Effect of Clinical and Laboratory Parameters on HDL Particle Composition.

The functional status of High-Density Lipoprotein (HDLs) is not dependent on the cholesterol content but is closely related to structural and compositional characteristics. We reported the analysis of HDL lipidome in the healthy population and the influence of serum lipids, age, gender and menopausal status on its composition. Our sample comprised 90 healthy subjects aged between 30 and 77 years. HDL lipidome was investigated by Nuclear Magnetic Resonance (NMR) spectroscopy. Among serum lipids, triglycerides, apoAI, apoB and the ratio HDL-C/apoAI had a significant influence on HDL lipid composition. Aging was associated with significant aberrations, including an increase in triglyceride content, lysophosphatidylcholine, free cholesterol, and a decrease in esterified cholesterol, phospholipids, and sphingomyelin that may contribute to increased cardiovascular risk. Aging was also associated with an atherogenic fatty acid pattern. Changes occurring in the HDL lipidome between the two genders were more pronounced in the decade from 30 to 39 years of age and over 60 years. The postmenopausal group displayed significant pro-atherogenic changes in HDLs compared to the premenopausal group. The influence of serum lipids and intrinsic factors on HDL lipidome could improve our understanding of the remodeling capacity of HDLs directly related to its functionality and antiatherogenic properties, and also in appropriate clinical research study protocol design. These data demonstrate that NMR analysis can easily follow the subtle alterations of lipoprotein composition due to serum lipid parameters.

Progressive, Qualitative, and Quantitative Alterations in HDL Lipidome from Healthy Subjects to Patients with Prediabetes and Type 2 Diabetes.

Prediabetes is a clinically silent, insulin-resistant state with increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Since glucose homeostasis and lipid metabolism are highly intersected and interrelated, an in-depth characterization of qualitative and quantitative abnormalities in lipoproteins could unravel the metabolic pathways underlying the progression of prediabetes to T2D and also the proneness of these patients to developing premature atherosclerosis. We investigated the HDL lipidome in 40 patients with prediabetes and compared it to that of 40 normoglycemic individuals and 40 patients with established T2D using Nuclear Magnetic Resonance (NMR) spectroscopy. Patients with prediabetes presented significant qualitative and quantitative alterations, potentially atherogenic, in HDL lipidome compared to normoglycemic characterized by higher percentages of free cholesterol and triglycerides, whereas phospholipids were lower. Glycerophospholipids and ether glycerolipids were significantly lower in prediabetic compared to normoglycemic individuals, whereas sphingolipids were significantly higher. In prediabetes, lipids were esterified with saturated rather than unsaturated fatty acids. These changes are qualitatively similar, but quantitatively milder, than those found in patients with T2D. We conclude that the detailed characterization of the HDL lipid profile bears a potential to identify patients with subtle (but still proatherogenic) abnormalities who are at high risk for development of T2D and CVD.

Elderly patients with non-cardiac admissions and elevated high-sensitivity troponin: the prognostic value of renal function.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) levels are frequently elevated in elderly patients presenting to the emergency department for non-cardiac events. However, most studies on the role of elevated hs-cTn in elderly populations have investigated the prognostic value of hs-cTn in patients with a specific diagnosis or have assessed the relationship between hs-cTn and comorbidities. AIM: To investigate the in-hospital prognosis of consecutive elderly patients admitted to the Internal Medicine Department with acute non-cardiac events and increased hs-cTnI levels. METHODS: In this retrospective study, we selected patients who were aged ≥ 65 years and admitted to the Internal Medicine Department of our hospital between January 2019 and December 2019 for non-cardiac reasons. Eligible patients were those who had hs-cTnI concentrations ≥ 100 ng/L. We investigated the independent predictors of in-hospital mortality by multivariable logistic regression analysis. RESULTS: One hundred and forty-six patients (59% female) were selected with an age range from 65 to 100 (mean ± SD: 85.4 ± 7.61) years. The median hs-cTnI value was 284.2 ng/L. For 72 (49%) patients the diagnosis of hospitalization was an infectious disease. The overall in-hospital mortality was 32% (47 patients). Individuals who died did not have higher hs-cTnI levels compared with those who were discharged alive (median: 314.8 vs 282.5 ng/L; P = 0.565). There was no difference in mortality in patients with infectious vs non-infectious disease (29% vs 35%). Multivariable analysis showed that age (OR 1.062 per 1 year increase, 95%CI: 1.000-1.127; P = 0.048) and creatinine levels (OR 2.065 per 1 mg/dL increase, 95%CI: 1.383-3.085; P < 0.001) were the only independent predictors of death. Mortality was 49% in patients with eGFR < 30 mL/min/1.73 m2. CONCLUSION: Myocardial injury is a malignant condition in elderly patients admitted to the hospital for non-cardiac reasons. The presence of severe renal impairment is a marker of extremely high in-hospital mortality.

Altered RBC membrane lipidome: A possible etiopathogenic link for the microvascular impairment in Type 2 diabetes.

AIMS: Disturbances in red blood cells' (RBCs) membrane structure, that result in altered rheological properties, have been implicated in the pathogenesis of microvascular complications of diabetes mellitus(T2DM). However, the compositional alterations in RBCs membranes of T2DM patients have not been characterized in detail. METHODS: NMR-based lipidomic approach used for the global investigation of the lipidome of RBCs membrane in 20 newly diagnosed T2DM patients. Twenty healthy individuals served as controls. RESULTS: In the lipidomic analysis, the discrimination power among the two groups was of high significance. T2DM patients characterized by an increased content of cholesterol, total sphingolipids, sphingomyelin and glycolipids, and decreased total phospholipids, mainly due to phosphatidylethanolamine, total ether glycerolipids and plasmalogen-phospholipids, and higher cholesterol-to-phospholipids molecular ratio compared to controls. In T2DM, lipids were esterified with saturated rather than unsaturated fatty acids, an atherogenic pattern that may be involved in the impairment of membrane fluidity and rigidity. CONCLUSIONS: NMR-based lipidomic analysis of RBCs can provide insights into molecular lipid features of membrane microenvironment that influence their vital function and rheological behavior in microvascular network in T2DM.Early identification of these disturbances, even before the onset of diabetes, could critically help to the development of novel preventative and curative therapies for reducing the risk of microvascular dysfunction.

Early Signs of Atherogenic Features in the HDL Lipidomes of Normolipidemic Patients Newly Diagnosed with Type 2 Diabetes.

Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is limited in routine to a pattern of high triglycerides and low HDL-cholesterol (HDL-C) and in research as dysfunctional HDLs. We used the emerging NMR-based lipidomic technology to investigate compositional features of the HDLs of healthy individuals with normal coronary arteries, drug-naïve; recently diagnosed T2DM patients with normal coronary arteries; and patients with recent acute coronary syndrome. Patients with T2DM and normal serum lipid profiles even at diagnosis presented significant lipid alterations in HDL, characterized by higher triglycerides, lysophosphatidylcholine and saturated fatty acids; and lower cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, plasmalogens and polyunsaturated fatty acids, an atherogenic pattern that may be involved in the pathogenesis of atherosclerosis. These changes are qualitatively similar to those found, more profoundly, in normolipidemic patients with established Coronary Heart Disease (CHD). We also conclude that NMR-based lipidomics offer a novel holistic exploratory approach for identifying and quantifying lipid species in biological matrixes in physiological processes and disease states or in disease biomarker discovery.

Lipidomics in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.

Lipidome of plasma lipoproteins and liver is zinc- modulated in High fat diet treated mice.

Zinc (Zn) and Zn-transcription Factors regulate the metabolic pathways of lipids and glucose, consequently nutritional zinc deficiency or excess, activates stress pathways and deranges the hepatic metabolism of lipids. High fat diet (HFD) also leads to lipids' profile disorders as well as to intracellular free radicals (FR) accumulation and finally to metabolic stress-syndrome. Study of nutritional Zn effects on the lipidome of plasma lipoproteins and liver, in HFD-mice, was the aim of the present research. Three Zn enriched HF-Diets as follows, 3 mg/kg feed (Zn deficient diet), 30 mg/kg feed (Zn sufficient diet), 300mgZn /kg feed (Zn excess diet) (Mucedola s.r.l Italy-55% cal) were applied respectively to three groups of male wild type (wt) mice (Hybrid F1/F1),C57Bl/6xCBA, one month old, for 10 weeks. Accordingly, mice body weight rate and 1H-NMR spectrum analysis of liver extracts and plasma HDL and non-HDL lipoproteins were evaluated at the end of the experimental period. It is concluded that Zn sufficient diet (30 mg/Kg Feed) creates a highly protective lipidomic profile on plasma and liver lipoproteins of HFD-mice, related to significantly increased antiatherogenic indicators in lipids' composition, compared to mice in nutritional Zn deficiency or excess.

NMR-Based Lipid Profiling of High Density Lipoprotein Particles in Healthy Subjects with Low, Normal, and Elevated HDL-Cholesterol.

Recent studies suggest that the cholesterol content of HDL (high density lipoproteins) may provide limited information on their antiatherogenic properties and that the composition and particles' structure provide more information on their functionality. We used NMR-based (nuclear magnetic resonance-based) lipidomics to study the relationships of serum HDL-C (HDL-cholesterol) levels with the lipid composition of HDL particles in three groups of subjects selected on the basis of their HDL-C levels. Subjects with low and high HDL-C levels exhibited differences in HDL lipidome compared to those with normal HDL-C levels. In pattern recognition analysis, the discrimination power among all groups was of high significance. The low HDL-C group presented enrichment of the core in triglycerides and depletion in cholesterol esters, whereas the high HDL-C group showed a decrease in triglycerides content. Additionally, as HDL-C increases, all lipid classes are esterified with higher percentage of unsaturated than saturated fatty acids. In addition to the aforementioned differences, the surface layer is enriched in sphingomyelin and free cholesterol in the high HDL-C level group. NMR-based lipidomic analysis of HDL can be particularly useful since it provides insights into molecular features and helps in the characterization of the atheroprotective function of HDL lipoproteins and in the identification of novel biomarkers of cardiovascular risk.

Vitamin D, parathormone, and insulin resistance in children born large for gestational age.

BACKGROUND: Low vitamin D [25(OH)D] levels have been associated with type-2 diabetes mellitus. Children born large for gestational age (LGA) may exhibit increased indices of insulin resistance early in life. OBJECTIVE: This study aims to prospectively examine serum 25(OH)D and parathormone (iPTH) levels in LGA and appropriate for gestational age (AGA) prepubertal children, in relation to the severity of macrosomia and insulin resistance. METHODS: Children were examined at age 5-7.5 years, 38 born LGA and 39 AGA, matched for age, gender, body weight, height and body mass index (BMI). Twenty-one LGA had birth weights in the 90th-97th percentile and 17 >97th percentile. Fasting serum levels of glucose, insulin, 25(OH)D, and iPTH were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) was estimated. RESULTS: The insulin resistance indices were higher in the LGA >97th percentile subgroup than in the AGA group: HOMA-IR 1.53±0.66 vs. 1.04±0.53 and fasting insulin 6.92±3.1 vs. 4.78±2.2 µIU/mL (but similar to the AGA group), and in the LGA 90th-97th percentile subgroup: HOMA-IR 1.17±0.61 and insulin 5.53±2.2. There was no difference in 25(OH)D among the three subgroups. The iPTH was higher in the LGA >97th percentile subgroup than in the AGA group (26.8±7.6 and 22.6±7.2 pg/mL, respectively, p<0.05), although it was not correlated with insulin resistance indices. Birth weight was correlated negatively with fasting insulin and HOMA-IR in the entire cohort, independent of age, sex, waist circumference, and BMI (ß=0.37, p<0.01 and ß=0.30, p<0.05, respectively), while waist circumference was positively correlated with HOMA-IR (R=0.40, p<0.001). CONCLUSION: Birth weight and current body composition appear to affect glucose homeostasis in LGA prepubertal children, while the serum levels of 25(OH)D and iPTH appear to be uninvolved.

Visceral leishmaniasis is associated with marked changes in serum lipid profile.

BACKGROUND: Infection is often accompanied by lipid profile alterations. The aim of this study was to evaluate the lipid profile changes in patients with visceral leishmaniasis (VL). MATERIALS AND METHODS: We included 15 patients [10 men, aged 50 (24-82) years old] with VL and 15 age- and sex-matched controls. The parameters estimated at diagnosis and 4 months after VL resolution were total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), apolipoproteins (apo) A-Ι, B, E, C-II, C-III, lipoprotein (a) [Lp(a)], activities of lipoprotein-associated phospholipase A2 (Lp-PLA2), HDL-Lp-PLA2, PON1 (paraoxonase 1) and cholesterol ester transfer protein (CETP), cytokines (interleukins 1ß and 6 and tumour necrosis factor α), as well as LDL subfraction profile. RESULTS: Patients with VL at diagnosis had lower levels of TC, LDL-C, apoΒ and Lp(a), and higher TG and apoE concentrations compared with 4 months after VL resolution. The activities of Lp-PLA2, HDL-Lp-PLA2 and ΡΟΝ1 were reduced at diagnosis compared with post-treatment values. VL patients had decreased levels of both large and sdLDL-C at diagnosis; no effect on mean LDL particle size was observed. Patients with VL at diagnosis had decreased HDL-C and apoA-I concentrations; these increased 4 months after VL resolution, but remained lower compared with controls. The activities of HDL-Lp-PLA2 and PON1 remained lower in patients after VL resolution compared with controls. CONCLUSIONS: Patients with VL exhibit increased TG levels and decreased cholesterol subclasses at diagnosis. HDL-C, apoA-I and associated enzymes remain lower 4 months after VL resolution compared with controls.

