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1.  Glycated Albumin and Direct Low Density Lipoprotein Cholesterol Levels in Type 2 Diabetes Mellitus 
Background
Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the utility of glycated albumin (GA) and direct LDL-C, 2 novel assays, as compared to HbA1c and calculated LDL-C, in evaluating diabetes control and lipid in a heterogeneous population and in specific subgroups of patients with type 2 diabetes mellitus.
Methods
We obtained fasting blood samples and measured HbA1c, GA, and direct LDL-C, as well as other parameters, in a multi-ethnic population of 616 male and female patients with type 2 diabetes and 895 non-diabetic controls.
Results
HbA1c and GA levels, which measure different periods of glycemia, had a correlation of r=0.70 (p<0.001), and mean values in patients were 38.7% and 43.4% higher, respectively, than controls in men, and 41.1% and 40.1% higher, respectively, than controls, in women (both p<0.001). Calculated and direct LDL-C values correlated very highly (r=0.96, p<0.001). The correlations between HbA1c and GA, and between calculated and direct LDL-C were similar for subgroups defined by gender, race, age, and other factors.
Conclusions
Calculated LDL-C provides an accurate assessment of fasting LDL-C compared with a direct measurement in most subjects, except for those with hypertriglyceridemia, and GA correlates with HbA1c in diabetic and non-diabetic subjects and may serve as a reasonable marker of short term diabetic control.
doi:10.1016/j.cca.2009.05.015
PMCID: PMC3927411  PMID: 19465013
glycated albumin; low density lipoprotein cholesterol; type 2 diabetes
2.  Effects of ezetimibe added to statin therapy on markers of cholesterol absorption and synthesis and LDL-C lowering in hyperlipidemic patients 
Atherosclerosis  2012;225(2):388-396.
Objective
Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to ongoing statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers.
Methods
Hypercholesterolemic subjects (n=874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n=133), medium- (n=582), and high- (n=159) statin potency groups defined by predicted LDL-C–lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively).
Results
The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p <0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p <0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (−29.1% vs. −25.0% vs. −22.7%; p <0.001) when evaluating unadjusted data. These effects and group differences were significantly (p <0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group.
Conclusion
Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed.
doi:10.1016/j.atherosclerosis.2012.09.001
PMCID: PMC3749834  PMID: 23040830
non-cholesterol sterol; lathosterol; β-sitosterol; statin potency; dyslipidemia
3.  Glycogen Storage Disease Type Ia: Linkage of Glucose, Glycogen, Lactic Acid, Triglyceride, and Uric Acid Metabolism 
Journal of clinical lipidology  2012;6(6):10.1016/j.jacl.2012.08.005.
Case Summary
A female presented in infancy with hypotonia, undetectable serum glucose, lactic acidosis, and triglycerides > 5,000 mg/dl. The diagnosis of type 1A glycogen storage disease (GSD) was made by liver biopsy that showed increased glycogen and absent glucose-6-phosphatase enzyme activity. She was treated with dextrose feeding, which was replaced by frequent cornstarch feeding, with improvement of her metabolic parameters. At age 18 years she had marked hypertriglyceridemia (3,860 mg/dl) and eruptive xanthomas, and was treated with fenofibrate, atorvastatin, and fish oil. At age 29 years she was noted to have multiple liver adenomas, severe anemia, and hyperuricemia. Aggressive cornstarch therapy was commenced with a goal of maintaining her blood glucose levels > 75 mg/dl and lactate levels < 2 mmol/L. After 15 months on this regimen, her lipids levels (measured in mg/dl) off all medications were: total cholesterol 222, triglycerides 179, high density lipoprotein cholesterol 32, and calculated low density lipoprotein cholesterol 154. Her weight was stable with a body mass index of 24.8 kg/m2. Her liver adenomas had decreased in size, and her anemia and hyperuricemia had improved. She was homozygous for the R83C missense mutation in G6PC. Our data indicate that optimized metabolic control to maintain blood glucose levels > 75 mg/dl is critical in the management of this disease.
doi:10.1016/j.jacl.2012.08.005
PMCID: PMC3812663  PMID: 23312056
Glycogen storage disease type Ia; high density lipoproteins (HDL); low density lipoproteins (LDL); small dense LDL (sdLDL)
4.  Small Dense Low Density Lipoprotein Cholesterol and Coronary Heart Disease: Results from the Framingham Offspring Study 
Clinical chemistry  2010;56(6):967-976.
Objective
A direct assay for small dense low density lipoprotein cholesterol (sdLDL-C) has been developed. Our goal was to establish normal ranges for this assay as well as to measure values in patients with established coronary heart disease (CHD) versus control subjects.
Methods
Direct LDL-C and sdLDL-C analyses were carried out on samples from 3,188 male and female participants of the Framingham Offspring Study, which included 173 male and 74 female CHD cases.
