Increased Low-density Lipoprotein Particle Size Research Articles

Modified ketogenic diets in adults with refractory epilepsy: Efficacious improvements in seizure frequency, seizure severity, and quality of life

ObjectiveThis study evaluates the efficacy of a modified ketogenic diet (MKD) on seizure frequency, severity, and quality of life (QOL), as well as potential complications of MKD therapy among adults with drug-resistant epilepsy (DRE). MethodsChanges in seizure frequency, severity, QOL, and side effects were retrospectively examined among adults, ≥17 years of age, with DRE (≥2 antiepileptic drugs [AEDs]), after 3 months of MKD therapy. Attention was paid to medication or vagus nerve stimulator (VNS) changes as well to evaluate potential confounders. ResultsA total of 60% (n = 33) of the 55 individuals reported ≥50% seizure frequency improvement, 42 (76%) reported improvement in seizure severity, and 48 (87%) reported improvement in QOL. More patients following a modified ketogenic diet — 15 g net carbohydrate daily (MKD-15) (95%) compared with a MKD-50 (69%) reported improvement in QOL (p = 0.02). Weight among the entire sample declined from 77.5 (20) kg to 73.9 (19.0) kg (p < 0.0001), and total cholesterol (TC), low density lipoprotein (LDL), and total cholesterol:high density lipoprotein (TC:HDL) increased significantly (p = 0.03, p = 0.04, and p = 0.02, respectively). Free carnitine values were available for a select number of patients, 26 (47%) at baseline, and 7 (13%) at follow-up, of which 8 (31%) at baseline, and 2 (29%) at follow-up had carnitine deficiency (<25 nmol/mL). Constipation was noted in 5 patients (9%), and no kidney stones were reported during the study period. There were no statistical differences in number or dose changes for AED or VNS during the study period. SignificanceModified ketogenic diet therapies reduce seizure frequency and severity and improve QOL among adults with DRE with few side effects outside of weight loss, a desired outcome among many adults with DRE. More restrictive MKDs may offer improved seizure severity and QOL. Modified ketogenic diet therapy increases LDL cholesterol, which may be cardioprotective if related to an increase in LDL particle size with high saturated fat intake; however, more research is needed examining LDL particle size changes among those receiving MKD therapy.

Ground Beef High in Total Fat and Saturated Fatty Acids Decreases X Receptor Signaling Targets in Peripheral Blood Mononuclear Cells of Men and Women.

We hypothesized that consumption of saturated fatty acids in the form of high-fat ground beef for 5 weeks would depress liver X receptor signaling targets in peripheral blood mononuclear cells (PBMC) and that changes in gene expression would be associated with the corresponding changes in lipoprotein cholesterol (C) concentrations. Older men (n = 5, age 68.0 ± 4.6 years) and postmenopausal women (n = 7, age 60.9 ± 3.1 years) were assigned randomly to consume ground-beef containing 18% total fat (18F) or 25% total fat (25F), five patties per week for 5 weeks with an intervening 4-week washout period. The 25F and 18F ground-beef increased (p < 0.05) the intake of saturated fat, monounsaturated fat, palmitic acid, and stearic acid, but the 25F ground-beef increased only the intake of oleic acid (p < 0.05). The ground-beefs 18F and 25F increased the plasma concentration of palmitic acid (p < 0.05) and decreased the plasma concentrations of arachidonic, eicosapentaenoic, and docosahexaenic acids (p < 0.05). The interventions of 18F and 25F ground-beef decreased very low-density lipoprotein C concentrations and increased particle diameters and low-density lipoprotein (LDL)-I-C and LDL-II-C concentrations (p < 0.05). The ground-beef 25F decreased PBMC mRNA levels for the adenosine triphosphate (ATP) binding cassette A, ATP binding cassette G1, sterol regulatory element binding protein-1, and LDL receptor (LDLR) (p < 0.05). The ground-beef 18F increased mRNA levels for stearoyl-CoA desaturase-1 (p < 0.05). We conclude that the increased LDL particle size and LDL-I-C and LDL-II-C concentrations following the 25F ground-beef intervention may have been caused by decreased hepatic LDLR gene expression.

