The long term objective of this SCOR application is to investigate the arrhythmogenic mechanisms responsible for sudden cardiac death in patients with coronary heart disease and ventricular hypertrophy. These two disorders are responsible for the vast majority of the 300,000 sudden cardiac deaths annually in the US. The unifying theme through all of the studies is that structural abnormalities of the myocardium that affect cell-to-cell communication lead to electrophysiological disturbances responsible for cardiac arrhythmias. Some of these abnormalities, once identified, can be corrected or modified, with elimination or reduction in the frequency of cardiac arrhythmias. Further, recognition of these abnormalities in animal models will lead to increased specificity and sensitivity in identifying patients at risk for sudden cardiac death and to new therapeutic interventions. Through interactive and collaborative studies, we will pursue the following four major hypotheses: 1) myocardial remodeling alters the number, distribution or function of several important cardiac structures, including gap junctions and autonomic innervation patterns, that are directly and indirectly responsible for normal cell-to-cell communication; 2) these alterations in gap junctions and innervation patterns are different in the various cardiomyopathies and produce different electrophysiological patterns that result in ventricular arrhythmias of different mechanisms; 3) correction of these abnormalities with genetically-engineered cells will restore the electrophysiology toward normal patterns and help prevent the development of ventricular arrhythmias; and 4) establishing the patterns of abnormalities in innervation and cell-to-cell communication in the animal models will provide insight into identifying and treating patients at risk for sudden cardiac death. Six projects and 2 cores have been assembled to address these objectives. Project 1 (Pressler) identifies and attempts to repair abnormalities in gap junctions; Project 2 (Warner) identifies and attempts to repair alterations in autonomic innervation and electrophysiology; Project 3 (Field) uses intracardiac grafting techniques in an effort to effect myocardial regeneration and long term delivery of cardioprotective compounds to repair or correct the underlying abnormalities; Project 4 (Hutchins) bridges the animal and clinical projects by providing noninvasive imaging patterns of sympathetic and muscarinic innervation as well as general myocardial function; Project 5 (Mulholland) develops new PET tracers to study abnormalities of the myocardium and innervation; and Project 6 (Zipes) interacts with all projects and investigates the autonomic and electrophysiologic patterns in a patients with coronary disease and ventricular hypertrophy. The cores include a histopathology core (Pressler) that will provide tissue histology resources, and an administration core (Zipes) responsible for the day-to-day operation of the SCOR. This SCOR application combines the methodologies of molecular biology and protein biochemistry with in vitro and in vivo animal electrophysiology studies in order to explore and understand the causes and mechanisms of arrhythmias responsible for sudden cardiac death in patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL052323-04
Application #
2638028
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Project Start
1995-02-01
Project End
1999-12-31
Budget Start
1998-01-26
Budget End
1998-12-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Sawada, Stephen; Hamoui, Omar; Barclay, Jennifer et al. (2005) Usefulness of positron emission tomography in predicting long-term outcome in patients with diabetes mellitus and ischemic left ventricular dysfunction. Am J Cardiol 96:2-8
Vereckei, Andras; Gorski, J Cristopher; Ujhelyi, Michael et al. (2004) Intrapericardial ibutilide administration fails to terminate pacing-induced sustained atrial fibrillation in dogs. Cardiovasc Drugs Ther 18:269-77
Zipes, Douglas P (2004) The year in electrophysiology. J Am Coll Cardiol 43:1306-14
Zipes, Douglas P (2003) Mechanisms of clinical arrhythmias. Pacing Clin Electrophysiol 26:1778-92
Zipes, Douglas P (2003) Mechanisms of clinical arrhythmias. J Cardiovasc Electrophysiol 14:902-12
Sawada, Stephen G; Lewis, Stephen J; Foltz, Judy et al. (2002) Usefulness of rest and low-dose dobutamine wall motion scores in predicting survival and benefit from revascularization in patients with ischemic cardiomyopathy. Am J Cardiol 89:811-6
Miyata, Akira; Dowell, Joshua D; Zipes, Douglas P et al. (2002) Rate-dependent [K+](o) accumulation in canine right atria in vivo: electrophysiological consequences. Am J Physiol Heart Circ Physiol 283:H506-17
Wu, J; Zipes, D P (2001) Transmural reentry during acute global ischemia and reperfusion in canine ventricular muscle. Am J Physiol Heart Circ Physiol 280:H2717-25
Zipes, D P (2001) Implantable cardioverter-defibrillator: A Volkswagen or a Rolls Royce: how much will we pay to save a life? Circulation 103:1372-4
Vereckei, A; Warman, E; Mehra, R et al. (2001) Comparison of the effects on drug concentrations, electrophysiologic parameters, and termination of atrial fibrillation in dogs when procainamide and ibutilide are delivered into the right atrium versus intravenously. J Cardiovasc Electrophysiol 12:330-6

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