Principal Investigator/Program Director (Last, first, middle): Zaitsev, Alexey, V. RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3031-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 7911-Abstract.pdf Mime Type: application/pdf 7. * Project Narrative 4070-Relevance.pdf Mime Type: application/pdf 8. Bibliography &References Cited 5814-References.pdf Mime Type: application/pdf 9. Facilities &Other Resources 4352-FacilitiesResources.pdf Mime Type: application/pdf 10. Equipment 2616-Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Zaitsev, Alexey, V. The broad, long-term goal of the proposed project is to provide a rational basis for the treatment of ventricular fibrillation (VF), a major cause of sudden cardiac death. The onset of VF causes the heart to stop pumping blood, which leads to ischemia (the lack of the blood flow) in the body and in the heart itself. Prolonged ischemia alters the cardiac state in such a way that it makes most of the attempts of defibrillation and cardio-pulmonary resuscitation futile. Empirical evidence indicate that the structure of VF ECG waveform is predictive of survival. The nature of this connection remains unknown. However, the ECG waveform reflects the spatiotemporal organization of electrical wavelets which sustain VF. Therefore, understanding the mechanisms linking the spatiotemporal organization of VF to ischemia is a necessary step towards determining the factors of survival, especially after prolonged times of VF/ischemia. Here we propose to use a combination of single cell, whole heart, and whole animal studies to establish a link between ischemia-specific alterations of cellular electrophysiology, spatiotemporal dynamics of fibrillatory waves, and the ECG waveform. The overall hypothesis is that the ischemia-induced changes in the balance between inward and outward currents, as well as in the coupling between the action potential and intracellular calcium cycling, lead to a dynamic instability in the action potential shape. This instability translates into a progressive disorganization of propagating wavelets and explains the progressive loss of periodicity in the ECG waveform. The specific aims are: 1. To analyze the mechanisms of dynamic instabilities of the action potential and Ca transient in isolated ventricular myocytes subjected to simulated conditions of ischemic VF. 2. To analyze mechanisms whereby dynamic instabilities of the AP and Ca transient cause conduction abnormalities during simulated and real ischemic VF in the whole heart. 3. To establish the link between the temporal regularity of the action potential, the dynamics of propagating wavelets, and the ECG during natural VF evolution in-situ. Project Description Page 6