Aims: Dronedarone's effectiveness as a Class III antiarrhythmic agent in preventing atrial fibrillation (AF) recurrence in patients with persistent AF is well-established. However, the mechanisms underlying its role in the genesis of cardiac arrhythmias during myocardial ischemia remain unclear. This study aims to provide a deeper understanding of dronedarone's therapeutic potential, particularly in the context of myocardial ischemia-induced arrhythmias.
Methods: Electrophysiological remodeling, based on experimental data of myocardial ischemia, was emulated and incorporated into a human ventricular model. Subsequently, the effects of dronedarone were integrated into the constructed models to analyze their influence on electrophysiological alterations in ventricular cells and tissues, in comparison with amiodarone. Employing the developed single-cell and one-dimensional tissue models, we examined the changes in action potentials of ventricular cells and the excitation wave propagation in ventricular tissues under four distinct conditions: normal, and myocardial ischemia at three severity levels.
Results: Simulation outcomes revealed that myocardial ischemia shortened the action potential duration (APD) of ventricular myocytes, increased the resting membrane potential, and decreased the action potential amplitude. Both dronedarone and amiodarone prolonged the APD of ischemic ventricular myocytes without altering the resting potential of ischemic ventricular cells. Specifically, 0.1 μM and 0.3 μM dronedarone increased APD by 18% and 23% under normal conditions and 15% and 20% under low-level ischemia conditions. Under ischemic conditions, an increase in dronedarone concentration significantly increased APD and effective refractory period (ERP) in ventricular cells, while amiodarone did not. In one-dimensional ventricular tissue simulations, heterogeneity within the ventricular tissues was diminished.
Conclusion: Simulation results suggest that, under ischemic conditions, dronedarone is more effective in preventing arrhythmia than amiodarone. The reduction of heterogeneity in ventricular tissues by dronedarone may represent an additional mechanism contributing to its effectiveness in counteracting arrhythmias.