Experimental and computational approach to understand regional heterogeneity and electro-mechanical interactions in the rabbit heart

了解兔心脏区域异质性和机电相互作用的实验和计算方法

• 批准号: 394630089
• 负责人: Professor Dr. Peter Kohl, since 2/2021
• 金额: --
• 依托单位: Institut für Experimentelle Kardiovaskuläre Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/394630089?language=en
• 关键词: Experimental; computational; approach; understand; regional

Pronounced electrical and mechanical heterogeneities exist in the healthy heart, enabling physiological cardiac function. This electro-mechanical (E-M) heterogeneity exits on all levels, from cellular to whole heart, and it is driven by regional apico-basal, transmural, and interventricular heterogeneities in ion channel and Ca2+ handling proteins. Alterations of physiological E-M heterogeneity have been identified in various "electrical" and "mechanical" cardiac diseases and can be causatively linked to arrhythmogenesis. The mechanisms driving the pathological heterogeneity and their role in arrhythmia formation are unclear.Electrical and mechanical processes interact in a bi-directional way via electro-mechanical (EMC) and mechano-electrical coupling (MEC), so that acute or chronic alterations of either will lead to consecutive changes of the other. This can be observed in long QT syndrome (LQTS), which is considered a typical "electrical" disease, but demonstrates also mechanical heterogeneity correlating with - and presumably altering - the individual arrhythmic risk.Information on the relative importance of the two directions of interaction, EMC and MEC, is sparse in healthy and diseased hearts. We hypothesize that 1) In the healthy heart, electrical heterogeneities are main sources of mechanical heterogeneities that enable physiological pump function.2) In the "acutely diseased" (drug-induced LQTS) heart, this ordered E-M heterogeneity becomes disturbed, and mechanical changes become important drivers for electrical heterogeneities that may be pro-arrhythmic.As E-M remodelling occurs in the "chronically" diseased heart, it is difficult to dissect drivers of bi-directional E-M-E interactions. In this project, we will therefore 1) characterize E-M heterogeneities and interactions in healthy and "acute" drug-induced LQTS hearts (without remodelling) and 2) investigate consequences of acute changes of electrics and/or mechanics on E-M-E cross-talk by using targeted interventions (change in preload, contractility). We will utilize multi-channel ECG, tissue-phase mapping MRI in vivo, and simultaneous Ca2+/voltage optical mapping combined with transmural ultrasound ex vivo (Objective 1). Multi-dimensional and -modal experimental data will be integrated into computational whole heart models to understand underlying bi-directional interactions (Objective 2). In silico alterations of electrical or mechanical parameters will be performed to elucidate drivers of E-M-E cross-talk that will then be validated experimentally in Langendorff-perfused hearts using pharmacological modulation of the identified "drivers" (Objective 3).A thorough understanding of EMC and MEC in healthy and "acute LQTS" hearts will allow us to predict the role of E-M-E cross-talk as causative link between E-M heterogeneity and arrhythmogenesis in more complex, chronic diseases with remodelled substrate - which will form a follow-on target for our research.

健康心脏中存在明显的电和机械异质性，从而实现生理心脏功能。这种机电 (E-M) 异质性存在于从细胞到整个心脏的各个层面，并且它是由离子通道和 Ca2+ 处理蛋白中的区域心尖基底、跨壁和心室间异质性驱动的。生理学电磁异质性的改变已在各种“电”和“机械”心脏病中被发现，并且可能与心律失常发生有关。驱动病理异质性的机制及其在心律失常形成中的作用尚不清楚。电和机械过程通过机电（EMC）和机电耦合（MEC）以双向方式相互作用，因此其中一方的急性或慢性改变将导致另一方的连续变化。这可以在长 QT 综合征 (LQTS) 中观察到，LQTS 被认为是一种典型的“电”疾病，但也表明机械异质性与个体心律失常风险相关，并且可能会改变个体心律失常风险。关于 EMC 和 MEC 这两个相互作用方向的相对重要性的信息在健康和患病心脏中很少。我们假设 1) 在健康的心脏中，电异质性是实现生理泵功能的机械异质性的主要来源。2) 在“急性患病”（药物诱导的 LQTS）心脏中，这种有序的 E-M 异质性受到干扰，机械变化成为可能导致心律失常的电异质性的重要驱动因素。 由于心脏“长期”患病，因此很难剖析双向 E-M-E 相互作用的驱动因素。因此，在本项目中，我们将 1) 描述健康和“急性”药物诱导的 LQTS 心脏（无重塑）中的 E-M 异质性和相互作用，2) 通过使用有针对性的干预措施（前负荷、收缩性的变化）研究电气和/或力学的急性变化对 E-M-E 串扰的影响。我们将利用多通道心电图、体内组织相位映射 MRI 以及同步 Ca2+/电压光学映射与离体透壁超声相结合（目标 1）。多维和模态实验数据将被集成到计算全心脏模型中，以了解潜在的双向相互作用（目标 2）。将进行电子或机械参数的计算机改变，以阐明 E-M-E 串扰的驱动因素，然后使用已确定的“驱动因素”的药理调节在 Langendorff 灌注的心脏中进行实验验证（目标 3）。对健康和“急性 LQTS”心脏中的 EMC 和 MEC 的透彻了解将使我们能够预测 E-M-E 串扰作为 E-M 之间因果关系的作用。 具有重塑底物的更复杂的慢性疾病的异质性和心律失常发生——这将成为我们研究的后续目标。