Download Atherosclerosis an Inflammatory Heart Disease

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 : 1. Lulus Dokter dari UGM, tahun 1974 2. Lulus Cardiologist dari Univ. Indonesia, tahun 1983 3. Lulus Internist dari Univ. Airlangga, tahun 1986 4. Lulus Doktor, Univ. Airlangga, tahun 1996 5. Advanced Cardiology Course, Univ. Hongkong, tahun 1984 6. Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 7. Fellow American College of Cardiology (FACC), September 2006. 8. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 9. Fellow European Sociaty of Cardiology (FESC), 2008 10. Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : 1. Dosen Pengajar Program Pascasarjana Universitas Brawijaya 2. Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya 3. Ketua PERKI Cabang Malang Raya 4. Anggota Kolegium Kardiovaskuler Indonesia 5. Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya 6. Ketua Dewan Pengawas Rumah Sakit Pendidikan

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INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE

Djanggan Sargowo

Surabaya, 15 April 2012 2

3

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

4

Atherosclerosis Start from very young To Old age ?

5

Atherothrombosis* is a Leading 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 Mortality (%)

20

25

30

* 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

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MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Ischemic stroke Myocardial infarction

Transient ischemic attack

Angina: • Stable • Unstable

Peripheral arterial disease: • • • • Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

Intermittent claudication Rest Pain Gangrene Necrosis

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THEORY AND CONCEPT OF ATHEROSCLEROSIS

Concept

Theory

 Dyslipidemia  Endothelial dysfunction Inflamation  Free radicals  Immunologic (Sargowo, 1996)

Disease

Atherosclerosis /CAD 8

ATHEROGENESIS

LDL Serum  LDL infiltration

Free Radical

LDL Oxidation

Endothelial dysfunction

Foam Cell

Growth Factor

Lipid

Platelet Agregation

Cell Proliferation (Sargowo, 1996)

Calsificasion

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IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Local factors • Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 • Blood flow patterns, vessel diameter, arterial wall structure

Generalized disorders • Obesity • Diabetes

Atherothrombosis manifestations (myocardial infarction, stroke, vascular death)

Genetic • Genetic traits • Gender • Age

Systemic conditions • History of vascular events • Hypertension • Hyperlipidemia • Hypercoagulable states • Homocystinemia

Lifestyle • Smoking • Diet • Lack of exercise

Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6.

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Risk Factors for Atherosclerosis Classic

Uremia Related

Infection

Hypertension, Hyperlipidemia, DM, Smoking

Increase ox-LDL, Free radicals, Uremic toxin

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

11 Arici. 2010

INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Vessel lumen

Monocyte LDL

Endothelium Adhesion molecules (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.

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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.

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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.: a. Fibrinogen b. Homocysteins

b. PAI-1 d. AT-1

e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging

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Acute Coronary Syndrome (endocrine viewpoints) a.atherosclerotic lesions b.vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque

c.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) 16

NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Physiologic coronary artery

Low ESS

• Local factors, e.g. low ESS • Systemic factors, e.g. hyperlipidemia 20%• Genetic factors

Early fibroatheroma 60%

20% Fibroproliferation

Microruptures

Physiologic ESS Limited inflammation

Compensatory expansive remodeling Quiescent plaque

Asymtomatic Chatzizisis et all. JACC. 2007.

High ESS

Contrictive remodeling Stenotic plaque

Stable Angina

Lower ESS Vulnerability

Intense inflammation Exessive expansive remodeling Thin cap fibroatheroma

Acute Coronary Syndrome

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ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Plaque rupture

Monocyte

LDL-C

Adhesion Macrophage molecule

Oxidized LDL-C Foam cell

CRP

Smooth muscle cells Endothelial dysfunction

Inflammation

Oxidation

Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.

Plaque instability and thrombus

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 Adhesion molecules  MCP-1

LDL Lumen

`

Monocyte  Colony stimulating  Tissue factors factors  MCP-1

Endothelial cells Intima

LDL

Mildly oxidized LDL

Extensively oxidized LDL

Monocyte

Cytokies and Growth factors Macrophage foam cell

Macrophage

Media Smooth muscle cell

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Reverse Cholesterol Transport

