Intermediate-density Lipoprotein Cholesterol Research Articles

Assessing the causal associations of different types of statins use and knee/hip osteoarthritis: A Mendelian randomization study.

This study comprehensively evaluated the causal relationship between different types of statins use and knee/hip osteoarthritis (OA) using a two-sample and multivariate Mendelian randomization (MR) method. MR analysis was conducted using publicly available summary statistics data from genome-wide association studies (GWAS) to assess the causal associations between total statins use (including specific types) and knee/hip OA. The primary analysis utilized the inverse variance-weighted (IVW) method, with sensitivity analysis conducted to assess robustness. Multivariable MR (MVMR) analysis adjusted for low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI). The MR analysis revealed a significant inverse association between genetically predicted total statins use and the risk of knee OA (OR = 0.950, 95%CI: 0.920-0.982, p = 0.002) as well as hip OA (OR = 0.932, 95%CI: 0.899-0.966, p <0.001). Furthermore, this study highlighted a reduced risk of knee/hip OA with the use of atorvastatin and simvastatin. Rosuvastatin use was associated with a decreased risk of hip OA but showed no association with knee OA. MVMR results indicated no correlation between exposure factors and outcomes after adjusting for LDL-C or IDL-C. HDL-C may not significantly contribute to statin-induced osteoarthritis, while BMI may play an important role. This study provides compelling evidence of the close relationship between statin use and a reduced risk of knee/hip OA, particularly with atorvastatin and simvastatin. LDL-C and IDL-C may mediate these effects. These findings have important implications for the clinical prevention and treatment of knee/hip OA.

Remnant cholesterol traits and risk of stroke: A multivariable Mendelian randomization study.

Observational epidemiological studies have reported a relationship between remnant cholesterol and stroke. However, the results are inconclusive, and causality remains unclear due to confounding or reverse causality. Our objective in this study was to investigate the causal relevance of remnant cholesterol and the risk of stroke and its subtypes using the Mendelian randomization (MR) approach. Genome-wide association studies (GWASs) including 115,082 European individuals (UK Biobank) were used to identify instruments for remnant cholesterol, including intermediate-density lipoprotein (IDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol. Summary-level data for total stroke, intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke (IS), and IS subtypes were obtained from GWAS meta-analyses conducted by the MEGASTROKE consortium. Univariable and multivariable MR analyses were performed. The GWAS identified multiple single-nucleotide polymorphisms after clumping for remnant cholesterol (n = 52), IDL cholesterol (n = 62), and VLDL cholesterol (n = 67). Assessed individually using MR, remnant cholesterol (weighted median: odds ratio [OR] 1.32 per 1-SD higher trait; 95% CI: 1.04-1.67; P = 0.024) had effect estimates consistent with a higher risk of LAS-IS, driven by IDL cholesterol (OR 1.32; 95% CI: 1.04-1.68; P = 0.022). In multivariable MR, IDL cholesterol (OR 1.46; 95% CI: 1.10-1.93; P = 0.009) retained a robust effect on LAS-IS after controlling for VLDL cholesterol and high-density lipoprotein cholesterol. The MR analysis did not indicate causal associations between remnant cholesterol and other stroke subtypes. This study suggests that remnant cholesterol is causally associated with the risk of LAS-IS driven by IDL cholesterol.

Triglyceride content increases while cholesterol content decreases in HDL and LDL+IDL fractions following normal meals: The Copenhagen General Population Study of 25,656 individuals

