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

19 Citations (Scopus)

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

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Interleukin-1
Myocardial Infarction
Interleukin 1 Receptor Antagonist Protein
Voltage-Sensitive Dye Imaging
Inflammation
Excitation Contraction Coupling
Connexin 43
Molecular Imaging
Interleukin-1 Receptors
Calcium-Transporting ATPases
Sarcoplasmic Reticulum
Membrane Potentials
Action Potentials
Extracellular Matrix
Lipopolysaccharides
Cardiac Arrhythmias
Cytokines

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

De Jesus, N. M., Wang, L., Lai, J., Rigor, R. R., Francis Stuart, S. D., Bers, D. M., ... 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

Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. / De Jesus, Nicole M.; Wang, Lianguo; Lai, Johnny; Rigor, Robert R.; Francis Stuart, Samantha D.; Bers, Donald M.; Lindsey, Merry L.; Ripplinger, Crystal M.

In: Heart Rhythm, Vol. 14, No. 5, 05.2017, p. 727-736.

Research output: Contribution to journalArticle

De Jesus, NM, Wang, L, Lai, J, Rigor, RR, Francis Stuart, SD, Bers, DM, Lindsey, ML & Ripplinger, CM 2017, 'Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction', Heart Rhythm, vol. 14, no. 5, pp. 727-736. https://doi.org/10.1016/j.hrthm.2017.01.027
De Jesus NM, Wang L, Lai J, Rigor RR, Francis Stuart SD, Bers DM et al. Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. Heart Rhythm. 2017 May;14(5):727-736. https://doi.org/10.1016/j.hrthm.2017.01.027
De Jesus, Nicole M. ; Wang, Lianguo ; Lai, Johnny ; Rigor, Robert R. ; Francis Stuart, Samantha D. ; Bers, Donald M. ; Lindsey, Merry L. ; Ripplinger, Crystal M. / Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. In: Heart Rhythm. 2017 ; Vol. 14, No. 5. pp. 727-736.
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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.",
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N2 - 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.

AB - 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.

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