Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction

Nicole M. De Jesus, Lianguo Wang, Johnny Lai, Robert R. Rigor, Samantha D. Francis Stuart, Donald M. Bers, Merry L. Lindsey, Crystal M. Ripplinger

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Background Interleukin 1β (IL-1β) is a key regulator of the inflammatory response after myocardial infarction (MI) by modulating immune cell recruitment, cytokine production, and extracellular matrix turnover. Elevated levels of IL-1β are associated with adverse remodeling, and inhibition of IL-1 signaling after MI results in improved contractile function. Objective The goal of this study was to determine whether IL-1 signaling also contributes to post-MI arrhythmogenesis. Methods MI was created in 2 murine models of elevated inflammation: atherosclerotic on the Western diet or wild-type with a subseptic dose of lipopolysaccharide. The role of IL-1β was assessed with the IL-1 receptor antagonist anakinra (10 mg/(kg·d), starting 24 hours post-MI). Results In vivo and ex vivo molecular imaging showed reduced myocardial inflammation after a 4-day course of anakinra treatment, despite no change in infarct size. At day 5 post-MI, high-speed optical mapping of transmembrane potential and intracellular Ca2+ in isolated hearts revealed that IL-1β inhibition improved conduction velocity, reduced action potential duration dispersion, improved intracellular Ca2+ handling, decreased transmembrane potential and Ca2+ alternans magnitude, and reduced spontaneous and inducible ventricular arrhythmias. These functional improvements were linked to increased expression of connexin 43 and sarcoplasmic reticulum Ca2+-ATPase. Conclusion This study revealed a novel mechanism for IL-1β in contributing to defective excitation-contraction coupling and arrhythmogenesis in the post-MI heart. Our results suggest that inhibition of IL-1 signaling post-MI may represent a novel antiarrhythmic therapy.

Original languageEnglish (US)
Pages (from-to)727-736
Number of pages10
JournalHeart Rhythm
Volume14
Issue number5
DOIs
StatePublished - May 2017

Keywords

  • Action potentials
  • Antiarrhythmic agents
  • Calcium
  • Interleukins
  • Myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    De Jesus, N. M., Wang, L., Lai, J., Rigor, R. R., Francis Stuart, S. D., Bers, D. M., Lindsey, M. L., & Ripplinger, C. M. (2017). Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. Heart Rhythm, 14(5), 727-736. https://doi.org/10.1016/j.hrthm.2017.01.027