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Nama : Prof. Dr. H. Djanggan Sargowo , dr., SpPD . , SpJP (K),

Curriculum Vitae. Nama : Prof. Dr. H. Djanggan Sargowo , dr., SpPD . , SpJP (K), FIHA, FACC , FESC, FCAPC, FASCC Tempat / Tgl lahir : Sragen , 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp . 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974

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Nama : Prof. Dr. H. Djanggan Sargowo , dr., SpPD . , SpJP (K),

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  1. Curriculum Vitae • Nama : Prof. Dr. H. DjangganSargowo, dr., SpPD.,SpJP(K), • FIHA, FACC, FESC,FCAPC, FASCC • Tempat/Tgllahir :Sragen, 21 September 1947 • Alamat :Wilis Indah E-10 Malang, Telp. 0341-552395 • Pendidikan : • Lulus Dokterdari UGM, tahun 1974 • Lulus Cardiologist dari Univ. Indonesia, tahun 1983 • Lulus Internist dari Univ. Airlangga, tahun 1986 • Lulus Doktor, Univ. Airlangga, tahun 1996 • Advanced Cardiology Course, Univ. Hongkong, tahun 1984 • Senior Visiting Program, InstitutJantung Negara, Kualalumpur, 1996 • Fellow American College of Cardiology (FACC), September 2006. • Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 • Fellow European Sociaty of Cardiology (FESC), 2008 • Fellow Asean Collage of Cardiology (FASCC), 2008 • Jabatan : • DosenPengajar Program PascasarjanaUniversitasBrawijaya • Ketua MKEK IkatanDokter Indonesia Cabang Malang Raya • Ketua PERKI Cabang Malang Raya • AnggotaKolegiumKardiovaskuler Indonesia • DekanFak. Kedokteran Univ. Wijaya Kusuma Surabaya • Ketua Dewan Pengawas Rumah Sakit Pendidikan • Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya

  2. INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE Djanggan Sargowo Surabaya, 15 April 2012

  3. RUDOLF VIRCHOW mid 19th century Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis Lamond, B. The American Journal of Pathology. 2008

  4. Atherosclerosis Start from very young To Old age ?

  5. Atherothrombosis* is aLeading Cause of Death Worldwide1† 5.1 AIDS Pulmonary disease 6 Injuries 9.1 Cancer 12.6 Infectious disease 17.8 Atherothrombosis* 28.7 0 5 10 15 20 25 30 Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) The World Health Report, 2002, WHO Geneva, 2002

  6. MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Ischemic stroke Transient ischemic attack Myocardial infarction • Angina: • Stable • Unstable • Peripheral arterial • disease: • Intermittent claudication • Rest Pain • Gangrene • Necrosis Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

  7. THEORY AND CONCEPT OF ATHEROSCLEROSIS Theory Disease Concept Dyslipidemia Endothelial dysfunction Free radicals Immunologic Atherosclerosis/CAD Inflamation (Sargowo, 1996)

  8. ATHEROGENESIS LDL Serum  LDL infiltration Endothelial dysfunction LDL Oxidation Growth Factor Foam Cell Lipid Platelet Agregation Cell Proliferation Calsificasion Free Radical (Sargowo, 1996)

  9. IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS • Local factors • Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 • Blood flow patterns, vessel diameter, arterial wall structure • Systemic • conditions • History of vascular events • Hypertension • Hyperlipidemia • Hypercoagulable states • Homocystinemia Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) • Generalized • disorders • Obesity • Diabetes • Genetic • Genetic traits • Gender • Age • Lifestyle • Smoking • Diet • Lack of exercise Yusuf S etal. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6.

  10. Risk Factors for Atherosclerosis Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Classic Hypertension, Hyper-lipidemia, DM, Smoking Endothelial dysfunction Proinflammatory cytokine release Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS Arici. 2010

  11. INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Vessel lumen Monocyte LDL Endothelium Adhesionmolecules (VCAM-1, ICAM-1) LDL Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Ox-LDL Foam cell Intima Macrophage CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126.

  12. Atherosclerosis is afibroproliferativeand inflammatoryprocess occurring ins response to a variety ofvascular insults The insults come fromclassical risk factors( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) andnovel risk factors(Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunctionis regarded as the first abnormality leading to atherosclerosis This implies thatmodulation ofendothelial function may be used as strategy to intervene the process.

