Low-density Lipoprotein Apolipoprotein Research Articles

Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases low-density lipoprotein apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial

BackgroundThe substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown. ObjectivesThis study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia. MethodsMales and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins. ResultsSubstituting MUFAs for SFAs had no impact on triglyceride-rich lipoprotein apoB-48 fractional catabolic rate (FCR) (Δ = –8.9%, P = 0.4) and production rate (Δ = 0.0%, P = 0.9), although it decreased very low-density lipoprotein apoB-100 pool size (PS) (Δ = −22.5%; P = 0.01). This substitution also reduced low-density lipoprotein cholesterol (LDL-C) (Δ = −7.0%; P = 0.01), non–high-density lipoprotein cholesterol (Δ = −2.5%; P = 0.04), and LDL apoB-100 PS (Δ = −6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet. ConclusionsThis study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia. Trial registrationThis trial was registered as clinicaltrials.gov as NCT03872349.

Lipids, lipoproteins, and apolipoproteins during the first year of life: a prospective cohort study

Abstract Background/Introduction Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally, and treatment of well-established lifestyle risk factors are cornerstones in CVD prevention. An atherogenic lipid profile with high concentrations of low-density lipoprotein (LDL) cholesterol and other apolipoprotein B containing lipoproteins is a driving force in the pathogenesis of atherosclerotic CVD (ASCVD). The lifelong atherosclerotic process is proportional to concentrations of apolipoprotein B-containing lipoproteins, hence risk of developing ASCVD is cumulative over time. The higher the baseline concentrations, the sooner the threshold for increased risk of ASCVD will be reached. It is therefore crucial to implement changes as early as possible and prevent risk factors in occurring – so-called primordial prevention. Childhood has been described as a "window of opportunity" for preventing risk factors in occurring and thus avoiding ASCVD. Whether concentrations of atherogenic lipoproteins at birth can predict future concentrations in early childhood and thus may indicate increased risk of dyslipidemia later in life remains unknown. Purpose The aim of the present study was to investigate atherogenic lipid traits during the first year of life, to identify influential factors for lipid concentrations, and to determine whether concentrations at birth can predict future lipid concentrations in early childhood. Methods For this purpose, we used the Copenhagen Baby Heart Study comprising more than 13,000 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n=444), at two months (n=363), and at 14-16 months (n=158). Lipid traits were determined in all samples. Results Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B increased during the first year of life. Girls had higher concentrations at birth and at two months compared with boys. Children born preterm had higher cord blood concentrations than children born at term. A linear mixed model showed that high concentrations of LDL cholesterol, non-HDL cholesterol and apolipoprotein B at birth predicted high concentrations at two months and at 14-16 months. Multivariable adjusted odds ratios (95% CI) for having high concentrations at two months when children had high concentrations at birth were 1.95 (1.01-3.79) for LDL cholesterol, 1.36 (0.69-2.67) for non-HDL cholesterol and 1.90 (1.02-3.53) for apolipoprotein B. Conclusion The lipid profile change during the first year of life and sex and gestational age influence concentrations. Children with high concentrations of LDL cholesterol, non-HDL cholesterol and apolipoprotein B at birth had higher levels at two and at 14-16 months. Concentrations at birth may thus be used to identify children at risk of dyslipidemia in later life.

Lipid Metabolism Traits Mediate the Effect of Psoriasis on Myocardial Infarction Risk: A Two-Step Mendelian Randomization Study.

Mendelian randomization (MR) analysis was performed to explore the effect of psoriasis on lipid metabolism traits and myocardial infarction (MI) risk and to analyze the proportion of the mediatory effect of lipid metabolism traits. Publicly accessible summary-level data for psoriasis, lipid metabolism traits, and MI were provided by the genome-wide association studies (GWASs) of the FinnGen Biobank, UK Biobank, and CARDIoGRAMplusC4D, respectively. A two-sample MR was carried out to evaluate the association of psoriasis with lipid metabolism traits and MI. Furthermore, the current research focused on determining if the impact of psoriasis on MI is mediated by lipid metabolism traits. The outcomes of the random effect inverse-variance-weighted (IVW) technique indicated a substantial link between genetically predicted psoriasis and a higher risk of low-density lipoprotein (LDL) cholesterol (OR: 1.006, 95% CI: 1.005-1.007, p = 0.024), apolipoprotein B (OR: 1.018, 95% CI: 1.010-1.026, p = 0.015), lipoprotein A (OR: 1.006, 95% CI: 1.002-1.010, p = 0.039), and MI (OR: 1.066, 95% CI: 1.014-1.121, p = 0.012). The percentages of the mediatory effect of LDL cholesterol, apolipoprotein B, and lipoprotein A under psoriasis conditions on MI risk was 7.4%, 10.2%, and 4.1%, respectively. Psoriasis was causally linked to an elevated risk of lipid metabolism levels and MI. This study further demonstrated that LDL cholesterol, apolipoprotein B, and lipoprotein A mediated the effect of psoriasis on MI risk. And timely lipid-lowering treatment should be given to MI patients.

