Abstract
Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease characterized by fibrotic or fibrofatty myocardial replacement, associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Originally described as a disease of the right ventricle, ACM is currently recognized as a biventricular entity, due to the increasing numbers of reports of predominant left ventricular or biventricular involvement. Research over the last 20 years has significantly advanced our knowledge of the etiology and pathogenesis of ACM. Several etiopathogenetic theories have been proposed; among them, the most attractive one is the dystrophic theory, based on the observation of similar histopathological features between ACM and skeletal muscle dystrophies (SMDs), such as progressive muscular degeneration, inflammation, and tissue replacement by fatty and fibrous tissue. This review will describe the pathophysiological and molecular similarities shared by ACM with SMDs.
Highlights
Three main etiopathogenetic theories have been proposed to explain the origin and development of the Arrhythmogenic cardiomyopathy (ACM) phenotype: (Basso et al, 1996; Towbin et al, 2019) the dysontogenetic theory considers ACM as a developmental disorder of the right ventricle (RV) (Marcus et al, 1982; Sen-Chowdhry et al, 2008), the myocarditis theory based on the evidence of inflammation in ACM hearts (Basso et al, 1996; Campian et al, 2010; Miles et al, 2019; Protonotarios et al, 2019) and the dystrophic theory, based on the histopathological similarities between ACM and skeletal muscle dystrophies (SMDs)
The findings suggest a primary role of autoimmunity in the pathogenesis of ACM, as observed previously in primary dilated cardiomyopathy (Caforio et al, 1994), and open the stage to the potential therapeutic use of immunosuppression in biopsy-proven virusnegative autoantibody-positive inflammatory ACM
Since ACM and SMD show similar fibroadipocytic replacement of muscle, we surmised that the heart, like skeletal muscle, might contain resident fibroadipocyte progenitors (FAPs), which could differentiate to adipocytes in the presence of chronic injury due to the presence of mutant desmosomal proteins
Summary
Arrhythmogenic cardiomyopathy (ACM) is a primary heritable disease of the myocardium, clinically characterized by increased risk of ventricular arrhythmias and sudden cardiac death (SCD) (Towbin et al, 2019).ACM includes arrhythmogenic right ventricular cardiomyopathy (ARVC), which affects the right ventricle (RV); left dominant arrhythmogenic cardiomyopathy (LD-ACM), in which the left ventricle is the first chamber to be affected; and biventricular ACM (Sen-Chowdhry et al, 2008; Miles et al, 2019).The histological feature of ACM is the progressive replacement of the myocardium with fibrotic or fibrofatty tissue, typically starting from the epicardium (Lombardi and Marian, 2010; Basso et al, 2011).Three main etiopathogenetic theories have been proposed to explain the origin and development of the ACM phenotype: (Basso et al, 1996; Towbin et al, 2019) the dysontogenetic (dysplasia) theory considers ACM as a developmental disorder of the RV (Marcus et al, 1982; Sen-Chowdhry et al, 2008), the myocarditis theory based on the evidence of inflammation in ACM hearts (Basso et al, 1996; Campian et al, 2010; Miles et al, 2019; Protonotarios et al, 2019) and the dystrophic theory, based on the histopathological similarities between ACM and skeletal muscle dystrophies (SMDs)Arrhythmogenic Cardiomyopathy and Skeletal-Muscle Dystrophy (Pearce et al, 1981; Hadar et al, 1983; Lombardi and Marian, 2010; Basso et al, 2011). ACM is a cardiac pathology while SMD affects mainly the skeletal muscle, the two diseases share histological features as well as molecular and cellular pathogenic mechanisms.
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