Endothelial Progenitor Cells (EPCs)

2

EPCs in CV diseases

EPCsEPCs

TherapeuticsTherapeuticsPathophysiologyPathophysiology

AtherosclerosisAtherosclerosis

Heart diseaseHeart disease

Peripheral vascular diseasePeripheral vascular disease

CV risk factorsCV risk factors

Endothelial dysfunctionEndothelial dysfunction

CollateralsCollaterals

RestenosisRestenosis

CV diseaseCV disease

Courtesy of Arshed A. Quyyumi, MD.

3

Circulating EPCs aid in cardiac repair

• CD34+, CD133+, and VEGF2R+

• Circulate in blood stream

• Contribute to repair of vascular or myocardial injury and collateral formation

Asahara T et al. Science. 1997;275:964-7.Takahashi T et al. Nature Med. 1999;5:434-8.

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EPC physiology

• Originate in bone marrow

• Circulate in blood stream

• Number and function (proliferation, migration, homing) modulated by age, CV risk factors, and disease

• Release stimulated by organ and vascular injury

• Participate in vascular repair (collateralization) and re-endothelialization, partly by paracrine effects

• Circulating numbers by exercise and drugs (statins and ACE inhibitors)

• Independent predictors of endothelial dysfunction and long-term prognosis in patients with CAD

Hill JM et al. N Engl J Med. 2003;348:593-600.

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Werner N et al. N Engl J Med. 2005;353:999-1007.

N = 519 males with CAD, mean age 66 y

EPC number has prognostic importance

1.00

0.98

0.96

0.94

0.92

0.90

0100 200 300 365

Group 3 (high EPC level)

Group 2 (medium EPC level)

Group 1 (low EPC level)

0

Days

Event-freesurvival

6

Association between CV risk factors and EPC colony counts

Framingham risk score

Hill JM et al. N Engl J Med. 2003;348:593-600.

N = 45 males without CAD, > 21 years (mean age 50.3)

r = –47.0

P = 0.001

-5 0 5 10 15 20

70

EPC colony-forming units

60

50

40

30

20

10

0

7

Mobilization of EPCs after myocardial infarction

Shintani S et al. Circulation. 2001;103:2776-9.

1 3 7 14 28

N = 16 patients with AMI, 8 controls

P < 0.001 P < 0.001

MNCCD34+ (/106WBCs)

Time after onset

Day

300

P < 0.001 P < 0.05

200

100

0

8

VEGF levels correlate with increase in EPCs

Shintani S et al. Circulation. 2001;103:2776-9.

MNCCD34+ (cells/106 WBCs)

Plasma VEGF (pg/mL)

r = 0.35

P = 0.01

0

50

100

150

200

250

300

350

400

450

0 50 100 150 200 250 300 350 400 450

9

EPC activity and coronary collaterals

• 30 patients with isolated left anterior descending disease

• Divided into groups with (0.33) and without (0.09) adequate Collateral Flow Index (CFI)

Lambiase PD et al. Circulation. 2004;109:2986-92.

CD

34/C

D13

3 D

ual

Po

siti

veC

ells

(%

of

tota

l lym

ph

ocy

tes)

B

R = 0.75P < 0.0001

CFI

0.8

0.6

0.4

0.2

0

0 0.1 0.2 0.3 0.4 0.5

CD

34/C

D13

3 D

ual

Po

siti

veC

ells

(%

of

tota

l lym

ph

ocy

tes)

A0.4

0.3

0.2

0.1

0

Colln=13

Colln=10

P = 0.017

Inadequate coronary collateral development associated with numbers of circulating EPCs and impaired chemotactic and pro-angiogenic activity

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Decrease in EPCs associated with CV disease

Werner N, Nickenig G. Arterioscler Thromb Vasc Biol. 2006;26:257-66.

Endothelial Progenitor Cells

Atherosclerosis

Improvement of endothelial function

Enhanced re-endothelialization

Reduced plaque size

Improved angiogenesis

Myocardial infarction

Ischemic stroke

Erectile dysfunction

Renal insufficiency

Peripheral artery disease

Disease Regression? Disease Progression

Vasculoprotective agents CV risk factors