TY - JOUR
T1 - Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction
AU - De Jesus, Nicole M.
AU - Wang, Lianguo
AU - Lai, Johnny
AU - Rigor, Robert R.
AU - Francis Stuart, Samantha D.
AU - Bers, Donald M
AU - Lindsey, Merry L.
AU - Ripplinger, Crystal M
PY - 2017
Y1 - 2017
N2 - 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 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. 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.
AB - 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 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. 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.
KW - Action potentials
KW - Antiarrhythmic agents
KW - Calcium
KW - Interleukins
KW - Myocardial infarction
UR - http://www.scopus.com/inward/record.url?scp=85015970599&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85015970599&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2017.01.027
DO - 10.1016/j.hrthm.2017.01.027
M3 - Article
C2 - 28111350
AN - SCOPUS:85015970599
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
ER -