Atherogenic Lipoprotein Cholesterol Research Articles

Lipoprotein(a) concentration and the blood content of INFγ-producing T-helpers 17 (Th17/1) in males with premature coronary artery disease

Aim. To analyze the relationship of blood lipid profile parameters, including the level of lipoprotein(a) (Lp(a)), and the content of circulating CD4+ T-lymphocytes with premature coronary artery disease (CAD).Material and methods. This retrospective cross-sectional study included 76 men aged 40 to 79 years. Patients were divided into following groups: main group — patients with CAD (58 [54;64] years, n=56) onset before the age of 55; control group — patients (62 [57;66] years, n=20) without CAD and obstructive CAD and peripheral arterial disease. Statins were taken by 51 (91%) and 9 (45%) patients in the main and control groups, respectively. In serum and plasma samples, lipid spectrum parameters and Lp(a) concentration were determined. Cellular phenotyping was performed by direct immunofluorescence in a culture of mononuclear leukocytes isolated from blood. To determine cytokines, cells were in vitro activated with inhibitor of intracellular transport of secretory proteins. Cell fluorescence was determined using flow cytometry.Results. Patients of both groups were comparable in age, body mass index, prevalence of hypertension and diabetes. Blood Lp(a) concentrations were higher in the CAD group than in the control group (49 [10;102] mg/dL vs 12 [4,3;32] mg/ dL, p<0,05). The content of INFγ-producing T-helpers 17 (Th17/1) was also higher in the CAD group (19 [15;24] vs 13 [11;22], % of Th17, p=0,05). Logistic regression revealed that elevated Lp(a) levels (≥30 mg/dL) and relative amounts of Th17/1 (>14% of Th17) independently of each other, atherogenic lipoprotein cholesterol levels, classical risk factors, and statin use were associated with premature CAD in the general group of patients with odds ratio (OR) of 4,6 (95% confidence interval (CI), 1,1-20,2) and 10,9 (2,1-56,7), p<0,05, respectively. The combination of Lp(a) >30 mg/dl and Th17/1 over 14% significantly increased the risk of premature CAD (OR, 28,0, 95% CI, 4,31-181,75, p=0,0005).Conclusion. We have shown for the first time that an increased Lp(a) concentration with an increased Th17/1 content is associated with the premature CAD in men.

Evaluation of atherogenic lipoprotein-cholesterol to HDL cholesterol ratio as a prognostic test for ST-segment elevation myocardial infarction.

Background: The detectable component of triglyceride-rich lipoproteins (TGRLs), remnant lipoprotein cholesterol (RLP-c), has been proven being correlated with the progression of atherosclerosis and myocardial infarction. However, when taken as a risk predictor, the prognostic and diagnostic potential of RLP-c remains controversial in studies. In this study, we evaluated the hypothesis that atherogenic lipoprotein-cholesterol (AL-c), representing the sum of RLP-c and the sd-LDL-c, to the HDL-c ratio, could represent a better predictive indicator than RLP-c alone in ST-segment elevation myocardial infarction (STEMI).Methods: The 316 consecutive patients suffering from persistent chest discomfort admitted to the Shanghai General Hospital between January 2018 and June 2018 were enrolled. 149 STEMI patients (62% men, mean age 69.6 ± 13.3 years) were included as the study cohort. The AL-c/HDL-c ratio was calculated on admission in a cohort of electrocardiogram-confirmed STEMI patients and compared to other lipid profiles as a predictive indicator.Results: The AL-c/HDL-c ratio was significantly increased in STEMI patients compared with apparently healthy adults (0.93; IQR [0.71-1.18] vs 0.70; IQR [0.45-1.04]; p < 0.001). Gender dependency existed, and the male and female patients had median AL-c/HDL-c ratios of 1.01 and 0.79, respectively (p < 0.001). Compared to RLP-c, the AL-c/HDL-c ratio had a better prognostic value to predict STEMI risk in both sexes (AUC of 0.672 with a sensitivity of 0.794 in males and 0.613 with a sensitivity of 0.684 in females).Conclusions: The AL-c/HDL-c ratio could represent a convenient and sensitive biomarker for screening and predicting STEMI risk.

