Chronic amiodarone therapy in heart failure patients induced a marked use-dependent depression of Vmax and prevented dofetilide-induced early afterdepolarizations compared to non-treated HF tissue.
Does chronic amiodarone therapy modify the electrophysiological response to IKr block in human failing ventricular myocardium?
Chronic amiodarone therapy in heart failure patients induces a use-dependent reduction in Vmax and prevents dofetilide-induced early afterdepolarizations, potentially explaining its low proarrhythmic potential.
Absolute Event Rate: 471% vs 488%
Abstract Introduction Amiodarone (AMIO) is a widely used antiarrhythmic agent with proven efficacy against both ventricular and supraventricular arrhythmias. Despite its extensive clinical use, the cellular mechanisms of its antiarrhythmic action remain incompletely understood. While extracardiac toxicity is a known concern, AMIO dis-plays relatively low proarrhythmic potential compared to other antiarrhythmic drugs. Objective To investigate the cellular electrophysiological effects of chronic amiodarone therapy in end-stage heart failure (HF) patients using human left ventricular tissue, and to compare responses to IKr inhibition with tissues from non-AMIO-treated HF patients and healthy donor hearts. Methods Left ventricular tissue slices were obtained from explanted hearts of end-stage HF patients treated or not treated with chronic AMIO, and from non-diseased donor hearts. Conventional microelectrode recordings were per-formed to assess action potential duration (APD), responses to 50 nM dofetilide (DOF; an IKr blocker), and the frequency dependence of the maximal upstroke velocity (Vmax). Results Both AMIO- and non-AMIO-treated HF tissues exhibited significantly prolonged APD compared to do-nor samples (donor: 382 ± 13.8 ms, n=7; HF+AMIO: 471±27.4 ms, n=6; HF–AMIO: 488±3.7 ms, n=6), but the two HF groups did not differ significantly from each other. Upon application of 50 nM DOF, donor and HF+AMIO samples showed moderate APD prolongation (donor: +21%; HF+AMIO: +37%) without early after depolarizations (EADs). In contrast, HF–AMIO samples developed EADs (see Figure 1) and failed repolarization. Furthermore, chronic AMIO treatment induced a marked use-dependent depression of Vmax, which was absent in donor and HF–AMIO groups. Conclusion Chronic amiodarone therapy in heart failure patients induces a pronounced use-dependent reduction in the Vmax, a phenomenon not observed in donor hearts or in HF patients without amiodarone treatment. This distinctive electrophysiological modulation may contribute to the drug’s low proarrhythmic potential and therapeutic efficacy in the failing human heart. These findings highlight a potentially protective mechanism of chronic amiodarone administration.Figure 1For image description, please refer to the figure legend and surrounding text.
Jost et al. (Fri,) conducted a other in End-stage heart failure (n=19). Chronic amiodarone therapy vs. No amiodarone treatment and healthy donor hearts was evaluated on Action potential duration (APD). Chronic amiodarone therapy in heart failure patients induced a marked use-dependent depression of Vmax and prevented dofetilide-induced early afterdepolarizations compared to non-treated HF tissue.