Seminar :”The Multiple Role of Antioxidant in The

Improvement of Life Quality
The role of OXIDATIVE STRESS
in CARDIOVASCULAR DISEASE
EPIDEMIOLOGY OF CAD
 MORTALITY RATE ROSE BY 36 % IN
MEN AND 23 % IN WOMEN.
 IN INDONESIA, MORTALITY RATE
ROSE BY 8,1 % (16,4 % IN 1992 TO
24,5 % IN 1995)
 DATA FROM USA SUGGESTS THAT
REDUCTION IN CAD MORTALITY (14
%), MAY HAVE RESULTED FROM NEW
THROMBOLYTIC THERAPIES AND
LIPID- LOWERING DRUGS.
Atherosclerosis
 Atherosclerosis is an inflammatory
disease of vascular wall initiated and
amplified by vascular oxidative stress
 Atherosclerosis is low grade chronic
inflamatory disease
Am J Cardiology 2001;87(suppl):25c-32c
ATHEROSCLEROSIS COMPRISES
THREE ESSENTIAL COMPONENTS
1. ATHEROSIS – THE ACCUMULATION OF
CHOLESTEROL- RICH “GRUEL” –
ATHEROMA.
2. SCLEROSIS –THE EXPANSION OF
FIBROUS TISSUE.
3. INFLAMMATION – WHICH INVOLVES
MONOCYTES/ MAKROPHAGES, T -
LIMFOCYTES AND MAST CELLS
Newby (1997): Medicine international, 40,11:31-34
Risk Factors for Atherothrombosis
Risk Factors for Atherothrombosis
Atherosclerosis Atherosclerosis
Atherothrombotic Atherothrombotic Manifestations Manifestations
(MI, (MI, Ischemic Ischemic Stroke, Vascular Death) Stroke, Vascular Death)
Age Age
Obesity Obesity
Diabetes Diabetes
Hyperlipidemia Hyperlipidemia Hypercoagulable Hypercoagulable states states
Hypertension Hypertension
Genetics Genetics
Infection? Infection?
Homocysteinemia Homocysteinemia
Life-style (e.g., Life-style (e.g.,
smoking, diet, smoking, diet,
lack of exercise) lack of exercise)
Gender Gender
9
American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21( American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21(suppl suppl 2): 2):
II -4–II -6; II -4–II -6; Laurila Laurila et al. et al. Arterioscler Thromb Vasc Biol Arterioscler Thromb Vasc Biol 1997; 17: 2910-2913; 1997; 17: 2910-2913; Grau Grau et al. Stroke 1997;28:1724-1729; et al. Stroke 1997;28:1724-1729;
Graham et al. JAMA 1997;277: 1775-1781; Graham et al. JAMA 1997;277: 1775-1781; Brigden Brigden.. Postgrad Postgrad Med 1997;101(5):249-262. Med 1997;101(5):249-262.
Risk factors:
diabetes
hypertension
Vascular
dysfunction
Tissue injury
(MI, stroke)
Pathological
remodeling
Endothelial
Dysfunction
Target Organ
Damage
Mild
Severe

The Cardiovascular Continuum:
Targeting Mechanisms and Mediators

Adapted 2003 from Dzau V, Braunwald E. Am Heart J. 1991; Gibbons 1999.
Vascular disease
Target organ dysfunction
(HF, renal)
THE ROLES OF OXIDATIVE STRESS
(ROS)
(Pepine 1998)
Thrombosis Inflammation Vasoconstriction
Vascular lesion
and remodelling
Plaque rupture
| LDL | BP Diabetes Smoking
Oxidative stress
Endothelial dysfunction
+ NO - | Local mediators - | Tissue ACE-Alt
PAI-1
VCAM-1
ICAM-1
CYTOKINE
Growth
factors
matrix
Endothelial Proteolysis
Risk Factors
Clinical Sequelae
Proatherogenic mechanisms
Ross R. NEJM 1999;340:115-126
Vascular
inflammation
Progression and clinical complications of atherosclerosis
Risk Factors
Vascular ROS production
Endothelial dysfunction
(Reduced NO availability)
LDL
oxidation
Pro-inflammatory
gene expression(eg.
VCAM-1 and MCP-1,Il-6)
(Landmesser & Drexler,
2003)
The inflammatory cascade.
Pro-Inflamatory Risk
Factors
Primary Pro-Inflammatory Cytokines
(eg.IL-1,TNF-o)
ICAM-1
Selectin, HSPs,etc
Endothelium
and other cells
IL-6
“Messenger” Cytokine
CRP
SAA
Liver
Circulation
Libby, Ridker. Circulation 1999;100:1148-1150
Hypertension
Hyperglycemia/Diabetes
Hypercholesterolemia
Oscillatory Shear Stress

