Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, 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, monitoring for adverse arrhythmogenic events could be considered.

Original languageEnglish
Pages (from-to)1001-1017
Number of pages17
JournalJACC: Basic to Translational Science
Issue number10
StatePublished - Oct 2022


  • GSK-3 inhibitor
  • SB216763
  • electrophysiology
  • human cardiac slices


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