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Cigarette smoking is one of the established risk factors for the premature development of atherosclerotic cardiovascular disease. This disease is manifested by an increased incidence of heart attacks, strokes, and loss of blood supply to the kidneys and limbs of the afflicted individuals. It constitutes, as a whole, the primary cause of age-adjusted mortality in Western countries, and will, early in the next century, occupy that position on a worldwide basis. Considerable progress has been made in identifying risk factors for this process, and in developing strategies to alter the impact of these risk factors. Perhaps, the greatest understanding and the greatest impact has been in the area of lipid metabolism. Here, an elevated LDL and a lowered HDL are well-established risk factors, and correcting these, particularly the elevated LDL level, has had a major impact in the subgroup of patients that have this risk factor. Similarly, identifying and treating hypertension has helped control morbidity and mortality in this group. Obviously, ceasing cigarette smoking is the best cure for the abnormalities induced by smoking cigarettes. Realistically, however, a large portion of the world's population will not do this. Accordingly, understanding and intervening in this population could become an important target for reducing cardiovascular morbidity and mortality. Several mechanisms whereby cigarette smoke can cause increased morbidity and mortality due to atherosclerotic cardiovascular disease, have been proposed. Direct effects of cigarette components on the vascular wall almost certainly occur and probably contribute to the pathology. In addition, the ability of some of the constituents of cigarette smoke to contribute to the sensitivity of LDL to oxidation has been postulated to be a cause of the vascular pathology that occurs. It is also well established that smoker's have a profile of blood lipids that is characteristic of the so-called metabolic syndrome. It has emerged that an important component of this syndrome is a delay in the rate at which lipids and lipoproteins that originate in the diet are removed from the circulation by the liver. A delay in the removal of chylomicron remnants is becoming established as an important risk factor for premature atherosclerosis independent of the other risk factors, including those related to lipids and lipoproteins. Several recent reports have documented that this abnormality also occurs in cigarette smokers. This is true in animal models as well as in humans. The purpose of this application is to study the genesis of this abnormality, study the role of certain proteins on the liver cell (LDL receptors) in the creation of this abnormality in cigarette smokers, and establish the ability of certain therapeutic agents to correct this abnormality. In addition, we will examine the composition and biological behavior of the chylomicron remnants that accumulate in cigarette smokers. The hypothesis to be tested here is that with delayed removal of chylomicron remnants from the circulation, the particles undergo changes in both their chemical and biological properties so that they are capable of initiating the process of atherosclerosis. Techniques that are either established or have been pioneered by our laboratory will be used to conduct these studies. Highly experienced collaborators in clinical investigation and the resources of the Stanford University General Clinical research Center are available for these studies, as are very sophisticated techniques for studying interactions of inflammatory cells with the vessel wall. |
