Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 219 Hackerman, Baltimore, MD, United States of America; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, Hackerman Hall 216, Baltimore, MD, United States of America.
Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 219 Hackerman, Baltimore, MD, United States of America.
J Mol Cell Cardiol. 2022 Jan;162:97-109. doi: 10.1016/j.yjmcc.2021.08.011. Epub 2021 Sep 3.
Acute engraftment arrhythmias (EAs) remain a serious complication of remuscularization therapy. Preliminary evidence suggests that a focal source underlies these EAs stemming from the automaticity of immature pluripotent stem cell-derived cardiomyocytes (PSC-CMs) in nascent myocardial grafts. How these EAs arise though during early engraftment remains unclear. In a series of in silico experiments, we probed the origin of EAs-exploring aspects of altered impulse formation and altered impulse propagation within nascent PSC-CM grafts and at the host-graft interface. To account for poor gap junctional coupling during early PSC-CM engraftment, the voltage dependence of gap junctions and the possibility of ephaptic coupling were incorporated. Inspired by cardiac development, we also studied the contributions of another feature of immature PSC-CMs, circumferential sodium channel (NaCh) distribution in PSC-CMs. Ectopic propagations emerged from nascent grafts of immature PSC-CMs at a rate of <96 bpm. Source-sink effects dictated this rate and contributed to intermittent capture between host and graft. Moreover, ectopic beats emerged from dynamically changing sites along the host-graft interface. The latter arose in part because circumferential NaCh distribution in PSC-CMs contributed to preferential conduction slowing and block of electrical impulses from host to graft myocardium. We conclude that additional mechanisms, in addition to focal ones, contribute to EAs and recognize that their relative contributions are dynamic across the engraftment process.
急性植入心律失常（EAs）仍然是肌肉再生成治疗的严重并发症。初步证据表明，这些 EAs 的起源是源于新生心肌移植物中幼稚多能干细胞衍生的心肌细胞（PSC-CMs）的自动性。然而，在早期植入过程中，这些 EAs 是如何产生的还不清楚。在一系列的计算机模拟实验中，我们探讨了 EAs 的起源，研究了新生 PSC-CM 移植物内和宿主-移植物界面改变冲动形成和改变冲动传播的各个方面。为了说明早期 PSC-CM 植入时缝隙连接偶联不良，我们纳入了缝隙连接的电压依赖性和电突触偶联的可能性。受心脏发育的启发，我们还研究了幼稚 PSC-CMs 的另一个特征——PSC-CMs 中环向钠通道（NaCh）分布的贡献。不成熟的 PSC-CMs 新生移植物中的异位传播率<96 bpm。源-汇效应决定了这个速率，并导致了宿主和移植物之间的间歇性捕获。此外，异位搏动也出现在宿主-移植物界面的动态变化部位。后者部分是由于 PSC-CMs 中环向 NaCh 分布导致电冲动从宿主向移植物心肌的优先传导减慢和阻滞。我们得出结论，除了局灶性机制外，还有其他机制导致 EAs 的发生，并认识到它们的相对贡献在植入过程中是动态变化的。
