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.