Do Stimulants Promote Arrhythmic Risk: Insights From a Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model

Abstract

Background

Stimulant medications are widely prescribed for ADHD. Although generally considered safe, their use in patients with underlying cardiac conditions remains a concern due to potential arrhythmic risk.

Objective

To evaluate the effects of commonly prescribed stimulants on key electrophysiological parameters associated with arrhythmia risk in chamber-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Methods

Atrial and ventricular hiPSC-CMs were plated on a multielectrode array (MEA) platform and exposed to clinically relevant plasma concentrations of methylphenidate, dextroamphetamine, atomoxetine, caffeine, or the β-agonist isoproterenol. Extracellular field potentials were recorded over 48 h to assess acute and prolonged effects on conduction velocity (CV), beat rate (BR), and corrected field potential duration (FPDc).

Results

CV was largely preserved across all stimulant conditions in both atrial and ventricular hiPSC-CMs, while isoproterenol produced a modest early increase. All stimulants transiently elevated BR during the first hour of exposure, followed by a progressive decline over time. Isoproterenol and caffeine induced robust and sustained increases in BR, confirming model responsiveness. FPDc was prolonged by all stimulant compounds, most prominently by atomoxetine, consistent with its known I_Kr inhibitory properties. Isoproterenol produced a rate-dependent FPDc shortening, particularly in hiPSC-vCMs.

Conclusion

At clinically relevant plasma concentrations, stimulants modulated automaticity and repolarization but had minimal impact on conduction in hiPSC-CMs. The preservation of CV suggests that these compounds are unlikely to alter myocardial conduction at therapeutic doses. The observed effects on BR and FPDc warrant further mechanistic studies to understand how these changes may contribute to arrhythmia risk in susceptible populations.