Pathogenesis of Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease. It is characterized by frequent ventricular arrhythmias and increased risk of sudden cardiac death typically arising as an early manifestation before the onset of significant myocardial remodelling. Myocardial degeneration, often confined to the right ventricular free wall, with replacement by fibrofatty scar tissue, develops in many patients. ACM is a familial disease but genetic penetrance can be low and disease expression is highly variable. Inflammation might promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbour mutations in genes that encode desmosomal proteins, which has raised the possibility that defective cell-cell adhesion might play a role in disease pathogenesis. Recent advances have implicated changes in the canonical wingless-type mouse mammary tumour virus integration site (Wnt)/β-catenin and Hippo signalling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. In this review we summarize the current understanding of the pathogenesis of ACM and highlight future research directions.

Figure 1

Schematic diagram of area composita: adherens junction and desmosomal proteins form a hybrid enforced junction structure that is attached to both the actin and the intermediate filament cytoskeleton (modified from Li and Radice. Dermatol Res Pract 2010).

Figure 2

Confocal immunofluorescence microscopy analysis of control and ACM left ventricular myocardium. Immunoreactive signal for plakoglobin at cardiac intercalated disks was markedly reduced in both ACM samples, while signal for the non-desmosomal protein N-cadherin was strong and indistinguishable from controls (modified from Asimaki et al. NEJM 2009).

Figure 3

Representative confocal immunofluorescence images of control ventricular myocardium and myocardium from two patients with ACM. Specific immunoreactive signal for Cx43 (A) and Nav1.5 (B) is significantly depressed at intercalated disks in both ACM cases. Changes in I_Na current density in zebrafish myocytes expressing 2057del2 plakoglobin (C).

Figure 4

Cultures of neonatal rat ventricular myocytes (NRVMs) were treated with anti-SAP97 shRNA for 72hrs. Non-specific shRNA was used as a negative control. Knock-down of SAP97 had no effect on the distribution of N-cadherin, desmoplakin, plakophilin2 and Cx43. It did, however, significantly reduce junctional signal for Nav1.5 and plakoglobin. Arrows point to immunoreactive signal concentrated at cell-cell junctions.

Figure 5

Representative confocal immunofluorescence images showing restoration of localization of plakoglobin and Cx43 in NRVMs expressing a mutant form of plakoglobin (2057del2) following 24hrs treatment with SB216763 (A). Western immunoblots showing the total cellular content for plakoglobin and Cx43 in transfected NRVMs in the presence or absence of SB216763 (B). TUNEL labeling of control NRVMs and NRVMs expressing 2057del2 plakoglobin in the presence or absence of SB2. White arrow point to apoptotic nuclei. *P<0.01 versus controls, **P<0.001 versus untreated transfected myocytes; 2-tailed student’s t-test (C). Effects of SB216763 on inflammatory cytokines secreted by NRVMs expressing 2057del2 plakoglobin (D).