Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice

Abstract

Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice. Methods and Results-Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin ϩ/Ϫ ) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all PϽ0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin ϩ/Ϫ hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin ϩ/Ϫ mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals. Conclusions-Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

“…13,14 Mice with heterozygous plakoglobin mutations (Jup+/−) were indistinguishable from their wild-type littermates at birth, but showed RV dilatation and dysfunction, and ventricular arrhythmias by 6 months of age. These phenotypes were exacerbated by exercise (daily swimming for 2 months), 15 supporting the impression that endurance training could accelerate disease progression among individuals with ARVD/C. Despite these findings, histologic analysis of myocardium from Jup+/− mice did not show any fibrofatty infiltration, and electron microscopy studies revealed no structural changes in the desmosomes or adherens junctions.…”

“…Furthermore, gene-expression profiling of wild-type and heterozygous mice showed no statistical differences in gene expression patterns. 15 …”

Impact of Exercise Restriction on Arrhythmic Risk Among Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

“…These recommendations are based on the evidence that exercise is associated with the development and increased severity of the ARVC phenotype both in animal18, 19 and human studies 2, 3, 4. However, whether reduction in exercise after diagnosis affects the disease trajectory is largely unknown.…”

Exercise: A Risky Subject in Arrhythmogenic Cardiomyopathy

“…The link between ACM diagnosis and increased risk of sudden cardiac death in the athletic population has been recognized since the early description of the disease, in both patients and animal models 3, 4. In recent years, the work of James et al5 and Sawant et al6 provided a strong quantitative set of data, further corroborated by additional studies,7, 8 showing that exercise is a major contributor to disease progression in ACM.…”