Anti-arrhythmic effects of interleukin-1 inhibition following myocardial infarction

Background— Interleukin-1 beta (IL-1 β ) is a key regulator of the inflammatory response following myocardial infarction (MI), by modulating immune cell recruitment, cytokine production, and extracellular matrix turnover. Elevated levels of IL-1 β are associated with adverse remodeling, and inhibition of IL-1 signaling following MI results in improved contractile function. Objective— The goal of this study was to determine if IL-1 signaling also contributes to post-MI arrhythmogenesis. Methods— MI was created in two murine models of elevated inflammation: atherosclerotic on Western diet or wild-type with a sub-septic dose of lipopolysaccharide. The role of IL-1 β was assessed with the IL-1 receptor antagonist, anakinra (10mg/kg/day, starting 24h post-MI). Results— In vivo and ex vivo molecular imaging showed reduced myocardial inflammation following 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 (V m ) and intracellular Ca 2+ in isolated hearts revealed that IL-1 β inhibition improved conduction velocity, reduced action potential duration dispersion, improved intracellular Ca 2+ handling, decreased V m and Ca 2+ alternans magnitude, and reduced spontaneous and inducible ventricular arrhythmias. Conclusions— This study revealed a novel mechanism for IL-1 β 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 anti-arrhythmic therapy. A four-day course of treatment with the FDA-approved IL-1 receptor antagonist, anakinra, reduced spontaneous and inducible arrhythmias despite no change in infarct size. Our findings demonstrate that IL-1 β inhibition improved cell-cell coupling and normalized Ca 2+ homeostasis, which collectively reduced the propensity to triggered and reentrant arrhythmias.