Cow's milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet

Milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia. However, it is unclear whether ingestion of milk PLs protect against atherosclerosis. To determine this, male LDLr−/− mice (age 6 weeks) were fed ad libitum either a high-fat, added-cholesterol diet (CTL; 45% kcal from fat, 0.2% cholesterol by weight; n=15) or the same diet supplemented with 1% milk PL (1% MPL; n=15) or 2% milk PL (2% MPL; n=15) added by weight from butter serum. After 14 weeks on diets, mice fed 2% MPL had significantly lower serum cholesterol (−51%) compared to CTL (P<.01), with dose-dependent effects in lowering VLDL- and LDL-cholesterol. Mice fed 2% MPL displayed lower inflammatory markers in the serum, liver, adipose and aorta. Notably, milk PLs reduced atherosclerosis development in both the thoracic aorta and the aortic root, with 2% MPL-fed mice having significantly lower neutral lipid plaque size by 59% (P<.01) and 71% (P<.02) compared to CTL, respectively. Additionally, the 2% MPL-fed mice had greater relative abundance of Bacteroidetes, Actinobacteria and Bifidobacterium, and lower Firmicutes in cecal feces compared to CTL. Milk PL feeding resulted in significantly different microbial communities as demonstrated by altered beta diversity indices. In summary, 2% MPL strongly reduced atherogenic lipoprotein cholesterol, modulated gut microbiota, lowered inflammation and attenuated atherosclerosis development. Thus, milk PL content may be important to consider when choosing dairy products as foods for cardiovascular disease prevention.

Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at "Extreme" ASCVD Risk.

To review randomized interventional clinical and imaging trials that support lower targeted atherogenic lipoprotein cholesterol goals in "extreme" and "very high" atherosclerotic cardiovascular disease (ASCVD) risk settings. Major atherosclerotic cardiovascular event (MACE) prevention among the highest risk patients with ASCVD requires aggressive management of global risks, including lowering of the fundamental atherogenic apolipoprotein B-associated lipoprotein cholesterol particles [i.e., triglyceride-rich lipoprotein remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)]. LDL-C has been the long-time focus of imaging studies and randomized clinical trials (RCTs). The 2004 adult treatment panel (ATP-III) update recognized that the long-standing targeted LDL-C goal of < 100mg/dL potentially fostered substantial undertreatment of the very highest coronary heart disease (CHD) risk individuals and was lowered to < 70mg/dL as an "optional" goal for "very high" 10-year CHD [CHD death + myocardial infarction (MI)] risk exceeding 20%. This evidence-based guideline change was supported by the observed benefits demonstrated in the high-risk primary and secondary prevention populations in the Heart Protection Study (HPS), the acute coronary syndrome (ACS) population in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial (PROVE-IT), and the secondary prevention population in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) intravascular ultrasound (IVUS) study. Subsequent national and international guidelines maintained a targeted LDL-C goal < 70mg/dL, or a threshold for management of > 70mg/dL for patients with CHD, CHD risk equivalency, or ASCVD. Subgroup or meta-analyses of several RCTs, IVUS imaging studies, and the ACS population in IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) supported the evidence-based 2017 American Association Clinical Endocrinologist (AACE) guideline change establishing a targeted LDL-C goal < 55mg/dL, non-HDL-C < 80mg/dl, and apolipoprotein B (apo B) < 70mg/dL for patients at "Extreme" ASCVD risk, i.e., 10-year 3-point-MACE-composite (CV death, non-fatal MI, or ischemic stroke) risk exceeding 30%. Moreover, with no recognized lower-limit-associated intolerance or safety issues, even more intensive lowering of atherogenic cholesterol levels is supported by the following evidence base: (1) analysis of eight high-intensity statin-based prospective secondary prevention IVUS atheroma volume regression trials; (2) a distribution analysis of on-treatment, ezetimibe and background-statin, of the very low LDL-C levels reached and CVD event risk in the IMPROVE-IT ACS population; (3) the secondary prevention Global Assessment of Pl\aque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) on background-statin; and (4) the secondary prevention population of Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER). By example, in FOURIER, the population on background-statin at a baseline median 92mg/dL achieved median LDL-C level of 30mg/dL and non-HDL-C to < 65mg/dl, and apo B to < 50mg/dL, and subgroup and post hoc analyses all demonstrated additional ASCVD event reduction benefits as LDL-C was further reduced. The level of ASCVD risk determines the degree, urgency, and persistence in global risk management, including fundamental atherogenic lipoprotein cholesterol particle lowering. "Extreme" risk patients may require extremely low targeted LDL-C, non-HDL-C and apo B goals; such efforts, implied by more recent interventional trials and analyses, are aimed at maximal atheroma plaque regression, stabilization, and MACE event reduction with the aspiration of improved quality lifespan.

