Mechanisms of flecainide induced negative inotropy: An in silico study

• Published in: Journal of molecular and cellular cardiology Vol. 158; pp. 26 - 37
• Main Authors: Yang, Pei-Chi, Giles, Wayne R., Belardinelli, Luiz, Clancy, Colleen E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2021
• Subjects: Action Potentials - drug effects; Anti-Arrhythmia Agents - adverse effects; Anti-Arrhythmia Agents - metabolism; Calcium Channels - metabolism; Cardiac inotropy; Computer Simulation; Flecainide; Flecainide - adverse effects; Flecainide - metabolism; Heart Rate - drug effects; Heart Ventricles - cytology; Heart Ventricles - drug effects; Homeostasis - drug effects; Humans; Ion channel; Models, Cardiovascular; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Pharmacology; Ryanodine Receptor Calcium Release Channel - metabolism; Safety pharmacology; Signal Transduction - drug effects; Sodium Channels - metabolism; Voltage-Gated Sodium Channel Blockers - adverse effects; Voltage-Gated Sodium Channel Blockers - metabolism; Pharmacology; Cardiac inotropy; Flecainide; Ion channel; Safety pharmacology
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2021.05.007

It is imperative to develop better approaches to predict how antiarrhythmic drugs with multiple interactions and targets may alter the overall electrical and/or mechanical function of the heart. Safety Pharmacology studies have provided new insights into the multi-target effects of many different classes of drugs and have been aided by the addition of robust new in vitro and in silico technology. The primary focus of Safety Pharmacology studies has been to determine the risk profile of drugs and drug candidates by assessing their effects on repolarization of the cardiac action potential. However, for decades experimental and clinical studies have described substantial and potentially detrimental effects of Na+ channel blockers in addition to their well-known conduction slowing effects. One such side effect, associated with administration of some Na+ channel blocking drugs is negative inotropy. This reduces the pumping function of the heart, thereby resulting in hypotension. Flecainide is a well-known example of a Na+ channel blocking drug, that exhibits strong rate-dependent block of INa and may cause negative cardiac inotropy. While the phenomenon of Na+ channel suppression and resulting negative inotropy is well described, the mechanism(s) underlying this effect are not. Here, we set out to use a modeling and simulation approach to reveal plausible mechanisms that could explain the negative inotropic effect of flecainide. We utilized the Grandi-Bers model [1] of the cardiac ventricular myocyte because of its robust descriptions of ion homeostasis in order to characterize and resolve the relative effects of QRS widening, flecainide off-target effects and changes in intracellular Ca2+ and Na+ homeostasis. The results of our investigations and predictions reconcile multiple data sets and illustrate how multiple mechanisms may play a contributing role in the flecainide induced negative cardiac inotropic effect. [Display omitted] •Safety Pharmacology studies have largely focused on repolarization abnormalities.•Experimental and clinical studies have described negative inotropy induced by Na+ channel blockers.•Flecainide exhibits strong rate-dependent block of INa and causes negative cardiac inotropy, but mechanisms are not clear.•Modeling and simulation was used to reveal plausible mechanisms of the negative inotropic effect of flecainide.•The predictions indicate multiple mechanisms underlying flecainide induced negative cardiac inotropy.