NMR-based lipidomic analysis of blood lipoproteins differentiates the progression of coronary heart disease.

Abnormal lipid composition and metabolism of plasma lipoproteins play a crucial role in the pathogenesis of coronary heart disease (CHD). A (1)H NMR-based lipidomic approach was used to investigate the correlation of coronary artery stenosis with the atherogenic (non-HDL) and atheroprotective (HDL) lipid profiles in 99 patients with CHD of various stages of disease and compared with 60 patients with normal coronary arteries (NCA), all documented in coronary angiography. The pattern recognition models created from lipid profiles predicted the presence of CHD with a sensitivity of 87% and a specificity of 88% in the HDL model and with 90% and 89% in the non-HDL model, respectively. Patients with mild, moderate, and severe coronary artery stenosis were progressively differentiated from those with NCA in the non-HDL model with a statistically significant separation of severe stage from both mild and moderate. In the HDL model, the progressive differentiation of the disease stages was statistically significant only between patients with mild and severe coronary artery stenosis. The lipid constituents of lipoproteins that mainly characterized the initial stages and then the progression of the disease were the high levels of saturated fatty acids in lipids in both HDL and non-HDL particles, the low levels of HDL-phosphatidylcholine, HDL-sphingomyelin, and omega-3 fatty acids and linoleic acid in lipids in non-HDL particles. The conventional lipid marker, total cholesterol, found in low levels in HDL and in high levels in non-HDL, also contributed to the onset of the disease but with a much lower coefficient of significance. (1)H NMR-based lipidomic analysis of atherogenic and atheroprotective lipoproteins could contribute to the early evaluation of the onset of coronary artery disease and possibly to the establishment of an appropriate therapeutic option.

Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery: results of a pilot study.

OBJECTIVE: Cardiovascular complications represent a major cause of morbidity and mortality in patients undergoing vascular surgery. This was a prospective randomized, open-label study to investigate the effect of lipid-lowering treatment by statin monotherapy or intensified by combining statin with ezetimibe on a  12-month  prognosis after vascular surgery. METHODS: Patients were randomly assigned to receive rosuvastatin (RSV) 10 mg/d or rosuvastatin 10 mg/d plus ezetemibe (RSV/EZT) 10 mg/d, starting prior to scheduled surgical procedure. The primary end point was the first major cardiovascular event, including death from cardiac causes, nonfatal myocardial infarction, ischemic stroke, and unstable angina. RESULTS: A total of 136 patients assigned to RSV and 126 to RSV/EZT completed the study protocol. As many as 6.6% of patients in the RSV group experience a major cardiovascular event within 30 days after surgery versus 5.6% in the RSV/EZT group (P = .72). From month 1 to 12 of the follow-up period, primary end point was observed (9 taking RSV vs 2 in the RSV/EZT group [P = .04]). Intensified lipid-lowering therapy with RSV/EZT was associated with a greater decrease in low-density lipoprotein cholesterol levels compared with RSV (75.87 ± 31.64 vs 87.19 ± 31.7, P = .004), while no differential effect on triglyceride, high-density lipoprotein cholesterol or high-sensitivity C-reactive protein levels was noted between groups. CONCLUSION: Our findings indicate that statin therapy intensified by ezetimibe may reduce the incidence of cardiovascular events within the first 12 months after vascular surgery. Nonetheless, whether the use of ezetimibe as an add-on therapy to reduce cardiovascular risk in these patients needs to be tested in larger future studies.

Prothrombotic state, cardiovascular, and metabolic syndrome risk factors in prepubertal children born large for gestational age.

