Diabetes mellitus adversely affects the prognosis of patients with acute myocardial infarction. Despite significant advances in the treatment of coronary artery disease, the mortality rate associated with myocardial infarction is 2 to 3 times greater in diabetic patients compared with those without this disorder. Hyperglycemia on hospital admission is an independent risk factor predicting an increase in mortality rate in patients with or without diabetes. Thus, diabetes and hyperglycemia are clear contributors to adverse outcome in patients at risk for myocardial ischemia, but the mechanisms responsible for this observation are poorly understood. Ischemic preconditioning is a powerful endogenous mechanism protecting the myocardium against infarction. Our work indicates that diabetes or hyperglycemia prevents reductions of myocardial infarct size by ischemic preconditioning. A critical role of glucose to modulate myocardial infarct size is also demonstrated by a linear relationship between blood glucose concentration and infarct size in diabetic or acutely hyperglycemic dogs with or without preconditioning stimuli. Diabetes or hyperglycemia block the cardioprotective effects of KATP channel agonists such as diazoxide or the volatile anesthetic agent isoflurane, and the protection afforded by these agents is interactive with the severity of hyperglycemia. Our data suggests that hyperglycemia and diabetes adversely affects mitochondrial KATP channel function and exacerbates myocardial ischemic injury.
Coronary Collateral Circulation
Chronic reduction of myocardial oxygen supply produced by severe coronary artery stenoses leading to coronary occlusion stimulates growth of collateral vessels that increase blood flow to myocardium at risk for ischemia. Coronary collateral perfusion is a major determinant of the degree of injury associated with an ischemic event. The vasodilator response of coronary collaterals to physiologic and pharmacological stimuli is an important factor that affects the extent of damage to ischemic myocardium. Coronary collateral vessels respond to endothelium-dependent and –independent vasodilators in vitro and in vivo. Nitric oxide has a tonic vasodilating effect on the coronary collateral circulation. Our work indicates that acute hyperglycemia alters the permissive action of nitric oxide on regulation of blood flow in the coronary collateral circulation. Hyperglycemia decreases retrograde coronary collateral blood flow by decreasing nitric oxide availability and this effect is reversed with L-arginine. Other evidence from our laboratory indicates that acute hyperglycemia or diabetes impairs coronary collateral development in conscious dogs undergoing repetitive periods of coronary artery occlusion and reperfusion. Impairment of nitric oxide signaling during hyperglycemia is likely to play an important role to attenuate collateral development in diabetes.
Volatile anesthetic agents protect myocardium against stunning and infarction. These beneficial actions appear to occur through a signal transduction pathway that is remarkably similar to that observed during ischemic preconditioning. Activation of adenosine receptors, protein kinase C, inhibitory guanine regulatory proteins, and mitochondrial and sarcolemmal KATP channels have been implicated in anesthetic-induced preconditioning. Recent evidence from our laboratory indicates that release of reactive oxygen species during administration of volatile anesthetics may function as a trigger to induce anesthetic-induced preconditioning. The reactive oxygen species scavengers N-acetylcysteine and 2-MPG blocked reductions of myocardial infarct size produced by isoflurane and decreased the release of reactive oxygen species as identified with dihydroethidium staining techniques. These important results indicate that reactive oxygen species are an important signal during anesthetic-induced preconditioning.
Gu W, Kehl F, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR: Simvastatin restores ischemic preconditioning in the presence of hyperglycemia through a nitric oxide-mediated mechanism. Anesthesiology 2008;108:634-42.
Amour J, Brzezinska AK, Weihrauch D, Zielonka J, Warltier DC, Pratt Jr PF, Kersten JR: Role of heat shock protein 90 and endothelial nitric oxide synthase during anesthetic and ischemic preconditioning. Anesthesiology 2009; 110:317-25.
Subramaniam B, Panzica P, Novack V, Mahmood F, Matyal R, Mitchell JD, Bose R, Sundar E, Pomposelli F, Kersten JR, Talmor D: Continuous perioperative insulin infusion decreases major cardiovascular events in patients undergoing vascular surgery—a prospective randomized trial. Anesthesiology 2009:970-7
Cannesson M, Earing M, Collange V, Kersten JR: Anesthesia for non-cardiac surgery in adults with congenital heart disease. Anesthesiology 2009;111:432-40
Ge ZD, Pravdic D, Bienengraeber M, Pratt Jr PF, Auchampach JA, Gross GJ, Kersten JR, Warltier DC: Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition via an eNOS-dependent mechanism. Anesthesiology 2010;112:73-85.
Amour J, Brzezinska A, Jager Z, Sullivan C, Weihrauch D, Du J, Vladic N, Shi Y, Warltier DC, Pratt Jr PF, Kersten JR: Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin and heat shock protein 90- mediated mechanisms. Anesthesiology 2010; 112:576-85.