyped series.

Genes are DSP (most common), FLNC truncating variants, DES, PLN, LMNA, DSG2, DSC2 and TMEM43. The underlying gene shapes both phenotype and risk.

Sudden death or arrhythmia can precede heart failure, and arrhythmic risk often exceeds that predicted by ejection fraction alone.

Pathophysiology.

Genotype specific mechanisms include desmosomal failure (DSP, DSG2, DSC2), cytoskeletal and filamin dysfunction (FLNC, DES), calcium handling disruption (PLN) and nuclear envelope defects (LMNA).

Subepicardial and mid-wall scar creates re-entry circuits. Inflammatory "hot phases" with troponin rise are common with DSP variants and often precede scar progression.

Phenotype ranges from isolated arrhythmia with preserved ejection fraction to arrhythmogenic dilated cardiomyopathy with heart failure.

Presentation includes palpitations, syncope, aborted sudden death, recurrent chest pain with troponin rise, and later heart failure. Genotype specific features include:

• LMNA and DES: atrioventricular block, atrial arrhythmia and, for DES, skeletal myopathy.
• FLNC and PLN: high ventricular arrhythmia burden even at modest LV dysfunction.
• TMEM43 (S358L): male sex with early, severe disease.

• ECG: low limb lead voltage, inferolateral or lateral T-wave inversion, and ventricular ectopy with right bundle branch block morphology; conduction disease points to LMNA or DES.
• Cardiac MRI: subepicardial or mid-wall ring like LGE with relatively normal RV; the key test, with fat infiltration.
• Echocardiography and ambulatory ECG for ejection fraction and ventricular ectopy burden.
• Coronary assessment to exclude ischaemia, and troponin in hot phases.
• Genetic testing with careful interpretation; creatine kinase when DES or skeletal myopathy is suspected.
• Exclusion of myocarditis, sarcoidosis, ischaemic cardiomyopathy and dilated cardiomyopathy.

Differential diagnosis.

• Acute or healed myocarditis and cardiac sarcoidosis.
• Dilated cardiomyopathy and ischaemic cardiomyopathy.
• Chagas cardiomyopathy (regional) and hypertrophic cardiomyopathy.
• Classic right ventricular arrhythmogenic cardiomyopathy.

Exercise. Avoid competitive and endurance sport, since exercise accelerates disease and arrhythmia.

Drug therapy.

• Beta blocker: 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), long term; monitor heart rate, blood pressure and conduction; avoid or use cautiously with high grade AV block unless paced; reduce bisoprolol in eGFR under 20 mL/min/1.73 m2.
• Sotalol: 80 to 160 mg orally twice daily; maximum 320 mg daily; QTc and electrolytes; stop if QTc over 500 ms; avoid if 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 daily; thyroid and liver tests every 6 months.
• Heart failure treatment for ejection fraction under 40%: sacubitril/valsartan 24/26 mg to 97/103 mg twice daily, spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30), dapagliflozin 10 mg daily (eGFR 25 or over); monitor potassium and creatinine.
• Catheter ablation for recurrent ventricular tachycardia (epicardial access is often needed).

Genotype directed device therapy.

• ICD for secondary prevention in all genotypes.
• Primary prevention: lower ejection fraction thresholds than the usual 35% are used for high risk genotypes. For FLNC truncating, PLN R14del, LMNA, DSP and TMEM43, discussion of ICD begins at an ejection fraction under 45 to 50%, earlier with extensive LGE, non-sustained ventricular tachycardia, syncope, or in men.
• For LMNA and DES with atrioventricular block, use a defibrillator capable device rather than a pacemaker alone.

Hot phases. Admit, avoid exercise, treat arrhythmia, and exclude coronary disease. Immunosuppression is of unproven benefit.

Anticoagulation for atrial fibrillation (common with LMNA and DES): apixaban 5 mg twice daily (2.5 mg 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. Clinical review, ECG, echocardiography and ambulatory ECG every 6 to 12 months; cardiac MRI every 2 to 3 years or with change; device interrogation every 3 to 6 months.

Referral and escalation. Refer all patients to an inherited cardiac condition service for genotype directed risk assessment. Urgent referral for syncope, sustained ventricular tachycardia, aborted sudden death, hot phase chest pain with raised troponin and normal coronaries, atrioventricular block (LMNA, DES), ejection fraction under 45%, heart failure, or a family history of sudden death under age 50.

Special groups.

• Pregnancy: counselling before conception; continue metoprolol; ARNI, ACE inhibitors, spironolactone and SGLT2 inhibitors are stopped; lamin and DES disease carry higher maternal risk.
• Relatives: cascade genetic testing with serial ECG, ambulatory ECG, echocardiography and MRI every 1 to 3 years, from adolescence or earlier with early onset family history.
• Region specific: exclude Chagas disease in endemic areas.