An inflammation resolution–promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction

• Published in: Cardiovascular research Vol. 120; no. 4; pp. 345 - 359
• Main Authors: Hiram, Roddy, Xiong, Feng, Naud, Patrice, Xiao, Jiening, Sosnowski, Deanna K, Le Quilliec, Ewen, Saljic, Arnela, Abu-Taha, Issam H, Kamler, Markus, LeBlanc, Charles-Alexandre, Al-U’Datt, Doa’a G F, Sirois, Martin G, Hebert, Terence E, Tanguay, Jean-François, Tardif, Jean-Claude, Dobrev, Dobromir, Nattel, Stanley
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 30.03.2024
• Subjects: Animals; Atrial Fibrillation - genetics; Atrial Fibrillation - prevention & control; Atrial Remodeling; Cardiomyopathies; Fibrosis; Inflammation - complications; Inflammation - prevention & control; Myocardial Infarction - metabolism; Original; Rats; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - prevention & control; Myocardial infarction; Electrophysiology; Resolvin; Atrial fibrillation; Fibrosis
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvad175

Abstract Aims Recent studies suggest that bioactive mediators called resolvins promote an active resolution of inflammation. Inflammatory signalling is involved in the development of the substrate for atrial fibrillation (AF). The aim of this study is to evaluate the effects of resolvin-D1 on atrial arrhythmogenic remodelling resulting from left ventricular (LV) dysfunction induced by myocardial infarction (MI) in rats. Methods and results MI was produced by left anterior descending coronary artery ligation. Intervention groups received daily intraperitoneal resolvin-D1, beginning before MI surgery (early-RvD1) or Day 7 post-MI (late-RvD1) and continued until Day 21 post-MI. AF vulnerability was evaluated by performing an electrophysiological study. Atrial conduction was analysed by using optical mapping. Fibrosis was quantified by Masson’s trichrome staining and gene expression by quantitative polymerase chain reaction and RNA sequencing. Investigators were blinded to group identity. Early-RvD1 significantly reduced MI size (17 ± 6%, vs. 39 ± 6% in vehicle-MI) and preserved LV ejection fraction; these were unaffected by late-RvD1. Transoesophageal pacing induced atrial tachyarrhythmia in 2/18 (11%) sham-operated rats, vs. 18/18 (100%) MI-only rats, in 5/18 (28%, P < 0.001 vs. MI) early-RvD1 MI rats, and in 7/12 (58%, P < 0.01) late-RvD1 MI rats. Atrial conduction velocity significantly decreased post-MI, an effect suppressed by RvD1 treatment. Both early-RvD1 and late-RvD1 limited MI-induced atrial fibrosis and prevented MI-induced increases in the atrial expression of inflammation-related and fibrosis-related biomarkers and pathways. Conclusions RvD1 suppressed MI-related atrial arrhythmogenic remodelling. Early-RvD1 had MI sparing and atrial remodelling suppressant effects, whereas late-RvD1 attenuated atrial remodelling and AF promotion without ventricular protection, revealing atrial-protective actions unrelated to ventricular function changes. These results point to inflammation resolution–promoting compounds as novel cardio-protective interventions with a particular interest in attenuating AF substrate development. Graphical Abstract Graphical Abstract Effects of RvD1 on an atrial fibrillation (AF) substrate resulting from myocardial infarction (MI)–induced left ventricular (LV) dysfunction. MI is characterized by a non-contractile scar that produces LV dysfunction. Early treatment with RvD1 (pre-MI) reduces the scar area and prevents LV dysfunction, whereas later RvD1 therapy (starting 7 days post-MI) does not affect MI scar or LV dysfunction. MI and associated LV dysfunction cause increased atrial inflammatory signalling and recruitment of pro-inflammatory M1 macrophages. RvD1 therapy reduces atrial inflammatory signalling and M1 macrophage recruitment, while enhancing the presence of anti-inflammatory M2 macrophages and increasing pro-resolution signalling. MI-induced inflammatory signalling causes fibrosis and atrial conduction abnormalities that lead to an AF-maintaining substrate; these changes are prevented by RvD1 treatment.