Mechanisms of Cardiac Alternans

项目概述/摘要心脏交替的特点是膜电位的搏动交替，在实验中已知会触发心脏再入，并与临床心律失常的风险相关。近年来，在阐明交替机制方面取得了进展。然而，重大的不确定性仍然存在。研究表明，交替可能是由于膜电压或钙循环的动态不稳定造成的。更具体地说，提出的两种机制是：(i)肌层离子电流动力学引起复极化交替，从而产生钙交替；（ii）肌浆网钙摄取和释放失配导致钙交替，而钙交替又通过钙与肌层电流的偶联产生复极化交替。多年来，机制(i)被认为是解释交替发生的原因。具体来说，我们使用动作电位持续时间（APD）恢复函数来预测交替，该函数的假设是，恢复斜率bbbb1决定了内在的APD变化将被放大为交替。然而，越来越多的证据表明，这种关系往往并不成立。相比之下，机制（ii）的证据已经积累起来，将该理论推向了前沿。话虽如此，尽管人们对确定替代的“机制”有广泛的兴趣，但我们假设替代不一定有一种通用的机制，而是机制(i)和（ii）对不同的心脏细胞类型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：量化细胞交替对动作电位形态的敏感性。2. 量化体外全细胞和亚细胞交替机制的细胞类型依赖性。3. 利用计算模型和离体光学作图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，本文提出的协同计算和实验研究将有助于提供对交替动力学的综合理解。此外，确定交替性心律失常的机制将有助于提高我们对交替性心律失常的理解，这可能具有临床意义。公共卫生相关性：项目叙述（用不超过两到三个句子，描述本研究与公共卫生的相关性。）交替是一种心律现象，细胞行为在搏动的基础上交替，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应用于协同计算建模和实验研究的新颖定量分析来阐明尚不清楚的替代机制。通过这样做，提出的工作可能有助于提高我们对交替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.