Effect of Mediterranean Diet With and Without Weight Loss on Apolipoprotein B 100 Metabolism in Men With Metabolic Syndrome

To assess the effect of a Mediterranean diet (MedDiet) with and without weight loss (WL) on apolipoprotein B100 (apoB100) metabolism in men with metabolic syndrome. The diet of 19 men with metabolic syndrome (age, 24-62 years) was first standardized to a North American isoenergetic control diet for 5 weeks, followed by an isoenergetic MedDiet for an additional 5 weeks under full-feeding conditions (MedDiet-WL). Participants next underwent a 20-week supervised WL program under free-living conditions (-10.2 ± 2.9% body weight; P<0.01) and finally consumed the MedDiet (5 weeks) under weight-stabilizing feeding conditions (MedDiet+WL). In vivo kinetic of apoB100 was assessed in the fasted state at the end of the 3 controlled diets using a bolus of D3-leucine. Compared with the control diet, MedDiet-WL reduced low-density lipoprotein (LDL)-apoB100 pool size (-14.2%, P<0.01) primarily through an increase in LDL-apoB100 fractional catabolic rate (+30.4%, P=0.02) and increased LDL particle size (P<0.01) but had no effect on very-LDL (VLDL)-apoB100 pool size or triglyceride concentrations, despite a significant increase in VLDL-apoB100 fractional catabolic rate (+25.6%; P=0.03). MedDiet+WL had no further effect on LDL-apoB100 pool size and fractional catabolic rate but further increased LDL particle size and reduced VLDL-apoB100 pool size versus the control diet primarily through an increase in VLDL-apoB100 fractional catabolic rate (+30.7%; P<0.01). Consumption of MedDiet increases LDL size and reduces LDL-apoB100 concentrations primarily by increasing the catabolism of LDL even in the absence of WL in men with metabolic syndrome. MedDiet seems to have a trivial effect on VLDL concentrations and kinetics unless accompanied by significant WL. http://www.clinicaltrials.gov. Unique identifier: NCT00988650.

Alternate day fasting increases LDL particle size independently of dietary fat content in obese humans

Alternate day fasting (ADF) with a low-fat (LF) diet increases low-density lipoprotein (LDL) particle size. Whether these beneficial effects can be reproduced by a high-fat (HF) ADF diet is unclear. This study compared an ADF-HF to an ADF-LF diet on plasma lipids, LDL size and high-density lipoprotein (HDL) size. Thirty-five obese subjects were randomized to an ADF-HF or ADF-LF diet for 10 weeks. Body weight decreased (P<0.0001) by 4.3±1.0 kg (4.8±1.1%) and 3.7±0.7 kg (4.2±0.8%) in the ADF-HF and ADF-LF group, respectively. LDL cholesterol was reduced (P<0.0001) by 19±8 mg/dl (18±5%) by ADF-HF and 28±7 mg/dl (25±3%) by ADF-LF. LDL particle size increased (P<0.005) by 3±1 Å in both groups. The proportion of small LDL particles decreased (P<0.005) by 8±2% and 11±3% in the ADF-HF and ADF-LF groups, respectively. HDL cholesterol and HDL size remained unchanged. Thus, our results suggest that the ADF-HF diet is equally as effective as the ADF-LF diet in improving LDL particle size and distribution.

