Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction.

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 Ca in isolated hearts revealed that IL-1β inhibition improved conduction velocity, reduced action potential duration dispersion, improved intracellular Ca handling, decreased transmembrane potential and Ca alternans magnitude, and reduced spontaneous and inducible ventricular arrhythmias. These functional improvements were linked to increased expression of connexin 43 and sarcoplasmic reticulum Ca-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.