Remodeling of cell-cell junctions in arrhythmogenic cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is a primary myocardial disorder characterized by a high incidence of ventricular arrhythmias often preceding the onset of ventricular remodeling and dysfunction. Approximately 50% of patients diagnosed with AC have one or more mutations in genes encoding desmosomal proteins, although non-desmosomal genes have also been associated with the disease. Increasing evidence implicates remodeling of intercalated disk proteins reflecting abnormal responses to mechanical load and aberrant cell signaling pathways in the pathogenesis of AC. This review summarizes recent advances in understanding disease mechanisms in AC that have come from studies of human myocardium and experimental models.

Figure 1

(A) Representative confocal immunofluorescence images of control myocardium and myocardium from a patient with Naxos disease and a patient with Carvajal syndrome. Specific immunoreactive signal for plakoglobin was significantly depressed in both cases compared to controls, as was signal for the major gap junction protein Cx43. Immunoreactive signal for desmoplakin was depressed at intercalated disks in Carvajal syndrome but not in Naxos disease. Signal for the non-desmosomal adhesion protein N-cadherin was present and control-like in both cases. (B) Western Immunoblots using an N-terminal plakoglobin antibody showed that the mutant plakoglobin form (2057del2) is expressed in left and right ventricular myocardium from a patient with Naxos disease. Mutant plakoglobin migrates at a lower molecular weight than the wildtype protein. 2057del2 plakoglobin cannot be detected when a C-terminal plakoglobin antibody is used (reproduced from Kaplan et al Heart Rhythm 2004; 1)

Figure 2

Representative confocal immunofluorescence images of control myocardium and myocardium from two patients with autosomal dominant ARVC. Specific immunoreactive signal for plakoglobin was depressed at cell-cell junctions in the great majority of cases regardless of the underlying pathogenic mutation. Signal for desmoplakin and plakophilin2 varied, while signal for N-cadherin was always present and indistinguishable from controls. The majority of cases examined showed gap junction remodeling as evidenced by decreased junctional signal for Cx43 (reproduced from Asimaki et al. NEJM 2009; 360:1078).

Figure 3

Immunofluorescence images of endomyocardial biopsy samples from two patients diagnosed with ARVC and one with idiopathic dilated cardiomyopathy, all carrying the PLN R14del mutation, compared to a control sample. Immunoreactive signal for plakoglobin at cell-cell junctions was significantly depressed in the ARVC subjects compared to controls and the dilated cardiomyopathy patient (reproduced from Van der Zwaag et al. Eur J Heart Fail 2012; 14:1204).