Highly Purified Eicosapentaenoic Acid May Increase Low-Density Lipoprotein Particle Size by Improving Triglyceride Metabolism in Patients With Hypertriglyceridemia

The purpose of this study was to evaluate the effect of highly purified eicosapentaenoic acid (EPA) in increasing low-density lipoprotein (LDL) particle size, as one of the possible mechanisms by which intake of EPA may prevent coronary events. Hypertriglyceridemic subjects were randomly assigned to a control group (n=72) or an EPA group (n=72; EPA regimen 1,800mg/day for 6 months). In the EPA group, the serum LDL-cholesterol and high-density lipoprotein cholesterol levels remained unchanged, but there was a significant increase in LDL particle size based on LDL-relative mobility measured on lipoprotein polyacrylamide-gel electrophoresis, and a significant decrease in serum triglyceride-rich lipoproteins (TRLs) level. None of these changes were observed in the control group. After adjustments for coronary risk factors, multivariate logistic regression analysis identified elevation of serum EPA-related markers (6-month EPA, 6-month EPA/arachidonic acid [AA] ratio, change in [Δ] EPA, and EPA/AA), and treatment with statins and EPA as independent variables associated with increase in LDL particle size. Negative correlations were found between ΔTRLs and ΔLDL particle size, suggesting that improvement in triglyceride metabolism was associated with an increase in LDL particle size. EPA increases LDL particle size by improving triglyceride metabolism; and serum EPA level and EPA/AA ratio after EPA treatment may be useful markers of increased LDL particle size.

Beneficial Effects of Omega-3 Fatty Acids on Low Density Lipoprotein Particle Size in Patients with Type 2 Diabetes Already under Statin Therapy

Beyond statin therapy for reducing low density lipoprotein cholesterol (LDL-C), additional therapeutic strategies are required to achieve more optimal reduction in cardiovascular risk among diabetic patients with dyslipidemia. To evaluate the effects and the safety of combined treatment with omega-3 fatty acids and statin in dyslipidemic patients with type 2 diabetes, we conducted a randomized, open-label study in Korea. Patients with persistent hypertriglyceridemia (≥200 mg/dL) while taking statin for at least 6 weeks were eligible. Fifty-one patients were randomized to receive either omega-3 fatty acid 4, 2 g, or no drug for 8 weeks while continuing statin therapy. After 8 weeks of treatment, the mean percentage change of low density lipoprotein (LDL) particle size and triglyceride (TG) level was greater in patients who were prescribed 4 g of omega-3 fatty acid with statin than in patients receiving statin monotherapy (2.8%±3.1% vs. 2.3%±3.6%, P=0.024; -41.0%±24.1% vs. -24.2%±31.9%, P=0.049). Coadministration of omega-3 fatty acids with statin increased LDL particle size and decreased TG level in dyslipidemic patients with type 2 diabetes. The therapy was well tolerated without significant adverse effects.

Effects of Extended-release Niacin/Laropiprant on Apolipoprotein B, LDL-Cholesterol, and Non-HDL-cholesterol Targets in Patients with Type 2 Diabetes

s 285 small low-density lipoprotein particle (LDL-P) and CHD risk. Purpose: To compare the effects of niacin extendedrelease/simvastatin (NER/S) therapy on lipoprotein particles to atorvastatin (Atv) from the SUPREME study. Methods: This is a post-hoc analysis of 137 patients with dyslipidemia from a 12-week, randomized, study of patients treated with daily NER/S (n 5 74, 1000/40 mg x 4 weeks; 2000/40 mg x 8 weeks) or Atv (n 5 63, 40 mg x 12 weeks). A total of 137 patients had particle concentration and size measurements at baseline (BL) and 12 wk by NMR spectroscopy. Results: Patients in both treatment groups had comparable particle values at BL. Treatment with NER/S resulted in a greater increase in large HDL-P concentration (P 5 .078), significantly greater decrease in small HDL-P concentration (P , .05), and significantly greater increase in HDL-P size (P , .001), HDL-C and apoA-I vs Atv. Treatment with NER/S also significantly decreased the concentration of total LDL-P (P , .05) and small LDL-P (P , .05) and significantly increased LDL-P size (P , .01) vs Atv (Table 1). Conclusions: Compared with Atv 40 mg monotherapy, combination therapy NER/S at 2000/40 mg results in multiple favorable changes in both HDL and LDLmetrics. These data show that NER/S treatment promotes a greater shift toward less atherogenic lipoprotein subclasses than Atv.

