This document discusses endothelial dysfunction as a marker for cardiovascular events. It summarizes that impaired endothelium-dependent dilation in the coronary and brachial arteries provides prognostic information about future cardiovascular events, with worse endothelial dysfunction correlating to higher event rates. Various clinical tests are presented that measure endothelial function in these arteries. The document also suggests endothelial dysfunction may serve as an index for gauging therapeutic responses, as certain treatments are shown to improve endothelial function and reduce cardiovascular event rates.

1. Endothelial Dysfunction as aEndothelial Dysfunction as a
Marker of Cardiovascular EventsMarker of Cardiovascular Events
Robert A. Vogel, M.D.Robert A. Vogel, M.D.

2. CoronaryCoronary
HeartHeart
DiseaseDisease
EndothelialEndothelial
DysfunctionDysfunction
↓↓NONO
↑↑InflammationInflammation
↑↑ThrombosisThrombosis
“Response-to-Injury” Hypothesis
GenesGenes
Coronary
Risk
Factors

3. Regulatory Functions of the Endothelium
Normal Dysfunction
Vasodilation Vasoconstriction
NO, PGI2, EDHF,
BK, C-NP
ROS, ET-1, TxA2,
A-II, PGH2
Thrombolysis Thrombosis
Platelet Disaggregation
NO, PGI2
Adhesion Molecules
CAMs, Selectins
Antiproliferation
NO, PGI2, TGF-β, Hep
Growth Factors
ET-1, A-II, PDGF, bFGF,
ILGF, Interleukins
Lipolysis Inflammation
ROS, NF-κB
PAI-1, TF, Tx-A2
tPA, Protein C, TF-I,
vonWF
LPL Vogel R

4. Fichtlscherer S et al, Circulation 2000;102;1000
Comparison of Forearm Responses to ACh and
C-Reactive Protein in 60 Men with CAD

5. Cayette et al, Nature 1990; Cooke et al, JCI 1992;90:1168
Effect of NO Inhibition and Augmentation on
Hypercholesterolemic Rabbit Aortic
Atherosclerosis Area at 6 Weeks
0
0.05
0.1
0.15
0.2
0.25
0.3
NO Inhibition NO Augmentation
L-NAME
Control
L-Arg
Control
L-NAME L-Arginine

6. Clinical Methods for AssessingClinical Methods for Assessing
Endothelium-Dependent DilationEndothelium-Dependent Dilation
Coronary ArteriesCoronary Arteries
• Epicardial Artery
Diameter ∆ with ACh
• CBF ∆ with ACh
• Epicardial Artery
Diameter ∆ with Adenosine
ForearmForearm
• Brachial Artery Diameter
∆ with Arterial Occlusion
• Forearm Blood Flow with
ACh

7. Takese B, Am J Cardiol 1998:82:1535
Comparison of Brachial and Coronary
Flow-Mediated Vasodilation

8. Furchgott RF & Zawadski JV, Nature 1980
Anderson TJ et al, NEJM 1995;332:488

9. Schachinger V et al, Circulation 2000;101:1899
CVE’s over 7.7 Years in 147 Subjects with CAD
According to Coronary Artery Responses to Ach,
Cold Pressor, and FMD
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Ach CP FMD
Vasodil
Vasocon
FMD >19%
FMD 10-19%
FMD <10%
CVE’s

10. Halcox JPJ et al, Circulation 2002;106:653
CVE’s over 4 Years in 176 Subjects without
CAD According to CVR and CA Diameters
Changes with ACh
0%
5%
10%
15%
20%
25%
30%
Cor Vasc Res
Change Ach
CA Diameter
Change Ach
vasodil or T1 CVR
vasocon or T2,3 CVR

11. Al Suwaidi J et al. Circulation 2000;101:948
Cardiac Events in 157 CAD Patients over 28
Months Stratified by CBF Responses to ACh
0
0.5
1
1.5
2
2.5
3
Normal Mild Dysfunction Severe Dysfunction
CHD Death
MI
CHF
CABG
PCI

