schematic time course of human schematic time course of human
TRANSCRIPT
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
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
AngiographicallyAngiographically Inapparent AtheromaInapparent Atheroma
Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.
Slide Source:Lipids Onlinewww.lipidsonline.org
The Matrix Skeleton of UnstableThe Matrix Skeleton of UnstableCoronary Artery PlaqueCoronary Artery Plaque
Fissures inthe fibrous cap
Davies MJ. Circulation. 1996;94:2013-2020.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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
Slide Source:Lipids Onlinewww.lipidsonline.org
Cell Types in the Human Cell Types in the Human AtheromaAtheroma
MonocyteMonocyte//MacrophageMacrophage
TT--lymphocyteslymphocytesTunicaMedia
Intima
Smooth musclecells
EndotheliumEndothelium
Slide Source:Lipids Onlinewww.lipidsonline.org
++ 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)
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Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
AttachmentAttachment
Slide Source:Lipids Onlinewww.lipidsonline.org
LeukocyteLeukocyte––Endothelial Adhesion MoleculesEndothelial Adhesion Molecules
MonoMonoTT
BB PMNPMN
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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
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
PenetrationPenetration
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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
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
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Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
Division
Slide Source:Lipids Onlinewww.lipidsonline.org
Molecular Mediators ofMolecular Mediators of AtherogenesisAtherogenesis
M-CSFMCP-1
VCAM-1
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.
Slide Source:Lipids Onlinewww.lipidsonline.org
Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis
Thrombus Fibrous cap
1 mmLipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Slide Source:Lipids Onlinewww.lipidsonline.org
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.