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Vogel endothelial function cv es
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.
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
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
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.