Mechanisms of depressed conduction from long-term amiodarone therapy in canine myocardium.

Abstract

Amiodarone therapy leads to a significant impairment in myocardial conduction, yet it causes only a modest decrease in the maximum rate of depolarization of the action potential (dV/dT). To determine whether the decrease in dV/dT solely accounts for the impaired myocardial conduction or whether passive membrane properties may also be involved, we studied 21 ventricular epicardial tissues from 14 beagles; six dogs received long-term treatment (3-6 weeks) of amiodarone orally, and the remaining dogs served as controls. Amiodarone therapy was associated with a decrease in conduction velocity (0.41 ± 0.15 vs. 0.56 ± 0.05 m/sec; p<0.01). There was a trend toward a decrease in dV/dT and a significant decrease in the space constant (0.69 ± 0.27 vs. 1.05 ± 0.25 mm; p = 0.01), of which the latter correlated closely with the decrease in conduction velocity measured in the amiodarone-treated tissues (r= 0.85, p<0.05). These data indicate that the decrease in myocardial conduction velocity caused by amiodarone is primarily due to effects on overall resistance to passive current flow rather than effects on the inward sodium current. (Circulation 1988;78:684-691) Amiodarone is singularly effective in the treatment of malignant ventricular tachyarrhythmias. In patients with ventricular tachycardia refractory to other antiarrhythmics, there is a 50-80% response rate to amiodarone. '-11 The mechanism of amiodarone's antiarrhythmic action is unknown. Ventricular tachycardia likely results from reentrant circuits that rely on critical interactions between the conduction characteristics and refractoriness of the myocardium. Pharmacological alterations of these interactions effect an antiarrhythmic (or proarrhythmic) response. Amiodarone

Atrial-selective effects of chronic amiodarone in the management of atrial fibrillation

“…Both acute and chronic amiodarone prolong ERP more than APD, due to development of PRR 12,13. While acute amiodarone reduces V max and blocks I Na in practically all studies,4 chronic amiodarone was reported to either depress V max 14, 15 or, in most studies, to cause no or little changes in V max in superfused ventricular muscle and Purkinje fibers 4,16. Ventricular CV is slowed and QRS duration is prolonged in both acutely and chronically amiodarone-treated humans and animals in vivo 16-18.…”

“…While acute amiodarone reduces V max and blocks I Na in practically all studies,4 chronic amiodarone was reported to either depress V max 14, 15 or, in most studies, to cause no or little changes in V max in superfused ventricular muscle and Purkinje fibers 4,16. Ventricular CV is slowed and QRS duration is prolonged in both acutely and chronically amiodarone-treated humans and animals in vivo 16-18. However, the QRS interval was significantly prolonged only at relatively rapid pacing rates (e.g., at CL of ≤ 500 ms in humans), displaying a non-statistically significant prolongation at normal or slow heart rates,18 consistent with our results in the dog.…”

Synergistic Electrophysiologic and Antiarrhythmic Effects of the Combination of Ranolazine and Chronic Amiodarone in Canine Atria

“…Both acute and chronic amiodarone have been shown to prolong the effective refractory period more than APD, resulting in post-repolarization refractoriness (PRR) 16,17. While acute amiodarone reduces V max and blocks I Na in practically all studies (for review see13), chronic amiodarone has been reported to either depress V max 9,18–20 or to cause little to no change in V max in superfused ventricular muscle and Purkinje fibers 13,15,21. Ventricular conduction velocity is slowed and QRS duration is prolonged in both acute and chronic amiodarone-treated humans and animals in vivo 21–23…”

Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve Preparations

“…Both acute and chronic amiodarone prolong the effective refractory period more than APD, due to development of postrepolarization refractoriness 24,25. Whereas acute amiodarone reduces V max and blocks I Na in practically all studies (for review see1), chronic amiodarone was reported to either depress V max 26,27 or, in most studies, to cause no or little changes in V max in superfused ventricular muscle and Purkinje fibers 1,21,28. Ventricular conduction velocity is slowed and QRS duration is prolonged in both acute and chronic amiodarone-treated humans and animals in vivo 28-30.…”