1. Hyperglycemia at the Vessel Wall

2. Potential hyperglycemia-induced tissue damage Brownlee M. Diabetes. 2005;54:1615-25. Repeated acute changes in cellular metabolism Cumulative long-term changes in stable macromolecules Genetic determinants Hyperglycemia Diabetic tissue damage Independent accelerating factors* *eg, hypertension, hyperlipidemia

3. Hyperglycemia in AMI: Treatment targets? Deranged metabolism Prothrombotic Serum FFA  Serum FFA Insulin secretion  Insulin secretion Glycolysis  Glycolysis Glucose oxidation  Glucose oxidation Platelet aggregation  Platelet aggregation Fibrinolysis  Fibrinolysis Clotting factors  Clotting factors Impaired LV function Ischemic preconditioning  Ischemic preconditioning LV remodeling Inflammation Cytokines, chemokines, biomarkers  Cytokines, chemokines, biomarkers Adapted from Zarich SW. Rev Cardiovasc Med. 2006;7(suppl 2).S35-43. Bauters C et al. Eur Heart J. 2007;28:546-52. FFA = free fatty acids LV = left ventricular Impaired perfusion  Endothelial function No-reflow phenomenon

4. Hyperglycemia: Independent predictor of impaired myocardial blood flow in STEMI Timmer JR et al. J Am Coll Cardiol. 2005;45:999-1002. *P = 0.03 vs TIMI 1-3; † P < 0.001 vs TIMI 0-2 ‡ After multivariate analysis Patients (%) OR P Glucose ≥140 mg/dL2.60.001 Nonsmoking1.60.13 Male gender1.10.96 Age (per year)1.00.17 Diabetes history0.50.15 Initial TIMI flow grade vs admission glucose ≥140 vs <140 mg/dL TIMI 0-2 predictors ‡ Glucose ≥140 mg/dL (hyperglycemia) Glucose <140 mg/dL TIMI flow grade * † N = 507 WorstBest

5. Hyperglycemia increases endothelial dysfunction N = 579 without diabetes or prior CV disease Rodriguez CJ et al. Am J Cardiol. 2005;96:1273-7. *Unadjusted 100 10 1 0.1 90–99100–109110–125 Odds ratio for abnormal flow- mediated brachial artery dilation* (95% Cl) Fasting plasma glucose (mg/dL)

6. Myocardial blood flow response to hyperemia in insulin-resistant states MBF* (mL/min per g) IS IRIGTDM DM + HTN *In response to adenosine or dipyridamole † P < 0.001 IS = insulin sensitive; IR = insulin resistant; MBF = myocardial blood flow Prior JO et al. Circulation. 2005;111:2291-8.  35%  17% † † N = 174

7.  MBF (mL/min per g) *P < 0.001 vs IS; † P < 0.05 vs IGT, DM, DM + HTN IS = insulin sensitive; IR = insulin resistant Prior JO et al. Circulation. 2005;111:2291-8. Myocardial blood flow response to cold pressor testing in insulin-resistant states ISIRIGTDMDM + HTN *†*† * * * P trend < 0.001 N = 174

8. Hyperglycemia associated with increased inflammatory markers in AMI Marfella R et al. Diabetes Care. 2003;26:3129-35. N = 108 *P < 0.005 vs normoglycemia CRP = C-reactive protein; IL = interleukin CRP (mg/dL) IL-18 (pg/mL) 0 2 4 6 8 10 0 50 100 150 200 * * Normo- glycemia New hyper- glycemia Known diabetes * * Normo- glycemia New hyper- glycemia Known diabetes

9. Acute hyperglycemia abolishes ischemic preconditioning in dogs Kersten JR et al. Am J Physiol Heart Circ Physiol. 1998;275:H721-5. Myocardial infarct size (% of AAR) *P < 0.05 AAR = area at risk; HG = hyperglycemia; IPC = ischemic preconditioning ** ControlHGIPCHG + IPC

10. Ferroni P et al. J Thromb Haemost. 2004;2:1282-91. Impact of hyperglycemia on platelet function PKC = protein kinase C; GlyLDL = glycated low-density lipoproteins; GP = glycoproteins; TXA = thromboxane Ca 2+ Activation of PKC  NO production Non-enzymatic glycation of GPs  ROS production Impaired Ca 2+ homeostasis Inhibition of Na/K ATPase T2DM GlyLDL, HG, hyperinsulinemia Platelet activation TXA 2 GPIV GPIIb-IIIa GPIb/IX/V Ca 2+

11. Glucose fluctuations correlate with oxidative stress Monnier L et al. JAMA. 2006;295:1681-7. MAGE = mean amplitude of glycemic excursions PG = prostaglandin n = 21 with T2DM 8-iso PGF 2α formed directly from free radical-mediated arachidonic acid oxidation r = 0.86 P < 0.001 MAGE (mg/dL) Urinary 8-Iso PGF 2α excretion rate (pg/mg creatinine) 020406080100120140160 0 200 400 600 800 1000 1200