Remnant-like Lipoprotein Particles Research Articles

Anti-Lipoprotein Lipase Antibody as a Useful Marker for Plaque Vulnerability in Patients with Stable Angina.

Identifying patients with vulnerable plaque who have poor prognosis among those with coronary artery disease (CAD) is crucial to deciding future therapeutic interventions. We previously reported that male CAD patients with low anti-apolipoprotein B-100 autoantibody (anti-apoB-100 Ab) levels were at an increased risk of developing unstable plaque lesions. This study focused on the autoantibodies against lipoprotein lipase (LPL), a key enzyme in triglyceride metabolism, which is another risk factor for atherosclerosis, and investigated their association with plaque characteristics. We measured serum anti-LPL Ab levels using a homemade enzyme-linked immunosorbent assay in 80 male CAD patients. Coronary plaque properties were evaluated using iMAP®-intravascular ultrasound. Serum anti-LPL Ab levels were not correlated with plaque burden but were significantly negatively and positively correlated with fibrotic and necrotic plaques, respectively. High-risk patients with low anti-apoB-100 Ab levels were divided into groups according to their anti-LPL Ab levels. The group with high anti-LPL Ab levels exhibited more necrotic plaques and fewer fibrotic plaques as well as higher remnant-like lipoprotein particle levels than the group with low anti-LPL Ab levels. Serum anti-LPL Ab levels can serve as a marker of plaque instability in CAD patients and can help identify higher-risk cases when combined with anti-apoB-100 Ab levels.

Endothelial Progenitor Cell Levels and Extent of Post-prandial Lipemic Response.

Background and ObjectiveDue to the frequency of meal ingestion, individuals spend the majority of the day, ~18 h, in a status of post-prandial (PP) stress. Remnant-like lipoprotein particles (RLPs) are predominant in PP phase playing an important role in the development of atherosclerosis. Endothelial progenitor cells (EPCs) have been suggested to play a role in vessel wall homeostasis and in reducing atherosclerosis. However, there is no information about peripheral blood EPCs number following PP stress. We investigated the association between circulating EPCs levels and extent of PP lipemia in healthy subjects following a high-fat meal.Materials and MethodsA total of 84 healthy subjects (42 men, 42 women) aged 17–55 years were included in the study. PP lipemic response of subjects was determined by Oral Fat-Loading Test (OFLT). All the subjects were classified on the basis of their plasma TG levels after PP lipemic stressors in categories 1 (low), 2 (moderate), and 3 (high). Circulating EPCs numbers were measured by the flow cytometry method.ResultsThere was a significant difference in terms of lipid parameters between men and women: high-density lipoprotein cholesterol (HDL-C) was significantly lower in men than in women (p < 0.001). Total cholesterol (TC) (p = 0.004), low-density lipoprotein cholesterol (LDL-C) (p < 0.001), triglyceride (TG) (p < 0.001), and TG-AUC (p < 0.001) were significantly higher in men than in women. There was no significant difference between the genders in terms of CD34+KDR+ and CD34+KDR+CD133+cell number and MMP-9 levels. Vascular endothelial growth factor (VEGF) levels were significantly higher in men than women (p = 0.004). TC, LDL-C, and TG were significantly higher in the 3rd category than 1st and 2nd categories (p < 0.001) in women. Age, body mass index (BMI), fat rate, TG, TC, and LDL-C were significantly higher in the 3rd category than 1st category (p < 0.001, p = 0.002, p = 0.002, p = 0.01, p = 0.007, p = 0.004; respectively), in men. Circulating numbers of EPCs in men were significantly higher in the PP hyperlipidemia group than in the low TG levels category, independently from age (p < 0.05). Circulating EPC levels showed a positive correlation with OFLT response in men (r = 0.414, p < 0.05). Also, OFLT response showed a strong positive correlation with fasting TG levels (r = 0.930, p < 0.001). EPC levels in categories of women were not different.ConclusionIncreased EPCs levels in subjects with different PP hyperlipidemia may be associated with a response to endothelial injury, related to increased atherogenic remnant particles at the PP phase.

