Exercise has a Disproportionate Role in the Pathogenesis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in Patients Without Desmosomal Mutations

PAPER OF February 2015

Authors: Abhishek C. Sawant, Aditya Bhonsale, Anneline S. J. M. te Riele, Crystal Tichnell, Brittney Murray, Stuart D. Russell, Harikrishna Tandri, Ryan J. Tedford, Daniel P. Judge, Hugh Calkins, Cynthia A. James.
J Am Heart Assoc. 2014 Dec;3(6):e001471. doi: 10.1161/JAHA.114.001471.

Presented by: Dr. Antonis Pantazis - Heart Hospital, University College London, London, United Kingdom. (UK)  E-mail: a.pantazis@nhs.net.

BACKGROUND

There is increasing evidence that exercise influences phenotypic penetrance of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). In the present study, authors aim to study the role of exercise in desmosomal gene negative patients.

METHODS AND RESULTS

82 ARVC patients were interviewed about their physical activity and were subdivided in endurance athletes (high dynamic demand done for at least 50 hours/year at a vigorous intensity) and non-athletes. 43 of them were genotype negative ARVC (so-called “gene-elusive”) patients. Duration of exercise was calculated for every activity separately and summed to achieve the total hours spent exercising. Intensity was calculated using MET-hours: a MET was assigned for every exercise activity.

All gene-elusive ARVC patients had been endurance athletes. The activities reported by patients were various (swimming, tennis, squash, running, soccer, rowing) and a sub-analysis considering the differences in sports is not available, probably because of the small numbers. Age of beginning of endurance exercise and duration of annual exercise were similar to desmosomal patients, but gene-elusive exercise was significantly more intense (p<0.001), particularly among cases presenting < age25 (p=0.027) and the ones without family history (p=0.004). Gene-elusive patients with history of most intensive exercise had a younger age of presentation (p=0.025) and shorter survival free from ventricular arrhythmia in follow up (p=0.002). Authors therefore conclude that gene-elusive non-familial ARVC is associated with very high intensity exercise, providing further evidence that exercise has a role in the pathogenesis of ARVC, also in gene-elusive ARVC patients.

Physical activity is associated with an increased risk of sudden cardiac death. The right ventricle is likely to be particularly susceptible to exercise-induced injury. This seems to be linked to high-intensity endurance activities, particularly those activities that are of long duration and combine endurance and power. An exercise-induced form of ARVC in which excessive, repetitive wall stress causes disruption of normal desmosomes resulting in the phenotype has been recognized.

This hypothesis is supported by a relatively low prevalence of both familial disease and desmosomal mutations in athletic cohorts. Additionally, animal models, case reports and recent human studies suggest that exercise can change the expression and course of ARVC. A study conducted on positive PKP2 mice trained for 10 months showed an increased right ventricular volume, spontaneous ventricular ectopic and reduced right ventricular function. The same authors of this paper have already shown that endurance exercise and frequent exercise increase the risk of VT/VF, HF and ARVC in desmosomal mutation carriers. A different study from another group has also shown that exercise influence the phenotype between genotype positive family members: mutation positive athletes family members show an impaired RV ejection fraction and impaired RV function by RV fractional area change and RV global longitudinal when compared with non-athletes family members.

In this paper, authors provide further evidence that exercise influences the right ventricle and the ARVC phenotype. They also point out that the intensity of exercise represents a primary difference between ARVC patients with and without desmosomal mutations. Gene-elusive patients had low incidence of familial disease and the history of exercise was not different between gene-elusive patients with familial disease and desmosomal patients. These results generate the suspicion that those gene-elusive patients have an acquired disease. This can be further hypothesized, if we consider that there is overlap between the electrophysiological imaging findings in ARVC and athlete’s heart. However, many of the electrical and morphological findings in athletes resolve with detraining. On the other hand, as mentioned by the authors, the incidence of familial cases is underestimated in the gene-elusive group of patients since families in which probands were deceased were excluded according to the study design.

Differences have been previously reported in exercise effects between females and males (ie, sudden cardiac death is more prevalent in male athletes than females). In this study, no gender differences were observed between gene-elusive and desmosomal patients but no further analysis according to gender have been performed.

Gene-elusive patients require a higher intensity of exercise to develop the disease compared to the desmosomal patients. This supports the hypothesis that exercise is an environmental factor for the disease expression and its combination with the genetic substrate facilitates the development of the phenotype. Further analysis by specific gene is not available.

CONCLUSIONS

ARVC phenotype is extremely variable, also between members of the same family. Several hypothesis and environmental factors have been postulated to influence ARVC phenotype. Among all of these, there is growing evidence that exercise play a role in the expression and course of the disease. Relevant evidence has been acquired in both cohorts of athletes and cohorts of gene positive ARVC patients and family members. This study suggests a pathogenic role of endurance exercise also among ARVC patients with negative genotype. However, these patients require a higher intensity of exercise for developing the disease. These observations have great clinical importance in the management of both athletes and ARVC patients. Competitive sports and vigorous exercise should be avoided by ARVC patients and at-risk families members, regardless the genetic status.