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Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder, and cardiovascular disease (CVD) is a significant cause of mortality and morbidity in diabetic individuals. In addition to hyperglycemia, lipid abnormalities associated with T2DM play a crucial role in the development of CVD complications. Diabetic dyslipidemia is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL) cholesterol, and impaired HDL function. Angiopoietin protein-like 3 (ANGPTL3) is a liver-derived protein that plays a crucial role in regulating plasma lipoprotein metabolism by inhibiting lipoprotein lipase and influencing lipid levels. Inhibiting ANGPTL3 has shown promising effects in promoting HDL-mediated cholesterol reverse transport and reducing the levels of TG-rich lipoproteins and LDL cholesterol. Here, we explore the potential of ANGPTL3 as a therapeutic target for lipid management in T2DM patients., (© 2024. The Author(s).)

Due to increasing lifespan and aging populations globally there has been a steep rise in late-life dementia, which is now the second most common cause of death in high-income countries. In general, dementia can be divided into two major groups: Alzheimer's disease (AD) and vascular-related dementia (VD). AD is pathologically characterised by senile plaques containing amyloid-β and neurofibrillary tangles composed of hyperphosphorylated tau, whereas VD is dominated by vascular pathology such as cerebral small vessel disease, major strokes, and white matter lesions. Recently, the importance of vascular components in AD is increasingly recognized and it is estimated that up to 45 % of all dementia cases can be prevented by preventing or treating midlife cardiovascular risk factors such as physical inactivity, diabetes, and hypertension. Even though the brain contains approximately 25 % of the total body cholesterol pool, and several genetic variants related to the lipid metabolism have been identified in genome-wide associations studies of AD, the role of lipids, lipoproteins, and apolipoproteins in dementia risk is less well-known. In this review, we go through the current literature on lipids, lipoproteins, and apolipoproteins and risk of dementia. We conclude that the evidence is primarily insufficient or conflicting, possibly due to nonoptimal study designs. The future calls for large, prospective studies of midlife measurements of lipids, lipoproteins, and apolipoproteins and one-sample, individual level data Mendelian randomization studies to overcome survival bias. However, the current literature suggests that it is safe to say that what is good for the heart is good for the brain., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Coagulopathy is part of the pathological host response to infection in sepsis. Higher plasma concentrations of both tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are associated with occurrence of disseminated intravascular coagulation (DIC), multi-organ dysfunction and increased mortality in patients with sepsis. Currently no treatment approaches specifically targeting this axis are available. We hypothesize that therapeutic plasma exchange (TPE) might limit this coagulopathy by restoring the balance of plasma proteins., Methods: This was a pooled post-hoc biobank analysis including 51 patients with early (shock onset < 24 h) and severe (norepinephrine dose > 0.4 μg/kg/min) septic shock, who were either receiving standard of care treatment (SOC, n = 14) or SOC + one single TPE (n = 37). Plasma concentrations of TF and TFPI were measured both at- and 6 h after study inclusion. The effect of TPE on concentrations of TF and TFPI was investigated and compared to SOC patients. Further, baseline TF and TFPI concentrations were used to modulate and predict clinical response to adjunctive TPE, indicated by longitudinal reduction of lactate concentrations over the first 24 h following study inclusion., Results: TPE led to a significant reduction in circulating concentrations of both TF and TFPI while no difference was observed in the SOC group. Relative change of TF within 6 h was + 14 (-0.8 to + 30.4) % (p = 0.089) in the SOC and -18.3 (-32.6 to -2.2) % (p < 0.001) in the TPE group (between group p < 0.001). Similarly, relative change of TFPI was + 14.4 (-2.3 to + 30.9) % (p = 0.076) in the SOC and -20 (-32.8 to -7.9) % (p < 0.001) in the TPE group (between group p = 0.022). The ratio of TF to TFPI remained unchanged in both SOC and TPE groups. SOC patients exhibited an increase in lactate over the initial 24 h when TF and TFPI concentrations were higher at baseline. In contrast, patients undergoing TPE experienced a sustained longitudinal reduction of lactate concentrations across all levels of baseline TF and TFPI elevations. In a multivariate mixed-effects model, higher baseline TF (p = 0.003) and TFPI (p = 0.053) levels led to greater longitudinal lactate concentration reduction effects in the TPE group., Conclusions: Adjunctive TPE in septic shock is associated with a significant removal of both TF and TFPI, which may contribute to the early hemodynamic improvement observed in septic shock patients receiving TPE. Higher baseline TF (and TFPI) plasma concentrations were identified as a putative predictor of treatment response that could be useful for predictive enrichment strategies in future clinical trials., (© 2024. The Author(s).)