Il-6
Ang II
ICAM-1
VCAM-1

Mo

LDL
Endothelia
l
Cells

Mo

Lox
Nox
Nox

Foam
cells
Migration
Proliferation
Ox-LDL
MCP-1
O
2
0-

Smooth Muscle Cells
Fibroblasts
O
2
0-

Risk factor, oxidative stress, and early
atherosclerosis
Weiss D, Sorescu D, Taylor WR. Am J Cardiol 2001;87(suppl):25C-32C

Mo

Faktor Resiko : Merokok, Hipertensi, DM, dan lain-lain


|VCAM-1
|hs - CRP
| hs- IL-6
Monocyt Infiltration|
LDL
INFILTRATION |
Mo |
ROS
MM LDL|
ox - LDL |
Growth Factor
Proliferation and migration
of fibroblast and muscle cell
Foam Cell
Advanced Lesion
(Rupture and Hemorrhage)
Acute Myocardial Infarction
Fibrinogen|
TNFo
ENDOTHELIAL DYSFUNCTION
RISK FACTORS : HYPERTENSION, SMOKING, DM, HYPERLIPIDEMI
Hs – CRP,
IL - 6
Oxidative Stress
HDL LDL Triglycerides
Oxidized LDL

Macrophage
Figure : Atherosclerotic Processes
(1) Oxidation of LDL depend on HDL/triglycerides
level; and (2) scavenging ox-LDL depend on
opsonizing by hs-CRP.
Pro- Atherogenic Effects of
0x- LDL
 Chemotactic to Monocytes, smooth muscle
cells and T lymphocytes
 Induced T –cell activation and monocyte
differentiation
 Inhibits macrophage motility, potentially
trapping macrophage
 Cytototoxic to cells
 Inhibits Endothelium –Dependent
Relaxation Factor

(Brown 1996)
Pro- Atherogenic Effects of
0x- LDL
 Induces the expression of adhesion
molecules on the endothelium
 Induces Interleukin synthesis and
secretion by mcrophage
 Increases tonus of vasomotor
 Increases hypercoagulation

(Brown 1996)
Protective effects of
HDL
 HDL is a reverse Cholesterol Transport
 HDL decreased LDL oxidation
 Decreased expression of VCAM-1 and MCP-1
 Prevent the plaques stability and plaques
rupture
 Prevent the endothelial cell integrity
 Anti inflammation

(Miller 1986, Tjokroprawiro A, 2001)
EFFECTS OF DIABETES MELLITUS
ON CAD
(Giugliano 1996)
Hyperglycemia
Polyol
pathway
Protein
glycation

Oxidative
stress

O
2
-
/ NO
• NO – dependent
vasodilatation
• Ca
2+

• VSMC
proliferation
Heparan
sulphate
Glucose
autoxidation
Antioxidant
defence
Oxidative
factors
LDL
oxidation
Vasculopathy Ratinopathy Neuropathty Nephropathy
• Hemorheologic
alterations
• Coagulation
activation
• Hypoxia
• NCV

• Endoneural
blood flow
Steady
Laminar
Blood Flow
Flow
Reversal
Effect of shear stress on endothelial cell ( Traub 1997
Antimigration
Antithrombotic
Promigration Prothrombotic
Pro-apoptosis
Pro-suvival
Low-mean shear
Shear Stress
Progrowth
Antigrowth
Ang II
PDGF
Endothelin I
Atherosclerotic Lesion
MCP-I
VCAM-I
NO
PGL
2
t-PA
Trombomodulin
Endothelium
Endothelium
Smooth muscle
Smooth muscle
NO
A primary effect of nicotine is to stimulate
the autonomic nervous system
Physiological and
PHYSIOLOGICAL & BIOCHEMICAL
CHANGES
| heart rate
| cardiac output
| blood pressure
| peripheral resistance

| fibrinogen levels


| platelet turnover

| platelet reactivity

| adipose tissue lipolysis
÷ | plasma FFA
÷ | myocardial oxygen consumption
HDL cholesterol
| LDL cholesterol