Results
Male gender and female postmenopausal status were both associated with significantly (p<0.0001) higher sdLDL-C values. Use of cholesterol-lowering medications was significantly (p<0.0001) higher in CHD cases than in controls (46.8% versus 11.4% in men, and 35.1% versus 8.8% in women). Direct LDL-C levels were significantly lower in male CHD patients than in male controls (3.22 versus 3.51 mmol/L, p<0.0001), but their mean sdLDL-C levels were similar to those in controls (0.83 versus 0.84 mmol/L, p=0.609). Female CHD patients had similar LDL-C values to female controls (3.53 versus 3.46 mmol/L, p=0.543), but had significantly higher sdLDL-C values (0.83 versus 0.68 mmol/L, p=0.0015). Both male and female cases also had significantly (p<0.01) higher percentages of LDL-C as sdLDLC than controls.
Conclusions
Despite four fold greater cholesterol lowering therapy use, CHD patients had mean LDL-C values well above the LDL-C goal of < 2.6 mmol/L or 100 mg/dl, and male CHD cases had similar sdLDL C values and female CHD cases had significantly higher values than controls. These findings may explain some of the high residual risk of future CHD events in CHD patients.
doi:10.1373/clinchem.2009.137489
PMCID: PMC3791882  PMID: 20431054
small dense LDL-cholesterol; coronary heart disease; risk factor; Framingham Offspring Study; obesity
5.  Adiponectin: an Independent Risk Factor for Coronary Heart Disease in the Framingham Offspring Study 
Atherosclerosis  2011;217(2):543-548.
Background
Our aim was to determine whether a low plasma adiponectin level is an independent predictor of coronary heart disease (CHD).
Methods and Results
We measured adiponectin levels in frozen plasma samples (−80°C) in a total of 3,188 male and female participants in cycle 6 of the Framingham Offspring Study, using a novel full-automated assay. CHD cases at baseline were excluded, and participants were followed for a mean of 7.5 years (mean age was 57 years in both men and women, and mean BMI 28.5 kg/m2 in men and 27.3 kg/m2 in women). Plasma adiponectin levels (median [25percentile, 75percentile]) were significantly higher in female than male controls (14.8 [10.7, 20.5] μg/mL versus 9.0 [7.0, 12.2] μg/mL, p< 0.001). After adjustment for age, body mass index, smoking status, systolic blood pressure, treatment for hypertension, diabetes status, use of cholesterol-lowering medication, total cholesterol level, and high-density lipoprotein cholesterol level. A decreased plasma adiponectin level was a highly significant predictor of future CHD events (n =117) in men, with a hazards ratio of 0.4728 (p=0.0024). A bottom-quartile value of < 7.0 μg/mL doubled the risk of CHD in men. The identical trend was observed in women; however, the statistical significance of these associations disappeared after multivariate adjustments, possibly due to a low number of female CHD cases (n=60).
Conclusion
An adiponectin level of < 7.0 μg/mL is a powerful independent predictor of CHD in men in the United States.
doi:10.1016/j.atherosclerosis.2011.05.035
PMCID: PMC3662557  PMID: 21741045
adiponectin; coronary heart disease; risk factor; Framingham Offspring Study; obesity
6.  Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease 
Archives of neurology  2012;69(5):10.1001/archneurol.2011.670.
Objective
To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.
Design
Prospective cohort study.
Setting
Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985–1988) and were followed up prospectively for the development of AD and all-cause dementia.
Participants
Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.
Main Outcome Measures
We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.
Results
Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00–1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00–1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03–2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13–3.10; P=.01) as compared with those with values less than the median.
Conclusion
In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.
doi:10.1001/archneurol.2011.670
PMCID: PMC3512190  PMID: 22213409
7.  Linkage between C-reactive protein and triglyceride-rich lipoprotein metabolism 
Objective
Inflammation plays an important role in atherosclerosis. Elevated C-reactive protein (CRP) levels are associated with a greater risk of cardiovascular disease. Our goal was to study CRP metabolism, and to determine its relationship with lipoprotein metabolism using stable isotope methodology.
Material/Methods
Eight subjects with combined hyperlipidemia underwent a 15-h primed-constant infusion with deuterated leucine. CRP was purified from the plasma density fraction greater than 1.21g/ml by affinity chromatography. Lipoprotein fractions were separated by sequential ultracentrifugation. Isotope enrichment was determined by gas chromatography/mass spectrometry.
Results
The subjects had mean LDL-C levels of 147.5mg/dl and mean CRP levels of 3.4mg/ l. The mean CRP production rate (PR) was 0.050±0.012mg/kg/day and the mean CRP fractional catabolic rate (FCR) was 0.343±0.056 pools/day (residence time 2.92days). CRP pool size (PS) was significantly related to production (r=0.93; p<0.001), but not FCR. CRP PS was also related to body mass index (r=0.79; p=0.02). There was a significant association between CRP FCR and TRL apoB-100 FCR (r=0.74, p=0.04), as well as between CRP PS and TRL apoB-48 FCR (r=-0.90, p=0.002), indicating linkage between CRP and TRL metabolism.
