Ischemic preconditioning and infarct mass: The effect of hypercholesterolemia and endothelial dysfunction

In an experimental model of atherosclerosis we investigated whether rabbits fed an atherogenic diet (0.25% cholesterol, 3% coconut oil) develop endoth elial dysfunction accompanied with increased infarct mass compared to norma l fed rabbits and, whether hypercholesterolemia would interfere with the be neficial outcome of ischemic preconditioning observed in normal rabbits. Af ter four weeks on either a normal or an atherogenic diet, New Zealand White rabbits (n=7 in each group) were subjected to 30 min of myocardial ischemi a by occlusion of a branch of the left anterior descending coronary artery (LAD) followed by 2 hours of reperfusion (infarct studies). For ischemic pr econditioning experiments, LAD was additionally occluded twice for 5 min fo llowed by 10 min reperfusion before the long-lasting (30 min) ischemia. Inf arct mass was evaluated by triphenyl-tetrazolium staining. Besides the asse ssment of aortic endothelium-dependent function and NO-release, aortic and cardiac vessels were inspected for atherosclerotic lesions. Total cholester ol serum levels in rabbits on an atherogenic diet were significantly higher (15.3+/-2.7 mmol/L) than those on a standard diet (0.65+/-0.08 mmol/L). Th e aortas and heart vessel were without any histological evidence of atheros clerosis. whereas endothelial dysfunction and significantly reduced calcium -ionophore stimulated endothelial NO-release were found in isolated aortic rings of hypercholesterolemic animals. Rabbits on a standard diet showed an infarct mass (related to the area at risk) of 41+/-3%, which was reduced t o 21+/-2% by ischemic preconditioning (49% decrease, p(0.05). In rabbits on an atherogenic diet, infarct mass was significantly increased to 63+/-3% ( 52% increase versus standard diet). Interestingly, hypercholesterolemia did not affect the beneficial influence of ischemic preconditioning; infarct m ass (21+/-3%, p<0.05 vs hypercholesterolemia) was similar to rabbits on a s tandard diet with ischemic preconditioning. Our results show that experimental hypercholesterolemia increases infarct m ass in nonpreconditioned hearts but it does not interfere with the reductio n of infarct mass elicited by preconditioning. This may suggest that NO pro duced by the endothelium is not a prime factor in the cardioprotective mech anism of preconditioning.