classification of endothelial dysfunction

Classification of Endothelial Dysfunction

Stefano TaddeiDepartment of Internal Medicine

University of Pisa, Italy

endothelial

dysfunction

stimuli-induced

vasodilation(e.g, to shear stress)

PGI EDHF NO

plaque growth

clinical

manifestations

acute

coronary

syndrome

ischemia /

angina pectoris

remodeling/

proliferation

Pathogenesis of atherosclerosisfrom endothelial dysfunction to clinical disease

Vasodilation

Platelet aggregation

VSMC migration and

proliferation

Monocyte adhesion

Adhesion molecules

expression

ET1

NO

Vasoconstriction

NO breakdown:


VSMC migration and

proliferation

Monocyte adhesion

Adhesion molecules

expression

EDCFs(ET-1; A-II; TXA2; PGH2; ·O2

-)

Vascular effects of principal endothelium-derived substances

Healthy conditions CV risk factors

Each effect is a different aspect of endothelial function or dysfunction

• Endothelial Dysfunction

reduced NO availability (vascular reactivity)

• Endothelial Activation

acquisition of flogistic activity

• Endothelial Injury and Repair

anathomical disruption and rigeneration of endothelial cells

Endothelial Pathology

• ENDOTHELIAL DYSFUNCTION– NO

– NO2/NO3 and other plasma nitrosylated species

– ADMA

• ENDOTHELIAL ACTIVATION– adhesion molecules: E-selectin, P-selectin, ICAM-1, VCAM-1

– Regulators of thrombosis: tPA, PAI-1

• ENDOTHELIAL DAMAGE– vWF

– soluble thrombomodulin

– circulating endothelial cells

– endothelial microparticles

• ENDOTHELIAL REPAIR– circulating endothelial progenitor cells

Markers and clinical significance of endothelial pathology

Evaluation of vascular

reactivity

Plasma ADMA is significantly associated with all-cause mortality The Framingham Offspring study

Böger RH et al Circulation 2009

ADMA as a prospective marker of CV disease and mortality

Boger RH et al. Pharmacological Research 2009

High risk

Intermediate risk

Low risk –

general population

Vascular Reactivity

• Vascular response to stimulation or inhibition of endothelial function

• Selectivity for vessel type and vascular district

• Large availability of agonists and antagonists

• Strong association with intermediate organ damage and clinical end-

points

Taddei S et al. Circulation 1995

Effect of aging on endothelium-dependent vasodilation in

the forearm microcirculation

Normotensive Subjects

(N=43)

µg/100 ml/min

Taddei S et al Circulation 1999

0

100

200

300

400

500

600

700

BRADYKININ

0.005 0.015 0.05

Normotensive Subjects

saline

L-NMMA

Ouabain

*

*

* p<0.05

FBFD%

0.005 0.015 0.05

BRADYKININ

*

*

Vitamin C

0.005 0.015 0.05

Essential Hypertensive

Patients

BRADYKININ

**

Control

Solzbach U et al, Circulation 1997

Coronary endothelial dysfunction in hypertensive patients

Role of oxidative stress

Association between endothelial dysfunctionand atherosclerosis

Zeiher AM et al. Circulation 1994

CORONARY ARTERIES

Ghiadoni L et al. Hypertension 1998

0

1000

2000

0,6 0,9 1,2 1,5 1,8 2,1

INTIMA-MEDIAL THICKNING (mm)

Maxim

al

Ach

eti

lch

oli

ne-i

nd

uced

FB

F i

ncre

ase (D

%)

r = -.58

p<.0001

CAROTID ARTERIES

Endothelial Function Assessed by Vascular Reactivity and

Cardiac Events

Lerman A & Zeiher A Circulation 2005

Multivariant analysis of hazard ratio of present studies reporting association between

coronary or peripheral endothelial function and cardiovascular events

Vasodilation


VSMC migration and

proliferation

Monocyte adhesion

Adhesion molecules

expression

ET1

NO

Vasoconstriction

NO breakdown:


VSMC migration and

proliferation

Monocyte adhesion

Adhesion molecules

expression

EDCFs(ET-1; A-II; TXA2; PGH2; ·O2

-)

Vascular effects of principal endothelium-derived substances

Healthy conditions CV risk factors

Effect of NO-synthase blockade by L-NMMA on t-PA release in

normotensive subjects and essential hypertensive patients

Giannarelli C et al Hypertension 2007

t-P

A b

ala

nce

(ng/1

00

ml/m

in)

0

0.5

1.0

ACh ACh +

L-NMMA

ACh + L-

NMMA

*

ACh induced release

Normotensive

subjects

Hypertensive

patients

† p<0.01 vs BDK+saline

0

0.5

1

1.5

2

*

†tPA

rele

ase

ng/1

00m

L/m

in

Hypertensive Patients

Baseline Bradykinin

Sulfaphenazole

Saline

Giannarelli C et al Circulation 2009

Effect of bradykinin on tPA release in the presence of saline or

sulfaphenazole in hypertensive patients

Relaxation

Smooth muscle cells

t-PA release

Endothelial cells

NO EDHF

Bradykinin



– ADMA


– regulators of thrombosis: tPA, PAI-1







Constans J et al Clinica Chimica Acta 2006

Endothelial activation represents a switch from a quiescent phenotype toward

one that involves the host defense response

Soluble e-selectin in essential hypertension: a correlate of vascular structural changes

De Caterina R et al Am J Hypertens 2001

Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis

Malik I et al Lancet 2001

• The odds ratio for CHD were 1·68 (95% Cl

1·32–2·14) for ICAM-1 and 1·27 (1·00–1·61)

for E-selectin, but became not significant

after adjustment for some classic coronary

risk factors and indicators of socioeconomic

status.

