Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study.

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Body weight, plasma insulin, and coronary events with gemfibrozil in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT).

BACKGROUND: The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that gemfibrozil significantly reduced major coronary events in men with known coronary heart disease (CHD). To better understand why therapy was especially effective with obesity, diabetes, and hyperinsulinemia, changes in body weight and plasma insulin were determined after 1 year of gemfibrozil or placebo therapy and related to changes in lipids and CHD events. RESULTS: With gemfibrozil significantly more subjects lost weight (51.7% versus 38.6%, P<0.0001) and significantly fewer subjects gained weight (42.5% versus 54.0%, P<0.0001) than with placebo. Both a greater loss and smaller gain in weight with gemfibrozil were age-related and significant in subjects > or =66 years (median age), but not in younger subjects. Weight change was paralleled by changes in insulin. With gemfibrozil, CHD events were significantly reduced with weight loss (hazard ratio [HR], 0.61; 95% CI, 0.44-0.84; P=0.002) and, particularly, with diabetes or hyperinsulinemia (HR, 0.53; 95% CI, 0.34-0.83; P=0.006). In contrast, CHD events were not significantly reduced without weight loss (HR, 0.83; 95% CI, 0.62-1.12; P=0.22). CONCLUSIONS: In VA-HIT, gemfibrozil resulted in weight loss associated with reductions in insulin. With weight loss gemfibrozil produced a significant reduction in CHD events that did not occur in the absence of weight loss.

Clinical utility of different lipid measures for prediction of coronary heart disease in men and women.

CONTEXT: Evidence is conflicting regarding the performance of apolipoproteins vs traditional lipids for predicting coronary heart disease (CHD) risk. OBJECTIVES: To compare performance of different lipid measures for CHD prediction using discrimination and calibration characteristics and reclassification of risk categories; to assess incremental utility of apolipoproteins over traditional lipids for CHD prediction. DESIGN, SETTING, AND PARTICIPANTS: Population-based, prospective cohort from, Framingham, Massachusetts. We evaluated serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, apolipoprotein (apo) A-I and apo B, and 3 lipid ratios (total cholesterol:HDL-C, LDL-C:HDL-C, and apo B:apo A-I) in 3322 middle-aged white participants who attended the fourth offspring examination cycle (1987-1991) and were without cardiovascular disease. Fifty-three percent of the participants were women. MAIN OUTCOME MEASURE: Incidence of first CHD event (recognized or unrecognized myocardial infarction, angina pectoris, coronary insufficiency, or coronary heart disease death). RESULTS: After a median follow-up of 15.0 years, 291 participants, 198 of whom were men, developed CHD. In multivariate models adjusting for nonlipid risk factors, the apo B:apo A-I ratio predicted CHD (hazard ratio [HR] per SD increment, 1.39; 95% confidence interval [CI], 1.23-1.58 in men and HR, 1.40; 95% CI, 1.16-1.67 in women), but risk ratios were similar for total cholesterol:HDL-C (HR, 1.39; 95% CI, 1.22-1.58 in men and HR, 1.39; 95% CI, 1.17-1.66 in women) and for LDL-C:HDL-C (HR, 1.35; 95% CI, 1.18-1.54 in men and HR, 1.36; 95% CI 1.14-1.63 in women). In both sexes, models using the apo B:apo A-I ratio demonstrated performance characteristics comparable with but not better than that for other lipid ratios. The apo B:apo A-I ratio did not predict CHD risk in a model containing all components of the Framingham risk score including total cholesterol:HDL-C (P = .12 in men; P = .58 in women). CONCLUSIONS: In this large, population-based cohort, the overall performance of apo B:apo A-I ratio for prediction of CHD was comparable with that of traditional lipid ratios but did not offer incremental utility over total cholesterol:HDL-C. These data do not support measurement of apo B or apo A-I in clinical practice when total cholesterol and HDL-C measurements are available.

Polyacrylamide gradient gel electrophoresis of lipoprotein subclasses.

