The 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.