Background and aimsDuring fat tolerance tests, plasma triglycerides increase while high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein (IDL) cholesterol decrease. However, it is unknown whether triglyceride content increases and cholesterol content decreases in HDL and LDL + IDL fractions following normal meals in the general population. Therefore, we tested the hypothesis that triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions following normal meals. MethodsIn this cross-sectional study, we included 25,656 individuals aged 20–100 years, all without lipid-lowering therapy at examination and selected for metabolomic profiling from the Copenhagen General Population Study. Triglyceride and cholesterol content of 14 lipoprotein fractions weas measured using nuclear magnetic resonance (NMR) spectroscopy. Time since last meal was recorded by the examiner immediately before blood sampling. ResultsFollowing normal meals in age and sex-adjusted analyses and when compared with fasting levels, plasma triglycerides were higher for up to 5–6 h, and triglyceride content was higher for up to 6–7 h in HDL fractions, for up to 6–7 h in LDL + IDL fractions, and for up to 5–6 h in very-low-density lipoprotein (VLDL) fractions. Further, plasma cholesterol was lower for up to 2–3 h, and cholesterol content was lower for up to 0–1 h in HDL fractions and for up to 4–5 h in LDL + IDL fractions, while cholesterol content was higher for up to 4–5 h in VLDL fractions. ConclusionsFollowing normal meals, triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions.

Dislipidemik Hastalarda Az Yağlı ve Az Kolesterollü Diyet Müdahalesinin LDL Alt Grupları Üzerine Etkisi: Epidemiyolojik Gözlemsel Çalışma

Aim: According to studies, the individual cardiovascular disease (CVD) risk is predicted and low density lipoprotein cholesterol (LDL&#x0D; cholesterol) sub-group concentration better than LDL cholesterol. High fat and cholesterol intakes are generally considered to pose a risk&#x0D; on CVD. The purpose of this study is to analogize LDL sub-group concentration pre and post a diet with LowFat and LowCholesterol&#x0D; written a prescription to dyslipidemic sicks along 3 months.&#x0D; Material and Methods: Diagnosticated dyslipidemia sicks (n=47) on the part of the endocrinologist were pursued along 3 months&#x0D; via a LowFat, LowCholesterol diet upon a lasting a month basis, on condition that they were proper for each. Before and after dietary&#x0D; intervention periods, biochemical parameters and anthropometric measurements were compared.&#x0D; Results: A sum of 47 participants (15 men and 32 women) with an average age of 48.51±9.86 years were involved. 13 women were at&#x0D; premenopausal and 19 women were at postmenopausal stages of 32 women involved. Small dense LDL (Sd-LDL) decreased from 11.0&#x0D; (0.0-37.0) mg/dL at the beginning to 7.0 (0.0-68.1) mg/dL after the dietary intervention, but this decline was unimportant (p=0.686).&#x0D; Midbands (MiDC, MidB, MidA) subgroups of intermediate density lipoprotein cholesterol (IDL-cholesterol) declined considerably after&#x0D; dietary interference (p

Postprandial fatty acid metabolism with coconut oil in young females: a randomized, single-blind, crossover trial

BackgroundApproximately 84% of the fatty acids contained in coconut oil (CO) are saturated fatty acids (SFAs), and approximately 47% of the SFA are lauric acid with 12 carbon atoms. Lauric acid carbon chain length is intermediate between medium and long-chain fatty acids (LCFAs). We examined how CO acts on lipid-related substances in the blood to determine whether its properties were similar to medium-chain fatty acids (MCFAs) or LCFAs. MethodsThis is a randomized controlled, single-blind, crossover study. Fifteen females were enrolled, using 3 test meals containing 30 g each of 3 different oils: CO (CO-meal), medium-chain triacylglycerol oil (MCT-meal), and long-chain triacylglycerol oil (LCT-meal). Blood samples were collected at fasted baseline and every 2 h for 8 h after the intake of each test meal. ResultsRepeated measures ANOVA of the ketone bodies and triglyceride (TG) showed an interaction between time and the test meal (P < 0.01 and P < 0.001, respectively). In subsequent Tukey’s honestly significant difference (HSD) test of the ketone bodies, statistically significant differences were observed between the CO-meal and the LCT-meal (P < 0.05) 83.8 (95% CI, 14.7, 153.0) and between the MCT-meal and the LCT-meal (P < 0.05) 79.2 (95% CI, 10.0, 148.4). The incremental area under the curve (iAUC) and maximum increase in very low–density lipoprotein cholesterol (VLDL-C) and intermediate-density lipoprotein cholesterol (IDL-C) were the lowest for CO-meal intake. ConclusionsThe characteristics of lauric acid contained in CO, including the kinetics of β-oxidation and effects on blood TG, were very similar to those of MCFA. Moreover, regarding the iAUC and peak increment, VLDL-C and IDL-C were the lowest with the CO-meal. These results suggest that the intake of CO after fasting does not increase the TG, VLDL-C, and IDL-C, and may help prevent dyslipidemia.This trial was registered at UMIN (URL of registration: https://www.umin.ac.jp) as UMIN000019959.

