Atherosclerosis: Basic mechanisms: Oxidation, inflammation, and genetics

Atherosclerosis: Basic mechanisms: Oxidation, inflammation, and genetics

KNOWLEDGE Dr. Davies: No, I think old peoples' atheroma are much the same as the middle-aged person's atheroma. The one exception is that the older y...

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Dr. Davies: No, I think old peoples' atheroma are much the same as the middle-aged person's atheroma. The one exception is that the older you are the more likely there is to be calcification. But calcification really does not play a part in plaque disruption or plaque vulnerability. Calcification is a nuisance to pathologists and surgeons but I don't think it's terribly important otherwise. Dr. Weinberg: May we return to the concept of cell death and apoptosis? Dr. Davies: Apoptosis is a very interesting phenomenon where the cell is told to commit suicide. To put it in a rather emotive way, the cell receives a message that causes it to start synthesizing proteases within the nucleus, the DNA is cleaved and the cell dies. Quite different from necrosis. In apoptosis, the cell collapses into itself and becomes a little dark body. Probably this is the mechanism by which macrophages die and the lipid they contain gets added to the lipid inside the core region. Dr. Weinberg: What is the trigger for this activity? Dr. Davies: It is very difficult to say. It was once thought that macrophage death was due to the cytotoxicity of the lipid itself. But I think we would now have to modify that slightly and say that for some reason the macrophage is given a message to commit suicide. Dr. Weinberg: What is the process by which macrophages destroy connective tissue? Dr. Davies: Macrophages when they're activated under inflammatory stimuli produce a range of substances known as metalloproteinases. There is a whole family of them. They are secreted in an inactive form and, interestingly, are activated by plasmin to an active enzyme. There is a great deal of evidence now that the evolving active plaque has very high levels of the whole range of metalloproteinases produced by macrophages. It is as if the plaque or the plaque connective tissue has been told to go into an autodestruct mode. Dr. Weinberg: It is clear that when we look at the results of the information we get in the cardiac catheterization laboratories, we are really dealing with very crude information about a very complex subject. Dr. Davies: I would agree. The angiogram tells you absolutely nothing about plaque composition or plaque activity. We need other tools. (Ed.)


tion factor and induce the expression of genes containing NF•B binding sites. The protein products of these genes initiate an inflammatory response that initially leads to the development of the fatty streak. The progression of the lesion is associated with the activation of genes that induce arterial calcification, which changes the mechanical characteristics of the artery wail and predisposes to plaque rupture at sites of monocytic infiltration. Plaque rupture exposes the flowing blood to tissue factor in the lesion, and this induces thrombosis, which is the proximate cause of the clinical event. There appear to be potent genetically determined systems for preventing lipid oxidation, inactivating biologically important oxidized lipids, and/or modulating the inflammatory response to oxidized lipids that may explain the differing susceptibility of individuals and populations to the development of atherosclerosis. Enzymes associated with HDL may play an important role in protecting against lipid oxidation in the artery wall and may account in part for the inverse relation between HDL and risk for atherosclerotic clinical events.

What Benefit Can be Derived From Treating Normocholesterolemic Patients With Coronary Artery Disease? B.G. Brown,B.F. Stewart,X.-Q. Zhao,L~ Hillger,D. Poulin,J.J.Albm. Cardiology Division,Departmentof Medicine,Univmi~ of WashingtonSchoolof Medicine, Seattle,W~ Am J Cardiol 1995;76:93C-7. Controversy still remains regarding the possible clinical or arteriographic benefit of intensive lipid-altering therapy in patients who have coronary artery disease and apparently normal lipid levels. Resolution of this controversy appears to depend on an improved understanding of the role of variables other than total or low density lipoprotein cholesterol levels. A comparison of the "normolipidemic" subgroup of The Familial Atherosclerosis Treatment Study patients and The Harvard Atherosclerosis Reversibility Project patients indicates that low levels of high density lipoprotein cholesterol and elevated levels of apolipoprotein B appear to increase considerably the likelihood of benefit from intensive lipid-altering therapy. Other risk-related variables such as systolic blood pressure and lipoprotein(a) further contribute to the prediction of risk and possibly to the potential for treatment benefit.

Atherosclerosis: Basic Mechanisms: Oxidation, Inflammation, and Genetics J~. Bediner,M. Navab,A.M. Fogelman,J.S.FrantqLL Demer,P~. Edwards,A.D. Watson,A.J.Lusis.Departmentof Medicine,UCLASchoolof Medicine,LosAngeles, CA. Circulation1995;91:2488-96.

The Influence of Pretreatment Low Density Lipoprotein Cholesterol Concentrations on the Effect of Hypocholesterolemic Therapy on Coronary Atherosclerosis in Angiographic Trials F.M. Sacks,C.M.Gibson,B. Rosner,R.C.PasternalqP.H. Stone.NutritionDepartment, HarvardSchoolof PublicHealth,Boston,MA. Am J Cardiol 1995;76:78C-85.

The clinical events resulting from atherosclerosis are directly related to the oxidation of lipids in LDLs that become trapped in the extracellular matrix of the subendothelial space. These oxidized lipids activate an NFKB-like transcrip-

Angiographic trials of coronary atherosclerosis treatment have demonstrated that lowering low density lipoprotein