Hyperglycemia at the Vessel Wall

1
Hyperglycemia at the Vessel Wall
2
Potential hyperglycemia-induced tissue damage
Genetic determinants
Repeated acute changes in cellular metabolism
Diabetic tissue damage
Hyperglycemia
Cumulative long-term changes in stable
macromolecules
Independent accelerating factors
eg, hypertension, hyperlipidemia
Brownlee M. Diabetes. 2005541615-25.
3
Hyperglycemia in AMI Treatment targets?
Deranged metabolism
Prothrombotic
Serum FFA Insulin secretion Glycolysis Glucose
oxidation
Platelet aggregation Fibrinolysis Clotting
factors
ImpairedLV function
Inflammation
Ischemic preconditioning LV remodeling
Cytokines, chemokines, biomarkers
FFA free fatty acidsLV left ventricular
Adapted from Zarich SW. Rev Cardiovasc Med.
20067(suppl 2).S35-43.Bauters C et al. Eur
Heart J. 200728546-52.
4
Hyperglycemia Independent predictor of impaired
myocardial blood flow in STEMI
N 507
Initial TIMI flow grade vs admission glucose 140
vs lt140 mg/dL
TIMI 0-2 predictors

Patients ()

Worst
Best
TIMI flow grade
Glucose 140 mg/dL (hyperglycemia)
Glucose lt140 mg/dL
P 0.03 vs TIMI 1-3 P lt 0.001 vs TIMI
0-2 After multivariate analysis
Timmer JR et al. J Am Coll Cardiol.
200545999-1002.
5
Hyperglycemia increases endothelial dysfunction
N 579 without diabetes or prior CV disease
100
10
Odds ratio for abnormal flow-mediated brachial
artery dilation(95 Cl)
1
0.1
9099
100109
110125
Fasting plasma glucose (mg/dL)
Unadjusted
Rodriguez CJ et al. Am J Cardiol. 2005961273-7.
6
Myocardial blood flow response to hyperemia in
insulin-resistant states
N 174


?17
?35
MBF (mL/min per g)
IR
IGT
DM
IS
DM HTN
In response to adenosine or dipyridamole P lt
0.001 IS insulin sensitive IR insulin
resistant MBF myocardial blood flow
Prior JO et al. Circulation. 20051112291-8.
7
Myocardial blood flow response to cold pressor
testing in insulin-resistant states
N 174
Ptrend lt 0.001

? MBF (mL/min per g)



IS
IR
IGT
DM
DM HTN
P lt 0.001 vs IS P lt 0.05 vs IGT, DM, DM
HTNIS insulin sensitive IR insulin resistant
Prior JO et al. Circulation. 20051112291-8.
8
Hyperglycemia associated with increased
inflammatory markers in AMI
N 108
10
200


8

150

6
CRP(mg/dL)
IL-18(pg/mL)
100
4
50
2
0
0
Normo-glycemia
Newhyper-glycemia
Knowndiabetes
Normo-glycemia
Newhyper-glycemia
Knowndiabetes
P lt 0.005 vs normoglycemia CRP C-reactive
protein IL interleukin
Marfella R et al. Diabetes Care. 2003263129-35.
9
Acute hyperglycemia abolishes ischemic
preconditioning in dogs


Myocardial infarct size ( of AAR)
Control
HG
IPC
HG IPC
P lt 0.05 AAR area at risk HG
hyperglycemiaIPC ischemic preconditioning
Kersten JR et al.Am J Physiol Heart Circ
Physiol. 1998275H721-5.
10
Impact of hyperglycemia on platelet function
T2DMGlyLDL, HG,hyperinsulinemia
Inhibition ofNa/K ATPase
Impaired Ca2homeostasis
Ca2
Activationof PKC
Ca2
Ca2
GPIb/IX/V
GPIV
GPIIb-IIIa
?NO production
?ROSproduction
Non-enzymaticglycation of GPs
PKC protein kinase C GlyLDL glycated
low-density lipoproteins GP glycoproteins TXA
thromboxane
Ferroni P et al. J Thromb Haemost.
200421282-91.
11
Glucose fluctuations correlate with oxidative
stress
n 21 with T2DM
1200
1000
Urinary 8-Iso PGF2a excretionrate (pg/mg
creatinine)
800
8-iso PGF2a formed directly from free
radical-mediated arachidonic acid oxidation
600
r 0.86P lt 0.001
400
200
0
0
20
40
60
80
100
120
140
160
MAGE (mg/dL)
MAGE mean amplitude of glycemic excursions PG
prostaglandin
Monnier L et al. JAMA. 20062951681-7.