Conclusion
The main determinant of plasma CRP levels was CRP production rate. Moreover a significant linkage between CRP metabolism and both TRL apoB-100 and apoB-48 catabolism was noted.
doi:10.1016/j.metabol.2012.08.008
PMCID: PMC4315144  PMID: 23018145
C-reactive protein; Lipoprotein; Metabolism
8.  Obesity Associated Molecular Forms of C-Reactive Protein in Human 
PLoS ONE  2014;9(10):e109238.
Objective
To describe novel C-reactive protein (CRP) molecular forms (mf) in human plasma.
Design and Methods
Five novel CRP-mfs, disctinct from the previously described native (nCRP) and modified (mCRP) C-reactive proteins, were separated from human plasma by polyacrylamide gel electrophoresis and immunodetected by western blot in subjects with or without increased BMI, cardiovascular disease (CVD), and diabetes (n = 1800).
Results
Three of the five CRP-mfs were present in all samples. One, CRPmf-4, was present in a subgroup of subjects and its presence was associated with elevated body mass index (BMI). CRP-mf-5 was present in about 2% of the subjects and was not associated with any other parameters. The presence or distribution of the 5 CRP-mfs were not Ca2+-dependent. Crossed immuno-localization experiments indicated that none of the CRP-mfs were complexed with any of the lipoprotein classes or with signature proteins of the complement-factor. Moreover, the distribution of CRP-mfs were not significantly correlated with plasma CRP levels. CRP-mf-4 was significantly associated with increased BMI, but not with other parameters of the metabolic syndrome (HDL-C and triglyceride levels, and diabetes).
Conclusions
We have identified five new CRP-mfs out of which CRP-mf-4 was significantly associated with obesity. We have shown that oligomerization of CRP was not calcium dependent. We hypothesize that adipose tissue produces a factor which influences the formation of CRP mf-4. CRP-mfs might be used as an obesity-associated inflammatory marker.
doi:10.1371/journal.pone.0109238
PMCID: PMC4192316  PMID: 25299074
9.  Effects of Therapeutic Lifestyle Change diets high and low in dietary fish-derived FAs on lipoprotein metabolism in middle-aged and elderly subjects 
Journal of Lipid Research  2012;53(9):1958-1967.
The effects of Therapeutic Lifestyle Change (TLC) diets, low and high in dietary fish, on apolipoprotein metabolism were examined. Subjects were provided with a Western diet for 6 weeks, followed by 24 weeks of either of two TLC diets (10/group). Apolipoprotein kinetics were determined in the fed state using stable isotope methods and compartmental modeling at the end of each phase. Only the high-fish diet decreased median triglyceride-rich lipoprotein (TRL) apoB-100 concentration (−23%), production rate (PR, −9%), and direct catabolism (−53%), and increased TRL-to-LDL apoB-100 conversion (+39%) as compared with the baseline diet (all P < 0.05). This diet also decreased TRL apoB-48 concentration (−24%), fractional catabolic rate (FCR, −20%), and PR (−50%) as compared with the baseline diet (all P < 0.05). The high-fish and low-fish diets decreased LDL apoB-100 concentration (−9%, −23%), increased LDL apoB-100 FCR (+44%, +48%), and decreased HDL apoA-I concentration (−15%, −14%) and PR (−11%, −12%) as compared with the baseline diet (all P < 0.05). On the high-fish diet, changes in TRL apoB-100 PR were negatively correlated with changes in plasma eicosapentaenoic and docosahexaenoic acids. In conclusion, the high-fish diet decreased TRL apoB-100 and TRL apoB-48 concentrations chiefly by decreasing their PR. Both diets decreased LDL apoB-100 concentration by increasing LDL apoB-100 FCR and decreased HDL apoA-I concentration by decreasing HDL apoA-I PR.
doi:10.1194/jlr.P024315
PMCID: PMC3413235  PMID: 22773687
fatty acids; hypercholesterolemia; apolipoproteins; dyslipidemias; fish oil; lipoproteins/linetics; lipoproteins/metabolism; nutrition; omega-3 fatty acids; mathematical modeling
10.  Direct assessment of plasma low density lipoprotein and high density lipoprotein cholesterol levels and coronary heart disease: results from the Framingham Offspring Study 
Atherosclerosis  2010;213(1):251-255.
BACKGROUND
We evaluated direct low density lipoprotein (LDL) cholesterol (C) and high density lipoprotein (HDL) cholesterol (C) versus standard methods using fasting plasma samples from participants in cycle 6 of the Framingham Offspring Study.