First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency

BackgroundFamilial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a severe inherited disease without effective treatment. Patients with FLD develop severe low HDL, corneal opacity, hemolytic anemia, and renal injury. ObjectiveWe developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for ex vivo gene therapy. GMACs were prepared from the patient’s adipocytes to express LCAT by retroviral gene transduction to secrete functional enzymes. This study aimed to evaluate the safety and efficacy of LCAT-GMAC implantation in an FLD patient. MethodsProliferative preadipocytes were obtained from a patient using a ceiling culture and retrovirally transduced with LCAT. After obtaining enough cells by expansion culture of the transduced cells, the resulting LCAT-GMACs were implanted into a patient with FLD. To evaluate the safety and efficacy, we analyzed the outcome of the autologous implantation for 24 weeks of observation and subsequent 240 weeks of the follow-up periods. ResultsThis first-in-human autologous implantation of LCAT-GMACs was shown to be safe by evaluating adverse events. The LCAT-GMAC implantation increased serum LCAT activity by approximately 50% of the baseline and sustained over three years. Consistent with increased LCAT activity, intermediate-density lipoprotein (IDL) and free cholesterol levels of the small and very small HDL fractions decreased. We found the hemoglobin/haptoglobin complex in the hemolyzed pre-implantation sera of the patient. After one week of the implantation, the hemoglobin/haptoglobin complex almost disappeared. Immediately after the implantation, the patient's proteinuria decreased temporarily to mild levels and gradually increased to the baseline. At 48 weeks after implantation, the patient's proteinuria deteriorated with the development of mild hypertension. By the treatment with antihypertensives, the patient's blood pressure normalized. With the normalization of blood pressure, the proteinuria rapidly decreased to mild proteinuria levels. ConclusionsLCAT-GMAC implantation in a patient with FLD is shown to be safe and appears to be effective, in part, for treating anemia and proteinuria in FLD.

Association between remnant lipoprotein cholesterol, high-sensitivity C-reactive protein, and risk of atherosclerotic cardiovascular disease events in the Multi-Ethnic Study of Atherosclerosis (MESA)

Elevated remnant-lipoprotein (RLP)-cholesterol (RLP-C) and high-sensitivity C-reactive protein (hsCRP) are each individually associated with atherosclerotic cardiovascular disease (ASCVD). To evaluate the interplay of nuclear magnetic resonance (NMR)-derived RLP-C and hsCRP and their association with ASCVD in the Multi-Ethnic Study of Atherosclerosis (MESA). Lipoprotein particles were measured using NMR spectroscopic analysis at baseline. RLP-C includes very-low-density lipoprotein cholesterol and intermediate-density lipoprotein cholesterol. Four groups were created as follows: Group 1: RLP-C ≤ median (≤29.14 mg/dL) and hsCRP < 2 mg/L; Group 2: RLP-C ≤ median and hsCRP≥ 2 mg/L; Group 3: RLP-C > median and hsCRP level < 2 mg/L; and Group 4: RLP-C > median and hsCRP level ≥ 2 mg/L. Kaplan-Meier survival curves and multivariable-adjusted Cox proportional hazard models were used to examine the relationship between RLP-C and hsCRP with incident ASCVD. A total of 6,720 MESA participants (mean age 62.2 y, 53% female) with a median follow-up of 15.6 years were included. In the fully adjusted model, compared to those in the reference group (Group 1), participants in Group 2, Group 3, and Group 4 demonstrated a 20% (95% CI, -2%-48%), 18% (-4%-44%), and 43% (18%-76%) increased risk of incident ASCVD events, respectively (p<0.01). An additive and multiplicative interaction between RLP-C and hsCRP was not statistically significant. NMR-derived RLP-C and hsCRP showed a similar independent association with incident ASCVD. Notably, the combination of increased RLP-C and hsCRP was associated with an increased risk of future ASCVD events.

