Development of Athersoclerosis - Barbados Underground · PDF fileDevelopment of Atheroclerosis. ... Occlusion Occlusive Thrombus 0 ... Development of Athersoclerosis Author: Nancy

Development of Atheroclerosis

Evolution and Progression ofCoronary Atherosclerosis

Intim al InjuryFatty Streak

Lip id-RichPlaque

PlaqueDisrup tion Throm bus Lysis Response

Fibrom uscularOcclusion

OcclusiveThrom bus

0 20 40 50 60

Age (years)

Atherogenic Risk Factors Throm bogenic Risk Factors

Adapted from Fuster, 1992

Endothelial Dysfunction

• Increased endothelial permeability to lipoproteins and plasma constituents mediated by NO, PDGF, AG-II, endothelin.

• Up-regulation of leukocyte adhesion molecules (L-selectin, integrins, etc).

• Up-regulation of endothelial adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1).

• Migration of leukocytes into artery wall mediated by oxLDL, MCP-1, IL-8, PDGF, M-CSF.

Ross, NEJM; 1999

Formation of Fatty Streak

• SMC migration stimulated by PDGF, FGF-2, TGF-B

• T-Cell activation mediated by TNF-a, IL-2, GM-CSF.

• Foam-cell formation mediated by oxLDL, TNF-a, IL-1,and M-CSF.

• Platelet adherence and aggregation stimulated by integrins, P-selectin, fibrin, TXA2, and TF.

Ross, NEJM; 1999

Formation of Advanced, Complicated Lesion

• Fibrous cap forms in response to injury to wall off lesion from lumen.

• Fibrous cap covers a mixture of leukocytes, lipid and debris which may form a necrotic core.

• Lesions expand at shoulders by means of continued leukocyte adhesion and entry.

• Necrotic core results from apoptosis and necrosis, increased proteolytic activity and lipid accumulation.

Ross, NEJM; 1999

Development of Unstable Fibrous Plaque

• Rupture or ulceration of fibrous cap rapidly leads to thrombosis.

• Occurs primarily at sites of thinning of the fibrous cap.

• Thinning is a result of continuing influx of and activation of macrophages which release metalloproteinases and other proteolytic enzymes.

• These enzymes degrade the matrix which can lead to hemorrhage and thrombus formation

Ross, NEJM; 1999

Plaque Rupture with Thrombus

Thrombus Fibrous cap

1 mmLipid core

Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.

Lipids Online

Growth Factors and CytokinesInvolved in Atherosclerosis

Growth Factor/Cytokine Abbr. Source Target

Epidermal growth factor EGF P EC, SMCAcidic fibroblast growth factor aFGF EC ,M, SMC ECBasic fibroblast growth factor bFGF EC ,M, SMC EC, SMCGranulocyte macrophage colony stimulating factor GM-CSF EC ,M, SMC, T EC, MHeparin-binding EGF-like growth factor HB-EGF EC ,M, SMC SMCInsulin-like growth factor-I IGF-I EC ,M, SMC, P EC, SMCInterferon λ IFN-λ T, M SMCInterleukin–1 IL-1 P, EC, M, SMC, T EC, M, SMCInterleukin-2 IL-2 T EC, M, TInterleukin-8 IL-8 EC ,M, SMC, T EC, TMacrophage colony stimulating factor M-CSF EC ,M, SMC, T MMonocyte chemotactic protein-1 MCP-1 EC ,M, SMC MPlatelet-derived growth factor PDGF EC ,M, SMC, P EC, M, SMCRANTES SIS T M, TTransforming growth factor-α TGF-α M ECTransforming growth factor-β TGF-β EC ,M, SMC, T, P M, SMCTumor necrosis factor-α TNF-α EC ,M, SMC, T ECTumor necrosis factor-β TNF-β T EC, M, SMCVascular endotholelial growth factor VEGF EC ,M, SMC EC

Role of Lipoproteins in Atherosclerosis

CHD Mortality is Correlated with Plasma Cholesterol Levels

LaRosa et al, 1990

1 40 1 60 1 80 200 220 240 260 280 300

Plasm a Cholesterol (m g/dl)

02468

1 01 21 41 61 8

CH

D D

eath

Rate

/1000

Six Year CHD Mortality from MRFIT

DesirableBorderline

High HIGH

Role of LDL in Atherosclerosis

Steinberg D et al. N Engl J Med 1989;320:915-924.