OBJECTIVE: To evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age (LGA) to nondiabetic, nonobese mothers. RESEARCH DESIGN AND METHODS: At 6-7 years of age, the comparison of various factors was made between 31 LGA and 34 appropriate-for-gestational-age (AGA) children: fibrinogen, antithrombin III, protein C and S, fasting insulin, glucose, homeostasis assessment model of insulin resistance (HOMA-IR) index, adiponectin, leptin, visfatin, IGF-1, IGF-binding protein (IGFBP)-1, IGFBP-3, lipids, and the genetic factors V Leiden G1691A mutation, prothrombin 20210A/G polymorphism, and mutation in the enzyme 5,10-methylenetetrahydrofolate-reductase gene (MTHFR-C677T). RESULTS: LGA children had higher levels of leptin (P<0.01), fasting insulin (P<0.01), and HOMA-IR (P<0.01), but lower IGFBP-3 (P=0.0001), fibrinogen (P=0.0001), and lipoprotein(a) (P<0.001) than AGA children. Significantly more LGA children were homozygous for the MTHFR-C677T mutation (P=0.0016). CONCLUSIONS: Being born LGA to nondiabetic, nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty.

Apolipoprotein B-to-A1 ratio as a predictor of acute ischemic nonembolic stroke in elderly subjects.

Among traditional cardiovascular risk factors, apolipoprotein (apo)B/apoA1 ratio is considered to have the strongest predictive value for ischemic stroke. Nevertheless, there are imsufficient data to support this ratio as an independent risk predictor of ischemic stroke in elderly individuals. In this case-control study, we evaluated apoB/apoA1 ratio as a predictor of ischemic stroke in a cohort of elderly subjects. A total of 163 patients aged>70 years (88 men) admitted due to a first-ever acute ischemic/nonembolic stroke and 166 volunteers (87 men) with no history of cardiovascular disease were included. The association between apoB/apoA1 ratio and stroke was determined by multivariate logistic regression modeling after adjusting for potential confounding factors, including lipid parameters. Stroke patients exhibited a higher apoB/apoA1 ratio than controls (1.04±0.33 vs 0.86±0.22; P<.001). In univariate analysis, crude odds ratio (OR) for apoB/apoA1 ratio was 1.27 per 0.1 increase (95% confidence interval [CI]=1.15-1.39; P<.001). Compared with subjects with an apoB/apoA1 ratio in the lowest quartile, those within the highest quartile had a 6.3-fold increase in the odds of suffering an ischemic stroke (95% CI=3.17-12.48; P<.001). This association remained significant after controlling for potential confounders, including sex, age, smoking status, body mass index, waist circumference, glucose and insulin levels, the presence of hypertension and diabetes mellitus, and lipid profile parameters (adjusted OR=3.02; 95% CI=1.16-7.83; P=.02). Our findings support elevated apoB/apoA1 ratio as an independent predictor of ischemic stroke in individuals over age 70.

Evaluation of established coronary heart disease on the basis of HDL and non-HDL NMR lipid profiling.

A (1)H NMR-based lipid profiling approach was used to investigate the prediction of coronary heart disease (CHD) and examine the confounding effect of factors such as gender, triglycerides, HDL-cholesterol and age levels on the prediction of disease. The HDL and non-HDL lipid profiles in 47 patients with triple vessel disease (TVD) and 41 patients with normal coronary arteries (NCA) both documented angiographically were generated. The presence of CHD was predicted with a sensitivity and specificity of 52% and 75% for HDL model and 78% and 80% for non-HDL, respectively. The lipid constituents of HDL lipoproteins which contributed to the separation between the two groups were the saturated fatty acids, cholesterol, total omega-3 fatty acids, degree of unsaturation, diallylic protons from polyunsaturated fatty acids, linoleic acid and, to a lesser extent, the number of fatty acids, triglycerides, unsaturated fatty acids and phosphatidylcholine. Respectively, for non-HDL, lipoproteins were the saturated fatty acids, number of fatty acids, cholesterol, unsaturated fatty acids and phosphatidylcholine. Gender, triglycerides, HDL-cholesterol and age influenced the lipid constituents of HDL and non-HDL lipoproteins that contributed to the separation between subgroups and confounded the predictive power of the models. NMR-based lipid profiling analysis could contribute to the identification of noninvasive markers for the presence and the development of the disease.

