Mechanically-Induced Spontaneous Arrhythmias in Acute Regional Ischemia

急性局部缺血时机械诱发的自发性心律失常

• 批准号: 0933029
• 负责人: Natalia Trayanova
• 金额: $ 30万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0933029&HistoricalAwards=false
• 关键词: Mechanically; Induced; Spontaneous; Arrhythmias; Acute

0933029TrayanovaThe overall objective of this research is to investigate the genesis of stretch-induced ventricular ectopy and the mechanisms by which it degrades into reentrant arrhythmias in the ischemic heart. The overarching hypothesis is that the origin of ectopic activations in acute regional ischemia arises from mechanical stretch of the ischemic region during systole. Specifically, it is hypothesized that: 1) Depolarization of the ischemic region caused by end-systolic stretch and subsequent opening of mechano-sensitive channels leads to ventricular premature beats originating at the ischemic border, and 2) The incidence of ventricular premature beats increases as ischemia progresses due to the higher level of strain developed as a result of increased end-diastolic pressure and tissue compliance. The hypothesis regarding the mechanism of degeneration of ventricular premature beats into reentrant arrhythmias posits that this degeneration stems from reduced excitability and dispersion in refractoriness and conduction velocity resulting from combined electrophysiological and mechanical changes in the ischemic region. To test these hypotheses, the project will develop a three-dimensional anatomically-accurate bidomain electromechanical model of the rabbit ventricles with acute regional ischemia. The model will be able to represent the mechanical and electrophysiological characteristics and behavior of ischemic tissue, including mechano-electric feedback mechanisms. This novel powerful model will be used to provide new mechanistic insight into the origins of ectopic activity and an understanding of how stretch-induced electrophysiological changes can exacerbate the existing pro-arrhythmic ischemic substrate and thus facilitate the degradation of ventricular ectopy into reentrant arrhythmias. The new insights into the role of mechano-electric feedback in arrhythmogenesis could ultimately lead to rational rather than empirical advancements in anti-arrhythmia therapies in patients with ischemic cardiac disease.In addition to the benefits to human health as outlined above, broader impacts resulting from the proposed activity include 1) advancement in the integration of research and education, 2) broadening the participation of underrepresented groups, and 3) fostering the development and dissemination of the next-generation engineering methods and technologies. The proposed research will provide an integrated array of simulation tools for electromechanical modeling of cardiac arrhythmogenesis in the diseased heart that will be made available to the broader community. Undergraduate and graduate students participating in the project will be trained in interdisciplinary approaches to clinically-relevant problems in biomedical engineering. Particular emphasis will be placed on the involvement of women and under-represented minority students in the project, consistent with the PI's long-term research activities.

这项研究的0933029Trayanovathe的总体目标是研究伸展性诱导的心室谱的起源以及其在缺血性心脏中降解为重入性心律失常的机制。总体假设是，急性区域缺血中异位活化的起源来自收缩期间缺血区的机械拉伸。具体而言，假设：1）由末端冲突伸展而引起的缺血区域的去极化，随后开放机械敏感的通道会导致源自缺血性边界的心室过早搏动，以及2）由于缺血水平的较高水平而导致较高的结构压力，并增加了较高的状态，并增加了心室过早的次数的发生率并增加了最终的压力。关于心律不齐的室过早节拍变性的机制的假设表明，这种退化是由于缺血性区域的电生理学和机械变化造成的耐火性和传导速度的兴奋性和传导速度的降低。为了检验这些假设，该项目将开发出三维的解剖学精确的双域动力构模型的兔心室，并具有急性区域缺血。该模型将能够代表缺血组织的机械和电生理特征和行为，包括机械电源反馈机制。这个新颖的强大模型将用于提供有关异位活性起源的新机械洞察力，并了解伸展诱导的电生理变化如何加剧现有的促进性缺血性缺血性底物，从而促进心室外形疾病降解为重新体质的心律失常。对机械反馈在心律失常发生中的作用的新见解最终可能导致抗心律失常性心脏病患者的理性而不是经验进步。除了上述概述的人类健康的益处外，还具有更广泛的影响，这是针对人类健康的益处，包括较广泛的活动，包括研究和教育的范围，包括2）构成2）的研究。 3）促进下一代工程方法和技术的发展和传播。拟议的研究将提供一系列的模拟工具，用于在患病心脏中心律失常发生的机电建模，并将提供给更广泛的社区。参加该项目的本科生和研究生将接受跨学科方法的培训，以解决生物医学工程中与临床相关的问题。与PI的长期研究活动一致的妇女和代表性不足的少数族裔学生的参与将特别强调。