Endothelial Dysfunction as a Endothelial Dysfunction as a Marker of Cardiovascular EventsMarker of Cardiovascular Events

Robert A. Vogel, M.D.Robert A. Vogel, M.D.

Coronary Coronary Heart Heart

DiseaseDisease

Endothelial Endothelial DysfunctionDysfunction

NO NO ↑↑Inflammation Inflammation ↑↑ThrombosisThrombosis

“Response-to-Injury” Hypothesis

GenesGenes

Coronary Risk

Factors

Regulatory Functions of the EndotheliumNormal Dysfunction

Vasodilation VasoconstrictionNO, PGI2, EDHF,

BK, C-NPROS, ET-1, TxA2,

A-II, PGH2

Thrombolysis Thrombosis

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

PAI-1, TF, Tx-A2tPA, Protein C, TF-I,

vonWF

LPLVogel 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

0

0.05

0.1

0.15

0.2

0.25

0.3

NO Inhibition NO Augmentation

L-NAMEControl

L-Arg

Control

L-NAME L-Arginine

Clinical Methods for Assessing Clinical 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

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

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Ach CP FMD

VasodilVasoconFMD >19%FMD 10-19%FMD <10%

CV

E’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

0%

5%

10%

15%

20%

25%

30%

Cor Vasc ResChange Ach

CA DiameterChange Ach

vasodil or T1 CVR

vasocon or T2,3 CVR

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

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

Rel

ativ

e R

isk

of

CV

A/T

IA

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

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

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

Brachial Artery Flow-Mediated Vasodilation

Baseline 5 Minutes Post-OcclusionBlood Pressure CuffOcclusion – 1 Minute Release

3.1 mm 3.6 mm

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%

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 EventsCV Events

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

0%

5%

10%

15%

20%

25%

30%

35%

MACE MACE + Trop

<4.2%

4.2-8.1%

>8.1%

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

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%

FMD and LDL-C at Baseline and 3 Months in the REVERSAL Trial15%

10%

5%

0%75 100 125 150 175

LDL-C (mg/dl)

Flo

w-M

edia

ted

Dil

atio

n

Pravastatin 40 mg

Atorvastatin 80 mg

3 Months

Baseline

% 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

Summary:

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