Infiltrated cardiac lipids impair myofibroblast-induced healing of the myocardial scar post-myocardial infarction

ObjectivesLipids 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.MethodsPigs, 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.ResultsAt 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 TGFβ/TβRII/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.ConclusionIntramyocardial lipid accumulation impairs TGFβ/TβRII/Smad2/3 signaling altering the fibrotic reparative process of the scar resulting in larger infarcts and cardiac dysfunction.

► Hypercholesterolemia induces ventricular dysrhythmias during ischemia. ► Intramyocardial lipids impair myofibroblast-related collagen synthesis. ► Excess cardiac lipids exacerbate apoptosis and lead to extensive infarcts. ► Lipid overload in the jeopardized myocardium impairs cardiac healing. ► Cardiac lipotoxicity deteriorates heart performance.