Eicosapentaenoic acid ethyl ester, cardiac metabolomic and lipidomic signatures, and cardioprotection in myocardial infarction.

Abstract (English)

BACKGROUND AND AIMS: The cardiovascular benefits of eicosapentaenoic acid ethyl ester (EPA-E) in MACE reduction might extend beyond its triglyceride (TG)-lowering effects. However, the mechanism behind remains unknown. This study investigated whether EPA-E exerts cardioprotection in the setting of myocardial infarction (MI). METHODS: Hypertriglyceridaemia (HTG) was induced in male rats by a high-sucrose diet (>175 mg&#xb7;dL-1; baseline). Hypertriglyceridaemia rats were administered for 2 weeks high-dose EPA-E supplementation (HTG + EPA-E; n = 21) or placebo (HTG; n = 27) in combination with the diet. A control diet group (CD; n = 15) was included. After 2 weeks, MI was induced by transient coronary ligation and animals were sacrificed 24 h thereafter for infarct size, molecular, histological, and -omic analyses. Echocardiography was performed. RESULTS: HTG + EPA-E animals displayed lower circulating TG levels and better cardiac function as compared to HTG group. HTG + EPA-E animals showed smaller infarcts (P < 0.05 vs both groups), and MI-related mortality was 29% in EPA-E-treated animals (reaching levels comparable to those of the CD group), whereas it was 56% in HTG animals (P = 0.07). No correlation was observed between circulating TG levels and MI-related infarct size or mortality. Cardiac function was similarly deteriorated in all animals post-MI. Eicosapentaenoic acid ethyl ester treatment was associated with lower TG-related cardiolipotoxicity, apoptosis, fibrosis, oxidative stress, pro-inflammatory cell recruitment and less mitochondrial dysfunction in the infarcted heart. EPA-E treatment favoured a pro-resolving response and improved metabolomic and lipidomic profiles both systemically and in the infarcted heart. CONCLUSIONS: Eicosapentaenoic acid ethyl ester treatment exerts direct cardioprotective effects and ameliorates cardiac metabolic and lipidomic signatures after MI regardless of its circulating TG-lowering effects.