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