ATEF ELBAHRY,FACA,FICA,MISCP,FVBWG.

Hyperglycemia and Coronary Events: where is the link? ATEF ELBAHRY,FACA,FICA,MISCP,FVBWG. Cardiovascular (CV) disease is the primary complication of diabetes ~65% of deaths are due to CV disease Coronary heart disease deaths 2- to 4-fold Cardiovascular complications of T2DM Stroke risk 2- to 4-fold T2DM = type 2 diabetes mellitus Heart failure 2- to 5-fold Bell DSH. Diabetes Care. 23;26:2433-41. Centers for Disease Control (CDC). www.cdc.gov. 1

CHD risk appears to begin at low blood glucose levels N = 17,869 men, aged 4 64 years; follow-up 33 years 1.6 1.2 CHD mortality (log hazard ratios).8.4 83 mg/dl. -.4 54 72 9 18 126 144 162 18 OGTT blood glucose (mg/dl) Relative to baseline group of all men with blood glucose <83 mg/dl Brunner EJ et al. Diabetes Care. 26;29:26-31. Even mild glucose elevations increase mortality in patients undergoing PCI N = 1612 with CAD; mean age 62 years 12 1 P-trend <.1 9.5 11.2 Mortality 8 6 6.6 4 2 1.9 NFG IFG Undx DM2 DM2 FG (mg/dl) <11 11 125 126 NFG = normal FG Undx DM2 = undiagnosed type 2 diabetes Muhlestein JB et al. Am Heart J. 23;146:351-8. 2

IVUS shows greater atherosclerotic disease burden in diabetes N = 654 with CHD; 128 (19.6%) with diabetes 1 P =.3 % 8 6 4 P =.2 P =.1 2 Percent atheroma volume Percent abnormal cross sections Percent area stenosis Diabetes No diabetes IVUS = intravascular ultrasound Nicholls SJ et al. J Am Coll Cardiol. 26;47:1967-75. New-onset hyperglycemia linked to highest rate of in-hospital mortality A retrospective study of medical records of 23 consecutive hospitalized patients 4 Newly Diagnosed 3 Mortality 2 1 Normoglycemia Known diabetes New hyperglycemia CCU patients Non-CCU patients P <.1 vs normoglycemia and known diabetes Umpierrez GE et al. J Clin Endocrinol Metab. 22;87:978-82. 3

Admission glucose in AMI associated with mortality, independent of T2DM diagnosis N = 141,68 hospitalized with AMI 6 3 days 1 year 6 5 5 Mortality 4 3 2 4 3 2 1 1 11 >11-14 >14-17 >17-24 >24 11 >11-14 >14-17 >17-24 >24 Admission glucose (mg/dl) Diabetes No diabetes AMI = acute myocardial infarction Kosiborod M et al. Circulation. 25;111:378-86. Stress hyperglycemia in AMI: Association with mortality risk in patients without known diabetes Reference Hyperglycemia definition (mg/dl) O Sullivan 1991 >144 Lewandowicz 1979 121 Soler 1981 11 Oswald 1986 144 Bellodi 1989 >121 Ravid 1975 >121 Sewdarsen 1989 144 Pooled 3.9-fold higher risk of in-hospital mortality. 1 2 3 4 5 6 7 8 9 1 11 12 13 Unadjusted RR of in-hospital mortality after MI vs patients with normoglycemia Capes SE et al. Lancet. 2;355:773-8. 4

Admission glucose and glucose change within 24 hours predict mortality risk N = 1469 with AMI (n = 1219 without DM) 12 3-day mortality 1 8 6 4 9% in 3-day mortality per 11 mg/dl glucose in first 24 hr (P =.2) 2 <125 125 <14 14 <17 17 Baseline glucose (mg/dl) ΔGlucose (24 hr vs baseline) 3 mg/dl decrease No change to <3 mg/dl decrease Increase Multivariate analysis Goyal A et al. Eur Heart J. 26;27:1289-97. Hyperglycemia in CORONARY EVENTS Deranged metabolism Serum FFA Insulin secretion Glycolysis Glucose oxidation Impaired perfusion Endothelial function No-reflow phenomenon Prothrombotic Platelet aggregation g Fibrinolysis Clotting factors Impaired LV function Ischemic preconditioning LV remodeling Inflammation Cytokines, chemokines, biomarkers FFA = free fatty acids LV = left ventricular Zarich SW. Rev Cardiovasc Med. 26;7(suppl 2).S35-43. Bauters C et al. Eur Heart J. 27;28:546-52. 5

