How to Evaluate Endothelial Function?

Ho-Joong Youn, M.D. & PhD

Division of Cardiology, Department of Internal Medicine

College of Medicine, The Catholic University of Korea

Seoul, Korea

200.8.27.혈관연구회

Normal EndotheliumE

nd

oth

eliu

m-D

epen

den

t S

tim

uli

NO, A-II , ET-1

Vasodilatation

In patients with risk factors for coronary

disease or with established atherosclerosis

NO , A-II , ET-1

Endothelial dysfunction becomes apparent by decreased or

paradoxical responses

How to Evaluate ?

2. With what ?

3.Where ?

4. Accuracy ? Gold standard?

5. Correlation between peripheral and coronary circulations ?

FlowAch Cold Pressor

Conduit Vessel Resistance Vessel

1. Invasive versus Noninvasive

Endothelium-Dependent Vasodilator

Acetylcholine (Ach)

Endothelial-mediated

Dilation

Smooth muscle-

mediated Constriction+

Before Ach After Ach

Assessment of endothelial vasomotion using Acetylcholine

Assessment of Endothelial Function of Coronary Resistance Vessels using Intracoronary Doppler Techniques

Baseline Acetylcholine

Normal endothelial function of resistance arterioles

Evidence of Impaired Endothelium-Dependent Coronary Vasodilatation

in Patients with Angina Pectoris and Normal Coronary Angiograms

Egashira K, et al. N Engl J Med 1993;328:1659

The loss of endothelium-dependent dilation occurs early in atherosclerosis,

even prior to its detection by angiography

Hollenberg SM, et al. Circulation 2001;104:3091

Coronary Endothelial Dysfunction After Heart Transplantation

Predicts Allograft Vasculopathy and Cardiac Death

Hollenberg SM, et al. Circulation 2001;104:3091

Change in epicardial coronary artery area

in response to acetylcholineChange in microvascular coronary artery flow

in response to acetylcholine

75±20%

149±16% 11.1±2.9%

1.7±2.2%

Methods used for in vivo endothelial function testing

Technique Vascular bed Invasiveness Accuracy/

reproducibility

Venous occlusion

plethysmography

(VOP)

Forearm resistance

vessels

Moderately

invasive

Highly accurate and reproducible.

Regarded by some

as the „Gold Standard‟

Flow-mediated

dilatation (FMD)

Brachial (conduit)

artery

Non-invasive Accuracy depends on quality of

equipment/software. Observer

variations

Laser Doppler

iontophoresis

Forearm skin

microvessels

Non-invasive Conflicting reports. No clear data

as yet

Pulse wave

analysis

„Global‟ endothelial

function

Non-invasive Unclear how accurately global

arterial stiffness reflects

endothelial function

Venous Occlusion Plethysmography(VOP)

40 mmHg

220mmHg

Strain gauge

- Function of Resistance vessel in the forearm

- Assessed by strain-gauge venous impedance plethysmography

- Examines the change in forearm blood flow in response

to direct intraarterial (brachial artery) administration of agonists

Str

ain

Gau

ge

Volt

ag

e

Ensink FBM & Hellige G. History and principle of strain-gauge plethysmography.

In Non-invasive methods on cardiovascular haemodynamics, ed Jageneau AHM.

Amsterdam: Elsevier/North Holland, 1981; 169

Time

VOP

Panza JA, et al. N Engl J Med 1990; 323: 22

Abnormal endothelium-dependent vascular relaxation

in patients with essential hypertension.

VOP

Brachial Artery Flow-mediated Dilatation

4.5 cm

250 mmHg

for 4.5-5 min

60 sec after

cuff releaseBaseline

Flow

BA Diameter

Reactive Hyperemia

Flow

BA Diameter

4.5 cm

Shear stress-induced NO release and subsequent vasodilatation

(Flow-Mediated Dilatation, FMD)

4.20mm4.88mm

%FMD=14%

FMD

FMD

Major limitations

1. Need for ultrasonographic expertise

2. Significant day-to-day variability (about 25%)

due to biological circadian rhythms.

Iontophoresis in Conjunction with Laser Doppler Imaging

Hansell Jet al. Clinical Physiology and Functional Imaging 2004;24:317

Non-invasive assessment of endothelial function-relation

between vasodilator responses in skin microcirculation

and brachial artery

Skin microvascular perfusion

R=0.43

P<0.05

Laser

Wilkinson, I. B. et al. Arterioscler Thromb Vasc Biol 2002;22:147

Augmentation Index

Radial artery waveforms

Pre

ssu

re (

mm

Hg

)

Time (ms)

P

PP

Stiffness

Adventitia

Collagen,

Fibroblast

Media

VSMC, Collagen,

AGE‟s, MMP

Elastin

Endothelial Cells:

Endothelial dysfunction

Increased permeability

Intima:

