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Endothelial Dysfunction as Marker of Cardiovascular Events

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Endothelial Dysfunction as Marker of Cardiovascular Events Powered By Docstoc
					 Endothelial Dysfunction as a
Marker of Cardiovascular Events
        Robert A. Vogel, M.D.
      “Response-to-Injury” Hypothesis



           Genes   Endothelial
Coronary           Dysfunction     Coronary
  Risk                              Heart
 Factors                NO
                   ↑Inflammation    Disease
                    ↑Thrombosis
Regulatory Functions of the Endothelium
     Normal                        Dysfunction
         Vasodilation           Vasoconstriction
        NO, PGI2, EDHF,         ROS, ET-1, TxA2,
          BK, C-NP                 A-II, PGH2

          Thrombolysis           Thrombosis
      tPA, Protein C, TF-I,     PAI-1, TF, Tx-A2
            vonWF
    Platelet Disaggregation     Adhesion Molecules
          NO, PGI2               CAMs, Selectins


      Antiproliferation           Growth Factors
    NO, PGI2, TGF-, Hep      ET-1, A-II, PDGF, bFGF,
                                ILGF, Interleukins
           Lipolysis               Inflammation
             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
                    L-NAME                          L-Arginine




                           Control
    Clinical Methods for Assessing
   Endothelium-Dependent Dilation
 Coronary Arteries                 Forearm
• Epicardial Artery           • Brachial Artery Diameter
  Diameter  with ACh            with Arterial Occlusion

• CBF  with ACh              • Forearm Blood Flow with
                                ACh
• Epicardial Artery
  Diameter  with Adenosine
         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
CVE’s
           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
          Al Suwaidi J et al. Circulation 2000;101:948

Cardiac Events in 157 CAD Patients over 28
Months Stratified by CBF Responses to ACh
        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




               CBF Increase with ACh
    Clinical Methods for Assessing
   Endothelium-Dependent Dilation
 Coronary Arteries                 Forearm
• Epicardial Artery           • Brachial Artery Diameter
  Diameter  with ACh            with Arterial Occlusion

• CBF  with ACh              • Forearm Blood Flow with
                                ACh
• Epicardial Artery
  Diameter  with Adenosine
             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)
                 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



        3.1 mm                             3.6 mm




      Baseline        5 Minutes         Post-Occlusion
                 Blood Pressure Cuff
                 Occlusion – 1 Minute
                       Release
           Neuntfeufl T et al, Am J Cardiol 2000;86:207

CHD Events over 5 Years in 76 CAD Patients
   According to Brachial Artery FMD
           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
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
             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
               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)



                                                                
                                                                
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         150   175
           LDL-C (mg/dl)
% Change in IVUS Atheroma Volume at
 18 Months in the REVERSAL Trial



                               P = 0.02


                 LDL-C         LDL-C
                  110            79




           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.

				
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