Adipocytokines as features of the metabolic syndrome determined using confirmatory factor analysis.

PURPOSE: Confirmatory factor analysis (CFA) was used to test the hypothesis whether adipocytokines are associated with the risk factor cluster that characterizes the metabolic syndrome (MetS). METHODS: Data from 134 nondiabetic subjects were analyzed using CFA. Insulin sensitivity (SI) was quantified using intravenous glucose tolerance tests, visceral fat area by computed tomography and fasting high-density lipoprotein, triglycerides, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA), tumor necrosis factor (TNF)-α, adiponectin, resistin, leptin, interleukin (IL)-6, C-reactive protein (CRP), and plasminogen activator inhibitor (PAI)-1 were measured. RESULTS: The basic model representing the MetS included six indicators comprising obesity, SI, lipids, and hypertension, and demonstrated excellent goodness of fit. Using multivariate analysis, MCP-1, SAA, and TNF-α were not independently associated with any of the MetS variables. Adiponectin, resistin, leptin, CRP, and IL-6 were associated with at least one of the risk factors, but when added to the basic model decreased all goodness-of-fit parameters. PAI-1 was associated with all cardiometabolic factors and improved goodness-of-fit compared with the basic model. CONCLUSIONS: Addition of PAI-1 increased the CFA model goodness of fit compared with the basic model, suggesting that this protein may represent an added feature of the MetS.

Plasma sterol evidence for decreased absorption and increased synthesis of cholesterol in insulin resistance and obesity.

BACKGROUND: The rise in LDL with egg feeding in lean insulin-sensitive (LIS) participants is 2- and 3-fold greater than in lean insulin-resistant (LIR) and obese insulin-resistant (OIR) participants, respectively. OBJECTIVE: We determined whether differences in cholesterol absorption, synthesis, or both could be responsible for these differences by measuring plasma sterols as indexes of cholesterol absorption and endogenous synthesis. DESIGN: Plasma sterols were measured by gas chromatography-mass spectrometry in a random subset of 34 LIS, 37 LIR, and 37 OIR participants defined by the insulin sensitivity index (S(I)) and by BMI criteria selected from a parent group of 197 participants. Cholestanol and plant sterols provide a measure of cholesterol absorption, and lathosterol provides a measure of cholesterol synthesis. RESULTS: The mean (±SD) ratio of plasma total absorption biomarker sterols to cholesterol was 4.48 ± 1.74 in LIS, 3.25 ± 1.06 in LIR, and 2.82 ± 1.08 in OIR participants. After adjustment for age and sex, the relations of the absorption sterol-cholesterol ratios were as follows: LIS > OIR (P < 0.001), LIS > LIR (P < 0.001), and LIR > OIR (P = 0.11). Lathosterol-cholesterol ratios were 0.71 ± 0.32 in the LIS participants, 0.95 ± 0.47 in the LIR participants, and 1.29 ± 0.55 in the OIR participants. After adjustment for age and sex, the relations of lathosterol-cholesterol ratios were as follows: LIS < OIR (P < 0.001), LIS < LIR (P = 0.03), and LIR < OIR (P = 0.002). Total sterol concentrations were positively associated with S(I) and negatively associated with obesity, whereas lathosterol correlations were the opposite. CONCLUSIONS: Cholesterol absorption was highest in the LIS participants, whereas cholesterol synthesis was highest in the LIR and OIR participants. Therapeutic diets for hyperlipidemia should emphasize low-cholesterol diets in LIS persons and weight loss to improve S(I) and to decrease cholesterol overproduction in LIR and OIR persons.

Comparative Effectiveness and Toxicity of Statins Among HIV-Infected Patients.

