Remnant-like Particle Cholesterol Levels Research Articles

High Level of Plasma Remnant-like Particle Cholesterol May Predispose to Development of Hypertension in Normotensive Subjects

Remnant-like lipoprotein particle cholesterol (RLP-C) is a highly atherogenic factor. RLP-C induces endothelial dysfunction and is associated with hyperinsulinemia. This study was designed to determine whether high plasma RLP-C levels predispose to the development of hypertension in subjects with normal blood pressure (BP). A total of 1,485 subjects aged >40 years in a Japanese Cohort of the Seven Countries Study received health examinations. We examined BP, anthropometric parameters, and blood chemistries, including fasting RLP-C levels. RLP-C levels were measured by an immune-separation method. We excluded from the analysis 676 subjects who had hypertension (BP ≥ 140/90mm Hg), or were on antihypertensive medication, and/or were on antihyperlipidemic medication at baseline. Ten years later, 681 subjects were re-examined. Of 681 normotensive subjects at baseline, 303 subjects had developed hypertension 10 years later. Baseline RLP-C level was significantly higher (P < 0.01) in the subjects who developed hypertension than in those who remained normotensive (3.7±1.9 vs. 3.3±1.6mg/dl). Multivariable logistic regression analysis demonstrated that baseline RLP-C was a significant factor for incident hypertension after adjustments for homeostasis model assessment index and other hypertension-related factors (odds ratio = 1.05, 95% CI = 1.00-1.10; P = 0.04). A high level of plasma RLP-C in normotensive subjects may predispose to the development of hypertension in a population of community-dwelling Japanese.

Association between Remnant-Like Particle Cholesterol and Gamma-Glutamyltransferase in Dyslipidemic Patients

Objective: To investigate the correlation between gamma-glutamyltransferase (GGT) and remnant-like particle cholesterol (RLP-C) in dyslipidemic patients. Subjects and Methods: General cardiometabolic variables, plus serum GGT and RLP-C levels, were measured in 118 dyslipidemic patients (59 males, mean age 58 ± 13 years). Correlation analyses of GGT with other variables, including RLP-C, were performed. Results: The median levels (interquartile ranges) of RLP-C and GGT were 0.21 mmol/l (0.14–0.35) and 26 IU/l (17–39), respectively. A stepwise multiple regression analysis revealed an independent, significant and positive correlation between GGT and RLP-C (β = 0.351, p < 0.001), followed by male gender and BMI. Conclusion: There was a significant positive association between GGT and RLP-C, thereby indicating that the association between GGT and cardiovascular disease may be partly due to the interaction with RLP-C in dyslipidemic patients. Further research is therefore warranted to confirm the observed relationship.

A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy

It remains undetermined whether the addition of ezetimibe to ongoing statin therapy is more effective than increasing the dose of statin for reducing remnant lipoprotein levels in patients with remnant lipoproteinemia on previous statin treatment. This study examined whether combined ezetimibe and statin therapy resulted in a greater improvement in remnant lipoprotein levels and endothelial function than with the dose of statin in patients with remnant lipoproteinemia on previous statin treatment. A total of 63 patients with stable coronary artery disease and high levels of remnant-like lipoprotein particle cholesterol (RLP-C) (≥5.0 mg/dL) on statin treatment were assigned randomly to two groups and treated with either addition of ezetimibe (10mg/day, n=32) or doubling of statin dose (n=31). The lipid profiles and flow-mediated dilation (FMD) of the brachial artery were measured at enrollment and after 6 months of treatment. Statin and ezetimibe combined therapy reduced RLP-C and improved FMD to a greater extent than doubling the statin dose (% reduction in RLP-C, 48 ± 18% vs. 33 ± 24%, respectively, p=0.01; % improvement in FMD, 47 ± 48% vs. 24 ± 23%, respectively, p=0.02). The addition of ezetimibe to ongoing statin treatment reduced RLP-C levels and improved endothelial dysfunction to a greater extent than doubling the statin dose in patients with high RLP-C levels on previous statin treatment. The present results are preliminary and should be confirmed by further studies on a larger number of study patients.

