Arrhythmogenic right ventricular cardiomyopathy is a disease of cardiac stem cells.
OBJECTIVE
To review recent developments in clinical aspects, molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC).


RESULTS
ARVC is a primary disease of the myocardium characterized by fibro-adipocytic replacement of myocytes, predominantly in the right ventricle. Phenotypic expression of ARVC is variable and a significant number of patients may exhibit a subtle phenotype, particularly in the early stages of the disease. Mutations in DSP, JUP, PKP2, DSG2 and DSC2, encoding desmosomal proteins desmoplakin, plakoglobin, plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), respectively, cause ARVC. Thus, ARVC, at least in a subset, is a disease of desmosomes. In addition, mutations in TMEM43 and TGFB1 have been associated with ARVC. Mechanistic studies indicate that suppressed canonical Wnt signaling, imposed by nuclear plakoglobin, is the responsible mechanism for the pathogenesis of ARVC. It leads to the differentiation of a subset of second heart field cardiac progenitor cells at the epicardium to adipocytes due to enhanced expression of adipogenic factors. This mechanism explains the predominant involvement of the right ventricle in ARVC. Hence, ARVC is the first identified disease of disrupted differentiation of cardiac progenitor cells.


CONCLUSIONS
Advances in molecular genetics and the pathogenesis of ARVC could afford the opportunity for a genetic-based diagnosis and development of novel diagnostic markers and therapeutic targets aimed to prevent, attenuate and reverse the evolving phenotype.
Lombardi
Raffaella
R
Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas 77030, USA.
Marian
Ali J
AJ
D017667:Adipocytes / Q000378:metabolism; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D002454:Cell Differentiation / Q000235:genetics; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008967:Molecular Biology; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*