BACKGROUND: dyslipidemia is common and is often treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins). Little is known about the comparative effectiveness of statins among human immunodeficiency virus (HIV)-infected patients. This study compared the effectiveness and toxicity of statins among HIV-infected patients in clinical care. METHODS: we conducted a retrospective cohort study of patients starting their initial statin medications at 2 large HIV clinics (N = 700). The primary observation was change in lipid levels during statin therapy. Secondary observations included whether individualized National Cholesterol Education Program (NCEP) goals for low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) levels were reached, and toxicity rates. We used linear regression to examine change in lipid levels, controlling for baseline lipid values and demographic and clinical characteristics. We conducted secondary analyses using propensity scores to address confounding by indication. RESULTS: the most commonly prescribed statins were atorvastatin (N = 303), pravastatin (N = 280), and rosuvastatin (N = 95). One year after starting a statin therapy, patients who received atorvastatin or rosuvastatin had significantly greater decreases in total cholesterol, LDL-C, and non-HDL-C than patients on pravastatin. The likelihood of reaching NCEP goals for LDL-C levels was higher with the use of rosuvastatin (OR 2.1; P = .03) and atorvastatin (odds ratio [OR], 2.1; P = .001) compared with that of pravastatin. The likelihood of reaching NCEP goals for non-HDL-C levels was higher for rosuvastatin (OR 2.3; P = .045) but not atorvastatin (OR, 1.5; P = .1) compared with pravastatin. Toxicity rates were similar for all 3 statins: 7.3% for atorvastatin, 6.1% for pravastatin, and 5.3% for rosuvastatin. CONCLUSIONS: our findings suggest that atorvastatin and rosuvastatin are preferable to pravastatin for treatment of HIV-infected patients with dyslipidemia, due to greater declines in total cholesterol, LDL-C, and non-HDL-C, with similar lower toxicity rates.

Association of combinations of lipid parameters with carotid intima-media thickness and coronary artery calcium in the MESA (Multi-Ethnic Study of Atherosclerosis).

OBJECTIVES: The purpose of this study was to determine the association of combinations of lipid parameters with subclinical atherosclerosis. BACKGROUND: Carotid intima-media thickness (CIMT) and coronary artery calcium (CAC) are significantly associated with incident cardiovascular disease (CVD). The association between common dyslipidemias (combined hyperlipidemia, [simple] hypercholesterolemia, dyslipidemia of metabolic syndrome, isolated low high-density lipoprotein cholesterol, and isolated hypertriglyceridemia) compared with normolipemia, and CIMT and CAC has not been previously examined. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) participants were White, Chinese, African-American, or Hispanic adults without clinical CVD. Subjects with diabetes mellitus or who were receiving lipid-lowering therapy were excluded. Every participant was classified into only 1 of 6 groups defined by specific low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride cut points. Multivariate linear and relative risk regressions evaluated the cross-sectional associations with CIMT and CAC after adjusting for CVD risk factors. Interactions with race, sex, and high-sensitivity C-reactive protein were evaluated for CIMT and CAC outcomes. RESULTS: Among 4,792 participants, only those with combined hyperlipidemia and hypercholesterolemia demonstrated both increased common CIMT (combined hyperlipidemia 0.048 mm thicker, 95% confidence interval [CI]: 0.016 to 0.080 mm; hypercholesterolemia 0.048 mm thicker, 95% CI: 0.029 to 0.067 mm) and internal CIMT (combined hyperlipidemia 0.120 mm thicker, 95% CI: 0.032 to 0.208 mm; and hypercholesterolemia 0.161 mm thicker, 95% CI: 0.098 to 0.223 mm) as well as increased risk for prevalent CAC (combined hyperlipidemia relative risk: 1.22, 95% CI: 1.08 to 1.38; hypercholesterolemia relative risk: 1.22, 95% CI: 1.11 to 1.34) compared with normolipemia. The interactions between lipid parameters and race, sex, or high-sensitivity C-reactive protein were not significant for any outcomes. CONCLUSIONS: Combined hyperlipidemia and simple hypercholesterolemia were associated with increased CIMT and prevalent CAC in a relatively healthy multiethnic population.

Low clusterin levels in high-density lipoprotein associate with insulin resistance, obesity, and dyslipoproteinemia.