METHODS
Direct LDL-C and HDL-C measurements were performed on fasting plasma from male (1335 controls, 173 CHD cases) and female (1606 controls, 74 cases) participants, and compared with LDL-C, as calculated with the Friedewald formula, and HDL-C, as measured after dextran-Mg2+ precipitation.
RESULTS
Values for direct LDL-C and HDL-C correlated well with standard methods (both about r2=0.94, p<0.001) with similar absolute values. Biases of > 10% were present for 7.7% of samples for LDL-C, while for HDL-C this value was 8.5%. Despite higher use of cholesterol lowering medication in CHD cases, calculated or direct LDL-C values were still well above recommended values [< 2.6 mmol/L, (100 mg/dl)] in CHD cases, especially in females.
CONCLUSIONS
Direct assays for both LDL-C and HDL-C provide an acceptable guide for lipid treatment. In the Framingham Offspring Study participants, most CHD cases have LDL-C levels above the recommended target.
doi:10.1016/j.atherosclerosis.2010.02.041
PMCID: PMC3707385  PMID: 20863498
cholesterol; LDL; HDL; coronary heart disease; Framingham Offspring Study
11.  Plasma Phosphatidylcholine Concentrations of Polyunsaturated Fatty Acids Are Differentially Associated With Hip Bone Mineral Density and Hip Fracture in Older Adults: The Framingham Osteoporosis Study 
Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN-BMD) (n = 765); (2) 4-year change in FN-BMD (n = 556); and (3) hip fracture risk (n = 765) over 17-year follow-up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN-BMD over 4 years in women (p-trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN-BMD in women (p-trend = 0.02), and increased hip fracture risk in women and men (p-trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p-trend = 0.12 and p-trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN-BMD in men (p-trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN-BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk.
doi:10.1002/jbmr.1581
PMCID: PMC3565380  PMID: 22392875
DOCOSAHEXAENOIC ACID; LINOLEIC ACID; ARACHIDONIC ACID; BMD; FRACTURE
12.  Sex‐Specific Differences in the Predictive Value of Cholesterol Homeostasis Markers and 10‐Year Cardiovascular Disease Event Rate in Framingham Offspring Study Participants 
Background
Available data are inconsistent regarding factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (CVD) events.
Methods and Results
To address this issue, the relationship between markers of cholesterol absorption (campesterol, sitosterol, cholestanol) and synthesis (squalene, desmosterol, lathosterol) and 10‐year CVD incidence was assessed in Framingham Offspring Study participants (cycle 6) who were without CVD at baseline and not taking lipid‐lowering medications (N=2616). The primary end point was “hard” coronary heart disease (HCHD; coronary death and myocardial infarction), and the secondary end point was full CVD (HCHD plus stroke, coronary insufficiency, angina pectoris, peripheral artery disease, and congestive heart failure). In cross‐sectional analysis, significant differences by sex, age, body mass index, blood pressure, and smoking status were observed. In both women and men, lower cholesterol absorption was associated with higher triglyceride and lower high‐density lipoprotein (HDL) cholesterol concentrations, whereas lower cholesterol synthesis was associated with higher low‐density lipoprotein (LDL) cholesterol concentrations (P for trend <0.05). In women only, lower cholesterol synthesis and absorption were associated with higher non–HDL cholesterol concentrations. Using Cox proportional hazards model adjusting for standard CVD risk factors, squalene concentrations were associated with lower HCHD in women (hazard ratio=0.70 [0.5 to 0.9]). In contrast, squalene (hazard ratio=1.40 [1.1 to 1.8]) concentrations were associated with higher HCHD in men (P<0.0001 for interaction). The cholesterol absorption markers were not predictive of HCHD or full CVD in either women or men.
Conclusions
These data suggest significant sex differences in the 10‐year prognostic value of cholesterol synthesis markers and HCHD, specifically coronary death and incidence of myocardial infarction.
Clinical Trial Registration
URL:http://ClinicalTrials.gov. Unique identifier: NCT00074464.
doi:10.1161/JAHA.112.005066
PMCID: PMC3603247  PMID: 23525441
cardiovascular disease; lipids; metabolism; mortality; myocardial infarction; risk factors
13.  Protection From Retinopathy and Other Complications in Patients With Type 1 Diabetes of Extreme Duration 
Diabetes Care  2011;34(4):968-974.
OBJECTIVE
To assess complication prevalence and identify protective factors in patients with diabetes duration of ≥50 years. Characterization of a complication-free subgroup in this cohort would suggest that some individuals are protected from diabetes complications and allow identification of endogenous protective factors.
RESEARCH DESIGN AND METHODS
Cross-sectional, observational study of 351 U.S. residents who have survived with type 1 diabetes for ≥50 years (Medalists). Retinopathy, nephropathy, neuropathy, and cardiovascular disease were assessed in relation to HbA1c, lipids, and advanced glycation end products (AGEs). Retrospective chart review provided longitudinal ophthalmic data for a subgroup.