Effects of CaCl2 on the structure of high-density lipoprotein and low-density lipoprotein isolated from rapidly salted separated egg yolk

According to previous research, adding CaCl2 to the salting solution improves the quality of salted separated egg yolk. To further understand the improvement mechanism of CaCl2, this paper investigated the effect of CaCl2 on the structure of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) during the salting process. The results indicated that the addition of CaCl2 can affect the composition of HDL and LDL apolipoproteins, improving the orderliness of the HDL structure and the looseness of the LDL structure. It was discovered by atomic force microscopy (AFM) that adding CaCl2 to the salting solution can weaken the aggregation behavior of HDL. Simultaneously, the addition of CaCl2 decreased the relative content of intermolecular β-sheets in the secondary structure of HDL and LDL, influenced their tertiary conformation, and prevented HDL and LDL from participating in the formation of a three-dimensional gel structure by influencing their hydrogen bonds and hydrophobic interactions.

Overall and Sex-Specific Effect of Berberine for the Treatment of Dyslipidemia in Adults: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

Berberine is a nutraceutical that can improve lipid metabolism. Berberine may also affect sex hormones and exert sex-specific lipid-modifying effects, which have been overlooked. This study aimed to comprehensively review the efficacy and safety of berberine in adults for the treatment of dyslipidemia with consideration of potential sex disparity. Data Sources We searched Medline, Embase, Wanfang, CNKI, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception to 13 December 2022. No language restrictions were applied. This study was registered in PROSPERO (CRD42021293218) prior to completing the literature search. Study Selection Two blinded reviewers assessed studies for inclusion. Eligible studies were randomized controlled trials in adults that compared berberine versus placebo, and measured blood lipids or lipoproteins. Data Extraction and Synthesis Data extraction was performed by two blinded reviewers using a structured form in Covidence. Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials. Mean differences (MD) were estimated using inverse variance weighting with random effects models for lipid outcomes using R. Adverse events (AEs) were described narratively. Main Outcomes Primary outcomes were low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B. Secondary outcomes were gastrointestinal and muscle-related AEs. Eighteen studies (n = 1788 participants), conducted mainly in mainland China and Hong Kong (15 studies [83%]), were included with treatment durations ranging from 4 to 24 weeks. Berberine reduced LDL cholesterol (-0.46 mmol/L, 95% CI -0.62 to -0.30, 14 studies, n = 1447), total cholesterol (-0.48 mmol/L, 95% CI -0.63 to -0.33, 17 studies, n = 1637), triglycerides (-0.34 mmol/L, 95% CI -0.46 to -0.23, 18 studies, n = 1661) and apolipoprotein B (-0.25 g/L, 95% CI -0.40 to -0.11, 2 studies, n = 127). Berberine increased HDL cholesterol by 0.06 mmol/L (95% CI 0.00to 0.11, 15 studies, n = 1471). Notably, the effect on HDL cholesterol was different in women (0.11 mmol/L, 95% CI 0.09 to 0.13) from that in men (-0.07 mmol/L, 95% CI -0.16 to 0.02). Among 16 studies that reported AEs, no serious AEs were reported for berberine. Gastrointestinal AEs were reported in 12 studies and tended to be more frequent in participants allocated to berberine versus placebo (2-23% vs 2-15%). Berberine produces small reductions in LDL cholesterol, triglycerides, and apolipoprotein B, with potential sex-specific effects on HDL cholesterol. Large-scale trials that consider sex disparity and assess clinical outcomes are required.

Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium.

High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.

The LDL Apolipoprotein B-to-LDL Cholesterol Ratio: Association with Cardiovascular Mortality and a Biomarker of Small, Dense LDLs.

