Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Department of Cardiology, Medical City Fort Worth and University of North Texas Health Science Center, Fort Worth, Texas.
Heart Rhythm. 2018 Mar;15(3):430-441. doi: 10.1016/j.hrthm.2017.10.008. Epub 2017 Oct 10.
Long-term aerobic exercise alters autonomic balance, which may not be favorable in heart rate (HR)-dependent arrhythmic diseases including catecholaminergic polymorphic ventricular tachycardia (CPVT) because of preexisting bradycardia and increased sensitivity to parasympathetic stimulation.
The purpose of this study was to determine whether long-term exercise-induced autonomic adaptations modify CPVT susceptibility.
We determined exercise-induced parasympathetic effects on HR, arrhythmia incidence, and intracellular sarcoplasmic reticulum (SR) Ca leak in atrial (ACM) and ventricular (VCM) cardiomyocytes, in exercised (EX) calsequestrin knockout (CASQ2) mice, a model of CPVT.
Although 8-week treadmill running improved exercise capacity in EX CPVT mice, the incidence and duration of ventricular tachycardia also increased. HR variability analyses revealed an increased high-frequency component of the power spectrum and root mean square of successive differences in R-R intervals indicating accentuated vagal antagonism during β-adrenergic stimulation resulting in negligible HR acceleration. In EX CASQ2 VCM, peak amplitude of Ca transient (CaT) increased, whereas SR Ca content decreased. Aberrant Ca sparks occurred at baseline, which was exacerbated with isoproterenol. Notably, although 10 μM of the cholinergic agonist carbachol prevented isoproterenol-induced Ca waves in ACM, CaT amplitude, SR Ca load, and isoproterenol-induced Ca waves paradoxically increased in VCM. In parallel, ventricular ryanodine receptor (RyR2) protein expression increased, whereas protein kinase A- and calmodulin-dependent protein kinase II-mediated phosphorylation of RyR2 was not significantly altered, which could imply an increased number of "leaky" channels.
Our novel results suggest that long-term exercise in CASQ2 mice increases susceptibility to ventricular arrhythmias by accentuating vagal antagonism during β-adrenergic challenge, which prevents HR acceleration and exacerbates abnormal RyR2 Ca leak in EX CASQ2 VCM.
长期的有氧运动改变了自主平衡，这可能对包括儿茶酚胺多形性室性心动过速（CPVT）在内的依赖心率的心律失常疾病不利，因为存在先前的心动过缓和对副交感神经刺激的敏感性增加。
本研究旨在确定长期运动引起的自主适应性是否会改变 CPVT 的易感性。
我们确定了运动引起的迷走神经对 HR、心律失常发生率以及心房（ACM）和心室（VCM）心肌细胞细胞内肌浆网（SR）Ca 渗漏的影响，在锻炼（EX）肌钙蛋白 C 敲除（CASQ2）小鼠中，这是 CPVT 的模型。
尽管 8 周的跑步机跑步提高了 EX CPVT 小鼠的运动能力，但室性心动过速的发生率和持续时间也增加了。HR 变异性分析显示，功率谱高频成分和 R-R 间期连续差异的均方根增加，表明在β-肾上腺素能刺激期间迷走神经拮抗作用增强，导致 HR 加速几乎可以忽略不计。在 EX CASQ2 VCM 中，钙瞬变（CaT）的峰值幅度增加，而 SR Ca 含量减少。在基线时出现异常的 Ca 火花，用异丙肾上腺素进一步加剧。值得注意的是，尽管 10 μM 胆碱能激动剂卡巴胆碱可防止 ACM 中的异丙肾上腺素诱导的 Ca 波，但 CaT 幅度、SR Ca 负荷和异丙肾上腺素诱导的 Ca 波在 VCM 中反而增加。同时，心室ryanodine 受体（RyR2）蛋白表达增加，而蛋白激酶 A 和钙调蛋白依赖性蛋白激酶 II 介导的 RyR2 磷酸化没有明显改变，这可能意味着通道数量增加。
我们的新结果表明，在 CASQ2 小鼠中进行长期运动通过在β-肾上腺素能挑战期间增强迷走神经拮抗作用来增加心室心律失常的易感性，这阻止了 HR 加速并加剧了 EX CASQ2 VCM 中异常的 RyR2 Ca 渗漏。