OBJECTIVE: To determine whether obesity and insulin resistance associate with changes in the protein content of high-density lipoprotein (HDL) in 2 different groups of men by using targeted proteomics. METHODS AND RESULTS: Insulin resistance and obesity are hallmarks of type 2 diabetes mellitus and the metabolic syndrome, which confer an increased risk of cardiovascular disease. Recent studies suggest that the protein cargo of HDL makes important contributions to the lipoprotein's cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDL's cardioprotective effects in 3 groups of healthy subjects: lean insulin-sensitive, lean insulin-resistant, and obese insulin-resistant individuals. We validated our findings in a different group of subjects. The clusterin concentration in HDL strongly and negatively associated with insulin resistance and body mass index in both populations. HDL clusterin levels were lower in subjects with low HDL and high triglycerides, key components of the metabolic syndrome. There was an inverse correlation between clusterin levels in HDL and very-low-density lipoprotein/low-density lipoprotein. CONCLUSIONS: Clusterin levels in HDL are lower in men with reduced insulin sensitivity, higher body mass index, and an unfavorable lipid profile. Our observations raise the possibility that clusterin depletion contributes to the loss of HDL's cardioprotective properties.

Endogenous red blood cell membrane fatty acids and sudden cardiac arrest.

Little is known of the associations of endogenous fatty acids with sudden cardiac arrest (SCA). We investigated the associations of SCA with red blood cell membrane fatty acids that are end products of de novo fatty acid synthesis: myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1 n7), vaccenic acid (18:1 n7), stearic acid (18:0), oleic acid (18:1 n9), and a related fatty acid, cis-7 hexadecenoic acid (16:1 n9). We used data from a population-based case-control study where cases, aged 25 to 74 years, were out-of-hospital SCA patients attended by paramedics in Seattle, WA (n = 265). Controls, matched to cases by age, sex, and calendar year, were randomly identified from the community (n = 415). All participants were free of prior clinically diagnosed heart disease. We observed associations of higher red blood cell membrane levels of 16:0, 16:1n-7, 18:1n-7, and 16:1n-9 with higher risk of SCA. In analyses adjusted for traditional SCA risk factors and trans- and n-3 fatty acids, a 1-SD-higher level of 16:0 was associated with 38% higher risk of SCA (odds ratio, 1.38; 95% confidence interval, 1.12-1.70) and a 1-SD-higher level of 16:1n-9 with 88% higher risk (odds ratio, 1.88; 95% confidence interval, 1.27-2.78). Several fatty acids that are end products of fatty acid synthesis are associated with SCA risk. Further work is needed to investigate if conditions that favor de novo fatty acid synthesis, such as high-carbohydrate/low-fat diets, might also increase the risk of SCA.

Red blood cell membrane alpha-linolenic acid and the risk of sudden cardiac arrest.

Higher levels of long-chain n-3 polyunsaturated fatty acids in red blood cell membranes are associated with lower risk of sudden cardiac arrest. Whether membrane levels of alpha-linolenic acid, a medium-chain n-3 polyunsaturated fatty acid, show a similar association is unclear. We investigated the association of red blood cell membrane alpha-linolenic acid with sudden cardiac arrest risk in a population-based case-control study. Cases, aged 25 to 74 years, were out-of-hospital sudden cardiac arrest patients attended by paramedics in Seattle, WA (n = 265). Controls, matched to cases by age, sex, and calendar year, were randomly identified from the community (n = 415). All participants were free of prior clinically diagnosed heart disease. Blood was obtained at the time of cardiac arrest (cases) or at the time of an interview (controls). Higher membrane alpha-linolenic acid was associated with a higher risk of sudden cardiac arrest: after adjustment for matching factors and smoking, diabetes, hypertension, education, physical activity, weight, height, and total fat intake, the odds ratios corresponding to increasing quartiles of alpha-linolenic acid were 1.7 (95% confidence interval [CI], 1.0-3.0), 1.9 (95% CI, 1.1-3.3), and 2.5 (95% CI, 1.3-4.8) compared with the lowest quartile. The association was independent of red blood cell levels of long-chain n-3 fatty acids, trans-fatty acids, and linoleic acid. Higher membrane levels of alpha-linolenic acid are associated with higher risk of sudden cardiac arrest.

The SLIM Study: Slo-Niacin® and Atorvastatin Treatment of Lipoproteins and Inflammatory Markers in Combined Hyperlipidemia.

