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11 Arrhythmogenic Right Ventricular Cardiomyopathy-Like Phenotype Induced by Endurance Training and Prevented by Preload Reduction in Heterozygeous Desmoglein-2 Mutants
  1. L Fabritz1,
  2. L Fortmueller2,
  3. E Vloumidi1,
  4. S Sakhtivel2,
  5. F Syeda1,
  6. R Leube3,
  7. P Kirchhof1,
  8. C Krusche3
  1. 1Centre for Cardiovascular Sciences, University of Birmingham and SWBH NHS Trust, Birmingham, UK
  2. 2University Hospital of Muenster, Germany
  3. 3RWTH Aachen University, Institute of Molecular and Cellular Anatomy, Germany

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) significantly contributes to sudden cardiac death in young otherwise healthy patients, especially endurance athletes. 5–10% of patients with ARVC harbour mutations in the extracellular domains of the desmoglein (DSG) 2 gene. To assess the role of DSG2 in ARVC pathomechanism, mice lacking exons 4–6 of the endogenous DSG2 gene (DSG2mt) were generated. Homozygous DSG2mt/mice developed dilatation of ventricles and pronounced fibrosis. Heterozygous DSG2mt/wt mutants did not show such morphological alterations.

Methods To study whether exercise provokes a cardiac phenotype in DGSwt/mt mice, they were subjected to endurance training and compared with wild-type (WT) littermates. We also studied if preload reduction can prevent right ventricular dilation with training by concomitant therapy with nitrates and diuretics. Echocardiography was performed with 2% isoflurane + oxygen, using a small animal ultrasound unit. Right ventricular (RV) dimensions were increased in DSG2wt/mt after training compared to pre-training and compared to WT after training. Electrophysiological studies in isolated Langendorff DSGwt/mt and WT hearts from mice terminally anaesthetised with urethane (2 mg/kg) showed a correlation of the DSG2 mutation with increased arrhythmia inducibility after endurance training. Ventricular arrhythmias were induced by a single extra stimulus during right ventricular stimulation in 5 of 8 DSG2wt/mt, but in none of the 7 WT hearts (p = 0.03). Preload reduction prevented excessive right ventricular enlargement with endurance training in DSG2wt/mt. In conclusion, endurance training revealed an ARVC-like phenotype in heterozygous desmoglein mutant mice. Right ventricular dilation could be prevented by preload-reducing therapy.

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