Milk Polar Lipids Reduce Atherogenic Lipoprotein Cholesterol and Attenuate Atherosclerosis Development in LDL-Receptor Knockout Mice Fed a Western-Type Diet (P06-051-19)

ObjectivesPurified milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia in high-fat, diet-fed mice. However, it is unclear whether ingestion of the total milk PL fraction can have similar hypolipidemic effects as purified SM, and if this confers protection from inflammation and atherosclerosis. To determine this, LDLr-/- mice were fed high-fat, high-cholesterol diets with and without added milk PL from butter serum, a dairy co-product rich in PLs and SM. MethodsMale LDLr-/- mice (age 6 weeks) were fed ad libitum either a high-fat, high-cholesterol diet (CTL; 45% kcal from fat, 0.22% cholesterol added by weight; n = 15), or the same diet supplemented with 1% milk PL (1% MPL; n = 15) or 2% milk PL (2% MPL; n = 15) added by weight from butter serum. All diets were adjusted to match in energy density, macronutrient composition, and calcium content. After 14 weeks on diets, mice were fasted for 6 hours prior to blood and tissue collection/processing at sacrifice. ResultsSupplementation with 2% MPL significantly reduced serum cholesterol (–51%) compared to CTL (p < 0.01), with fast protein liquid chromatography (FPLC) showing dose-dependent effects in lowering VLDL- and LDL-cholesterol. Serum CCL2 was 56% lower in 2% MPL compared to CTL (p < 0.05). No other significant differences were found in serum markers of inflammation or insulin resistance. Compared to CTL, 2% MPL-fed mice had significantly lower mRNA expression of Scd1 and Mip1b in liver, and Ccl2 in epididymal adipose tissue (p < 0.05). Notably, milk PL dose-dependently reduced atherosclerosis development in thoracic aorta, with 2% MPL significantly lowering neutral lipid plaque size by 59% (p < 0.01). Ccl2 mRNA expression was also significantly reduced by 67% in the descending aorta with 2% MPL (p < 0.05). ConclusionsMilk PL strongly reduced atherogenic lipoprotein cholesterol in LDLr-/- mice fed a Western-type diet, and modestly lowered inflammatory markers in the serum, liver, adipose, and aorta. These factors likely contributed to the strong reduction in atherosclerosis development in thoracic aorta seen with 2% MPL. Milk PL content may be important to consider when choosing dairy products as food. Funding SourcesThis work was supported by a research grant to C. Blesso from the National Dairy Council.

The Association between Cardiovascular Risk and Elevated Triglycerides

BACKGROUND: The association between elevated triglycerides and cardiovascular risk has been extensively studied. The elevated level of triglycerides occurs through abnormalities in hepatic very low-density lipoprotein (VLDL) production and intestinal chylomicron synthesis, dysfunctional lipoprotein lipase (LPL)-mediated lipolysis or impaired remnant clearance.CONTENT: Hypertriglyceridemia (HTG) commonly leads to a reduction in high-density lipoprotein (HDL) and increase in atherogenic small dense low-density lipoprotein (LDL) cholesterol, called the atherogenic dyslipidemia (AD). Triglycerides may also stimulate atherogenesis by mechanisms, such excessive release of free fatty acids, and production of pro-inflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia (HTG) and high concentration of triglyceride-rich lipoprotein (TRL) as causal risk factors for cardiovascular disease. Therefore, lipid management is crucial in reducing cardiovascular risk. Combination of lipid lowering drug therapy may be needed to achieve both LDL and non-HDL cholesterols treatment goal for cardiovascular disease prevention in patients with elevated triglyceride levels, particularly those with triglyceride ≥500 mg/dL.SUMMARY: LDL and non-HDL cholesterol can be a promising target therapy in HTG. Additional clinical outcomes data are needed to provide a more evidence-based rationale for clinical lipid management of hypertriglyceridemic patients.KEYWORDS: hypertriglyceridemia, non-HDL cholesterol, dyslipidemia, CV risk

Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers.