Interstitial postprandial hyperlipidemia and remnant lipoproteins in type 2 diabetes mellitus

Background and Aims: Diabetic dyslipidemia is characterized by elevated fasting serum TG and VLDL and low HDL-c. Postprandial hypertriglyceridemia and changes in remnant-like lipoprotein particles are well recognized in T2D, but the metabolism and /or clearance of these triglyceride-rich lipoproteins (TGRL) is less clear. The interstitial fluid (IF) represents the immediate environment of most cells in the body and studying postprandial changes in this compartment should provide novel insights into the increased cardiovascular risk observed in T2D.

PROGNOSTIC UTILITY OF TRIGLYCERIDE RICH LIPOPROTEINS RELATED MARKERS IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE ON STATIN THERAPY

Triglyceride-rich lipoproteins (TRL)-related markers, containing cholesterol subset [TRL-cholesterol (TRL-C) and remnant-like lipoprotein particles cholesterol (RLP-C)] and apolipopoprotein C-III (apoC-III), were reported to be involved in atherosclerosis. This multicenter prospective cohort study

P1227Remnant lipoprotein is a residual risk of future cardiovascular events in patients with stable coronary artery disease and on statin LDL-cholesterol levels less than 70 mg/dl

Abstract Background Recent guidelines recommend a target of low density lipoprotein cholesterol (LDL-C) &lt;70 mg/dL in patients at very high risk of cardiovascular disease (CVD). However, a considerable residual risk of CVD persists despite achievement of the LDL-C goal on statin treatment. Purpose This study examined the predictive value of remnant lipoprotein levels for cardiovascular events (CVE) in patients with stable coronary artery disease (CAD) and LDL-C levels &lt;70 mg/dL on statin treatment. Methods Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 247 consecutive patients with CAD who had on-statin LDL-C levels &lt;70 mg/dL. All the patients were followed prospectively for a period of ≤60 months or until the occurrence of the primary composite endpoint of cardiac death, nonfatal myocardial infarction, unstable angina requiring coronary revascularization, worsening heart failure, peripheral artery diseases requiring endovascular or surgical intervention, aortic events, and ischemic stroke. Results During a mean follow-up period of 38 months, 33 CVEs occurred. Kaplan-Meier estimates in time-to-first-event analysis demonstrated that higher RLP-C levels (&gt;3.9 mg/dL, determined by ROC-curve) resulted in a significantly higher probability for the primary endpoint than did lower RLP-C levels (&lt;3.9 mg/dL) (p&lt;0.01 by log-rank test). Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of the primary endpoint after adjustment for known risk factors and lipid variables including triglycerides (TG), and total apolipoprotein B (ApoB) (HR 1.62, 95% CI 1.26–2.07, p&lt;0.01). The c-statistics showed that addition of RLP-C had a significant incremental effect on the predictive value of traditional risk factors (area under curve; traditional risk factors: 0.68 vs. traditional risk factors + RLP-C: 0.77, p=0.02). Category-free NRI and IDI demonstrated the additive value of RLP-C to the traditional risk factors plus non-high-density lipoprotein (HDL)-C and ApoB levels (NRI 0.52, p&lt;0.01; IDI 0.06, p&lt;0.01). Conclusions RLP-C levels are a residual risk factor for future CVEs in patients with CAD and on-statin LDL-C &lt;70 mg/dL.

Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease

BackgroundRemnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. MethodsA total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6–9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. ResultsTreatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = −0.18, p = 0.03), RLP-C (r = −0.39, p < 0.001), RLP-C/TG (r = −0.34, p < 0.001), and CRP (r = −0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. ConclusionImprovement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.

Lipid Profiles in Out-of-Hospital Sudden Unexpected Death.

