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The human ether-a-go-go-related gene (hERG) current inhibition selectively prolongs action potential of midmyocardial
C Yasuda1, S Yasuda2, H Yamashita2
1Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Insights
Drug-induced arrhythmias stem from prolonged action potential duration due to hERG channel inhibition. This study reveals disopyramide disproportionately lengthens M-cell action potentials, increasing repolarization dispersion and arrhythmogenesis risk.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
- Computational Biology
Background:
- Drug-induced arrhythmias are a significant clinical concern.
- Prolongation of action potential duration (APD) by hERG channel inhibition is a known risk factor.
- Sustained arrhythmias require both APD prolongation and transmural dispersion of repolarization.
Purpose of the Study:
- To investigate the effect of hERG inhibition on transmural dispersion of APD.
- To elucidate the cellular mechanisms underlying drug-induced proarrhythmia.
- To evaluate the utility of the action potential clamp technique in studying hERG-mediated arrhythmogenesis.
Main Methods:
- Utilized the action potential clamp technique, integrating in silico myocyte models with experimental I(Kr) measurements.
- Measured whole-cell I(Kr) in hERG-expressing cells.
- Coupled experimental data with ventricular endocardial, M-, and epicardial cell models to simulate action potentials under control and disopyramide conditions.
Main Results:
- Disopyramide dose-dependently increased APDs in all simulated cell types.
- M-cell APD prolongation was disproportionate at higher disopyramide concentrations, leading to significant dispersion of repolarization.
- Disopyramide's effects on peak I(Kr) and current-voltage relationships were similar across cell types, suggesting M-cell specific electrophysiological properties contribute to dispersion.
Conclusions:
- Disopyramide induces significant transmural dispersion of repolarization by disproportionately affecting M-cells.
- Reduced repolarization reserve in M-cells, potentially due to lower levels of other potassium currents, explains the observed dispersion.
- The action potential clamp technique is a valuable tool for dissecting hERG inhibition-induced arrhythmogenesis via transmural repolarization dispersion.
Abstract:
The majority of drug induced arrhythmias are related to the prolongation of action potential duration following inhibition of rapidly activating delayed rectifier potassium current (I(Kr)) mediated by the hERG channel. However, for arrhythmias to develop and be sustained, not only the prolongation of action potential duration but also its transmural dispersion are required. Herein, we evaluated the effect of hERG inhibition on transmural dispersion of action potential duration using the action potential clamp technique that combined an in silico myocyte model with the actual I(Kr) measurement. Whole cell I(Kr) current was measured in Chinese hamster ovary cells stably expressing the hERG channel. The measured current was coupled with models of ventricular endocardial, M-, and epicardial cells to calculate the action potentials. Action potentials were evaluated under control condition and in the presence of 1, 10, or 100 μM disopyramide, an hERG inhibitor. Disopyramide dose-dependently increased the action potential durations of the three cell types. However, action potential duration of M-cells increased disproportionately at higher doses, and was significantly different from that of epicardial and endocardial cells (dispersion of repolarization). By contrast, the effects of disopyramide on peak I(Kr) and instantaneous current-voltage relation were similar in all cell types. Simulation study suggested that the reduced repolarization reserve of M-cell with smaller amount of slowly activating delayed rectifier potassium current levels off at longer action potential duration to make such differences. The action potential clamp technique is useful for studying the mechanism of arrhythmogenesis by hERG inhibition through the transmural dispersion of repolarization.
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