Women with polycystic ovarian syndrome (PCOS) have evidence of subclinical cardiovascular disease (CVD). However, insulin resistance, an important factor in the development of CVD in adults, is common in adolescents with PCOS, yet data in adolescents are limited. Therefore, we sought to measure insulin resistance and CVD markers in obese youth with and without PCOS. Thirty-six PCOS and 17 non-PCOS adolescent girls who were obese, sedentary, and non-hypertensive were recruited from clinics located within the Children's Hospital Colorado. Following 3 days of controlled diet and restricted exercise, fasting plasma samples were obtained prior to a hyperinsulinemic euglycemic clamp. PCOS girls were more insulin resistant than controls (glucose infusion rate 5.24±1.86 mg/kg/min vs 9.10±2.69; p<0.001). Girls with PCOS had blood pressure in the normal range, but had greater carotid intima-media thickness (cIMT) (0.49±0.07 mm vs 0.44±0.06; p=0.038), beta stiffness index (5.1±1.3 U vs 4.4±0.9; p=0.037), and reduced arterial compliance (1.95±0.47 mm2/mmHg × 10-1 vs 2.13±0.43; p=0.047). PCOS girls had a normal mean lipid profile, yet had a more atherogenic lipoprotein cholesterol distribution and had persistent elevations of free fatty acids despite hyperinsulinemia (68±28 μmol/mL vs 41±10; p=0.001), both potential contributors to CVD. Free fatty acid concentrations correlated best with all CVD markers. In summary, adolescent girls with PCOS have greater cIMT and stiffer arteries than girls without PCOS, perhaps related to altered lipid metabolism, even when clinical measures of blood pressure and cholesterol profiles are 'normal'. Therefore, management of adolescent PCOS should include assessment of CVD risk factor development.

Corn oil intake favorably impacts lipoprotein cholesterol, apolipoprotein and lipoprotein particle levels compared with extra-virgin olive oil.

Corn oil (CO) and extra-virgin olive oil (EVOO) are rich sources of unsaturated fatty acids (UFA), but UFA profiles differ among oils, which may affect lipoprotein levels. The objective of this study was to assess the effects of CO versus EVOO intake on fasting lipoprotein and subfraction cholesterol levels, apolipoprotein (apo) A1, apo B, and low-density lipoprotein particle concentrations in men and women. As part of a weight maintenance diet, men and women were provided with food items prepared with 54 g per day of CO or EVOO (21-day treatment, 21-day washout) in a randomized, double-blind, controlled-feeding, crossover trial. Fasting lipoprotein cholesterol and related variables were determined with density gradient ultracentrifugation. Among the 54 completers, CO reduced total cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apo B and LDL particle concentration to a greater extent compared with EVOO intake. Changes in LDL-C and VLDL-C contributed to the larger reduction in non-HDL-C with CO compared with EVOO intake (-0.39 mmol/l vs -0.04 mmol/l; P<0.001). The larger reduction in LDL-C by CO intake was attributable to changes (P<0.05) caused by CO vs EVOO in large LDL1+2-C (-0.22 mmol/l) and intermediate-density lipoprotein cholesterol (-0.12 mmol/l). HDL-C responses did not differ between treatments, but apo A1 increased more with EVOO compared with CO intake (4.6 versus 0.7 mg/dl, respectively, P=0.016). CO intake reduced atherogenic lipoprotein cholesterol and particle concentrations to a larger extent than did EVOO, which may have implications for cardiovascular disease risk.

Tannerella forsythia is associated with increased levels of atherogenic low density lipoprotein and total cholesterol in chronic periodontitis.

Background Accumulating evidence suggests that acute and chronic infections with periodontopathogens are associated with an increased risk of cardiovascular disease. The objective of this study was to assess whether Tanerella forsythia and Porphyromonas gingivalis are associated with increased levels of atherogenic low-density lipoprotein (LDL), high-density lipoprotein, total cholesterol (TC), triglycerides and body mass index (BMI) in chronic periodontitis patients. Material and Methods Medical history and clinical and radiographic examination were conducted in 80 chronic periodontitis patients and 28 healthy individuals. Fasting blood samples were drawn for the measurement of the parameters of dyslipidemia. Anthropometric measurements such as height in meters and weight in kilograms were recorded. Both periodontitis and control subjects were asked to answer a questionnaire with regard to their socio-demographic and smoking status. The presence of T. forsythia, and P. gingivalis was detected using primers designed to target the respective 16S rRNA gene sequences. Results The occurrence of T. forsythia and P. gingivalis was higher in the group of subjects with periodontitis. Superior levels of triglycerides were observed in chronic periodontitis patients compared to healthy individuals. High levels of TC in periodontitis persons were significantly associated with increased bleeding on probing. Greater mean levels of TC and LDL were shown in the presence of T. forsythia (P<0.05). Likewise, higher proportions of patients with BMI ≥25 kg/m2 related with T. forsythia (P<0.05). T. forsythia was a significant discriminating factor in the multivariate linear regression model emerging as significant explanatory of increased levels of TC (β=17,879, 95% CI = 4,357-31,401; p=0.01) and LDL (β=17,162, 95% CI= 4,009-30,316; p=0.01). Conclusions Higher levels of serum total cholesterol and LDL were observed in the occurrence of T. forsythia and the presence of this periodontopathogen may increase the atherogenic potency of low-density lipoprotein that may augment the risk for atherosclerosis in periodontal disease patients. Key words:Periodontitis, dyslipidemia, Tannerella forsythia, cardiovascular disease.

