title: Malignant arrhythmias and acute myocardial ischemia: interaction between flecainide and the autonomic nervous system.
abstract: The antiarrhythmic and proarrhythmic effects of flecainide were assessed in 21 anesthetized cats. Ventricular arrhythmias can be reproducibly induced in cats by the combination of acute myocardial ischemia and sympathetic stimulation. Premature ventricular contractions (PVCs), sustained (sVT) and nonsustained (nsVT) ventricular tachycardia (VT), or ventricular fibrillation (VF) may be induced by a 1-minute left stellate ganglion stimulation during a 3-minute coronary artery occlusion. After three trials yielding consistent results, flecainide (2 mg/kg intravenous bolus plus 2 mg.kg-1.hr-1 intravenous infusion) was injected and two additional trials performed. Eight cats also underwent two trials after propranolol (0.2 mg/kg) administered while flecainide infusion was maintained. Flecainide decreased heart rate and blood pressure and slightly prolonged JTc (9%, p < 0.05). It markedly augmented QRS duration (61%, p < 0.0001), which was increased by an additional 61% (p < 0.0001) during sympathetic stimulation. VF was observed in 8 animals and never after flecainide (p < 0.05). However, after drug administration all cats had VT (2 nsVT and 6 sVT), and 5 required cardiac massage. Flecainide did not prevent the occurrence of nsVT in 6 cats, and it worsened arrhythmias by inducing VT (4 nsVT and 2 sVT) in 6 cats with only PVCs or without arrhythmias in the control trials. Propranolol, administered while flecainide infusion was maintained, prevented the increase in heart rate and the marked QRS prolongation during sympathetic stimulation (4 +/- 3 vs 52 +/- 16 msec, p < 0.05) and abolished the proarrhythmic effect of flecainide in 4 of 5 animals. Thus flecainide, despite an antifibrillatory effect, does not prevent and actually may favor the occurrence of sVT during acute myocardial ischemia and enhanced sympathetic activity. Propranolol, by countering the increase in heart rate during sympathetic stimulation, prevented the rate-dependent conduction delay and abolished the proarrhythmic effect of flecainide. The exacerbation, whenever a transient ischemic episode is accompanied by elevated sympathetic activity, of the ischemia-induced conduction delay caused by flecainide may in part explain the mortality data in the Cardiac Arrhythmia Suppression Trial.
authors.affiliation: Istituto di Clinica Medica Generale e Terapia Medica, Universitá di Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Stramba-Badiale
authors.forename: M
authors.initials: M
authors.lastname: Lazzarotti
authors.forename: M
authors.initials: M
authors.lastname: Facchini
authors.forename: P J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D005117:Cardiac Complexes, Premature / Q000139:chemically induced* / Q000503:physiopathology; D002415:Cats; D004562:Electrocardiography; D005424:Flecainide / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D006329:Heart Conduction System / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D011433:Propranolol / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D011433:Propranolol; D005424:Flecainide