Background and Objective: Small, dense low-density lipoproteins (LDLs) are considered more atherogenic than normal size LDLs. However, the measurement of small, dense LDLs requires sophisticated laboratory methods, such as ultracentrifugation, gradient gel electrophoresis, or nuclear magnetic resonance. We aimed to analyze whether the LDL apolipoprotein B (LDLapoB)-to-LDL cholesterol (LDLC) ratio is associated with cardiovascular mortality and whether this ratio represents a biomarker for small, dense LDLs. Methods: LDLC and LDLapoB were measured (beta-quantification) and calculated (according to Friedewald and Baca, respectively) for 3291 participants of the LURIC Study, with a median (inter-quartile range) follow-up for cardiovascular mortality of 9.9 (8.7–10.7) years. An independent replication cohort included 1660 participants. Associations of the LDLapoB/LDLC ratio with LDL subclass particle concentrations (ultracentrifugation) were tested for 282 participants. Results: In the LURIC Study, the mean (standard deviation) LDLC and LDLapoB concentrations were 117 (34) and 85 (22) mg/dL, respectively; 621 cardiovascular deaths occurred. Elevated LDLapoB/LDLC (calculated and measured) ratios were significantly and independently associated with increased cardiovascular mortality in the entire cohort (fourth vs. first quartile: hazard ratio (95% confidence interval) = 2.07 (1.53–2.79)) and in statin-naïve patients. The association between calculated LDLapoB/LDLC ratio and cardiovascular mortality was replicated in an independent cohort. High LDLapoB/LDLC ratios were associated with higher LDL5 and LDL6 concentrations (both p < 0.001), but not with concentrations of larger LDLs. Conclusions: Elevated measured and calculated LDLapoB/LDLC ratios are associated with increased cardiovascular mortality. Use of LDLapoB/LDLC ratios allows estimation of the atherogenic risk conferred by small, dense LDLs.

Discordantly Elevated Apolipoprotein B versus Low-Density Lipoprotein Cholesterol is Associated with Remnant Lipoproteins and Increased Cardiovascular Events

Abstract Atherosclerotic cardiovascular disease is a result of low-density lipoprotein (LDL) particles becoming trapped in arterial walls and forming plaques which ultimately restrict blood-flow. LDL cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of plaque-causing LDL particles. Both have been shown to predict major adverse cardiac events (MACE). ApoB is also carried on remnant lipoproteins (RLP). RLP-cholesterol (RLP-C) is increasingly appreciated as a MACE risk-factor. This study aimed to define discordances between apoB and LDL-C in a large data set from a clinical reference laboratory. We then applied this definition to evaluate which measure predicted the risk of MACE in a patient cohort referred for coronary angiography with &amp;gt;10 years follow-up. LDL-C was measured by beta-quantification and RLP-C was defined as total cholesterol – LDL-C – HDL-C. Apo B discordance relative to LDL-C was determined by linear regression in a discovery cohort (n=17,203) using beta quantification. Discordance was defined by quartiles of the residual-apoB (expected–actual); discordant-low (&amp;lt;25th percentile), concordant (25th to 75th percentile) and discordant-high (&amp;gt;75th percentile). Associations with prevalence and incident of MACE were evaluated by odds-ratio and logistic regression. Risk of MACE was calculated based on the apoB-discordance and reported MACE events by several years follow up in a separate cohort (n=501). In the discovery cohort, age ranged from 18-95 years, 51% were female and mean (±SD) lipid values were: ApoB: 100.4 ± 30.0mg/dl, LDL-C: 121.7 ± 47.9mg/dl, and RLP-C: 17.2 ± 26.9mg/dl. Expected-apoB was described by the formula: (LDL-c X 0.6278 + 24.07, R=0.88). Residual-apoB (discordance) ranged from -1037 to 581.2 with a mean 0.01±18.6, and notably increased with triglyceride concentration (rho=0.65) and with RLP-C (rho=0.64), but was minimally influenced by apoB (rho=0.35) and LDL-C (rho=0.009) (p&amp;lt;0.001 all cases). In the clinical follow-up cohort, age ranged from 26-77 years, 42% were female, 64% were current/former smokers, and 28% were on lipid-lowering therapy. Mean (±SD) lipids were: apoB: 97.8 ± 20.9mg/dl, LDL-C: 124.6 ± 36.6mg/dl, and RLP-C: 34.9 ± 25.6mg/dl. Serum triglycerides among subjects discordant-low apoB, concordant and discordant-high apoB were 148mg/dL, 157mg/dL and 238mg/dL, respectively; similarly for RLP-C. A total of 192 events occurred during a mean of 9 years follow-up. Subjects with discordantly elevated apoB had a significantly higher incidence of MACE compared to those with concordant values (47% vs. 36%, p=0.03). There was no difference in MACE for subjects with discordantly low apoB (35% vs. 36%). These data support previous reports of an association between apoB and LDL-C and the superior performance of apoB when discordantly elevated. Our data expand on previous studies by applying an externally defined threshold for discordant-apoB. Our data indicate that triglycerides, RLP-C are associated with discordances and MACE.

