Coronary heart disease (CHD) remains a leading cause of death and disability. Significant risk factors for CHD include age, gender, hypertension, smoking, increased low density lipoprotein cholesterol (LDL-C), and decreased high density lipoprotein cholesterol (HDL-C). The major HDL proteins are apolipoprotein (apo) A-I and A-II, and one of the minor protein constituents is apo C-III. Within HDL are particles containing apo A-I with apo A-II (LpA-I/A-II) and without apo A-II (LpA-I). In addition, HDL can be further separated in 12 apo A-I-containing subclasses of different size and charge, when subjected to two-dimensional gel electrophoresis immunoblot image analysis. It has been reported that CHD patients have significantly less large alpha 1 HDL particles, LpA-I, and apo C-III in HDL than control subjects. This application focuses on two distinct populations: 1) the Veterans Administration High Density Lipoprotein Intervention Trial (VA-HIT), a lipid intervention trial in men with CHD and low HDL-C levels (placebo: n=1,267; gemfibrozil: n=1,264), and 2) the Framingham Offspring Study (FOS), a prospective epidemiologic study in subjects without CHD (n=1,681). The investigators propose to measure in both populations the following parameters: apo A-I-containing HDL subspecies (prebeta, alpha, and prealpha) in plasma by two-dimensional gel electrophoresis immunoblot and image analysis, LpA-I and LpA-I/A-II in plasma by differential electroimmunoassay, and apo C-III in HDL by immuboturbidometric assay. The study hypotheses are as follow. a) Subjects from the placebo arm of VA-HIT will have significantly lower alpha l HDL subspecies, LpA-I, and apo C-III in HDL, and higher HDL/alpha l and apo A-I/alpha l ratios than subjects free of CHD from FOS. b) These parameters will also predict prospectively risk of CHD in both groups. c) In the VA-HIT study, treatment with gemfibrozil, which has been shown to be associated with a 22 percent reduction in myocardial infarction and CHD death, will be associated with increases in alpha l HDL subspecies, LpA-I, and apo C-III in HDL, as well as decreases in HDL/alpha l and apo A-I/alpha l ratios, compared to placebo. d) The hypothesis that subjects with specific mutations in the lipoprotein lipase gene have less beneficial changes in HDL subspecies with gemfibrozil than subjects with no mutations will also be tested. The investigators state that these studies should provide better understanding about the diagnosis and treatment of HDL deficiency for the prevention of CHD.
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