Collagen, AGE‟s, Mø

Leukocyte, I-CAM

MMP, TGF-β, VSMC

Elastin

Zieman, S. J. et al. Arterioscler Thromb Vasc Biol 2005;25:932

Extrinsic influences :NaCl, lipid, angiotensin,Sympathetic

Neurohormone, shear stress, increased luminal diameter

Summary of the multiple causes and locations of arterial stiffness

Factor contributing to increase arterial stiffness

Stiffness

Dyslipidemia Hyperinsulinemia

Hyperglycemia Hypertension

Endothelial

Dysfunction

Aging Elastin

fracture

Arterial

Stiffbness

Collagen

deposition

Aging

Left ventricular

Dysfunction/

Hypertrophy

Pulse pressure/

Hypertension

Myocardial ischemia/

Metabolicdemand

Oxidative Stress

PP Vascular endothelial damage

& mechanical fatigue

Atherosclerosis

Aortic stiffness

Central wave

reflection

Relationship between Pulse pressure and Atherosclerosis

Stiffness

Small

Artery

Response

Conduit

Artery

Response

Small

Artery

Structure

Conduit

Artery

Structure

Aorta

Structure

Flow

Response

C2

Caliber

Response

(FMD)

C2

Biopsy

AIxRetina

Microalbumiuria

BP

IMT

C1

Pres:Vol

Exer Bp

PWV

AIxC1

PP

Function

(Early)

Structure

(Late)

Time Course of Change in Arterial Stiffness

C2, small artery elasticity; C1, large artery elasticity; Pres: Vol, pressure/volume

relationship of a single artery; Exer BP, blood pressure rise in response to programmed

exercise test; PWV, pulse wave velocity; Pulse Pres, auscultatory pulse pressure.

Stiffness

Reduced small artery but not large artery elasticity is an

independent risk marker for cardiovascular events

Reduced small artery elasticity, which is a measure of endothelial

dysfunction, is significantly associated with cardiovascular events

independent of age.

Grey E, et al. Am J Hypertension 2003;16:265-269

Stiffness

Reduced arterial elasticity is associated with endothelial dysfunction in persons of advancing age

: Comparative study of noninvasive pulse wave analysis and laser Doppler blood flow measurement

Tao J, et al.Am J Hypertension 2004;17:654

Stiffness

Assessment of peripheral vascular endothelial function with

finger arterial Pulse Wave Amplitude

Jeffrey T et al. Am Heart Journal 2003;146:1684

r = 0.55,

P < 0.0001

: Finger plethysmograph (Peripheral arterial tonometry [PAT])

PWA

Relationship Between Carotid Artery Intima-Media Thickness and

Brachial Artery Flow-Mediated Dilation in Middle-Aged Healthy Men

Yan RT, et al, JACC 2005;45:1980

n-=1,578

r= -0.006, p = 0.82

Interrelations Between Brachial Endothelial Function

and Carotid IMT in Young Adults.

The Cardiovascular Risk in Young Finns Study

Juonala, M. et al. Circulation 2004;110:2918

IMT

(mm

)

0.2

0.4

0.6

0.8

1.0

1.2

Plot 1

SLE Healthy controls

(n= 202) (n=87)

P < 0.0001

Comparison of IMT in SLE patients and healthy controls

0.60±0.13 mm

0.45±0.06 mm

Shin YJ & Youn HJ. 2005(unpublished data)

IMT

0.2 0.4 0.6 0.8 1.0 1.2

FM

D

-10

-5

0

5

10

15

20

25

Relationships between FMD and IMT in patients with SLE

N=202

r =-0.254, P=0.016

Shin YJ & Youn HJ. 2005(unpublished data)

Flow Improvement after Adenosine infusion: Study using Transthoracic Doppler Echocardiography

Baseline Hyperemia

Hyperemic PDVCFR =

Baseline PDV

PDV=22.6 PDV=56.2

CFR=2.5

Paul Smits P et al. Circulation. 1995;92:2135

Endothelial Release of Nitric Oxide Contributes

to the Vasodilator Effect of Adenosine in Humans

1. Both endothelium-independent

and endothelium-dependent dilation;

at high concentration of adenosine,

endothelium independent dilation

dominates while NO contributes to

the dilator effects of adenosine at

lower adenosine concentration.

2. Triggered nonspecifically by the

increase in flow (shear stress) rather

than by the specific stimulation of

endothelial adenosine receptors

Relation between Peripheral Vascular Endothelial Function

and Coronary Flow Reserve in Patients

with Chest Pain and Normal Coronary Angiogram

% FMD and CFR

11.77

6.04

0

5

10

15

20

1 20

5

10

15

20

0 0.5 1 1.5 2 2.5 3 3.5 4

Relation between %FMD and CFR

N=32

r=0.36

p<0.05

CFR2 CFR2

CFR

%F

MD

*, p<0.05

Peripheral vascular endothelial function is impaired

in patients with microvascular angina.

Park CS, Youn HJ et al. Int J Cardiol 2005(in press)

%

Penetrating Intramyocardial Coroanry Artery(PICA)

Adenosine

Baseline Hyperemia

Adenosine 140 g/kg/min

Width of color signals

Pulsed Doppler signals

Width Ratio

PICA-CFRPDV

Measurement of PICA-CFR

Youn HJ et al. J Am Soc Echocardiogr 2005;18:128

Inhibition of Nitric Oxide Synthesis During Cold Pressor Test

in Patients With Coronary Artery Disease

Tousoulis D et al. Am J Cardiol 1997;79:1676

PreCPT CPT 90s Post-CPT

PreAdeno Adeno Post-Adeno

Changes of Coronary Artery Flow During Cold Pressor Test

using Transthoracic Doppler Echocardiography

Is endothelial function testing ready

for “prime time” clinical use ?

?

CPTFMD

VOP

Laser Doppler

PWA

Stiffness

EPC