Increased levels of small dense low-density lipoprotein cholesterol associated with hemorheological abnormalities in untreated, early-stage essential hypertensives.

Among subfractions of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (SdLDL-C) has been highlighted as the most atherogenic lipoprotein cholesterol. The present study aimed to compare the relationship of SdLDL-C with blood viscosity, a surrogate marker for cardiovascular disease, with that of other lipid fractions with blood viscosity in essential hypertensives (EHTs). In 128 untreated, early-stage EHTs, blood viscosity was measured with a falling-ball microviscometer, and serum levels of lipid fractions were determined. Blood and plasma viscosity was significantly higher in 49 patients with dyslipidemia (fasting serum level of LDL-C > 140 mg dl(-1), triglyceride > 150 mg dl(-1) or high-density lipoprotein cholesterol (HDL-C) < 40 mg dl(-1)) compared with 79 patients without dyslipidemia, although hematocrit and RBC rigidity index 'k' did not differ between the two groups. Together, SdLDL-C, LDL-C, triglyceride and large LDL-C were positively correlated with blood viscosity, but for HDL-C, the correlation was negative. After adjusting for non-lipid variables that correlated with blood viscosity (that is, the age, body mass index, resting diastolic blood pressure, sex, hematocrit, plasma viscosity and homeostasis model of assessment of insulin resistance), SdLDL-C was most strongly associated with blood viscosity among the lipid fractions. These data suggest that SdLDL-C could strongly increase blood viscosity in EHTs.

Narrowing sex differences in lipoprotein cholesterol subclasses following mid-life: the very large database of lipids (VLDL-10B).

BackgroundWomen have less risk of atherosclerotic cardiovascular disease compared with men up until midlife (ages 50 to 60), after which the gap begins to narrow post menopause. We hypothesized that the average lipid profile of women undergoes unfavorable changes compared with men after midlife.Methods and ResultsWe examined lipids by sex and age in the Very Large Database of Lipids 10B (VLDL 10B) study. The analysis included 1 350 908 unique consecutive patients clinically referred for lipoprotein testing by density gradient ultracentrifugation from 2009 to 2011. Ratio variables were created for density subclasses of LDL‐C, HDL‐C, and VLDL‐C (LLDR, LHDR, LVDR, respectively). Men showed higher median LDL‐C values than women for ages 20 to 59, with the greatest difference in their 30s: 146 mg/dL in men versus 130 mg/dL in women. In contrast, women consistently had higher values after midlife (age 60), for example ages 70 to 79: 129 mg/dL in women versus 112 mg/dL in men. After age 50, women had higher LDL‐C each decade, for example 14% higher from their 30s to 50s, while HDL‐C concentrations did not differ. Women had more buoyant LDL‐C and HDL‐C (lower LLDR and LHDR) than men at all ages but the gap closed in higher age groups. In contrast, women had a generally denser VLDL‐C (higher LVDR) leading into midlife, with the gap progressively closing in higher age groups, approximating that of men in their 60s and 70s.ConclusionThe narrowing sex differential in cardiovascular disease risk after midlife is mirrored by a higher total atherogenic lipoprotein cholesterol burden in women and a closer approximation of the less favorable density phenotype characteristic of men.

Alteration of Relation of Atherogenic Lipoprotein Cholesterol to Apolipoprotein B by Intensive Statin Therapy in Patients With Acute Coronary Syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial)