The ratio of HDL-C to apoA-I interacts with free triiodothyronine to modulate coronary artery disease risk

ObjectiveIn the present work, research was carried out to explore the correlation between the high-density lipoprotein cholesterol (HDL-C)/apolipoprotein A-I (apoA-I) ratio and serum free triiodothyronine (FT3) and their interaction on the risk of coronary artery disease (CAD).MethodsA total of 1686 patients who underwent selective coronary angiography were enrolled in the present study, including 1279 patients with CAD and 407 controls. The subjects were divided into three groups according to tertiles of the HDL-C/apoA-I ratio. Binary logistic regression analysis was used to evaluate the interaction of the HDL-C/apoA-I ratio and FT3 level with the risk of CAD.ResultsThe group with the highest HDL-C/apoA-I ratio had the lowest levels of FT3. Multiple linear regression analysis showed that the HDL-C/apoA-I ratio was negatively associated with FT3 after adjusting for age, sex, body mass index (BMI), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), FT4 and TSH. A logistic regression model showed that a high HDL-C/apoA-I ratio (> 0.89 mmol/g) and high FT3 levels (> 4.5 pmol/l) were protective factors for CAD. Patients with a lower HDL-C/apoA-I ratio (≤ 0.89 mmol/g) and lower FT3 level (≤ 4.5 pmol/l) had an increased risk of CAD (OR = 2.441, P = 0.000, S = 1.13, AP = 0.068, AP* = 0.116, RERI = 0.168).ConclusionsThe HDL-C/apoA-I ratio was negatively associated with FT3, and there was a significant interaction between the HDL-C/apoA-I ratio and FT3 with the risk of CAD.

Kaempferol ameliorates symptoms of metabolic syndrome by improving blood lipid profile and glucose tolerance.

Kaempferol (KPF) is a dietary polyphenol reported to have various beneficial effects on human health. However, its molecular mechanisms in regulating lipid and glucose metabolism are not fully understood. This study examined the effects of KPF on obesity, dyslipidemia, and diabetes in Tsumura, Suzuki, Obese Diabetes mice. The 6-week administration of KPF decreased fat weight, serum total cholesterol, and low-density lipoproteins (LDLs); increased high-density lipoproteins (HDLs); and improved glucose tolerance. Additionally, KPF increased LDL receptor (LDLR) and apolipoprotein A1 (ApoA1) gene expression and decreased serum resistin levels. These findings suggest that the decrease in LDL and the increase in HDL caused by KPF may be due to increases in hepatic LDLR and ApoA1 expression, respectively. Furthermore, it is possible that the improvement in glucose tolerance by KPF may occur via resistin reduction. These mechanisms may be parts of complex mechanism by which KPF improves metabolic syndrome.

Divergence of Cardiovascular Biomarkers of Lipids and Subclinical Myocardial Injury Among Rheumatoid Arthritis Patients With Increased Inflammation.

