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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL064738-02
Application #
6324948
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
2000-04-01
Project End
2004-02-28
Budget Start
2000-08-01
Budget End
2001-02-28
Support Year
2
Fiscal Year
2000
Total Cost
$502,617
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Asztalos, Bela F; Horan, Michael S; Horvath, Katalin V et al. (2014) Obesity associated molecular forms of C-reactive protein in human. PLoS One 9:e109238
Asztalos, Bela F; Swarbrick, Michael M; Schaefer, Ernst J et al. (2010) Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women. J Lipid Res 51:2405-12
Asztalos, Bela F; Collins, Dorothea; Horvath, Katalin V et al. (2008) Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Metabolism 57:77-83
Lamon-Fava, Stefania; Herrington, David M; Reboussin, David M et al. (2008) Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in postmenopausal women. Arterioscler Thromb Vasc Biol 28:575-9
Asztalos, Bela F; Schaefer, Ernst J; Horvath, Katalin V et al. (2007) Role of LCAT in HDL remodeling: investigation of LCAT deficiency states. J Lipid Res 48:592-9
Asztalos, Bela F; Demissie, Serkalem; Cupples, L Adrienne et al. (2006) LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial. Atherosclerosis 188:59-67
Asztalos, Bela F; Schaefer, Ernst J; Horvath, Katalin V et al. (2006) Protease inhibitor-based HAART, HDL, and CHD-risk in HIV-infected patients. Atherosclerosis 184:72-7
Asztalos, Bela F; de la Llera-Moya, Margarita; Dallal, Gerard E et al. (2005) Differential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux. J Lipid Res 46:2246-53
Asztalos, Bela F; Collins, Dorothea; Cupples, L Adrienne et al. (2005) Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol 25:2185-91
Asztalos, Bela F; Horvath, Katalin V; Kajinami, Kouji et al. (2004) Apolipoprotein composition of HDL in cholesteryl ester transfer protein deficiency. J Lipid Res 45:448-55

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