The low-density lipoprotein (LDL) cholesterol goal of <70 mg/dl, recommended for patients with acute coronary syndrome, typically requires intensive therapy with high-dose statins. The secondary goals of non-high-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl have been recommended to reduce excess cardiovascular risk not captured by LDL cholesterol. The present post hoc analysis from the Limiting UNdertreatment of lipids in Acute coronary syndrome with Rosuvastatin (LUNAR) study examined the relation of ApoB with LDL cholesterol and non-HDL cholesterol at baseline and during treatment with intensive statin therapy. The LUNAR participants had acute coronary syndrome and received rosuvastatin 40 mg/day or 20mg/day or atorvastatin 80 mg/day for 12 weeks. Linear regression analyses were used to compare ApoB, direct LDL cholesterol, and non-HDL cholesterol at baseline and during therapy. Of the 682 patients included in the analysis, 220 had triglycerides ≥200 mg/dl. Linear regression analysis showed that correlation of ApoB and non-HDL cholesterol was stronger than that of ApoB and LDL cholesterol and stronger with statin therapy than at baseline (R(2)= 0.93 for ApoB vs non-HDL cholesterol with statins). The target of ApoB of80mg/dl correlated with LDL cholesterol of 90 mg/dl and non-HDL cholesterol of 110mg/dl at baseline and with LDL cholesterol of 74 mg/dl and non-HDL cholesterol of 92mg/dl with statin therapy. For high-triglyceride patients, the corresponding on-treatment targets were LDL cholesterol of 68 mg/dl and non-HDL cholesterol of 92 mg/dl. In conclusion, non-HDL cholesterol is an adequate surrogate of ApoB during statin therapy, independent of triglyceride status. However, to match LDL cholesterol and ApoB treatment goals in the very-high-risk category, the current non-HDL cholesterol goal should be lowered by 8to 10mg/dl.

Lipid effects of a dietary supplement softgel capsule containing plant sterols/stanols in primary hypercholesterolemia

ObjectiveThis randomized, placebo-controlled, crossover trial assessed the lipid-altering efficacy of a softgel capsule dietary supplement, providing esterified plant sterols/stanols 1.8 g/d, in 28 participants (∼75% women) with primary hypercholesterolemia (fasting low-density lipoprotein cholesterol [LDL-C] levels ≥130 and <220 mg/dL), a mean age of 58.4 y, and a mean body mass index of 27.9 kg/m2. MethodsAfter a 5-wk National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Changes (TLC) diet and a single-blinded placebo lead-in, subjects received double-blinded placebo or sterol/stanol softgel capsules for 6 wk and then crossed over to the opposite product for 6 wk while continuing the TLC diet. Fasting lipids were assessed in duplicate at the end of the diet lead-in (baseline) and the end of each treatment. ResultsThe mean baseline lipid concentrations (milligrams per deciliter) were 223 for total cholesterol (TC), 179 for non–high-density lipoprotein cholesterol (non-HDL-C), 154 for low-density lipoprotein cholesterol, 44 for HDL-C, 125 for triacylglycerols, and 5.2 for TC/HDL-C. Differences from the control responses (plant sterol/stanol minus control) in the per-protocol sample were significant (P < 0.05) for LDL-C (−9.2%), non-HDL-C (−9.0%), TC (−7.4%), TC/HDL-C (−5.4%), and triacylglycerols (−9.1%). The HDL-C responses were not significantly different between treatments. ConclusionThe incorporation of softgel capsules providing esterified plant sterols/stanols 1.8 g/d into the NCEP TLC diet produced favorable changes in atherogenic lipoprotein cholesterol levels in these subjects with hypercholesterolemia.

Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipaemia

The effects of atorvastatin on the atherogenic and anti-atherogenic lipoprotein-cholesterol (C-LP) and lipoprotein-triglyceride (TG-LP) fractions and subfractions at the early stage of murine acute hyperlipidaemia, and its pleiotropic anti-inflammatory effects via the activity of matrix metalloproteinases (MMPs) were studied. Atorvastatin (75 mg/kg) was administered to ICR mice with acute lipaemia induced by a single injection of Triton WR 1339 (500 mg/kg). A novel small-angle X-ray scattering (SAXS) method was used for the determination of the fractional and subfractional composition of C-LP and TG-LP. In Triton WR 1339-treated mice, there was a drastic increase in the atherogenic low-density C-LP (C-LDL) fraction, intermediate density lipoprotein-cholesterol (C-IDL) subfraction, and very low-density C-LP (C-VLDL) fractions (C-VLDL(3-5) subfraction). Additionally, there was an increase in the C-HDL(3) subfraction. Treatment of lipaemia with atorvastatin resulted in the normalization of the atherogenic C-LDL fraction and the C-IDL subfraction. A decrease in C-VLDL (C-VLDL(3-5) subfraction), total cholesterol and, especially, triglyceride (TG) concentrations was also demonstrated. Similar results were obtained with the TG-LP fractions and subfractions. Additionally, atorvastatin treatment resulted in an increase in the serum and liver MMP activity. High-dose atorvastatin therapy exerts its rapid lipid-lowering and pleiotropic effect(s) in the early stages of acute lipaemia induced with Triton WR-1339.

