Transcript 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
6
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
7
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
9
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.
10
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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13
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.
14
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
15
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
19
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
23
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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25
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
29
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
31
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
32
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.
33
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)
35
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
37
Inflammation
Repair
Unstable plaque
Stable plague
38
Inflammation
Repair
- STATINS
- ACEI / AIIRA
- CCB
Unstable plaque
Stable plague
Weissberg, 1999
39
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
43
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.
44
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)
47
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.
55
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
62