EndotheliumEndothelium

Vessel LumenVessel LumenLDLLDL

LDL Readily Enter the Artery Wall Where They May be ModifiedLDL Readily Enter the Artery Wall Where They May be Modified

LDLLDL

IntimaIntimaModified LDLModified LDL

Modified LDL are ProinflammatoryModified LDL are Proinflammatory

Hydrolysis of PhosphatidylcholineHydrolysis of Phosphatidylcholineto Lysophosphatidylcholineto Lysophosphatidylcholine

Other Chemical ModificationsOther Chemical Modifications

Oxidation of LipidsOxidation of Lipidsand ApoBand ApoB

AggregationAggregation

Lipids Online


LDLLDL

LDLLDL

Navab M et al. J Clin Invest 1991;88:2039-2046.


Vessel LumenVessel Lumen

IntimaIntima

MonocyteMonocyte

Modified LDLModified LDL

MCP-1MCP-1

Lipids Online


LDLLDL

LDLLDL



Vessel LumenVessel Lumen

IntimaIntima

MonocyteMonocyte


Modified LDL PromoteModified LDL PromoteDifferentiation ofDifferentiation ofMonocytes intoMonocytes intoMacrophagesMacrophages

MCP-1MCP-1

MacrophageMacrophage

Lipids Online


LDLLDL

LDLLDL

Nathan CF. J Clin Invest 1987;79:319-326.


Vessel LumenVessel LumenMonocyteMonocyte



MCP-1MCP-1

AdhesionAdhesionMoleculesMolecules

CytokinesCytokines

IntimaIntima

Lipids Online


LDLLDL

LDLLDLEndotheliumEndothelium



MCP-1MCP-1

AdhesionAdhesionMoleculesMolecules


Foam CellFoam Cell

Modified LDL Modified LDL Taken up by Taken up by MacrophageMacrophage

IntimaIntima

Lipids Online





MCP-1MCP-1AdhesionAdhesionMoleculesMolecules

Foam CellFoam Cell

IntimaIntimaModifiedModifiedRemnantsRemnantsCytokinesCytokines

Cell ProliferationCell ProliferationMatrix DegradationMatrix Degradation

Doi H et al. Circulation 2000;102:670-676.

Growth FactorsGrowth FactorsMetalloproteinasesMetalloproteinases

Remnant LipoproteinsRemnant Lipoproteins

RemnantsRemnants

Lipids Online

HDL is Protective

110

3021

0

20

40

60

80

100

120

< 35 35–55 > 55

Inci

denc

epe

r 1,

000

(in

6 ye

ars)

HDL-C (mg/dL)

Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993

186 events in 4,407 men (aged 40–65 y)

Lipids Online

HDL Prevent Foam Cell Formation

LDLLDL

LDLLDL

Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.






CytokinesCytokines

IntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux

Foam Foam CellCell

Lipids Online

HDL Inhibits Oxidative Modificationof LDL

LDLLDL

LDLLDL

Mackness MI et al. Biochem J 1993;294:829-834.






CytokinesCytokines

Foam Foam CellCell

HDL Promote Cholesterol EffluxHDL Promote Cholesterol EffluxIntimaIntima

HDL InhibitHDL InhibitOxidationOxidation

of LDLof LDL

Lipids Online

HDL Inhibits Expression ofAdhesion Molecules

LDLLDL

LDLLDL

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.






CytokinesCytokines

IntimaIntima

HDL InhibitHDL InhibitOxidationOxidation

of LDLof LDL

HDL Inhibit Adhesion Molecule ExpressionHDL Inhibit Adhesion Molecule Expression

Foam Foam CellCell

HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux

Lipids Online

Suggested Risk Factors for CVD• LDL Oxidation

LDL-CAnti-OxLDLOxLDLLDL Oxid. Lag TimeNegative LDLHDL-C ParaoxonasePAF acetylhydrolaseF2-IsoprostanesTBARSORACBreath Ethane

• Endothelial InjuryTriglycerides/VLDLNon-HDL-CapoA-1/apoBHDL-2/HDL-3LDL sizePostprandial TGIDLChylo. RemnantsBlood PressureHomocysteine

• Thrombi FormationFactor VIIFibrinogenPAI-1Factor VIITissue Plasminogen ActivatorD-DimerPlasmin-Antiplasmin ComplexProthrombin Fragment 1+2Platelet Activation

