title: Exercise has a disproportionate role in the pathogenesis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations.
abstract: BACKGROUND
  Exercise is associated with age‐related penetrance and arrhythmic risk in carriers of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)‐associated desmosomal mutations; however, its role in patients without desmosomal mutations (gene‐elusive) is uncertain. This study investigates whether exercise is (1) associated with onset of gene‐elusive ARVD/C and (2) has a differential impact in desmosomal and gene‐elusive patients.
  
  
  RESULTS
  Eighty‐two ARVD/C patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10. Participation in endurance athletics, duration (hours/year), and intensity (MET‐Hours/year) of exercise prior to clinical presentation were compared between patients with desmosomal and gene‐elusive ARVD/C. All gene‐elusive patients were endurance athletes. Gene‐elusive patients were more likely to be endurance athletes (P<0.001) and had done significantly more intense (MET‐Hrs/year) exercise prior to presentation (P<0.001), particularly among cases presenting < age 25 (P=0.027). Family history was less prevalent among gene‐elusive patients (9% versus 40% desmosomal, P<0.001), suggesting a greater environmental influence. Gene‐elusive patients without family history did considerably more intense exercise than other ARVD/C patients (P=0.004). Gene‐elusive patients who had done the most intense (top quartile MET‐Hrs/year) exercise prior to presentation had a younger age of presentation (P=0.025), greater likelihood of meeting ARVD/C structural Task Force Criteria (100% versus 43%, P=0.02), and shorter survival free from a ventricular arrhythmia in follow‐up (P=0.002).
  
  
  CONCLUSIONS
  Gene‐elusive, non‐familial ARVD/C is associated with very high intensity exercise suggesting exercise has a disproportionate role in the pathogenesis of these cases. As exercise negatively modifies cardiac structure and promotes arrhythmias, exercise restriction is warranted.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Abhishek C
authors.initials: AC
authors.lastname: Sawant
authors.forename: Aditya
authors.initials: A
authors.lastname: Bhonsale
authors.forename: Anneline S J M
authors.initials: AS
authors.lastname: te Riele
authors.forename: Crystal
authors.initials: C
authors.lastname: Tichnell
authors.forename: Brittney
authors.initials: B
authors.lastname: Murray
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Russell
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tandri
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Tedford
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Hugh
authors.initials: H
authors.lastname: Calkins
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: James
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D003896:Desmosomes / Q000235:genetics*; D018572:Disease-Free Survival; D015444:Exercise; D017079:Exercise Tolerance; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult