Novel Markers of Arterial Dysfunction

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2 혈관연구회창립심포지움, 3 월 3 일, 2005 Novel Markers of Arterial Dysfunction Kwang Kon Koh, MD, FACC, FAHA Cardiology Gachon Medical School Incheon, Korea

3 Atherosclerosis: A progressive process PHASE I: Initiation PHASE II: Progression PHASE III: Complication Disease progression

4 Nitric Oxide Regulates vasomotor tone Inhibits inflammatory cell attachment Inhibits platelet aggregation and attachment Inhibits release of procoagulant factors Inhibits release of growth factors Koh KK. Cardiovasc Res 2000;47:648 (Review) Koh KK. Cardiovasc Res 2002;55:714 (Review)

5 Baseline 1

7 Reactive Hyperemia

9 Baseline 1 Reactive Hyperemia

10 40 Subjects with a Parental History of Premature Myocardial Infarction N Engl J Med 2000; 343: 840

11 Sensitivity and Specificity of Tests in Predicting CAD Test Sensitivity (95% CI) Specificity (95% CI) Angina Pectoris (n = 112) Exercise ECG testing (n = 112) Myocardial Perfusion Imaging (n = 34) 96/101; 95.1% ( ) 5/21; 23.8% ( ) 75/91; 82.4% ( ) 12/21; 57.1% ( ) 30/30; 100.0% ( ) 0/4; 0.0% (0-60.2) FMD% (n = 122) 72/101; 71.3% ( ) 17/21; 81% ( ) Schroeder et al. Am Heart J 1999;138:731

12 Kaplan-Meier Analysis of Patients w/o CV Events (10 yrs) Schachinger et al. Circulation 2000;101:1899

13 Inflammatory Response to Injury TxA 2 vwf Tissue Factor Adhesion Molecules Chemokines Cytokines Cytokines Growth Factors Metalloproteinases Colony Stimulating Factors Growth Factors Reactive Oxygen Species LDL Oxidation

14 Cytokines LDL ox Ang II LPS CMV NADH / NADPH oxidase Cyclooxygenase Lipoxygenase Xanthine oxidase Mitochondria Activation of Nuclear Transcription Factor, NFkB NO, HDL Antioxidant LDL, Lp(a) Oxygen Free Radicals p50 p65 MCP-1 M-CSF E Selectin ICAM-1 VCAM-1 Tissue factor PAI-1 p65 p50 IkB IkB P Koh KK. Cardiovasc Res 2002;55:714 (Review)

15 PDGF complement thromboxane A 2 metalloproteinases tissue factor PAI-1 oxygen free radicals Adhesion Molecule Expression IL-1 TNF Lymphocyte Activation IL-6 IL-11 Cytokines Initiate Hepatic Synthesis of Some Proteins (Acute Phase Reactants C-reactive protein amyloid A haptoglobin ceruloplasmin C3, C4 fibrinogen vwf PAI-1 Lp(a) + - albumin transferrin A-I, A-II + C3 amyloid A a 1 -acid glycoprotein Koh KK. Cardiovasc Res. 2002;55:714. (Review)

16 Association Between MCP-1 Levels and Prevalence of Subclinical Atherosclerosis In Dallas Heart Study, 3,499 subjects <65 yrs Coronary artery calcium measured by EBCT Deo R, et al. JACC 2004;44:1812

17 CRP, Metabolic Syndrome, and Prediction of CV Events in the Framingham Offspring Study Both CRP and MetS are independent predictors of new CVD events over 7 years Rutter MK, et al. Circulation. 2004;110:380.

18 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 Zouridakis E. Circulation. 2004; 110:1747.

19 Adiponectin, cytokines secreted by adipose cells, Have insulin-sensitizing, anti-inflammatory, And anti-atherogenic properties Adiponectin Adiponectin Receptor AMPK enos reductase PI 3-kinase-dependent Pathways p reductase oxydase L-Arginine oxydase L-Citruline NO NFkB p65 p50 IkB IkB P p50 p65 Han SH, et al. Circulation (Review, submitted)

20 Therapeutic Intervention Cytokines LDL ox Ang II LPS CMV NADH / NADPH oxidase Cyclooxygenase Lipoxygenase Xanthine oxidase Mitochondria Ramipril, ARBs Fenofibrate Oxygen Free Radicals p50 p65 MCP-1 M-CSF E Selectin ICAM-1 VCAM-1 Tissue PAI-1 factor p65 p50 IkB IkB P Fenofibrate HDL, NO Antioxidant TG, LDL

21 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* Diabetes Unit, NIH, USA* ACC 2005, Orlando, USA Diabetes Care 2005 (in press)

22 Effects of Fenofibrate on Inflammation in 46 Hypertriglyceridemic Patients Fibrinogen (mg/dl) 1.0 hscrp (mg/l) P< % P= ( ) 0.70 ( ) Placebo Fenofibrate 0.0 Placebo Fenofibrate

