Koh KK, et al. Circulation. 2004
Koh KK, et al. Circulation. 2004
Koh KK, et al. Circulation. 2004
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혈관연구회 창립 심포지움, 3월 3일, 2005<br />
Novel Markers of<br />
Arteri<strong>al</strong> Dysfunction<br />
Kwang Kon <strong>Koh</strong>, MD, FACC, FAHA<br />
Cardiology<br />
Gachon Medic<strong>al</strong> School<br />
Incheon, Korea
Atherosclerosis: A progressive process<br />
PHASE I: Initiation PHASE II: Progression PHASE III: Complication<br />
Disease progression
Nitric Oxide<br />
• Regulates vasomotor tone<br />
• Inhibits inflammatory cell attachment<br />
• Inhibits platel<strong>et</strong> aggregation and<br />
attachment<br />
• Inhibits release of procoagulant<br />
factors<br />
• Inhibits release of growth factors<br />
<strong>Koh</strong> <strong>KK</strong>. Cardiovasc Res 2000;47:648 (Review)<br />
<strong>Koh</strong> <strong>KK</strong>. Cardiovasc Res 2002;55:714 (Review)
Baseline 1
Reactive Hyperemia
Baseline 1<br />
Reactive Hyperemia
40 Subjects with a Parent<strong>al</strong> History<br />
of Premature Myocardi<strong>al</strong> Infarction<br />
N Engl J Med 2000; 343: 840
Sensitivity and Specificity of Tests<br />
in Predicting CAD<br />
Test Sensitivity (95% CI) Specificity (95% CI)<br />
Angina Pectoris<br />
(n = 112)<br />
Exercise ECG testing<br />
(n = 112)<br />
Myocardi<strong>al</strong> Perfusion<br />
Imaging (n = 34)<br />
96/101; 95.1% (88.8-98.4) 5/21; 23.8% (8.2-47.2)<br />
75/91; 82.4% (73.0-89.6) 12/21; 57.1% (34.0-78.2)<br />
30/30; 100.0% (88.4-100.0) 0/4; 0.0% (0-60.2)<br />
FMD% (n = 122)<br />
72/101; 71.3%<br />
(61.4-79.6)<br />
17/21; 81%<br />
(58.1-94.6)<br />
Schroeder <strong>et</strong> <strong>al</strong>. Am Heart J 1999;138:731
Kaplan-Meier An<strong>al</strong>ysis of Patients w/o CV Events<br />
(10 yrs)<br />
Schachinger <strong>et</strong> <strong>al</strong>. <strong>Circulation</strong> 2000;101:1899
Inflammatory Response to Injury<br />
TxA 2<br />
vWF<br />
Tissue Factor<br />
Adhesion Molecules<br />
Chemokines<br />
Cytokines<br />
Cytokines<br />
Growth Factors<br />
M<strong>et</strong><strong>al</strong>loproteinases<br />
Colony Stimulating<br />
Factors<br />
Growth<br />
Factors<br />
Reactive<br />
Oxygen<br />
Species<br />
LDL Oxidation
Cytokines<br />
LDL ox<br />
Ang II<br />
LPS<br />
CMV<br />
NADH / NADPH oxidase<br />
Cyclooxygenase<br />
Lipoxygenase<br />
Xanthine oxidase<br />
Mitochondria<br />
Activation of Nuclear<br />
Transcription Factor, NFkB<br />
NO•, HDL<br />
Antioxidant<br />
LDL, Lp(a)<br />
Oxygen Free<br />
Radic<strong>al</strong>s<br />
p50<br />
p65<br />
MCP-1 M-CSF<br />
E Selectin ICAM-1<br />
VCAM-1 Tissue factor<br />
PAI-1<br />
p65<br />
p50<br />
IkB<br />
IkB<br />
P<br />
<strong>Koh</strong> <strong>KK</strong>. Cardiovasc Res 2002;55:714 (Review)
PDGF<br />
complement<br />
thromboxane A 2<br />
m<strong>et</strong><strong>al</strong>loproteinases<br />
tissue factor<br />
PAI-1<br />
oxygen free radic<strong>al</strong>s<br />
Adhesion<br />
Molecule<br />
Expression<br />
IL-1<br />
TNF<br />
Lymphocyte<br />
Activation<br />
IL-6<br />
IL-11<br />
Cytokines Initiate<br />
Hepatic Synthesis of<br />
Some Proteins<br />
(Acute Phase Reactants<br />
C-reactive protein<br />
amyloid A<br />
haptoglobin<br />
ceruloplasmin<br />
C3, C4<br />
fibrinogen<br />
vWF<br />
PAI-1<br />
Lp(a)<br />
+<br />
-<br />
<strong>al</strong>bumin<br />
transferrin<br />
A-I, A-II<br />
+<br />
C3<br />
amyloid A<br />
a 1 -acid glycoprotein<br />
<strong>Koh</strong> <strong>KK</strong>. Cardiovasc Res.<br />
2002;55:714. (Review)
Association B<strong>et</strong>ween MCP-1 Levels and<br />
Prev<strong>al</strong>ence of Subclinic<strong>al</strong> Atherosclerosis<br />
In D<strong>al</strong>las Heart Study, 3,499 subjects
CRP, M<strong>et</strong>abolic Syndrome, and Prediction of<br />
CV Events in the Framingham Offspring Study<br />
Both CRP and M<strong>et</strong>S are independent predictors<br />
of new CVD events over 7 years<br />
Rutter MK, <strong>et</strong> <strong>al</strong>. <strong>Circulation</strong>. <strong>2004</strong>;110:380.
