schematic time course of human schematic time course of human

Slide Source:Lipids Onlinewww.lipidsonline.org

Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis

Transition from chronic to acuteTransition from chronic to acute atheromaatheroma

Ischemic Ischemic HeartHeartDiseaseDisease

CerebrovascularCerebrovascularDiseaseDisease

Peripheral VascularPeripheral VascularDiseaseDisease


NormalNormalFattyFatty

StreakStreakFibrousFibrousPlaquePlaque

OcclusiveOcclusiveAtheroscleroticAtherosclerotic

PlaquePlaque

PlaquePlaqueRupture/Rupture/Fissure &Fissure &

ThrombosisThrombosis

MIMI

StrokeStroke

Critical LegCritical LegIschemiaIschemia

Clinically SilentClinically Silent

Coronary Coronary DeathDeath

Increasing AgeIncreasing Age

Effort AnginaEffort AnginaClaudicationClaudication

UnstableUnstableAnginaAngina

AtherosclerosisAtherosclerosis: A Progressive Process: A Progressive Process

Courtesy of P Ganz.


The Anatomy ofThe Anatomy of AtheroscleroticAtherosclerotic PlaquePlaque

– T lymphocyte

– Macrophagefoam cell (tissue factor+)

– “Activated” intimal SMC (HLA-DR+)– Normal medial SMC

Fibrouscap

Intima

Lipidcore

LumenMedia

Libby P. Lancet. 1996;348:S4-S7.


AngiographicallyAngiographically Inapparent AtheromaInapparent Atheroma

Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.


The Matrix Skeleton of UnstableThe Matrix Skeleton of UnstableCoronary Artery PlaqueCoronary Artery Plaque

Fissures inthe fibrous cap

Davies MJ. Circulation. 1996;94:2013-2020.


Characteristics of Plaques Prone to RuptureCharacteristics of Plaques Prone to Rupture

– T lymphocyte

– Macrophagefoam cell (tissue factor+)

– “Activated” intimal SMC (HLA-DR+)– Normal medial SMC“Stable” plaque

“Vulnerable” plaque

Lumenarea ofdetail

MediaFibrous cap

Lumen

Lipidcore

Lipidcore

Libby P. Circulation. 1995;91:2844-2850.


Proposed Mechanisms of Event Reduction by Proposed Mechanisms of Event Reduction by LipidLipid--Lowering TherapyLowering Therapy

! Improved endothelium-dependent vasodilation

! Stabilization of atherosclerotic lesions! especially nonobstructive, vulnerable plaques

! Reduction in inflammatory stimuli! lipoproteins and modified lipoproteins

! Prevention, slowed progression, or regression ofatherosclerotic lesions

Libby P. Circulation. 1995;91:2844-2850.


Atheroma Atheroma are not merely filled with lipid, are not merely filled with lipid, but contain cells whose functions critically but contain cells whose functions critically influence influence atherogenesisatherogenesis::

Intrinsic Vascular Wall Cells:

! Endothelium

! Smooth Muscle Cells

Inflammatory Cells:

! Macrophages

! T Lymphocytes

! Mast Cells


Cell Types in the Human Cell Types in the Human AtheromaAtheroma

MonocyteMonocyte//MacrophageMacrophage

TT--lymphocyteslymphocytesTunicaMedia

Intima

Smooth musclecells

EndotheliumEndothelium


++ SymptomsSymptoms SymptomsSymptoms

Ischemic Ischemic HeartHeartDiseaseDisease

CerebrovascularCerebrovascularDiseaseDisease

Peripheral VascularPeripheral VascularDiseaseDisease

Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis

Lesion initiationLesion initiation

No No symptomssymptoms

Time (y)Time (y)


Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis

AttachmentAttachment


LeukocyteLeukocyte––Endothelial Adhesion MoleculesEndothelial Adhesion Molecules

MonoMonoTT

BB PMNPMN


Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1(VCAM(VCAM--1)1)

! Binds monocytes and lymphocytes- Cells found in atheroma

! Expressed by endothelium over nascent fatty streaks

! Expressed by microvessels of the mature atheroma


An An atherogenic atherogenic diet rapidly induces diet rapidly induces

VCAMVCAM--1, a cytokine1, a cytokine--regulatable regulatable

mononuclear leukocyte adhesion mononuclear leukocyte adhesion

molecule, in rabbit aortic endotheliummolecule, in rabbit aortic endothelium

Li H et al. Arterioscler Thromb 1993;13:197-204.


VCAMVCAM--1 Expression in Rabbit Aorta1 Expression in Rabbit Aorta

3 weeks on atherogenic diet

Li H et al. Arterioscler Thromb 1993;13:197-204.



PenetrationPenetration


Monocyte Chemoattractant Monocyte Chemoattractant Protein 1Protein 1(MCP(MCP--1)1)

! A potent mononuclear cell chemoattractant

! Produced by endothelial and smooth muscle cells

! Localizes in human and experimental atheroma


Absence of Absence of monocyte chemoattractant monocyte chemoattractant

proteinprotein--1 reduces 1 reduces atherosclerosis atherosclerosis in in

lowlow--density lipoprotein receptordensity lipoprotein receptor––

deficient micedeficient mice

Gu L et al. Mol Cell 1998;2:275-281.


Reduced Lipid Deposition in MCPReduced Lipid Deposition in MCP--11––Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice

LDLLDL--R R ––//––MCPMCP--1 +/+1 +/+

LDLLDL--R R ––//––MCPMCP--1 1 ––//––

Gu L et al. Mol Cell 1998;2:275-281.


Reduced Lipid Deposition in MCPReduced Lipid Deposition in MCP--11––Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice

0

5

10

15

20

25

30

Oil

Red

Sta

inin

g

% A

ort

ic S

urf

ace

Sta

ined

Time on Diet: 12 – 14 weeks+/+ -/-

***

+/+ -/-20 – 25 weeks

*P = 0.001 compared to +/+**p = 0.005 compared to +/+Gu L et al. Mol Cell 1998;2:275-281.



Division


Molecular Mediators ofMolecular Mediators of AtherogenesisAtherogenesis

M-CSFMCP-1

VCAM-1


Matrix Metabolism and Integrity of the Matrix Metabolism and Integrity of the Plaque’s Fibrous CapPlaque’s Fibrous Cap

+ + + +

++

–

Synthesis Breakdown

Lipid core

IL-1TNF-αMCP-1M-CSF

FibrouscapIFNIFN--γγ

CD-40L

CollagenCollagen--degradingdegradingProteinasesProteinases

Tissue FactorTissue FactorProcoagulantProcoagulant

Libby P. Circulation 1995;91:2844-2850.


Increased Expression of Interstitial Increased Expression of Interstitial Collagenase Collagenase (CL) by Smooth Muscle Cells (CL) by Smooth Muscle Cells (SMC) and Macrophages (M(SMC) and Macrophages (Mφφ) in Human ) in Human AtheromaAtheroma

Galis ZS et al. J Clin Invest 1994;94:2493-2503.


Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis

Thrombus Fibrous cap

1 mmLipid core

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


Thrombosis of a Disrupted Thrombosis of a Disrupted AtheromaAtheroma, the , the Cause of Most Acute Coronary Syndromes, Cause of Most Acute Coronary Syndromes, Results from:Results from:

! Weakening of the fibrous cap

!! ThrombogenicityThrombogenicityof the lipid coreof the lipid core

Illustration courtesy of Michael J. Davies, M.D.

schematic time course of human schematic time course of human

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