atherosclerosis presentation

7/30/2019 Atherosclerosis Presentation

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Pathogenesis ofPathogenesis of

AtherosclerosisAtherosclerosis


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Various immunodeficiencies

Hyperinflammatory but inadequate

immune response

Clinical picture of (Hemophagocyticlymphohistiocytosis) HLH


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HLHVariable course of disease

Rapidly progressive leading to death within

weeks

Transient improvements with unspecifictherapies

Disappearance of symptoms without therapy

Disappearance of symptoms with immuno-suppressive/immunomodulatory drugs


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HLHClassification

Genetic, primary HLH Acquired, secondary HLHFHLH

- Perforin mutations (chr.10) Exogenous agents

- infectious organisms, toxins- Chromosom 9 linkage (VAHS, IAHS)

- Unknown mutations HLH Endogenous products- tissue damage

- radical stress

- Immune deficiencies - metabolic productsCHSGriscelli syndrome Rheumatic disorders

XLP Malignancies

SCID


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HLH

Diagnostic criteria Histiocyte Society 1991

Clinical

Fever > 38.5

Splenomegaly

LaboratoryCytopenia of => 2/3 cell lines

Hypertriglyceridemia and/or

hypofibrinogenemiaHistopathology

Hemophagocytosis in bone marrow

or spleen or liver or lymphnode

Strong supportive evidence are spinal fluid pleocytosis, liver

histology resembling chronic persistent hepatitis, low natural

killer cell activity


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HLH

Therapy

Cytostatic and immunsuppressive/

immunomodulatory drugs:

Corticosteroids, Cyclosporin A,Etoposide

Immunoglobulins, Antithymocyte globulin

h Bone marrow transplantation

Prognosis

In 20% no response to therapy

After BMT 60-70% relapse-free survival


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IntroductionIntroduction

ArteriosclerosisArteriosclerosis Thickening and loss of elasticity of arterialThickening and loss of elasticity of arterial

wallswalls

Hardening of the arteriesHardening of the arteries

Greatest morbidity and mortality of allGreatest morbidity and mortality of all

human diseases viahuman diseases viaNarrowingNarrowing

WeakeningWeakening


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Atherosclerotic DiseaseAtherosclerotic Disease

PrevalencePrevalence In US there are 6 million with CADIn US there are 6 million with CAD

3 million Americans have had strokes3 million Americans have had strokes

MortalityMortality

1.5 million deaths/yr in US due to1.5 million deaths/yr in US due to

myocardial infarctionmyocardial infarction 0.5 million deaths/yr in US due to strokes0.5 million deaths/yr in US due to strokes


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Three patterns of arteriosclerosis

Atherosclerosis Thedominant pattern of arteriosclerosis

Primarily affects the elastic (aorta, carotid,

iliac) and large to medium sized muscular

arteries (coronary, popliteal)

Monckeberg medial calcific sclerosis Arteriolosclerosissmall arteries and

arterioles (hypertension and DM)


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NonNon--Modifiable Risk FactorsModifiable Risk Factors

AgeAge A dominant influenceA dominant influence

Atherosclerosis begins in the young, but does notAtherosclerosis begins in the young, but does notprecipitate organ injury until later in lifeprecipitate organ injury until later in life

GenderGender Men more prone than women, but by age 60Men more prone than women, but by age 60--7070

about equal frequencyabout equal frequency

Family HistoryFamily History Familial cluster of risk factorsFamilial cluster of risk factors

Genetic differencesGenetic differences


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Modifiable Risk FactorsModifiable Risk Factors

(potentially controllable)(potentially controllable)

HyperlipidemiaHyperlipidemia

HypertensionHypertension

Cigarette smokingCigarette smoking

Diabetes MellitusDiabetes Mellitus Elevated HomocysteineElevated Homocysteine

Factors that affect hemostasis andFactors that affect hemostasis andthrombosisthrombosis

Infections: Herpes virus; ChlamydiaInfections: Herpes virus; Chlamydiapneumoniaepneumoniae

Obesity, sedentary lifestyle, stressObesity, sedentary lifestyle, stress


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Fig. 11.7

AHA Classification of atherosclerosis


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Normal Artery


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Normal Artery


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AtherosclerosisAtherosclerosis

A disease of the intimaA disease of the intima

A disease of the intimaA disease of the intima A disease of the intimaA disease of the intima

