Transcript Endothelial Dysfunction as a Marker of Cardiovascular

Endothelial Dysfunction as a
Marker of Cardiovascular Events
Robert A. Vogel, M.D.
“Response-to-Injury” Hypothesis
Genes
Coronary
Risk
Factors
Endothelial
Dysfunction
NO
↑Inflammation
↑Thrombosis
Coronary
Heart
Disease
Regulatory Functions of the Endothelium
Normal
Dysfunction
Vasodilation
NO, PGI2, EDHF,
BK, C-NP
Vasoconstriction
ROS, ET-1, TxA2,
A-II, PGH2
Thrombolysis
Thrombosis
PAI-1, TF, Tx-A2
tPA, Protein C, TF-I,
vonWF
Platelet Disaggregation
Adhesion Molecules
NO, PGI2
CAMs, Selectins
Antiproliferation
Growth Factors
NO, PGI2, TGF-, Hep
ET-1, A-II, PDGF, bFGF,
ILGF, Interleukins
Inflammation
Lipolysis
LPL
ROS, NF-B
Vogel R
Fichtlscherer S et al, Circulation 2000;102;1000
Comparison of Forearm Responses to ACh and
C-Reactive Protein in 60 Men with CAD
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
0.3
L-NAME
L-Arginine
0.25
0.2
L-NAME
Control
L-Arg
0.15
0.1
Control
0.05
0
NO Inhibition
NO Augmentation
Clinical Methods for Assessing
Endothelium-Dependent Dilation
Coronary Arteries
Forearm
• Epicardial Artery Diameter • Brachial Artery Diameter
 with ACh
 with Arterial Occlusion
• CBF  with ACh
• Epicardial Artery Diameter
 with Adenosine
• Forearm Blood Flow with
ACh
Takese B, Am J Cardiol 1998:82:1535
Comparison of Brachial and Coronary
Flow-Mediated Vasodilation
Furchgott RF & Zawadski JV, Nature 1980
Anderson TJ et al, NEJM 1995;332:488
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
45%
40%
35%
CVE’s
30%
Vasodil
Vasocon
FMD >19%
FMD 10-19%
FMD <10%
25%
20%
15%
10%
5%
0%
Ach
CP
FMD
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
30%
25%
20%
15%
vasodil or T1 CVR
vasocon or T2,3 CVR
10%
5%
0%
Cor Vasc Res
Change Ach
CA Diameter
Change Ach
Al Suwaidi J et al. Circulation 2000;101:948
Cardiac Events in 157 CAD Patients over 28
Months Stratified by CBF Responses to ACh
3
2.5
2
CHD Death
MI
1.5
CHF
CABG
1
PCI
0.5
0
Normal
Mild Dysfunction
Severe Dysfunction
Targonski PV et al, Circulation 2003;107:2805
Relative Risk of CVA or TIA in 503 NonObstructive CAD Subjects over 88 Months
According to CBR Responses to ACh
14
12
10
8
6
4
2
0
>108%
44-108%
14-44%
CBF Increase with ACh
<14%
Clinical Methods for Assessing
Endothelium-Dependent Dilation
Coronary Arteries
Forearm
• Epicardial Artery Diameter • Brachial Artery Diameter
 with ACh
 with Arterial Occlusion
• CBF  with ACh
• Epicardial Artery Diameter
 with Adenosine
• Forearm Blood Flow with
ACh
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)
8
7
6
5
ACh FBF
%CVE's
4
3
2
1
0
Tertile 1
Tertile 2
Tertile 3
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
ACh-induced FBF Responses
Vitamin C Responses
Brachial Artery Flow-Mediated Vasodilation
3.6 mm
3.1 mm
Baseline
5 Minutes
Blood Pressure Cuff
Occlusion – 1 Minute
Release
Post-Occlusion
Neuntfeufl T et al, Am J Cardiol 2000;86:207
CHD Events over 5 Years in 76 CAD Patients
According to Brachial Artery FMD
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
FMD >10%
FMD <10%
PTCA
CABG
MI
ANY
EVENT
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
25%
20%
15%
CHD Events
CV Events
10%
5%
0%
<4%
4%-8%
>8%
Endothelial Dysfunction as
a Therapeutic
Prognosticator
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
35%
30%
25%
20%
<4.2%
4.2-8.1%
>8.1%
15%
10%
5%
0%
MACE
MACE + Trop
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
7
6
5
4
3
2
1
0
Premenopausal
No HRT
HRT
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)
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
d-FMD <10%

d-FMD >10%

CVE's
Hosp-CHF
TIA's
FMD and LDL-C at Baseline and 3
Months in the REVERSAL Trial
15%
3 Months
10%
5%
Baseline
Pravastatin 40 mg
Atorvastatin 80 mg
0%
75
100
125
LDL-C (mg/dl)
150
175
% Change in IVUS Atheroma Volume at
18 Months in the REVERSAL Trial
3
2.7
2
P = 0.02
1
0
LDL-C
110
LDL-C
79
-0.4
-1
Pravastatin 40 mg
Atorvastatin 80 mg
Summary:
Coronary and brachial artery
endothelium-mediated dilation
provide significant CVE
prognostic information and
may be indexes of therapeutic
responses.