Triglyceride-rich lipoproteins in chronic kidney disease patients undergoing maintenance haemodialysis treatment

Plasma triglyceride (TG) levels were reported to be high in chronic kidney disease (CKD) patients undergoing haemodialysis (HD) treatment. One of the atherogenic causes of hypertriglyceridemia is the increase in TG-rich lipoprotein remnants, which are equivalent to remnant-like particle cholesterol (RLP-C). Here, we compared the plasma levels of TG, a representative indicator of TG-rich lipoproteins and RLP-C, as well as the TG/RLP-C ratio between CKD patients undergoing HD and controls, in an effort to elucidate the atherogenicity of TG-rich lipoproteins in CKD patients on HD. Plasma lipid and apo(lipo)protein levels and the TG/RLP-C ratio were compared between 49 CKD patients undergoing HD and 627 controls. Blood sampling for lipid and apoprotein analysis was performed in a 12-h fasting state. Controls were divided into four subgroups according to TG level (from highest to lowest). RLP-C and apo(lipo)proteins were measured using the immunoprecipitation method and turbidimetric immunoassay, respectively. In addition, a comparison between HD patients and age-, gender-, and plasma TG level-matched controls was performed. Plasma TG levels were 107 ± 70 (mean ± SD) mg/dl in HD patients and 115 ± 72 mg/dl in controls. Plasma RLP-C levels were 6.7 ± 4.5 mg/dl in HD patients and 4.6 ± 3.5 mg/dl in the controls (p < 0.0001). RLP-C levels decreased in descending order from the highest to the lowest TG group in controls. RLP-C levels were higher in HD patients than in controls with plasma TG levels of < 150 mg/dl (p < 0.0001). TG/RLP-C ratios were 19.0 ± 12.0 in HD patients and 25.9 ± 9.5 in controls (p < 0.0001). This ratio was significantly lower in HD patients than in all four TG subgroups. The comparison between HD patients and age-, gender-, plasma TG-matched controls revealed identical results. Plasma RLP-C levels were high, and the TG/RLP-C ratio was low in CKD patients undergoing HD treatment. These findings indicate that total plasma TG-rich lipoprotein levels were not increased, but the distribution of plasma TG-rich lipoproteins were skewed towards remnant fractions in CKD patients undergoing HD treatment; these plasma TG-rich lipoproteins appear to be more atherogenic than those in controls.

Effect of Ezetimibe on Remnant-Like Particle Cholesterol in Subjects with Metabolic Syndrome

Objective: To investigate the influence of ezetimibe monotherapy on remnant-like particle cholesterol (RLP-C) in subjects with metabolic syndrome (MetS). Materials and Methods: Ezetimibe (10 mg/daily) was prescribed over a 12-week period for hypercholesterolemic subjects divided into groups with MetS (n = 28; male/female = 13/15; mean age 67 years) and without MetS (n = 22; male/female = 9/13; mean age 66 years). In the pre- and post-treatment phases, BMI, blood pressure and fasting blood levels of glucose, lipid panels and RLP-C were measured. Results: The group with MetS showed significantly higher RLP-C levels than the group without MetS [median level: 0.18 vs. 0.12 mmol/l (7.1 vs. 4.4 mg/dl), p < 0.01] in the pre-treatment phase. In the post-treatment phase, the low-density lipoprotein cholesterol levels were significantly reduced in both groups to a similar level (p < 0.001 in both), while there was a significantly greater reduction in RLP-C in the group with MetS than the group without MetS [median level: 0.12 vs. 0.11 mmol/l (4.8 vs. 4.1 mg/dl), p < 0.05]. This difference in RLP-C remained significant after adjusting for confounding factors. Conclusion: Ezetimibe monotherapy may be associated with a greater reduction in RLP-C levels in subjects with MetS than in those without MetS.