High-density (HDL), low-density (LDL), and very-low-density (VLDL) lipoproteins are heterogeneous cholesterol-containing particles that differ in their metabolism, environmental interactions, and association with disease. Several protocols use polyacrylamide gradient gel electrophoresis (GGE) to separate these major lipoproteins into known subclasses. This article provides a brief history of the discovery of lipoprotein heterogeneity and an overview of relevant lipoprotein metabolism, highlighting the importance of the subclasses in the context of their metabolic origins, fates, and clinical implications. Various techniques using polyacrylamide GGE to assess HDL and LDL heterogeneity are described, and how the genetic and environmental determinations of HDL and LDL affect lipoprotein size heterogeneity and the implications for cardiovascular disease are outlined.

A brief history of lipid and lipoprotein measurements and their contribution to clinical chemistry.

The study of modern lipid chemistry began in the 17th and 18th centuries with early observations by Robert Boyle, Poulletier de la Salle, Antoine François de Fourcroy and others. The 19th century chemist, Chevreul, identified several fatty acids, suggested the name 'cholesterine' for the fatty substance in gallstones, coined the word 'glycerine', and showed that fats were comprised of glycerol and fatty acids. The 20th century brought many advances in the understanding of lipoprotein structure and function, and explored relationships between lipoproteins and disease states. The development of the ultracentrifuge and other lipoprotein separation techniques, and reagents for accurate, standardized quantitative measurement have steadily increased our understanding of the important role of lipoprotein metabolism in both healthy and disease states.

Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial.

BACKGROUND: Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease (CHD) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). We examined whether measurement of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses provides additional information relative to CHD risk reduction. METHODS AND RESULTS: This is a prospective nested case-control study of 364 men with a new CHD event (nonfatal myocardial infarction or cardiac death) during a 5.1-year (median) follow-up and 697 age-matched controls. Nuclear magnetic resonance (NMR) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo. Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models. Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles (-5%) while raising numbers of HDL particles (10%) and small HDL subclass particles (21%). Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant, independent predictors of new CHD events. For total LDL and HDL particles, odds ratios predicting CHD benefit were 1.28 (95% CI, 1.12 to 1.47) and 0.71 (95% CI, 0.61 to 0.81), respectively. Mean LDL and HDL particle sizes were not associated with CHD events. CONCLUSIONS: The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, which are not reflected by conventional lipoprotein cholesterol measures, help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol.

Are remnant-like particles independent predictors of coronary heart disease incidence? The Honolulu Heart study.

BACKGROUND: Remnant-like particles have been proposed as a new risk factor for coronary heart disease (CHD). This is the first long-term prospective investigation of the relationship between remnant-like particles and a cardiovascular disease outcome in healthy men. METHODS AND RESULTS: A cohort of 1156 Japanese-American men aged 60 to 82 from the Honolulu Heart Program was followed for 17 years. During that period 164 incident cases of CHD were identified. In multivariate Cox regression analyses, baseline remnant-like particle cholesterol (RLP-C) and triglyceride (RLP-TG) levels were significantly related to CHD incidence independently of nonlipid cardiovascular risk factors and of total cholesterol or high-density and low-density lipoprotein cholesterol levels. Total triglyceride levels were an independent predictor of CHD incidence. However, in models including RLP and triglyceride level simultaneously, neither variable was significant when adjusted for the other. This finding can be attributed to the strong correlation between RLP-C and RLP-TG levels and total triglycerides. When individuals with normal triglyceride levels (n=894) were separated from those with elevated triglycerides (n=260), the association between RLPs and CHD relative risk was only significant for the group with elevated triglyceride levels. CONCLUSIONS: RLP levels predicted CHD incidence independently of nonlipid risk factors and of total cholesterol or high-density and low-density lipoprotein cholesterol levels. However, RLP levels did not provide additional information about CHD incidence over and above total triglyceride levels. Therefore, this study does not support the need for testing of remnants in men if measures of fasting triglycerides are available.

Differences in serum sex hormone and plasma lipid levels in Caucasian and African-American premenopausal women.