  13. Two theories gain more acceptance: (a) the lipid theory (b) inflammation theoryEndothelial dysfunctionis now regarded as thefirst abnormalityleading to AS. More novel cardiovascular risk factors are known, e.g.: • Fibrinogen b. PAI-1 • Homocysteins d. AT-1 • e. CRP f. Lp(a) • g. small-dense LDL h. infectious agents • i. and more are emerging

  14. Acute Coronary Syndrome (endocrine viewpoints) • atherosclerotic lesions • vascular funtions • b.1. inflammatory reaction • b.2. thrombogeneity • b.3. vasoreactivity • b.4. plaque stability • b.5. shoulder of plaque • endothelium balance between • c.1. vasodilating, antithrombotic, antiproliferative factors • (NO, prostacyclin, C-natriuretic peptide, EDHF) • c.2. vasoconstricting, prothrombotic, proliferative factors • (ET, superoxide, thromoboxan A2)

  15. NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Lower ESS Vulnerability Intense inflammation Low ESS 20% 60% 20% High ESS Physiologic coronary artery • Local factors, e.g. low ESS • Systemic factors, e.g. hyperlipidemia • Genetic factors Early fibroatheroma Fibroproliferation Microruptures Physiologic ESS Limited inflammation Exessive expansive remodeling Thin cap fibroatheroma Contrictive remodeling Stenotic plaque Compensatory expansive remodeling Quiescent plaque Erosion Asymtomatic Acute Coronary Syndrome Stable Angina Chatzizisis et all. JACC. 2007.

  16. ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Plaque rupture Adhesion molecule Macrophage OxidizedLDL-C Monocyte LDL-C Foam cell CRP Smooth muscle cells Endothelial dysfunction Oxidation Plaque instability and thrombus Inflammation Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.

  17. ` Monocyte  Adhesion molecules  Colony stimulating factors LDL  Tissue factors  MCP-1 Lumen  MCP-1 Endothelial cells LDL Mildly oxidized LDL Intima Extensively oxidized LDL Monocyte Cytokies and Growth factors Macrophage Macrophage foam cell Media Smooth muscle cell

  18. Reverse Cholesterol Transport Monocyte CRP LDL Platelets HDL P-selectin Thrombin TXA2 CD 40L PGI2 PDGF ICAM-1 VCAM-1 E-selectins T cell IL-1 MCP-1 CD 40L Foam cell HDL Ox-LDL MMP Macrophage Reilly, et.all. 2005

  19. THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Plaque Formation Cytokines Adhesion Molecules Oxidated LDL Lp-PLA2 Macrophage Foam Cell INTIMA Lyso-PC OxFA MEDIA

  20. T MC LDL Cytokines FC T C5a MCP-1 ? Oxidation C’ Lyso-PC Cytokines Ox-chol F FC SMC

  21. LDL HDL Blood stream Endothelium Mast cell Arterial intima Binding of LDL Proteolysis of HDL Reduced efflux Macrophage foam cell Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima Intracelluler proteolysis and fusion of LDL

  22. Procoagulant, antifibrinolytic matrix- degrading, leukocyte binding endothelial cell Resting endothelial cell Resting smooth muscle cell IL-1, TNF Collagen Elastin IL-1 TNF Activated matrix-degrading smooth muscle cell Collagenase Gelatinases Elastolytic enzimes Class II MHC Antigen Apoptotic smooth muscle cell IFN  TNF T-cell antigen receptor T-lymphocyte HSCRP

  23. LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES Oxidative Stress Transcription Factors : NF-xB AP-1 Endothelial Cell Pro-inflammatory Genes GM-CSF VCAM-1 MPC-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97

  24. TNFR-1 IL-1R MEKK1? SEK-1 JNK TNFR-1 Shear stress Ox-LDL T R A D D R I P R I P T R A D D T R A F 6 T R A F 2 ROIs ??? Lipid peroxides ? H2O2 F A D D NIK IKK complex  ? ? Ub MEKK1?  CKII Caspases p65 IB IB Ub p50 pKAc Ubiquitination and proteosome degradation p38 c-Jun activation Apoptosis • Target genes : • - IL-1, IL-8, IL-6, IFN  • - TNF, MCP-1 • - CSFs, c-myc • - VCAM-1, ICAM-1, E-selectin • - Tissue factor • - Survival factor CBP/p300 Gene activation p65 p50 Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998