Remnant-like particle cholesterol and serum amyloid A–low-density lipoprotein levels in obese subjects with metabolic syndrome

Although the circulating levels of remnant-like particle cholesterol (RLP-C) or serum amyloid A-low-density lipoprotein (SAA-LDL) can individually be increased in subjects with metabolic syndrome (MetS), the correlation between the two markers has not yet been previously studied. In the present study, we aimed to investigate the correlation between RLP-C and SAA-LDL in obese subjects with MetS in comparison to those without MetS. A total of 436 obese subjects were divided into groups with MetS and without MetS (male/female 75/143, mean age 49 years, current smokers 16% in both groups) by applying the age-, gender-, and smoking habit-matching method based on the database in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The data, including RLP-C and SAA-LDL, were compared in each group. Significantly greater levels of RLP-C or SAA-LDL were observed in subjects with MetS in comparison with those without MetS. There was a significantly positive correlation between RLP-C and SAA-LDL, with a relatively greater correlation in subjects with MetS (coefficient= 0.290, P<.01) in comparison with those without MetS (coefficient= 0.181, P < .01). Multivariate-adjusted correlation analyses showed a greater correlation between RLP-C and SAA-LDL in subjects with MetS, relative to those without MetS, although the significant correlation decreased in both groups when the hypertriglyceridemic states were taken into account. A relatively greater and positive correlation between greater levels of RLP-C and SAA-LDL in obese subjects with MetS, in comparison with those without MetS, may be linked to the development of MetS-related cardiovascular disease.

Pitavastatin Reduces Elevated IL-18 Levels in Japanese Subjects with Hypercholesterolemia: Sub-analysis of Kansai Investigation of Statin for Hyperlipidemic Intervention in Metabolism and Endocrinology (KISHIMEN)

Pitavastatin significantly improved lipid profiles and reduced serum high-sensitivity C-reactive protein (hs-CRP) levels in a multi-center and prospective study. The aim of this study was to explore the effect of pitavastatin on serum levels of another inflammatory biomarker, interleukin-18 (IL-18), in a sub-analysis of the previous multi-center prospective study. The subjects were 83 patients derived from the KISHIMEN study. Pitavastatin (1-2 mg/day) was administered for 12 months. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), remnant-like particle cholesterol (RLP-C), triglycerides (TG), IL-18, and high sensitivity C-reactive protein (hs-CRP) levels were measured. TC, LDL-C, and RLP-C levels were significantly reduced by 18.3%, 30.1%, and 21.0% (mean values) at 12 months after pitavastatin administration. TG levels were decreased by 9.8% in subjects whose basal TG levels were above 150 mg/dL. HDL-C levels were significantly increased at 6 months (11.9%). Pitavastatin did not significantly alter IL-18 levels in overall subjects, but reduced IL-18 levels in the highest quartile by 24.5% (median value) at 12 months. Pitavastatin significantly reduced hs-CRP levels by 28.6% in overall subjects and by 62.4% in the highest quartile at 12 months. There was a significant correlation between IL-18 and hs-CRP at baseline after both values were transformed into logarithms (Pearson's correlation coefficient, r = 0.259, p = 0.0181); however, percent changes in these levels were not significantly correlated. Pitavastatin significantly improves lipid profiles, and reduces enhanced inflammation monitored by IL-18, as well as by hs-CRP, in hypercholesterolemic subjects.

Atorvastatin treatment lowers fasting remnant-like particle cholesterol and LDL subfraction cholesterol without affecting LDL size in type 2 diabetes mellitus: Relevance for non-HDL cholesterol and apolipoprotein B guideline targets

