Action Potential Triangulation Explains Acute Proarrhythmic Effect of Aliskiren in a Whole-Heart Model of Atrial Fibrillation.

Abstract

Recent experimental studies showed a protective effect of the renin inhibitor aliskiren regarding atrial structural remodeling. Purpose of this study was to assess acute electrophysiologic effects of aliskiren in a whole-heart model of atrial fibrillation (AF) and to investigate its impact on the ventricle. Twelve rabbit hearts were excised, retrogradely perfused, and paced at different cycle lengths. To enhance atrial vulnerability, a combination of acetylcholine (ACh) and isoproterenol (Iso) was infused and significantly reduced atrial action potential duration (aAPD90) and atrial effective refractory period (aERP). Additional infusion of aliskiren prolonged aAPD90 but did not alter aERP. A triangulation of action potential with ACh/Iso and a further triangulation after treatment with aliskiren were noted. Vulnerability to AF was tested by employing trains of burst pacing. Administration of ACh/Iso provoked more episodes of AF (baseline: 26 episodes, Iso/Ach: 48 episodes). Additional treatment with aliskiren induced AF significantly more often (108 episodes). Another nine hearts were perfused with aliskiren to examine its ventricular effects. Infusion with aliskiren abbreviated ventricular APD90 and ERP. Utilizing programmed ventricular stimulation, a trend towards more ventricular arrhythmias in aliskiren-treated hearts was observed. Though aliskiren did not reduce aAPD90 or aERP, acute treatment with aliskiren promoted AF. Triangulation of atrial action potentials, which is an established risk factor for ventricular proarrhythmia, may contribute to the increased atrial vulnerability. This effect may interfere with its recently demonstrated beneficial properties in atrial remodeling. Of note, aliskiren might have a proarrhythmic effect on the ventricular level.

• Authors: Christian Ellermann, André Mittelstedt, Julian Wolfes, Kevin Willy, Patrick Leitz, Florian Reinke, Lars Eckardt, Gerrit Frommeyer
• Journal: Cardiovascular toxicology (Cardiovasc Toxicol) Vol. 20 Issue 1 Pg. 49-57 (02 2020) ISSN: 1559-0259 [Electronic] United States
• PMID: 31175534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Fumarates
• aliskiren
• Isoproterenol
• Acetylcholine

Topics

• Acetylcholine
• Action Potentials (drug effects)
• Amides (toxicity)
• Animals
• Atrial Fibrillation (chemically induced, physiopathology)
• Cardiac Pacing, Artificial
• Disease Models, Animal
• Female
• Fumarates (toxicity)
• Heart Atria (drug effects, physiopathology)
• Heart Rate (drug effects)
• Heart Ventricles (drug effects, physiopathology)
• Isolated Heart Preparation
• Isoproterenol
• Rabbits
• Refractory Period, Electrophysiological (drug effects)
• Time Factors