Clinical significance

CLINICAL SIGNIFICANCE


altered hemodynamics


fibrinogen is an independent risk factor
for stroke and coronary mortality

promotes thrombosis and atherosclerosis ?

alterations in coronary artery tone ?


ischemic injury ?


reduction in an independent negative risk
factor for CHD
increase in an independent positive risk
factor for CHD
|
|
.
|
|
.
Adelphi Communications ,1987
|
|
22
Endothelial dysfunction:
Pathogenesis of Atherosclerosis (I)
Monocyte
adhesion
Endothelial
adhesion
Monocyte
migration
Endothelial
permeability
Monocyte transmigration Vessel wall
Ross R, N Engl J Med 340 (1999) & Lusis AJ, Nature 407 (2000)
Monocy
te
Lipid-Cluster
0.5 µm
Endothelial
barrier
Monocy
te
Subintima
10.078
x
Formation of an Advanced, Complicated lesion :
Falk et al, Circulation 92 (1995),Epstein, NEJM 14(1999)
Fibrous cap
formation
Macrophage
accumulation
Formation of
necrotic core
Pathogenesis of Atherosclerosis (III)
Vessel wall Coronary plaque with lipid core
STATINS STABILIZE VULNERABLE PLAQUE
Statin treated
ACE
ENDOTHELIAL CELL
ACE
SMOOTH MUSCLE CELL
INFLAMMATORY CELLS
Mast Cell (Chymase)
Macrophage (ACE)
Neutrophil
Tissue AII
VASOCONSTRICTION
INFLAMMATION
PLAQUE
INSTABILITY
THROMBOSIS
VASCULAR
REMODELING
• Endothelin • MCP-1
• VCAM
• Cytokines (IL-6)
• Metalloproteinase
• PAI-1
• Platelet
aggregation
• PDGF, FGF,
IGF, TGF-|
• Proliferation
• Migration
• Extracellular
matrix modulation
ROLES OF MOLECULE IN ATHEROSCLEROSIS
(Dzau et al, 2001)
Angiotensin II-stimulated Release of
Interleukine 6 (IL-6) in Plaques
Role of cytokines in atherosclerosis:
adapt. from Schieffer et al., Hypertension 35 (2000)
1.0
0.5
1.5
10
-9
10
-8
10
-7
Stimulation of cultured smooth muscle
cells for 6 h
0
Angiotensin II (mM)
Control
I
n
t
e
r
l
e
u
k
i
n
e
-
6

P
r
o
t
e
i
n


(
n
g
/
m
l
)