The extent to which atorvastatin treatment affects LDL size, LDL subfraction levels and remnant-like particle cholesterol (RLP-C) was determined in type 2 diabetes. We also compared LDL size and RLP-C in relation to guideline cut-off values for LDL cholesterol, non-HDL cholesterol and apolipoprotein (apo) B. Changes in LDL size and RLP-C were determined in fasting plasma from type 2 diabetic patients after 30 weeks administration of atorvastatin (10 mg daily, n = 65; 80 mg daily, n = 62) or placebo ( n = 58). LDL subfraction cholesterol was measured in 74 participants. Atorvastatin lowered LDL cholesterol, non-HDL cholesterol, triglycerides, apo B and RLP-C ( P < 0.001 for all at each dose) and LDL mean peak particle diameter remained unchanged. Atorvastatin treatment decreased cholesterol concentrations in all LDL subfractions ( P < 0.001 for each dose). RLP-C at follow-up was lower in those patients achieving the non-HDL cholesterol or the apo B guideline targets ( P < 0.01), but the LDL cholesterol cut-off value failed to discriminate. In conclusion, atorvastatin lowers fasting RLP-C and LDL subfraction cholesterol in diabetes. The proposed guideline cut-off levels for non-HDL cholesterol and apo B may be superior to the LDL cholesterol target in discriminating between higher and lower RLP-C levels.

Effects of rosuvastatin on electronegative LDL as characterized by capillary isotachophoresis: the ROSARY Study

Electronegative LDL, a charge-modified LDL (cm-LDL) subfraction that is more negatively charged than normal LDL, has been shown to be inflammatory. We previously showed that pravastatin and simvastatin reduced the electronegative LDL subfraction, fast-migrating LDL (fLDL), as analyzed by capillary isotachophoresis (cITP). The present study examined the effects of rosuvastatin on the more electronegative LDL subfraction, very-fast-migrating LDL (vfLDL), and small, dense charge-modified LDL (sd-cm-LDL) subfractions. Patients with hypercholesterolemia or those who were being treated with statins (n = 81) were treated with or switched to 2.5 mg/d rosuvastatin for 3 months. Rosuvastatin treatment effectively reduced cITP cm-LDL subfractions of LDL (vfLDL and fLDL) or sdLDL (sd-vfLDL and sd-fLDL), which were closely related to each other but were different from the normal subfraction of LDL [slow-migrating LDL (sLDL)] or sdLDL (sd-sLDL) in their relation to the levels of remnant-like particle cholesterol (RLP-C), apolipoprotein (apo) C-II, and apoE. The percent changes in cm-LDL or sd-cm-LDL caused by rosuvastatin were correlated with those in the particle concentrations of LDL or sdLDL measured as LDL-apoB or sdLDL-apoB and the levels of HDL-C, RLP-C, apoC-II, and apoE. In conclusion, rosuvastatin effectively reduced both the vfLDL subfraction and sd-cm-LDL subfractions as analyzed by cITP.

Serum levels of remnant lipoprotein cholesterol and oxidized low-density lipoprotein in patients with coronary artery disease

Oxidized low-density lipoprotein (OxLDL) and remnant lipoprotein play a crucial role in the development of atherosclerosis. Recently, a novel method for measuring remnant cholesterol levels (remnant lipoproteins cholesterol homogenous assay: RemL-C) has been established. However, the correlation between OxLDL and remnant lipoprotein, including RemL-C, has not been fully investigated. We enrolled 25 consecutive patients with documented coronary artery disease (CAD) and 20 controls. Remnant-like particle cholesterol (RLP-C) and RemL-C were used to determine the levels of remnant lipoprotein cholesterol. Serum levels of malondialdehyde-modified LDL (MDA-LDL) and OxLDL using a monoclonal antibody DLH3 (OxPC) were used to measure the concentration of circulating OxLDL. The CAD group had high levels of fasting glucose and glycosylated hemoglobin (HbA1c), and low levels of high-density lipoprotein cholesterol compared with the control group. Serum levels of total cholesterol or LDL cholesterol were not significantly different between the two groups. The levels of RemL-C (p = 0.035), MDA-LDL (p = 0.018), and MDA-LDL/LDL-C (p = 0.036) in the CAD group were significantly higher than those in the control group. The levels of RLP-C tended to be higher in the CAD group than those in the control group (p = 0.096). Positive correlations were demonstrated between remnant lipoprotein cholesterol and OxLDL (RLP-C and MDA-LDL/LDL-C, r = 0.45, p = 0.0024, RLP-C and OxPC, r = 0.51, p = 0.0005, RemL-C and MDA-LDL/LDL-C, r = 0.42, p = 0.0044, RemL-C and OxPC, r = 0.43, p = 0.0043). Similar trends were observed in non-diabetic subjects and in subjects without metabolic syndrome. Positive correlations were also observed between RLP-C and RemL-C (r = 0.94, p < 0.0001) and between MDA-LDL/LDL-C and OxPC (r = 0.40, p = 0.0074). These results suggest that the association between high levels of remnant lipoprotein cholesterol and high OxLDL levels might be linked to atherogenesis in patients with CAD.

