In his presentation, Dr. Schwartz addressed the key role of a cell given little attention in the literature on atherosclerosis, the macrophage. After providing a basis for understanding the key role of macrophage cell death in precipitation of rupture and hemorrhage in atherosclerotic plaques, he used new, unpublished data to explain the current state of knowledge about the process through which these cells die.

Dr. Schwartz, whose research work utilizes a mouse model of atherosclerosis, began with a comparison review of atherosclerotic lesions in mice and humans. Progression of atherosclerosis in both species moves from reversible fatty streaks to development of complex plaques with thick fibrous caps. In mice, it is clear that these advanced plaques invariably have a cystic, necrotic core (a plaque feature originally described by Virchow). Once this core develops, roughly 80-90% of lesions will quickly show evidence of plaque rupture with hemorrhage near the edges (shoulders) of the lesions.

One contribution from this mouse research is the documentation of macrophage cell death as the precipitating event in the formation of the cystic core and in rupture and hemorrhage at the shoulders of the lesion. If macrophages do not die in the center of the plaque, the necrotic core does not develop. The development of the cystic core is key to the plaque fragility that precedes rupture. Rupture in the lesion's shoulder regions is also preceded by the death of macrophages.

After establishing that macrophages are vital and poorly understood players in the atherosclerotic process, Dr. Schwartz laid out the hypotheses on the cause of macrophage death that have propelled research in the field. The hypotheses involve three molecules: Fas, a ligand vital to apoptotic cell death, oxidized (esterified) low-density-lipoprotein cholesterol, also called oxidized LDL, and caspases, a family of proteases involved in the proteolysis that characterizes apoptotic cell death.

Although he didn't cite the supporting evidence, Dr. Schwartz stated that Fas clearly is not the molecular trigger for cell death. In part this is intuitive because macrophages, after their development from monocytes, become activated to produce the Fas molecule themselves.

Oxidized LDL cholesterol not only can kill macrophages, but it has been shown to do so very potently and in a dose response manner. Molecular study of macrophage death triggered by oxidized LDL has identified the presence of caspase activity in the dying cells. Researchers verified that it is a true (apoptotic) response through blockade with the caspase inhibitor called DVD.

Additional research with mice has shown that the pathway of oxidized LDL-caspase acitvity- cell death requires the ability of the cell to form Fas-Fas complexes. This pathway, which ends in creation of P17caspase-3, the molecule Dr. Schwartz termed the canonical killing agent of apoptosis, is very similar to the process that normally leads neutrophils to cell death.

Current and future work may enable researchers to identify targets for therapeutic intervention.