Immunostaining of IL-6 (brown) in a human
coronary artery plaque
Foam-cell
Role of Macrophages and Angiotensin II:
Dysregulation of Extracellular Matrix
Synthesis in Vulnerable Plaques
fibrous
cap
Adapt. from Libby P, Circulation 91 (1995)
Matrix synthesis Matrix degradation
smooth
muscle cells
Collagen
Elastin
endothelial
cells
T-lymphocyte
Metallo-
proteinases
ACE
Peptides,
amino acids
TNF-o
M-CSF
MCP-1 etc.
INF-¸
TGF-ß
Ang II, IL-6
Plaque
INF-¸ = Interferon-¸
Amino
acids
INF-¸
©
©
©
©
Nomenclature and main
histology
Sequences in progression
Main growth
mechanism
Earliest
onset
Clinical
correlation
Type I (initial) lesion isolated
macrophage foam cells
Type II (fatty streak) lesion
mainly intracellular lipid
accumulation
From
first
decade
Type III (intermediate) lesion
Type II changes & small
extracellular lipid pools
Clinically
silent
Type IV (atheroma) lesion
Type II changes & core of
extracellular lipid
Growth
mainly
by
lipid
accumu-
lation
From
third
decade
Type V (fibroatheroma)
lesion lipid core & fibrotic
layer, or multiple lipid cores &
fibrotic layers, or mainly
calcific, or mainly fibrotic
Accelerated
smooth
muscle
and
collagen
increase
Type VI (complicated) lesion
surface defect, hematoma-
hemorrhage, thrombus
Trombosis,
hematoma
From
fourth
decade
Clinically
silent
or
overt
III
II
I
IV
V
VI
PROGRESSION OF ATHEROSCLEROSIS ( Stary 2000)
Rupture of shoulder region with occlusive thrombosis:
from Burke et al., N Engl J Med 336 (1997)
x120 x30
ruptured cap
lipid core
human coronary artery, postmortem
Ruptured Plaque in Coronary Artery
Disease
Characteristics a Vulnerable
Plaques
 Usually < 70 % stenosis
 Eccentric shape with irregular borders
 Large , lipid-rich core,high in cholesterol esters
 Thin fibrous cap
High in macrophages
Low in smooth muscle cells and
collagen
 Presence of inflammation
 Tissue fatigue of the fibrous cap
( Doering , 1919 )
External triggering event :
Circadian variation
( morning )
Seasonal variation ( winter )
Physical exertion
Emotional stress
Internal triggering event :
+ Cap tension
+ Cap Compression
+ Cap flexion
+ Coagulability
+ Vasoconstriction
THROMBOSIS
Intermittent Occlusion
or Occlusion < 1 hour
Persistent
Occlusion
Unstablbe angina
Non-Q-Wave MI
Q-Wave MI
SCD
Role of triggering events in acute coronary events .
Vulnerable atherosclerotic plaque
( Doering , 1919 )
SCD = Sudden cardiac death
THE ROLES OF OXIDATIVE STRESS


EPIDEMIOLOGY
PATHOBIOLOGY
CLINICAL MANIFESTATION
TREATMENT
PROGNOSIS/EVALUATION
CONCLUSSION
 Morbidity and mortality rate of atherosclerosis
were increased
 Atherosclerosis is low grade chronic inflamatory
disease
 Atherosclerosis is an inflammatory disease of
vascular wall initiated and amplified by vascular
oxidative stress
 Hs – CRP level and hs – IL – 6 level were
correlated with prognosis of atherosclerosis
 Immunoregulatory treatments were the ideal
treatment of atherosclerosis

THANK YOU FOR
YOUR ATTENTION






Oxidative damage
potential
by free radicals
Defence capacity
by antioxidants
Internal Antioxidants
Enzymatics
- Superoxide Dismutase
- Glutathione Peroxydase
- Catalyse
Metal binding Proteins
- Albumin, Ferritins,
Ceruloplasmin
External Antioxidants
Non-Enzymatics
- Water-soluble : vitamin C, Thiols
- Lipid-soluble : vitamin E, b-caroten
Co-Q10 , flavonoids
Radicals
Superoxide
.
O2
-
Hydroxyl
.
OH
Peroxyl ROO
.
Alkoxyl RO
.
Hydroperoxyl HO2
.
Thiyl radical RS
.
Non-radicals
Hydrogen peroxide H2O2
Singlet oxygen
1
O2
Ozone O3
Peroxynitrite ONOO
-
Nitric oxide NO
.
Hypochlor acid HOCl
OXIDATIVE STRESS
Faisal Baraas : Buku REHABILITASI JANTUNG, 2003-2004
20

EPIDEMIOLOGY OF CAD
 

MORTALITY RATE ROSE BY 36 % IN MEN AND 23 % IN WOMEN. IN INDONESIA, MORTALITY RATE ROSE BY 8,1 % (16,4 % IN 1992 TO 24,5 % IN 1995) DATA FROM USA SUGGESTS THAT REDUCTION IN CAD MORTALITY (14 %), MAY HAVE RESULTED FROM NEW THROMBOLYTIC THERAPIES AND LIPID- LOWERING DRUGS.

Atherosclerosis

Atherosclerosis is an inflammatory disease of vascular wall initiated and amplified by vascular oxidative stress Atherosclerosis is low grade chronic inflamatory disease

Am J Cardiology 2001;87(suppl):25c-32c

RICH “GRUEL” – ATHEROMA. ATHEROSIS – THE ACCUMULATION OF CHOLESTEROL. T LIMFOCYTES AND MAST CELLS Newby (1997): Medicine international. SCLEROSIS –THE EXPANSION OF FIBROUS TISSUE. 40. INFLAMMATION – WHICH INVOLVES MONOCYTES/ MAKROPHAGES. 3.11:31-34 .ATHEROSCLEROSIS COMPRISES THREE ESSENTIAL COMPONENTS 1. 2.

