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

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Endothelial Dysfunction as a Marker of
Cardiovascular EventsRobert A. Vogel, M.D.
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Response-to-Injury Hypothesis
Genes
Endothelial Dysfunction ?NO ?Inflammation
?Thrombosis
Coronary Risk Factors
Coronary Heart Disease
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Regulatory Functions of the EndotheliumNormal D
ysfunction
Vasodilation
Vasoconstriction
NO, PGI2, EDHF, BK, C-NP
ROS, ET-1, TxA2, A-II, PGH2
Thrombolysis
Thrombosis
PAI-1, TF, Tx-A2
tPA, Protein C, TF-I, vonWF
Platelet Disaggregation NO, PGI2
Adhesion Molecules CAMs, Selectins
Antiproliferation NO, PGI2, TGF-?, Hep
Growth Factors ET-1, A-II, PDGF, bFGF, ILGF,
Interleukins
Lipolysis
Inflammation ROS, NF-?B
LPL
Vogel R
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Fichtlscherer S et al, Circulation
20001021000Comparison of Forearm Responses to
ACh and C-Reactive Protein in 60 Men with
CAD
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Cayette et al, Nature 1990 Cooke et al, JCI
1992901168Effect of NO Inhibition and
Augmentation on Hypercholesterolemic Rabbit
Aortic Atherosclerosis Area at 6 Weeks
L-NAME
L-Arginine
Control
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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

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Takese B, Am J Cardiol 1998821535Comparison of
Brachial and Coronary Flow-Mediated
Vasodilation
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Furchgott RF Zawadski JV, Nature 1980
Anderson TJ et al, NEJM 1995332488
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Schachinger V et al, Circulation
20001011899CVEs over 7.7 Years in 147
Subjects with CAD According to Coronary Artery
Responses to Ach, Cold Pressor, and FMD
CVEs
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Halcox JPJ et al, Circulation 2002106653CVEs
over 4 Years in 176 Subjects without CAD
According to CVR and CA Diameters Changes with ACh
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Al Suwaidi J et al. Circulation
2000101948Cardiac Events in 157 CAD Patients
over 28 Months Stratified by CBF Responses to ACh
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Targonski PV et al, Circulation
20031072805Relative Risk of CVA or TIA in 503
Non-Obstructive CAD Subjects over 88 Months
According to CBR Responses to ACh
Relative Risk of CVA/TIA
CBF Increase with ACh
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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

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Perticone F et al, Circulation 2001104191Effect
of ACh-Induced Forearm Vasodilation on 32-Month
CVEs () in 225 Never Treated Hypertensive
Subjects( Relative Flow Increase)
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Heitzer T et al, Circulation 20011042673CVEs
According to FBF Responses to ACh and I.V.
Vitamin C in 281 Subjects with CHD
Vitamin C Responses
ACh-induced FBF Responses
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Brachial Artery Flow-Mediated
Vasodilation Baseline 5
Minutes Post-Occlusion Blood Pressure
Cuff Occlusion 1 Minute
Release
3.6 mm
3.1 mm
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Neuntfeufl T et al, Am J Cardiol 200086207CHD
Events over 5 Years in 76 CAD Patients According
to Brachial Artery FMD
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Murakami T et al. J Am Coll Cardiol
200137294ACVEs over 4 Years in 480 Patients
with Suspected CAD According to Brachial Artery
FMD
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Endothelial Dysfunction as a Therapeutic
Prognosticator
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Gokce N et al, Circulation 20021051567Effect
of Preoperative FMD on 30-Day MACE and MACE
Elevated Troponin in 187 Patients Undergoing
Vascular Surgery
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Sorensen KE et al, Circulation 1998971234Effect
of HRT on Brachial Artery FMD at 3 Years in 100
Postmenopausal Women Randomized to HRT/Placebo
and 30 Premenopausal Women
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Modena MG et al. J Am Coll Cardiol
2002405055-Year Outcome in 350 Postmenopausal
Hypertensive Women with Controlled BP (lt140/90)
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)
?
?
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FMD and LDL-C at Baseline and 3 Months in the
REVERSAL Trial
15 10 5 0
3 Months
Flow-Mediated Dilation
Baseline
Pravastatin 40 mg Atorvastatin 80 mg
75 100 125 150
175
LDL-C (mg/dl)
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Change in IVUS Atheroma Volume at 18 Months in
the REVERSAL Trial
Percent Change in Atheroma Volume by IVUS
P 0.02
LDL-C 110
LDL-C 79
Pravastatin 40 mg Atorvastatin 80 mg
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Summary Coronary and brachial artery
endothelium-mediated dilation provide significant
CVE prognostic information and may be indexes of
therapeutic responses.