Mechanisms of Cardiac Alternans

描述(由申请人提供)：项目摘要/摘要心脏交替的特征是膜电位的节拍交替，这在实验中已知会触发心脏折返，并与临床快速性心律失常的风险相关。近年来，在阐明交替物的机制方面取得了进展。然而，巨大的不确定性依然存在。研究表明，交替可能是膜电压或钙循环中的一种或两种情况下的动态不稳定造成的。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，进而产生钙交替；(Ii)肌浆网钙摄取和释放不匹配导致钙交替，进而通过钙耦合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菌的发生。具体地说，基于恢复斜率1指示内在的动作电位时程变化将被放大为交替的假设，动作电位时程恢复函数被用来预测交替。然而，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，将这一理论推向了前沿。综上所述，尽管人们普遍对确定交替的机制感兴趣，但我们假设交替的机制不一定只有一种通用机制，而是机制(I)和(II)对不同类型的心肌细胞起着不同的但可量化的作用。为了研究这一假说，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.通过计算模型和体外光学标测实验，研究细胞交替机制在组织水平上的意义。通过跨越几个空间尺度，从亚细胞到组织水平，这里提出的协同计算和实验研究将有助于提供对Alternans动力学的综合理解。此外，对交链霉菌机制的识别将有助于我们加深对交链菌群心律失常发生机制的理解，这可能具有临床意义。公共卫生相关性：项目叙述(使用不超过两到三句话，描述这项研究与公共卫生的相关性。)交替是一种心脏节律的发生，其中细胞行为在每一次跳动的基础上发生变化，在实验中已被证明会引发心律失常，并与致命性心律失常的风险相关。我们的中心目标是通过将新的定量分析应用于协同计算建模和实验研究来阐明交替的机制，这些机制尚不清楚。通过这样做，拟议的工作可能有助于提高我们对交替菌如何引发心律失常的理解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Project Narrative (Using no more than two or three sentences, describe the relevance of this research to public health.) Alternans, which is a cardiac rhythm occurrence in which cellular behavior alternates on a beat-to-beat basis, has been shown to trigger cardiac arrhythmias in experiments and has been correlated with risk for lethal cardiac arrhythmias. Our central objective is to illuminate the mechanisms of alternans, which remain unclear, through novel quantitative analyses applied to synergistic computational modeling and experimental studies. By doing so, the proposed work may help improve our understanding of how alternans may trigger cardiac arrhythmias.