Kim Seunghyun, Sato Daisuke
Department of Mathematics, University of California, Davis, Davis, CA, United States.
Department of Pharmacology, University of California, Davis, Davis, CA, United States.
Front Phys. 2018;6. doi: 10.3389/fphy.2018.00117. Epub 2018 Oct 12.
Early afterdepolarizations (EADs) are abnormal oscillations during the plateau phase of the cardiac action potential and have been linked to cardiac arrhythmias. At the cellular level, EADs can be caused by reactivation of the L-type calcium (Ca) channels, spontaneous Ca releases from the sarcoplasmic reticulum, or both. In tissue, these EADs can trigger action potentials in neighboring cells, which may propagate as a nonlinear wave. In this scenario, EADs are attributed to cellular/subcellular/channel properties. In this study, we show a novel mechanism of EADs due to heterogeneous distribution of excitable and non-excitable cells in tissue, using a physiologically detailed computational model and mathematical analysis. In tissue, excitability of cells depends on the cell type and physiological and pathological conditions. Non-excitable cells create a non-excitable gap in tissue, which has been thought to be a cause of slow waves and reflected waves. Here, we show that the non-excitable gap also can be responsible for EAD generation. However, EADs occur only when the non-excitable gap size is optimal. If the gap size is too small, no EADs occur. If the gap size is too large, the action potential wave cannot propagate through the gap region. We also demonstrate that EADs caused by the non-excitable gap can initiate reentry in tissue, which has been linked to ventricular tachycardia and fibrillation. Thus, the non-excitable gap can lead to both focal and reentrant arrhythmias. EADs shown in this study are spatial phenomena and require tissue heterogeneity. Our study sheds light on the role of tissue heterogeneity on focal and reentrant arrhythmias.
早期后除极（EADs）是心脏动作电位平台期的异常振荡，与心律失常有关。在细胞水平上，EADs可由L型钙（Ca）通道的重新激活、肌浆网的自发Ca释放或两者共同引起。在组织中，这些EADs可触发邻近细胞的动作电位，并可能以非线性波的形式传播。在这种情况下，EADs归因于细胞/亚细胞/通道特性。在本研究中，我们使用生理细节计算模型和数学分析，展示了一种由于组织中可兴奋细胞和不可兴奋细胞的异质分布而导致EADs的新机制。在组织中，细胞的兴奋性取决于细胞类型以及生理和病理状况。不可兴奋细胞在组织中形成一个不可兴奋间隙，这被认为是慢波和反射波的一个原因。在此，我们表明不可兴奋间隙也可能是EADs产生的原因。然而，只有当不可兴奋间隙大小最佳时才会出现EADs。如果间隙太小，则不会出现EADs。如果间隙太大，动作电位波无法穿过间隙区域。我们还证明，由不可兴奋间隙引起的EADs可在组织中引发折返，这与室性心动过速和颤动有关。因此，不可兴奋间隙可导致局灶性和折返性心律失常。本研究中显示的EADs是空间现象，需要组织异质性。我们的研究揭示了组织异质性在局灶性和折返性心律失常中的作用。