Top, Rapid angiographic stenosis progression<br />
Classified according to sICAM-1 and CRP levels.<br />
Bottom, according to neopterin and MMP-9 levels<br />
P
Adiponectin, cytokines secr<strong>et</strong>ed by adipose cells,<br />
Have insulin-sensitizing, anti-inflammatory,<br />
And anti-atherogenic properties<br />
Adiponectin<br />
Adiponectin<br />
Receptor<br />
AMPK<br />
eNOS reductase<br />
PI 3-kinase-dependent<br />
Pathways<br />
p<br />
reductase<br />
oxydase<br />
L-Arginine<br />
oxydase<br />
L-Citruline<br />
NO<br />
NFkB<br />
p65<br />
p50 IkB<br />
IkB P<br />
p50<br />
p65<br />
Han SH, <strong>et</strong> <strong>al</strong>. <strong>Circulation</strong> (Review, submitted)
Therapeutic Intervention<br />
Cytokines<br />
LDL ox<br />
Ang II<br />
LPS<br />
CMV<br />
NADH / NADPH oxidase<br />
Cyclooxygenase<br />
Lipoxygenase<br />
Xanthine oxidase<br />
Mitochondria<br />
Ramipril, ARBs<br />
Fenofibrate<br />
Oxygen Free<br />
Radic<strong>al</strong>s<br />
p50<br />
p65<br />
MCP-1 M-CSF<br />
E Selectin ICAM-1<br />
VCAM-1 Tissue<br />
PAI-1 factor<br />
p65<br />
p50<br />
IkB<br />
IkB<br />
P<br />
Fenofibrate<br />
HDL, NO•<br />
Antioxidant<br />
TG, LDL
Benefici<strong>al</strong> Effects of Fenofibrate to<br />
Improve Endotheli<strong>al</strong> Dysfunction and<br />
Raise Adiponectin Levels In Patients<br />
With Primary Hypertriglyceridemia<br />
Kwang Kon <strong>Koh</strong>, Seung Hwan Han<br />
Eak Kyun Shin, ……. Michael J. Quon*<br />
Diab<strong>et</strong>es Unit, NIH, USA*<br />
ACC 2005, Orlando, USA<br />
Diab<strong>et</strong>es Care 2005 (in press)
Effects of Fenofibrate on Inflammation<br />
in 46 Hypertriglyceridemic Patients<br />
Fibrinogen (mg/dl)<br />
1.0<br />
hsCRP (mg/l)<br />
300<br />
200<br />
P
Additive Benefici<strong>al</strong> Effects of<br />
Fenofibrate Combined with<br />
Atorvastatin In Treatment of<br />
Combined Hyperlipidemia<br />
Kwang Kon <strong>Koh</strong>, Seung Hwan Han<br />
Eak Kyun Shin, ……. Michael J. Quon*<br />
Diab<strong>et</strong>es Unit, NIH, USA*<br />
ACC 2005, Orlando, USA<br />
JACC 2005 (in press)
Combined therapy or fenofibrate <strong>al</strong>one significantly increases<br />
Adiponectin levels in patients with combined hyperlipidemia<br />
30<br />
% Change in Adiponectin Levels (%)<br />
20<br />
10<br />
P
Combined therapy or fenofibrate <strong>al</strong>one significantly increases<br />
Insulin sensitivity in patients with combined hyperlipidemia<br />
15<br />
% Change in QUICKI (%)<br />
10<br />
5<br />
P
Ramipril Combined with Simvastatin<br />
on MCP-1 Levels (pg/ml) (HC)<br />
P=0.015<br />
600<br />
600<br />
P=0.019<br />
P
200<br />
Simvastatin Combined with Ramipril<br />
on PAI-1 Antigen Levels (ng/ml) (HC)<br />
P=0.828<br />
P=0.003<br />
200<br />
P
Additive Benefici<strong>al</strong> Effects of Ramipril<br />
Combined with Simvastatin in the Treatment<br />
of Type II Diab<strong>et</strong>ic Patients<br />
Kwang Kon <strong>Koh</strong>, Seung Hwan Han<br />
Eak Kyun Shin, ……. Michael J. Quon<br />
AHA <strong>2004</strong>, New Orleans, USA<br />
Hypertension 2005 (in press)
Ramipril Combined with Simvastatin<br />