BACKGROUND: The combination of niacin and statin has proven value in hyperlipidemia management and heart disease prevention. However, the efficacy of the non-prescription time-release niacin, Slo-Niacin®, is little studied alone and not at all with atorvastatin. We gave Slo-Niacin® and atorvastatin, singly and together to determine efficacy on the combined abnormalities of triglyceride, LDL and HDL. METHODS: 42 men and women with LDL-C>130mg/dL HDL-C <45 (men or 55mg/dL (women) were randomized to 3 months of atorvastatin 10 mg/day or incremental doses of Slo-Niacin® to 1500 mg/day. The alternate drug was added in the next 3-month segment. Lipid profiles and transaminases were measured monthly and other measures at baseline and the end of each treatment sequence. RESULTS: Mean entry lipids (mg/dL) were: TG 187, LDL-C 171, and HDL-C 39. Mean BMI was 32.6 Kg/m(2). Monotherapy with Slo-Niacin® decreased median triglyceride 15%, mean LDL-C 12% and non-HDL-C 15% and increased HDL-C 8%. Atorvastatin decreased median triglyceride 26%, and mean LDL-C 36%, non-HDL-C 36% and increased HDL-C 6%. Combined therapy decreased median triglyceride 33% and mean LDL-C and non-HDL-C each 43%. HDL-C increased 10% (all p<0.001). Median remnant-like lipoprotein-C decreased 55%, mean apo-B 40%, median hsCRP 23% (all p<0.05), TNFa 12% and no change in IL-6. Mean LDL buoyancy increased 15%, apo-A-I 5% and median HDL(2)-C 20% (all p<0.05). ALT declined with Slo-Niacin® treatment alone compared to atorvastatin and also decreased when Slo-Niacin® was added to atorvastatin. Six subjects dropped out, 3 for niacin related symptoms. CONCLUSIONS: Slo-Niacin® 1.5g/day with atorvastatin 10 mg/day improved lipoprotein lipids, apoproteins and inflammation markers without hepatotoxicity. Slo-Niacin® deserves further study as a cost-effective treatment of hyperlipidemia.

Combined statin and niacin therapy remodels the high-density lipoprotein proteome.

BACKGROUND: Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL(3) of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels-combined statin and niacin therapy-might reverse these changes. METHODS AND RESULTS: HDL(3) isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography-Fourier transform-mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL(3) while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL(3) were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL(3) proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL(3) in healthy control subjects. CONCLUSIONS: Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL(3) in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.

Comprehensive lipid management versus aggressive low-density lipoprotein lowering to reduce cardiovascular risk.

Five lines of evidence justify comprehensive lipoprotein management over aggressive low-density lipoprotein (LDL) lowering alone in most cases of cardiovascular disease (CVD) prevention. First, lipoprotein lipid transport consists of a single, recycling system involving very-low-density lipoprotein, LDL, and high-density lipoprotein (HDL). Single lipid interventions affect all lipoprotein classes to varying degrees. These effects can be expanded by using different drug classes in combination. Second, observational studies support the unitary nature of lipoprotein risk. A family of curves describes increasing CVD risk from increasing LDL as other risk factors are present. Conversely, a family of curves describes increasing CVD risk from decreasing levels of HDL in mirror image to LDL. The LDL and HDL risks are additive. Third, clinical trials that raise HDL and lower triglyceride ameliorate CVD, as does lowering LDL. Lowering LDL prevents heart disease, but by only 22%-36% with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy. Studies indicate that better CVD prevention is obtained when drugs for triglyceride and HDL reduction are combined with LDL reduction. Fourth, HDL and its apolipoprotein (apo), apo A-I, as well as apo A-I analogues, decrease atherosclerosis. Each modality decreases atherosclerosis in animal models, and apo A-I Milano acutely decreases human coronary luminal stenosis. Apo A-I analogues have similar promise. Fifth, combined hyperlipidemia is the most common lipid disorder, has the strongest risk for CVD, and combines elevated LDL, hypertriglyceridemia, and low HDL. This condition requires the comprehensive treatment approach described above. In conclusion, 5 lines of evidence justify comprehensive diet and drug treatment for combined hyperlipidemia and, at lesser LDL elevations, the atherogenic dyslipidemias of obesity, diabetes mellitus, and the metabolic syndrome.

Survey correlations: proficiency and adequacy of nutrition training of medical students.

