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.

本研究的总体目标是探讨牵张诱发的室性异位的发生机制，以及它在缺血心脏中降解为折返性心律失常的机制。最重要的假设是，急性局部缺血时异位激活的起源是由于收缩时缺血区的机械拉伸。具体地说，假设：1)收缩末期牵张引起的缺血区去极化和随后机械敏感通道的开放导致起源于缺血边缘的室性早搏，以及2)室性早搏的发生率随着缺血的进展而增加，这是由于舒张末压力和组织顺应性增加而产生的更高水平的应变。关于室性早搏退变为折返性心律失常的机制的假说认为，这种退变源于缺血区综合电生理和机械变化导致的不应性和传导速度的兴奋性和离散性降低。为了验证这些假说，该项目将开发一个三维解剖学上准确的兔脑室急性局部缺血的双向机电模型。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-电反馈机制。这一新的强大的模型将被用来为异位活动的起源提供新的机制见解，并理解拉伸诱导的电生理变化如何加剧现有的促心律失常缺血底物，从而促进室性异位症向折返性心律失常的降解。对力-电反馈在心律失常形成中作用的新见解可能最终导致在缺血性心脏病患者的抗心律失常治疗方面取得理性而不是经验上的进展。除了上述对人类健康的好处外，拟议活动产生的更广泛的影响包括：1)促进研究和教育的整合，2)扩大未被充分代表的群体的参与，以及3)促进下一代工程方法和技术的开发和传播。拟议的研究将提供一系列集成的模拟工具，用于对患病心脏的心律失常形成进行机电建模，并将提供给更广泛的社区。参与该项目的本科生和研究生将接受关于生物医学工程中临床相关问题的跨学科方法的培训。将特别重视妇女和代表性不足的少数族裔学生参与该项目，这与国际和平协会的长期研究活动相一致。