Nivala Michael, Song Zhen, Weiss James N, Qu Zhilin
Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
J Mol Cell Cardiol. 2015 Feb;79:32-41. doi: 10.1016/j.yjmcc.2014.10.018. Epub 2014 Nov 6.
In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in "orphaned" RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF.
在心力衰竭（HF）中，横管（TT）破坏会导致钙（Ca）释放不同步和收缩功能受损，但其在心律失常发生中的作用仍不清楚。在本研究中，我们使用计算机建模研究TT破坏和其他HF重塑因素对心室肌细胞中钙交替现象的影响。我们使用了一个通过耦合钙释放单元（CRU）网络对详细的时空钙循环进行建模的心室肌细胞模型，其中L型钙通道和兰尼碱受体（RyR）通道通过随机马尔可夫跃迁进行模拟。TT破坏会从相关的CRU中移除L型钙通道，导致“孤立”的RyR簇，从而增加了由火花诱发钙火花发生的机会。这种效应与其他HF重塑因素通过两种不同机制促进了交替现象：1）对于正常的肌浆网钙ATP酶（SERCA）活性，交替现象是由CRU不应期和耦合共同引起的。TT破坏增加了由火花诱发火花的机会，再加上在存在或不存在增加的RyR渗漏情况下，钙升高增强了CRU耦合，促进了交替搏动时的火花同步，从而促进钙交替现象；2）对于下调的SERCA，交替现象是由肌浆网（SR）钙负荷依赖性机制引起的，与CRU不应期无关。TT破坏和增加的RyR渗漏使SR钙释放-负荷关系发生移位并变陡，这与下调的SERCA相结合，促进了钙交替现象。总之，正常和下调的SERCA时钙交替现象的机制不同，TT破坏通过这两种机制促进钙交替现象，这可能在HF的不同阶段导致交替现象。
