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

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL088444-02S1
Application #
7842049
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2009-07-15
Project End
2011-06-30
Budget Start
2009-07-15
Budget End
2011-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$134,893
Indirect Cost
Name
University of Utah
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Garg, Vivek; Taylor, Tyson; Warren, Mark et al. (2015) ?-Adrenergic stimulation and rapid pacing mutually promote heterogeneous electrical failure and ventricular fibrillation in the globally ischemic heart. Am J Physiol Heart Circ Physiol 308:H1155-70
Diakos, Nikolaos A; Selzman, Craig H; Sachse, Frank B et al. (2014) Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery. J Am Coll Cardiol 64:1602-12
Taylor, Tyson G; Venable, Paul W; Booth, Alicja et al. (2013) Does the combination of hyperkalemia and KATP activation determine excitation rate gradient and electrical failure in the globally ischemic fibrillating heart? Am J Physiol Heart Circ Physiol 305:H903-12
Venable, Paul W; Taylor, Tyson G; Sciuto, Katie J et al. (2013) Detection of mitochondrial depolarization/recovery during ischaemia--reperfusion using spectral properties of confocally recorded TMRM fluorescence. J Physiol 591:2781-94
Shibayama, Junko; Taylor, Tyson G; Venable, Paul W et al. (2013) Metabolic determinants of electrical failure in ex-vivo canine model of cardiac arrest: evidence for the protective role of inorganic pyrophosphate. PLoS One 8:e57821
Taylor, Tyson G; Venable, Paul W; Shibayama, Junko et al. (2012) Role of KATP channel in electrical depression and asystole during long-duration ventricular fibrillation in ex vivo canine heart. Am J Physiol Heart Circ Physiol 302:H2396-409
Warren, Mark; Spitzer, Kenneth W; Steadman, Bruce W et al. (2010) High-precision recording of the action potential in isolated cardiomyocytes using the near-infrared fluorescent dye di-4-ANBDQBS. Am J Physiol Heart Circ Physiol 299:H1271-81
Venable, Paul W; Taylor, Tyson G; Shibayama, Junko et al. (2010) Complex structure of electrophysiological gradients emerging during long-duration ventricular fibrillation in the canine heart. Am J Physiol Heart Circ Physiol 299:H1405-18
Wasmund, Stephen L; Pai, Rakesh K; Freedman, Roger A et al. (2009) Modulation of the sinus rate during ventricular fibrillation. J Cardiovasc Electrophysiol 20:187-92
Shvedko, Alexander G; Warren, Mark D; Shome, Shibaji et al. (2008) Influence of the skeletal muscle activity on time and frequency domain properties of the body surface ECG during evolving ventricular fibrillation in the pig. Resuscitation 78:215-23

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