科研之友
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摘要
BACKGROUND Interleukin 1 beta (IL-1 beta) 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-1 beta 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-1 beta 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, highspeed optical mapping of transmembrane potential and intracellular Ca2+ in isolated hearts revealed that IL-1 beta inhibition improved conduction velocity, reduced action potential duration dispersion, improved intracellular Ca2+ handling, decreased trans membrane potential and Ca2+ alternans magnitude, and reduced spontaneous and inducible ventricular arrhythmias. These functional improvements were linked to increased expression of con nexin 43 and sarcoplasmic reticulum Ca2+-ATPase. CONCLUSION This study revealed a novel mechanism for IL-beta 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.
- 出版日期2017-5
