Arrhythmogenic
cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in
proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from
premature ventricular contractions to
sudden cardiac death and
heart failure. Among other drivers and modulators of phenotype,
inflammation in response to
viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and
necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active
myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk
autoantibodies in patients with
arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to
genetic predisposition to progressive myocardial damage, a heritable susceptibility to
viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of
inflammation/immune response in ACM is not entirely clear,
inflammation as a driver of phenotype and a potential target for mechanism-based
therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.