AtheromasAtheromas,, atheromatous/fibrofattyatheromatous/fibrofatty

plaques, fibrous plaquesplaques, fibrous plaques Narrowing/occlusion; weakness of wallNarrowing/occlusion; weakness of wall


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Major components of plaque

Cells (SMC, macrophages and other WBC)

ECM (collagen, elastin, and PGs)

Lipid = Cholesterol (Intra/extracellular)

(Often calcification)


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Two major processes in plaque

formation

Intimal thickening (SMC proliferation and

ECM synthesis)

Lipid accumulation


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Consequences of plaque

formation

Generalized

Narrowing/Occlusion

Rupture

Emboli

Leading to specific problems: Myocardial and cerebral infarcts

Aortic aneurysms

Peripheral vascular disease


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Fatty Streak-Aorta


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Fatty Streak-Coronary Artery


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Altered Vessel Function

Consequence

Ischemia, turbulence

Aneurysms, vessel

rupture Narrowing, ischemia,

embolization

Athero-embolization

Increase systolic blood

pressure

Vessel change Plaque narrows

lumen

Wall weakened

Thrombosis

Breaking loose ofplaque

Loss of elasticity


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Late Changes

Calcification

An example of dystrophic calcification

Cracking, ulceration, rupture Usually occurs at edge of plaque

Thrombus formation

Caused by endothelial injury,ulceration, turbulence Organization of thrombus

More thrombus

Encroachment Weakens vessel wall

Bleeding

Ulceration, cracking and angiogenesis


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ATHEROSCLEROSIS:

Pathology, Pathogenesis, Complications, Natural History


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Complicated LesionsFibrous Plaques


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Neovas.Calcification

Inflam. cells

Fibrous cap

Cholesterol clefts

Elastin membrane

destroyed


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Hemorrhage into Plaque


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Ulceration/Hemorrhage/Cholesterol Crystals


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Complicated Lesion/Calcification


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Cholesterol Crystals/Foam Cells


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Thrombosis/Complicated Lesion


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Complicated Lesion/Ulceration/Thrombosis

A ti A


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Aortic Aneurysm


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Aortic Aneurysm


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Pathogenesis of Atherosclerosis

Cause? Current hypothesis: Response to Injury

Initiated by endothelial dysfunction

Disease of the intima

Intimal thickening

Intra- and extra-cellular lipid accumulation Chronic Inflammation

Basic Lesion: is termed atheroma, fibro-fatty

plaque, or atheromatous plaque


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Response to injury hypothesis

* Injury to the endothelium

(dysfunctional endothelium)

* Chronic inflammatory response

* Migration of SMC from media to intima

* Proliferation of SMC in intima

Excess production of ECM Enhanced lipid accumulation


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Response to injury hypothesis (I)

1. Chronic EC injury (subtle?)

EC dysfunction

Increased permeability

Leukocyte adhesion (via VCAM-1)

Thrombotic potential


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Response to injury hypothesis (II)

2. Accumulation of LDL (cholesterol)

3. Oxidation of lesional LDL

4. Adhesion & migration of blood

monocytes; transformation intomacrophages and foam cells

5. Adhesion of platelets6. Release of factors from platelets,

macrophages and ECs


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Response to injury hypothesis (III)

7. Migration of SMC from media to intima

8. Proliferation of SMC

9. ECM production by SMC

10. Enhanced lipid accumulation

Intracellular (SMC and macrophages)

Extracellular


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Endothelial dysfunction

Induced by oxidized LDL, can be worsened by

cigarette smoking, and can be reversed with

correction of hyperlipidemia by diet or by therapy

with a statin, which increases the bioavailability of

nitric oxide, with ACE inhibitors, or with

antioxidants such as vitamin C or flavonoids

contained in red wine Anderson et al., 1996; Harison et al 1987; John et al., 1998; Mancini et al 1996; Levineet al 1996


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Endothelial dysfunction

Expression of VCAM-1 on endothelial

surfaces is an early, and necessary, step in

the pathogenesis of atherosclerosis.

Increased cellular adhesion and associatedendothelial dysfunction then sets the stage

for the recruitment of inflammatory cells,release of cytokines and recruitment of lipid

into the atherosclerotic plaque.Li et al., 1993


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Dyslipidaemia

Lipid abnormalities play a critical role in

the development of atherosclerosis

Early experiments demonstrated accelerated

atherosclerosis with a high cholesterol diet.