12. Targonski PV et al, Circulation 2003;107:2805
Relative Risk of CVA or TIA in 503 Non-
Obstructive CAD Subjects over 88 Months
According to CBR Responses to ACh
0
2
4
6
8
10
12
14
>108% 44-108% 14-44% <14%
CBF Increase with ACh
RelativeRiskofCVA/TIA

13. Clinical Methods for Assessing
Endothelium-Dependent Dilation
Coronary Arteries
• Epicardial Artery
Diameter ∆ with ACh
• CBF ∆ with ACh
• Epicardial Artery
Diameter ∆ with Adenosine
Forearm
• Brachial Artery Diameter
∆ with Arterial Occlusion
• Forearm Blood Flow with
ACh

14. Perticone F et al, Circulation 2001;104:191
Effect of ACh-Induced Forearm Vasodilation* on
32-Month CVE’s (%) in 225 Never Treated
Hypertensive Subjects
(* Relative Flow Increase)
0
1
2
3
4
5
6
7
8
Tertile 1 Tertile 2 Tertile 3
ACh FBF
%CVE's

15. Heitzer T et al, Circulation 2001;104:2673
CVE’s According to FBF Responses to ACh
and I.V. Vitamin C in 281 Subjects with CHD
Vitamin C ResponsesACh-induced FBF Responses

16. Brachial Artery Flow-Mediated Vasodilation
Baseline 5 Minutes Post-Occlusion
Blood Pressure Cuff
Occlusion – 1 Minute
Release
3.1 mm 3.6 mm

17. Neuntfeufl T et al, Am J Cardiol 2000;86:207
CHD Events over 5 Years in 76 CAD Patients
According to Brachial Artery FMD
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
PTCA CABG MI ANY
EVENT
FMD >10%
FMD <10%

18. Murakami T et al. J Am Coll Cardiol 2001;37:294A
CVE’s over 4 Years in 480 Patients with Suspected
CAD According to Brachial Artery FMD
0%
5%
10%
15%
20%
25%
<4% 4%-8% >8%
CHD Events
CV Events

19. Endothelial Dysfunction as
a Therapeutic
Prognosticator

20. Gokce N et al, Circulation 2002;105:1567
Effect of Preoperative FMD on 30-Day MACE and
MACE + Elevated Troponin in 187 Patients
Undergoing Vascular Surgery
0%
5%
10%
15%
20%
25%
30%
35%
MACE MACE + Trop
<4.2%
4.2-8.1%
>8.1%

21. Sorensen KE et al, Circulation 1998:97:1234
Effect of HRT on Brachial Artery FMD at 3 Years
in 100 Postmenopausal Women Randomized to
HRT/Placebo and 30 Premenopausal Women
0
1
2
3
4
5
6
7
Premenopausal No HRT HRT

22. Modena MG et al. J Am Coll Cardiol 2002;40:505
5-Year Outcome in 350 Postmenopausal Hypertensive
Women with Controlled BP (<140/90) Based on the
Change in Brachial Artery Flow-Mediated Vasodilation
during the First 6 Months of Treatment
(Similar initial FMD values, treatment, and on-treatment BP)
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
CVE's Hosp-CHF TIA's
d-FMD <10%
d-FMD >10%
∆
∆

23. FMD and LDL-C at Baseline and 3
Months in the REVERSAL Trial
15%
10%
5%
0%
75 100 125 150 175
LDL-C (mg/dl)
Flow-MediatedDilation
Pravastatin 40 mg
Atorvastatin 80 mg
3 Months
Baseline

24. % Change in IVUS Atheroma Volume at
18 Months in the REVERSAL Trial
-0.4
2.7
-1
0
1
2
3
Percent
Change in
Atheroma
Volume by
IVUS
Pravastatin 40 mg Atorvastatin 80 mg
P = 0.02
LDL-C
110
LDL-C
79

25. Summary:
Coronary and brachial artery
endothelium-mediated dilation
provide significant CVE
prognostic information and
may be indexes of therapeutic
responses.