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles., Methods: This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters., Results: Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m 2 . Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use., Conclusions: MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population., (© 2024. The Author(s).)

Background: The familial hypercholesterolemia (FH) diagnosis is based on clinical and genetic criteria. A relevant proportion of FH patients fulfilling the criteria for definite FH have negative genetic testing. Increasing the identification of true genetic-based FH is a clinical challenge. Deepening the analysis of lipoprotein alterations could help increase the yield of genetic testing. We evaluated whether the number, size, and composition of lipoproteins assessed by 1H-NMR could increase the identification of FH patients with pathogenic gene variants., Methods: We studied 294 clinically definite FH patients, 222 (75.5%) with positive genetic testing, as the discovery cohort. As an external validation cohort, we studied 88 children with FH, 72 (81%) with positive genetic testing. The advanced lipoprotein test based on 1H-NMR (Liposcale®) was performed at baseline after a lipid-lowering drug washout of at least 6 weeks. The association of variables with genetic variants was evaluated by random forest and logistic regression. Areas under the curve (AUCs) were calculated. A predictive formula was developed and applied to the validation cohort., Results: A formula derived from nuclear magnetic resonance (NMR) lipoprotein analyses improved the identification of genetically positive FH patients beyond low-density lipoprotein (LDL)-cholesterol levels (AUC = 0.87). The parameters contributing the most to the identification formula were LDL particle number, high-density lipoprotein size, and remnant cholesterol. The formula also increases the classification of FH children with a pathogenic genetic variation., Conclusion: NMR lipoprotein profile analysis identifies differences beyond standard lipid parameters that help identify FH with a positive pathogenic gene variant, increasing the yield of genetic testing in FH patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Among heart failure patients with obesity, the prognosis is better than those with normal weight, a phenomenon known as the obesity paradox. However, it is unclear whether lipoprotein levels play a mediating role in the machine of the obesity paradox., Methods: The study included 1663 heart failure patients hospitalized from January, 2019 through August, 2022. Kaplan-Meier survival analysis and Log-rank tests were performed for three endpoints in order to determine cumulative event-free survival. We investigated the correlation between Body Max Index (BMI) and outcomes by multifactorial Cox models. Mediation analysis was applied to study the presence and magnitude of mediation effects of triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A1 and apolipoprotein B, with the association between BMI and endpoints., Results: In MACCEs, the median follow-up period was 679 days. In Cox model, compared with the underweight group, a high BMI level was significantly associated with lower all-cause mortality (HR=0.47, 95%CI 0.31~0.69, p<0.001, obese vs underweight), cardiovascular mortality (HR=0.46, 95%CI 0.30~0.73, p<0.001, obese vs underweight) and the incidence of MACCEs (HR=0.68, 95%CI 0.53~0.88, p=0.003, obese vs underweight). Mediation analysis revealed that TG was the strongest mediator between BMI and endpoints, with proportions of mediated effects of 6.6% (95%CI 2.2%~18.0%, p=0.0258, in all-cause death),7.0% (95%CI 2.3%~18.9%, p=0.0301, in cardiovascular death) and 10.2% (95%CI 3.3%~27.4%, p=0.0185, in MACCEs)., Conclusions: There is an "obesity paradox" in patients with heart failure, and lipoprotein levels especially triglyceride mediate the association between BMI and cardiovascular outcomes., (© 2024. The Author(s).)