Effects of risperidone and olanzapine on remnant-like lipoprotein particle cholesterol (RLP-C) in schizophrenic patients

Second generation antipsychotics are associated with the risk of metabolic disorders such as diabetes mellitus and hyperlipidemia. Remnant-like lipoprotein particles cholesterol (RLP-C) are a known risk factor for cardiovascular events. The present study was performed to determine possible differences in fasting blood RLP-C levels between schizophrenic patients treated with risperidone as compared to olanzapine. Patients on olanzapine had significantly higher RLP-C levels than those on risperidone (p < 0.01). In olanzapine-treated patients there was no abnormality in fasting blood glucose levels, but fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) were elevated. RLP-C levels were significantly correlated with plasma triglyceride concentrations in both the olanzapine- (p < 0.01) and risperidone-treated patients (p < 0.01). The regression line slope was greater for the olanzapine group, suggesting a greater influence of olanzapine on RLP-C. There was a significant correlation between RLP-C and HOMA-IR in the risperidone group (p < 0.01) but not in the olanzapine group (p = 0.80). These results suggest that blood glucose monitoring may not be sufficient to detect metabolic disorder and that measurement of RLP-C might be helpful for the screening for metabolic disorders associated with olanzapine therapy.

Plasma Levels of HDL Subpopulations and Remnant Lipoproteins Predict the Extent of Angiographically-Defined Coronary Artery Disease in Postmenopausal Women

The association of coronary heart disease (CHD) with subpopulations of triglyceride (TG)-rich lipoproteins and high-density lipoproteins (HDL) is established in men, but has not been well characterized in women. Plasma HDL subpopulation concentrations, quantified by 2-dimensional gel electrophoresis, and plasma remnant-like particle cholesterol (RLP-C) concentrations were measured in 256 postmenopausal women with established CHD and in 126 CHD-free postmenopausal women. Coronary artery disease was assessed in women with CHD by quantitative coronary angiography. Plasma RLP-C and prebeta1 HDL concentrations were higher and alpha1 and alpha2 HDL concentrations were lower in CHD than in CHD-free women. After adjustment for conventional CHD-risk factors, plasma levels of RLP-C were positively associated with the degree of coronary artery disease. In similar analyses, plasma prebeta1 HDL particle concentrations were positively associated and alpha2 HDL particle concentrations were inversely associated with the extent of coronary atherosclerosis. Plasma TG, low density lipoprotein cholesterol, and HDL cholesterol levels were not associated with the degree of coronary atherosclerosis. The degree of coronary atherosclerosis in postmenopausal women is linked to a dysregulation of the TG/HDL metabolism. Subpopulations of TG-rich and HDL lipoproteins are better predictors of disease than TG and HDL cholesterol concentrations.

Effects of Statin on Small Dense Low-Density Lipoprotein Cholesterol and Remnant-Like Particle Cholesterol in Heterozygous Familial Hypercholesterolemia

