Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart

Int J Mol Sci. 2021 Oct 18;22(20):11249. doi: 10.3390/ijms222011249.


In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.

Keywords: QT prolongation; cytokines; guinea pig; inflammation; interleukin-6; lipotoxicity; ventricular myocytes.

MeSH terms

  • Action Potentials*
  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology*
  • Cardiotoxicity / physiopathology
  • Female
  • Guinea Pigs
  • Interleukin-6 / metabolism*
  • Ion Channel Gating
  • Lipid Metabolism
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / pathology*
  • Macrophages / metabolism*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Potassium Channels / chemistry*


  • Interleukin-6
  • Potassium Channels