Abstract: 83
Arrhythmogenic right ventricular cardiomyopathy-like phenotype induced by endurance training in heterozygous desmoglein-2 mutant mice

E. Vloumidi1, L. Fortmueller2, S. Sakhtivel2, F. Syeda1, P. Kirchhof1, R. Leube3, C. Krusche3, L. Fabritz1, 1Centre for Cardiovascular Sciences, University of Birmingham and SWBH NHS Trust - Birmingham - United Kingdom, 2University Hospital of Munster - Munster - Germany, 3RWTH Aachen University, Institute of Molecular and Cellular Anatomy - Aachen - Germany,

Mechanism (Basic Science in Arrhythmias)
Europace ( 2013 ) 15 ( S2 ), S10

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare cardiomyopathy but 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/wt) were generated. Homozygous DSG2 mutant mice (DSG2mt/mt, loss-of-function) developed dilatation of ventricles and pronounced fibrosis. Heterozygous DSG2 mutants (DSG2mt/wt) 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 and compared with Wild-Type (WT) littermates.

Methods/Results:ÿTraining sessions were performed 6 times a week, incrementing to 90 minutes per day for 7 weeks. Echocardiography was performed before and after training using a small animal ultrasound unit. Rightÿventricular dimensions were increased in DSG2wt/mt after training compared to WT after training andÿto DSG2wt/mt pre-training (see table for values).

Electrophysiological studies in isolated Langendorff DSG2wt/mtÿhearts showed that DSG2 mutation correlated with increased arrhythmia inducibility after endurance training. Ventricular arrhythmias were induced by a single extrastimulus during right ventricular stimulation in 5 of 8 DSG2wt/mt, but in none of the 7 WT hearts (p<0.05).

In conclusion, endurance training reveals an ARVC-like phenotype in otherwise healthy and morphologically inconspicuous DSG2wt/mt mice.

trainingbefore trainingbefore trainingafter trainingafter training

n (females)





HR (bpm)

451 ñ 10

451 ñ 11

422 ñ 6

434 ñ 6

RVsav d (mmý)

4.4 ñ 0.5

4.8 ñ 0.3†

4.7 ñ 0.3

5.9 ñ 0.3*

RVsav s (mmý)

2.7 ñ 0.3

2.6 ñ 0.4†

2.2 ñ 0.3

3.6 ñ 0.3*

Age (weeks)

12 ñ 1

12 ñ 1

19 ñ 1

19 ñ 1

*p<0.05 WT after training vs DSG2wt/mt after training, †p<0.05 DSG2wt/mt before training vs DSG2wt/mt after training, d= diastolic, s= systolic, sav= short axis view