ATHEROSCLEROSIS - REVERSAL WITH THERAPY

Evidence for atherosclerosis reversal comes from studies in animals wh erein atherosclerosis is induced and then allowed to regress, autopsy studies of starved humans, and angiographic studies testing antiathero sclerosis treatment. Animal models and autopsy studies have provided d etailed histologic and biochemical descriptions of regression. Cellula r and subcellular information exists on what can occur, but because th e same lesions are not re-examined, what actually does occur is unknow n. Studies of isolated arterial cell systems and intact lesions indica te that atherogenesis involves at least the following: Increased perme ability of the endothelium to macromolecules such as low-density lipop rotein; platelet adherence to areas of functional endothelial injury o r denudation; the entrance of monocytes or macrophages and lymphocytes into the subintimal space; and the secretion of growth factors by pla telets, injured endothelium, and macrophages. These processes can be i nitiated or enhanced by various vasoactive agents that induce endothel ial cell constriction with the opening of endothelial junctions. These processes also can recruit smooth muscle cells from the media to the subintima where they proliferate. Proliferating smooth muscle cells, a long with macrophages, can internalize lipids and lipoproteins to form foam cells. Subintimal smooth muscle cells can also synthesize collag en, elastin, glycosaminoglycans, and other connective tissue elements that trap lipoproteins. Peroxidative injury increases the atherogenic potential of both cholesteryl ester-rich (low-density) and triglycerid e-rich (very-low-density and intermediate-density) lipoproteins. Steep oxygen gradients within the arterial wall create local conditions for free radical generation, and any increase in residence time of lipopr otein particles can be atherogenic. In summary, there are many areas w here treatment may retard or reverse atherogenesis. Angiographic trial s that identify and track individual human lesions have shown that red ucing known atherogenic risk factors can lessen coronary and femoral a therosclerosis. But they provide no information on events within arter ial wall cells or the intracellular matrix. They deal only with lesion s that intrude into the vessel lumen and obtain measurements at infreq uent intervals. The weight of evidence is that regression is possible, but there is no consensus on the most effective therapy. The challeng e for future trials is to select optimal targets for intervention amon g the known atherogenic processes.