Zissimopoulos Spyros, Kirilenko Pavel, Braza-Boïls Aitana, Zorio Esther, Wang Yueyi, Gomez Ana Maria, Cannell Mark B, Latinkic Branko, Fowler Ewan D
Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK.
School of Biosciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3AX, UK.
J Mol Cell Cardiol. 2025 Jul 24;206:127-140. doi: 10.1016/j.yjmcc.2025.07.014.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca leak during systole disrupts repolarization in a transgenic mouse model of CPVT.
Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.
R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca leak during the Ca transient decay, in the form of late Ca sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.
Ca-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.
儿茶酚胺能多形性室性心动过速（CPVT）是一种恶性遗传性心脏病，其特征为应激诱导的心律失常，被认为是由异常钙循环导致的延迟后除极引起的。一些患者表现出异常大的心电图U波，这可能与心室复极改变有关，但与功能失调的兰尼碱受体2（RyR2）之间的可能联系尚不清楚。我们研究了在CPVT转基因小鼠模型中，收缩期钙泄漏增加是否会破坏复极。
记录携带RyR2-R420Q CPVT突变（R420Q）患者的心电图。在对照小鼠和R420Q基因敲入小鼠的心脏及心室肌细胞上进行实验。
R420Q患者静息U波比家族成员对照更大。R420Q小鼠心脏在起搏暂停后及β肾上腺素能刺激期间，单相动作电位（AP）延长更明显。在起搏暂停后及过早电刺激期间，R420Q小鼠心脏复极期间的室性异位搏动更常见。在β肾上腺素能刺激期间，分离的R420Q心肌细胞出现早期后除极（EADs），且与钙瞬变衰减期间以晚期钙火花（LCS）形式出现的钙泄漏增加同时发生。AP电压钳电生理实验、LCS恢复分析以及对过度活跃的RyR2的计算机模拟支持了一种机制，该机制涉及RyR2敏感性增加和/或不应期缩短，从而增加LCS频率和内向钠/钙交换电流，导致AP延长和EADs。
钙介导的AP延长和EADs可能促成由功能获得性R420Q突变引起的CPVT中的促心律失常行为。复极储备丧失并非CPVT治疗的特异性靶点，但可能是治疗干预的一个机会。
