Modelling structural and functional heterogeneity in heart failure reveals arrhythmic impact

项目总结 心脏是一个高度复杂的生物系统。这个项目的总体目标是使用多尺度计算 从分子水平到器官水平的心脏建模以识别结构性心律失常的促心律失常效应 和功能异质性，并阐明延迟的钙波的分子和离子机制 后除极(DAD)、室性早搏(PVCs)，从而导致室颤(VF)。一个 主要成果将是为抗心律失常药物的开发、基因治疗和 新的治疗策略。该项目建立在我们最新发现的基础上：1)不同种类的细胞间耦合 在组织水平上促进触发的心律失常；2)兰尼定受体(RyR)分布不均 在亚细胞水平上促进致心律失常的钙离子火花和波动。这里提出的工作的目的是 在弥合组织尺度心律失常机制和亚细胞尺度之间的知识鸿沟 应用多尺度计算建模和最新实验的心律失常机制 测量心脏细节异质性的方法。目标1是在RyR属性之间建立联系 和亚细胞内钙动力学。为此，我们将扩展这项研究，研究心力衰竭(HF)细胞，它 应该是更加异质的。我们将测量正常细胞和高频细胞中的RyR分布，并建立 检验我们假设异质RyR分布促进的生理和病理模型 CA2波、DADS、室上性心动过速，从而导致局灶性心律失常。我们将在目标1中解决的关键问题是：1)如何 RyR簇的大小和RyR在裂隙间隙的空间排列对钙离子火花的影响；2)RyR簇是如何聚集的 细胞内的分布促进致心律失常的钙波。RyR门控，因此钙火花和波，是 也受翻译后修饰(PTM)的影响。目标2是检验这样一个假设，即PTMS进一步 增加与结构RyR异质性相互作用的异质性钙瞬变。SERCA再摄取是 卡地亚自行车赛的另一位关键选手。SERCA泵活性增加SR钙负荷，从而促进 波的传播。同时，SERCA泵活性的增加减少了胞浆钙瞬变，这 抑制波的传播。在目标3中，我们检验了增加SERCA泵功能的假设 双相效应对致心律失常钙波倾向的影响。当钙波出现时，它们会使细胞去极化 并可导致组织中的触发活动。如果细胞耦合良好，去极化将立即 被周围的细胞吸收。然而，当细胞间的耦合减少时，去极化不能 更容易被周围的细胞和PVCs吸收。然而，与此同时，减少了细胞间的 耦合使波的传播变得更加困难。因此，我们假设存在一个最佳的细胞对细胞 用于聚氯乙烯成型的联轴器(目标4)。提出的工作将建立一个新的范式，即几个不规则的钙 当心功能异质性增加时，火花可导致整个心律失常。 病理情况。

PROJECT SUMMARY The heart is a highly complex biological system. The overall goal of this project is to use multiscale computational modeling of the heart from the molecular level to the organ level to identify the pro-arrhythmic effects of structural and functional heterogeneity and elucidate molecular and ionic mechanisms of calcium (Ca2+) waves, delayed afterdepolarizations (DADs), premature ventricular contractions (PVCs), and thus ventricular fibrillation (VF). A key outcome will be to provide physiological bases for antiarrhythmic drug development, gene therapies, and novel therapeutic strategies. The project builds on our recent discoveries 1) heterogeneous cell-to-cell coupling promotes triggered arrhythmias at the tissue scale; 2) heterogeneous ryanodine receptor (RyR) distribution promotes arrhythmogenic Ca2+ sparks and waves at the subcellular scale. The work proposed here is aimed at bridging the knowledge gap between the tissue scale arrhythmia mechanisms and the subcellular scale arrhythmia mechanisms utilizing multiscale computational modeling and the state-of-the-art experimental approaches to measure detailed heterogeneity in the heart. Aim #1 is to establish link between RyR properties and subcellular Ca2+ dynamics. To do this, we will extend this study and investigate heart failure (HF) cells, which are supposed to be more heterogeneous. We will measure RyR distributions in normal and HF cells and build the physiological and pathological models to test our hypothesis that heterogeneous RyR distribution promotes Ca2+ waves, DADs, PVCs, and thus focal arrhythmias. Key questions that we will address in Aim #1 are: 1) how RyR cluster size and spatial arrangements of RyRs at the cleft space affect Ca2+ sparks; 2) how RyR cluster distribution in the cell promotes arrhythmogenic Ca2+ waves. RyR gating, and thus Ca2+ sparks and waves, are also influenced by posttranslational modifications (PTMs). Aim #2 is to test the hypothesis that PTMs further increase heterogeneous Ca2+ transients interacting with structural RyR heterogeneity. SERCA reuptake is another key player in the Ca2+ cycling. Increasing SERCA pump activity increases SR Ca2+ load, which promotes wave propagation. At the same time, increasing SERCA pump activity reduces cytosolic Ca2+ transients, which suppresses wave propagation. In Aim #3, we test the hypothesis that increasing SERCA-pump function has a biphasic effect on propensity of arrhythmogenic Ca2+ waves. When Ca2+ waves occur, they depolarize the cell membrane and can lead to triggered activity in tissue. If cells are well-coupled, depolarization will be immediately absorbed by surrounding cells. However, when cell-to-cell coupling is reduced, depolarization cannot be absorbed by surrounding cells and PVCs occur more easily. However, at the same time, reduced cell-to-cell coupling makes wave propagation more difficult. Therefore, we hypothesize that there is an optimal cell-to-cell coupling for PVC formation (Aim #4). The proposed work will establish a new paradigm that a few irregular Ca2+ sparks can lead to the whole heart arrhythmias when cardiac heterogeneity is increased in HF and other pathological conditions.