Epidemiologic studies showed increasing

incidence of atherosclerosis when serumcholesterol above 3.9 mM


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Dyslipidaemia High levels of LDL and low levels of HDL

important risk factors for atherosclerosis Macrophage uptake of LDL may initially be

adaptive response, which prevents LDL-induced

endothelial injury

However, cholesterol accumulation in foam cellsleads to mitochondrial dysfunction, apoptosis, andnecrosis, with resultant release of cellular

proteases, inflammatory cytokines, andprothrombotic molecules


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Dyslipidaemia

Oxidized LDL can cause disruption of the

endothelial cell surface, promote

inflammatory and immune changes via

cytokine release from macrophages andantibody production and increase platelet

aggregation


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Dyslipidaemia

HDL, in contrast to LDL, has

antiatherogenic properties that include

reverse cholesterol transport, maintenance

of endothelial function, protection againstthrombosis, and maintenance of low blood

viscosity through a permissive action on red

cell deformability


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Inflammation

Best evidence supporting the importance of

inflammation in the pathogenesis of

atherosclerosis comes from the observation

that markers of increased or decreasedsystemic inflammation are directly

associated with the risk of atherosclerosis

Inflammation and chronic


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endothelial injury

VCAM-1 expression increases recruitment of

monocytes and T-cells to sites of endothelial

injury

Subsequent release of MCP-1 by leukocytesmagnifies the inflammatory cascade by recruiting

additional leukocytes, activating leukocytes in the

media, and causing recruitment and proliferationof smooth muscle cells


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Atherosclerosis is initiated when

leucocytes adhere to the

endothelium as a result ofexpression of adhesive proteins.

Crowther et al., 2005



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endothelial injury

Monocytes adhere to the endothelium and

then migrate through the endothelium and

basement membrane by elaborating

enzymes, including locally activated matrixmetaloproteinases (MMP) that degrade the

connective tissue matrix



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Leucocytes than cross the

endothelial barrier and begin to

accumulate




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endothelial injury

Macrophages both release additional cytokines

and begin to migrate through the endothelial

surface into media of the vessel.

This process is further enhanced by the localrelease of M-CSF, which causes monocytic

proliferation

Local activation of monocytes leads to bothcytokine-mediated progression of atherosclerosis,

and oxidation of LDL



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Monocytes within the sub-

endothelial space subsequentlyorchestrate the development of

atherosclerosis through cytokine

release.




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endothelial injury

CD40L elaborated within the plaque has

been shown to increase the expression of

tissue factor in atherosclerotic plaques

anti-CD40L abrogates evolution ofestablished atherosclerotic lesions in animal

models

Schonbeck et al., 2000


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Clinically apparent disease if first

noted as a result of the

accumulation of foam cells.



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Inflammatory mediators

Include IL-1, TNF and , IL-6, M-CSF,

MCP-1, IL-18 and CD-40L.

The impact of these mediators is diverse

and includes mitogenesis, intracellularmatrix proliferation, angiogenesis and foam

cell development



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The clinically important lesion is characterized by

intimal narrowing, many foam cells,

neovascularization and flow limiting narrowing.

However, this stage of the disease is sufficiently

advanced that treatments aimed at it do not

impact the pathogenesis of the underlying disorder.


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CRP CRP may be only a marker of inflammation and

thrombotic risk CRP binds to LDL, allowing LDL to be taken up

by macrophages without the need for modification

CRP induces adhesion molecule expression andproduction of IL-6 and MCP-1 in humanendothelial cells; these effects might enhance a

local inflammatory response within theatherosclerotic plaque by the recruitment ofmonocytes and lymphocytes


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CRP The proinflammatory and prothrombotic effects of

CRP on monocytes and endothelial cells in vivoby subjecting wild-type mice, which do not

express CRP, and human CRP-transgenic (CRPtg)

mice to two models of arterial injury.

In an arterial injury model complete thrombotic

occlusion of the femoral artery at 28 days wasseen in 17% of wild-type mice compared with

75% of CRPtg arteries.

