Many sudden cardiac arrests (SCAs) are caused by ventricular fibrillation (VF) that has been present for several minutes before defibrillation is attempted (long duration VF, LDVF). Yet, most studies of the basic mechanisms of VF have been performed during the first tens of seconds of VF (short duration VF, SDVF). However, LDVF and SDVF differ. Most studies of the mechanism of defibrillation have investigated shocks following SDVF, not LDVF. Spontaneous refibrillation after defibrillation is common following LDVF and survival progressively decreases as the number of refibrillation episodes increase. Therefore, a vitally important goal is the development of improved therapies for the treatment of LDVF, including better defibrillation techniques and ways to prevent refibrillation. During the last grant period, we made many new findings about the importance of focal activity arising in Purkinje fibers in the mechanisms of LDVF maintenance, defibrillation of LDVF, and spontaneous refibrillation following defibrillation of LDVF. The goals of this application are (1) to verify these new findings and investigate the mechanisms responsible for them, and (2) to obtain knowledge of how these basic mechanisms are altered by acute ischemia, an important cause of SCA, with the expectation that this knowledge will lead to the rational, directed development of improved therapy for SCA. The 3 specific aims listed below will be accomplished using intramural and endocardial electrical recordings, optical recordings, and microelectrode recordings. An advantage of the proposed studies is that the 3 specific aims will all be accomplished during the same experiments.
Specific Aim 1. Investigate the mechanisms of LDVF maintenance. We will test the hypotheses that (1) focal activation arising in Purkinje fibers and (2) subendocardial mother rotors are the primary mechanism for LDVF maintenance. If hypothesis 1 is true, we will perform studies to help differentiate if the foci occur because of EADs, DADs, or abnormal automaticity. If hypothesis 2 is true, we will determine if the rotors are located in a particular ventricular region because of the anatomic structure there.
Specific Aim 2. Investigate the mechanisms of failed defibrillation following LDVF. We will test the hypothesis that earliest post-shock activation following failed shocks arises focally in Purkinje fibers. If so, we will perform studies to help differentiate if the foci occur because of EADs, DADs, or abnormal automaticity.
Specific Aim 3. Investigate the mechanisms of spontaneous refibrillation occurring ~1 min following defibrillation for LDVF. We will test the hypothesis that refibrillation following LDVF and defibrillation in HF is caused by focal activation arising in Purkinje fibers. If so, we will perform studies to help differentiate if the foci occur because of EADs, DADs, or abnormal automaticity. ) For all 3 aims, we will determine how these mechanisms are altered by acute regional ischemia. )

Public Health Relevance

Sudden cardiac arrest caused by ventricular fibrillation (VF) is an important problem in patients with coronary heart disease. The attempt to develop better therapies to improve survival from sudden cardiac arrest at all stages of its resuscitative treatment can best be performed by first understanding the basic mechanisms of VF initiation, the maintenance of VF, defibrillation failure, and spontaneous refibrillation. Because coronary heart disease affects more than a million Americans a year and sudden cardiac arrest is a leading cause of death in these patients, we believe our research grant application, the goal of which is to obtain this basic information, is highly significant.)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085370-06
Application #
8248778
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2006-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$366,250
Indirect Cost
$116,250
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Kong, Wei; Fast, Vladimir G (2014) The role of dye affinity in optical measurements of Cai(2+) transients in cardiac muscle. Am J Physiol Heart Circ Physiol 307:H73-9
Jin, Qi; Dosdall, Derek J; Li, Li et al. (2014) Verapamil reduces incidence of reentry during ventricular fibrillation in pigs. Am J Physiol Heart Circ Physiol 307:H1361-9
Killingsworth, Cheryl R; Melnick, Sharon B; Litovsky, Silvio H et al. (2013) Evaluation of acute cardiac and chest wall damage after shocks with a subcutaneous implantable cardioverter defibrillator in Swine. Pacing Clin Electrophysiol 36:1265-72
Kong, Wei; Ideker, Raymond E; Fast, Vladimir G (2012) Intramural optical mapping of V(m) and Ca(i)2+ during long-duration ventricular fibrillation in canine hearts. Am J Physiol Heart Circ Physiol 302:H1294-305
Cheng, Kang-An; Dosdall, Derek J; Li, Li et al. (2012) Evolution of activation patterns during long-duration ventricular fibrillation in pigs. Am J Physiol Heart Circ Physiol 302:H992-H1002
Osorio, Jose; Ideker, Raymond (2011) Commotio cordis: size matters, so does shape. Heart Rhythm 8:1582-3
Robichaux, Robert P; Dosdall, Derek J; Osorio, Jose et al. (2010) Periods of highly synchronous, non-reentrant endocardial activation cycles occur during long-duration ventricular fibrillation. J Cardiovasc Electrophysiol 21:1266-73
Jennings, John M; Ideker, Raymond E (2010) Why do thrombi form in the left but not the right atrium in atrial fibrillation: differences in platelet P-selectin levels? Heart Rhythm 7:1184-5
Dosdall, Derek J; Fast, Vladimir G; Ideker, Raymond E (2010) Mechanisms of defibrillation. Annu Rev Biomed Eng 12:233-58

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