Proarrhythmia of a class Ic drug: suppression by combination with a drug prolonging repolarization in the dog late after infarction

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 274; no. 1; p. 508
• Main Authors: Duff, H J, Stemler, M, Thannhauser, T, Laganiere, S, Rude, E, Lester, W
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.1995
• Subjects: Animals; Barium Compounds - therapeutic use; Chlorides - therapeutic use; Death, Sudden; Dogs; Drug Therapy, Combination; Electric Stimulation; Encainide - adverse effects; Encainide - therapeutic use; Myocardial Infarction - complications; Myocardial Infarction - drug therapy; Tachycardia, Ventricular - chemically induced; Tachycardia, Ventricular - prevention & control
• ISSN: 0022-3565; 1521-0103

Encainide treatment in patients after myocardial infarction is associated with increased risk of sudden cardiac death. This may relate to drug-induced changes in the electrophysiologic milieu, thus predisposing the patient to sustained ventricular tachyarrhythmias. The goals of this study were to first develop a model of class Ic-induced ventricular tachycardia (VT) and then to design treatments to oppose this prodysrhythmic activity. Dogs with time-dependent loss of inducible sustained VT in the antiarrhythmic drug-free state were studied late after infarction. These dogs received a series of three loading and maintenance infusions of O-demethyl encainide (ODME) to achieve concentrations of 60 +/- 31, 136 +/- 46 and 339 +/- 171 ng/ml. Drug maintenance continued until programmed stimulation induced monomorphic sustained VT. When ODME infusion allowed this induction, barium chloride infusions were added. ODME treatment allowed induction of monomorphic sustained VT in 9 of 10 dogs studied. Prodysrhythmic monomorphic VT was significantly related (P < .01) to prolongation of conduction velocity in the peri-infarct zone. ODME modestly increased ventricular refractoriness at some but not all peri-infarct sites. Infusion of barium chloride in the above nine dogs caused their hearts to return to the noninducible state. Prolongation of refractoriness in the peri-infarct zone was correlated to this suppression of prodysrhythmia. Prolongation of conduction velocity in the absence of substantial prolongation of refractoriness may underlie ODME-facilitated induction of monomorphic VT. Prolongation of refractoriness in the peri-infarct zone by combination treatment with barium chloride reversed prodysrhythmic VT in all of the dogs.