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1 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
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, Institut Jantung 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 :
Dosen Pengajar Program Pascasarjana Universitas Brawijaya
Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya
Ketua PERKI Cabang Malang Raya
Anggota Kolegium Kardiovaskuler Indonesia
Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya
Ketua Dewan Pengawas Rumah Sakit Pendidikan
Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS :
FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis
Start from very young
To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS 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) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina:
Stable
Unstable Ischemic
stroke Myocardial infarction Peripheral arterial
disease:
Intermittent claudication
Rest Pain
Gangrene
Necrosis 8 Dyslipidemia
Endothelial dysfunction
Free radicals
Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle
Smoking
Diet
Lack of exercise Genetic
Genetic traits
Gender
Age Generalized
disorders
Obesity
Diabetes Systemic
conditions
History of vascular events
Hypertension
Hyperlipidemia
Hypercoagulable states
Homocystinemia Local factors
Elevated prothrombotic factors: fibrinogen, CRP, PAI-1
Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations
(myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic
Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related
Increase ox-LDL, Free radicals, Uremic toxin Infection
Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones
Acute phase response Elevated CRP
Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL 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.
Vessel lumen Monocyte Macrophage Adhesionmolecules
(VCAM-1, ICAM-1) Inflammatory mediators
(CRP, CD40/CD40L,
TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults
The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc)
Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis
This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading 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 16 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) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS
Systemic factors, e.g. hyperlipidemia
Genetic factors Physiologic ESS
Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability
and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion
Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC
OxFA Cytokines Plaque
Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler
proteolysis
and fusion
of LDL Figure :
Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription
Factors : Endothelial
Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS :
IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun
activation Caspases Apoptosis NIK ? ? MEKK1? CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene
activation p65 p50 IB pKAc IB Ub 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 Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ???
Lipid peroxides ?
H2O2 Ubiquitination and
proteosome degradation T
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6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines:
MCO-1 Atherosclerotic
plaque MONOCYTE Inflammatory
Mediators:
CRP Prothrombotic
factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell
attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis
Atherosclerosis
Multiple sclerosis
Asthma
Inflammatory bowel disease
Helicobacter pylori-associated gastritis
Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase
Inducide cylooxigenase-2
5-Lipoxigenase
Cytosolic phospolipase A2
ICAM-1
VCAM-1
E-selectin
Receptor Interlekin-2 receptor (alpha chain)
T-cell receptors (beta chain)
NEJM, 1997 33 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. 34 Are you hungry
or
sleepy ????
Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM,
intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk
Factors Primary Pro-Inflammatory Cytokines
(eg. IL-1, TNF-) IL-6
“Mesenger” Cytokine CRP
SAA Endothelium
and other cells LIVER Circulation 36 (Ridker, 2004) 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 dependent monocyte
recruitment into arterial wall CRP induced production of
tissue factor in monocytes CRP based blunting of
endothelial vasoreactivity CRP mediated LDL uptake
by macrophages CRP triggered oxidation
of LDL cholesterol CRP induced PAI-1 expression
stabilizes PAI-1 mRNA CRP attenuates NO production
and decreases eNOS expression CRP induced production of
cell adhesion moleculas MCP-1, ET-1 37 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) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL
DYSFUNCTION & ACTIVATION O2– OH H2O2 NO Activity
G-Protein Function
Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND
ACUTE CORONARY SYNDROMES Vasoconstriction
Platelet Aggregation
SMC Proliferation
Leukocyte Adhesion
LDL Oxidation
Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND
ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE
CORONARY
SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL NO • ∆ Local Mediators • Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs
ACEI / ARB
Peroxisome proliferators-activated receptor (PPAR)
Chemokine receptor antagonist
TNF Inhibitor
MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR
ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR
ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 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) 48 SURREGATE BIOMARKERS FOR ACS HS CRP
MMP
Stromelysin
Kalogenase
Elastase
INFj, TNF, IL1
Gelatinase LDH
CPK
MBCK
Troponin T-I
Fibrinogen
Albuminuri
D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion
Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC
OxFA Cytokines Plaque
Formation Foam Cell Macrophage 53 Intracelluler
proteolysis
and fusion
of LDL Figure :
Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary
disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA
MEMBRANE Chlamydia and virus Proteasome IKK
complexes Inhibitors :
IKB-
IKB-
IKB-r
Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57 58 The Role of T-Lymphocyte in Atherogenesis Libby, P. 2002 59 p38 c-Jun
activation Caspases Apoptosis NIK ? ? MEKK1? CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene
activation IB Ub 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 Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ???
Lipid peroxides ?
H2O2 Ubiquitination and
proteosome degradation 60 GM-CSF VCAM-1 MPC-1 Transcription
Factors : Endothelial
Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 Leucocyte Activation in Atherogenesis :
Implications for Acute Ischemic Syndromes 61 Protein Regulated by NF-kB Proinflammatory Cytokine Chemokine TNF-α
IL-1 β
IL-2
IL-6
Granulocyte-macrophage colony stimulating factor
Macrophage colony stimulating factor
Granulocyte colony stimulating factor IL-8
Macrophage inflammatory protein 1 alpha
MCP-1
Gro α, β dan γ
NEJM, 1997
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