Sato Daisuke, Xie Lai-Hua, Sovari Ali A, Tran Diana X, Morita Norishige, Xie Fagen, Karagueuzian Hrayr, Garfinkel Alan, Weiss James N, Qu Zhilin
Cardiovascular Research Laboratory, Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):2983-8. doi: 10.1073/pnas.0809148106. Epub 2009 Feb 13.
The synchronization of coupled oscillators plays an important role in many biological systems, including the heart. In heart diseases, cardiac myocytes can exhibit abnormal electrical oscillations, such as early afterdepolarizations (EADs), which are associated with lethal arrhythmias. A key unanswered question is how cellular EADs partially synchronize in tissue, as is required for them to propagate. Here, we present evidence, from computational simulations and experiments in isolated myocytes, that irregular EAD behavior is dynamical chaos. We then show in electrically homogeneous tissue models that chaotic EADs synchronize globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electrotonic coupling can no longer globally synchronize EADs, resulting in regions of partial synchronization that shift in time and space. These regional partially synchronized EADs then form premature ventricular complexes that propagate into recovered tissue without EADs. This process creates multiple premature ventricular complexes that propagate as [corrected] "shifting" foci resembling polymorphic ventricular tachycardia. Shifting foci encountering shifting repolarization gradients can also develop localized wave breaks leading to reentry and fibrillation. As predicted by the theory, rabbit hearts exposed to oxidative stress (H(2)O(2)) exhibited multiple shifting foci causing polymorphic tachycardia and fibrillation. This mechanism explains how collective cellular behavior integrates at the tissue scale to generate lethal cardiac arrhythmias over a wide range of heart rates.
耦合振荡器的同步在包括心脏在内的许多生物系统中起着重要作用。在心脏病中，心肌细胞可表现出异常的电振荡，如早期后去极化（EADs），这与致死性心律失常有关。一个关键的未解决问题是细胞EADs如何在组织中部分同步，因为这是它们传播所必需的。在此，我们通过计算模拟和分离心肌细胞实验提供证据表明，不规则的EAD行为是动态混沌。然后我们在电均匀组织模型中表明，当组织小于临界大小时，混沌EADs会全局同步。然而，当组织超过临界大小时，电紧张耦合不再能全局同步EADs，导致部分同步区域在时间和空间上移动。这些局部部分同步的EADs随后形成室性早搏复合体，并传播到没有EADs的心内膜恢复组织中。这个过程会产生多个室性早搏复合体，它们作为[校正后]“移动”灶传播，类似于多形性室性心动过速。遇到移动复极梯度的移动灶也会产生局部波裂，导致折返和颤动。正如理论所预测的，暴露于氧化应激（H₂O₂）的兔心脏表现出多个移动灶，导致多形性心动过速和颤动。这一机制解释了集体细胞行为如何在组织尺度上整合，从而在很宽的心率范围内产生致死性心律失常。
