In spite of important advances in cardiology over the past couple of decades, pharmacologic treatment of cardiac arrhythmias, espiecally life threatening ventricular arrhythmias, remains largely empiric. The reason stems from a fundamental lack of understanding of the mechanisms that give rise to cardiac rhythm disturbances, incomplete understanding of the mechanisms by which antiarrhythmic drugs act to suppress and in some cases aggravate arrhythmias, and a lack of criteria by which to base a differential diagnosis of specific arrhythmia mechanisms. The proposed study addresses all of these areas through a multilevel approach involving work with dissociated myocytes, syncytial tissues, intact hearts, mathematical models and clinical ECG analyses. We will focus on two classes of arrhythmia mechanisms, namely reentry (reflection) and early afterdepolarization-induced triggered activity. Utilizing biologic models of these arrhythmias, we will describe the behavioral characteristics of the preparations and assess in depth the cellular and membrane electrophysiologic basis for the phenomena as well as their modulation by drugs. Mathematical models, both empiric and theoretical (Hodgkin-Huxley type), will be employed to facilitate comparison of the experimental findings with the clinical observations and to provide future experimental direction. Clinical correlative data will be sought with the aid of clinical colleagues worldwide and diagnostic criteria will be carefully formulated based on the experimental findings. The ultimate goal of the study is to provide information that will lead to a more definitive and less empiric approach in the pharmacologic and medical management of cardiac rhythm disturbances.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037396-03
Application #
3353007
Study Section
Cardiovascular Study Section (CVA)
Project Start
1987-05-01
Project End
1992-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Masonic Medical Research Laboratory, Inc
Department
Type
DUNS #
077307437
City
Utica
State
NY
Country
United States
Zip Code
13501
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Di Diego, Jose M; Antzelevitch, Charles (2003) Cellular basis for ST-segment changes observed during ischemia. J Electrocardiol 36 Suppl:1-5
Yan, G X; Antzelevitch, C (1999) Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 100:1660-6
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Antzelevitch, C; Sun, Z Q; Zhang, Z Q et al. (1996) Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 28:1836-48
Gintant, G A (1996) Two components of delayed rectifier current in canine atrium and ventricle. Does IKs play a role in the reverse rate dependence of class III agents? Circ Res 78:26-37
Lukas, A; Antzelevitch, C (1996) Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. Cardiovasc Res 32:593-603
Di Diego, J M; Sun, Z Q; Antzelevitch, C (1996) I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol 271:H548-61
Liu, D W; Antzelevitch, C (1995) Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ Res 76:351-65
Sicouri, S; Antzelevitch, C (1995) Electrophysiologic characteristics of M cells in the canine left ventricular free wall. J Cardiovasc Electrophysiol 6:591-603

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