Postgrad Med 1997..21( suppl 2): 1990. . Vascular Death) 9 American Heart Association. 17: 2910-2913. Stroke 1997. lack of exercise) Hyperlipidemia Hypertension Infection? Age Atherothrombotic Manifestations (MI. Wolf. smoking.21(suppl II -4–II -6. Heart and Stroke Facts: 1997 Statistical Supplement. Graham et al. Brigden. Stroke 1990. Brigden . Laurila et al. Arterioscler Thromb Vasc Biol 1997.g.Risk Factors for Atherothrombosis Hypercoagulable states Homocysteinemia Diabetes Obesity Genetics Atherosclerosis Gender Life-style (e.277: 1775-1781.28:1724-1729. Ischemic Stroke. Grau et al. diet.101(5):249-262. JAMA 1997.

stroke) Pathological remodeling Severe Target Organ Damage Vascular disease Target organ dysfunction (HF. Braunwald E.The Cardiovascular Continuum: Targeting Mechanisms and Mediators Mild Endothelial Dysfunction Tissue injury (MI. Gibbons 1999. 1991. . Am Heart J. renal) Vascular dysfunction Risk factors: diabetes hypertension Adapted 2003 from Dzau V.

THE ROLES OF OXIDATIVE STRESS (ROS) Risk Factors  LDL  BP Oxidative stress Endothelial dysfunction  NO   Local mediators   Tissue ACE-Alt Diabetes Smoking PAI-1 VCAM-1 ICAM-1 CYTOKINE Inflammation Endothelial Growth factors matrix Vascular lesion and remodelling Proteolysis Thrombosis Vasoconstriction Plaque rupture Clinical Sequelae (Pepine 1998) .

NEJM 1999.340:115-126 .Proatherogenic mechanisms Ross R.

2003) . LDL oxidation VCAM-1 and MCP-1.Il-6) Vascular inflammation Progression and clinical complications of atherosclerosis (Landmesser & Drexler.Risk Factors Vascular ROS production Endothelial dysfunction (Reduced NO availability) Pro-inflammatory gene expression(eg.

100:1148-1150 . Ridker. Circulation 1999.IL-1.TNF-) ICAM-1 Selectin. HSPs. Pro-Inflamatory Risk Factors Primary Pro-Inflammatory Cytokines (eg.The inflammatory cascade.etc Endothelium and other cells IL-6 “Messenger” Cytokine CRP SAA Liver Circulation Libby.

Am J Cardiol 2001.87(suppl):25C-32C . and early atherosclerosis ICAM-1 VCAM-1 Mo LDL Endothelia l Cells Nox MoLox Il-6 Ang II MCP-1 Nox Ox-LDL Mo Foam cells Migration Proliferation O20- O20- Smooth Muscle Cells Fibroblasts Weiss D. Sorescu D. Taylor WR.Hypertension Hyperglycemia/Diabetes Hypercholesterolemia Oscillatory Shear Stress Risk factor. oxidative stress.

LDL  Fibrinogen TNF Foam Cell Growth Factor Proliferation and migration of fibroblast and muscle cell Advanced Lesion (Rupture and Hemorrhage) Acute Myocardial Infarction . DM. Hipertensi. SMOKING. VCAM-1 hs .RISK FACTORS Faktor Resiko : Merokok.CRP ENDOTHELIAL DYSFUNCTION  hs. DM.IL-6 Monocyt Infiltration LDL INFILTRATION  Mo  ROS MM LDL ox . dan lain-lain HYPERLIPIDEMI : HYPERTENSION.

6 Figure : Atherosclerotic Processes 1) Oxidation of LDL depend on HDL/triglycerides level. and (2) scavenging ox-LDL depend on opsonizing by hs-CRP. Macrophage .Oxidative Stress HDL LDL Triglycerides Oxidized LDL Hs – CRP. IL .