The effects of statin on small dense low-density lipoprotein cholesterol (sd-LDL-C) and remnant-like particle cholesterol (RLP-C) levels in heterozygous familial hypercholesterolemia (FH) have not been examined. This study aimed to clarify the effects of statin on sd-LDL-C and RLP-C levels in heterozygous FH. Seventeen patients with heterozygous FH were randomly assigned to 2 mg/day pitavastatin or 10 mg/day atorvastatin. At baseline and 12 weeks after treatment with statin, we measured sd-LDL-C and RLP-C levels. Sd-LDL-C levels significantly decreased from 43 +/- 24 to 16 +/- 10 mg/dL (-63%, p=0.001) in the pitavastatin group, and from 44 +/- 17 to 19 +/- 10 mg/dL (-55%, p<0.001) in the atorvastatin group. RLP-C levels decreased from 8.4 +/- 2.8 to 6.6 +/- 2.7 mg/dL (-16%, p=0.156) in the pitava-statin group, and from 9.8 +/- 4.7 to 5.9 +/- 5.4 mg/dL (-45%, p=0.044) in the atorvastatin group. There were no significant differences in percent changes of sd-LDL-C (p=0.370) and RLP-C levels (p=0.097) between the two groups. Sd-LDL-C measured by the heparin-magnesium precipitation method and RLP-C levels in heterozygous FH were decreased by 12 weeks of statin therapy. Statin might have additional anti-atherogenic effects by reducing not only LDL-C but also sd-LDL-C and RLP-C.

Effects of Pitavastatin on Lipid Profiles and High-Sensitivity CRP in Japanese Subjects with Hypercholesterolemia: Kansai Investigation of Statin for Hyperlipidemic Intervention in Metabolism and Endocrinology (KISHIMEN) Investigatars

The effect of pitavastatin on high-sensitivity C-reactive protein (hs-CRP) has not been reported, yet, in humans. We, therefore, investigated the effects of pitavastatin on lipid profiles and hs-CRP in Japanese subjects with hypercholesterolemia. The subjects were 178 Japanese with hypercholesterolemia, including 103 (58%) with type 2 diabetes. Pitavastatin (12 mg/day) was administered for 12 months. Serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), remnant-like particle cholesterol (RLP-C), triglycerides (TG) and hs-CRP levels were measured for 12 months. Serum LDL-C and RLP-C levels were significantly decreased by 30.3% and 22.8%, respectively. Serum TG levels were decreased by 15.9% in subjects with basal TG levels above 150 mg/dl. Serum HDL-C levels were significantly increased. The administration of pitavastatin reduced serum hs-CRP levels by 34.8%. No serious adverse events were observed, including changes in glycosylated hemoglobin levels of diabetic patients. These results suggest that pitavastatin significantly improves lipid profiles and reduces proinflammatory responses, without adverse effects, in Japanese subjects with hypercholesterolemia, including those with diabetes mellitus.

Characteristic comparison of triglyceride-rich remnant lipoprotein measurement between a new homogenous assay (RemL-C) and a conventional immunoseparation method (RLP-C)

BackgroundIncreased serum remnant lipoproteins are supposed to predict cardiovascular disease in addition to increased LDL. A new homogenous assay for remnant lipoprotein-cholesterol (RemL-C) has been developed as an alternative to remnant-like particle-cholesterol (RLP-C), an immunoseparation assay, widely used for the measurement of remnant lipoprotein cholesterol.MethodsWe evaluated the correlations and data validation between the 2 assays in 83 subjects (49 men and 34 women) without diabetes, hypertension and medications for hyperlipidemia, diabetes, and hypertension, and investigated the characteristics of remnant lipoproteins obtained by the two methods (RLP-C and RemL-C) and their relationships with IDL-cholesterol determined by our developed HPLC method.ResultsA positive correlation was significantly found between the two methods (r = 0.853, 95%CI 0.781–0.903, p < 0.0001). Bland & Altman analysis revealed that RemL-C values were likely to be significantly higher than RLP-C values, particularly in samples with high levels of remnant lipoproteins. Several data dissociations between the RemL-C and RLP-C were also observed. The HPLC chromatograms show high concentrations of chylomicron cholesterol in serum samples with RemL-C level < RLP-C level, but high concentrations of IDL-cholesterol in samples with RemL-C level > RLP-C level. RemL-C (r = 0.339, 95%CI 0.152–0.903; p = 0.0005) significantly correlated with IDL-cholesterol, but not RLP-C (r = 0.17, 95%CI -0.047–0.372; p = 0.1237) in all the samples (n = 83).ConclusionThese results suggest that there is generally a significant correlation between RemL-C and RLP-C. However, RemL-C assay is likely to reflect IDL more closely than RLP-C.

