novel markers of arterial dysfunction

Novel Markers of

Arterial Dysfunction

Kwang Kon Koh, MD, FACC, FAHA

Cardiology

Gachon Medical School

Incheon, Korea

혈관연구회 창립 심포지움, 3월 3일, 2005

Atherosclerosis: A progressive process

Disease progression

PHASE I: Initiation PHASE II: Progression PHASE III: Complication

Koh KK. Cardiovasc Res 2000;47:648 (Review)


• Regulates vasomotor tone

• Inhibits inflammatory cell attachment

• Inhibits platelet aggregation and

attachment

• Inhibits release of procoagulant

factors

• Inhibits release of growth factors

Nitric Oxide

Baseline 1

Reactive Hyperemia

Baseline 1 Reactive Hyperemia

40 Subjects with a Parental History

of Premature Myocardial Infarction

N Engl J Med 2000; 343: 840

Test Sensitivity (95% CI) Specificity (95% CI)

Angina Pectoris (n = 112)

96/101; 95.1% (88.8-98.4) 5/21; 23.8% (8.2-47.2)

Exercise ECG testing (n = 112)

75/91; 82.4% (73.0-89.6) 12/21; 57.1% (34.0-78.2)

Myocardial Perfusion Imaging (n = 34)

30/30; 100.0% (88.4-100.0) 0/4; 0.0% (0-60.2)

FMD% (n = 122) 72/101; 71.3%

(61.4-79.6) 17/21; 81% (58.1-94.6)

Sensitivity and Specificity of Tests

in Predicting CAD

Schroeder et al. Am Heart J 1999;138:731

Kaplan-Meier Analysis of Patients w/o CV Events

Schachinger et al. Circulation 2000;101:1899

(10 yrs)

TxA2

Tissue Factor

Adhesion Molecules

Reactive

Oxygen

Species

Colony Stimulating

Factors

Growth

Factors

Growth Factors

Cytokines

Cytokines

LDL Oxidation

vWF Chemokines

Metalloproteinases

Inflammatory Response to Injury

MCP-1 M-CSF

E Selectin ICAM-1

VCAM-1 Tissue factor

PAI-1

NADH / NADPH oxidaseCyclooxygenase

Lipoxygenase

Xanthine oxidase

Mitochondria

Oxygen Free

Radicals

p65p50

p65p50

IkB

Cytokines

LDLox

Ang IILPS

CMV

PIkB

NO•, HDL

Antioxidant

LDL, Lp(a)

Activation of Nuclear

Transcription Factor, NFkB


PDGF

complement

thromboxane A2

metalloproteinases

tissue factor

PAI-1

oxygen free radicals

Lymphocyte

Activation

IL-1

TNF

IL-6IL-11

C-reactive protein

amyloid A

haptoglobin

ceruloplasmin

C3, C4

fibrinogen

vWF

PAI-1

Lp(a)

albumin

transferrin

A-I, A-II

C3

amyloid A

a1-acid glycoprotein

Adhesion

Molecule

Expression

+

+

-

Cytokines Initiate

Hepatic Synthesis of

Some Proteins

(Acute Phase Reactants)

Koh KK. Cardiovasc Res.

2002;55:714. (Review)

Association Between MCP-1 Levels and

Prevalence of Subclinical Atherosclerosis

In Dallas Heart Study, 3,499 subjects <65 yrs

Coronary artery calcium measured by EBCTDeo R, et al.

JACC 2004;44:1812

CRP, Metabolic Syndrome, and Prediction of

CV Events in the Framingham Offspring Study

Rutter MK, et al. Circulation. 2004;110:380.

Both CRP and MetS are independent predictors

of new CVD events over 7 years

Zouridakis E.

Circulation.

2004;

110:1747.

Top, Rapid angiographic stenosis progression

Classified according to sICAM-1 and CRP levels.