Patients with rheumatoid arthritis (RA) are 1.5 times more likely to develop cardiovascular disease (CVD) attributed to chronic inflammation. A decrease in inflammation in patients with RA is associated with increased low-density lipoprotein (LDL) cholesterol. This study was undertaken to prospectively evaluate the changes in lipid levels among RA patients experiencing changes in inflammation and determine the association with concomitant temporal patterns in markers of myocardial injury. A total of 196 patients were evaluated in a longitudinal RA cohort, with blood samples and high-sensitivity C-reactive protein (hsCRP) levels measured annually. Patients were stratified based on whether they experienced either a significant increase in inflammation (an increase in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the increased inflammation cohort [n = 103]) or decrease in inflammation (a decrease in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the decreased inflammation cohort [n = 93]). Routine and advanced lipids, markers of inflammation (interleukin-6, hsCRP, soluble tumor necrosis factor receptor II), and markers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro-brain natriuretic peptide) were measured. Among the patients in the increased inflammation cohort, the mean age was 59 years, 81% were women, and the mean RA disease duration was 17.9 years. The average increase in hsCRP levels was 36 mg/liter, and this increase was associated with significant reductions in LDL cholesterol, triglycerides, total cholesterol, apolipoprotein (Apo B), and Apo A-I levels. In the increased inflammation cohort at baseline, 45.6% of patients (47 of 103) had detectable circulating hs-cTnT, which further increased during inflammation (P = 0.02). In the decreased inflammation cohort, hs-cTnT levels remained stable despite a reduction in inflammation over follow-up. In both cohorts, hs-cTnT levels were associated with the overall estimated risk of CVD. Among RA patients who experienced an increase in inflammation, a significant decrease in routinely measured lipids, including LDL cholesterol, and an increase in markers of subclinical myocardial injury were observed. These findings highlight the divergence in biomarkers of CVD risk and suggest a role in future studies examining the benefit of including hs-cTnT for CVD risk stratification in RA.

Reconstruction and analysis of correlation networks based on GC–MS metabolomics data for hypercholesterolemia

Background and aimsHypercholesterolemia is characterized by the elevation of plasma total cholesterol level, especially low-density lipoprotein (LDL) cholesterol. This disease is usually caused by a mutation in genes such as LDL receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9. However, a considerable number of patients with hypercholesterolemia do not have any mutation in these candidate genes. In this study, we examined the difference in the metabolic level between patients with hypercholesterolemia and healthy subjects, and screened the potential biomarkers for this disease. MethodsAnalysis of plasma metabolomics in hypercholesterolemia patients and healthy controls was performed by gas chromatography-mass spectrometry and metabolic correlation networks were constructed using Gephi-0.9.2. ResultsFirst, metabolic profile analysis confirmed the distinct metabolic footprints between the patients and the healthy ones. The potential biomarkers screened by orthogonal partial least-squares discrimination analysis included l-lactic acid, cholesterol, phosphoric acid, d-glucose, urea, and d-allose (Variable importance in the projection > 1). Second, arginine and methionine metabolism were significantly perturbed in hypercholesterolemia patients. Finally, we identified that l-lactic acid, l-lysine, l-glutamine, and l-cysteine had high scores of centrality parameters in the metabolic correlation network. ConclusionPlasma l-lactic acid could be used as a sensitive biomarker for hypercholesterolemia. In addition, arginine biosynthesis and cysteine and methionine metabolism were profoundly altered in patients with hypercholesterolemia.

Abstract 14845: Remnant Cholesterol and Incident Atherosclerotic Cardiovascular Disease: A Pooled Cohort Primary Prevention Study

Introduction: Emerging evidence suggests that remnant cholesterol (RC) promotes future atherosclerotic cardiovascular disease (ASCVD) events. Our aim was to estimate the risk associated with RC beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Hypothesis: RC provides incremental prognostic information regarding incident ASCVD, independent of LDL-C and apoB. Methods: We pooled data from 17,532 individuals from Atherosclerosis Risk in Communities study (n=9,748), Multi-Ethnic Study of Atherosclerosis (n=3,049) and Coronary Artery Risk Development in Young Adults (n=4,735), who were ASCVD-free at baseline and had measurements of lipids, apoB and apolipoprotein A1. RC was calculated as non-high-density cholesterol (non-HDL-C) minus LDL-C estimated by the Martin/Hopkins equation. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in discordant/concordant groups of RC and LDL-C across median cutpoints and cutpoints of percentile equivalence to LDL-C targets (70 and 100 mg/dL). Results: Mean age of participants was 52.3±17.9 years, 56.7% women and 34% black. There were 2,143 ASCVD events over median follow-up of 18.7 years. After multivariable adjustment including apoB and HDL-C, logRC was associated with higher ASCVD risk [HR 1.42, 95% CI (1.23-1.63)]. In discordance analyses, the high RC and low LDL-C group (≥/&lt;median) was associated with increased ASCVD risk compared to the low/low concordant group [1.17, (1.01-1.35)] but the low RC and high LDL-C group was not. Similar results were shown when examining discordance across lower cutpoints. Conclusion: In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors and LDL-C and apoB levels. RC assessment and management in primary prevention, beyond LDL-C and apoB, is useful and requires further scrutiny.

Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.

BackgroundCirculating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD.Methods and findingsWe conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39–73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10−8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%–93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10−8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation–higher trait; 95% CI: 1.49–1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25–1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56–1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31–2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57–1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02–1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation–higher HDL cholesterol (OR 0.80; 95% CI: 0.75–0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77–0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components.ConclusionsThese findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.

Abstract WP212: Arterial Stiffness is Associated With Apolipoprotein B 100, Not LDL-Cholesterol in Patients With Acute Ischemic Stroke

Background: Arterial stiffness has been reported to be associated with hypertension, vascular disease including cerebral small vessel disease and increased mortality. Also, dyslipidemia is one of the potent risk factors for atherosclerosis. We aim to investigate the association of arterial stiffness and various lipid fractions including low density lipoprotein cholesterol (LDL-cholesterol), lipoprotein(a), and apolipoprotein B 100 in patients with acute ischemic stroke. Methods: We identified 2187 consecutive patients with acute ischemic stroke confirmed on MR imaging or CT. Brachial-ankle pulse wave velocity (baPWV) was measured using a volume-plethysmography device (VP-1000; Collin, Komaki, Japan). Lipid fractions were measured with blood sample taken after at least 8-hour fast. Vascular risk factors and demographics of patients were assessed by our prospectively collected stroke database. The association between baPWV and lipid fractions was tested using linear regression analysis. Results: Mean age of patients was 68.5 +/- 12.3 years and male was 1214 (55.5%). Mean baPWV was 20.85 +/- 5.55 m/sec. On simple regression analysis, baPWV was associated with lipoprotein(a) and LDL-cholesterol (p &lt; 0.05). However, on multivariable linear regression adjusting for age, sex, lipid fractions and other vascular risk factors, apolipoprotein B 100 was the only significant lipid fraction for baPWV (beta 1.42; 95% confidence interval 0.45 - 2.40; p &lt; 0.001). We included LDL-cholesterol instead of apolipoprotein B 100 in another model due to multicollinearity, which showed that neither LDL-cholesterol nor lipoprotein(a) was significant. Conclusion: Among lipid fractions, apolipoprotein B 100 is associated with systemic arterial stiffness in patients with acute ischemic stroke. Our finding suggests that apolipoprotein B 100 might be a better predictor for arterial stiffness than LDL-cholesterol and lipoprotein(a).

3259Next-generation sequencing to confirm clinical FH in The Netherlands

Abstract Background Pathogenic variants in the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9)) are known to cause familial hypercholesterolemia (FH), a disease characterized by high LDL-C levels. We set out to investigate which proportion of patients with extremely elevated LDL-C levels, who were referred for molecular analysis, carry a mutation in any of the three FH genes or other, putative FH genes. Methods Targeted next-generation sequencing of 28 genes involved in lipid metabolism was performed in 1475 clinical FH patients with LDL-C levels &gt;5mmol/L (corresponding with possible, probable and definite FH score according to the Dutch Lipid Clinic Network criteria) and triglyceride levels &lt;4.5 mmol/L. Genetic variants and copy number variants were curated consecutively using specialist analysis software. (Likely) pathogenic variants in LDLR, APOB, or PCSK9 were annotated as FH-causing variants. Results 14.3% of the 1475 patients with clinical FH were heterozygous carriers of a mutation in LDLR, APOB, or PCSK9. This number ranged from 8% in the lowest LDL-C group (5–5.99 mmol/L) to 56% in patients with the highest LDL-C levels (&gt;8 mmol/L). Patients with LDLR, APOB, or PCSK9 variants had median LDL-C levels of 6.8 [5.7–7.9], 6.2 [5.1–7.0], and 6.4 [5.7–6.8] mmol/L [interquartile range], respectively. Mutation-negative FH patients had median LDL-C levels of 5.8 [5.2–6.5] mmol/L. Of the FH mutation-negative patients 7.4% had a (likely) pathogenic variant in the gene encoding lipoprotein lipase (LPL) and 1.3% in the apolipoprotein E (APOE) gene. The proportion of FH mutation-negative patients carrying an APOE variant increased from 1.2% in the lowest LDL-C group to 7.5% in patients with LDL-C &gt;8 mmol/L. Mutation-positive FH patients were significantly younger (41.61±17.53 years vs 52.62±13.28 years P&lt;0.001) and had a significant lower BMI (25.86±4.87 vs 26.55±4.07kg/m2, P=0.02) compared to mutation negative patients. Figure 1 Conclusions A genetic defect in LDLR, APOB or PCSK9 is identified in only 14.3% of the patients with a clinical FH phenotype (defined as LDL-C &gt;5 mmol/L) referred for molecular testing in the Netherlands. Mutations in LPL and APOE were found in a minor proportion of the FH mutation-negative patients. Our finding that a mutation is only found 56% of patients who present with LDL-C levels above 8 mmol/L indicates that either misclassification of FH and/or other genetic defects may be present in this group. Acknowledgement/Funding Grant [016.156.445] from The Netherlands Organisation for Scientific Research (NWO)