Pioglitazone-Mediated Changes in Lipoprotein Particle Composition Are Predicted by Changes in Adiponectin Level in Type 2 Diabetes

In animal and observational studies, adiponectin is associated with lipoprotein risk factors for cardiovascular disease. We analyzed data from a randomized clinical trial to evaluate the relationship between changes in adiponectin to changes in lipoprotein risk factors after an intervention that alters adiponectin levels. Adiponectin levels were measured at baseline and follow-up, as were lipoprotein risk factors for cardiovascular disease, at academic medical centers and ambulatory care centers. Participants included 361 men and women with type 2 diabetes. Intervention included randomization to treatment with glimepiride or pioglitazone for 72 wk. The relationship of treatment-related differences in adiponectin level to treatment-related differences in lipoprotein cardiovascular risk factors at 72 wk was evaluated. Pioglitazone led to an increase in adiponectin compared with glimepiride. Compared with baseline, pioglitazone treatment at 72 wk led to an increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle size and a decrease in very-low-density lipoprotein (VLDL) particle size and LDL particle number. Glimepiride treatment more modestly decreased LDL particle number and increased LDL particle size. At 72 wk, there were significant treatment group differences for HDL, LDL, and VLDL particle size, and triglyceride and HDL cholesterol level. The increase in adiponectin predicted treatment-related improvement for triglyceride and HDL cholesterol level and LDL and HDL particle size. Increased adiponectin contributed to treatment-related benefit in lipoprotein cardiovascular disease risk factors in obese diabetic subjects treated with pioglitazone. These results provide support for a model that mechanistically links changes in adiponectin level to changes in lipoprotein composition in humans.

Effects of fenofibrate on lipid profiles, cholesterol ester transfer activity, and in-stent intimal hyperplasia in patients after elective coronary stenting

BackgroundThe association between modulation of detailed lipoprotein profiles and cholesterol ester transfer (CET) activity by peroxisome proliferator-activated receptor (PPAR)-a agonists in patients with coronary artery disease remains unclear. We assessed lipid profiles, plasma CET activity, and in-stent intimal hyperplasia after fenofibrate treatment in patients who underwent elective coronary stenting.MethodsForty-three consecutive patients who underwent elective coronary stenting were randomized to the fenofibrate group (300 mg/day for 25 weeks, n = 22) or the control group (n = 21). At baseline and follow up, CET activity and lipoprotein profiles were measured, and quantitative coronary angiography was performed.ResultsIn the fenofibrate group, the levels of large very low-density lipoprotein cholesterol, and small low-density lipoprotein (LDL) cholesterol decreased and those of small high-density lipoprotein (HDL) cholesterol increased. Besides, CET activity decreased independent of the effect of fenofibrate on total and LDL cholesterol. The reduction of CET activity significantly correlated with the increase in LDL particle size (r = 0.47, P = 0.03) and the decrease of triglycerides in large HDL subclasses (r = 0.48, P = 0.03). Although there were no significant differences in restenosis parameters between the two groups, low CET activity significantly correlated with the inhibition of neointimal hyperplasia (r = 0.56, P = 0.01).ConclusionsFenofibrate inhibited CET activity and thereby improved atherogenic lipoprotein profiles, and reduced intimal hyperplasia after coronary stenting.

Effect of l-carnitine on the size of low-density lipoprotein particles in type 2 diabetes mellitus patients treated with simvastatin

