Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca(2+) uptake to the sarcoplasmic reticulum and Ca(2+)-dependent inhibition of ryanodine channels, leading to diastolic Ca(2+) leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 ± 5 vs. 51 ± 7% in controls, P < 0.05) and improved after training (43 ± 12 and 51 ± 9% in KO and control mice, respectively, P = nonsignificant). The exercise tolerance was low in KO mice (16 ± 1 vs. 29 ± 2 min in controls, P < 0.01), but improved in trained animals (26 ± 2 vs. 30 ± 3 min, P = nonsignificant). The hearts of KO mice had a higher basal expression of the brain natriuretic peptide gene. After training, the expression of natriuretic peptide genes markedly decreased, with no difference between KO and controls. Exercise training was not associated with a change in ventricular tachycardia prevalence, but appeared to reduce arrhythmia load, as manifested by a decrease in ventricular beats during stress. We conclude that, in KO mice, which recapitulate the phenotype of human CPVT2, exercise training is well tolerated and could offer a strategy for heart conditioning against stress-induced arrhythmia.

Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+release

“…10 Regular exercise training has been shown to reduce the propensity for VT in a CASQ2 mutant CPVT2 mouse model. 11 Furthermore, results from mice with RyR2 dysfunction due to diabetic cardiomyopathy indicated that exercise training might improve RyR2 function through a CaMKIIdependent mechanism. 12 However, the therapeutic strategy that exercise directly reduces RyR2-dependent Ca 2+ leak in CPVT1 has never been shown before.…”

Accentuated vagal antagonism paradoxically increases ryanodine receptor calcium leak in long-term exercised Calsequestrin2 knockout mice

“…Our findings are in keeping with previous reports, which also showed that CPVT mice and human patients are able to perform moderate-intensity exercise. 6,10,11 In addition to absence of abnormal ventricular remodeling (Figure 3E), no difference in atrial weight, P-wave amplitude, and duration between SED and EX CASQ2 −/− mice indicates unaltered atrial structural and electrical remodeling after AIT (Figures 2A, 2B, and 3D, and Supplemental Table 1). 3 …”

Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice

“…CASQ2 Δ/Δ mice were implanted with a telemetry device (DSI St. Paul MM, device weight 3.8g) as previously described 14 . Provocation testing was performed at baseline and 15 min after IP drug injection of each drug (Table 1).…”

“…Proteins were extracted from frozen hearts and separated as previously described 14 . Electro-blotting to Hybond-C Extra membranes (Habersham, USA) was followed by incubation with rabbit anti-alpha 1 adrenergic receptor antibodies (1:400), (Acris Antibodies, Germany).…”