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.