Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
J Appl Physiol (1985). 2012 Dec 1;113(11):1677-83. doi: 10.1152/japplphysiol.00818.2012. Epub 2012 Oct 4.
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.
儿茶酚胺多形性室性心动过速（CPVT）是一种由体力或情绪压力诱发的致命性室性心律失常。隐性遗传 CPVT 是由心脏肌浆网钙结合蛋白（CASQ2）基因的错义或无效等位基因突变引起的。有人认为，CASQ2 的缺陷导致蛋白缺失，并损害肌浆网的 Ca2+摄取和 Ca2+依赖性ryanodine 通道抑制，导致舒张期 Ca2+渗漏、后除极和心律失常。为了研究运动训练对左心室重构和心律失常的影响，CASQ2 敲除（KO）小鼠和野生型对照在进行 6 周跑步机运动训练前后进行了超声心动图和心脏节律遥测。采用 qRT-PCR 和 Western blot 检测基因和蛋白表达。KO 组左心室短轴缩短率受损（33 ± 5%比对照组的 51 ± 7%，P < 0.05），但训练后改善（KO 和对照组分别为 43 ± 12%和 51 ± 9%，P = 无显著性差异）。KO 小鼠的运动耐量较低（16 ± 1 比对照组的 29 ± 2 分钟，P < 0.01），但在训练动物中有所提高（26 ± 2 比对照组的 30 ± 3 分钟，P = 无显著性差异）。KO 小鼠的脑钠肽基因基础表达较高。训练后，利尿肽基因的表达明显下降，KO 组与对照组无差异。运动训练与室性心动过速发生率的变化无关，但似乎减少了应激时心律失常的负荷，表现为应激时室性搏动减少。我们的结论是，在模拟人类 CPVT2 表型的 KO 小鼠中，运动训练耐受良好，可能为对抗应激性心律失常的心脏调理提供一种策略。
