Arrhythmogenic Cardiomyopathy

Inherited disease of the myocardium in which myocytes are progressively replaced by fibrofatty tissue, producing ventricular arrhythmia, sudden cardiac death and heart failure. It begins in the right ventricle in most cases but often involves the left ventricle (biventricular or left dominant forms).

• Prevalence is about 1 in 2000 to 1 in 5000. Inheritance is mostly autosomal dominant with incomplete penetrance and variable expression; recessive forms with skin and hair features (palmoplantar keratoderma, woolly hair) occur.
• Genes: desmosomal (PKP2 in about 40%, DSP, DSG2, DSC2, JUP) and non-desmosomal (TMEM43, PLN, FLNC, DES). Some variants (TMEM43 in particular) carry high risk of sudden death.
• Presentation is in the second to fourth decades, often with sudden death in young athletes. Endurance exercise accelerates disease and raises arrhythmic risk. Episodes of "hot phases" (chest pain, troponin rise, ventricular arrhythmia, resembling myocarditis) occur.

• Palpitations, presyncope, syncope, and sustained ventricular tachycardia (usually with left bundle branch block morphology from the right ventricle), cardiac arrest, or sudden death; chest pain in hot phases; heart failure late in the course.
• Family history of premature sudden death or cardiomyopathy; skin changes in recessive forms.
• Differential diagnosis: idiopathic right ventricular outflow tract tachycardia (benign, structurally normal heart), sarcoidosis, myocarditis, dilated cardiomyopathy (with left ventricular involvement), Brugada syndrome, athlete's heart (right ventricular enlargement with preserved function), congenital heart disease with right ventricular volume overload (atrial septal defect, anomalous pulmonary venous return), Uhl anomaly, and pulmonary hypertension.
• Complications: sustained ventricular tachycardia and fibrillation, sudden cardiac death, right and left heart failure, atrial fibrillation, and intracardiac thrombus.

• Diagnosis rests on a combination of structural abnormality, tissue characterisation, ECG abnormalities, arrhythmia and family or genetic evidence; a definite diagnosis needs two major, or one major plus two minor, or four minor features from different categories.
• ECG: T wave inversion in V1 to V3 beyond age 14 (without right bundle branch block), epsilon waves (small deflections after the QRS in V1 to V3), prolonged terminal QRS activation (55 ms or more), low voltage in limb leads in late disease. Signal averaged ECG for late potentials.
• Holter monitoring: more than 500 ventricular ectopic beats per 24 hours is abnormal; non-sustained and sustained ventricular tachycardia of left bundle branch block morphology.
• Echocardiography and cardiac MRI: right ventricular dilatation, regional akinesia, dyskinesia or aneurysm, reduced right ventricular ejection fraction (less than 40% is major), left ventricular involvement; MRI shows late gadolinium enhancement (fibrosis) and, less reliably, fatty infiltration.
• Endomyocardial biopsy of the right ventricular septum is rarely needed (residual myocytes less than 60% with fibrous replacement). Genetic testing in the proband and cascade screening.
• Exercise testing for ventricular ectopy; electrophysiology testing for risk stratification in selected cases.

• Lifestyle: avoid competitive and endurance sport and high intensity exercise in all patients, including gene carriers; light to moderate recreational activity is acceptable.
• Drug therapy:
  • Beta blocker for all patients: bisoprolol 2.5 to 10 mg daily, or nadolol 40 to 160 mg daily, or metoprolol succinate 50 to 200 mg daily.
  • Sotalol 80 to 160 mg twice daily for recurrent ventricular arrhythmia (monitor QT, potassium and renal function).
  • Amiodarone 400 mg daily for 2 to 4 weeks then 200 mg daily for refractory arrhythmia (thyroid, liver and lung monitoring).
  • Flecainide 50 to 100 mg twice daily, only combined with a beta blocker, for selected patients without severe structural disease under specialist care (evidence is limited).
• Implantable cardioverter defibrillator:
  • Secondary prevention: survivors of cardiac arrest, sustained ventricular tachycardia or haemodynamically unstable arrhythmia.
  • Primary prevention: syncope presumed arrhythmic, severe right or left ventricular dysfunction (ejection fraction 35% or less), or high estimated risk from a validated risk calculator (age, sex, recent syncope, non-sustained ventricular tachycardia, ectopic burden, number of leads with T inversion, right ventricular ejection fraction).
• Catheter ablation (endocardial and epicardial) for recurrent ventricular tachycardia or shocks despite drugs; success is about 50 to 80% initially, with recurrence in about half at 5 years. It does not remove the need for a defibrillator.
• Heart failure therapy: ramipril 2.5 to 10 mg daily, bisoprolol 1.25 to 10 mg daily, spironolactone 25 to 50 mg daily, furosemide 20 to 80 mg daily; sacubitril/valsartan 24/26 mg twice daily titrated to 97/103 mg twice daily as an alternative to the ACE inhibitor.
• Anticoagulation: warfarin to INR 2.0 to 3.0 for atrial fibrillation, intracardiac thrombus or aneurysm with thrombus.
• Heart transplantation for refractory heart failure or incessant arrhythmia (about 5 to 10% over the course of disease).
• Genetic counselling and cascade screening of first degree relatives: ECG, echocardiography, cardiac MRI, Holter, and genetic testing for the family variant from age 10 to 12, repeated every 1 to 3 years (yearly in adolescence and young adulthood).
• Special groups:
  • Pregnancy: usually tolerated with preserved function; continue metoprolol and avoid atenolol, amiodarone, ACE inhibitors, sacubitril/valsartan, spironolactone and SGLT2 inhibitors; manage with a cardiology team.
  • Children and adolescents: restrict sport; screen from pre-adolescence if the family variant is known.
  • Athletes: advise permanent withdrawal from competitive sport.
• Red flags: syncope, palpitations, implantable defibrillator shock, chest pain with troponin rise, new heart failure, family history of sudden death.
• Follow up: every 6 to 12 months with ECG, Holter, and echocardiography; cardiac MRI every 1 to 3 years or with a change in symptoms; defibrillator interrogation every 3 to 6 months.