CONTEXT: Risk of coronary heart disease is higher in African-American than in Caucasian women. OBJECTIVE: The aim of this study was to evaluate the contribution of sex hormone levels, race, and measures of body fat to the variation in plasma lipid levels, a well-established risk factor for coronary heart disease. DESIGN: This was a cross-sectional study. SETTING: The study was conducted in the general community. STUDY PARTICIPANTS: Sixty Caucasian and 117 African-American premenopausal women participated. MAIN OUTCOME MEASURES: Body weight, body mass index (BMI), and waist to hip circumference ratio (WHR), as well as plasma lipid and serum sex hormone levels, were assessed. RESULTS: Relative to Caucasian women, African-American women had significantly higher mean BMI (23.92 +/- 3.87 vs. 26.99 +/- 5.87 kg/m2, respectively; P < 0.001), and WHR (0.733 +/- 0.052 vs. 0.757 +/- 0.068; P < 0.03). Also, plasma triglyceride (TG) levels were significantly lower in African-American women (81 +/- 61 vs. 55 +/- 24 mg/dl; P < 0.0001). Serum estrone sulfate (556 +/- 323 vs. 442 +/- 332 pg/ml, Caucasian vs. African-American; P < 0.001), estradiol (E2) (55.1 +/- 43.6 vs. 35.8 +/- 17.7 pg/ml; P < 0.0001), androstenedione (2.6 +/- 0.9 vs. 1.6 +/- 0.7 ng/ml; P < 0.0001), and testosterone (0.36 +/- 0.12 vs. 0.31 +/- 0.19 ng/ml; P < 0.002) levels were significantly lower in African-American women than in Caucasian women. After correction for the effects of age, BMI, and WHR, serum E2 levels were significantly and positively associated with plasma high-density lipoprotein cholesterol levels in all women, and serum estrone sulfate levels with plasma total cholesterol and TG levels in African-American women. CONCLUSIONS: Our results indicate that race is an important determinant of plasma TG and serum sex hormone levels, even after adjustment for differences in body size. A significant association between endogenous E2 and high-density lipoprotein cholesterol levels exists in premenopausal women, independent of their race.

Effects of atorvastatin versus other statins on fasting and postprandial C-reactive protein and lipoprotein-associated phospholipase A2 in patients with coronary heart disease versus control subjects.

The effects of atorvastatin (40 mg/day) versus placebo on fasting and postprandial plasma levels of high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were examined over 36 weeks in 84 patients who had coronary heart disease and low-density lipoprotein cholesterol levels >130 mg/dl and compared directly with the effects of fluvastatin, lovastatin, pravastatin, and simvastatin. Results were also compared with those obtained in age- and gender-matched control subjects (n = 84). Feeding increased median hs-CRP levels by 2% in patients (p = NS) and 22% in controls (p <0.01) and increased mean Lp-PLA2 values by 9% in patients (p = NS) but decreased values by 21% in controls (p <0.0001). Patients had 51% higher median hs-CRP values and 29% higher mean Lp-PLA2 values than did controls (p <0.05 for hs-CRP and Lp-PLA2) in the fasting state; however, Lp-PLA2 values were 62% higher (p <0.0001) in the fed state in patients compared with controls. Atorvastatin decreased median hs-CRP levels by 32% (p <0.01) and mean Lp-PLA2 values by 26% in patients (p <0.0001), with similar decreases in the fed state, and none of the other statins had any significant effect on these parameters. Change in Lp-PLA2 was significantly related to change in low-density lipoprotein cholesterol (p <0.01), with no significant relations with change in hs-CRP. Our data indicate greater differences in patients with coronary heart disease compared with controls in Lp-PLA2 in the fed state than in the fasting state and that atorvastatin is more effective than fluvastatin, lovastatin, pravastatin, or simvastatin for decreasing not only low-density lipoprotein cholesterol but also hs-CRP and Lp-PLA2.

Fish consumption shifts lipoprotein subfractions to a less atherogenic pattern in humans.

The effect of fish consumption on plasma lipoprotein subfraction concentrations was studied in 22 men and women (age > 40 y). Subjects were provided an average American diet (AAD, 35% of energy as fat, 14% as saturated fat, and 35 mg cholesterol/MJ) for 6 wk before being assigned to a National Cholesterol Education Program (NCEP) Step 2 high-fish diet (n = 11, 26% of energy as fat, 4.5% as saturated fat, and 15 mg cholesterol/MJ) or a NCEP Step 2 low-fish diet (n = 11, 26% of energy as fat, 4.0% as saturated fat, and 11 mg cholesterol/MJ) for 24 wk. All food and drink were provided to study participants. Consumption of the high-fish NCEP Step 2 diet was associated with a significant reduction in medium and small VLDL, compared with the AAD diet, whereas the low-fish diet did not affect VLDL subfractions. Both diets significantly reduced LDL cholesterol concentrations, without modifying LDL subfractions. Both diets also lowered HDL cholesterol concentrations. However, the high-fish diet significantly lowered only the HDL fraction containing both apolipoprotein (apo) AI and AII (LpAI:AII) and did not change HDL subfractions assessed by NMR, whereas the low-fish diet significantly lowered the HDL fraction containing only apo AI (LpAI) and the large NMR HDL fractions, resulting in a significant reduction in HDL particle size. Neither diet affected VLDL and LDL particle size. Our data indicate that within the context of a diet restricted in fat and cholesterol, a higher fish content favorably affects VLDL and HDL subspecies.

