Pathogenesis of Acute

1
Pathogenesis of Acute Coronary Syndromes
Nathan Wong
2
Schematic Time Course of Human Atherogenesis
Ischemic HeartDisease
CerebrovascularDisease
Peripheral VascularDisease
Transition from chronic to acute atheroma
3
Atherosclerosis A Progressive Process
PlaqueRupture/Fissure Thrombosis
Occlusive AtheroscleroticPlaque
FattyStreak
FibrousPlaque
Unstable Angina
Normal
MI
Coronary Death
Stroke
Effort Angina Claudication
Clinically Silent
Critical Leg Ischemia
Increasing Age
Courtesy of P Ganz.
4
The Anatomy of Atherosclerotic Plaque
Intima
Lipidcore
Fibrouscap
Lumen
Media
T lymphocyte
Macrophagefoam cell (tissue factor)
Activated intimal SMC (HLA-DR)
Normal medial SMC
Libby P. Lancet. 1996348S4-S7.
5
Angiographically Inapparent Atheroma
Nissen et al. In Topol. Interventional
Cardiology Update. 141995.
6
The Matrix Skeleton of UnstableCoronary Artery
Plaque
Fissures in the fibrous cap
Davies MJ. Circulation. 1996942013-2020.
7
Characteristics of Plaques Prone to Rupture
Fibrous cap
Media
Lumen
Lipid core
area ofdetail
Vulnerable plaque
T lymphocyte
Lumen
Macrophagefoam cell (tissue factor)
Lipid core
Activated intimal SMC (HLA-DR)
Normal medial SMC
Stable plaque
Libby P. Circulation. 1995912844-2850.
8
Proposed Mechanisms of Event Reduction 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

Libby P. Circulation. 1995912844-2850.
9
Atheroma are not merely filled with lipid, but
contain cells whose functions critically
influence atherogenesis

• Intrinsic Vascular Wall Cells
• Endothelium
• Smooth Muscle Cells
• Inflammatory Cells
• Macrophages
• T Lymphocytes
• Mast Cells

10
Cell Types in the Human Atheroma
Monocyte/Macrophage
Endothelium
Intima
TunicaMedia
T-lymphocytes
Smooth musclecells
11
Schematic Time Course of Human Atherogenesis
Ischemic HeartDisease
Cerebrovascular Disease
Peripheral VascularDisease
Lesion initiation
No symptoms
Symptoms
Symptoms
Time (y)
12
Macrophage Functions in Atherogenesis
Attachment
13
LeukocyteEndothelial Adhesion Molecules
Mono
T
PMN
B
14
Vascular Cell Adhesion Molecule 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

15
An atherogenic diet rapidly induces VCAM-1, a
cytokine-regulatable mononuclear leukocyte
adhesion molecule, in rabbit aortic endothelium
Li H et al. Arterioscler Thromb 199313197-204.
16
VCAM-1 Expression in Rabbit Aorta
3 weeks on atherogenic diet
Li H et al. Arterioscler Thromb 199313197-204.
17
Macrophage Functions in Atherogenesis
Penetration
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Monocyte Chemoattractant Protein 1(MCP-1)

• A potent mononuclear cell chemoattractant
• Produced by endothelial and smooth muscle cells
• Localizes in human and experimental atheroma

19
Absence of monocyte chemoattractant protein-1
reduces atherosclerosis in low-density
lipoprotein receptordeficient mice
Gu L et al. Mol Cell 19982275-281.
20
Reduced Lipid Deposition in MCP-1Deficient
Atherosclerotic Mice
LDL-R /MCP-1 /
LDL-R /MCP-1 /
Gu L et al. Mol Cell 19982275-281.
21
Reduced Lipid Deposition in MCP-1Deficient
Atherosclerotic Mice
Oil Red Staining Aortic Surface Stained


/
-/-
/
-/-
Time on Diet
12 14 weeks
20 25 weeks
P 0.001 compared to /p 0.005 compared
to /
22
Macrophage Functions in Atherogenesis
Division
23
Molecular Mediators of Atherogenesis
VCAM-1
MCP-1
M-CSF
24
Matrix Metabolism and Integrity of the Plaques
Fibrous Cap
Synthesis
Breakdown
Fibrouscap
Collagen-degrading Proteinases
IFN-?

CD-40L




IL-1TNF-?MCP-1M-CSF


Tissue Factor Procoagulant
Lipid core
Libby P. Circulation 1995912844-2850.
25
Increased Expression of Interstitial Collagenase
(CL) by Smooth Muscle Cells (SMC) and Macrophages
(M?) in Human Atheroma
Galis ZS et al. J Clin Invest 1994942493-2503.
26
Plaque Rupture with Thrombosis
Fibrous cap
Thrombus
1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen,
M.D., Ph.D.
27
Thrombosis of a Disrupted Atheroma, the Cause of
Most Acute Coronary Syndromes, Results from

• Weakening of the fibrous cap
• Thrombogenicity of the lipid core

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