Proarrhythmia of a class Ic drug: suppression by combination with a drug prolonging repolarization in the dog late after infarction.
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.
Duff
H J
HJ
Department of Medicine, University of Calgary, Canada.
Stemler
M
M
Thannhauser
T
T
Laganiere
S
S
Rude
E
E
Lester
W
W
D000818:Animals; D017609:Barium Compounds / Q000627:therapeutic use*; D002712:Chlorides / Q000627:therapeutic use*; D003645:Death, Sudden; D004285:Dogs; D004359:Drug Therapy, Combination; D004558:Electric Stimulation; D016700:Encainide / Q000009:adverse effects / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000517:prevention & control*
D017609:Barium Compounds; D002712:Chlorides; C024986:barium chloride; D016700:Encainide