Therapeutic modulation of low-density lipoprotein (LDL) size could be of benefit in reducing the risk of cardiovascular events in diabetic patients. This study evaluated the efficacy of l-carnitine on the size of LDL particles in type 2 diabetes mellitus patients treated with simvastatin. Eighty diabetic patients were randomly assigned to 1 of 2 treatment groups for 3 months. The 2 groups received either simvastatin monotherapy 20 mg (n = 40) or l-carnitine 2 g/d and simvastatin 20 mg (n = 40). The following variables were assessed at baseline; after washout; and at 1, 2, and 3 months of treatment: body mass index, fasting plasma glucose, glycosylated hemoglobin, total cholesterol, LDL cholesterol, LDL subclasses, LDL size, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-1, and apolipoprotein B-100. After 12 weeks, comparing the 2 groups, we observed a decrease in fasting plasma glucose (1.45 vs 0.61 mmol/L, P < .001) and an increase in glycosylated hemoglobin (0.2% vs 0.4%, P < .05). Moreover, there was a decrease in total cholesterol (2.07 vs 1.45 mmol/L, P < .001), LDL (1.65 vs 1.29 mmol/L, P < .001), triglycerides (1.36 vs 0.41 mmol/L, P < .001), apo B-100 (49 vs 9 g/L, P < .001), and small-sized LDL proportion (10.8% vs 4.9%, P < .001), whereas LDL particle size increased (6 vs 3 Å, P < .001) and HDL increased (0.2 vs 0.11 mmol/L, P < .001). We observed that patients treated with carnitine and simvastatin showed a reduction in small-sized LDL proportion and an increase in LDL particle size.

Statins but not fibrates improve the atherogenic to anti-atherogenic lipoprotein particle ratio: a randomized crossover study

BackgroundPrior studies suggested low density lipoprotein particle (LDLP) size is a predictor of atherosclerosis. Knowledge of effects of lipid lowering drugs on lipoprotein subclasses is useful. We treated subjects with hyperlipidemia sequentially with statins and fibrates, the 2 main classes of lipid lowering therapy and studied changes in NMR lipoprotein subclasses.Methods35 subjects (21 males; 60 ± 12 y) were enrolled in a crossover study. Subjects had baseline lipid profile & apoB. Lipoprotein subclasses, particle numbers and diameters were assessed with NMR spectroscopy. Subjects were randomized to simvastatin 20 mg or fenofibrate 200 mg. Repeat testing was done at 12 weeks. After 6 week washout, subjects were started on alternate drug for 12 weeks with pre/post tests.ResultsBoth therapies resulted in expected changes in lipids and apoB. Decreases in total cholesterol, LDL and apoB were greater with simvastatin. Fenofibrate led to small increase in HDL. Both therapies decreased LDLP. Reduction in LDLP was greater with simvastatin (32%, p < .001) compared to fenofibrate (17%; p = .036 vs pre; p = .027 vs simvastatin end). Fenofibrate resulted in 17% rise in large LDLP (p = .06 vs pre) and 32% drop in small LDLP (p = .007 vs pre). Simvastatin led to decrease in both LDLP fractions (19% large LDLP; p = .001 vs fenofibrate end; 34% small LDLP, p = .019 vs pre). With fenofibrate, LDLP size increased from 20.4 nm to 20.8 nm (p = .037). There was no change in LDLP size with simvastatin. There was 18% increase in HDL particle number (HDLP) with fenofibrate (p = .05). There were no changes in HDLP with simvastatin. There were no changes in HDLP size with either drug. Pre- and post-therapy LDLP/HDLP ratio was similar with fenofibrate but was reduced by simvastatin (p = .045).ConclusionSimvastatin reduced LDLP across all subclasses with no effect on size. Simvastatin had no effect on HDLP. Fenofibrate had weak effect on LDLP number but increased LDLP size by raising large LDLP and reducing small LDLP. Fenofibrate had weak effect on HDLP number with no change in size. Importantly, net atherogenic to antiatherogenic lipoprotein ratio (LDLP/HDLP) was reduced by simvastatin but not by fenofibrate.

Tracking and determinants of LDL particle size in healthy children from 7 to 11 years of age: the STRIP Study