on Blood Pressure (mmHg)<br />
150<br />
***<br />
**<br />
Systolic BP<br />
125<br />
ANOVA<br />
p=0.003<br />
100<br />
75<br />
**<br />
***<br />
Diastolic BP<br />
ANOVA<br />
p=0.040<br />
50<br />
B1 S B 2 C B 3 R<br />
*=p
Effects of Simvastatin, Combined Therapy,<br />
% Change in Adiponectin Levels (%)<br />
30<br />
20<br />
10<br />
0<br />
and Ramipril on Insulin Sensitivity<br />
Adiponectin<br />
P
Combined Therapy Significantly Improves<br />
Flow-mediated Dilator Response<br />
0<br />
M<strong>al</strong>ondi<strong>al</strong>dehyde<br />
100<br />
FMD<br />
% Change in MDA Levels (%)<br />
-10<br />
-20<br />
-30<br />
-40<br />
P
ThankQ!
Markers of Inflammation and Rapid CAD Progression<br />
In 124 Patients with Stable Angina Awaiting PCI<br />
Neopterin<br />
MMP-9<br />
Waiting<br />
Time<br />
4.8 Mo<br />
sICAM-1<br />
CRP<br />
Zouridakis E.<br />
<strong>Circulation</strong>.<br />
<strong>2004</strong>;<br />
110:1747
Fenofibrate<br />
• Peroxisome Proliferator-Activated Receptors<br />
Transcription factors belonging to nuclear<br />
receptor superfamily<br />
PPARa, PPARb/d, PPARγ<br />
• Fibrates<br />
Synth<strong>et</strong>ic ligands for PPARa<br />
• PPARa<br />
1. Anti-inflammatory function<br />
2. Reduce oxidative stress<br />
3. Expression of inhibitory protein IkBa<br />
Inhibit NF-kB activation
Femofibrate increases NO Synthase<br />
Expression in BAECs (Western blot)<br />
Goya <strong>et</strong> <strong>al</strong>, ATVB <strong>2004</strong>;24:658
Fenofibrate suppresses inflammatory<br />
Responses associated with NFkB and IkB<br />
in LV of DOCA-s<strong>al</strong>t hypertensive rats
Effects of Fenofibrate on Lipoproteins,<br />
Vasomotor Function, and Serologic<strong>al</strong><br />
Markers of Inflammation,<br />
Plaque Stabilization, and Hemostasis<br />
Kwang Kon <strong>Koh</strong>, Seung Hwan Han,<br />
………… Eak Kyun Shin<br />
Atherosclerosis <strong>2004</strong>;174:379
10<br />
Effects of Fenofibrate on Vasomotion<br />
in 25 Hypertriglyceridemic Patients<br />
FMD (%) NTG (%)<br />
15<br />
P
Additive Effects of Ramipril<br />
Combined with Statin on<br />
Inflammation and Fibrinolysis in<br />
Patients with CAD<br />
Kwang Kon <strong>Koh</strong>, Seung Hwan Han,<br />
………. Eak Kyun Shin<br />
Atherosclerosis. <strong>2004</strong>;177:147
% Change in MDA Levels (%)<br />
Effects of Simvastatin, Combined Therapy,<br />
0<br />
-10<br />
-20<br />
-30<br />
-40<br />
and Ramipril on MDA Levels and FMD<br />
M<strong>al</strong>ondi<strong>al</strong>dehyde<br />
P
Additive Benefici<strong>al</strong> Effects of Losartan<br />
Combined with Simvastatin in Treatment of<br />
Hypercholesterolemic, Hypertensive Patients<br />
Kwang Kon <strong>Koh</strong>, Seung Hwan Han<br />
Eak Kyun Shin, .. Michael J. Quon*<br />
Cardiology, Gachon Medic<strong>al</strong> School,<br />
Incheon, Korea<br />
Diab<strong>et</strong>es Unit, NIH, USA*<br />
<strong>Circulation</strong> <strong>2004</strong>;110:3687
Combined Therapy Significantly Reduces<br />
MCP-1 Levels<br />
0<br />
% Change in MCP-1 Levels (%)<br />
-10<br />
-20<br />
P
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