In the normal heart, when heart rate increases, ventricular repolarization shortens (QT adaptation, normal restitution). This adaptive mechanism prevents the occurrence of excessively long QT intervals at short cycle lengths with the attendant risk for life-threatening arrhythmias. Failure of the QT interval to appropriately adapt to heart rate increases, defined as """"""""ventricular electrical remodeling"""""""", may represent one of the key factors in increasing the risk for sudden death in several clinical conditions. One, well defined, is LQT1, the variant of the long QT syndrome with mutations affecting the Iks current. Another, of major social importance, is heart failure. The present proposal is designed to test the hypothesis that different degrees of electrical remodeling (different degrees of loss of repolarization adaptation) represent one of the key targets for interventions destined to alter the progression of ischemic cardiomyopathy toward heart failure and lethal arrhythmias. A novel model of chronic ischemic cardiomyopathy that develops after myocardial infarction, secondary to repeated coronary microembolizations will be used in this project. This model has the unique characteristic to allow chronic study of dogs at high and low risk for spontaneous life-threatening and lethal ventricular tachyarrhythmias. The preparation allows the study of contributions to electrical instability by changes in autonomic tone and reflexes and to assess the concurrent changes in the expression of the ionic currents playing a major role in repolarization. We will evaluate the possibility that specific interventions that are already clinically available, such as beta-blockers or left stellate gangionectomy, or under development, such as activators of repolarizing currents, might prevent or alter favorably this specific type of electrical remodeling. These clinically applicable interventions may modify the natural history of diseases, such as heart failure, characterized by ventricular electrical remodeling leading to a high risk for lethal arrhythmias.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-O (S1))
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Lathrop, David A
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University of Oklahoma Health Sciences Center
Internal Medicine/Medicine
Schools of Medicine
Oklahoma City
United States
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Adamson, Philip B; Barr, Roger C; Callans, David J et al. (2005) The perplexing complexity of cardiac arrhythmias: beyond electrical remodeling. Heart Rhythm 2:650-9
Swann, Michael H; Nakagawa, Hiroshi; Vanoli, Emilio et al. (2003) Heterogeneous regional endocardial repolarization is associated with increased risk for ischemia-dependent ventricular fibrillation after myocardial infarction. J Cardiovasc Electrophysiol 14:873-9
Adamson, Philip B; Vanoli, Emilio; Mattera, Giovan G et al. (2003) Hemodynamic effects of a new inotropic compound, PST-2744, in dogs with chronic ischemic heart failure. J Cardiovasc Pharmacol 42:169-73