Bottom, according to neopterin and MMP-9 levels

P<0.001

P<0.001

NO

PI 3-kinase-dependent

Pathways

eNOS reductase

oxydase

Adiponectin

reductasep

oxydase

L-Arginine

L-Citruline

AMPK

Adiponectin

Receptor

p65p50

p65p50

IkB

PIkB

Han SH, et al. Circulation (Review, submitted)

Adiponectin, cytokines secreted by adipose cells,

Have insulin-sensitizing, anti-inflammatory,

And anti-atherogenic properties

NFkB

MCP-1 M-CSF

E Selectin ICAM-1

VCAM-1 Tissue

PAI-1 factor

NADH / NADPH oxidaseCyclooxygenase

Lipoxygenase

Xanthine oxidase

Mitochondria

Oxygen Free

Radicals

p65p50

p65p50

IkB

Cytokines

LDLox

Ang IILPS

CMV

PIkB

HDL, NO•

Antioxidant

TG, LDL

Therapeutic Intervention

Feno-

fibrate

Ramipril, ARBs

Fenofibrate

Beneficial Effects of Fenofibrate to

Improve Endothelial Dysfunction and

Raise Adiponectin Levels In Patients

With Primary Hypertriglyceridemia

Kwang Kon Koh, Seung Hwan Han

Eak Kyun Shin, ……. Michael J. Quon*

ACC 2005, Orlando, USA

Diabetes Care 2005 (in press)

Diabetes Unit, NIH, USA*

0.0

0.2

0.4

0.6

0.8

1.0

Placebo Fenofibrate

0

100

200

300

Placebo Fenofibrate

Effects of Fenofibrate on Inflammationin 46 Hypertriglyceridemic Patients

Fibrinogen (mg/dl) hsCRP (mg/l)

P<0.001

281

230

-16%

0.80(0.50-2.50)

0.70(0.40-1.20)

P=0.001

Additive Beneficial Effects of

Fenofibrate Combined with

Atorvastatin In Treatment of

Combined Hyperlipidemia


Eak Kyun Shin, ……. Michael J. Quon*

ACC 2005, Orlando, USA

JACC 2005 (in press)


% C

han

ge in

Ad

ipo

necti

n L

evels

(%

)

0

10

20

30

Atorvastatin CombinedTherapy

Fenofibrate

P<0.05

P<0.05

P=0.022by ANOVA

Combined therapy or fenofibrate alone significantly increases Adiponectin levels in patients with combined hyperlipidemia

% C

han

ge in

QU

ICK

I (%

)

0

5

10

15

Atorvastatin CombinedTherapy

Fenofibrate

P<0.05

P=0.049by ANOVA

Combined therapy or fenofibrate alone significantly increases Insulin sensitivity in patients with combined hyperlipidemia

*QUICKI=Quantitative Insulin-Sensitivity Check Index, a surrogate index of

insulin sensitivity, QUICKI = 1/[log(insulin)+log(glucose)]

0

200

400

600

Baseline 1 Simvastatin+Placebo

0

200

400

600

Baseline 2 Simvastatin+Ramipril

P=0.019 P<0.001

P=0.015

Ramipril Combined with Simvastatin on MCP-1 Levels (pg/ml) (HC)

Koh KK, et al. Hypertension. 2004;44:180

0

50

100

150

200

Baseline 1 Simvastatin+Placebo

0

50

100

150

200

Baseline 2 Simvastatin+Ramipril

P=0.828 P<0.001

Simvastatin Combined with Ramipril on PAI-1 Antigen Levels (ng/ml) (HC)

P=0.003

Koh KK, et al. Hypertension. 2004;44:180

Additive Beneficial Effects of Ramipril

Combined with Simvastatin in the Treatment

of Type II Diabetic Patients


Eak Kyun Shin, ……. Michael J. Quon

AHA 2004, New Orleans, USA

Hypertension 2005 (in press)

Ramipril Combined with Simvastatin

on Blood Pressure (mmHg)

50

75

100

125

150

B1 S B 2 C B 3 R

*=p<0.05; **=p<0.01; ***=p<0.001 vs. Baseline.

B= Baseline, S=simvastatin+placebo, C=simvastatin+ramipril, R=ramipril+placebo.