Monocyte CRP LDL

HDL

Platelets Thrombin

P-selectin

TXA2

CD 40L

PGI2 ICAM-1

MCP-1

HDL

VCAM-1

IL-1

PDGF

E-selectins

CD 40L

T cell

Foam cell

Ox-LDL

Macrophage

MMP

20 Reilly, et.all. 2005

THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules

Cytokines

Plaque Formation

Oxidated LDL

Lp-PLA2 Macrophage Foam Cell INTIMA

Lyso-PC OxFA

MEDIA

21

T

MC

LDL

Cytokines

FC

T

C5a Oxidation

MCP-1

? Lyso-PC

C’ Cytokines

Ox-chol

FC

F

SMC

22

Blood stream Endothelium

LDL

HDL

Mast cell Arterial intima

Figure :

Proposed Dual Action of Exocytosed Mast Cell Granules

Binding of LDL Intracelluler proteolysis and fusion of LDL

Proteolysis of HDL

(The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima

Reduced efflux

Macrophage foam cell

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Resting endothelial cell Resting smooth muscle cell

Procoagulant, antifibrinolytic matrixdegrading, leukocyte binding endothelial cell

IL-1, TNF Collagen Elastin

IL-1 TNF Activated matrix-degrading smooth muscle cell Class II MHC

Collagenase Gelatinases Elastolytic enzimes

Antigen Apoptotic smooth muscle cell

IFN  TNF T-lymphocyte

T-cell antigen receptor

HSCRP

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LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES Oxidative Stress Transcription NF-xB Factors : Pro-inflammatory Genes

GM-CSF

AP-1

VCAM-1

Leucocyte infiltration / activation Gibbons, 97

Endothelial Cell

MPC-1

Plaque Rupture 26

TNFR-1

TNFR-1

IL-1R

Shear stress Ox-LDL T R A D D

T R R I A P D D F A D D

R I P T R A F 2

NIK

T R A F 6

ROIs ??? Lipid peroxides ? H2O2

IKK complex

 

MEKK1?

?

?

Ub

MEKK1?

CKII

Caspases

SEK-1 p65

p38

JNK

p50 pKAc

c-Jun activation

Apoptosis

CBP/p300 p65 p50

Ub

IB

IB

Ubiquitination and proteosome degradation

Target genes :

Gene activation

- IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor

27 Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998

28 Visual Medica. 2009

Prothrombotic factors

MONOCYTE

Inflammatory Mediators: CRP

CRP

FCR Receptor Chemokines: MCO-1

CRP

Atherosclerotic plaque

Cytokines : IL-6, TNF-α MACROPHAGE

FOAM CELL

Oxidized LDL

Stockley. 2006

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POTENTIAL MECHANISM OF CRP CRP

LDL opsonisation

Increased MCP-1 and CAM

Monocyte infiltration

EC activation

Foam cell formation

Inflammatory cell recruitment

Atherosclerosis plaque formation Stevens, R. 2005

Complement activation

EC sensitisation T-cell attack

EC damage

Atherosclerotic plaque rupture 30

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

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PROTEIN REGULATED BY NF-KB Inflammatory Enzyme

Adhesion Molecule

 Inducible nitric oxide

 ICAM-1

synthase  Inducide cylooxigenase-2  5-Lipoxigenase  Cytosolic phospolipase A2

 VCAM-1  E-selectin

Receptor  Interlekin-2 receptor

(alpha chain)  T-cell receptors (beta chain) NEJM, 1997

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BIOMARKERS OF ACTIVITY STUDIED FOR CAD  Cytokines (IL-1β, IL-6, IL-

 Erythrocyte

8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase)  Adhesion molecules (sICAM-1, sVCAM-1, pselectin)  Acute phase reactans (fibrinogen, AAS, CRP)  White blood cells

sedimentation rate  Neopterin  Heat shock proteins  Adiponectin  Lipoprotein associated phospholipase A2  Placental growth factos  Cystatin C

Kaski, JC. 2006.

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Are you hungry or sleepy ????

Sciences 34

Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) ICAM-1 Selectins, HSPs, etc Endothelium and other cells

IL-6 “Mesenger” Cytokine CRP SAA

LIVER

Circulation The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999)

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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

36 (Ridker, 2004)

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 (New England Journal of Medicine)

1.0

2.0

4.0

Relative Risk

6.0

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Inflammation Repair

Unstable plaque

Stable plague 38

Inflammation

Repair

- STATINS - ACEI / AIIRA - CCB

Unstable plaque

Stable plague Weissberg, 1999

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REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION

O2– H2O2 OH

Oxidation

(D. Sargowo)

 NO Activity  G-Protein Function  Protein Kinase C

Endothelial Dysfunction

40

ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES • Vasoconstriction • Platelet Aggregation • SMC Proliferation • Leukocyte Adhesion • LDL Oxidation • Activation of MMPs

(D. Sargowo)

Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling

41

ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture

ACUTE CORONARY SYNDROMES

Thrombosis Matrix Remodeling

(D. Sargowo)

42

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Risk Factors LDL

BP

Diabetes

Smoking AII

Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation  NO • ∆ Local Mediators •  Tissue ACE, AII

Endothelin Catecholamines

Vasoconstriction

PAI-1, Platelet Aggregation, Tissue Factor

VCAM/1CAM Cytokines

Proteolysis Inflammation

Thrombosis

Inflammation

Plaque Rupture

Growth Factors Cytokines Matrix Vascular Lesion and Remodeling

Clinical Sequelae

Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052.