RESULTS
A high proportion of Medalists remain free from proliferative diabetic retinopathy (PDR) (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). Current and longitudinal (the past 15 years) glycemic control were unrelated to complications. Subjects with high plasma carboxyethyl-lysine and pentosidine were 7.2-fold more likely to have any complication. Of Medalists without PDR, 96% with no retinopathy progression over the first 17 years of follow-up did not experience retinopathy worsening thereafter.
CONCLUSIONS
The Medalist population is likely enriched for protective factors against complications. These factors might prove useful to the general population with diabetes if they can be used to induce protection against long-term complications. Specific AGE combinations were strongly associated with complications, indicating a link between AGE formation or processing with development of diabetic vasculopathy.
doi:10.2337/dc10-1675
PMCID: PMC3064059  PMID: 21447665
14.  The effect of 17β-estradiol on cholesterol content in human macrophages is influenced by the lipoprotein milieu 
Estrogen and testosterone are thought to modulate coronary heart disease (CHD) risk. To examine how these hormones affect human macrophage cholesterol transport, a key factor in atherogenesis, we obtained monocytes from healthy male and postmenopausal female donors (age 50–70 y). Cells were allowed to differentiate in autologous serum. Human monocyte-derived macrophages (HMDMs) were exposed to estrogen, testosterone, or vehicle, during differentiation. Cells were cholesterol-enriched with oxidized LDL (oxLDL) in the presence of treatment. Cell cholesterol mass, efflux, and the expression of proteins involved in HMDM cholesterol transport were examined. Estrogen significantly reduced cholesteryl ester content in both female and male HMDMs while having no measurable effect on cholesterol efflux. Testosterone did not affect cholesterol content or efflux. Both hormones significantly but modestly affected the gene expression of several proteins involved in HMDM transport, yet these effects did not translate into significant changes in protein expression. In THP-1 macrophages, the effect of estrogen on cholesteryl ester content was more potent in unloaded macrophages and was estrogen receptor-dependent. A trend for a reduction in non-oxidized LDL uptake by estrogen was observed and was also found to be dependent upon ER activation. Our data indicate that estrogen, but not testosterone, reduces cholesteryl ester accumulation in HMDMs obtained from a CHD-age relevant population, independent of changes in the expression of proteins important to macrophage cholesterol transport. In THP-1 cells, this effect is reduced in the presence of oxLDL indicating that a pro-atherogenic lipoprotein milieu is an important variable in sex hormone modulation of CHD.
PMCID: PMC3168528  PMID: 21830321
Sex hormones; macrophage; cholesterol transport; oxidized LDL
15.  Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion 
Objective
Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues.
Methods and Results
Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2H3)-L-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily torcetrapib increased the amount of apoA-I in α1-migrating HDL in the atorvastatin (136%; P<0.001) and nonatorvastatin (153%; P<0.01) cohorts, whereas an increase of 382% (P<0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8±15% in the atorvastatin cohort (P=0.16) and by 16±7% (P<0.0001) and 34±8% (P<0.0001) in the nonatorvastatin 120 mg QD and BID cohorts, respectively. These changes were attributable to reductions in HDL apoA-I fractional catabolic rate (FCR), with torcetrapib reducing HDL apoA-I FCR by 7% (P<0.10) in the atorvastatin cohort, by 8% (P<0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% (P=0.01) in the nonatorvastatin 120 mg BID cohort. Torcetrapib did not affect HDL apoA-I production rate. In addition, torcetrapib did not significantly change serum markers of cholesterol or bile acid synthesis or fecal sterol excretion.
Conclusions
These data indicate that partial inhibition of CETP via torcetrapib in patients with low HDL-C: (1) normalizes apoA-I levels within α1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.
doi:10.1161/01.ATV.0000161928.16334.dd
PMCID: PMC3229922  PMID: 15761191
apolipoprotein A-I; bile acids; cholesteryl ester transfer protein; CETP inhibition; high-density lipoproteins; kinetics
16.  Role of the Estrogen and Progestin in Hormonal Replacement Therapy on Apolipoprotein A-I Kinetics in Postmenopausal Women 
Objective
Plasma high-density lipoprotein (HDL) cholesterol levels are inversely correlated with the risk of developing coronary heart disease. Hormonal replacement therapy (HRT) affects plasma HDL cholesterol levels, with estrogen increasing HDL cholesterol levels and progestins blunting this effect. This study was designed to assess the mechanism responsible for these effects.
