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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.

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“Response-to-Injury” Hypothesis

Genes

Coronary Risk Factors

Endothelial Dysfunction

NO ↑Inflammation ↑Thrombosis

Coronary Heart Disease

regulatory functions of the endothelium normal dysfunction
Regulatory Functions of the EndotheliumNormal Dysfunction

Vasodilation

Vasoconstriction

NO, PGI2, EDHF, BK, C-NP

ROS, ET-1, TxA2, A-II, PGH2

Thrombolysis

Thrombosis

tPA, Protein C, TF-I, vonWF

PAI-1, TF, Tx-A2

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

slide4
Fichtlscherer S et al, Circulation 2000;102;1000Comparison of Forearm Responses to ACh and C-Reactive Protein in 60 Men with CAD
slide5

Cayette et al, Nature 1990; Cooke et al, JCI 1992;90:1168Effect 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

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

Clinical Methods for Assessing Endothelium-Dependent Dilation
takese b am j cardiol 1998 82 1535 comparison of brachial and coronary flow mediated vasodilation
Takese B, Am J Cardiol 1998:82:1535Comparison of Brachial and Coronary Flow-Mediated Vasodilation
slide8

Furchgott RF & Zawadski JV, Nature 1980

Anderson TJ et al, NEJM 1995;332:488

slide9

Schachinger V et al, Circulation 2000;101:1899CVE’s over 7.7 Years in 147 Subjects with CAD According to Coronary Artery Responses to Ach, Cold Pressor, and FMD

CVE’s

slide10

Halcox JPJ et al, Circulation 2002;106:653CVE’s over 4 Years in 176 Subjects without CAD According to CVR and CA Diameters Changes with ACh

slide11
Al Suwaidi J et al. Circulation 2000;101:948Cardiac Events in 157 CAD Patients over 28 Months Stratified by CBF Responses to ACh
slide12

Targonski PV et al, Circulation 2003;107:2805Relative 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

clinical methods for assessing endothelium dependent dilation1
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

Clinical Methods for Assessing Endothelium-Dependent Dilation
slide14

Perticone F et al, Circulation 2001;104:191Effect of ACh-Induced Forearm Vasodilation* on 32-Month CVE’s (%) in 225 Never Treated Hypertensive Subjects(* Relative Flow Increase)

slide15
Heitzer T et al, Circulation 2001;104:2673CVE’s According to FBF Responses to ACh and I.V. Vitamin C in 281 Subjects with CHD

ACh-induced FBF Responses

Vitamin C Responses

slide16

Brachial Artery Flow-Mediated VasodilationBaseline5 MinutesPost-OcclusionBlood Pressure Cuff Occlusion – 1 Minute Release

3.6 mm

3.1 mm

slide17
Neuntfeufl T et al, Am J Cardiol 2000;86:207CHD Events over 5 Years in 76 CAD Patients According to Brachial Artery FMD
slide18
Murakami T et al. J Am Coll Cardiol 2001;37:294ACVE’s over 4 Years in 480 Patients with Suspected CAD According to Brachial Artery FMD
slide20

Gokce N et al, Circulation 2002;105:1567Effect of Preoperative FMD on 30-Day MACE and MACE + Elevated Troponin in 187 Patients Undergoing Vascular Surgery

slide21

Sorensen KE et al, Circulation1998:97:1234Effect of HRT on Brachial Artery FMD at 3 Years in 100 Postmenopausal Women Randomized to HRT/Placebo and 30 Premenopausal Women

slide22

Modena MG et al. J Am Coll Cardiol 2002;40:5055-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
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)

change in ivus atheroma volume at 18 months in the reversal trial
% 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

slide25

Summary:

Coronary and brachial artery endothelium-mediated dilation provide significant CVE prognostic information and may be indexes of therapeutic responses.

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