1. Role of Apoptosis in Vulnerable Plaques
Pedro R. Moreno, MD, FACC
Associate Professor of Medicine
Director
Interventional Cardiology Research
Mount Sinai Medical Center
New York, New York

2. Pedro R. Moreno, MD DISCLOSURES
I have no real or apparent conflicts of interest to report.

3. Three Pathways of Cell Death
Hotchkiss R et al. N Engl J Med 2009;361:

4. Compacted & Fragmented
Spleen lymphocytes
Nuclear debris
Caspase 9
Pathways of Cellular Apoptosis
Spleen
Compacted & Fragmented
Thymus
Compacted & Fragmented
nuclei
DNA strand breaks
Hotchkiss R et al. N Engl J Med 2009;361:

5. Macrophage and oxLDL LDL CAMs
Starry – Atlas of Athero 2001
Shear Stress
LDL
Mechanical
CAMs
PDGF ET
Adapted from Moreno PR, Sanz, Fuster V. JACC 2009

6. Plaque Rupture and Thrombosis
Apoptosis
Macrophage Apoptosis
Plaque Rupture and Thrombosis
Shrinkage of Cell membrane
Condensation of nuclear chromatin
Compaction and cellular fragmentation
Engulfment of apoptotic bodies
Egress from plaque (Efferocytosis)
Shear Stress
LDL
Mechanical
CAMs
Apoptosis
MMPs TF
PDGF ET
Galis Z, et al JCI 1994; 94: Mallat Z, et al. Circulation 1999;348-53
Kockx MM, et al. Circulation 1996; 94: Kolodgie FD, wt al. Am J Pathol 2000;157:
Kockx MM, et al. Circulation 1998; 97: Hutter R, et al. Circulation 2004;109:

7. Macrophage Apoptosis and Plaque Rupture
DAB (Brown)
In Macs only
Fragmented Nuclei
EMC confirmed shrinkage and concentration of chromatin with fragmented nuclei
Kolodgie FD, wt al. Am J Pathol 2000;157:

8. Macrophage Apoptosis and Plaque Rupture
Kolodgie FD, wt al. Am J Pathol 2000;157:

9. Human Macrophage Apoptosis and Thrombosis
Carotid Plaques
Coronary Plaques
Tissue Factor
TUNEL
Shed-membrane
microparticles
Hutter RH. Cir 2004;109;
Mallat Z. Cir 1999;99:

10. Expansion of Necrotic Core
Apoptosis
Macrophage Apoptosis
Expansion of Necrotic Core
Shrinkage of Cell membrane
Condensation of nuclear chromatin
cellular fragmentation
Engulfment of apoptotic bodies
Egress from plaque (Efferocytosis)
Shear Stress
LDL
Mechanical
CAMs
PDGF ET
Adapted from Moreno PR, Sanz, Fuster V. JACC 2009

11. Two Key Processes in Resolution of Inflammation
Decreased entry of Inflammatory cells.
Increased egress of cells from site of inflammation.
Tabas I. Nat Rev Immunol 2010;10:36-46

12. Abnormal Increased Entry of Inflammatory Cells
PNAS 2006;103:
JCI 2007;117:

13. Abnormal Decreased Egress (Efferocytosis) of Inflammatory Cells
PNAS 2004;101:
PNAS 2006;103:

14. Role of Macrophage Apoptosis in Expansion of Necrotic Core
Tabas I. Nat Rev Immunol 2010;10:36-46

15. Macrophage Efferocytosis of Apoptotic Cells
Tabas I. Nat Rev Immunol 2010;10:36-46

16. Apoptosis and Macrophage Efferocytosis
Montavani, et al
ATVB 2009;29:
Martinez FO, et al. Ann Rev Immunol 2009;10:

17. Macrophage Apoptosis and Expansion of Necrotic Core
Montavani, et al. ATVB 2009;29:
Tabas I. Nat Rev Immunol 2010;10:36-46

18. Conclusions
Programmed cell death is characteristic of Atherosclerosis.

19. Conclusions
Programmed cell death is characteristic of Atherosclerosis.
Apoptosis may be a significant contributor to plaque rupture.

20. Conclusions
Programmed cell death is characteristic of Atherosclerosis.
Apoptosis may be a significant contributor to plaque rupture.
Predominant apoptotic cell type in plaque rupture is the macrophage.

21. Conclusions
Programmed cell death is characteristic of Atherosclerosis.
Apoptosis may be a significant contributor to plaque rupture.
Predominant apoptotic cell type in plaque rupture is the macrophage.
Apoptosis is related to thrombosis through Tissue Factor pathway.

22. Conclusions
Programmed cell death is characteristic of Atherosclerosis.
Apoptosis may be a significant contributor to plaque rupture.
Predominant apoptotic cell type in plaque rupture is the macrophage.
Apoptosis is related to thrombosis through Tissue Factor pathway.
Apoptosis contributes to the expansion of lipid core through a disable efferocytosis pathway