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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.
Afiliación
  • De Jesus NM; Department of Biomedical Engineering, School of Engineering, and.
  • Wang L; Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
  • Lai J; Department of Biomedical Engineering, School of Engineering, and.
  • Rigor RR; Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
  • Francis Stuart SD; Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
  • Bers DM; Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California.
  • Lindsey ML; Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi.
  • Ripplinger CM; Department of Pharmacology, School of Medicine, University of California, Davis, Davis, California. Electronic address: cripplinger@ucdavis.edu.
Heart Rhythm ; 14(5): 727-736, 2017 05.
Article en En | MEDLINE | ID: mdl-28111350
BACKGROUND: Interleukin 1ß (IL-1ß) 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-1ß 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-1ß 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-1ß 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-1ß 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arritmias Cardíacas / Proteína Antagonista del Receptor de Interleucina 1 / Interleucina-1beta / Acoplamiento Excitación-Contracción / Antiarrítmicos / Infarto del Miocardio Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Heart Rhythm Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arritmias Cardíacas / Proteína Antagonista del Receptor de Interleucina 1 / Interleucina-1beta / Acoplamiento Excitación-Contracción / Antiarrítmicos / Infarto del Miocardio Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Heart Rhythm Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos