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At a glance

A usually inherited and progressive cardiomyopathy with an increased risk of ventricular arrhythmias and dysfunction and sudden cardiac death in typically otherwise healthy young adults.

Synonyms

(Familial) Arrhythmogenic Right Ventricular Dysplasia; ARVD Syndrome.

Incidence

The exact prevalence is unknown, but estimates range from 0.2 to 1 in 1,000 in the general population, with higher rates in Caucasians (higher prevalence in certain parts of Italy [Veneto] and Greece [Naxos Island]) and people participating in physically strenuous activities (eg, athletes). Young adult men are approximately three times more often affected than women. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is estimated to account for up to 20% of unexpected sudden cardiac deaths (SCD) in young individuals and for 3 to 4% of SCD occurring during sports.

Genetic inheritance

Autosomal dominant with incomplete penetrance and variable expressivity. A more severe expression with autosomal recessive inheritance, similar to Naxos disease, has been described. However, a substantial proportion of patients have neither a detectable mutation nor a family history of ARVC. ARVC Type 1 is the most common form with mutations in the Beta-type 3 transforming growth factor (TGFB3) that has been mapped to chromosome 14q24.3. However, depending on the gene mutations, twelve different types of ARVC have been described to date (ARVC 7 is now considered a Desmin-related myofibrillar myopathy). The spectrum of phenotypic variation and age-related penetrance is wide. Because of age-dependent penetrance, symptomatic gene carriers require life-long surveillance, while family members who are non-carriers are unlikely to develop the disease.

Pathophysiology

Progressive replacement of the right ventricular (RV) free wall myocardium by fibrofatty tissue starts in the subepicardium (or midmyocardium) and then spreads transmurally. Further progression results in wall thinning and aneurysms, earlier considered to typically affect the so-called “triangle of dysplasia” (ie, the apex, RV in- and outflow tract), while recent findings suggest that more commonly the basal RV free wall, LV lateral wall, and the epicardial subtricuspid region are affected. While the name ARVC implies isolated right ventricular disease, left ventricular involvement is present in more than half of the patients and although it is usually limited to the posterolateral subepicardium and sparing the endocardium, it can nevertheless lead to severely reduced left ventricular function. Early attempts to explain the cause and progression of ARVC involved dysplastic, dystrophic, and inflammatory hypotheses. However, the discovery of desmosomal mutations favored the theory of a genetically triggered impairment of desmosomal function resulting in detachment and death of cardiomyocytes, particularly when exposed to increased mechanical stress. Desmosomes consist of multiple proteins that form a macromolecular complex and attach cells to each other and connect the intermediate filaments of neighboring cells at the intercalated disc. Abnormal desmosome function secondary to the genetic defect causes injury and eventually death of cardiomyocytes in response to mechanical stress, which might explain why ...

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