ObjectiveTo determine the association between serum lipid measurements and the occurrence of out-of-hospital sudden unexpected death (OHSUD).Patients and MethodsWe compared 139 OHSUD cases (43 female patients [30.9%]) and 968 controls (539 female patients [55.7%]) from Wake County, North Carolina, from March 1, 2013, through February 28, 2015. Individuals were included if they were aged 18 to 64 years and had lipid measurements in the 5 years before their death (cases) or the most recent health care encounter (controls). Covariates were abstracted from medical records for all subjects, and those with triglyceride (TG) levels greater than 400 mg/dL (to convert to mmol/L, multiply by 0.0259) were excluded for low-density lipoprotein (LDL)–related analyses.ResultsBy linear regression using age- and sex-adjusted models, cases of OHSUD had lower adjusted mean total cholesterol (170.3±52.2 mg/dL vs 188.9±39.7 mg/dL; P<.001), LDL cholesterol (90.9±39.6 mg/dL vs 109.6±35.2 mg/dL; P<.001), and non–high-density lipoprotein (HDL) (121.6±49.8 mg/dL vs 134.3±39.6 mg/dL; P<.001) levels and a higher adjusted TG/HDL-C ratio (4.7±7 vs 3±2.7; P<.001) than did controls. By logistic regression using age- and sex-adjusted models, the odds of OHSUD were elevated per unit increase in TG/HDL-C ratio (1.08; 95% CI, 1.03-1.12).ConclusionOut-of-hospital sudden unexpected death cases had more favorable levels of total cholesterol, LDL cholesterol, and non-HDL, possibly indicating a lack of association between traditional lipid cardiovascular risk factors and sudden unexpected death. A comparatively elevated TG/HDL-C ratio in cases may corroborate an evolving hypothesis of how vasoactive and prothrombotic remnant-like lipoprotein particles contribute to sudden unexpected death.

Patients with Concurrent Tuberculosis and Diabetes Have a Pro-Atherogenic Plasma Lipid Profile

BackgroundType 2 diabetes mellitus (DM) is a major risk factor for development of tuberculosis (TB), however the underlying molecular foundations are unclear. Since lipids play a central role in the development of both DM and TB, lipid metabolism may be important for TB-DM pathophysiology. MethodsA 1H NMR spectroscopy-based platform was used to determine 225 lipid and other metabolic intermediates in plasma samples of healthy controls (n = 50) and patients with TB (n = 50), DM (n = 50) or TB-DM (n = 27). ResultsTB patients presented with wasting disease, represented by decreased amino acid levels including histidine and alanine. Conversely, DM patients were dyslipidemic as evidenced by high levels of very low-density lipoprotein triglycerides and low high-density lipoprotein cholesterol. TB-DM patients displayed metabolic characteristics of both wasting and dyslipidemia combined with disease interaction-specific increases in phospholipid metabolites (e.g. sphingomyelins) and atherogenic remnant-like lipoprotein particles. Biomarker analysis identified the ratios of phenylalanine/histidine and esterified cholesterol/sphingomyelin as markers for TB classification regardless of DM-status. ConclusionsTB-DM patients possess a distinctive plasma lipid profile with pro-atherogenic properties. These findings support further research on the benefits of improved blood lipid control in the treatment of TB-DM.

Oral Fat Tolerance Test for Sitosterolemia and Familial Hypercholesterolemia: A Study Protocol.

Aim: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plasma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH).Methods: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading.Results: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients.Conclusion: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).

Abstract P126: Unanticipated Lipid Profiles in Victims of Sudden Unexpected Death: Low Low-density Lipoprotein Cholesterol and an Elevated Triglyceride to High-density Lipoprotein Cholesterol Ratio

