Clinically Relevant Doses of Remimazolam Modulate Cardiac Electrophysiology: Late Repolarization Prolongation and Increased Conduction Dispersion With Preserved QTc

Background Remimazolam, an ultra‐short‐acting benzodiazepine with rapid metabolism and cardiovascular stability, is increasingly used for anesthesia, yet its cardiac electrophysiologic effects are incompletely characterized. Methods We conducted a multimodal evaluation in Langendorff‐perfused guinea pig hearts and human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs), using surface electrocardiogram (ECG), multielectrode mapping, optical mapping, and whole‐cell patch‐clamp across remimazolam doses (0, 1, 2, 3 mg/kg/h). Results High‐dose remimazolam (3 mg/kg/h) prolonged the PR interval ( p = 0.027), and T‐wave duration was prolonged at 2 and 3 mg/kg/h ( p = 0.017 and p < 0.001), while QT interval and corrected QT interval (QTc) remained unchanged ( p > 0.1). Multielectrode mapping showed prolonged activation time at 2 and 3 mg/kg/h versus NC ( p = 0.02 and 0.003) and increased conduction dispersion at 2 and 3 mg/kg/h ( p = 0.0193 and 0.0101). Conduction velocity (CV) was reduced at 3 mg/kg/h compared with NC and 1 mg/kg/h ( p = 0.01 and 0.02). Optical mapping demonstrated prolonged action potential duration at 90% repolarization (APD 90 ) (NC: 107.93 ± 0.63 ms vs 3 mg/kg/h: 118.94 ± 1.83 ms, p < 0.001) and calcium transient duration at 90% recovery (CTD 90 ) (NC: 116.20 ± 1.04 ms vs 3 mg/kg/h: 125.63 ± 1.15 ms, p < 0.001), accompanied by increased APD 90 interquartile range (APD 90 ‐IQR; p ≤ 0.02 vs NC) and increased CTD 90 interquartile range (CTD 90 ‐IQR; p = 0.005). In hiPSC‐CMs, 1500 ng/mL remimazolam selectively prolonged APD 90 ( p = 0.04) without significant effects on action potential amplitude, upstroke velocity, or early repolarization indices (all p > 0.05). Conclusion These findings indicate that at higher clinically relevant exposures, remimazolam selectively lengthens late repolarization and increases conduction heterogeneity—features consistent with an arrhythmogenic substrate—while QT and QTc remains stable, supporting cautious use and ECG monitoring in at‐risk populations.