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THERAPEUTICS : WHERE DO WE STAND TODAY ?  Lipid lowering drugs  ACEI / ARB  Peroxisome proliferators-

activated receptor (PPAR)  Chemokine receptor antagonist  TNF Inhibitor  MMP Inhibitor 45

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

(D. Sargowo)

46

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)

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SURREGATE BIOMARKERS FOR ACS  HS CRP

 LDH

 MMP

 CPK

 Stromelysin

 MBCK

 Kalogenase

 Troponin T-I

 Elastase

 Fibrinogen

 INFj, TNF, IL1

 Albuminuri

 Gelatinase D. Sargowo

48

SUMMARY

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

49

50

51

LUMEN

The Role of Lp-PLA2 in CHD Monocytes Adhesion Molecules

Cytokines

Plaque Formation

Oxidated LDL

Lp-PLA2 Macrophage Foam Cell INTIMA

Lyso-PC OxFA

MEDIA

52

Blood stream Endothelium

LDL

HDL

Mast cell Arterial intima

Figure :

Proposed Dual Action of Exocytosed Mast Cell Granules

Binding of LDL Intracelluler proteolysis and fusion of LDL

Proteolysis of HDL

(The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima

Reduced efflux

Macrophage foam cell

53

T

MC

LDL

Cytokines

FC

T

C5a Oxidation

MCP-1

? Lyso-PC

C’ Cytokines

Ox-chol

FC

F

SMC

54

ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT*

Cerebrovascular disease

24.7%

Coronary disease

7.4%

29.9%

3.3% 3.8%

11.8% 19.2% Peripheral arterial disease

* Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268.

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LPS/LBP Oxidized Hemodynamic Cytokines Ang II AGE lipids Matrix forces CD14

Integrin PLASMA Cytokines MEMBRANE receptor Chlamydia and virus

NF-KB

IKK- IKK

SR

TLR

IKK

AT1 RAGE

IKK P

I KB P65 P50 P65

P50

P65

P50

CYTOPLASM

IKK complexes Inhibitors : (Ub)n IKB- I KB IKB- IKB-r Bcl-3 Proteasome

P

NUCLEUS

56

 Adhesion molecules  MCP-1

LDL Lumen

`

Monocyte  Colony stimulating  Tissue factors factors  MCP-1

Endothelial cells Intima

LDL

Mildly oxidized LDL

Extensively oxidized LDL

Monocyte

Cytokies and Growth factors Macrophage foam cell

Macrophage

Media Smooth muscle cell

57

The Role of T-Lymphocyte in Atherogenesis

58 Libby, P. 2002

TNFR-1

TNFR-1

IL-1R

Shear stress Ox-LDL T R A D D

T R R I A P D D F A D D

R I P T R A F 2

NIK

T R A F 6

ROIs ??? Lipid peroxides ? H2O2

IKK complex

 

MEKK1?

?

?

Ub

MEKK1?

CKII

Caspases

SEK-1 p65

p38

JNK

p50 pKAc

c-Jun activation

Apoptosis

CBP/p300 p65 p50

Ub

IB

IB

Ubiquitination and proteosome degradation

Target genes :

Gene activation

- IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor

59

Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998

Leucocyte Activation in Atherogenesis : Implications for Acute Ischemic Syndromes Oxidative Stress Transcription NF-xB Factors : Pro-inflammatory Genes

GM-CSF

AP-1

VCAM-1

Leucocyte infiltration / activation Gibbons, 97

Endothelial Cell

MPC-1

Plaque Rupture 60

Protein Regulated by NF-kB Proinflammatory Cytokine • • • • •

TNF-α IL-1 β IL-2 IL-6 Granulocyte-macrophage colony stimulating factor • Macrophage colony stimulating factor • Granulocyte colony stimulating factor

Chemokine • IL-8 • Macrophage inflammatory protein 1 alpha • MCP-1

• Gro α, β dan γ

61 NEJM, 1997

Thank You

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