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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