Exploration of Arrhythmogenic Triggers and Substrates in Heart Failure
心力衰竭致心律失常触发因素和基质的探索
基本信息
- 批准号:9392927
- 负责人:
- 金额:$ 66.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-01-01 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adrenergic AgentsAffectArrhythmiaBehaviorCardiac MyocytesCaveolaeCell physiologyCellsCessation of lifeChemosensitizationClinical ResearchComplexCouplingDataDevelopmentDiseaseElectrophysiology (science)FiberFibrosisGenerationsGenesGeometryHealth ExpendituresHealthcare SystemsHeartHeart RateHeart failureHeterogeneityHospitalizationHot SpotHumanIncidenceIon ChannelLinkLocationMRI ScansMembraneModelingMolecularMorbidity - disease rateMuscle CellsOrganPathologicPatientsPharmacologyPhosphorylationProteinsResearchResolutionRestRiskRisk stratificationScanningSignal TransductionSourceStructureSudden DeathThinnessTubular formationValidationVentricularVentricular Fibrillationaging populationend of lifeexperimental studyglobal healthimprovedinsightmortalitynerve supplynon-Nativenovelpatch clamppreventpublic health relevancesimulationspatiotemporalstatisticssudden cardiac deathvoltage
项目摘要
DESCRIPTION (provided by applicant): Heart failure (HF) is a major cause of morbidity and mortality, contributing significantly to global health expenditure. Sudden death due to arrhythmia
is responsible for over 50% of deaths among HF patients; however, the mechanisms linking HF-induced molecular remodeling to increased sudden death risk remain poorly understood. This has resulted in ineffective pharmacologic therapy for preventing sudden arrhythmic death and in inadequate approaches to arrhythmia risk stratification of HF patients. The overall objective of the proposed research is to explore a novel set of mechanisms by which HF remodeling, from the sub-cellular microdomain to the whole heart, leads to increased risk of lethal arrhythmias in human HF. Specifically, we propose to investigate how the impact of the degradation of myocyte microdomains on L-type Ca channel and cellular function is amplified regionally by the heterogeneities in electrophysiological remodeling and adrenergic innervation as well as by the disease-induced remodeling in ventricular structure to produce i) arrhythmia triggers and ii) their
degeneration into ventricular fibrillation (VF). The project presents an integrated experimental/computational approach to arrhythmogenesis in human HF. Super-resolution scanning patch clamp will provide novel insight into how disruption of sub-cellular compartments affects L-type Ca channel functioning in the HF cell. This data will be used as input into an integrative human HF myocyte model, which following validation, will be implemented in organ-level HF models. Protein and microstructure distribution data informing the organ-level models will be gathered in experiments with explanted HF human hearts. Model components will be combined with MRI scans of HF human heart geometry/structure to develop multiscale HF ventricular models which will then be used to determine the mechanisms responsible for the formation of 1) "hot spots", from which triggered activity emanates, and 2) arrthythmogenic substrates at heart rates near rest, causing the degradation of triggered activity into VF. Simulation results regarding the arrhythmogenic substrate and VF likelihood at these heart rates will be validated in a clinical study of HF patients. Completion of the studies proposed here will result in a greater understanding of the mechanisms leading to arrhythmias and sudden death in human HF. Such mechanistic understanding is expected to reduce the impact of HF on its victims and on the health-care system 1) by suggesting targeted and effective new molecular therapies, and 2) by leading to new and improved approaches to arrhythmia risk stratification of HF patients.
描述(由申请人提供):心力衰竭(HF)是发病率和死亡率的主要原因,对全球卫生支出有很大的贡献。fi。心律失常猝死
占心力衰竭患者死亡的50%以上;然而,心力衰竭诱导的分子重构与猝死风险增加之间的联系机制仍然知之甚少。这导致了预防心律失常猝死的药物治疗无效,以及对心力衰竭患者心律失常风险策略的处理不力。这项研究的总体目标是探索一套新的机制,通过这种机制,从亚细胞微域到整个心脏的HF重塑,会增加人类HF发生致命性心律失常的风险。具体地说,我们建议研究心肌细胞微域的退化对L钙通道和细胞功能的影响是如何通过电生理重构和肾上腺素能神经支配的异质性以及通过疾病诱导的心室结构重构来产生i)心律失常触发和ii)它们的区域fi放大的。
退行性变为室性颤动(VF)。(2)室性心动过速(fi)该项目提出了一种综合的实验/计算方法来研究人类心力衰竭的心律失常。超分辨率扫描膜片钳将提供新的洞察力,了解亚细胞室的破坏如何影响高频细胞中L型钙通道的功能。这些数据将被用作一个整合的人类心力衰竭心肌细胞模型的输入,该模型经过验证后,将在器官水平的心力衰竭模型中实施。器官水平模型的蛋白质和微结构分布数据将在移植的HF人类心脏实验中收集。模型组件将与高频人体心脏几何/结构的MRI扫描相结合,以开发多尺度的高频心室模型,然后将用于确定1)“热点”的形成机制,触发活动从“热点”发出,2)心率接近静止时的致心律底物,导致触发活动降解为室颤。在这些心率下有关致心律失常底物和室颤可能性的模拟结果将在对心力衰竭患者的临床研究中得到验证。这些研究的完成将使我们更好地理解导致人类心力衰竭心律失常和猝死的机制。这种对机制的理解有望减少心力衰竭对其受害者和医疗保健系统的影响,1)通过建议有针对性和有效的新的分子疗法,以及2)通过导致新的和改进的方法来控制心力衰竭患者的心律失常风险fi。
项目成果
期刊论文数量(0)
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