Serum low-density lipoprotein (LDL) particle composition varies according to lifestyle and age. To analyze its long-term tracking, we studied LDL particle size consecutively in 100 children at the ages of 7, 9 and 11 years using a high-resolution 3% polyacrylamide gel tube, electrophoresis method, searching also for long-term determinants of the particle size. The mean LDL particle sizes at 7 and 9 years, and at 7 and 11 years correlated directly (r=0.72 and 0.39, respectively). The probability that children would remain in the same LDL particle size tertile between 7 and 11 years of age was 48% (p=0.008). Longitudinally, total, high-density lipoprotein (HDL) and LDL cholesterol concentrations and body mass index (BMI) associated directly with mean LDL particle size, and triglyceride concentration and triglyceride/HDL cholesterol ratio correlated inversely. A shift from pre-puberty to puberty was associated with an increase in LDL particle size. Sex, serum insulin concentration, or energy nutrient intakes did not associate with LDL particle size. In conclusion, although mean LDL particle size tracks in 7- to 11-year-old healthy children, changes in serum triglycerides, HDL, LDL, and total cholesterol concentration, BMI, and pubertal status all modify LDL particle size.

Effects of Increasing Particle Size of Low-Density Lipoprotein on Restenosis After Coronary Stent Implantation

Small dense low-density lipoprotein (LDL) has emerged as an important risk factor in coronary atherosclerosis and vascular inflammation, which is related to neointimal hyperplasia. Therefore, the aim of the present study was to investigate whether changes in LDL particle size are related to in-stent restenosis (ISR). The LDL subfraction and lipid profiles were measured in 274 patients (412 stents) at both baseline and follow-up coronary angiography (CAG). The incidence of ISR (80 lesions, 19.4%) was lower in the patients with increased LDL particle size than in those with no change or decrease (14.2% vs 25.8%, p=0.004). Logistic multivariate analysis revealed that stent length (>or=24 mm) (odds ratio (OR) =1.913, p=0.027), post minimal luminal diameter (>3 mm) (OR =0.528, p=0.028), acute coronary syndrome (OR =2.294, p=0.005), decrease in high-density lipoprotein-cholesterol (OR =1.028, p=0.047) and increase in LDL particle size (OR =0.528, p=0.031) were independent predictors for ISR. In the present study, an increase in the LDL particle size between baseline and follow-up CAG was associated with reduced incidence of ISR. Therefore, modification of LDL particle size may have a beneficial effect on the risk of ISR.

The Effects of Niacin on Lipoprotein Subclass Distribution

Dyslipidemia is a heterogeneous metabolic condition; high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein represent families of lipoprotein particles that differ in size and composition and vary in atherogenicity. Lipoprotein subclasses containing apolipoprotein B promote atherosclerosis, of which the most atherogenic appear to be the small, dense LDL and large very-low-density lipoprotein subclasses, while the large HDL2 subclass, which transports esterified cholesterol from the periphery to the liver, is considered the more cardioprotective. Niacin has long been known to improve concentrations of all major lipids and lipoproteins, but it also has consistently favorable effects on subclass distribution. A MEDLINE search was conducted for clinical studies reporting the effects of niacin on lipoprotein subclasses. The niacin-associated elevations in HDL cholesterol likely stem from differential drug effects on subclasses, producing favorable changes in levels of HDL2 and apolipoprotein A-I. Niacin has more moderate LDL cholesterol-lowering efficacy, but this change is associated with an increase in LDL particle size and a shift from small LDL to the less atherogenic, large LDL subclasses. In addition, it also tends to decrease concentrations of the larger very-low-density lipoprotein subclasses. Niacin confers diverse benefits with respect to both the quantity and quality of lipid and lipoprotein particles.

Peroxisome Proliferator-Activated Receptor-γ Agonist Increases Both Low-Density Lipoprotein Cholesterol Particle Size and Small High-Density Lipoprotein Cholesterol in Patients with Type 2 Diabetes Independent of Diabetic Control

