Defibrillation is the only therapy available for victims of sudden cardiac death. However, high energy deflbrillation shocks may result in myocardial dysfunction and damage. A rising number of ICD malfunctions in recent years is associated with the failure of high-voltage components. We propose to develop a novel approach to defibrillation, which may result in a 20-fold reduction in delivered energy. Presently, implantable cardioverter-defibrillators terminate ventricular tachycardia (VT) by low-energy anti-tachycardia pacing (ATP). A high energy defibrillation shock is applied only when ATP fails. We hypothesize that ATP fails in cases of anatomically defined reentrant VT pinned to scars, areas of fibroses, because scars stabilize the reentry. We propose to convert anchored reentry into a functionally defined (unpinned) arrhythmia by a properly timed low-energy unpinning shock. We further hypothesize that following unpinning, VT can be terminated by anti-repinning pacing (ARP) which will prevent its degeneration into ventricular fibrillation (VF). We will use state-of-the art panoramic imaging with voltage-sensitive dye, multielectrode mapping, and bidomain modeling to pursue the following Specific Aims in rabbit and canine models of infarction: 1. To investigate the role of small scale endocardial structural heterogeneity in anchoring reentrant arrhythmias and their unpinning in the rabbit isolated right ventricle. Based on the elucidated biophysical mechanisms, to optimize unpinning and VT termination by an ARP protocol;2. To investigate the role of global structural and functional heterogeneity in anchoring reentrant arrhythmias and their unpinning in isolated preparations and intact rabbit hearts with myocardial infarction. Based on the elucidated biophysical mechanisms, to optimize sensing, unpinning, and VT termination by ARP protocol;3. Using open-chest epicardial mapping, to demonstrate the feasibility of unpinning and ARP termination of VT in canines with 4-day myocardial infarction. To optimize sensing, unpinning and ARP protocols. This research will lead to the development of a novel defibrillation strategy, which will reduce the number of applications of high-energy shocks, replacing them with low-energy unpinning shocks and ARP. This energy reduction will improve the life time and reliability of implantable devices and will reduce the side-effects of defibrillation. It is also likely to reduce the number of ICD malfunctions and reimplantations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067322-08
Application #
7849004
Study Section
Special Emphasis Panel (ZRG1-CVS-A (02))
Program Officer
Lathrop, David A
Project Start
2001-08-06
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
8
Fiscal Year
2010
Total Cost
$480,888
Indirect Cost
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lou, Qing; Fedorov, Vadim V; Glukhov, Alexey V et al. (2011) Transmural heterogeneity and remodeling of ventricular excitation-contraction coupling in human heart failure. Circulation 123:1881-90
Bordas, R; Gillow, K; Lou, Q et al. (2011) Rabbit-specific ventricular model of cardiac electrophysiological function including specialized conduction system. Prog Biophys Mol Biol 107:90-100

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