Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50 % of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/ digenic heterozygosity was identified in up to 25 % of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis. AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC. Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.Arrhythmogenic Cardiomyopathy-key points summary

Inherited cardiomyopathies

“…A US population based study estimated the prevalence of DCM at 1 in 2500 adults,5 but this is considered an underestimate and true prevalence is possibly closer to 1 in 250 6. ACM is rarer, with a global prevalence of approximately 1 in 2000 to 1 in 5000 adults 78…”

Cardiomyopathies

“…52 The increasing recognition of left ventricular involvement has been responsible for the change in designation from arrhythmogenic right ventricular cardiomyopathy to arrhythmogenic cardiomyopathy. 7 Treatment consists of the cessation of heavy physical exertion and competitive athletics. For patients with recurrent ventricular tachycardia, epicardial catheter ablation may be effective.…”

To Seek the Holy Grail of Cardiac Progenitor Cells

“…The prominent role of cell junctions in regulating the Hippo pathways is exemplified in arrhythmogenic right ventricular cardiomyopathy (ARVC), which is primarily a disease of cell junction proteins. 7 The Hippo pathway is markedly activated in ARVC and contributes to the pathogenesis of its phenotype. 8 Likewise, mechanisms that affect cell cytoskeleton and F-actin organization, such as the G-protein-coupled receptor (GPCR) signaling, also regulate gene expression through the YAP1-WWTR1-TEAD transcriptional complex.…”