Danenberg et al., 2003


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Multivariable-adjusted relative risks of

cardiovascular disease according to levels of CRP

and the estimated 10-year risk based on theFramingham Risk Score. CHD indicates coronary

heart disease. Data from Ridker and colleagues


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IL-1 and TNF-alpha Enhance expression of cell surface

molecules such as ICAM-1, VCAM-1,

CD40, CD40L, and selectins on endothelial

cells, smooth muscle cells, & macrophages Induce cell proliferation, contribute to the

production of ROS, stimulate matrixmetalloproteinases, & induce TF expression


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Leukocyte activation mRNA profiles showing increased levels of

most inflammatory mRNAs in individuals

with prior AMI


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Toll-like receptor 4 Polymorphisms in the toll-like receptor 4 gene that

confer differences in the inflammatory response toGram negative pathogens

Carriers of the Asp299Gly polymorphism,compared to wild-type alleles, have reduced

circulating levels of inflammatory markers,

including CRP, adhesion molecules, and IL-6, anda reduced incidence of carotid atherosclerosis

Molecular Targets to address chronic


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g

inflammation

Peroxisome proliferator-activated receptors

(PPARs) have emerged as important anti-atherogeneic targets

Endothelial specific roles of PPAR- include inhibition of adhesion molecules, including VCAM-1

increased endothelial NO release

reduced foam cell formation reduced uptake of glycated LDL and triglyceride-rich

remnant lipoproteins


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PPARs Ligands of PPAR- include fatty acids and

the oral hypoglycemic drugs belonging to

the glitazone family

PPAR- is expressed in numerous cell typesfound within the atherosclerotic lesion,

including endothelial cells, smooth muscle-cells, macrophages, and T cells


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Potential anti-atherogenic activities of peroxisomeproliferator-activated receptors (PPARs)

1. Increased nitric oxide synthesis and release2. Decreased recruitment of T cells

3. Reduced angiogenesis

4. Inhibition of smooth muscle cell (SMC) migration

5. Decreased SMC expression of matrix-degrading enzymes

6. Decreased macrophage-dependent expression of matrix

metalloproteinase (MMP)-9 and osteopontin

7. Enhanced release of the interleukin-1 receptor antagonist8. Enhanced reverse cholesterol transport


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Lucas et al., 2006


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Angiogenesis Angiogenic signaling and proliferation of

microvessels within the plaque is only now

beginning to be understood

Plaque hemorrhage is likely attributable tobleeding from fragile microvessels that

proliferate within the plaque itself,presumably in response to local angiogenic

stimuli.


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Angiogenesis Kockx et al identified intraplaque hemorrhage

from microvessels triggering macrophageactivation and foam cell formation in carotid

lesions

These authors propose that intraplaque

microhemorrhage may initiate platelet and

erythrocyte deposition, lead to iron deposition,activate macrophages and contribute to foam cell

formation.

Kockx et al.,2003


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Angiogenesis The importance of angiogenesis in the

pathogenesis of plaque growth was recentlybolstered by the finding that intra-plaquemicrovessels were an independent predictor of

plaque rupture

The potential importance of angiogenesis in thedevelopment of atherosclerosis is found inexperiments that demonstrate that antiangiogenic

therapy reduced atherosclerotic lesiondevelopment in a placebo controlled trial inatherosclerosis prone mice

Moreno et al., 2004; Chew


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Moreno et al., 2006


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General features of insulin signal transduction pathways.

PI 3-kinase branch of insulin signaling regulates GLUT4

translocation and glucose uptake in skeletal muscle and NO

production and vasodilation in vascular endothelium. MAPkinase

branch of insulin signaling generally regulates growth and

mitogenesis and controls secretion of ET-1 in vascularEndothelium Kim et al., 2006


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Kim et al., 2006


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Shared and interacting mechanisms of

glucotoxicity, lipotoxicity, and inflammation underlie

reciprocal relationships between insulin resistanceand endothelial dysfunction that contribute

to linkage between metabolic and cardiovascular

diseases. CAD indicates coronary artery disease


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Mechanisms for the contribution of

insulin resistance to atherosclerosis.

VSMC indicates vascular smoothmuscle cell; CHF, congestive heart

failure.

Kim et al., 2006


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Tissue factor: A key regulator of coagulation. Tissue factor (TF) is a key

initiator of the coagulation cascade. Formation of a complex with factor VIIa

(FVIIa) leads to activation of factor IX (FIX) and factor X (FX), resulting in

thrombin generation and, ultimately, clot formation. Tissue factor pathway inhibitor

(TFPI), the endogenous inhibitor of TF activity, is synthesized and secreted mainly by

endothelial cells. TFPI binds to FXa and thereby inhibits TF/FVIIa activity.