Materials and Methods
HDL apolipoprotein A-I (apoA-I) kinetics were studied in 8 healthy postmenopausal women participating in a double-blind, randomized, crossover study comprising 3 phases: placebo, conjugated equine estrogen (CEE) (0.625 mg/d), and CEE plus medroxyprogesterone acetate (MPA) (2.5 mg/d). Compared with placebo, treatment with CEE resulted in an increase in apoA-I pool size (+20%, P<0.01) because of a significant increase in apoA-I production rate (+47%, P<0.05) and no significant changes in apoA-I fractional catabolic rate. Compared with the CEE alone phase, treatment with the CEE plus MPA resulted in an 8% (P<0.02) reduction in apoA-I pool size and a significant reduction in apoA-I production rate (−13%, P<0.04), without changes in apoA-I fractional catabolic rate.
Conclusion
Postmenopausal estrogen replacement increases apoA-I levels and production rate. When progestin is added to estrogen, it opposes these effects by reducing the production of apoA-I.
doi:10.1161/01.ATV.0000199248.53590.e1
PMCID: PMC3229925  PMID: 16339502
apolipoprotein A-I; estrogen; progestin; kinetics stable isotopes
17.  Effect of hormone replacement therapy on plasma lipoprotein levels and coronary atherosclerosis progression in postmenopausal women according to type 2 diabetes mellitus status 
Metabolism: clinical and experimental  2010;59(12):1794-1800.
Type 2 diabetes mellitus is associated with dyslipidemia and with an increased risk of coronary heart disease (CHD). Our objective was to compare the effects of hormone replacement therapy (HRT) on plasma lipoproteins and coronary disease progression in postmenopausal women with and without diabetes. Study subjects were participants in the Estrogen Replacement and Atherosclerosis trial, a placebo-controlled, randomized trial of HRT (conjugated equine estrogen 0.625 mg/day with or without medroxyprogesterone acetate 2.5 mg/day) in postmenopausal women with established CHD (men age 65±7 y). Plasma remnant lipoprotein levels and HDL subpopulation levels were measured at baseline and year 1. Quantitative coronary angiography was assessed at baseline and at follow-up. At baseline, remnant lipoprotein levels were significantly higher and HDL-C levels significantly lower in diabetic women than in women without diabetes. HRT lowered remnant lipoproteins and increased HDL-C and large HDL particle levels in both groups. However, during HRT, levels of these parameters were still significantly worse in diabetic women than in non-diabetic women. A significant interaction between HRT and diabetes status, with greater increases in plasma atheroprotective HDL α1 particles in non-diabetic women than in diabetic women during HRT, was observed. CHD progressed significantly more in women with diabetes than in women without diabetes. Our findings indicate that diabetes attenuates the HRT-related increase in atheroprotective HDL α1 particles. Faster progression of coronary atherosclerosis in women with diabetes could be mediated in part by a worse lipoprotein profile in these women than in women without diabetes, both before and during HRT.
doi:10.1016/j.metabol.2010.05.012
PMCID: PMC2947588  PMID: 20580029
Hormone replacement therapy; diabetes mellitus; lipoproteins; cholesterol; triglycerides; coronary heart disease
18.  C-Reactive Protein and Genetic Variants and Cognitive Decline in Old Age: The PROSPER Study 
PLoS ONE  2011;6(9):e23890.
Background
Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is causally linked to cognitive decline.
Methods and Findings
Within the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, with 5680 participants with a mean age of 75 years, we examined associations of CRP levels and its genetic determinants with cognitive performance and decline over 3.2 years mean follow-up. Higher plasma CRP concentrations were associated with poorer baseline performance on the Stroop test (P = 0.001) and Letter Digit Tests (P<0.001), but not with the immediate and delayed Picture Learning Test (PLT; both P>0.5). In the prospective analyses, higher CRP concentrations associated with increased rate of decline in the immediate PLT (P = 0.016), but not in other cognitive tests (all p>0.11). Adjustment for prevalent cardiovascular risk factors and disease did not change the baseline associations nor associations with cognitive decline during follow-up. Four haplotypes of CRP were used and, compared to the common haplotype, carrierships associated strongly with levels of CRP (all P<0.007). In comparison to strong associations of apolipoprotein E with cognitive measures, associations of CRP haplotypes with such measures were inconsistent.
Conclusion
Plasma CRP concentrations associate with cognitive performance in part through pathways independent of (risk factors for) cardiovascular disease. However, lifelong exposure to higher CRP levels does not associate with poorer cognitive performance in old age. The current data weaken the argument for a causal role of CRP in cognitive performance, but further study is warranted to draw definitive conclusions.
doi:10.1371/journal.pone.0023890
PMCID: PMC3168438  PMID: 21915265
19.  Sex hormone modulation of proinflammatory cytokine and CRP expression in macrophages from older men and postmenopausal women 
The Journal of endocrinology  2010;206(2):217-224.
