title: Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction.
abstract: 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.
  
  
  
  The goal of this study was to determine whether IL-1 signaling also contributes to post-MI arrhythmogenesis.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Biomedical Engineering, School of Engineering, and.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: De Jesus
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
authors.forename: Lianguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, School of Engineering, and.
authors.forename: Johnny
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Rigor
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
authors.forename: Samantha D
authors.initials: SD
authors.lastname: Francis Stuart
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California. Electronic address: cripplinger@ucdavis.edu.
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Ripplinger
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling / Q000187:drug effects* / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta
keywords: Action potentials; Antiarrhythmic agents; Calcium; Interleukins; Myocardial infarction