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Hyperglycemia at the Vessel Wall
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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
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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
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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
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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)
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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
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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
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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
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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
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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+
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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
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