OBJECTIVE: The majority of graduating US medical students reported inadequate nutrition training over the past decade. This trend could in part be due to the lack of valid measures to assess the relationship between adequacy of nutrition training and proficiency on nutrition topics deemed essential. The study's objective was to test the hypothesis that self-reported nutrition proficiency is positively correlated with the perceived adequacy (quality, quantity, coverage and importance) of nutrition training of University of Washington medical students. METHOD: Cross-sectional e-mail survey of 1st to 4th year medical students (n = 708), including a survey prompt and three e-mail follow-up measures. To reduce and interpret the survey data, principal components analysis was employed, followed by Varimax rotation with Kaiser normalization. To assess internal consistency reliability, alpha (alpha) of nutrition proficiency items and factors was determined. RESULTS: A 44.5% response rate was achieved (n = 315 respondents). The 31-item questionnaire was reduced to 6 factors, explaining 60.2% of the total variance (alpha = 0.947). Self reported nutrition proficiency was positively correlated with the perceived quality, quantity and coverage of nutrition training in all 6 essential nutrition factors or topics determined after factor analysis (P < 0.01). CONCLUSION: Quality and coverage may be effective gauges of adequacy of nutrition training and related nutrition proficiency in medical education. Current national medical education evaluation measures focus on the quantity of nutrition instruction. The lowest reported proficiency topics; nutrition and disease management, micronutrients and complementary and alternative medicine are recommended for particular curricular emphasis.

Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia: the OCEANS study.

INTRODUCTION: High-dose HMG-CoA reductase inhibitors (statins) fail to prevent approximately two-thirds of cardiovascular events. This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol (non-HDL-C), HDL-C, and triglycerides in national guidelines and has intensified interest in combination therapy. METHODS: The OCEANS study (Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia; ClinicalTrials.gov identifier: NCT00080275) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin (NER/S; SIMCOR) over 52 weeks in 520 patients with mixed dyslipidemia. After a >or=4-week run-in phase of diet modification and simvastatin 40 mg/day, median baseline values (mg/dL) were: non-HDL-C = 141, low-density lipoprotein-cholesterol (LDL-C) = 110, HDL-C = 45, and triglyceride = 151. Patients were randomized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2,000/40 mg/day. RESULTS: Differences between titration groups in tolerability, safety, and efficacy were minimal; therefore, all results are for pooled titration groups. The safety of NER/S was consistent with the safety profile of each individual component. Treatment with NER/S was well tolerated: 71% of patients experienced flushing and 92% of flushing episodes were mild or moderate in intensity. Overall, 61% of patients experienced flushing episodes that were rated as mild or moderate in intensity. Flushing decreased over time: <40% of those who had flushing during titration experienced flushing during the final 12 weeks. A total of 20% of patients discontinued treatment because of a treatment-related adverse event, including 7% who discontinued because of flushing. Median changes from baseline (following the simvastatin 40 mg/day run-in phase) to 24 weeks were: non-HDL-C = -27.3%, LDL-C = -25.0%, HDL-C = +23.9%, and triglycerides = -35.9% (all p < 0.0001 vs baseline). In lipid-treatment-naive patients, NER/S 2,000/40 mg/day decreased non-HDL-C, LDL-C, and triglycerides by approximately 50% and increased HDL-C by approximately 25% when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in. All three therapeutic lipid targets (LDL-C [risk-adjusted goal], HDL-C >or=40 mg/dL, and triglycerides <150 mg/dL) were achieved concurrently by 65% of patients treated with NER/S. CONCLUSION: Treatment with NER/S 2,000/40 mg/day is well tolerated, has no unanticipated adverse events, and provides additional, clinically relevant improvements in multiple lipid parameters beyond statin monotherapy.

Enhancing recruitment of healthy African American volunteers in a city with a small African American community: results from a dietary supplement crossover trial.

