Prolongation of cardiac repolarization (increased QT duration) is linked to provocation of serious ventricular arrhythmias in some settings, but to arrhythmia suppression in others. Up to 11% of patients started on quinidine develop marked increases in QT and potentially fatal polymorphic ventricular tachycardia (""""""""Torsades de Pointes""""""""). On the other hand, marked QT increases are an invariable accompaniment of arrhythmia suppression by amiodarone, which only very rarely causes Torsades de Pointes. The research proposed will test the hypothesis that a specific in vitro electrophysiologic abnormality, bradycardia-dependent early afterdepolarization (EADs), triggers Torsades de Pointes in vivo. This hypothesis has its foundation in a series of clinical and laboratory studies we have conducted on quinidine-induced prolonged repolarization. In patients, we found that the occurrence of Torsades de Pointes was associated with a high incidence of hypokalemia and invariably started after an abrupt increase in cycle length. In canine Purkinje fibers superfused with low concentrations of quinidine, lowering potassium during slow stimulation consistently triggered EADs. Furthermore, interventions abolishing EADs (increasing potassium or stimulation rate) were the same as those which are most effective in Torsades de Pointes. The hypothesized role of EADs in triggering Torsades de Pointes will be further explored in three ways in this proposal. First, agents thought to cause Torsades de Pointes (disopyramide, procainamide, quinidine metabolites) will be tested in canine Purkinje fibers for their ability to induce EADs; interventions which prolong action potential but do not induce this arrhythmia (amiodarone, hypocalcemia) will be similarly evaluated. Second, ventricular monophasic action potentials will be recorded in an animal model of Torsades de Pointes, hypokalemic dogs with slow heart rates (AV block) treated with quinidine or other agents reported to induce EADs in vitro (N-acetylprocainamide, cesium). We have observed abnormalities in monophasic action potentials in such animals which we believe to represent EADs. The relationship of such abnormalities to previous cycle length, Torsades de Pointes onset, and drugs which prevent Torsades de Pointes will be evaluated to confirm this finding, thereby strengthening the link between the in vitro and in vivo abnormalities. Third, monophasic action potential will be recorded in patients receiving action potential prolonging drugs and in patients with previous Torsades de Pointes. In this way, methods to identify patients at risk for Torsades de Pointes will be improved. This research will identify circumstances under which prolongation of cardiac repolarization induces arrhythmias, thereby providing the basis for improved antiarrhythmic drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032694-02
Application #
3344118
Study Section
Cardiovascular Study Section (CVA)
Project Start
1984-08-01
Project End
1987-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
Wong, W; Pavlou, H N; Birgersdotter, U M et al. (1992) Pharmacology of the class III antiarrhythmic agent sematilide in patients with arrhythmias. Am J Cardiol 69:206-12
Balser, J R; Bennett, P B; Hondeghem, L M et al. (1991) Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine and amiodarone. Circ Res 69:519-29
Balser, J R; Roden, D M; Bennett, P B (1991) Single inward rectifier potassium channels in guinea pig ventricular myocytes. Effects of quinidine. Biophys J 59:150-61
Tamkun, M M; Knoth, K M; Walbridge, J A et al. (1991) Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle. FASEB J 5:331-7
Balser, J R; Bennett, P B; Roden, D M (1990) Time-dependent outward current in guinea pig ventricular myocytes. Gating kinetics of the delayed rectifier. J Gen Physiol 96:835-63
Campbell, R M; Woosley, R L; Iansmith, D H et al. (1990) Lack of triggered automaticity despite repolarization abnormalities due to bepridil and lidoflazine. Pacing Clin Electrophysiol 13:30-6
Balser, J R; Roden, D M; Bennett, P B (1990) Global parameter optimization for cardiac potassium channel gating models. Biophys J 57:433-44
Fish, F A; Prakash, C; Roden, D M (1990) Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators. Circulation 82:1362-9
Fish, F A; Roden, D M (1989) A prolonged QTc interval. Is it an important effect of antiarrhythmic drugs? Med Toxicol Adverse Drug Exp 4:400-11
Thompson, K A; Murray, J J; Blair, I A et al. (1988) Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes. Clin Pharmacol Ther 43:636-42

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