60 - Plasma Total Peroxyl Radical-Trapping Antioxidant Potential Responsiveness to Flaxseed Lignan Complex Dictates Plasma Low-Density Lipoprotein Oxidation Reduction in Older Type 2 Diabetes Patients

Plasma low-density lipoprotein apolipoprotein B oxidation (LDL-Box) contributes significantly to atherosclerosis in type 2 diabetes (T2D) patients. Unknown is the impact of antioxidant-containing flaxseed lignan complex (FLC) on plasma total peroxyl radical-trapping antioxidant potential responsiveness (TRAPR) and, consequently, LDL-Box reduction responsiveness (LDLBoxRR). It was hypothesised that in older T2D patients, TRAPR to FLC consumption would dictate LDLBoxRR. The objective was to test this hypothesis.

Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid’s LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

Could ornithine supplementation be beneficial to prevent the formation of pro-atherogenic carbamylated low-density lipoprotein (c-LDL) particles?

Carbamylation (or carbamoylation) is a non-enzymatic post-translational modification process of lysine residues and protein N-termini, which occurs throughout the lifespan of both various plasma proteins and low-density lipoprotein (LDL) particles. Carbamylation results from the binding of isocyanates spontaneously derived from high levels of blood urea, environmental pollutants, nutritional sources and leads to the formation of potentially atherogenic carbamylated-LDL (c-LDL) particles. The carbamylation of LDL apolipoproteins is associated unfavorable downstream effects.Ornithine is a non-proteinogenic amino acid, which plays a central role at the urea cycle function. The primary use of ornithine in supplements is to support athletic performance, liver function and wound recovery. Ornithine is structurally highly similar to lysine, and is only one carbon atom shorter in its side-chain. Therefore, we hypothesize that supplemented ornithine could compete with ε-amino groups of lysine residues found in apolipoproteins of native LDL particles in their binding to isocyanates and decrease c-LDL formation. This issue still remains unresolved in current literature and needs to be elucidated in experimental studies.

Lipoprotein (a) and Low-density lipoprotein apolipoprotein B metabolism following apheresis in patients with elevated lipoprotein(a) and coronary artery disease.

Lipoprotein apheresis effectively lowers lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) by approximately 60%-70%. The rebound of LDL and Lp(a) particle concentrations following lipoprotein apheresis allows the determination of fractional catabolic rate (FCR) and hence production rate (PR) during non-steady state conditions. We aimed to investigate the kinetics of Lp(a) and LDL apolipoprotein B-100 (apoB) particles in patients with elevated Lp(a) and coronary artery disease undergoing regular apheresis. A cross-sectional study was carried out in 13 patients with elevated Lp(a) concentration (>500mg/L) and coronary artery disease. Lp(a) and LDL-apoB metabolic parameters, including FCR and PR were derived by the fit of a compartment model to the Lp(a) and LDL-apoB concentration data following lipoprotein apheresis. The FCR of Lp(a) was significantly lower than that of LDL-apoB (0.39 [0.31, 0.49] vs 0.57 [0.46, 0.71] pools/day, P=0.03) with no significant differences in the corresponding PR (14.80 [11.34, 19.32] vs 15.73 [11.93, 20.75] mg/kg/day, P=0.80). No significant associations were observed between the FCR and PR of Lp(a) and LDL-apoB. In patients with elevated Lp(a), the fractional catabolism of Lp(a) is slower than that of LDL-apoB particles, implying that different metabolic pathways are involved in the catabolism of these lipoproteins. These findings have implications for new therapies for lowering apolipoprotein(a) and apoB to prevent atherosclerotic cardiovascular disease.