Plasma lipid and lipoprotein levels during the follicular and luteal phases of the menstrual cycle.

Estrogen levels are higher during the luteal compared with the follicular phase of the menstrual cycle. It was hypothesized that the luteal compared with the follicular phase has a lipid and lipoprotein profile associated with decreased coronary heart disease (CHD) risk. This was tested using well-defined data from healthy, well-characterized premenopausal Caucasian women under very controlled metabolic conditions. The percent differences in lipid, lipoprotein, and sex hormone levels between the follicular and luteal phases were estimated using generalized estimating equations after adjusting for age, body mass index, calendar time, and season. The low-density lipoprotein cholesterol (LDL-C) level was 6.2% lower (P = 0.015), and the total cholesterol/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were 5.1% (P = 0.0006) and 8.4% (P = 0.002) lower, respectively, during the luteal phase. Levels of estradiol and other estrogens were significantly higher (by>100% each; P < 0.0001 in all cases) in the luteal phase. These findings support the study hypothesis. Fluctuations in levels of LDL-C and the total cholesterol/HDL-C and LDL-C/HDL-C ratios between menstrual cycle phases need to be considered in the screening and medical monitoring of premenopausal women, especially those with borderline levels. Although small, such fluctuations may prove to be clinically significant in the long run. Studies involving premenopausal women need to more clearly define and validate menstrual cycle phase in the design and interpretation of study results.

Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects.

The effects of atorvastatin at 20, 40, and 80 mg/day on plasma lipoprotein subspecies were examined in a randomized, placebo-controlled fashion over 36 weeks in 97 patients with coronary heart disease (CHD) with low-density lipoprotein (LDL) cholesterol levels of >130 mg/dl and compared directly with the effects of fluvastatin (n = 28), pravastatin (n = 22), lovastatin (n = 24), and simvastatin (n = 25). The effects of placebo and 40 mg/day of each statin were also examined in subjects with CHD with subjects in the fasting state and in the fed state 4 hours after a meal rich in saturated fat and cholesterol and compared with results in age- and gender-matched control subjects. At all doses tested in the fasting and fed states, atorvastatin was significantly (p <0.01) more effective in lowering LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol than all other statins, and significantly (p <0.05) more effective than all statins, except for simvastatin, in lowering triglyceride and remnant lipoprotein (RLP) cholesterol. At 40 mg/day in the fasting state, atorvastatin was significantly (p <0.01) more effective than all statins, except for lovastatin and simvastatin, in lowering cholesterol levels in small LDL, and was significantly (p <0.05) more effective than all statins, except for simvastatin, in increasing cholesterol in large HDL and in lowering LDL particle numbers. Our data indicate that atorvastatin was the most effective statin tested in lowering cholesterol in LDL, non-HDL, and RLP in the fasting and fed states, and getting patients with CHD to established goals, with fluvastatin, pravastatin, lovastatin, and simvastatin having about 33%, 50%, 60%, and 85% of the efficacy of atorvastatin, respectively, at the same dose in the same patients.

Men and women differ in lipoprotein response to dietary saturated fat and cholesterol restriction.

A diet restricted in saturated fat and cholesterol is recommended for subjects with elevated LDL cholesterol concentrations before and during drug therapy. Gender differences in lipoprotein subspecies response to such diets have not been studied in detail. We examined the effects of a diet low in total fat, saturated fat and cholesterol (Therapeutic Lifestyle Changes, TLC, diet: 26% of energy as fat, 4% as saturated fat, and 45 mg cholesterol/4.2 MJ), compared with an average American diet (AAD: 35% of energy as fat, 14% as saturated fat, and 147 mg cholesterol/4.2 MJ), on plasma lipoprotein subspecies in men and women. Each diet period lasted 6 wk. Body weight was kept constant during each diet period. Men (n = 19) and postmenopausal women (n = 14) >40 y old with moderate hypercholesterolemia participated in this study. Plasma lipoprotein concentrations were assessed by standardized methodology, and lipoprotein sizes were determined by gradient gel electrophoresis and NMR spectroscopy. The TLC diet resulted in greater reductions in total cholesterol and plasma apolipoprotein B concentrations in men than in women (-19% vs. -12%, P < 0.05, and -18% vs. -9%, P < 0.05, respectively). Postprandial triacylglycerol and LpAI:AII concentrations were reduced in men, but not in women (-15% vs. 8%, P < 0.05, and -9% vs. -2%, respectively, P < 0.05). Similar decreases in LpAI concentrations and LDL and HDL particle size were observed in men and women. These data are consistent with the concept that middle aged/elderly men may have a more favorable lipoprotein response to a low fat, low cholesterol diet than postmenopausal women.

Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients.

We investigated the effects of atorvastatin on the lipid and the apoA-I-containing HDL subpopulation profiles in 86 patients with established coronary heart disease (CHD). The entire drug treatment period lasted 12 weeks (4-week periods of 20 then 40, then 80 mg/day). Each dose of atorvastatin treatment resulted in significant reductions in plasma total-C, LDL-C, and triglyceride (TG), and non-significant increases in HDL-C levels compared with placebo treatment. ApoA-I levels did not change significantly during any of the treatment periods. Despite the modest increase of HDL-C (6%, 7%, 5%) and no change in apoA-I levels, the distribution of the apoA-I-containing HDL subpopulations changed significantly during each treatment period. There were significant increases in the concentrations of the large LpA-I alpha-1 (24%, 39%, 26%) and pre alpha-1 (51%, 61%, 63%) subpopulations at the expense of the small lipoprotein LpA-I:A-II alpha-3 subpopulations which decreased on all doses, and the decreases were significant on the 40 and 80 mg/day doses (6%, 5%). Atorvastatin influences the lipid-related risk for CHD in two ways: first, it significantly decreases LDL-C and TG levels while increasing HDL-C, and second, it significantly shifts the HDL subpopulation profile of CHD patients toward that observed in subjects without CHD.

Effects of atorvastatin on fasting and postprandial lipoprotein subclasses in coronary heart disease patients versus control subjects.

The effects of atorvastatin at 20, 40, and 80 mg/day on plasma lipoprotein subclasses were examined in a randomized, placebo-controlled fashion over 24 weeks in 103 patients in the fasting state who had coronary heart disease (CHD) with low-density lipoprotein (LDL) cholesterol levels >130 mg/dl. The effects of placebo and atorvastatin 40 mg/day were examined in 88 subjects with CHD in the fasting state and 4 hours after a meal rich in saturated fat and cholesterol. These findings were compared with results in 88 age- and gender-matched control subjects. Treatment at the 20, 40, and 80 mg/day dose levels resulted in LDL cholesterol reductions of 38%, 46%, and 52% (all p <0.0001), triglyceride reductions of 22%, 26%, and 30% (all p <0.0001), and high-density lipoprotein (HDL) cholesterol increases of 6%, 5%, and 3%, respectively (all p <0.05 at the 20- and 40-mg doses). The lowest total cholesterol/HDL cholesterol ratio was observed with the 80 mg/day dose of atorvastatin (p <0.0001 vs placebo). Remnant-like particle (RLP) cholesterol decreased 33%, 34%, and 32%, respectively (all p <0.0001). Lipoprotein(a) [Lp(a)] cholesterol decreased 9%, 16%, and 21% (all p <0.0001), although Lp(a) mass increased 9%, 8%, and 10%, respectively (all p <0.01). In the fed state, atorvastatin 40 mg/day normalized direct LDL cholesterol (29% below controls), triglycerides (8% above controls), and RLP cholesterol (10% below controls), with similar reductions in the fasting state. At this same dose level, atorvastatin treatment resulted in 39%, 35%, and 59% decreases in fasting triglyceride in large, medium, and small very LDLs, as well as 45%, 33%, and 47% reductions in cholesterol in large, medium, and small LDL, respectively, as assessed by nuclear magnetic resonance (all significant, p <0.05), normalizing these particles versus controls (77 cases vs 77 controls). Moreover, cholesterol in large HDL was increased 37% (p <0.001) by this treatment. Our data indicate that atorvastatin treatment normalizes levels of all classes of triglyceride-rich lipoproteins and LDL in both the fasting and fed states in patients with CHD compared with control subjects.

Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients.

We compared the effects of five different statins (atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin) on the lipid, lipoprotein, and apolipoprotein (apo) A-I-containing high-density lipoprotein (HDL) subpopulation profiles of 86 coronary heart disease (CHD) patients. Patients with established CHD, and low density lipoprotein (LDL) cholesterol (C)>130 mg/dl, and triglyceride (TG)<400 mg/dl, were treated with atorvastatin 20, 40, and 80 mg/day and one of the other four statins at 20, 40, and when available 80 mg/day in increasing doses (4 weeks of each dose) in a randomized crossover fashion. There was an 8-week placebo controlled washout period between different drug treatments. All five statins on each dose resulted in significant reductions in total- and LDL-C compared to placebo treatment. There were also decreases in plasma TG and increases in HDL-C and apoA-I concentrations, but not all treatments changed these parameters significantly. Each statin except fluvastatin improved the HDL subpopulation profile by increasing the concentrations of the large, cholesterol-rich, LpA-I alpha-1 and prealpha-1 HDL subpopulations. CHD patients have significantly lower concentration of the large, LpA-I alpha-1 HDL particles compared to controls. Our data indicate that statins which are the most effective in lowering LDL-C and TG are also the most effective agents in modifying the HDL subpopulation profile in CHD patients towards the patterns found in healthy individuals. The order of efficacy of statins in increasing alpha-1 HDL subpopulation was: atorvastatin, simvastatin, pravastatin, lovastatin and fluvastatin.

Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.

OBJECTIVE: We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. METHODS AND RESULTS: We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08). CONCLUSIONS: Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.

Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study.

OBJECTIVE: Remnants of triglyceride-rich lipoproteins are thought to be atherogenic. A new antibody-based assay allows for the isolation of remnant-like particles (RLPs) from plasma or serum, and the subsequent measurement of RLP cholesterol (RLPC) and triglycerides (RLPTGs). We hypothesized that diabetic patients would have higher remnant levels than nondiabetic patients. DESIGN AND METHODS: We compared RLPC and RLPTG levels of diabetic subjects (68 women, 121 men) participating in the Framingham Heart Study with those of nondiabetic subjects (1,499 women, 1,357 men). RESULTS: Mean RLPC values for diabetic women were 106% higher than those for nondiabetic women (0.367 +/- 0.546 mmol/l [14.2 +/- 21.1 mg/dl] vs. 0.179 +/- 0.109 mmol/l [6.9 +/- 4.2 mg/dl]; P < 0.0001), and RLPTG values for diabetic women were 385% higher than those for nondiabetic women (1.089 +/- 2.775 mmol/l [93.1 +/- 245.6 mg/dl] vs. 0.217 +/- 0.235 mmol/l [19.2 +/- 20.8 mg/dl]; P < 0.0001). Similar but less striking differences were observed in diabetic men, who had mean RLPC values 28% higher than those seen in nondiabetic men (0.285 +/- 0.261 mmol/l [11.0 +/- 10.1 mg/dl] vs. 0.223 +/- 0.163 mmol/l [8.6 +/- 6.3 mg/dl]; P < 0.001) and mean RLPTG values 70% higher than those seen in nondiabetic men (0.606 +/- 1.019 mmol/l [53.6 +/- 90.2 mg/dl] vs. 0.357 +/- 0.546 mmol/l [31.6 +/- 48.3 mg/dl]; P < 0.001). Moreover, diabetic men and women had significantly higher total triglycerides and lower HDL cholesterol levels than nondiabetic subjects. CONCLUSIONS: The data indicate that RLP particles are elevated in diabetic subjects. To achieve optimal reduction of risk for cardiovascular disease, treatment of elevated RLP values, along with the control of LDL cholesterol levels, should be considered.