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111 Arrhythmogenic right ventricular cardiomyopathy-like phenotype revealed by endurance training in heterozygeous desmoglein2 mutants
  1. L Fabritz1,
  2. L Fortmueller2,
  3. D Kucerova2,
  4. S Sakhtivel2,
  5. F Syeda1,
  6. P Kirchhof1,
  7. R E Leube3,
  8. C Krusche3
  1. 1Centre for Cardiovascular Sciences, University of Birmingham, Birmingham, UK
  2. 2Department of Cardiology, University Hospital Muenster, Muenster, Germany
  3. 3Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany

Abstract

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiomyopathy but significantly contributes to sudden cardiac death in young otherwise healthy patients, especially long durance 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 the ARVC pathomechanism, mice lacking exons 4–6 of the endogenous DSG2 gene (DSG2mt) were generated. Homozygous DSG2mt/mt mice developed dilatation of ventricles and pronounced fibrosis. Heterozygous DSG2mt/wt mutants, however, did not show such morphological alterations.

Objective To study whether physical exercise provokes a cardiac phenotype in DSG2wt/mt mice they were subjected to endurance training together with wild-type (WT) littermates.

Methods/Results Group swimming training sessions were performed 6 times a week starting with 5 min and gradually incrementing to 90 min/d for 7 weeks. Echocardiography was performed before and after training using a small animal ultrasound unit. Right ventricular (RV) diameters were increased in DSG2wt/mt both compared to pretraining and compared to WT after training. Right ventricular function was also decreased after training compared to pretraining and compared to WT littermates (see Abstract 111 table 1 for values, *p<0.05, d = diastolic, s = systolic, lav = long, sav = short axis view, FAC = fractional area shortening, HR = heart rate). Neither left ventricular diameters nor function differed between DSG2wt/mt and WT littermates. Electrophysiological studies in Isolated Langendorff DSG2wt/mt and WT hearts showed comparable ventricular action potential duration and effective refractory periods. DSG2 mutation correlated with increased arrhythmia inducibility after endurance training. Ventricular arrhythmias were induced in 5 of 8 DSG2wt/mt, but in none of 7 WT hearts during right ventricular stimulation by a single extrastimulus (p=0.03). In conclusion, endurance training reveals an ARVC-like phenotype in otherwise healthy and morphologically inconspicuous DSG2wt/mt mice presenting right ventricular dilatation, decreased right ventricular contractility and increased inducibility of ventricular arrhythmias during right ventricular pacing.

Abstract 111 Table 1
  • Mechanisms of arrhythmias
  • mechanisms of cardiomyopathy
  • murine models

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