Lipoprotein subfractions in patients with sarcopenia and their relevance to skeletal muscle mass and function.

Loss of skeletal muscle mass is a characteristic of aging. Growing evidence suggests the role of fatty acids and their derived lipid intermediates in the regulation of skeletal muscle and function. However, the exact association between lipoprotein subfractions and sarcopenia in elderly individuals remains unclear. In this study, we aimed to investigate the levels of lipoprotein subfractions in sarcopenia patients and their relationship with skeletal muscle mass and function. A total of 84 elderly Chinese subjects aged ≥65years who did not have diseases that obviously affected lipid metabolism were included. Concentrations of lipoprotein subfractions, including total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), HDL2, HDL3, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), VLDL3, LDL-particle (LDL-P), lipoprotein(a) and remnant-like particle cholesterol (RLP-C), were determined by vertical auto profile. Triglyceride (TG) was measured by an enzymatic colorimetric assay. The skeletal muscle index (SMI) was assessed by bioelectrical impedance analysis. Handgrip strength was measured using a hand-held dynamometer. The levels of TC, TG, LDL-C, LDL-P, IDL, VLDL, VLDL3, RLP-C and C-reactive protein were significantly higher in sarcopenia patients than in controls (p<0.05). Pearson Product-Moment Correlation Coefficient analysis showed that the TC, TG, LDL-C, IDL, VLDL, VLDL3, and RLP-C levels were negatively associated with the SMI; The TG, IDL, VLDL, VLDL3, and RLP-C were negatively correlated with handgrip strength. In multivariate stepwise regression analysis, the VLDL and RLP-C levels were significantly correlated with the SMI. The sensitivity and specificity of the combined measurement of VLDL and RLP-C in predicting sarcopenia were 69.8% and 92.5% (AUC: 0.831; 95% CI:(0.739, 0.924); p<0.05). The occurrence of sarcopenia is associated with disorders of lipid metabolism, particularly VLDL and RLP-C.

Metabolic and Lipidomic Markers Differentiate COVID-19 From Non-Hospitalized and Other Intensive Care Patients.

Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus, there is increasing interest in metabolic and lipoprotein signatures of the disease, and early analyses have demonstrated a metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether this is specific for COVID-19 and whether the observed signature is caused by the disease or rather represents an underlying risk factor. To answer this question, we have analyzed 482 serum samples using nuclear magnetic resonance metabolomics, including longitudinally collected samples from 12 COVID-19 and 20 cardiogenic shock intensive care patients, samples from 18 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody-positive individuals, and single time point samples from 58 healthy controls. COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared with healthy controls. Specifically, very-low-density lipoprotein and intermediate-density lipoprotein particles and associated apolipoprotein B and intermediate-density lipoprotein cholesterol were significantly increased, whereas cholesterol and apolipoprotein A2 were decreased. Moreover, a similarly perturbed profile was apparent when compared with other patients with cardiogenic shock who are in the intensive care unit when looking at a 1-week time course, highlighting close links between COVID-19 and lipid metabolism. The metabolic profile of COVID-19 patients distinguishes those from healthy controls and also from patients with cardiogenic shock. In contrast, anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared with age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized low- and high-density lipoprotein subfractions. Our data suggest that COVID-19 is associated with dyslipidemia, which is not observed in anti-SARS-CoV-2 antibody-positive individuals who have not developed severe courses of the disease. This suggests that lipoprotein profiles may represent a confounding risk factor for COVID-19 with potential for patient stratification.

Clinical Significance of Intermediate-Density Lipoprotein Cholesterol Determination as a Predictor for Coronary Heart Disease Risk in Middle-Aged Men.