To ascertain whether troglitazone, independent of control of diabetes, increases low-density lipoprotein (LDL) particle size. We administered 600 mg of troglitazone (a peroxisome proliferator-activated receptor-gamma agonist) daily for 8 weeks to 10 patients with type 2 diabetes (8 of whom completed the study). Then troglitazone therapy was discontinued, and alternative medication for diabetic control was used for another 4 weeks. The LDL, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) concentrations and subpopulations, as well as blood glucose and hemoglobin A1c (HbA1c), were determined at weeks 0, 4, 8, and 12 and analyzed statistically. Small, dense LDL cholesterol is commonly seen in patients with diabetes and is thought to be associated with an increased risk for coronary artery disease. After both 4 and 8 weeks of troglitazone therapy, control of diabetes was significantly improved (mean HbA1c values at baseline, week 4, and week 8 were 8.0 +/- 0.7%, 7.4 +/- 0.5%, and 7.0 +/- 0.7%, respectively; P<0.05). HbA1c (6.5 +/- 0.6% at 12 weeks) and blood glucose levels (126 +/- 19 mg/dL at 8 weeks versus 145 +/- 9 mg/dL at 12 weeks) were not significantly different 4 weeks after troglitazone therapy was discontinued. Troglitazone treatment increased the large LDL particle at 4 and 8 weeks, a change that significantly (P<0.05) enlarged the LDL particle size (20.5 +/- 0.3 nm, 21.2 +/- 0.3 nm, and 21.3 +/- 0.2 nm at baseline, week 4, and week 8, respectively). After 8 weeks of troglitazone therapy, VLDL triglycerides were reduced (195 +/- 37 mg/dL versus 136 +/- 28 mg/dL; P<0.05) and HDL was increased (31.6 +/- 2.4 mg/dL versus 35.5 +/- 2.9 mg/dL; P<0.05). This greater HDL value was due to an increase in the small HDL particles. A decrease in the larger VLDL particles (V5 and V6) resulted in a reduction in the mean VLDL particle size (59 +/- 3 nm versus 46 +/- 2 nm; P<0.05). Despite the fact that control of diabetes remained significantly improved after troglitazone therapy was discontinued, the LDL particle size decreased to the baseline value. This change was due to a reduction in the large LDL cholesterol particle (L3). This study shows that troglitazone therapy increases LDL particle size, reduces VLDL particle size, and increases small HDL particles. These changes may lower the risk for coronary artery disease.

Fluvastatin increases LDL particle size and reduces oxidative stress in patients with hyperlipidemia.

The effects of fluvastatin on levels of urinary 8-iso-prostaglandin F2alpha (iPF2alphaIII), a marker of oxidative stress, and low-density lipoprotein (LDL) particle size in serum were investigated in patients with hypercholesterolemia. After 6 months of fluvastatin therapy, levels of urinary iPF2alphaIII decreased from 1720.1 +/- 392.0 to 539.6 +/- 75.5 pg/mg (p < 0.01), and LDL particle size increased from 24.3 +/- 0.3 to 26.5 +/- 0.2 nm (p < 0.001). These changes from the treatment of fluvastatin were not correlated with those of the serum LDL cholesterol (LDL-C) levels. The results imply that fluvastatin, with its unique antioxidant property among statins, reduces oxidative stress and increases LDL particle size simultaneously in hyperlipidemic patients.

CETP gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease

Background: Small, dense low-density lipoprotein (LDL) in subjects with the atherogenic pattern B has been established as a risk factor of atherosclerosis. Cholesteryl ester transfer protein (CETP) plays an important role in the transfer and exchange of cholesteryl esters and triglycerides between the lipoprotein classes of human plasma. It has been shown that CETP can also change the particle size of high-density lipoprotein (HDL) and LDL subfractions in vitro. Previous clinical studies about CETP gene mutations mainly focused on abnormalities in HDL, few involved those in LDL. Objectives: To investigate the effect of the D442G mutation in the CETP gene on major peak size of LDL particles in patients with coronary heart diseases (CHD). Methods: D442G mutation in the CETP gene was detected using the PCR-RFLP. LDL particles sizes were analyzed by 2–16% nondenaturing polyacrylamide gradient gels in CHD patients with D442G mutation in the CETP gene. Results: Six heterozygotes and one homozygote were found to have the D442G mutation among 200 CHD patients. The frequency of this mutation was 3.5%. The major peak size of LDL in patients with gene mutation ( n=7) was significantly larger than that in patients without the mutation ( n=40) (26.92±0.79 nm vs. 25.71±0.66 nm, respectively; P<0.01). All the patients with the gene mutation expressed pattern A, whereas only about half of the patients without the mutation expressed this pattern. The patients with gene mutation had decreased plasma CETP concentration, while increased concentration of HDL-C and apolipoprotein A-I compared with controls. Conclusions: CETP gene mutation (D442G) increases LDL particle size. This suggests that CETP play an antiatherogenic role.