• Inflammatory ResponseC-Reactive ProteinIL-6Lp-PLA2

• Endothelial Dysfunctionvon Willibrand’s FactorP-SelectinsICAM-1sVCAM-2Assymetric Dimethyl ArginineNitrate/Nitrite

• Plaque InstabilityPlasma Metaloproteinase-9

Diet, Lipoproteins and CVD

Seven Countries Study: CHD Events are

Correlated with Saturated Fat

0 5 1 0 1 5 20

% Calories from Saturated Fat

0

1

2

3

4

5

CH

D D

eath

s an

d M

I/100

R = 0.84

V

MC

DG

SW

B

Z

UN

E

K

Keys, 1970

Step 1 Step 2

-20

-1 5

-1 0

-5

0

³TC

, mg/

dl

Total Cholesterol

DAIRY DELTA

Step 1 Step 2

-1 6

-1 2

-8

-4

0

³LD

L-C

, mg/

dl

LDL CholesterolDAIRY DELTA

Step 1 Step 20

5

1 0

1 5

20

³TG

, mg/

dl

TriglyceridesDAIRY DELTA

Step 1 Step 2

-6

-4

-2

0

³HD

L-C, m

g/dl

HDL CholesterolDAIRY DELTA

Changes in Lipids with Step 1 and Step 2 Diets

Regression Equations Have Been Developed to Predict Average Lipid Responses to Dietary

Changes• Keys (1965) ∆TC = 1.35* (2*∆S - ∆P) + 1.52*∆Z• Hegsted (1965) ∆TC = 2.16*∆S - 1.65*∆P + 0.067*∆C - 0.53• Mensink (1992) ∆TC = 1.51*∆S - 0.12*∆M - 0.60*∆P• Hegsted (1993) ∆TC = 2.10*∆S - 1.16*∆P + 0.067*∆C• Yu (1995) ∆TC = 2.02*∆c12:0-c16:0 - 0.03*∆c18:0

- 0.48*∆M - 0.96*∆P• Howell (1997) ∆TC = 1.918*∆S - 0.900*∆P

+ 0.0222*∆C

Newer Equations Can Accurately Predict Population Response to Changes in Dietary Fat

-8.7% Milkfat -1 3. 1 % Milkfat

% Kcal Reduction in Milkfat

0

5

1 0

1 5

20

25

³ C

hole

stero

l (m

g/d

l) Observe Howell Hegsted Mensink Keys

Dietary Mechanisms to Lower LDL

• Reduce cholesterol intake• Increase ACAT activity (↓SFA)• Inhibit cholesterol absorption (plant sterols)• Inhibit bile acid uptake (soluble fibers)• Inhibit HMGCoA-reductase (tocotrienols)• Inhibit FXR activation (guggelsterone)

• Fibrinogen: Upper tertile for fibrinogen associated with 2.3-fold increase in risk for myocardial infarction.

• Factor VII: 25% increase in factor VIIc is associated with a 55% increase in risk of a fatal CHD events within 5 years.

Thrombogenic Risk Factors May be as Important as Lipid Risk Factors

Changes in Hemostasis Factors withStep 1 and Step 2 Diets

Step 1 Step 2

-6

-4

-2

0

³Fac

tor

VII,

%

Factor VIIDAIRY DELTA

Step 1 Step 20

3

6

9

1 2

1 5

³Fib

rinog

en, m

g/dl

FibrinogenDAIRY DELTA

Dietary Components and CHD RiskSummary of the Nurses’ Health Study

Vit E (Supplement vs no Supplement)Margarine (<1 tsp/mo vs >4 tsp/d)Alcohol (1 drink/d vs none)Nuts (5 servings/wk vs almost never)Folic Acid (>545 ug/d vs <190 ug/d)Fiber (23g/d vs 12 g/d)Whole grains (>1.7 serv vs <0.25 serv)

Eggs (<1/wk vs >1/d)

Saturated Fat (10.7% vs 18.8%)Total Fat (29.1% vs 46.1%)

-60 -50 -40 -30 -20 -1 0 0 1 0 20

Percent Change in CHD Risk

Fruit (3.8 serv vs 0.6 serv)Vegetables (6.8 serv vs 1.5 serv)

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Development of Athersoclerosis - Barbados Underground · PDF fileDevelopment of Atheroclerosis. ... Occlusion Occlusive Thrombus 0 ... Development of Athersoclerosis Author: Nancy