Impact of hypercholesterolemia on endothelium function after myocardial ischemia–reperfusion in aged downsized model of pig with defective LDL receptor

The aim of this study was to evaluate the endothelium function after post-ischemic episodes in the context of hypercholesterolemia. A familial hypercholesterolemia downsized pig model (FBM) described as human-like coronary atherosclerosis was used. In FBM groups, plasma LDL-cholesterol was significantly increased by 3-fold, without changes of HDL-cholesterol and triglycerides. Myocardial ischemia (30 min)/reperfusion (3 h) was performed on female (28-month-old) control and hypercholesterolemic pigs by occlusion of the left anterior descending coronary artery. Regional myocardial blood flow (RMBF), assessed by microspheres, returned to baseline value after post-ischemic hyperemia in the normal group, conversely post-ischemic hyperemia was blunted and RMBF was 30% of its baseline value in the FBM group. At the end of the experiment, the heart was isolated and 300 μm-diameter coronary arteries were dissected and perfused at a constant pressure. Endothelial function of segments obtained from ischemic and non-ischemic zones were compared. Bradykinin-induced endothelium dependent dilations were not modified by hypercholesterolemia or/and ischemia–reperfusion. Conversely, flow-mediated dilations (FMD) measured in non-ischemic microvessels were decreased by 30% in the FBM compared to normocholesterolemic pigs. Moreover, after ischemia-reperfusion, FMD were slightly reduced in control animals while constriction replaced dilation in FBM pigs. This vasoconstriction is in perfect agreement with the default of reperfusion illustrated by low regional myocardial blood flow. This study shows that hypercholesterolemia as well as endothelial dysfunction actively participate to the so called “no-reflow phenomena” after acute myocardial infarction.