.

potentially trapping macrophage Cytototoxic to cells Inhibits Endothelium –Dependent Relaxation Factor (Brown 1996) .Pro.LDL      Chemotactic to Monocytes. smooth muscle cells and T lymphocytes Induced T –cell activation and monocyte differentiation Inhibits macrophage motility.Atherogenic Effects of 0x.

Atherogenic Effects of 0x.LDL     Induces the expression of adhesion molecules on the endothelium Induces Interleukin synthesis and secretion by mcrophage Increases tonus of vasomotor Increases hypercoagulation (Brown 1996) .Pro.

Tjokroprawiro A. 2001) .Protective effects of HDL       HDL is a reverse Cholesterol Transport HDL decreased LDL oxidation Decreased expression of VCAM-1 and MCP-1 Prevent the plaques stability and plaques rupture Prevent the endothelial cell integrity Anti inflammation (Miller 1986.

EFFECTS OF DIABETES MELLITUS ON CAD Hyperglycemia Polyol pathway Antioxidant defence Oxidative stress O2./ NO • NO – dependent vasodilatation • Ca2+ • VSMC proliferation LDL oxidation • Hemorheologic alterations • Coagulation activation • Hypoxia Heparan sulphate Protein glycation Oxidative factors Glucose autoxidation • NCV • Endoneural blood flow Vasculopathy Ratinopathy Neuropathty Nephropathy (Giugliano 1996) .

Shear Stress Steady Laminar Blood Flow Antigrowth Antithrombotic NO PGL2 t-PA Trombomodulin Antimigration NO Pro-suvival Endothelium Smooth muscle Low-mean shear Prothrombotic MCP-I VCAM-I Promigration Pro-apoptosis Endothelium Smooth muscle Flow Reversal Progrowth Ang II PDGF Endothelin I Atherosclerotic Lesion Effect of shear stress on endothelial cell ( Traub 1997 .

  Physiological and PHYSIOLOGICAL & BIOCHEMICAL  CHANGES  heart rate  cardiac output  blood pressure  peripheral resistance  fibrinogen levels  platelet turnover  platelet reactivity A primary effect of nicotine is to stimulate the autonomic nervous system Clinical significance CLINICAL SIGNIFICANCE 22 altered hemodynamics  fibrinogen is an independent risk factor for stroke and coronary mortality promotes thrombosis and atherosclerosis ?  adipose tissue lipolysis   plasma FFA   myocardial oxygen consumption HDL cholesterol  LDL cholesterol    alterations in coronary artery tone ? ischemic injury ? Adelphi Communications .1987  reduction in an independent negative risk factor for CHD increase in an independent positive risk factor for CHD .

Nature 407 (2000) .078 x Ross R.5 µm Vessel wall Monocyte transmigration 10. N Engl J Med 340 (1999) & Lusis AJ.Pathogenesis of Atherosclerosis (I) Endothelial dysfunction: Monocy te Lipid-Cluster Endothelial barrier Monocy te Subintima Endothelial permeability Monocyte migration Endothelial adhesion Monocyte adhesion 0.

.

Circulation 92 (1995). Complicated lesion : Macrophage accumulation Formation of necrotic core Fibrous cap formation Vessel wall Falk et al.STATINS STABILIZE V Pathogenesis of Atherosclerosis (III) Formation of an Advanced.Epstein. NEJM 14(1999) Coronary plaque with lipid core .

ROLES OF MOLECULE IN ATHEROSCLEROSIS INFLAMMATORY CELLS Macrophage (ACE) ENDOTHELIAL CELL SMOOTH MUSCLE CELL ACE Mast Cell (Chymase) ACE Neutrophil Tissue AII VASOCONSTRICTION INFLAMMATION • Endothelin • MCP-1 • Metalloproteinase • VCAM • Cytokines (IL-6) PLAQUE INSTABILITY THROMBOSIS VASCULAR • PAI-1 • Platelet REMODELING aggregation • PDGF. 2001) . TGF- • Proliferation • Migration • Extracellular matrix modulation (Dzau et al. IGF. FGF.