***

**

**

***

Systolic BP

ANOVA

p=0.003

ANOVA

p=0.040

Diastolic BP

Effects of Simvastatin, Combined Therapy,

and Ramipril on Insulin Sensitivity%

Ch

an

ge in

Ad

ipo

necti

n L

evels

(%

)

-10

0

10

20

30

Simvastatin CombinedTherapy

Ramipril

P<0.05

P<0.05

P=0.013by ANOVA

% C

han

ge in

QU

ICK

I (%

)-5

0

5

10


Ramipril

P<0.05

P<0.05

P=0.015by ANOVA

*QUICKI=Quantitative Insulin-Sensitivity Check Index, a surrogate index

of insulin sensitivity, QUICKI = 1/[log(insulin)+log(glucose)]

Shin M-S, et al.

AHA 2004 Presented

Adiponectin QUICKI

Combined Therapy Significantly Improves

Flow-mediated Dilator Response

% C

ha

ng

e in

Flo

w-M

ed

iate

d D

ila

tio

n (

%)

0

20

40

60

80

100


Losartan

P<0.05 P<0.05

P<0.001by ANOVA

Koh KK, et al. Circulation. 2004;110:3687

% C

ha

ng

e in

MD

A L

ev

els

(%

)

-40

-30

-20

-10

0


Losartan

P<0.05 P<0.05

P<0.001by ANOVA

Malondialdehyde FMD

ThankQ!

Markers of Inflammation and Rapid CAD Progression

In 124 Patients with Stable Angina Awaiting PCI

Zouridakis E.

Circulation.

2004;

110:1747

Neopterin MMP-9

sICAM-1 CRP

Waiting

Time

4.8 Mo

• Peroxisome Proliferator-Activated ReceptorsTranscription factors belonging to nuclear

receptor superfamily PPARa, PPARb/d, PPARγ

• FibratesSynthetic ligands for PPARa

• PPARa

1. Anti-inflammatory function 2. Reduce oxidative stress 3. Expression of inhibitory protein IkBa

Inhibit NF-kB activation

Fenofibrate

Femofibrate increases NO Synthase

Expression in BAECs (Western blot)

Goya et al, ATVB 2004;24:658

Fenofibrate suppresses inflammatory

Responses associated with NFkB and IkB

in LV of DOCA-salt hypertensive rats

Effects of Fenofibrate on Lipoproteins,

Vasomotor Function, and Serological

Markers of Inflammation,

Plaque Stabilization, and Hemostasis

Kwang Kon Koh, Seung Hwan Han, ………… Eak Kyun Shin

Atherosclerosis 2004;174:379

0

5

10

15

Placebo Fenofibrate

0

5

10

Placebo Fenofibrate

Effects of Fenofibrate on Vasomotionin 25 Hypertriglyceridemic Patients

FMD (%) NTG (%)

P<0.001

4.99

6.3333%

Koh KK et al, Atherosclerosis 2004;174:379

Additive Effects of Ramipril

Combined with Statin on

Inflammation and Fibrinolysis in

Patients with CAD

Kwang Kon Koh, Seung Hwan Han,

………. Eak Kyun Shin

Atherosclerosis. 2004;177:147

Effects of Simvastatin, Combined Therapy,

and Ramipril on MDA Levels and FMD

% C

ha

ng

e in

MD

A L

ev

els

(%

)

-40

-30

-20

-10

0


Ramipril

P<0.05 P<0.05

P<0.001by ANOVA

% C

han

ge in

Flo

w-M

ed

iate

d D

ilati

on

(%

)

0

20

40

60

80

100


Ramipril

P<0.001 P<0.001

P<0.001by ANOVA

Combined Therapy on Flow-Mediated Dilation (%)in Type II Diabetic Patients

P=0.027

Malondialdehyde FMD

Additive Beneficial Effects of Losartan

Combined with Simvastatin in Treatment of

Hypercholesterolemic, Hypertensive Patients


Eak Kyun Shin, .. Michael J. Quon*

Cardiology, Gachon Medical School,

Incheon, Korea


Circulation 2004;110:3687

Combined Therapy Significantly Reduces

MCP-1 Levels

% C

han

ge in

MC

P-1

Levels

(%

)

-30

-20

-10

0


Losartan

P<0.05

P=0.030by ANOVA

P<0.05

Koh KK, et al. Circulation 2004;110:3687

novel markers of arterial dysfunction

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