Mechanically-Induced Spontaneous Arrhythmias in Acute Regional Ischemia

本研究的总体目的是探讨在缺血性心脏中拉伸诱导的心室异位的发生及其降解为可重入性心律失常的机制。总的假设是，急性局部缺血的异位激活的起源是由于缺血区域在收缩期的机械拉伸。具体来说，我们假设：1)收缩末期拉伸引起的缺血区去极化和随后的机械敏感通道的打开导致起源于缺血边界的室性早搏，2)由于舒张末期压力和组织顺应性的增加而产生的更高水平的应变，室性早搏的发生率随着缺血的进展而增加。关于室性早搏退变为再入性心律失常的机制假说认为，这种退变是由于缺血区电生理和机械的联合变化导致的兴奋性、难固性和传导速度的分散性降低。为了验证这些假设，该项目将开发急性局部缺血兔脑室的三维解剖精确的双域机电模型。该模型将能够表征缺血组织的机械和电生理特征和行为，包括机电反馈机制。这个新颖的强大模型将为异位活动的起源提供新的机制见解，并了解拉伸诱导的电生理变化如何加剧现有的促心律失常的缺血性底物，从而促进室性异位降解为可重入性心律失常。关于机电反馈在心律失常发生中的作用的新见解可能最终导致缺血性心脏病患者抗心律失常治疗的理性而非经验进展。除了上文概述的对人类健康的好处之外，拟议活动产生的更广泛影响包括：1)促进研究和教育一体化；2)扩大代表性不足群体的参与；3)促进下一代工程方法和技术的发展和传播。提出的研究将为患病心脏心律失常的机电建模提供一个集成的仿真工具阵列，这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。将特别强调妇女和代表性不足的少数民族学生参与该项目，以符合PI的长期研究活动。

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.