Hypertension 35 (2000) .5 0 Control 10-9 10-8 Angiotensin II (mM) 10-7 Immunostaining of IL-6 (brown) in a human coronary artery plaque adapt.. from Schieffer et al.5 1.Angiotensin II-stimulated Release of Interleukine 6 (IL-6) in Plaques Role of cytokines in atherosclerosis: Stimulation of cultured smooth muscle cells for 6 h Interleukine-6 Protein (ng/ml) 1.0 0.

amino acids fibrous cap  INF- INF- = Interferon- ACE Foam-cell TNF- M-CSF MCP-1 etc.Dysregulation of Extracellular Matrix Synthesis in Vulnerable Plaques Role of Macrophages and Angiotensin II: Matrix synthesis endothelial cells smooth muscle cells Collagen Matrix degradation Metalloproteinases  Elastin Amino acids INF- TGF-ß Ang II. Plaque T-lymphocyte Adapt. from Libby P. IL-6   Peptides. Circulation 91 (1995) .

or mainly calcific. hematomahemorrhage. or multiple lipid cores & fibrotic layers.Nomenclature and main histology Type I (initial) lesion isolated macrophage foam cells Type II (fatty streak) lesion mainly intracellular lipid accumulation Type III (intermediate) lesion Type II changes & small extracellular lipid pools Type IV (atheroma) lesion Type II changes & core of extracellular lipid Sequences in progression Main growth mechanism Earliest onset Clinical correlation I Growth mainly by lipid accumulation From first decade II Clinically silent III From third decade IV Accelerated smooth muscle and collagen increase Type V (fibroatheroma) lesion lipid core & fibrotic layer. hematoma PROGRESSION OF ATHEROSCLEROSIS ( Stary 2000) . or mainly fibrotic V From fourth decade Clinically silent or overt Type VI (complicated) lesion surface defect. thrombus VI Trombosis.

.Ruptured Plaque in Coronary Artery Disease Rupture of shoulder region with occlusive thrombosis: x30 x120 ruptured cap lipid core human coronary artery. N Engl J Med 336 (1997) . postmortem from Burke et al.

.

lipid-rich core.high in cholesterol esters Thin fibrous cap High in macrophages Low in smooth muscle cells and collagen Presence of inflammation Tissue fatigue of the fibrous cap ( Doering . 1919 ) .Characteristics a Vulnerable Plaques       Usually < 70 % stenosis Eccentric shape with irregular borders Large .

External triggering event : Circadian variation ( morning ) Seasonal variation ( winter ) Physical exertion Emotional stress Internal triggering event :  Cap tension  Cap Compression  Cap flexion  Coagulability  Vasoconstriction Role of triggering events in acute coronary events . 1919 ) . Vulnerable atherosclerotic plaque THROMBOSIS Intermittent Occlusion or Occlusion < 1 hour Persistent Occlusion Q-Wave MI SCD SCD = Sudden cardiac death Unstablbe angina Non-Q-Wave MI ( Doering .

THE ROLES OF OXIDATIVE STRESS EPIDEMIOLOGY PATHOBIOLOGY CLINICAL MANIFESTATION TREATMENT PROGNOSIS/EVALUATION .

CONCLUSSION      Morbidity and mortality rate of atherosclerosis were increased Atherosclerosis is low grade chronic inflamatory disease Atherosclerosis is an inflammatory disease of vascular wall initiated and amplified by vascular oxidative stress Hs – CRP level and hs – IL – 6 level were correlated with prognosis of atherosclerosis Immunoregulatory treatments were the ideal treatment of atherosclerosis .

THANK YOU FOR YOUR ATTENTION .

.

.

.

.

.

.

flavonoids Nitric oxide NO. Metal binding Proteins .Lipid-soluble : vitamin E. Hydroperoxyl HO2 . .Catalyse Alkoxyl RO. Ceruloplasmin Thiyl radical RS Non-radicals External Antioxidants Hydrogen peroxide H2O2 Non-Enzymatics Singlet oxygen 1O2 . Hypochlor acid HOCl Faisal Baraas : Buku REHABILITASI JANTUNG.Albumin.OXIDATIVE STRESS Oxidative damage potential by free radicals Defence capacity by antioxidants 20 Radicals Internal Antioxidants Enzymatics Superoxide . Ferritins.Glutathione Peroxydase Peroxyl ROO. . Thiols Ozone O3 .Superoxide Dismutase Hydroxyl . 2003-2004 .OH .O2.Water-soluble : vitamin C. b-caroten Peroxynitrite ONOO Co-Q10 .