Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several dis-eases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, moni-toring for adverse arrhythmogenic events could be considered. (J Am Coll Cardiol Basic Trans Science 2022;7:1001-10 17) (c) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardi-ology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).