School of Biomedical Engineering, Wenzhou Medical University, University Town, Chashan, Wenzhou, 325035, PR China.
Department of Biomedical Engineering, Zhejiang University, 38 Zheda Road, Hangzhou, 310027, PR China.
Comput Biol Med. 2019 May;108:234-241. doi: 10.1016/j.compbiomed.2019.04.007. Epub 2019 Apr 13.
Excitation-contraction coupling (E-C coupling) is thought to be based on elementary calcium release units (CRUs) in which clusters of ryanodine receptors (RyRs) localized on the sarcoplasmic reticulum (SR) are in close apposition to L-type Ca channels (LCCs) on the transverse tubules (TTs). However, a fraction of LCC-RyR structure may be uncoupled due to the remodelling of TTs, which would tend to destroy the E-C coupling in the failing heart. Here we proposed a multiscale model of the ventricular myocyte to investigate the relationship between LCC-RyR structure and cardiac electro-mechanical function. The mathematical model consisted of a two-dimensional (2D) subcellular Ca reaction-diffusion sub-model, a cellular electrophysiological sub-model and a cardiomyocyte contraction sub-model. The simulation results showed that the remodelling of CRU microstructure would disturb Ca homeostasis, leading to a dyssynchronous Ca transient, and postpone the generation of isometric force. Our study suggests that structural remodelling is an important mechanism for dysfunction of Ca handling, cellular electrophysiology and contractility in failing heart.
兴奋-收缩偶联（E-C 偶联）被认为是基于基本的钙释放单位（CRU），其中肌浆网（SR）上的兰尼碱受体（RyR）簇与横管（TT）上的 L 型钙通道（LCC）紧密相邻。然而，由于 TTs 的重构，LCC-RyR 结构的一部分可能会失去偶联，这将倾向于破坏衰竭心脏中的 E-C 偶联。在这里，我们提出了一个心室肌细胞的多尺度模型，以研究 LCC-RyR 结构与心脏电机械功能之间的关系。该数学模型由二维（2D）亚细胞 Ca 反应-扩散子模型、细胞电生理子模型和心肌细胞收缩子模型组成。模拟结果表明，CRU 微结构的重构会干扰 Ca 稳态，导致 Ca 瞬变不同步，并延迟等长力的产生。我们的研究表明，结构重构是心力衰竭时 Ca 处理、细胞电生理和收缩性功能障碍的重要机制。
