Computer simulations predict exacerbation of action potential prolongation in human ventricular cardiomyocytes during chronic administration of amiodarone and dronedarone

Amiodarone and dronedarone are commonly used antiarrhythmic drugs, affecting a wide range of ion channels. Emerging data suggest that both drugs have distinct acute and chronic effects, but the underlying mechanisms and their electrophysiological consequences remain incompletely understood. To address this, we employed an integrated experimental and computational approach to characterize their proarrhythmic potential over time. This abstract focuses on cellular action potential (AP) simulations. Simulations were conducted using a modified computer model of human ventricular cardiomyocyte electrophysiology [Tomek et al., 2019; 2020], in which the native peak and late Na + -current formulations were replaced with an established Na V 1.5 Markov model that captures drug-channel interactions for charged and neutral drug fractions [Moreno et al., 2013]. The Na V 1.5 Markov model was calibrated for acute and chronic drug effects using literature data [Maltsev et al., 2001; Ramon de Lime Conceicao et al., 2023; 2024] and whole-cell patch-clamp recordings in CHO cells, respectively. Additional effects of amiodarone and dronedarone on Ca V 1.2, K V 4.3, K V 11.1, K V 7.1 [Crumb et al., 2016], and NCX1 [Watanabe and Kimura, 2000] were incorporated, with chronic effects on K V 11.1 and K V 7.1 informed by our recordings obtained after 48 h of incubation with 1 μM amiodarone or dronedarone. During acute exposure (0.3 and 1 μM), amiodarone and dronedarone induced a concentration-dependent prolongation of the AP duration at 50% (APD 50 ) and 90% repolarization (APD 90 ) and for both drugs, an increasing pacing rate (1–3 Hz) led to progressive shortening of APD 50 and APD 90 . Chronic exposure to either drug (1 μM) induced an increase in late Na + current and a reduction in K V 11.1 current in CHO cells. Accordingly, simulations highlighted prolonged APD 50 and APD 90 with both drugs during chronic application, while still exhibiting rate-dependent shortening at higher pacing rates (1, 2, and 3 Hz). These results highlight distinct acute and chronic electrophysiological profiles for amiodarone and dronedarone. The exacerbation of APD prolongation during chronic exposure warrants attention in safety evaluations, as it may impact the Torsades de Pointes risk during sustained drug administration.