Athletic Status and Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy: From Physiological Observations to Pathological Explanation

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heritable condition characterized by replacement of cardiomyocytes, primarily in the right ventricle, by fibrofatty tissue. A number of genetic studies have identified mutations in various components of cardiac desmosomes that appear to precede fibrofatty replacement. The resulting disruption of normal myocardial architecture in ARVD/C results in right ventricular (RV) dysfunction, life-threatening arrhythmias and sudden cardiac death. There is a striking incidence of athletic individuals affected by this disease. Currently there is no explanation for the association between athletic activity and development of ARVD/C. The goal of this paper is to suggest that increased levels of nitric oxide (NO) and reactive oxygen species, secondary to endurance exercise, initiates a cascade of reactions leading to fibrofatty changes in the RV and thus ARVD/C. This involves increased expression of adipogenic and fibrogenic genes as one of the steps in pathogenesis. According to the hypothesis, arrhythmias can happen in the presence or absence of pathological changes secondary to NO effects on remodeling and ion channels, respectively. Furthermore, the different effects of prolonged exercise on the RV and left ventricle (LV) could help explain the incidence of ARVD/C as a primarily RV disease. Verification of this hypothesis would have prognostic and management implications. Drugs inhibiting NO production might benefit patients with ARVD/C. A better understanding of exercise physiology in terms of NO production would help to redefine the management scheme in terms of exercise in patients with ARVD/C. A redirection of research towards identification of special physiological markers would be appropriate, and may reveal additional steps leading from tissue exposure to NO, to pathological changes.