Arrhythmogenic right ventricular cardiomyopathy is a disease of cardiac stem cells

Abstract

Purpose: To review recent developments in clinical aspects, molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC).

Recent findings: 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.

Summary: 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.

Figure 1

Myocardial section stained with Masson trichrome showing replacement of cardiac myocytes by adipocytes and fibrosis in a patient with ARVC

Figure 2

Schematic structure of a desmosome and its protein constituents.

Figure 3

Pathogenesis of ARVC. Mutations in desmosomal proteins interfere with efficient and proper assembly of desmosomes, which allows the plakoglobin (PG) to translocate from desmosomes to the nucleus. In the nucleus, PG interferes with proper assembly of the Wnt canonical signaling protein complex and suppresses gene expression through the β-catenin/Lef7l2 transcriptional assembly. The net effect is removal of the inhibitory effects of the canonical Wnt signaling and hence increased expression of bone morphogenic protein 7 (BMP7) and noncanonical Wnt5b, which are known promoters of adipogenesis. Likewise, suppression of the canonical Wnt signaling reduces expression of connective tissue growth factor (CTGF), which is a known inhibitor of adipogenesis. The transcriptional switch from myogenesis to adipogenesis promotes the differentiation of a subset of second heart field progenitor cells to adipocytes.