1. Pathogenesis of Acute Coronary Syndromes Nathan Wong
BIOGRAPHICAL SKETCH(../lec5081/sketch.htm)

2. Schematic Time Course of Human Atherogenesis
Ischemic Heart Disease
Cerebrovascular Disease
Peripheral Vascular Disease
BIOGRAPHICAL SKETCH(../lec5081/sketch.htm)
Transition from chronic to acute atheroma

3. Atherosclerosis: A Progressive Process
Plaque Rupture/ Fissure & Thrombosis
Occlusive
Atherosclerotic Plaque
Fatty Streak
Fibrous Plaque
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
Lipid core
Fibrous cap
Lumen
Media
– T lymphocyte
– Macrophage foam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR+)
– Normal medial SMC
Libby P. Lancet. 1996;348:S4-S7.

5. Angiographically Inapparent Atheroma
Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.

6. The Matrix Skeleton of Unstable Coronary Artery Plaque
Fissures in
the fibrous cap
Davies MJ. Circulation. 1996;94:

7. Characteristics of Plaques Prone to Rupture
Fibrous cap
Media
Lumen
Lipid
core
area of detail
“Vulnerable” plaque
Lumen
– T lymphocyte
– Macrophage foam cell (tissue factor+)
Lipid
core
– “Activated” intimal SMC (HLA-DR+)
– Normal medial SMC
“Stable” plaque
Libby P. Circulation. 1995;91:

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. 1995;91:

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
Intima
Endothelium
Tunica Media
T-lymphocytes
Smooth muscle cells

11. Schematic Time Course of Human Atherogenesis
Ischemic Heart Disease
Cerebrovascular
Disease
Peripheral Vascular Disease
Lesion initiation
No symptoms
+ Symptoms
Symptoms
Time (y)

12. Macrophage Functions in Atherogenesis
Attachment

13. Leukocyte–Endothelial 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 1993;13:

16. VCAM-1 Expression in Rabbit Aorta
3 weeks on atherogenic diet
Li H et al. Arterioscler Thromb 1993;13:

17. Macrophage Functions in Atherogenesis
Penetration

18. 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 receptor–deficient mice
Gu L et al. Mol Cell 1998;2:

20. Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice
LDL-R –/– MCP-1 +/+
LDL-R –/– MCP-1 –/–
Gu L et al. Mol Cell 1998;2:

21. Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice
% Aortic Surface Stained
Oil Red Staining ** *
Gu L et al. Mol Cell 1998;2:
+/+
-/-
+/+
-/-
Time on Diet:
12 – 14 weeks
20 – 25 weeks
*P = compared to +/+ **p = 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 Plaque’s Fibrous Cap
Synthesis
Breakdown
Collagen-degrading
Proteinases
Fibrous cap
IFN- –
CD-40L + + + +
IL-1 TNF- MCP-1 M-CSF + +
Lipid core
Tissue Factor
Procoagulant
Libby P. Circulation 1995;91:

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 1994;94:

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.