Institute of Cardiovascular Science, University College London, London, UK.
Department of Electrophysiology, Barts Heart Centre at St Bartholomew's Hospital, London, UK.
Europace. 2019 Jun 1;21(6):981-989. doi: 10.1093/europace/euz007.
Action potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo.
We developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans.
Combined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.
动作电位时程（APD）交替是心律失常和心脏性猝死的一个既定先兆。在实验模型与体内病变的人类心脏之间，与心律失常相关的基本电生理特性存在重要差异。本研究旨在采用一种新方法，结合在体人心动周期的完整心脏和细胞心脏电生理学，来研究 APD 交替的机制。
我们开发了一种新方法，将心脏手术期间的完整心脏电生理图与快速现场数据分析相结合，以指导心肌活检进行实验室分析，从而将在器官水平观察到的复极动力学与潜在的离子通道表达联系起来。通过递增起搏方案来识别易发生 APD 交替和不易发生 APD 交替的区域。来自这些部位的活检（n=13）显示，易发生 APD 交替的部位的 Calsequestrin（CSQN）和 Ryanodine（RyR）以及 IK1 和 Ito 下的离子通道的 RNA 表达更高。易发生 APD 交替和不易发生 APD 交替的部位之间的电折返特性（n=7）没有差异，而易发生 APD 交替的部位的复极空间梯度大于不易发生 APD 交替的部位（P=0.001）。易发生 APD 交替和不易发生 APD 交替的部位之间的组织纤维化程度相当。对这些变化的数学建模表明，CSQN 和 RyR 的上调都是 APD 交替的关键决定因素。
结合完整心脏和细胞电生理学表明，在体人心肌中出现 APD 交替的部位与 CSQN 和 RyR 的表达更高有关，与非 APD 交替部位相比，其折返特性没有差异。计算机建模确定了 CSQN 与 RyR 的上调和相互作用是 APD 交替的主要机制。
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