A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients

Objective: The objective of the present study was to compare the effects of a 16-week pharmacotherapy with fenofibrate (200 mg) or pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) on low density lipoprotein (LDL) particle size assessed by gradient gel electrophoresis among patients with type IIa dyslipidemia. Methods: For that purpose, type IIa dyslipidemic patients (cholesterol, 7.45±1.18 (S.D.) mmol/l; LDL cholesterol, 5.57±1.16 mmol/l; triglycerides (TGs), 1.66±0.43 mmol/l) were randomized to either fenofibrate ( n=36) or pravastatin ( n=43) therapy for 16 weeks. Fasting plasma lipoprotein levels as well as the LDL peak particle size (using 2–16% polyacrylamide gel electrophoresis) were assessed at baseline and after the 16-week treatment period. Results: Whereas significant improvements in the plasma lipoprotein–lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased with fenofibrate therapy (+2.11±5.18 Å, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size ( r=−0.54, P<0.0007), whereas no such association was found in pravastatin-treated patients. The prevalence of patients with small, dense LDL particles (as defined by LDL particle diameter <255.5 Å) was reduced from 69.4 to 30.6% ( P<0.05) among fenofibrate-treated patients as opposed to 81.4 to 72.1% (NS) in patients who received pravastatin. Conclusion: As pravastatin treatment had no effect on LDL size, it is suggested that the additional effect of fenofibrate therapy on LDL size may contribute to reduce the risk of coronary heart disease (CHD) beyond what can be expected from the reduction in LDL cholesterol concentration in type IIa dyslipidemic patients.

LDL particle size: an important drug target?

Low density lipoprotein (LDL) is the main carrier of plasma cholesterol and a major component of atherosclerotic plaque [1]. Lowering LDL cholesterol reduces coronary events and mortality from coronary artery disease (CAD) [2–4], however, the relation between LDL cholesterol concentration and (CAD) is complex. Many patients with CAD have plasma LDL cholesterol concentrations in the normal rangefor the general population [5]. Thus, it could be that coronary risk goes beyond LDL cholesterol concentration to the characteristics of the LDL particles themselves. The purpose of this communication is to address the issue of whether LDL particle size and density influences its atherogenecity and how this might be modified by drug therapy.

Acute changes in lipid, lipoprotein, apolipoprotein, and low-density lipoprotein particle size after an endurance triathlon

The effect of an endurance triathlon (2.4-mile swim, 112-mile bicycle ride, 26.2-mile run, in succession) on plasma total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) A-I and B levels, and LDL particle size was determined in 34 male and six female participants 6 to 12 hours before and immediately after the completion of the triathlon. Plasma TG decreased significantly (70% decrease) in both men and women. In men the change in plasma TG was inversely associated with baseline TG values ( P < .0001). Plasma TC and LDL cholesterol did not change significantly in male athletes but decreased significantly in women. A significant increase in HDL cholesterol was observed in both men (18% increase, P < .0001) and women (5% increase, P < .01). In men the increase in HDL cholesterol was inversely correlated with the decrease in triglycerides ( P < .0002). Plasma apo A-I levels increased significantly only in the male group ( P < .005), whereas plasma apo B levels decreased significantly in both men and women ( P < .0005). LDL particle size increased in seven males, whereas in the remaining males and all females no change in LDL size was observed. The increase in LDL particle size in these seven subjects was associated with a greater decline in plasma TG compared with the remaining men ( P < .005) and women ( P < .03). These results indicate that prolonged strenuous physical exercise can induce acute modifications of plasma lipoproteins, which may in part be related to enhanced lipolysis.