  25. Visual Medica. 2009

  26. Prothrombotic factors MONOCYTE Inflammatory Mediators: CRP CRP FCR Receptor Chemokines: MCO-1 Atherosclerotic plaque CRP Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL Stockley. 2006

  27. POTENTIAL MECHANISM OF CRP CRP EC sensitisation Increased MCP-1 and CAM LDL opsonisation Complement activation T-cell attack Monocyte infiltration EC activation Foam cell formation Inflammatory cell recruitment EC damage Atherosclerotic plaque rupture Atherosclerosis plaque formation Stevens, R. 2005

  28. NF-KB ACTIVATION INFLAMMATORY DISEASE • Rheumatoid arthritis • Atherosclerosis • Multiple sclerosis • Asthma • Inflammatory bowel disease • Helicobacter pylori-associated gastritis • Systemic inflammatory response syndrome The Journal of Clinical Investigation, 2001

  29. PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Receptor • Interlekin-2 receptor (alpha chain) • T-cell receptors (beta chain) • Inducible nitric oxide synthase • Inducide cylooxigenase-2 • 5-Lipoxigenase • Cytosolic phospolipase A2 • ICAM-1 • VCAM-1 • E-selectin NEJM, 1997

  30. BIOMARKERS OF ACTIVITY STUDIED FOR CAD • Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) • Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) • Acute phase reactans (fibrinogen, AAS, CRP) • White blood cells • Erythrocyte sedimentation rate • Neopterin • Heat shock proteins • Adiponectin • Lipoprotein associated phospholipase A2 • Placental growth factos • Cystatin C Kaski, JC. 2006.

  31. Are you hungry or sleepy ???? Sciences

  32. Pro-Inflammatory Risk Factors ICAM-1 Selectins, HSPs, etc Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA LIVER Endothelium and other cells Circulation The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999)

  33. MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP induced production of cell adhesion moleculas MCP-1, ET-1 CRP attenuates NO production and decreases eNOS expression CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP based blunting of endothelial vasoreactivity CRP triggered oxidation of LDL cholesterol CRP mediated LDL uptake by macrophages (Ridker, 2004)

  34. ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine)

  35. Inflammation Repair Stable plague Unstable plaque

  36. - STATINS - ACEI / AIIRA - CCB Stable plague Unstable plaque Inflammation Repair Weissberg, 1999

  37. REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2–  NO Activity  G-Protein Function  Protein Kinase C H2O2 OH Oxidation Endothelial Dysfunction (D. Sargowo)

  38. ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Endothelial Dysfunction • Vasoconstriction • Platelet Aggregation • SMC Proliferation • Leukocyte Adhesion • LDL Oxidation • Activation of MMPs Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo)

  39. ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo)

  40. Risk Factors Smoking AII LDL BP Diabetes Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Growth FactorsCytokinesMatrix EndothelinCatecholamines VCAM/1CAMCytokines Proteolysis Inflammation Vascular Lesion and Remodeling Vasoconstriction Thrombosis Inflammation Plaque Rupture Clinical Sequelae Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052.

  41. THERAPEUTICS : WHERE DO WE STAND TODAY ? • Lipid lowering drugs • ACEI / ARB • Peroxisome proliferators-activated receptor (PPAR) • Chemokine receptor antagonist • TNF Inhibitor • MMP Inhibitor

  42. BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - vWF - Thrombomodulin - Thrombomodulin - E-Selection - E-Selection - ICAM-1 - VCAM-1 - NO - NO - Microalbuminuria - Microalbuminuria - PAI-1 - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - LP – PLA2 - Lyso-PC OxFA - Lyso-PC OxFA (D. Sargowo)

  43. INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003)

  44. SURREGATE BIOMARKERS FOR ACS • HS CRP • MMP • Stromelysin • Kalogenase • Elastase • INFj, TNF, IL1 • Gelatinase • LDH • CPK • MBCK • Troponin T-I • Fibrinogen • Albuminuri D. Sargowo

  45. Rudolf Virchow SUMMARY mid 19th century Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis Lamond, B. The American Journal of Pathology. 2008

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