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Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart
S Sicouri1, S Moro, S Litovsky
1Division Cardiologia, Hospital Ramos Mejia, Buenos Aires, Argentina.
Insights
Chronic amiodarone reduces transmural dispersion of repolarization in canine ventricles, explaining its antiarrhythmic efficacy and low proarrhythmia risk. This study clarifies amiodarone
Area of Science:
- Cardiovascular Electrophysiology
- Pharmacology
- Cardiac Arrhythmia Management
Background:
- Amiodarone is a potent antiarrhythmic drug with complex electropharmacology, used for atrial and ventricular arrhythmias.
- Its high efficacy and low proarrhythmia incidence compared to other Class III agents are not fully understood.
- The study investigates amiodarone's effects on canine ventricular cells.
Purpose of the Study:
- To examine the effects of chronic amiodarone administration on the electrophysiology of canine ventricular epicardial, endocardial, and M cells.
- To elucidate the cellular mechanisms underlying amiodarone's antiarrhythmic effectiveness and low proarrhythmic potential.
Main Methods:
- Standard microelectrode techniques were employed to record transmembrane action potentials.
- Ventricular tissue strips (endocardial, epicardial, mid-myocardial) were isolated from control and amiodarone-treated dogs.
- Dogs received oral amiodarone (30–40 mg/kg/day) for 30–45 days.
Main Results:
- Chronic amiodarone prolonged action potential duration in epicardial and endocardial cells.
- It showed less prolongation, or even a decrease at slow rates, in M cells, reducing transmural dispersion of repolarization.
- Amiodarone suppressed d-sotalol-induced dispersion of repolarization and early afterdepolarizations.
Conclusions:
- Chronic amiodarone differentially alters ventricular myocyte electrophysiology, significantly decreasing transmural dispersion of repolarization.
- This reduction, particularly under exaggerated dispersion conditions, likely contributes to amiodarone's antiarrhythmic efficacy.
- The findings help explain the low incidence of proarrhythmia with chronic amiodarone compared to other Class III agents.
Introduction:
Amiodarone is a potent antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. In addition to its beta-blocking properties, amiodarone is known to block the sodium, potassium, and calcium channels in the heart. Its complex electropharmacology notwithstanding, the reasons for the high efficacy of the drug remain unclear. Also not well understood is the basis for the low incidence of proarrhythmia seen with amiodarone relative to other agents with Class III actions. The present study was designed to examine the effects of chronic amiodarone in epicardial, endocardial, and M cells of the canine left ventricle.
Methods And Results:
We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. Tissues were obtained from mongrel dogs receiving amiodarone orally (30 to 40 mg/kg per day) for 30 to 45 days or from untreated controls. Chronic amiodarone produced a greater prolongation of action potential duration in epicardium and endocardium, but less of an increase, or even a decrease at slow rates, in the M region, thereby reducing transmural dispersion of repolarization. In addition, chronic amiodarone therapy suppressed the ability of the IKr blocker, d-sotalol, to induce a marked dispersion of repolarization or early afterdepolarization activity.
Conclusion:
Our data demonstrate for the first time a direct effect of chronic amiodarone treatment to differentially alter the cellular electrophysiology of ventricular myocardium so as to produce an important decrease in transmural dispersion of repolarization, especially under conditions in which dispersion is exaggerated. These results may contribute to our understanding of the effectiveness of amiodarone in the treatment of life-threatening arrhythmias as well as to our understanding of the low incidence of proarrhythmia attending therapy with chronic amiodarone in comparison with other Class III agents.
