Modelling structural and functional heterogeneity in heart failure reveals arrhythmic impact

心力衰竭的结构和功能异质性建模揭示了心律失常的影响

• 批准号: 10199780
• 负责人: Donald M Bers
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199780
• 关键词: Action Potentials; Address; Affect; Anti-Arrhythmia Agents; Arrhythmia; Blood; Calcium; Cardiac; Cause of Death; Cell membrane; Cells; Computer Models; Coupled; Coupling; Electrophysiology (science); Exhibits; Feedback; Frequencies; Gap Junctions; Goals; Heart; Heart failure; Heterogeneity; Hot Spot; Individual; Ion Channel; Ions; Knowledge; Lead; Link; Measures; Modeling; Molecular; Movement; Muscle Cells; Organ; Outcome; Pathologic; Phosphorylation; Physiological; Post-Translational Protein Processing; Process; Property; Pump; Regulation; Ryanodine Receptor Calcium Release Channel; Safety; Source; Structural Models; Structure; Techniques; Testing; Time; Tissues; Travel; United States; Variant; Ventricular; Ventricular Fibrillation; Ventricular Premature Complexes; Work; base; calmodulin-dependent protein kinase II; complex biological systems; driving force; drug development; experimental study; gene therapy; innovation; insight; mathematical analysis; mathematical model; novel therapeutic intervention; oxidation; phospholamban; recruit; reuptake; sudden cardiac death; theories; uptake

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.

项目摘要 心脏是一个高度复杂的生物系统。该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，以识别结构的促性心律失常作用 钙（Ca2+）波的功能异质性以及阐明分子和离子机制，延迟 造影后（父亲），过早的心室收缩（PVC），因此心室纤颤（VF）。一个 关键结果将是为抗心律失常药物开发，基因疗法和 新颖的治疗策略。该项目以我们最近的发现为基础1）异质细胞到细胞耦合 在组织尺度上促进心律不齐。 2）异质ryanodine受体（RYR）分布 在亚细胞尺度上促进心律失常Ca2+火花和波浪。这里提出的工作是针对的 在弥合组织尺度心律失常机制和亚细胞尺度之间的知识差距时 使用多尺度计算建模和最新实验的心律失常机制 测量心脏中详细异质性的方法。 AIM＃1是在RYR属性之间建立链接 和亚细胞Ca2+动力学。为此，我们将扩展这项研究并研究心力衰竭（HF）细胞，该细胞 应该更异构。我们将在正常和HF细胞中测量RYR分布并构建 生理和病理模型，以检验我们的假设，即异质RYR分布促进 Ca2+波，爸爸，PVC，因此局灶性心律不齐。我们将在AIM＃1中解决的关键问题是：1） RYR簇的大小和Ryrs在裂口空间上的空间排列会影响Ca2+火花； 2）RYR群集如何 细胞中的分布促进心律失常Ca2+波。 Ryr Gating，因此Ca2+火花和波浪是 也受翻译后修饰（PTM）的影响。目标＃2是检验PTM的假设 增加与结构RYR异质性相互作用的异质Ca2+瞬态。 Serca Reuteake是 CA2+骑自行车中的另一个关键球员。增加SERCA泵活动会增加SR Ca2+负载，从而促进 波传播。同时，增加SERCA泵活性会减少胞质Ca2+瞬变，这 抑制波传播。在AIM＃3中，我们检验了以下假设：增加Serca-Pump功能具有 双相对心律失常Ca2+波倾向的影响。当发生Ca2+波时，它们会使细胞去极化 膜，可能导致组织中的活性。如果细胞耦合良好，将立即去极化 被周围细胞吸收。但是，当细胞对细胞耦合减少时，去极化不能 周围细胞和PVC吸收更容易发生。但是，同时减少了细胞到细胞 耦合使波传播更加困难。因此，我们假设有一个最佳的细胞到细胞 耦合PVC组（AIM＃4）。拟议的工作将确定一些不规则Ca2+的新范式 当心脏异质性增加时，火花会导致心脏心律不齐 病理状况。