In the human heart, the rapid delayed rectifier K+ current (I Kr) contributes significantly to ventricular action potential (AP) repolarization and to set the duration of the QT interval of the surface electrocardiogram (ECG). The pore-forming (α) subunit of the I Kr channel is encoded by KCNH2 or human ether-à-go-go-related gene 1 (hERG1). Impairment of hERG function through either gene mutation (congenital) or pharmacological blockade by diverse drugs in clinical use (acquired) can cause a prolongation of the AP duration (APD) reflected onto the surface ECG as a prolonged QT interval or Long QT Syndrome (LQTS). LQTS can increase the risk of triggered activity of ventricular cardiomyocytes and associated life-threatening arrhythmia. Current treatments all focus on reducing the incidence of arrhythmia or terminating it after its onset but there is to date no prophylactic treatment for the pharmacological management of LQTS. A new class of hERG modulators (agonists) have been suggested through direct interaction with the hERG channel to shorten the action potential duration (APD) and/or increase the postrepolarisation refractoriness period (PRRP) of ventricular cardiomyocytes protecting thereby against triggered activity and associated arrhythmia. Although promising drug candidates, there remain major obstacles to their clinical development. The aim of this review is to summarize the latest advances as well as the limitations of this proposed pharmacotherapy.
Keywords: Long QT syndrome; arrhythmia; hERG K+ channel pharmacology; hERG agonists; mutation.
© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.