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Slide Source:Lipids Onlinewww.lipidsonline.org
Pathogenesis of AcuteCoronary Syndromes
Nathan Wong
Slide Source:Lipids Onlinewww.lipidsonline.org
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Transition from chronic to acute atheromaTransition from chronic to acute atheroma
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
Slide Source:Lipids Onlinewww.lipidsonline.org
NormalNormalFattyFatty
StreakStreakFibrousFibrousPlaquePlaque
Occlusive Occlusive AtheroscleroticAtherosclerotic
PlaquePlaque
PlaquePlaqueRupture/Rupture/Fissure &Fissure &
ThrombosisThrombosis
MIMI
StrokeStroke
Critical Leg Critical Leg IschemiaIschemia
Clinically SilentClinically Silent
Coronary Coronary DeathDeath
Increasing AgeIncreasing Age
Effort AnginaEffort AnginaClaudicationClaudication
UnstableUnstableAnginaAngina
Atherosclerosis: A Progressive ProcessAtherosclerosis: A Progressive Process
Courtesy of P Ganz.
Slide Source:Lipids Onlinewww.lipidsonline.org
Libby P. Lancet. 1996;348:S4-S7.
Media
– T lymphocyte
– Macrophagefoam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR+)
– Normal medial SMC
Fibrouscap
IntimaLipidcore
Lumen
The Anatomy of Atherosclerotic PlaqueThe Anatomy of Atherosclerotic Plaque
Slide Source:Lipids Onlinewww.lipidsonline.org
Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.
Angiographically Inapparent AtheromaAngiographically Inapparent Atheroma
Slide Source:Lipids Onlinewww.lipidsonline.org
The Matrix Skeleton of UnstableThe Matrix Skeleton of UnstableCoronary Artery PlaqueCoronary Artery Plaque
Davies MJ. Circulation. 1996;94:2013-2020.
Fissures inthe fibrous cap
Slide Source:Lipids Onlinewww.lipidsonline.org
Libby P. Circulation. 1995;91:2844-2850.
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
Lumen
area ofdetail
MediaFibrous cap
Lumen
Lipidcore
Lipidcore
Slide Source:Lipids Onlinewww.lipidsonline.org
Libby P. Circulation. 1995;91:2844-2850.
Proposed Mechanisms of Event Proposed Mechanisms of Event Reduction by Lipid-Lowering TherapyReduction by Lipid-Lowering 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 of atherosclerotic lesions
Slide Source:Lipids Onlinewww.lipidsonline.org
Atheroma are not merely filled with lipid, Atheroma are not merely filled with lipid, but contain cells whose functions critically but contain cells whose functions critically influence atherogenesis:influence atherogenesis:
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 AtheromaCell Types in the Human Atheroma
Monocyte/Monocyte/MacrophageMacrophage
T-lymphocytesT-lymphocytesTunicaMedia
Intima
Smooth musclecells
EndotheliumEndothelium
Slide Source:Lipids Onlinewww.lipidsonline.org
No No symptomssymptoms ++ Symptoms Symptoms
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Time (y)Time (y)
SymptomsSymptoms
Lesion initiationLesion initiation
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
Slide Source:Lipids Onlinewww.lipidsonline.org
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
AttachmentAttachment
Slide Source:Lipids Onlinewww.lipidsonline.org
Leukocyte–Endothelial Adhesion MoleculesLeukocyte–Endothelial Adhesion Molecules
MonoMonoTT
BB PMNPMN
Slide Source:Lipids Onlinewww.lipidsonline.org
Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1(VCAM-1)(VCAM-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 atherogenic diet rapidly induces An atherogenic diet rapidly induces
VCAM-1, a cytokine-regulatable VCAM-1, a cytokine-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
VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit Aorta
Li H et al. Arterioscler Thromb 1993;13:197-204.
3 weeks on atherogenic diet
Slide Source:Lipids Onlinewww.lipidsonline.org
PenetrationPenetration
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Slide Source:Lipids Onlinewww.lipidsonline.org
Monocyte Chemoattractant Protein 1Monocyte Chemoattractant Protein 1(MCP-1)(MCP-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 monocyte chemoattractant Absence of monocyte chemoattractant
protein-1 reduces atherosclerosis in protein-1 reduces atherosclerosis in
low-density lipoprotein receptor–low-density 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 MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
Gu L et al. Mol Cell 1998;2:275-281.
LDL-R –/–LDL-R –/–
MCP-1 +/+MCP-1 +/+
LDL-R –/–LDL-R –/–
MCP-1 –/–MCP-1 –/–
Slide Source:Lipids Onlinewww.lipidsonline.org
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
0
5
10
15
20
25
30
Oil
Red S
tain
ing
% 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 +/+
Slide Source:Lipids Onlinewww.lipidsonline.org
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Division
Slide Source:Lipids Onlinewww.lipidsonline.org
Molecular Mediators of AtherogenesisMolecular Mediators of Atherogenesis
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
Libby P. Circulation 1995;91:2844-2850.
+ + + +
++
–
Synthesis Breakdown
Lipid core
IL-1TNF-MCP-1M-CSF
FibrouscapIFN-IFN-
CD-40L
Collagen-degradingCollagen-degradingProteinasesProteinases
Tissue FactorTissue FactorProcoagulantProcoagulant
Slide Source:Lipids Onlinewww.lipidsonline.org
Increased Expression of Interstitial Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M(SMC) and Macrophages (M) 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 Atheroma, the Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Cause of Most Acute Coronary Syndromes, Results from:Syndromes, Results from:
Weakening of the fibrous cap
Thrombogenicity Thrombogenicity of the lipid coreof the lipid core
Illustration courtesy of Michael J. Davies, M.D.