Evaluation of the proximal tubular function in individuals with primary renal hypouricemia: an NMR-based metabonomic study.

Primary renal hypouricemia (PRH) refers to a rare condition of increased renal urate clearance, caused by an isolated inborn error of membrane transport of urate in the renal proximal tubule. Several cases of exercise-induced acute renal failure and urolithiasis have been reported. This is the first study that assessed tubular function in PRH using NMR-based metabonomic urine analysis. The study groups consisted of 36 unrelated asymptomatic subjects with PRH, defined as serum uric acid levels (sUA) <2.5 mg/dL and fractional excretion of uric acid (FEUA) >10%, after exclusion of diseases and drugs that may affect urate homeostasis, and 39 sex and age-matched healthy individuals with normal sUA levels (>4.0 mmol/L) and FEUA<10%. Individuals with primary hypouricemia presented similar biochemical profiles to the controls without significant differences with regard to FE of electrolytes and renal threshold for phosphate excretion. Individuals with primary hypouricemia were differentiated from healthy individuals in the orthogonal signal correction/partial least-squares-discriminant analysis models of the NMR data with a statistically significant separation. The components that contributed to this separation were the lower levels of hippurate, creatinine, and trimethylaminoxide, and the higher levels of phenylalanine, alanine, glycine, glutamate, acetate, and of an unidentified metabolite (3.3 ppm) observed in hypouricemic subjects compared with controls. Primary hypouricemia, though considered an isolated renal tubular defect, is often associated with a more generalized proximal tubular disorder that mimics a partial Fanconi syndrome.

Dose-dependent effect of rosuvastatin treatment on HDL-subfraction phenotype in patients with primary hyperlipidemia.

Although the raising effect of rosuvastatin on high-density lipoprotein cholesterol is well-established, there is a paucity of data regarding the effect of this statin on the high-density lipoprotein subfraction phenotype. A total of 150 participants without evidence of cardiovascular disease were randomized to therapeutic lifestyle modification (nonstatin-treated group) or to therapeutic lifestyle modification plus rosuvastatin at 10 mg/d (RSV10 group) or 20 mg/d (RSV20 group). We assessed the effect of rosuvastatin on the cholesterol mass of high-density lipoprotein subfractions at baseline as well as after 12 weeks post-treatment. Rosuvastatin treatment dose-dependently increased the high-density lipoprotein cholesterol (3.4% vs 5.3% in the RSV10 and RSV20 groups, respectively, P = .02). A dose-related rosuvastatin-induced increase in the cholesterol concentration of large high-density lipoprotein particles was also noted (by 11.4% in RSV10 group vs 22.0% in the RSV20 group, P = .01). Rosuvastatin treatment increases the high-density lipoprotein cholesterol by increasing the cholesterol mass only of the larger high-density lipoprotein particles in a dose-dependent manner.

Analysis of 6-month effect of orlistat administration, alone or in combination with fenofibrate, on triglyceride-rich lipoprotein metabolism in overweight and obese patients with metabolic syndrome.

BACKGROUND: Orlistat significantly reduced serum triglycerides (TG) in most clinical trials. Orlistat-induced TG reduction has not been studied to determine the factors contributing to TG alterations in clinical settings. OBJECTIVE: We examined the factors influencing TG reduction during orlistat administration, alone or in combination with fenofibrate, and we investigated the effects of these treatments on apolipoprotein C-II (ApoC-II) and C-III (ApoC-III) levels. METHODS: Patients with the metabolic syndrome were randomly allocated to receive orlistat 120 mg three times daily (n = 28, O group), micronized fenofibrate 200 mg/day (n = 28, F group), or both (n = 27, OF group) for 6 months. Plasma ApoC-II and ApoC-III were determined by an immunoturbidimetric assay. RESULTS: In the O group, we observed reductions of plasma ApoC-III (P < 0.05) and ApoC-II (P = NS) levels. Fenofibrate administration significantly reduced concentrations of ApoC-II and ApoC-III, whereas the combination of orlistat and fenofibrate had an additive effect on these apolipoproteins. There were significant in-group reductions in serum TG levels in all treatment groups. Multivariate analysis showed that in O group's baseline TG levels were independently positively correlated, whereas the baseline ApoC-II levels were negatively correlated with TG-lowering. In the F group, baseline TG levels and ApoC-III reduction were significantly and independently correlated with TG reduction. OF group's baseline TG levels and ApoC-III reduction were independently positively correlated and baseline ApoC-II levels were negatively correlated with TG-lowering. CONCLUSIONS: Orlistat-mediated TG-lowering is independently associated with baseline TG and ApoC-II levels. When orlistat is combined with fenofibrate, ApoC-III reduction is another independent contributor to TG alterations.