Lipoprotein Subfraction Cholesterol Distribution Is Proatherogenic in Women With Type 1 Diabetes and Insulin Resistance

OBJECTIVEIndividuals with type 1 diabetes have a less atherogenic fasting lipid profile than those without diabetes but paradoxically have increased rates of cardiovascular disease (CVD). We investigated differences in lipoprotein subfraction cholesterol distribution and insulin resistance between subjects with and without type 1 diabetes to better understand the etiology of increased CVD risk.RESEARCH DESIGN AND METHODSFast protein liquid chromatography was used to fractionate lipoprotein cholesterol distribution in a substudy of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (n = 82, age 46 ± 8 years, 52% female, 49% with type 1 diabetes for 23 ± 8 years). Insulin resistance was assessed by a hyperinsulinemic-euglycemic clamp.RESULTSAmong men, those with type 1 diabetes had less VLDL and more HDL cholesterol than control subjects (P < 0.05), but among women, those with diabetes had a shift in cholesterol to denser LDL, despite more statin use. Among control subjects, men had more cholesterol distributed as VLDL and LDL but less as HDL than women; however, among those with type 1 diabetes, there was no sex difference. Within sex and diabetes strata, a more atherogenic cholesterol distribution by insulin resistance was seen in men with and without diabetes, but only in women with type 1 diabetes.CONCLUSIONSThe expected sex-based less atherogenic lipoprotein cholesterol distribution was not seen in women with type 1 diabetes. Moreover, insulin resistance was associated with a more atherogenic lipoprotein cholesterol distribution in all men and in women with type 1 diabetes. This lipoprotein cholesterol distribution may contribute to sex-based differences in CVD in type 1 diabetes.

Influence of low-density lipoprotein (LDL) receptor on lipid composition, inflammation and parasitism during Toxoplasma gondii infection

Intracellular replication of Toxoplasma gondii requires cholesterol uptake by host cell low-density lipoprotein receptor (LDLr), a critical element in atherosclerosis. We evaluated host parasitism, inflammatory responses and development of atherosclerosis in LDLr knockout (LDLr −/−) and their controls C57BL/6 mice infected with T. gondii. Our results show that T. gondii cysts were reduced in LDLr −/− mice when compared to C57BL/6 mice. However, in presence of hypercholesterolemic diet, parasite growth in LDLr −/− mice was similar to that seen in infected C57BL/6 mice. In presence of a hypercholesterolemic diet, T. gondii infection leads to a 60% reduction of serum triacylglycerol, total and atherogenic lipoprotein cholesterol. When aortic valve lesion was analyzed, infected mice showed a reduction of atherosclerotic lesion area as well as CD36 expression. MCP-1, SRA-I, SRA-II, ICAM-1 and VCAM-1 mRNA expression was kept similar between infected and control groups. Thus, despite the intense inflammatory process, the drastic reduction in serum lipids seems to limit the development of atherosclerosis in LDLr −/− mice infected with T. gondii. In conclusion, our results indicate that T. gondii employs host LDLr to acquire cholesterol and favor its growth. However, in the presence of hypercholesterolemia, T. gondii parasites are able to acquire cholesterol-rich lipoproteins through an alternative host receptor, and overcome LDLr deficiency, favoring host parasitism and impairing lipid loading of foam cells.

HDL and triglyceride as therapeutic targets.

Epidemiological studies have shown that plasma HDL-cholesterol is inversely related to coronary artery disease and that there is an inverse relationship between HDL-cholesterol and triglyceride levels, but it is now demonstrated that hypertriglyceridemia is an independent risk factor for coronary heart disease (CHD). The goal of this review is to discuss if triglycerides and HDL-cholesterol could be therapeutic targets to reduce cardiovascular risk. Triglyceride measurement is not informative on the specificity of the triglyceride-rich lipoproteins present in the plasma because some of these are not atherogenic (chylomicrons, large VLDLs) while others are highly atherogenic (small VLDLs, remnants, IDL...). Statins, in addition to reducing LDL-cholesterol, significantly reduced atherogenic remnant lipoprotein cholesterol levels. 4S, CARE+LIPID, and AFCAPS/TexCAPS studies, suggested enhanced therapeutic potential of statins for improving triglyceride and HDL-cholesterol levels in patients with CHD. A fibrate (gemfibrozil) was shown to reduce death from CHD and non-fatal myocardial infarction in secondary prevention of CHD in men with low levels of HDL-cholesterol (VA-HIT); during the treatment these levels predicted the magnitude of reduction in risk for CHD events. ATP III recommendations state, on triglycerides and HDL-cholesterol as targets to reduce cardiovascular risk: (1) that lowering LDL-cholesterol levels is the primary target of therapy, (2) a secondary target is to achieve a triglyceride level < 150 mg/dL and (3) clinical trial data are considered to be insufficient to support recommended a specific HDL-cholesterol goal even if HDL-cholesterol < 40 mg/dL is considered to be a major risk factor of CHD.

Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene

The fatty liver dystrophy (fld) mutant mouse is characterized by neonatal fatty liver and hypertriglyceridemia that resolve at weaning, and neuropathy affecting peripheral nerve in adulthood. We now report additional significant manifestations of this single gene mutation, which include adipose tissue deficiency, glucose intolerance, and increased susceptibility to atherosclerosis. In adult fld/fld mice, both white and brown fat pads exhibit an 80% reduction in mass compared with wild-type controls, and consist of immature adipocytes as assessed by morphological and molecular criteria. The lack of lipid accumulation in fld/fld adipose tissue could be attributed, in part, to a failure to induce expression of lipoprotein lipase and enzymes involved in fatty acid synthesis, such as fatty acid synthase and acetyl-CoA carboxylase. Related to the deficiency of adipose tissue, fld/fld mice were also found to exhibit profound glucose intolerance, modest hyperinsulinemia, and reduced tissue response to insulin. As insulin resistance is a important risk factor in vascular disease, we examined susceptibility of fld/fld mice to diet-induced atherosclerosis.Mutant mice fed an atherogenic diet developed 2-fold greater aortic lesions than their wild-type counterparts, despite having a less atherogenic lipoprotein cholesterol profile. The fld adipose-deficient phenotype has both similarities to and distinctions from the group of rare human diseases known as lipodystrophies.

Lipoproteins in Children Treated with Continuous Peritoneal Dialysis

Total lipids, lipoprotein-lipids, and apolipoproteins were studied in plasma of 20 patients, aged 13.9 +/- 3.4 y (mean +/- SD; range 7.4 to 19 y), who were treated with continuous peritoneal dialysis for a period of 2.1 +/- 1.2 (range 0.5 to 4.9) y. Measurements included total plasma cholesterol and triglycerides, triglycerides in the very low density fraction, and cholesterol in the very low density, low density, and high density fractions, as well as apo A-I and apo B. The results were compared with values in 17 healthy control subjects, aged 13.0 +/- 5.1 (range 5.1 to 19) y. The patients had significantly elevated levels of total plasma triglycerides, triglycerides in the very low density fraction, total plasma cholesterol, cholesterol in the very low density fraction, and cholesterol in the low density fraction, whereas levels of cholesterol in the high density fraction were normal. Plasma apo B levels were elevated, but apo A-I levels were not different from controls. In addition, the nutritional status of the patients was assessed and apo A-I and apo B concentrations were measured in the dialysate of 10 patients. The losses of apo A-I and apo B in dialysate averaged 13.4 +/- 7.4 and 2.1 +/- 3.1 mg/kg/d, respectively. Lipoprotein profiles were not correlated with nutritional status. We conclude that pediatric patients treated with continuous peritoneal dialysis have atherogenic lipoprotein profiles, cholesterol ratios, and apolipoprotein ratios, but normal cholesterol in the high density fraction and apo A-I levels despite considerable apo A-I losses in the dialysate.

Estrogen in Patients with Prostatic Cancer An Assessment of the Risks and Benefits

Estrogen therapy of patients with prostatic carcinoma appears to be at least as effective in antitumour activity as surgical castration: the recent therapeutic alternative of gonadorelin (gonadotrophin-releasing hormone) analogues has not to date been shown to improve patient outcome. Oral estrogen therapy in these patients increases the incidence of arterial ischaemic events, thromboembolic events and congestive heart failure. A plausible mechanism behind the enhanced cardiovascular morbidity is an increase in the formation of proteins synthesised by the liver, including coagulation factors. Oral estrogens induce a 'hypercoagulable state' which can be expected to have an adverse influence on the cardiovascular system. The effect of estrogen on cholesterol metabolism is likely to be beneficial for the cardiovascular system, with decreased levels of the atherogenic low density lipoprotein (LDL) cholesterol and increased levels of the putatively beneficial high density lipoprotein (HDL) cholesterol. The effects of estrogen on platelets and cardiovascular prostanoids are difficult to evaluate at present. A possible approach to reduce its impact on the liver, and thereby possibly to minimise the risk of cardiovascular side effects, is parenteral administration. The promising results obtained in a pilot study of parenteral estrogen therapy in patients with prostatic carcinoma await confirmation in a randomised study, but where treatment with estrogen is considered for these patients, it may be that parenteral administration would be preferable.