Remnant lipoprotein metabolism is improved more when body weight is reduced by exercise than by dietary restriction

Background Remnant lipoprotein levels during weight-loss programs have not been examined in detail. We investigated the effects of reducing body weight by exercise and by dietary restriction on lipid metabolism including remnant-like particle-cholesterol (RLP-C) and apolipoprotein B48 (apo B48). Methods Six adult male volunteers participated in 2 experiments over 10 days. The first 5 days were an adjustment period (energy intake, 2656 ±150 kcal/day; mean ± SEM). During the second 5 days, the participants either exercised on a bicycle ergometer to consume 886 ± 50 kcal/day or reduced their energy intake to 1770 ± 100 kcal/day. Results Serum triglyceride (TG) and RLP-C levels were significantly lower, whereas the increase in high density lipoprotein-cholesterol (HDL-C) level was significantly larger after exercise than after dietary restriction. We measured changes (Δ) in serum levels and identified positive correlations between Δ insulin and Δ TG, Δ apo B48 ( p < 0.05) and Δ RLP-C ( p = 0.050) only during exercise. Conclusions Reducing body weight by exercise has more beneficial effects on lipid metabolism than a dietary approach, and improved insulin resistance accompanies the decrease of serum remnant lipoprotein levels.

Old Drug, New Tricks

See related article, pages 156–165 Ironically, even though there are currently only a few drugs to specifically treat low high-density lipoprotein (HDL), numerous drugs have been observed to inadvertently alter HDL levels.1 This has been particularly noted for some antihypertensive drugs. Because they are used long-term, any positive or negative effect of antihypertensive drugs on lipids and lipoproteins can significantly impact on their effectiveness in preventing cardiovascular disease. Recently, advances in our understanding of HDL metabolism have helped us to unravel the mechanism of action of these and other drugs that unexpectedly alter HDL levels. This work has largely been led by the laboratory of Shinji Yokoyama and colleagues, who have previously identified the mechanism of action of three drugs on HDL metabolism. Probucol, which has been used to treat patients at risk for cardiovascular disease, is an antioxidant and lowers LDL, but it also lowers HDL. Probucol is now known to decrease HDL by inhibiting the activity of the ABCA1 transporter,2 a key protein involved in reverse cholesterol transport pathway and in HDL biogenesis.3 Verapamil, a calcium channel blocker, which can be used as antihypertensive and antiarrhythmic agent, and fenofibrate, a lipid-lowering drug, both raise HDL by increasing the gene expression of the ABCA1 transporter.4,5 In this issue of Circulation Research ,6 Iwamoto et al describe the mechanism of action of a fourth agent that unexpectedly alters HDL, namely the antihypertensive agent doxazosin. The results of this study raise the possibility of a new strategy for developing drugs to increase HDL. Doxazosin (Cardura) is a quinazoline based compound that is sold by Pfizer and is a long lasting selective inhibitor of the α-1a subtype of adrenergic receptors. It blocks the binding of norepinephrine to adrenergic receptors in the autonomic nervous system, which leads …

Remnant-like lipoprotein particle level and insulin resistance are associated with in-stent restenosis in patients with stable angina

The aim of this study was to evaluate the independent effect of serum remnant-like lipoprotein particle level and insulin resistance on in-stent restenosis in nondiabetic patients with stable angina. The study included 64 nondiabetic patients with stable angina who underwent successful coronary stenting. At the time of stenting, we evaluated the patients' lipid profiles including remnant-like lipoprotein particles cholesterol, plasma glucose and insulin levels, and insulin resistance by the homeostasis model assessment. There was no significant difference in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels between two patient groups with (n=15) and without (n=49) in-stent restenosis. Plasma remnant-like lipoprotein particles cholesterol level was significantly higher in patients with restenosis than in patients without restenosis (8.2+/-7.0 mg/dl vs. 4.5+/-2.6 mg/dl, P=0.006). Although plasma glucose level was similar between the two groups, insulin level and homeostasis model assessment were significantly higher in patients with restenosis, compared with those without restenosis (11.2+/-12.4 vs. 7.1+/-2.8, P=0.039; and 2.6+/-2.9 vs. 1.7+/-0.7, P=0.040, respectively). In multivariate logistic regression analysis, plasma remnant-like lipoprotein particles cholesterol level (>4.8 mg/dl; the 75th percentile of the distribution of remnant-like lipoprotein particles cholesterol level) was the independent predictor of in-stent restenosis (odds ratio: 8.15; confidence interval: 1.02-65.16; P=0.048). Our findings suggest that high serum remnant-like lipoprotein particles cholesterol level, and not insulin resistance may be an independent risk factor on in-stent restenosis in nondiabetic patients with stable angina.

