Mechanisms of Cardiac Alternans

项目摘要/摘要 心脏交替的特征是膜电位的节拍交替，已知 在实验中触发心脏折返，并与临床快速性心律失常的风险相关。在……里面 近年来，在阐明交替物的机制方面取得了进展。然而，重要的是 不确定性依然存在。 研究表明，交替现象可能是任一种膜或两种膜中的动力学不稳定性造成的。 电压或钙循环。更具体地说，提出的两种机制是：(I)肌膜离子 电流动力学引起复极交替，继而产生钙交替，以及(Ii) 肌浆网钙摄取和释放不匹配导致钙交替，进而 通过钙偶联到肌膜电流产生复极交替。多年来, 机制(I)被认为可以解释交替现象的发生。具体地说，动作电位持续时间 基于恢复斜率&gt；1的假设，使用恢复函数来预测交替 内在的动作电位变化将被放大为交替信号。然而，有越来越多的证据表明 这种关系往往站不住脚。相比之下，机制(II)的证据已经积累起来，推动了 这一理论走在了前列。话虽如此，尽管人们普遍对确定“该”机制感兴趣 对于Alternans，我们假设对于Alternans，不一定有一种通用机制，而是存在一种通用机制 机制(I)和(II)对不同类型的心肌细胞起着不同但可量化的作用。 为了研究这一假设，我们将使用协同计算和实验方法： 1.量化细胞交替对动作电位形态的敏感性。 2.体外定量研究全细胞和亚细胞交替机制的细胞类型依赖性。 3.使用计算方法研究细胞交替机制在组织水平的影响 建模和体外光学标测实验。 通过跨越几个空间尺度，从亚细胞到组织水平，协同计算和 这里提出的实验研究将有助于提供对Alternans动力学的综合理解。 此外，对交替物的机制的识别将有助于促进我们对 Alternans心律失常的发生，可能具有临床意义。

Project Summary/Abstract Cardiac alternans is characterized by a beat-to-beat alternation in membrane potential that is known to trigger cardiac reentry in experiments and has been correlated with risk for clinical tachyarrhythmias. In recent years progress has been made in illuminating the mechanisms of alternans. However, significant uncertainty remains. Studies have suggested that alternans may result from dynamical instabilities in either or both membrane voltage or calcium cycling. More specifically, the two proposed mechanisms are: (i) sarcolemmal ion current dynamics cause repolarization alternans, which in turn produces calcium alternans, and (ii) sarcoplasmic reticulum calcium uptake and release mismatch causes calcium alternans, which in turn produces repolarization alternans via calcium coupling to sarcolemmal currents. For many years, mechanism (i) was thought to explain the occurrence of alternans. Specifically, the action potential duration (APD) restitution function was used to predict alternans based on the hypothesis that restitution slopes >1 dictate that intrinsic APD variations will be amplified into alternans. However, evidence has mounted that this relationship often does not hold. In contrast, evidence for mechanism (ii) has accumulated, pushing that theory to the forefront. All that being said, in spite of widespread interest in identifying "the" mechanism of alternans, we hypothesize that there is not necessarily one generic mechanism for alternans, but rather that mechanisms (i) and (ii) play varying, but quantifiable, roles for different cardiac cell types. To investigate this hypothesis, we will use synergistic computational and experimental approaches: 1. To quantify the sensitivity of cellular alternans to action-potential morphology. 2. To quantify the cell-type dependence of whole-cell and subcellular alternans mechanisms in vitro. 3. To investigate the tissue-level implications of cellular alternans mechanisms using computational modeling and ex vivo optical mapping experiments. By spanning several spatial scales, from subcellular to tissue-level, the synergistic computational and experimental studies proposed here will help to provide an integrated understanding of alternans dynamics. Furthermore, identification of the mechanisms of alternans will help advance our understanding of alternans arrhythmogenesis, which may have clinical implications.