Steffel et al; 2006


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Induction of tissue factor expression and activity. Induction of tissue factor (TF) is

exemplified in an endothelial cell. Various mediators induce TF expression through

activation of their receptors. Induction of TF primarily occurs at the transcriptional

level, resulting in an increase in TF mRNA and, eventually, TF protein expression. TF

is distributed in three cellular pools as cytoplasmatic TF, surface TF, and encrypted TF.

Moreover, TF-containing microparticles are released from the cell. Alternative splicing

results in a soluble secreted form of TF (asTF). IL-1 indicates interleukin-1; LPS,

lipopolysaccharide; TNF-, tumor necrosis factor ; VEGF, vascular endothelial growth

factor; HB1B, histamine HB1B-receptor; 5-HTB2aB, 5-hydroxytryptamineB2aB

receptor; IL1-R, interleukin-1 receptor; TLR-4, toll-like receptor 4; PAR, protease-

activated rece tor; KDR, VEGF rece tor-2. Steffel et al 2006


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Tissue factor in the atherosclerotic plaque. In the inflammatory environment of atherosclerotic

plaques, tissue factor (TF) is present at high levels in endothelial cells, vascular smooth muscle

cells, macrophages/foam cells, and in the necrotic core. TF induction is exemplified by selected

mediators in endothelial cells (EC, left panel), macrophages (M, middle panel), and vascular

smooth muscle cells (VSMC, right panel). On plaque rupture, highly procoagulant material

including TF-containing microparticles is released into the blood, leading to rapid initiation of

coagulation, platelet aggregation, and, ultimately, thrombus formation with vessel occlusion.

Steffel et al; 2006


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Therapeutic approaches. Several therapeutic strategies have been developed to specifically interfere with

the action of tissue factor (TF). Molecular approaches such as ribozymes or antisense oligonucleotidesspecifically inhibit TF production. Monoclonal or polyclonal anti-TF antibodies directly target and inactivate

the TF protein. Site-inactivated factor VIIa (FVIIai) binds to TF but lacks catalytic activity for conversion of

factor X (FX) or factor IX (FIX). Recombinant tissue factor pathway inhibitor (rTFPI) interferes with the

activity of the TF/FVIIa complex by binding to the active site of factor Xa (FXa), leading to formation of a

quaternary inhibitory complex with TF/FVIIa. Similarly, recombinant nematode anticoagulant protein c2(rNAPc2) interferes with the TF/FVIIa complex by binding to FXa or FX before formation of a quarternary

inhibitory complex with TF/FVIIa. Steffel et al 2006


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Response to Injury


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Endothelial Dysfunction


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Initiation of Fatty Streak

Fatty Streak


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ib f A h


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Fibro-fatty Atheroma

Summary of Atherosclerotic ProcessSummary of Atherosclerotic Process


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Multifactorial process (risk factors)Multifactorial process (risk factors)

Initiated by endothelial dysfunctionInitiated by endothelial dysfunction

Up regulation of endothelial and leukocyte adhesionUp regulation of endothelial and leukocyte adhesionmoleculesmolecules

Macrophage diapedesisMacrophage diapedesis

LDL transcytosisLDL transcytosis LDL oxidationLDL oxidation

Foam cellsFoam cells

Recruitment and proliferation of smooth muscle cellsRecruitment and proliferation of smooth muscle cells(synthesis of connective tissue proteins)(synthesis of connective tissue proteins)

Formation and organization of arterial thrombiFormation and organization of arterial thrombi


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Is AtherosclerosisIs Atherosclerosis

R iblR ibl


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ReversibleReversible Primate experimentsPrimate experiments High fat diet discontinued; atherosclerotic lesionsHigh fat diet discontinued; atherosclerotic lesions

regressregress HumansHumans

Decrease fat and caloric intake (wars, famine,Decrease fat and caloric intake (wars, famine,

wasting disease), atheromas decrease.wasting disease), atheromas decrease. Angiography after cholesterol lowering, plaqueAngiography after cholesterol lowering, plaque

size decreasessize decreases

What has to happen for plaques to regress?What has to happen for plaques to regress? LDL loweredLDL lowered

Mac ingest lipidsMac ingest lipids

Reverse cholesterol transport, depends on HDLReverse cholesterol transport, depends on HDL

atherosclerosis presentation

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