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The role of exercise in gene-elusive ARVD/C

Comment by Luis Serratosa, EACPR Sports Cardiology Section


Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterised by ventricular arrhythmias, predominant right ventricular disfunction and an increased risk of sudden cardiac death. We already know that up to 60% of ARVD/C patients have mutations in genes encoding the cardiac desmosome, and the authors of this article have previously reported that this group of patients have an increased risk of developing ARVD/C.

It has been suggested that, in these ARVD/C patients with desmosomal mutations, the mechanical load of exercise may render the desmosomal junctions, susceptible to pathogenic remodelling. The aim of this study was to elucidate whether exercise is associated with disease in ARVD/C patients without desmosomal mutations (gene-elusive), and whether exercise intensity and duration associated with disease expression differs in patients with and without desmosomal mutations.

Eighty two ARVD/C patients, who met 2010 ARVD/C Task Force Criteria (39 with desmosomal mutations, all probands) from the ARVD/C Johns Hopkins registry, were interviewed about regular physical activity since age 10. Duration (hours/year) and intensity (Metabolic Equivalent of Task [MET]-hours/year) of exercise prior to clinical presentation were calculated. Patients were classified as endurance athletes if they had participated in sports with a high dynamic demand (Classification of Sports, 36th Bethesda Conference) for at least 50 hours/year of vigorous intensity.

The main findings of this study were that all gene-elusive ARVD/C patients fell into the endurance athletes category and did significantly more intense exercise prior to presentation than desmosomal mutation carriers. The results also revealed that the prevalence of family history among gene-elusive patients was significantly lower (9% vs 40% desmosomal) and that the gene-elusive non familial ARVD/C patients had done the most intense exercise by far. These findings suggest the greater importance of the environmental influence and specifically of exercise as a key factor, in the pathogenesis of ARVD/C in patients without desmosomal mutations. Finally, phenotype appears also to be influenced by exercise. Gene-elusive patients, who had done the most intense exercise prior to presentation, had a younger age of presentation, worse structural disease, and shorter freedom from ventricular arrhythmias in follow-up.

While it is true that the study findings suggest a strong influence of exercise on the pathogenesis of at least some cases of gene-elusive ARVD/C, it would be completely inappropriate, as the authors recognise, to conclude that these patients have an entirely acquired disease. Susceptibility to develop the disease in these gene-elusive ARVD/C patients is likely based largely on genetic background. The authors point to investigating other genes, which expression could be influenced by regular exercise, like those encoding proteins of the adherens junction and the ones involved in the hemodynamic response to exercise.

The study has also clinical implications. As exercise negatively influences cardiac structure and function in at least some gene-elusive ARVD/C patients, exercise restriction should be recommended in these patients.