Background: Though low-density lipoprotein cholesterol (LDL) is a proven cardiovascular risk factor, substantive data on LDL levels in victims of sudden cardiac or sudden unexpected death is lacking. Additionally, post-mortem studies have shown higher concentrations of remnant-like lipoprotein particles (RLP) in sudden cardiac death victims. Triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL) is associated with RLP concentration, but has not been reported for victims prior to sudden death. Hypothesis: We assessed the hypothesis that out-of-hospital sudden unexpected death (OHSUD) victims would have similar or higher calculated LDL levels and higher TG/HDL ratios when compared with National Health and Nutrition Examination Survey (NHANES) participants. Methods: From 2013-15, all free living adults aged 18-64 who died out-of-hospital as reported by emergency medical services in Wake County, North Carolina (population 974,289) were adjudicated to identify OHSUD victims (n=408). Medical records were requested from area healthcare providers; 138 victims had a lipid panel available at an average of 1.2 years prior to death. To emulate a similar follow-up period, 18-64 year old NHANES (2009-2010) participants with a lipid panel who were alive at the end of 2011 served as a comparison group (n=1316). Covariates were abstracted from medical records for OHSUD victims and self-reported in NHANES participants. Subjects with triglycerides&gt;400 mg/dL were excluded for analysis pertaining to LDL. We used multiple linear regression to assess the difference in lipid measures between OHSUD victims and NHANES participants, adjusting for demographics, prevalent dyslipidemia, diabetes, hypertension, body mass index, and coronary artery disease, use of lipid-lowering medication and clinic visits per year. Results: OHSUD victims had a lower mean LDL than NHANES participants (91.6 mg/dL; 95% CI 84.7, 98.5 vs. 115.8 mg/dL; 95%CI 113.8, 117.7 respectively). After multivariate adjustment, mean LDL of victims was still 22.3 mg/dL lower than NHANES participants (p&lt;0.001). OHSUD victims had a higher unadjusted mean TG/HDL ratio than NHANES participants (4.2; 95% CI 3.2, 5.2 vs. 2.9; 95% CI 2.7, 3.2 respectively); this difference was mildly attenuated on adjustment for age, gender and race and insignificant upon additional adjustment for dyslipidemia and diabetes status. Conclusion: Contrary to expectations, out-of-hospital sudden unexpected death victims had a more favorable LDL cholesterol profile unexplained by differences in demographics, comorbid conditions or use of lipid lowering medication. The elevated TG/HDL ratio in victims, though explained by a higher prevalence of comorbidities, corroborates an evolving hypothesis on the contributory nature of vasoactive, prothrombotic remnant-like lipoprotein particles to sudden unexpected death.

Remnant lipoproteinemia predicts cardiovascular events in patients with type 2 diabetes and chronic kidney disease

BackgroundPatients having type 2 diabetes mellitus (DM) and chronic kidney disease (CKD) are at high risk of cardiovascular events. Triglyceride-rich lipoprotein levels are synergistically increased in patients with DM and CKD. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with DM and CKD. MethodsThree hundred and sixty-five patients with type 2 DM and CKD were enrolled. Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. All patients were followed prospectively for a period of 45±23 months or until occurrence of one of the following events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or ischemic stroke. ResultsDuring the follow-up period, 59 patients had cardiovascular events. Multivariate Cox analysis revealed that high levels of RLP-C (≥4.3mg/dL; median value) were a significant risk factor for cardiovascular events, independent of traditional risk factors (HR: 1.30; 95% CI: 1.04–1.63; p=0.02). The addition of high levels of RLP-C to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.36, p=0.01; and IDI 0.03, p=0.02). ConclusionsRLP-C is useful for risk assessment of future cardiovascular events in patients having type 2 DM and CKD.

Is There a Relation Between Triglyceride Concentrations in Very Low Density Lipoprotein and the Index of Insulin Resistance in Nondiabetic Subjects?

Serum very low density lipoprotein (VLDL) levels increase during the early stages of insulin resistance; therefore, determination of VLDL levels would be useful for evaluating the progression of metabolic syndrome and diabetes mellitus. The aim of this study was to clarify the clinical utility of triglyceride in VLDL (VLDL-TG) level, determined using a homogeneous assay kit (Shino-test Corporation, Tokyo, Japan), as an index of insulin resistance. We enrolled 74 subjects in this study (diabetic subjects, n = 42; nondiabetic subjects, n = 32). The levels of VLDL-TG, remnant-like lipoprotein particle cholesterol, preheparin lipoprotein lipase mass, and other biochemical markers were determined. VLDL-TG levels were significantly higher in the diabetic group (1.04 ± 0.84 mmol/l vs. 0.64 ± 0.42 mmol/l, P < 0.01) than in the nondiabetic group. In the nondiabetic group, VLDL-TG was significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), the index for insulin resistance (r = 0.513, P = 0.003). VLDL-TG levels, but not TG levels, were higher in the highest quartile (HOMA-IR) of the nondiabetic group. VLDL-TG level was a useful early marker for insulin resistance, especially in nondiabetic subjects. The homogeneous VLDL-TG assay is a simple, low-cost method for determining insulin resistance.