Background: Not only low-density lipoprotein (LDL) cholesterol but also non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein (VLDL) cholesterol (VLDL-C), and intermediate-density lipoprotein (IDL) cholesterol (IDL-C) are reported to be significant risk markers for coronary heart disease (CHD). We reported the relevance of IDL-C to Framingham risk score (F-score), but the present study addressed the relevance of IDL-C to Suita score (S-score), a risk score for coronary heart disease (CHD) developed for the Japanese individuals in addition to F-score.Methods: The cholesterol levels of lipoproteins, including triglyceride (TG)-rich lipoproteins (IDL and VLDL), were measured by an anion exchange high-performance liquid chromatography (AEX-HPLC). This study enrolled 476 men, aged mean 51 years and free of CHD and stroke.Results: Non-HDL-C, IDL-C, and VLDL-C significantly correlated with F-score and S-score. In the multiple stepwise regression analysis, IDL-C as well as body mass index (BMI) significantly correlated with both F-score and S-score in both the total subjects and the subjects without drug therapy. The multivariate logistic analysis with the model composed of BMI and IDL-C as the predictor variables demonstrated that 1 SD increase in IDL-C was an independent predictor for 10-year CHD risk >10% of F-score (OR 1.534, 95% CI 1.266–1.859, p < 0001) and that of S-score (OR 1.372, 95% CI 1.130–1.667, p = 0.0014) in the total subjects. Even in the subjects without the drug therapy, the increased IDL-C, as well as BMI, were significant predictors for 10-year CHD risk >10% of S-score as well as F-score.Conclusion: These results suggest the significant relevance of the increased IDL-C for CHD risk scores in middle-aged men free of CHD and stroke. Further investigations are needed in women and elderly subjects.

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.

Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.

PCSK9 Levels and Metabolic Profiles in Elderly Subjects with Different Glucose Tolerance under Statin Therapy.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of glu-cose metabolism and statin therapy are still unclear. Method: we investigated a large cohort of 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR metabolomics and PCSK9 plasma levels. Results: PCSK9 plasma levels did not significantly differ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost. Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, but statins reduced the LDL-C and VLDL-C levels.

VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial Infarction Associated With apoB-Containing Lipoproteins

BackgroundPlasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs). ObjectivesThe authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins. MethodsNested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs). ResultsDuring a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk. ConclusionsVLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.

Very Low-Density Lipoprotein Cholesterol May Mediate a Substantial Component of the Effect of Obesity on Myocardial Infarction Risk: The Copenhagen General Population Study.

Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL)cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity. We included 29010 individuals free of myocardial infarction at baseline, nested within 109751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy. Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%). VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity.

Comparison of calculated remnant lipoprotein cholesterol levels with levels directly measured by nuclear magnetic resonance

BackgroundRemnant cholesterol (RC) can partly explain the residual risk in atherosclerotic cardiovascular disease (ASCVD). A consensus method of measuring RC levels has not been established yet. In clinical practice, RC levels are usually calculated from the standard lipid profile, which are not true RC. Nuclear magnetic resonance (NMR) can measure RC levels directly. This study aimed to characterize RC at fasting and non-fasting states in more details and establish the performance of calculated RC and NMR-measured RC.MethodsBlood samples at fasting state and at 2 h and 4 h postprandial states were collected in 98 subjects. Lipid parameters including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), subfractions 3, 4, and 5 of very low-density lipoprotein cholesterol (VLDL3-C, VLDL4-C, and VLDL5-C, respectively), and intermediate-density lipoprotein cholesterol (IDL-C) were measured by enzymatic method and NMR. RC levels calculated from the standard lipid profile or measured by NMR were referred here as RCe or RCn.ResultsThe RCe and RCn levels were different, but both of them increased after a meal (P < 0.05), especially at 4 h postprandial state. Low correlations were found between RCe and RCn in the 1st, 2nd, and 3rd quartiles of TG, but RCn showed great correlation with RCe in the highest quartile regardless of the fasting or non-fasting state (R = 0.611, 0.536, and 0.535 for 0 h, 2 h, and 4 h, respectively). However, across the 2nd and 3rd quartiles, RCe levels were nearly close to RCn levels. RCe levels tended to overestimate RCn levels in the 1st quartile of TGe levels with median differences of 0.23(− 0.13, 0.63) and underestimate RCn levels with median differences of − 0.23(− 0.33, 0.07) in the highest quartile of TGe levels.ConclusionsRC calculated from the standard lipid profile as TC minus LDL-C minus HDL-C is different from the NMR-measured RC. According to different TG levels, RC could overestimate or underestimate the actual RC level. Developing a consensus clinical method to measure RC levels is necessary, so that results from different studies and platforms can be more directly compared.Trial registrationChinese Clinical Trial Registry, ChiCTR1900020873. Registered in 21 January 2019 - Retrospectively registered.

