The overall goal of the proposed research is to define the electrophysiologic mechanisms underlying malignant ventricular arrhythmias in the failing heart. Congestive heart failure is a highly prevalent and lethal disorder, with nearly one-half of deaths occurring suddenly due to malignant ventricular arrhythmias. Current therapy is empiric and of limited efficacy; therefore, an understanding of the underlying electrophysiologic mechanisms is critical to the development of new agents to effectively treat patients with these arrhythmias. Studies of the electrophysiologic alterations accompanying heart failure to date have been limited by a lack of both a direct method to assess electrophysiologic mechanisms and an animal model of heart failure which exhibits spontaneous arrhythmias. These studies will involve both in vivo cardiac activation mapping, by use of a unique computerized three-dimensional mapping system capable of simultaneous recording from 240 intramural sites, and in vitro electrophysiologic analyses. Studies will be performed in three newly developed models of heart failure with marked ventricular dysfunction, spontaneous ventricular arrhythmias, and morphologic features similar to those of human dilated cardiomyopathy. These studies will define the role of intramural reentry and nonreentrant mechanisms (such as delayed or early afterdepolarizations or abnormal automaticity) in the initiation and maintenance of ventricular arrhythmias in the failing heart. Intraoperative three-dimensional mapping will be performed in patients with cardiomyopathy to define the electrophysiologic mechanisms responsible for ventricular tachycardia in the failing human heart, and to validate the data obtained in the experimental models. Since alterations in adrenergic neural input may influence the development of ventricular arrhythmias in the failing heart, analysis of the electrophysiologic effects of catecholamines will be assessed both in vivo by cardiac mapping and in vitro. The role of altered adrenergic responsiveness on the development of arrhythmias will be explored in vivo and in vitro by defining the electrophysiologic responses to alpha- and beta-adrenergic receptor stimulation. To determine whether nonreentrant excitation is due to delayed or early afterdepolarizations, studies will be performed in vitro in an isolated blood-perfused ventricular preparation that will combine on- line mapping with recordings of monophasic action potentials and transmembrane potentials. The results of these studies will define the electrophysiologic mechanisms underlying ventricular arrhythmias in the failing heart, and provide the crucial foundation for further assessment of the underlying subcellular mechanisms and for the development of pharmacologic agents that will modify the incidence of sudden death in this setting.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL046929-01
Application #
3473591
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1991-08-09
Project End
1996-07-31
Budget Start
1991-08-09
Budget End
1992-07-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Johnson, Carolyn M; Pogwizd, Steven M (2012) Focal initiation of sustained and nonsustained ventricular tachycardia in a canine model of ischemic cardiomyopathy. J Cardiovasc Electrophysiol 23:543-52
Rinne, Andreas; Kapur, Nidhi; Molkentin, Jeffery D et al. (2010) Isoform- and tissue-specific regulation of the Ca(2+)-sensitive transcription factor NFAT in cardiac myocytes and heart failure. Am J Physiol Heart Circ Physiol 298:H2001-9
Ideker, Raymond E; Rogers, Jack M; Fast, Vladimir et al. (2009) Can mapping differentiate microreentry from a focus in the ventricle? Heart Rhythm 6:1666-9