OBJECTIVE: To describe strategies for enhancing recruitment of African Americans to a longterm intervention study requiring frequent blood draws and follow-up visits, in a city with relatively few African Americans. DESIGN: The intervention study was a 14-month, double-blind, crossover study evaluating the effects of three oral folic acid doses on blood homocysteine levels. The goal was to have 40 African Americans complete the study, in addition to 160 participants from other races and ethnicities. RESULTS: Of 707 healthy, adult men and women recruited, 57 were African Americans. Recruitment advice was sought from African American community leaders interested in health research and the advice can be attributable to the success of recruitment. As suggested by the community leaders, our female African American project manager made oral presentations to select community groups. Word-of-mouth support from community leaders and study participants helped recruitment. Although the adult Seattle population is 7.4% African American, the group completing the study comprised 15% African Americans. Retention in the dietary intervention was 74% (31 out of 42) among African Americans, 81% (158 out of 196) among non-African Americans--a statistically non-significant difference. CONCLUSIONS: Advice from African American community leaders about targeting appropriate civic/professional groups, churches, and community organizations can lead to effective recruitment of African Americans. Advice should be sought before beginning recruitment and endorsement for the study should be obtained. Effective retention of African American participants is possible for intervention studies requiring multiple blood draws and follow-up visits.

Relationship of liver enzymes to insulin sensitivity and intra-abdominal fat.

OBJECTIVE: The purpose of this study was to determine the relationship between plasma liver enzyme concentrations, insulin sensitivity, and intra-abdominal fat (IAF) distribution. RESEARCH DESIGN AND METHODS: Plasma gamma-glutamyl transferase (GGT), aspartate transaminase (AST), alanine transaminase (ALT) levels, insulin sensitivity (insulin sensitivity index [S(I)]), IAF area, and subcutaneous fat (SCF) area were measured in 177 nondiabetic subjects (75 men and 102 women, aged 31-75 years) with no history of liver disease. On the basis of BMI (< or > or = 27.5 kg/m2) and S(I) (< or > or = 7.0 x 10(-5) min/pmol) subjects were divided into lean insulin sensitive (LIS, n = 53), lean insulin resistant (LIR, n = 60), and obese insulin resistant (OIR, n = 56) groups. RESULTS: Levels of all three liver enzymes were higher in men than in women (P < 0.0001 for each). In men, GGT levels were higher in insulin-resistant than in insulin-sensitive subjects (P < 0.01). In women, GGT levels were higher in the OIR than in the LIS group (P < 0.01) but no different in the LIR group. There was no difference in ALT and AST levels among the LIS, LIR, and OIR groups. GGT was associated with S(I) (r = -0.26, P < 0.0001), IAF area (r = 0.22, P < 0.01), waist-to-hip ratio (WHR) (r = 0.25, P = 0.001), BMI (r = 0.17, P < 0.05), and SCF area (r = 0.16, P < 0.05) after adjustments for age and sex. In men, only S(I) (r = -0.29, P < 0.05) remained independently correlated with GGT in multiple regression analysis. In women, IAF area (r = 0.29, P < 0.01) and WHR (r = 0.29, P < 0.01) were independently associated with GGT, but S(I) was not. CONCLUSIONS: In nondiabetic men GGT but not AST or ALT levels, are inversely related to insulin sensitivity independent of IAF area. However in women, GGT is related to measures of central body fat rather than to insulin sensitivity.

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.

HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.

Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study).

International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides for patients at moderately high to high coronary heart disease (CHD) risk. Combination therapy is often required to achieve multiple lipid treatment goals, and > or =50% reduction in low-density lipoprotein cholesterol (LDL-C) is needed in some patients to achieve aggressive LDL-C targets. In this context, we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin (niacin ER), a statin plus ezetimibe, and a highly potent statin alone. This was an open-label, multicenter, 12-week study in 292 patients (50% women) who qualified for drug therapy based on number of CHD risk factors. Patients were randomized to four parallel arms, titrated from low to moderate or high doses: atorvastatin/niacin ER, rosuvastatin/niacin ER, simvastatin/ezetimibe, or rosuvastatin alone. Baseline mean values were, for LDL-C 197 mg/dL (5.1 mmol/L), HDL-C 49 mg/dL (1.3 mmol/L), triglycerides 168 mg/dL (1.9 mmol/L). There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment. All groups lowered LDL-C by approximately 50% or more (range -49 to -57%), achieving mean levels of 82-98 mg/dL (2.1-2.5 mmol/L). Changes in non-HDL-C (range -46 to -55%) mirrored those for LDL-C and did not differ among treatment groups. Statin/niacin ER combination regimens also increased HDL-C and large HDL (HDL2) and lowered triglycerides and lipoprotein (a) significantly more than other regimens. No drug-related myopathy or hepatotoxicity was observed. In this study, low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD.