In this project the PI will establish the role of short term memory in action potential duration (APD) restitution and the formation of spatially discordant alternans (SDA) in the heart using nonlinear spatio-temporal analysis of the heart's dynamics. The PI will use patch clamp and optical mapping techniques to perform recording from isolated cells and intact rabbit hearts. In the theoretical studies, the PI will use a phenomenological mathematical model, as well as 2D numerical simulations utilizing the recently developed detailed ionic rabbit ventricular cell model. The first objective of the proposed research is to demonstrate that the spatial distribution of short-term memory in the heart correlates with the onset of alternans and ventricular fibrillation (VF). The second objective of the proposal is to establish inter-ventricular differences in mechanisms of SDA formation in the heart. Using optical mapping of the isolated rabbit heart, the PI will test the hypothesis that the formation of SDA in the right and left ventricles of the heart occurs predominantly through different mechanisms: steep conduction velocity restitution and short term memory. The third objective of the research proposal is to assess the specific roles of short term memory and steep conduction velocity restitution in SDA formation. The PI will use a pharmacological approach to further tease out the individual contributions of these mechanisms to SDA formation in the heart. The project will train graduate and undergraduate students in a multidisciplinary environment. The project will have significant impact on our understanding of the fundamental causes and precursors of ventricular fibrillation, a major cause of death in humans.
Sudden cardiac death is a major public health problem; it is one of the leading causes of mortality in the Western world. Sudden cardiac death is caused primarily by ventricular fibrillation. It has been established that alternans is a precursor of ventricular fibrillation, and consequently, sudden cardiac death. The aim of the project was to investigate the influences of short-term memory, which is an intrinsic property of cardiac tissue, on the formation of alternans in the heart. We have made a significant contribution to the field by revealing spatio-temporal evolution of both voltage and calcium alternans in the heart, both under control and diseased conditions. Specifically, we investigated the effect of mitochondria uncoupling and ischemia on the dynamics of alternans. We also developed a technique that helps predicting the local onset of alternans formation in the heart. Our findings might be potentially useful for developing techniques for alternans control, and thus preventing ventricular fibrillation. Results of the research have been reported in eight peer-reviewed journal publications (such as American Journal of Physiology, Biophysical Journal, Applied Optics, Nonlinear Dynamics, Physical Review E), one book chapter, two conference proceedings, fourteen presentations at the international and local conferences, and eleven invited seminars. The NSF grant helped me to develop and support a highly interdisciplinary research and education environment, and to attract students from different disciplines: biomedical engineering, electrical engineering, physics, and mathematics. Over the duration of the grant, one post-doc, seven graduate students, five undergraduate students, and three high school volunteers were involved in the project. Two graduate students obtained their Master degree, and four graduate students are scheduled to defend PhD thesis within one year. Several students received prestigious awards (such as NSF Graduate Research Fellowship, AHA summer fellowship, and Doctoral Dissertation Fellowship from the University of Minnesota). Our lab was involved in several outreach activities. Specifically, I participated in President's Distinguished Faculty Mentor Program, served as a judge in the FIRST Robotics competition, and in the State Science & Engineering Fair. Members of my lab provided a mentorship to high-school students to participate in the Minnesota Science Fair competition, and presented a seminar to 6th-grade students in the FIRST LEGO league.