Excessive myocardial triglyceride accumulation in IGT and T2DM N = 134 1.2.9.81.95 1.6 Intramyocardial triglycerides (fat/water ratio, %).6.3.46 P <.1 vs lean individuals IGT = impaired glucose tolerance T2DM = type 2 diabetes mellitus Lean Normoglycemic IGT T2DM Obese McGavock JM et al. Circulation. 27;116:117-5. Hyperglycemia: Independent predictor of impaired myocardial blood flow in STEMI N = 57 Thrombolysis In Myocardial Infarction (TIMI) Initial TIMI flow grade vs admission glucose 14 vs <14 mg/dl TIMI -2 predictors 6 OR P 5 Glucose 14 mg/dl 2.6.1 Patients No Flow 4 3 2 1 Glucose 14 mg/dl (hyperglycemia) 1 2 3 Worst Best Complete Perfusion TIMI flow grade Nonsmoking 1.6.13 Male gender 1.1.96 Age (per year) 1..17 Diabetes history.5.15 Glucose <14 mg/dl P =.3 vs TIMI 1-3; P <.1 vs TIMI -2 After multivariate analysis Timmer JR et al. J Am Coll Cardiol. 25;45:999-12. 6

Hyperglycemia increases endothelial dysfunction N = 579 without diabetes or prior CV disease 1 Odds ratio for abnormal flowmediated brachial artery dilation (95% Cl) 1 1.1 9 99 1 19 11 125 Fasting plasma glucose (mg/dl) Unadjusted Rodriguez CJ et al. Am J Cardiol. 25;96:1273-7. Myocardial blood flow response to hyperemia in insulin-resistant states N = 174 2.5 2. 17% 1.5 MBF (ml/min per g) 1. 35%.5. IS IR IGT DM DM + HTN In response to adenosine or dipyridamole P <.1 IS = insulin sensitive; IR = insulin resistant; MBF = myocardial blood flow Prior JO et al. Circulation. 25;111:2291-8. 7

Myocardial blood flow response to cold pressor testing in insulin-resistant states N = 174.3 P trend <.1.2 Δ MBF.1 (ml/min per g). -.1 IS IR IGT DM DM + HTN P <.1 vs IS; P <.5 vs IGT, DM, DM + HTN IS = insulin sensitive; IR = insulin resistant Prior JO et al. Circulation. 25;111:2291-8. Hyperglycemia associated with increased inflammatory markers in AMI N = 18 CRP (mg/dl) 1 2 8 6 4 IL-18 (pg/ml) 15 1 2 5 New hyperglycemia New Known Normoglycemia hyperglycemia diabetes Known diabetes Normoglycemia P <.5 vs normoglycemia CRP = C-reactive protein; IL = interleukin Marfella R et al. Diabetes Care. 23;26:3129-35. 8

Impact of hyperglycemia on platelet function Inhibition of Na/K ATPase Activation of PKC T2DM GlyLDL, HG, hyperinsulinemia Ca Ca 2+ 2+ Impaired Ca 2+ Ca homeostasis 2+ Platelet activation TXA 2 NO production GPIb/IX/V GPIV GPIIb-IIIa Non-enzymatic glycation of GPs ROS production TXA 2 PKC = protein kinase C; GlyLDL = glycated low-density, ROS = reactive oxygen species lipoproteins; GP = glycoproteins; TXA = thromboxane Ferroni P et al. J Thromb Haemost. 24;2:1282-91. Take Home message 1. Hyperglycemia is an independent risk factor in patients with UA/NSTEMI. 2. Cardiovascular events occur in impaired glucose tolerance & undiagnosed DM subjects more than diagnosed ones 3. Hyperglycemia induces, endothelial dysfunction,impaired myocardial blood flow, platelet aggregation and increases inflammatory markers. 9