Inflammation plays a central role in the development and progression of coronary heart disease (CHD). The sex hormones estrogen and testosterone have been shown to modify the inflammatory response by influencing cytokine expression in human macrophage cells obtained from younger individuals. The effect of these hormones on the expression of proinflammatory markers in macrophages obtained from a CHD-age relevant population has not been studied. Human monocyte-derived macrophage cells (HMDM) were obtained from healthy normolipidemic men and postmenopausal women (age 50-70 years), and cultured in autologous serum along with both physiological and supraphysiological concentrations of estrogen or testosterone. HMDM were stimulated with oxidized low density lipoproteins (oxLDL) and the expression of the cytokines TNF-α, IL-6, and IL-1β, and of the acute-phase protein CRP was measured. Both physiological and supraphysiological concentrations of testosterone reduced the expression and secretion of TNF-α and reduced the expression of IL-1β, but did not affect IL-6 or CRP expression. Estrogen did not modify the expression of TNF-α, IL-6, and IL-1β. Estrogen caused a variable response in CRP expression that was positively associated with the donor’s plasma small dense LDL cholesterol concentration. There were no gender differences in any of the observed effects.
Our results indicate that testosterone may exert anti-inflammatory effects by reducing macrophage TNF-α expression while the effects of estrogen on macrophage CRP expression may depend upon the extracellular lipid environment.
doi:10.1677/JOE-10-0057
PMCID: PMC2954460  PMID: 20484148
Sex Hormones; Inflammation; Coronary Heart Disease; Macrophage; Cytokine; CRP
20.  Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults 
Atherosclerosis  2009;210(2):555-562.
Background
Information is scarce regarding the effect of dietary protein type, with specific focus on the lysine to arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans.
Objective
Determine effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults.
Design
Randomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 y, LDL cholesterol ≥120 mg/dL). Diets had 20% energy (E) protein, 30%E fat, 50%E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT).
Results
No differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (−24%, P=0.001) and triglycerides (−23%, P=0.001), and small but significant differences in fasting (−3%, P=0.003) and postprandial (−3%, P=0.018) apo AI, and fasting adiponectin concentrations (+7%, P=0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P=0.020 for both).
Conclusions
Diets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity.
doi:10.1016/j.atherosclerosis.2009.12.002
PMCID: PMC2878850  PMID: 20042191
lysine:arginine ratio; lipoproteins; small dense LDL (sdLDL)-cholesterol; remnant lipoprotein cholesterol (RemLC); cholesterol fractional synthesis rate (FSR); flow mediated dilation (FMD); peripheral artery tonometry (PAT)
21.  Clinical Trial of Lutein in Patients with Retinitis Pigmentosa Receiving Vitamin A 
Archives of ophthalmology  2010;128(4):403-411.
Objective
To determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A.
Design
Randomized, controlled, double-masked trial of 225 non-smoking patients, age 18-60 years, evaluated over a 4-year interval. Patients received lutein 12 mg or a control tablet daily. All were given vitamin A palmitate 15,000 IU/day. Randomization took into account genetic type and baseline serum lutein.
Main Outcome Measures
The primary outcome was the total point score for the Humphrey Field Analyzer (HFA) 30-2 program; pre-specified secondary outcomes were the total point scores for the 60-4 program and for the 30-2 and 60-4 combined, 30-Hz electroretinogram amplitude, and ETDRS acuity.
Results
No significant difference in rate of decline was found between the lutein + A and control + A groups over a 4-year interval for the HFA 30-2 program. For the HFA 60-4 program a decrease in mean rate of sensitivity loss was observed in the lutein + A group (p=0.05). Mean decline with the 60-4 program was slower among those with the highest serum lutein or with the highest increase in macular pigment optical density (MPOD) at follow-up (p= 0.01 and p=0.006 respectively). Those with the highest increase in MPOD also had the slowest decline in 30-2 and 60-4 combined field sensitivity (p=0.005). No significant toxic side effects of lutein supplementation were observed.
Conclusion
Lutein supplementation 12 mg/d slowed loss of midperipheral visual field on average among nonsmoking adults with retinitis pigmentosa taking vitamin A.
Application to Clinical Practice
Data are presented that support use of lutein 12 mg/day to slow visual field loss among non-smoking adults with retinitis pigmentosa on vitamin A.
Trial Registry
Randomized Clinical Trial for Retinitis Pigmentosa, NCT00346333, www.ClinicalTrial.gov
doi:10.1001/archophthalmol.2010.32
PMCID: PMC2987594  PMID: 20385935
22.  Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women 
Clinical endocrinology  2009;72(2):169-175.
SUMMARY
Objective
A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor α gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT.
Subjects
Postmenopausal Caucasian women (N=208) participating in a placebo-controlled randomized trial of 3.2 years of hormone therapy (HT).
Methods
Plasma triglycerides (TG), remnant lipoprotein cholesterol (RLP-C), and high-density lipoprotein cholesterol (HDL-C) levels and HDL subpopulations were assessed at baseline and at follow-up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT-related changes in levels of RLP-C and HDL subpopulations.
