novel markers of arterial dysfunction
TRANSCRIPT
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)
Koh KK. Cardiovasc Res 2002;55:714 (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
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
Koh KK. Cardiovasc Res 2002;55:714 (Review)
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
Kwang Kon Koh, Seung Hwan Han
Eak Kyun Shin, ……. Michael J. Quon*
ACC 2005, Orlando, USA
JACC 2005 (in press)
Diabetes Unit, NIH, USA*
% 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
Kwang Kon Koh, Seung Hwan Han
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
Simvastatin CombinedTherapy
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
Simvastatin CombinedTherapy
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
Simvastatin CombinedTherapy
Losartan
P<0.05 P<0.05
P<0.001by ANOVA
Malondialdehyde FMD
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
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
Simvastatin CombinedTherapy
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
Simvastatin CombinedTherapy
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
Kwang Kon Koh, Seung Hwan Han
Eak Kyun Shin, .. Michael J. Quon*
Cardiology, Gachon Medical School,
Incheon, Korea
Diabetes Unit, NIH, USA*
Circulation 2004;110:3687