Comparison of nonfasting and fasting lipoprotein subfractions and size in 15,397 apparently healthy individuals: An analysis from the VITamin D and OmegA-3 TriaL

Elevated postprandial triglycerides reflect a proatherogenic milieu, but underlying mechanisms are unclear. We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and remnants, or small dense lipid depleted LDL (sdLDL) particles. We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [<8hours since last meal]) from the VITamin D and OmegA-3 TriaL. Baseline cholesterol subfractions were measured by the vertical auto profile method and particle subfractions by ion mobility. We performed multivariable linear regression adjusting for cardiovascular and lipoprotein-modifying risk factors. Mean age (SD) was 68.0years (±7.0), with 50.9% women. Adjusted mean triglyceride concentrations were higher nonfasting by 17.8±1.3%, with higher nonfasting levels of directly measured VLDL cholesterol (by 3.5±0.6%) and total VLDL particles (by 2.0±0.7%), specifically large VLDL (by 12.3±1.3%) and medium VLDL particles (by 5.3±0.8%), all P<.001. By contrast, lower concentrations of low density lipoprotein (LDL) and IDL cholesterol and particles were noted for nonfasting participants. sdLDL cholesterol levels and particle concentrations showed no statistically significant difference by fasting status (-1.3±2.1% and 0.07±0.6%, respectively, P>.05). Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the proatherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia.

Comparing different assessments of remnant lipoprotein cholesterol: The very large database of lipids

Remnant lipoprotein cholesterol (RLP-C) is a risk factor for atherosclerotic cardiovascular disease, but there is no standard method for measurement. Some studies have used very low-density lipoprotein cholesterol estimated by the Friedewald equation to approximate RLP-C using a basic lipid panel, whereas others have attempted to measure RLP-C with ultracentrifugation. The aim of the study was to compare RLP-C levels estimated from basic lipid parameters to those measured by ultracentrifugation. We analyzed 1,350,908 individuals from the Very Large Database of Lipids, comparing one estimate of RLP-C using basic lipid parameters (RLP-Cestimated=non-high-density lipoprotein cholesterol - Friedewald-estimated low-density lipoprotein cholesterol for triglycerides <355mg/dL [4mmol/L], or non-high-density lipoprotein - directly measured low-density lipoprotein for triglycerides ≥355mg/dL) to levels measured by vertical auto profile ultracentrifugation (RLP-Cmeasured=dense subfraction of very low-density lipoprotein cholesterol+intermediate-density lipoprotein cholesterol). We calculated correlations between RLP-Cestimated and RLP-Cmeasured along with median within-subject differences between RLP-Cestimated and RLP-Cmeasured across quintiles of RLP-Cestimated. We also assessed correlations with RLP-C estimated from basic lipid parameters using a novel method of calculating low-density lipoprotein cholesterol with a patient-specific conversion factor (RLP-Cestimated-N). Our cohort was 48% male, and median (interquartile range) age was 59 (49-69) years. Median (interquartile range) RLP-Cestimated and RLP-Cmeasured were 23 (16.4-33.2) and 24 (19-32) mg/dL, respectively. The correlation between RLP-Cestimated and RLP-Cmeasured was 0.76. Based on the specified definition of RLP-Cestimated, the correlation between RLP-Cestimated and triglyceride/5 for triglyceride<355mg/dL was exactly 1.0. RLP-Cestimated was lower than RLP-Cmeasured in the firstandsecond quintiles of RLP-Cestimated but greater in the highest quintile. The correlations with RLP-Cestimated-N were 0.98 and 0.81 for RLP-Cestimated and RLP-Cmeasured, respectively. A previously used estimate of RLP-C using basic lipid parameters correlates weakly with remnants measured by ultracentrifugation. Our findings emphasize the need to standardize definitions and measurements of RLP-C.

Distribution of Paraoxonase-1 (PON-1) and Lipoprotein Phospholipase A2 (Lp-PLA2) across Lipoprotein Subclasses in Subjects with Type 2 Diabetes.

Paraoxonase-1 (PON1) and lipoprotein phospholipase A2 (Lp-PLA2) may exert an important protective role by preventing the oxidative transformation of high- and low-density lipoproteins (HDL and LDL, respectively). The activity of both enzymes is influenced by lipidome and proteome of the lipoprotein carriers. T2DM typically presents significant changes in the molecular composition of the lipoprotein subclasses. Thus, it becomes relevant to understand the interaction of PON1 and Lp-PLA2 with the subspecies of HDL, LDL, and other lipoproteins in T2DM. Serum levels of PON1-arylesterase and PON1-lactonase and Lp-PLA2 activities and lipoprotein subclasses were measured in 202 nondiabetic subjects (controls) and 92 T2DM outpatients. Arylesterase, but not lactonase or Lp-PLA2 activities, was inversely associated with TD2M after adjusting for potential confounding factors such as age, sex, smoking, body mass index, hypertension, and lipoprotein subclasses (odds ratio = 3.389, 95% confidence interval 1.069–14.756). Marked difference between controls and T2DM subjects emerged from the analyses of the associations of the three enzyme activities and lipoprotein subclasses. Arylesterase was independently related with large HDL-C and small intermediate-density lipoprotein cholesterol (IDL-C) in controls while, along with lactonase, it was related with small low-density lipoprotein cholesterol LDL-C, all IDL-C subspecies, and very low-density lipoprotein cholesterol (VLDL-C) in T2DM (p < 0.05 for all). Concerning Lp-PLA2, there were significant relationships with small LDL-C, large IDL-C, and VLDL-C only among T2DM subjects. Our study showed that T2DM subjects have lower levels of PON1-arylesterase compared to controls and that T2DM occurrence may coincide with a shift of PON1 and Lp-PLA2 towards the more proatherogenic lipoprotein subclasses. The possibility of a link between the two observed phenomena requires further investigations.

Cholesterol concentrations in lipoprotein fractions separated by anion-exchange–high-performance liquid chromatography in healthy dogs and dogs with hypercholesterolemia

Anion-exchange (AEX)–high-performance liquid chromatography (HPLC) for measurement of cholesterol can be used to separate serum lipoproteins (high-density lipoprotein (HDL); low-density lipoprotein (LDL); intermediate-density lipoprotein (IDL); very-low-density lipoprotein (VLDL)) in humans. However, AEX–HPLC has not been applied in veterinary practice. We had three objectives: (i) the validation of AEX-HPLC methods including the correlation of serum cholesterol concentration in lipoprotein fraction measured by AEX–HPLC and gel permeation–HPLC (GP–HPLC) in healthy dogs and those with hypercholesterolemia was investigated; (ii) the reference intervals of lipoprotein fractions measured by AEX–HPLC from healthy dogs (n=40) was established; (iii) lipoprotein fractions from the serum of healthy dogs (n=12) and dogs with hypercholesterolemia (n=23) were compared. Analytic reproducibility and precision of AEX–HPLC were acceptable. Positive correlation between serum concentrations of total cholesterol (Total-Chol), HDL cholesterol (HDL-Chol), LDL cholesterol (LDL-Chol)+IDL cholesterol (IDL-Chol), and VLDL cholesterol (VLDL-Chol) was noted for AEX–HPLC and GP–HPLC in healthy dogs and dogs with hypercholesterolemia. Reference intervals measured by AEX–HPLC for serum concentrations of Total-Chol, HDL-Chol, and LDL-Chol were determined to be 2.97–9.32, 2.79–6.57, 0.16–3.28mmol/L (2.5–97.5% interval), respectively. Furthermore, there was significant difference in lipoprotein profiles between healthy and dogs with hypercholesterolemia. These results suggest that AEX–HPLC can be used to evaluate lipoprotein profiles in dogs and could be a new useful indicator of hyperlipidemia in dogs.

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

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