23 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* Diabetes Unit, NIH, USA* ACC 2005, Orlando, USA JACC 2005 (in press)

24 Combined therapy or fenofibrate alone significantly increases Adiponectin levels in patients with combined hyperlipidemia 30 % Change in Adiponectin Levels (%) P<0.05 P<0.05 P=0.022 by ANOVA 0 Atorvastatin Combined Therapy Fenofibrate

25 Combined therapy or fenofibrate alone significantly increases Insulin sensitivity in patients with combined hyperlipidemia 15 % Change in QUICKI (%) 10 5 P<0.05 P=0.049 by ANOVA 0 Atorvastatin Combined Therapy Fenofibrate *QUICKI=Quantitative Insulin-Sensitivity Check Index, a surrogate index of insulin sensitivity, QUICKI = 1/[log(insulin)+log(glucose)]

26 Ramipril Combined with Simvastatin on MCP-1 Levels (pg/ml) (HC) P= P=0.019 P< Baseline 1 Simvastatin +Placebo 0 Baseline 2 Simvastatin +Ramipril Koh KK, et al. Hypertension. 2004;44:180

27 200 Simvastatin Combined with Ramipril on PAI-1 Antigen Levels (ng/ml) (HC) P=0.828 P= P< Baseline 1 Simvastatin +Placebo 0 Baseline 2 Simvastatin +Ramipril Koh KK, et al. Hypertension. 2004;44:180

28 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)

29 Ramipril Combined with Simvastatin on Blood Pressure (mmhg) 150 *** ** Systolic BP 125 ANOVA p= ** *** Diastolic BP ANOVA p= 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.

30 Effects of Simvastatin, Combined Therapy, % Change in Adiponectin Levels (%) and Ramipril on Insulin Sensitivity Adiponectin P<0.05 P<0.05 P=0.013 by ANOVA % Change in QUICKI (%) QUICKI P<0.05 P<0.05 P=0.015 by ANOVA -10 Simvastatin Combined Therapy Ramipril -5 Simvastatin Combined Therapy Ramipril *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

31 Combined Therapy Significantly Improves Flow-mediated Dilator Response 0 Malondialdehyde 100 FMD % Change in MDA Levels (%) P<0.05 P<0.05 Simvastatin Combined Therapy P<0.001 by ANOVA Losartan % Change in Flow-Mediated Dilation (%) P<0.05 P<0.05 Simvastatin Combined Therapy P<0.001 by ANOVA Losartan Koh KK, et al. Circulation. 2004;110:3687

32 ThankQ!

33 Markers of Inflammation and Rapid CAD Progression In 124 Patients with Stable Angina Awaiting PCI Neopterin MMP-9 Waiting Time 4.8 Mo sicam-1 CRP Zouridakis E. Circulation. 2004; 110:1747

34 Fenofibrate Peroxisome Proliferator-Activated Receptors Transcription factors belonging to nuclear receptor superfamily PPARa, PPARb/d, PPARγ Fibrates Synthetic ligands for PPARa PPARa 1. Anti-inflammatory function 2. Reduce oxidative stress 3. Expression of inhibitory protein IkBa Inhibit NF-kB activation

35 Femofibrate increases NO Synthase Expression in BAECs (Western blot) Goya et al, ATVB 2004;24:658

36 Fenofibrate suppresses inflammatory Responses associated with NFkB and IkB in LV of DOCA-salt hypertensive rats

37 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

38 10 Effects of Fenofibrate on Vasomotion in 25 Hypertriglyceridemic Patients FMD (%) NTG (%) 15 P< % Placebo Fenofibrate 0 Placebo Fenofibrate Koh KK et al, Atherosclerosis 2004;174:379

39 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

40 % Change in MDA Levels (%) Effects of Simvastatin, Combined Therapy, and Ramipril on MDA Levels and FMD Malondialdehyde P<0.05 P<0.05 Simvastatin Combined Therapy P<0.001 by ANOVA Ramipril Combined Therapy on Flow-Mediated Dilation in Type II Diabetic Patients % Change in Flow-Mediated Dilation (%) P<0.001 FMD P=0.027 P<0.001 Simvastatin Combined Therapy P<0.001 by ANOVA Ramipril

41 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

42 Combined Therapy Significantly Reduces MCP-1 Levels 0 % Change in MCP-1 Levels (%) P<0.05 P<0.05 P=0.030 by ANOVA -30 Simvastatin Combined Therapy Losartan Koh KK, et al. Circulation 2004;110:3687

Welcome! Mark May 14, Sat!

Welcome! Mark May 14, Sat! Do We Have All Answers with Statins In Treating Patients with Hyperlipidemia? Kwang Kon Koh, MD, PhD, FACC, FAHA Cardiology, Gil Heart Center, Gachon Medical School, Incheon,