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Hyperglycemia at the Vessel Wall
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
HyperglycemiaDiabetic tissue
damage
Independent accelerating factors*
*eg, hypertension, hyperlipidemia
Hyperglycemia in AMI: Treatment targets?
Deranged Deranged metabolismmetabolism ProthromboticProthrombotic
Serum FFASerum FFA
Insulin secretionInsulin secretion
GlycolysisGlycolysis
Glucose oxidationGlucose oxidation
Platelet aggregationPlatelet aggregation
FibrinolysisFibrinolysis
Clotting factorsClotting factors
ImpairedImpairedLV functionLV function
Ischemic Ischemic preconditioningpreconditioning
LV remodelingLV remodeling
InflammationInflammation
Cytokines, chemokines, Cytokines, chemokines, biomarkersbiomarkers
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 acidsLV = left ventricular
Impaired perfusionImpaired perfusion
Endothelial function Endothelial function
No-reflow phenomenonNo-reflow phenomenon
0
10
20
30
40
50
60
0 1 2 3
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/dL 2.6 0.001
Nonsmoking 1.6 0.13
Male gender 1.1 0.96
Age (per year) 1.0 0.17
Diabetes history 0.5 0.15
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
Worst Best
Hyperglycemia increases endothelial dysfunctionN = 579 without diabetes or prior CV disease
Rodriguez CJ et al. Am J Cardiol. 2005;96:1273-7.*Unadjusted
100
10
1
0.1
90–99 100–109 110–125
Odds ratio for abnormal flow-
mediated brachial artery dilation*
(95% Cl)
Fasting plasma glucose (mg/dL)
0.0
0.5
1.0
1.5
2.0
2.5
Myocardial blood flow response to hyperemia in insulin-resistant states
MBF*(mL/min per g)
IS IR IGT DM DM + HTN
*In response to adenosine or dipyridamole †P < 0.001IS = insulin sensitive; IR = insulin resistant; MBF = myocardial blood flow Prior JO et al. Circulation. 2005;111:2291-8.
35%
17%
†
†
N = 174
MBF(mL/min per g)
*P < 0.001 vs IS; †P < 0.05 vs IGT, DM, DM + HTNIS = 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
-0.1
0.0
0.1
0.2
0.3
IS IR IGT DM DM + HTN
*†
*
* *
Ptrend < 0.001
N = 174
Hyperglycemia associated with increased inflammatory markers in AMI
Marfella R et al. Diabetes Care. 2003;26:3129-35.
N = 108
*P < 0.005 vs normoglycemiaCRP = 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
Newhyper-
glycemia
Knowndiabetes
*
*
Normo-glycemia
Newhyper-
glycemia
Knowndiabetes
Acute hyperglycemia abolishes ischemic preconditioning in dogs
Kersten JR et al.Am J Physiol Heart Circ Physiol. 1998;275:H721-5.
24
34
8
30
0
10
20
30
40
Myocardial infarct size (% of AAR)
*P < 0.05AAR = area at risk; HG = hyperglycemia;IPC = ischemic preconditioning
* *
Control HG IPC HG + IPC
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
Ca2+
Ca2+
Activationof PKC
NO production
Non-enzymaticglycation of GPs
ROSproduction
Impaired Ca2+
homeostasis
Inhibition ofNa/K ATPase
T2DMGlyLDL, HG,
hyperinsulinemia
Platelet activationTXA2
TXA2
GPIV GPIIb-IIIaGPIb/IX/V
Ca2+
Glucose fluctuations correlate with oxidative stress
Monnier L et al. JAMA. 2006;295:1681-7.
MAGE = mean amplitude of glycemic excursionsPG = prostaglandin
n = 21 with T2DM
8-iso PGF2α formed directly from free radical-mediated arachidonic acid oxidation
r = 0.86P < 0.001
MAGE (mg/dL)
Urinary 8-Iso PGF2α excretion
rate (pg/mg creatinine)
0 20 40 60 80 100 120 140 1600
200
400
600
800
1000
1200