Effect of pioglitazone on atherogenic outcomes in type 2 diabetic patients: A comparison of responders and non-responders

The aim of this study was to evaluate the anti-atherogenic efficacy of pioglitazone, a thiazolidinedione derivative, on the change in atherogenic outcomes by comparing responder and non-responder groups in type 2 diabetic patients. Twenty-three patients with poor diabetic control were treated with 15 mg of pioglitazone for 12 months. The levels of fasting plasma glucose (FPG), HbA1c, triglycerides (TG), total cholesterol (T-Cho), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) were measured monthly, and those of remnant-like particle-cholesterol (RLP-C) and lipoprotein (a) [Lp (a)] were measured every 3 months. In Month 6, the patients were divided into two groups according to the decrease in HbA1c level: the responder group showed a decrease of ≥1%; the non-responder group, a decrease of <1%. In the responder group, the levels of FPG and HbA1c decreased significantly after Month 3. The values of the body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) index, LDL-C, and RLP-C were significantly higher in the responder group than in the non-responder group. Although the levels of T-Cho and HDL-C were unchanged in both groups, those of TG and RLP-C were drastically reduced in the responder group. Interestingly, the relative change in Lp (a) was significantly decreased in both groups. These results strongly suggest that pioglitazone is beneficial for type 2 diabetic patients with high levels of BMI, HOMA-IR, LDL-C, and RLP-C, as it helps to prevent the progression of atherosclerosis, including coronary heart diseases.

High Plasma Level of Remnant-Like Particles Cholesterol in Familial Combined Hyperlipidemia

The traditional lipid and lipoprotein levels in patients with familial combined hyperlipidemia (FCH) are relatively mildly elevated and do not fully explain the increased risk of cardiovascular disease (CVD). In other populations, high remnant-like particles cholesterol (RLP-C) levels are an independent risk factor for CVD. The objective of the study was to investigate whether plasma RLP-C concentrations are elevated in patients with FCH and contribute to the increased prevalence of CVD. In this cross-sectional study, we studied RLP-C levels in 37 FCH families comprising 582 subjects, of whom 134 subjects were diagnosed FCH based on total cholesterol, triglyceride, and apolipoprotein-B levels. Plasma RLP-C concentrations were determined using an immune-separation technique. For both men and women, the mean plasma RLP-C concentration (mmol/liter) was 2-fold elevated in FCH patients [0.59 (0.54-0.66) and 0.40 (0.37-0.43), respectively] compared with both normolipidemic relatives [0.27 (0.26-0.29) in male and 0.22 (0.21-0.23) in female, all P<0.000]; and spouses [0.27 (0.23-0.31) in male and 0.24 (0.21-0.27) in female, all P<0.000]. Plasma RLP-C levels above the 90th percentile predicted prevalent CVD, independently of nonlipid cardiovascular risk factors [odds ratio 2.18 (1.02-4.66)] and triglyceride levels [odds ratio 2.35 (1.15-4.83)]. However, in both FCH patients and controls, RLP-C did not provide additional information about prevalent CVD over and above non-high-density lipoprotein cholesterol levels. Patients with FCH have 2-fold elevated plasma RLP-C levels, which add to the atherogenic lipid profile and contribute to the increased risk for CVD. However, for clinical practice, non-high-density lipoprotein cholesterol is the best predictor of prevalent CVD.