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.

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.

Effects of Pitavastatin on Remnant-Like Lipoprotein Particle Cholesterol in Patients with Dyslipidemia: A Randomized Controlled Trial

Effects of Pitavastatin on Remnant-Like Lipoprotein Particle Cholesterol in Patients with Dyslipidemia: A Randomized Controlled Trial

Abstract 9322: Remnant Lipoproteinemia is a Predictor of Coronary Events in Patients with Coronary Artery Disease and Chronic Kidney Disease

Although triglyceride (TG) levels are increased in chronic kidney disease (CKD), the independence of high TG levels as a risk for coronary events remains debatable. We have previously shown that remnant lipoproteins, one of TG-rich lipoproteins, is a strong risk for future coronary events independent of low HDL-C levels and high LDL-C levels in patients with coronary artery disease (CAD). Thus, this study examined predictive value of remnant lipoproteins for coronary events in CAD patients with CKD. Methods: Fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 229 patients with CAD and CKD (estimated GFR &lt; 60 ml/min/1.73m 2 , excluding hemodialysis patients). All patients were prospectively followed up for a period of 18 months or until occurrence of one of following events: cardiac death, nonfatal myocardial infarction (MI), unstable angina requiring unplanned coronary revascularization or worsening heart failure requiring hospitalization. Results: During follow-up period, events occurred in 28 (37%) patients with higher levels of RLP-C (&gt; 5.0 mg/dL, 75 th percentile of the distribution) (5 cardiac death, 4 MI, 15 unstable angina, 4 heart failure), while events occurred in 18 (11.7%) patients with lower RLP-C levels (&lt; 5.0 mg/dL) (2 MI, 14 unstable angina, 2 heart failure) (p&lt;0.0001). In Kaplan-Meier analysis, higher RLP-C levels resulted in a higher probability for the development of coronary events than lower RLP-C levels (p &lt; 0.01). In multivariate Cox proportional hazards analysis, higher RLP-C levels were a significant predictor of coronary events (HR 1.8, 95%CI 1.3 - 6.9, p &lt; 0.01), that was independent of TG levels and the Framingham risk variables. In c -statistics, RLP-C levels had an incremental effect on the predictive value of the Framingham risk variables for coronary events (area under ROC curve: RLP-C + Framingham risks 0.83 vs. Framingham risks alone 0.75, p &lt; 0.01). Conclusions: High remnant lipoprotein levels are an independent predictor of coronary events in CAD patients with CKD. Assessment of remnant lipoprotein levels may be useful for risk stratification for coronary events in patients with CKD.

Comparative reactivity of remnant-like lipoprotein particles (RLP) and low-density lipoprotein (LDL) to LDL receptor and VLDL receptor: Effect of a high-dose statin on VLDL receptor expression

Background Comparison of the reactivity of remnant-like lipoprotein particles (RLP) and LDL particles to LDL receptor and VLDL receptor has not been investigated. Methods LDL receptor- or VLDL receptor-transfected ldlA-7, HepG2 and L6 cells were used. Human LDL and rabbit β-VLDL were isolated by ultracentrifugation. Human RLP was isolated using an immunoaffinity mixed gel. The effect of statin on lipoprotein receptors was examined. Results Both LDL receptor and VLDL receptor recognized RLP. In LDL receptor transfectants, RLP, β-VLDL and LDL all bound to LDL receptor. Cold RLP competed efficiently with DiI-β-VLDL; however, cold LDL competed weakly. In VLDL receptor transfectants, RLP and β-VLDL bound to VLDL receptor, but not LDL. RLP bound to VLDL receptor with higher affinity than β-VLDL because of higher apolipoprotein E in RLP. LDL receptor expression was induced in HepG2 by the low concentration of statin while VLDL receptor expression was induced in L6 myoblasts at higher concentration. Conclusions RLP are bound to hepatic LDL receptor more efficiently than LDL, which may explain the mechanism by which statins prevent cardiovascular risk by primarily reducing plasma RLP rather than by reducing LDL. Additionally, a high-dose of statins also may reduce plasma RLP through muscular VLDL receptor.

