Journal
ATHEROSCLEROSIS
Volume 224, Issue 2, Pages 368-376Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2012.07.003
Keywords
Lipids; Myocardial infarction; Cardiac healing; Cardiac function
Funding
- SAF [2010-16549]
- TERCEL
- CIBEROBN06
- Fundacion Jesus Serra-FIC, Barcelona
- Innovation and Science Spanish Ministry, MICINN, Spain [RyC-2009-5495]
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Objectives: Lipids have been detected in the ischemic myocardium of patients' post-myocardial infarction (MI). However, their effect on the cardiac healing process remains unknown. We investigated whether intramyocardial lipids affect the signaling pathways involved in the fibrotic reparative response impairing cardiac healing post-MI. Methods: Pigs, fed either a high-cholesterol diet (HC) or a regular-chow (NC), were subjected to experimentally-induced acute MI (90 min mid-LAD balloon occlusion) and then, upon reperfusion (R), maintained for 21 days with the same diet regime (HC/R+ and NC/R+, respectively). A group of hypercholesterolemic animals were sacrificed after ischemia without reperfusion (HC/R-). Cardiac tissue was obtained for molecular/cellular/histological analysis. Infarct size and echocardiography were assessed. Results: At the time of acute MI, hypercholesterolemic animals showed a higher incidence of ventricular dysrhythmias. At sacrifice, intramyocardial lipids were absent in HC/R-. HC/R+ showed higher lipid content (ApoB, cholesteryl-ester and triglycerides) and lower expression/activity of the TGF beta/T beta RII/Smad2/3 pathway (involved in scar reparative fibrosis) than NC/R+ in the forming scar. Collagen synthesis was accordingly reduced in the scar of HC/R+. Infarct size was 44% larger in HC/R+ which had higher apoptosis and lower Akt/eNOS activity in the jeopardized myocardium. Systolic function was similarly deteriorated post-MI in all animals whereas no changes were detected in diastolic-related parameters. No changes were detected in systolic parameters 21 days post-MI in NC/R+ animals. In contrast, both systolic- and diastolic-related parameters were further deteriorated in HC/R+ animals. Conclusion: Intramyocardial lipid accumulation impairs TGF beta/T beta RII/Smad2/3 signaling altering the fibrotic reparative process of the scar resulting in larger infarcts and cardiac dysfunction. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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