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

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

Three Pathways of Cell Death Hotchkiss R et al. N Engl J Med 2009;361:1570-1583

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;361:1570-1583

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

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; 94:2493-503 Mallat Z, et al. Circulation 1999;348-53 Kockx MM, et al. Circulation 1996; 94:1255-62 Kolodgie FD, wt al. Am J Pathol 2000;157:1259-68 Kockx MM, et al. Circulation 1998; 97:2307-15 Hutter R, et al. Circulation 2004;109:2001-2008

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;157:1259-68

Macrophage Apoptosis and Plaque Rupture Kolodgie FD, wt al. Am J Pathol 2000;157:1259-68

Human Macrophage Apoptosis and Thrombosis Carotid Plaques Coronary Plaques Tissue Factor TUNEL Shed-membrane microparticles Hutter RH. Cir 2004;109;2001-2008 Mallat Z. Cir 1999;99:348-353

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

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

Abnormal Increased Entry of Inflammatory Cells PNAS 2006;103:10340-10345 JCI 2007;117:195-205

Abnormal Decreased Egress (Efferocytosis) of Inflammatory Cells PNAS 2004;101:11779-11784 PNAS 2006;103:5781-5786

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

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

Apoptosis and Macrophage Efferocytosis Montavani, et al ATVB 2009;29:1419-23 Martinez FO, et al. Ann Rev Immunol 2009;10:451-483

Macrophage Apoptosis and Expansion of Necrotic Core Montavani, et al. ATVB 2009;29:1419-23 Tabas I. Nat Rev Immunol 2010;10:36-46

Conclusions Programmed cell death is characteristic of Atherosclerosis.

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

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.

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.

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