Inherited arrhythmogenic cardiomyopathy (ORPHA:247)
A heart muscle disease that consists in progressive dystrophy of primarily the right ventricular myocardium with fibro-fatty replacement and ventricular dilation, and that is clinically characterized by ventricular arrhythmias and a risk of sudden cardiac death.
Epidemiology
Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a reported prevalence of 1/2,500 to 1/5,000.
Clinical description
ARVC has a variable clinical picture. ARVC can be asymptomatic, or present, usually during adolescence, with ventricular arrhythmias with palpitations, chest pain, dizziness, fatigue, or syncope. All patients are at risk of sudden death, particularly during exertion. Although predominantly a disease of the right ventricle, ARVC may also involve the left ventricle (ARVC left dominant form) or both (ARVC biventricular form), the latter leading in later stages to progressive biventricular failure. ARVC can be associated with palmoplantar keratoderma and woolly hair, the so-called cardio cutaneous syndromes (Naxos disease and Carvajal syndromes, see these terms).
Etiology
ARVC results from a fibro-fatty replacement of myocardium. It is believed to be a disease of desmosomes with impaired cell-to-cell contact and signaling Mutations have been observed in genes encoding for proteins of the cardiac desmosomes (JUP;  DSP;  PKP2;  DSG2; and  DSC2). However, in a minority of patients, mutations in non-desmosomal genes (TGFβ3;  TMEM43/LUMA; DES; CTNNA3; PLN; LMNA; TTN) have also been detected. Variable penetrance is found, suggesting a role for additional genetic or environmental modifiers. Compound/digenic heterozygosity is identified in up to 25% of mutation carriers and seems an additional risk factor. Recent investigations point to a role of the canonical Wnt signaling pathway in the pathogenesis of ARVC.
Diagnostic methods
Diagnosis is based on a scoring system taking into account right ventricle structural and functional abnormalities (dilatation, akinesia, dyskinesia, aneurysms) detected by echocardiography, MRI and angiography; electrocardiographic features (inverted T waves in right precordial leads, epsilon waves and late potentials by signal averaged ECG (SAECG), left bundle branch block ventricular tachycardia, >500 ventricular extrasystoles per 24 h); tissue characterization at endomyocardial biopsy (fibro-fatty replacement of myocardium); and family history. Contrast enhanced MRI substantially enhances the diagnostic sensitivity, particularly in left ventricle variants, while electroanatomic mapping is superior in detecting early RV involvement.
Differential diagnosis
Differential diagnosis includes idiopathic RV outflow tract tachycardia, myocarditis, sarcoidosis and congenital heart diseases (see these terms).
Antenatal diagnosis
Although prenatal diagnosis through amniocentesis is feasible, it is subject to ethical and legal considerations.
Genetic counseling
In more than half of the patients, the disease is familial, primarily autosomal dominant with variable penetrance and polymorphic expressivity. Naxos disease and Carvajal syndrome show an autosomal recessive mode of inheritance. The success rate of genotyping depends on several factors (such as cohort location and ethnicity) and hence requires specialized counseling.
Management and treatment
Risk stratification remains largely empiric and therapeutic interventions include antiarrhythmic drugs like beta-blockers, sotalol and amiodarone, catheter ablation, implantable cardioverter-defibrillator. In refractory congestive heart failure or untreatable ventricular arrhythmias, heart transplantation can be also considered. Since effort is a trigger for disease progression and arrhythmias, competitive sport and moderate to high intense physical activity should be avoided.
Prognosis
The disease progression is variable. Risk factors for sudden death include a history of aborted sudden death, syncope, young age, decreased left ventricular function, and marked decrease in right ventricular function.

                            Last update: 
                            December 2015


                            - Expert reviewer(s): 
                            Pr Cristina BASSO  - Dr Domenico CORRADO  - Pr Kalliopi PILICHOU  - Pr Gaetano THIENE