Gender-related and age-related urinalysis of healthy subjects by NMR-based metabonomics.

NMR-based metabonomic analysis is a well-established approach to characterizing healthy and diseased states. The aim of this study was to investigate inter-individual variability in the metabolic urinary profile of a healthy Greek population, not subjected to strict dietary limitations, by NMR-based metabonomics. The overall metabonomic urinalysis showed a homogeneous distribution among the population. The metabolic profile was examined in relation to gender and age, and reference intervals of major metabolites were determined. Multivariate data analysis led to the construction of two robust models that were able to predict the class membership of the subjects studied according to their gender and age. The most influential low molecular weight metabolites responsible for the differences in gender groups were citrate, creatinine, trimethylamine N-oxide, glycine, creatine and taurine, and for the differences in age groups they were citrate, creatinine, trimethylamine N-oxide and an unidentified metabolite (delta 3.78).

A 12-week, prospective, open-label analysis of the effect of rosuvastatin on triglyceride-rich lipoprotein metabolism in patients with primary dyslipidemia.

BACKGROUND: Although the effect of statins on lowering low-density lipoprotein cholesterol (LDL-C) has been extensively studied, their hypotriglyceridemic capacity is not fully understood. OBJECTIVE: The present study examined clinical and laboratory factors potentially associated with the triglyceride (TG)-lowering effect of rosuvastatin. METHODS: Eligible patients had primary dyslipidemia and a moderate risk of heart disease. Patients were prescribed rosuvastatin 10 mg/d in an open-label fashion and kept 3-day food diaries. Laboratory measurements, performed at baseline and 12 weeks, included serum lipid parameters (total cholesterol [TC], TGs, LDL-C, high-density lipoprotein cholesterol [HDL-C], and apolipoprotein [apo] levels), non-lipid metabolic variables (including carbohydrate metabolism parameters and renal, liver, and thyroid function tests), and LDL-subfraction profile (by high-resolution 3% polyacrylamide gel electrophoresis). Tolerability was assessed at each visit. RESULTS: Participants were 75 hyperlipidemic patients (39 men and 36 women; mean age, 51.7 years). At 12 weeks, TC levels were reduced by 35.1% (P < 0.001), TGs by 15.2% (P < 0.001), LDL-C by 48.5% (P < 0.001), apoE by 35.4% (P < 0.001), and apoE by 17.3% (P < 0.001) from baseline, whereas HDL-C and apoA1 levels were not significantly changed. Stepwise linear regression analysis showed that baseline TG levels were most significantly correlated (R(2) = 42.0%; P < 0.001) with the TG-lowering effect of rosuvastatin, followed by the reduction in apoCIII levels (R(2) = 13.6%; P < 0.01). Rosuvastatin use was associated with a reduction in cholesterol mass of both large LDL particles (mean [SD], from 150.5 [36.6] to 90.5 [24.3] mg/dL; P < 0.001) and small, dense LDL (sdLDL) particles (from 11.5 [8.4] to 6.6 [4.5] mg/dL; P < 0.001). Rosuvastatin had no effect on cholesterol distribution of the LDL subfractions (mean [SD], large particles, from 90.8% [7.0%] to 91.8% [5.1%]; sdLDL, from 7.1% [4.7%] to 7.5% [4.8%]) or the mean LDL particle size (from 26.5 [4.2] to 26.6 [4.0] rim). A significant increase in mean LDL particle size after rosuvastatin treatment (mean [SD], from 26.4 [0.4] to 26.9 [0.4] rim; P = 0.02) was observed only in patients with baseline TG levels > or =120 mg/dL. No serious adverse events requiring study treatment discontinuation were reported. One patient who presented with headache and 2 patients who presented with fatigue quickly recovered without discontinuing rosuvastatin treatment. A posttreatment elevation in aminotransferase levels <3-fold the upper limit of normal (ULN) was recorded in 5 (6.7%) patients, and 2 (2.7%) patients experienced elevated creatine kinase concentrations <5-fold ULN. CONCLUSION: Baseline TG levels were the most important independent variable associated with the TG-lowering effect of rosuvastatin.