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Endothelial Dysfunction as aEndothelial Dysfunction as a
Marker of Cardiovascular EventsMarker of Cardiovascular Events
Ro...
CoronaryCoronary
HeartHeart
DiseaseDisease
EndothelialEndothelial
DysfunctionDysfunction
↓↓NONO
↑↑InflammationInflammation...
Regulatory Functions of the Endothelium
Normal Dysfunction
Vasodilation Vasoconstriction
NO, PGI2, EDHF,
BK, C-NP
ROS, ET-...
Fichtlscherer S et al, Circulation 2000;102;1000
Comparison of Forearm Responses to ACh and
C-Reactive Protein in 60 Men w...
Cayette et al, Nature 1990; Cooke et al, JCI 1992;90:1168
Effect of NO Inhibition and Augmentation on
Hypercholesterolemic...
Clinical Methods for AssessingClinical Methods for Assessing
Endothelium-Dependent DilationEndothelium-Dependent Dilation
...
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 ...
Halcox JPJ et al, Circulation 2002;106:653
CVE’s over 4 Years in 176 Subjects without
CAD According to CVR and CA Diameter...
Al Suwaidi J et al. Circulation 2000;101:948
Cardiac Events in 157 CAD Patients over 28
Months Stratified by CBF Responses...
Targonski PV et al, Circulation 2003;107:2805
Relative Risk of CVA or TIA in 503 Non-
Obstructive CAD Subjects over 88 Mon...
Clinical Methods for Assessing
Endothelium-Dependent Dilation
Coronary Arteries
• Epicardial Artery
Diameter ∆ with ACh
• ...
Perticone F et al, Circulation 2001;104:191
Effect of ACh-Induced Forearm Vasodilation* on
32-Month CVE’s (%) in 225 Never...
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...
Brachial Artery Flow-Mediated Vasodilation
Baseline 5 Minutes Post-Occlusion
Blood Pressure Cuff
Occlusion – 1 Minute
Rele...
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...
Murakami T et al. J Am Coll Cardiol 2001;37:294A
CVE’s over 4 Years in 480 Patients with Suspected
CAD According to Brachi...
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 Pat...
Sorensen KE et al, Circulation 1998:97:1234
Effect of HRT on Brachial Artery FMD at 3 Years
in 100 Postmenopausal Women Ra...
Modena MG et al. J Am Coll Cardiol 2002;40:505
5-Year Outcome in 350 Postmenopausal Hypertensive
Women with Controlled BP ...
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-MediatedD...
% 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 ...
Summary:
Coronary and brachial artery
endothelium-mediated dilation
provide significant CVE
prognostic information and
may...
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Vogel endothelial function cv es

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Vogel endothelial function cv es

  1. 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. 2. CoronaryCoronary HeartHeart DiseaseDisease EndothelialEndothelial DysfunctionDysfunction ↓↓NONO ↑↑InflammationInflammation ↑↑ThrombosisThrombosis “Response-to-Injury” Hypothesis GenesGenes Coronary Risk Factors
  3. 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. 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. 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. 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. 7. Takese B, Am J Cardiol 1998:82:1535 Comparison of Brachial and Coronary Flow-Mediated Vasodilation
  8. 8. Furchgott RF & Zawadski JV, Nature 1980 Anderson TJ et al, NEJM 1995;332:488
  9. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 19. Endothelial Dysfunction as a Therapeutic Prognosticator
  20. 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. 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. 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. 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. 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. 25. Summary: Coronary and brachial artery endothelium-mediated dilation provide significant CVE prognostic information and may be indexes of therapeutic responses.

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