Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands.
Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands.
Prog Biophys Mol Biol. 2020 Nov;157:54-75. doi: 10.1016/j.pbiomolbio.2020.02.008. Epub 2020 Mar 15.
Calcium (Ca) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca levels are regulated by a variety of Ca-handling proteins. In turn, Ca modulates numerous electrophysiological processes. Accordingly, Ca-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca handling under physiological and pathological conditions. However, numerous questions involving the Ca-dependent regulation of different macromolecular complexes, cross-talk between Ca-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.
钙（Ca）在心肌细胞兴奋-收缩偶联中起着核心作用。为了确保最佳的电脉冲传播和心脏收缩，Ca 水平由各种 Ca 处理蛋白调节。反过来，Ca 调节许多电生理过程。因此，Ca 处理异常可通过多种机制促进心律失常，包括促进后除极、离子通道调制和结构重塑。在过去的 30 年中，在生理和病理条件下对心肌细胞 Ca 处理的计算模型进行了重大改进。然而，许多涉及不同大分子复合物的 Ca 依赖性调节、在广泛时间尺度上运行的 Ca 依赖性调节途径之间的串扰以及电生理学和力学之间的双向相互作用的问题仍有待通过体外和计算研究来解决。更好地了解与疾病相关的 Ca 依赖性致心律失常机制可能有助于开发改进的治疗策略。在这篇综述中，我们描述了心肌细胞在健康和疾病状态下 Ca 处理的基本机制，并概述了目前可用的心肌细胞 Ca 处理计算模型。最后，我们讨论了心肌细胞 Ca 处理的重要不确定性和悬而未决的问题，并强调了体外和计算研究之间的协同作用如何有助于回答其中的一些问题。