•The measurement of adhesion

molecules is unlikely to add much

predictive information to that provided by

more established risk factors.



– ADMA



• ENDOTHELIAL DAMAGE– Von Willebrand Factor






Von Willebrand Factor, Soluble P-Selectin, and TargetOrgan Damage in Hypertension

A Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

Spencer CGC et al Hypertension 2002

* p<0.05

*

*

Hypertensive patients

** p<0.05

A comparison of FMD and VWF as markers of endothelial cell function in health and in hypertension

A substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

r=0.517, p < 0.001

vWF and FMD both correlated with 10-year cardiovascular risk using the Framingham

equation (vWF, r=0.48, p< 0.001; FMD, r =0.624, p< 0.001).

Felmeden DC et al Blood Coagulation and Fibrinolysis 2003

Soluble thrombomodulin

• Thrombomodulin (TM) is specifically expressed by endothelial cells

• Soluble TM can be reliably measured by ELISA

• Controversial clinical significance:

– TM is released from injured endothelial cells high levels indicate a greater

extent of endothelial damage?

– TM plays a role as a protein C cofactor and has anticoagulant activity high

levels may be protective?

High Soluble thrombomodulin predicts recurrence after CAD and mortality after stroke

• 54 patients who had survived a myocardial infarction

• Soluble thrombomodulin was 65+/-24 ng/mL in patients who suffered an end-point

and was 49+/-19 ng/mL in patients who were free of an end-point (p=0.009).

• Using life tables, soluble thrombomodulin had a significant effect on survival free of

an end-point (p=0.011).Blann AD et al. Eur J Haematol. 1997

Olivot GM et al Stroke 2004

• 492 patients with previous brain

infarction

• 5 years follow up

• Soluble thrombomodulin among

the upper tertile confers risk of

recurrence of 2.04 (1.34–3.11),

as compared to the lower tertile

Low sTM predicts CHD in healthy individualsThe ARIC study

Possible explanation: In healthy people, concentrations of soluble thrombomodulin may reflect

the quantity of thrombomodulin expressed on the endothelial surface. Increased expression of

thrombomodulin will increase production of activated protein C, which suppresses the

coagulation reaction by degrading factors Va and VIIIa.

<24.7 24.8-30.6 30.7-40.2 40.3-66.2 >66.3

Quintiles of soluble thrombomodulin (ng/ml)

Ra

te r

atio

of in

cid

en

t co

ron

ary

he

art

dis

ea

se

Salomaa V et al Lancet 1999

Endothelial Dysfunction (FMD) and Damage (CEC) in Congestive Heart Failure

r=0.423, p=0.002

Chong AY et al. Circulation. 2004;110:1794-1798

Circulating endothelial cells and prognosis in 156 patients with acute coronary syndromes

Kaplan-Meier cumulative 1-year event-free survival curves

between more than median versus less than median values

of (A) CECs at 48 hours

Numbers of circulating endothelial cells (CECs) on

admission according to diagnosis and compared with

patients with stable angina and healthy control subjects.

STEMI indicates ST-segment elevation myocardial

infarction; NSTEMI, non-STEMI; UAP, unstable angina

pectoris; SA, stable angina.

Lee KW et al. Blood 2005;105:526–32

Circulating endothelial cells in hypertension and acute ischaemic stroke

•29 hypertensive patients with previous stroke, 30 hypertensive patients and 30 normotensive controls

•Patients with an acute ischaemic stroke had significantly higher numbers of CECs/ml of blood (p<0.001)

plasma vWf (p=0.008), soluble E-selectin (p=0.002) and higher SBP as compared to the other groups

•The number of CECs significantly correlated with soluble E-selectin (r=0.432, p<0.001) and vWf (r=0.349,

p=0.001) but not with SBP (r=0.198, p=0.069)

Nadar SK et al, Thromb Haemost 2005; 94: 707–12

Microparticles

• Microparticles are submicron vesicles derived from cell membranes

• They are shed from plasma membranes in response to cell activation, injury, and/or

apoptosis

• Microparticles originating from platelets, endothelial cells and leukocytes have been most

extensively studied

Chironi NG et al, Cell Tissue Res (2009) 335:143–151

Circulating Endothelial Microparticles Are Associated with Vascular Dysfunction in Patients with End-Stage Renal Failure

• Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that

circulating levels of Annexin V+ microparticles were increased compared with 32 healthy

subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets

(16.5-fold), and erythrocytes (1.6-fold).

Circu

latin

g m

icro

pa

rtic

les (

eve

nts

/µl)

End stage renal failure

Healthy subjects

Platelet-derived MP

Endothelium-derived MP

Endothelium-derived MP

Erythrocytes-derived MP

Amabile N et al. J Am Soc Nephrol 16: 3381-3388, 2005



– ADMA









• Classification of endothelial dysfunction is important to understand

the pathophysiology of atherosclerotic disease and in the next

future might be useful for a better determination of CV risk and the

effectiveness of treatment.

Conclusions

• In addition, no large scale intervention trials are available to

consider endothelial dysfunction as a target of CV treatment.

• However, at the present time, the different aspects of endothelial

dysfunctions are not related to a specifc clinical significance.

Further investigation is necessary to establish the exact

relationship between the different types of endothelial alterations

and the development of CV disease.

classification of endothelial dysfunction

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