Results
Carriers of the ESR1 PvuII or IVS1-1505 variants had lower plasma TG concentrations and higher plasma HDL-C and α-1 and preα-1 HDL particle levels at baseline and showed greater increases in HDL-C, apo A-I and α-1 particle levels after HT than wild-type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower α-2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL-C and HDL subpopulation profile.
Conclusions
SNPs in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG-rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.
doi:10.1111/j.1365-2265.2009.03644.x
PMCID: PMC2866027  PMID: 19489872
high-density lipoprotein; remnant lipoproteins; single nucleotide polymorphism hormone therapy
23.  Familial Combined Hyperlipidemia is Associated with Alterations in the Cholesterol Synthesis Pathway 
Objectives
Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members.
Methods and Results
Plasma levels of squalene, desmosterol and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (p<0.001) and 51% (p<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR.
Conclusions
Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.
doi:10.1161/ATVBAHA.109.196550
PMCID: PMC2813691  PMID: 19834104
Cholesterol; Lipids; Sterols; Familial Combined Hyperlipidemia
24.  Substitution of vegetable oil for a partially-hydrogenated fat favorably alters cardiovascular disease risk factors in moderately hypercholesterolemic postmenopausal womena,b 
Atherosclerosis  2009;207(1):208-212.
Objective
Compared to vegetable oils in their unmodified state, partially-hydrogenated fat is associated with less favorable effects on cardiovascular disease (CVD) risk factors. Acceptable alternatives must be adjudicated. Our objective was to assess the effect of a recent commercial fat substitution, corn oil for partially-hydrogenated soybean oil.
Methods
Using a double-blind cross-over design, 30 postmenopausal women ≥50 y with LDL-cholesterol concentrations ≥120 mg/dL were randomly assigned to each of two 35-day phases; all food and beverage was provided to maintain body weight. Corn or partially-hydrogenated soybean oil was incorporated throughout the diet and contributed two-thirds of fat. Primary outcomes included fasting and non-fasting lipid, lipoprotein, apolipoprotein, and fasting high sensitivity C-reactive protein (hsCRP) concentrations; secondary outcomes included fasting small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, and endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities.
Results
Relative to the partially-hydrogenated soybean oil-enriched diet, the corn oil enriched diet resulted in lower fasting total cholesterol (7%; P<0.0001), LDL-cholesterol (10%; P<0.0001), VLDL-cholesterol (7%; P=0.052), apo B (9%; P<0.0001), Lp(a) (5%; P=0.024), sdLDL-cholesterol (17%; P=0.001), and RemLC (20%; P=0.007) concentrations, and no significant effect on the other outcomes. Changes in postprandial (4-h post-meal) lipid, lipoprotein and apolipoprotein concentrations were similar to the fasting state.
Conclusion
The replacement of partially-hydrogenated soybean oil with corn oil favorably affects a range of CVD risk factors and is an appropriate option to decrease cardiovascular disease risk factors in moderately hypercholesterolemic individuals.
doi:10.1016/j.atherosclerosis.2009.03.039
PMCID: PMC2905850  PMID: 19423109
cardiovascular disease; trans fatty acids; polyunsaturated fatty acids; lipoproteins; partially-hydrogenated fat; vegetable oil; LDL-cholesterol; HDL-cholesterol; hsCRP; CETP; LCAT
25.  Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women 
Atherosclerosis  2008;205(1):325-330.
Objective
This study examined the effect of hormone therapy (HT) on the plasma concentration of remnant lipoprotein cholesterol (RLP-C) and high density lipoprotein (HDL) subpopulations and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease (CHD) in postmenopausal women.
Methods
Study participants were 256 women who completed the Estrogen Replacement and Atherosclerosis (ERA) trial, a placebo-controlled, randomized trial that examined the effects of 3.2 years of conjugated equine estrogen (CEE, 0.625 mg/day) or CEE (0.625 mg/day) plus medroxyprogesterone acetate (MPA, 2.5 mg/day) on post-menopausal women with established coronary atherosclerosis. Quantitative coronary angiography and plasma RLP-C and HDL subpopulations were assessed at baseline and at follow-up.
Results
Relative to placebo, both CEE and CEE+MPA caused a significant reduction in plasma RLP-C concentrations and a significant increase in α1 and α2 HDL subpopulations. However, in the HT-treated subjects, faster progression of coronary atherosclerosis was observed in women who experienced the greatest reductions in RLP-C and in preβ1 HDL subpopulations.
Conclusions
Our data suggest that individual variability in RLP-C and HDL subpopulation response to HT is a predictor of CHD progression. Lipoprotein response to HT may be an indirect marker of susceptibility to other harmful effect of HT in postmenopausal women with established CHD or an indication of formation of dysfunctional lipoproteins.
doi:10.1016/j.atherosclerosis.2008.12.020
PMCID: PMC2700198  PMID: 19155011
Lipoproteins; hormone therapy; coronary heart disease; angiography

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