Predictive value of remnant lipoprotein for cardiovascular events in patients with coronary artery disease after achievement of LDL-cholesterol goals

ObjectivesTriglycerides-rich lipoproteins are related to residual cardiovascular risk in patients on lipid-lowering treatment who achieve low-density lipoprotein cholesterol (LDL-C) goals. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with coronary artery disease (CAD) with LDL-C levels <100mg/dL on lipid-lowering therapy. MethodsSerum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 560 patients with CAD who had LDL-C levels <100mg/dL on lipid-lowering therapy, including statin (58%), fibrate (13%) or diet only (29%). All the patients were followed prospectively for a period of ≤36 months or until occurrence of one of the following events: cardiac death, non fatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke. ResultsDuring a mean follow-up period of 33 months, 40 events occurred. Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of cardiovascular events after adjustment for known risk factors and lipid variables including triglycerides, non-high-density lipoprotein (HDL)-C, and total apolipoprotein B (HR 1.53, 95% CI 1.35–1.97, p<0.01). The c-statistics showed that addition of RLP-C had a greater incremental effect on the predictive value of conventional risk factors than addition of non-HDL-C or total apolipoprotein B. ConclusionsRLP-C was superior to non-HDL-C for predicting cardiovascular events in CAD patients with LDL-C levels <100mg/dL on lipid-lowering treatment. Remnant lipoprotein may therefore be an important target for residual risk reduction after LDL-C goals on lipid lowering therapy.

Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients

It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering alone or whether other pleiotropic effects may contribute. Thus, we compared the endothelial function among two groups of diabetic patients treated with fluvastatin 60 mg (F60) or fluvastatin 20 mg combined with ezetimibe 10 mg (F20/E10). The endothelial function was evaluated by measuring flow-mediated vasodilatation (FMD) at baseline and follow-up at 10 weeks. Similar improvements in FMD were observed in the two groups. The reduction in low-density lipoprotein cholesterol (LDL-C) was less pronounced in the F60 group, compared with the F20/E10 group. A significant reduction in remnant-like lipoprotein particles cholesterol (RLP-C) was observed in the F20/E10 group, but not in the F60 group. A correlation between the observed reduction in LDL-C or RLP-C and the improvement in FMD was observed in F20/E10 group. These results suggest that high-dose fluvastatin might have pleiotropic effects of potential clinical benefit, and that the combination of ezetimibe with a reduced dose of fluvastatin may also significantly improve endothelial function with reduction of LDL-C and RLP-C.

Particle size of apoB-48 carrying lipoproteins in remnant lipoproteins isolated from postprandial plasma

Particle size of apoB-48 carrying lipoproteins in remnant-like lipoprotein particles (RLP) in postprandial plasma has not been well characterized. Plasma lipids, lipoproteins and apolipoproteins in 12 healthy subjects were analysed after an oral fat load. RLP isolated by immunoaffinity gel from plasma of a normolipidaemic and a hyperlipidaemic subject in four hours after an oral fat load was fractionated by high-performance liquid chromatography (HPLC) and monitored by total cholesterol (TC), triglycerides (TG), apoB-48 and apoB-100. TC, low-density lipoprotein (LDL)-C and apoB did not change after an oral fat load, while TG, RLP-C, RLP-TG and apoB-48 increased significantly in postprandial plasma. HPLC profiles monitored by TC and TG revealed that major lipoproteins increased in RLP after an oral fat load was VLDL size particles. The percentage of RLP-TG in total TG and the ratio of RLP-TG/RLP-C were significantly increased in four hours after an oral fat load compared with the fasting state (P < 0.01). RLP in four hours after an oral fat load fractionated by HPLC and monitored by TC, TG, apoB-48 and apoB-100 revealed that VLDL size or smaller particles were the major lipoproteins. ApoB-48 carrying lipoproteins in RLP isolated from a normolipidaemic and a hyperlipidaemic subject after an oral fat load showed a similar particle size with apoB-100 carrying VLDL remnants. Therefore, the most apoB-48 carrying particles found in postprandial RLP can be classified as CM remnants. The majority of remnants in the postprandial state were not CM remnants, but VLDL remnants.