Extracellular vesicles (EVs) are valuable targets for liquid biopsy. However, attempts to introduce EV-based biomarkers into clinical practice have not been successful to the extent expected. One of the reasons for this failure is the lack of reliable methods for EV baseline purification from complex biofluids, such as cell-free plasma or serum. Because available one-step approaches for EV isolation are insufficient to purify EVs, the majority of studies on clinical samples were performed either on a mixture of EVs and lipoproteins, whilst the real number of EVs and their individual specific biomarker content remained elusive, or on a low number of samples of sufficient volume to allow elaborate 2-step EV separation by size and density, resulting in a high purity but utmost low recovery. Here we introduce Fast Protein Liquid Chromatography (FPLC) using Superose 6 as a matrix to obtain small EVs from biofluids that are almost free of soluble proteins and lipoproteins. Along with the estimation of a realistic number of small EVs in human samples, we show temporal resolution of the effect of the duration of postprandial phase on the proportion of lipoproteins in purified EVs, suggesting acceptable time frames additionally to the recommendation to use fasting samples for human studies. Furthermore, we assessed a potential value of pure EVs for liquid biopsy, exemplarily examining EV- and tumour-biomarkers in pure FPLC-derived fractions isolated from the serum of patients with pancreatic cancer. Consistent among different techniques, showed the presence of diseases-associated biomarkers in pure EVs, supporting the feasibility of using single-vesicle analysis for liquid biopsy., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Aim: Peripheral artery disease (PAD) severely impairs patient prognosis and quality of life (QOL). Although lipoprotein apheresis (LA) has been applied to patients with PAD and elevated serum atherogenic lipoproteins, we hypothesized that LA can be effective for treating PAD even in patients with controlled serum lipoproteins through pleiotropic anti-atherosclerotic effects beyond lipoprotein removal. This study aimed to evaluate the efficacy of LA in patients with treatment-resistant PAD and controlled serum lipoproteins focusing on QOL., Methods: In a single-arm prospective study, 30 patients with refractory PAD who had controlled serum lipoproteins underwent sequential LA sessions using dextran sulfate adsorption columns, aiming to complete 10 sessions. The ankle-brachial pressure index (ABI) and vascular QOL (VascuQOL) score were evaluated as the primary outcomes. Secondary outcomes included reactive hyperemia index (RHI) and biological antioxidant potential (BAP) as an endothelial function test and serum antioxidative-capacity evaluation, respectively., Results: ABI significantly increased after LA sessions (pre-treatment 0.60±0.09 vs. post-treatment 0.65±0.13, p=0.023). Total VascuQOL score (3.7±1.1 vs 4.6±1.1, p＜0.001) and RHI (1.70±0.74 vs 2.34±1.76, p=0.023) significantly improved after the LA sessions. BAP tended to increase after the LA sessions, and the change reached statistical significance 3 months after treatment., Conclusion: ABI and QOL improved after a series of LA sessions in conventional treatment-resistant PAD patients with controlled serum lipoprotein levels. Increased antioxidative capacity and ameliorated endothelial function were observed after the LA treatment.

Background: Tissue factor pathway inhibitor (TFPI) regulates tissue factor-triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane-anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein-associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein-associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks., Objectives: To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice., Methods: Engineered TFPI isoform-specific, hemophilic (factor VIII-null) mice were evaluated for clotting., Results: Mice expressing any single TFPI isoform were healthy. Thrombin generation assays identified TFPIγ as the dominant anticoagulation isoform in mouse plasma. Hemostasis was assessed by serial bleeding times from a tail vein laceration. Repeatedly, after a clot forms, it was manually disrupted; the number of clots/disruptions occurring over a 15-minute period were reported. C57BL/6 and hemophilic mice clot on average 25.6 vs 5.4 times, respectively. On a hemophilia background, TFPIβ or TFPIγ-specific deletion improved clotting to 14.6 and 15.2 times, respectively (P < .0001). TFPIα-specific deletion was without impact, clotting 5.1 times. Heterozygous deletion of TFPIβ was effective, clotting 11.8 times (P < .0001). Heterozygous deletion of TFPIα or TFPIγ alone was ineffective, clotting 3.0 and 6.1 times, respectively, but heterozygous TFPIαγ deletion improved clotting to 11.2 times (P < .001)., Conclusion: In hemophilic mice, endothelial TFPIβ and plasma γ-derived 2-Kunitz TFPI individually contribute more to bleeding than total TFPIα., Competing Interests: Declaration of competing interests All authors have no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: An elevated lipoprotein insulin resistance (LP-IR) score corresponds to insulin resistance in adults with overweight and obesity, yet data are lacking regarding the impact of exercise interventions on LP-IR. The purpose of this secondary analysis was to evaluate the effects of a weight loss and weight maintenance intervention on LP-IR score in adults with overweight and obesity. Methods: Thirty sedentary adults with overweight and obesity completed a 10-week OPTIFAST ® weight loss program with supervised aerobic exercise to achieve clinical weight loss (CWL) (≥7% from baseline). Aerobic exercise volume increased weekly until 700 MET min/week was reached. Participants who reached CWL were randomized to groups at volumes at either physical activity (PA-REC) or weight maintenance (WM-REC) recommendations (weeks 11-28). Plasma blood samples were analyzed via nuclear magnetic resonance spectroscopy at baseline, after weight loss (week 10), and following weight maintenance (week 28). Results: Following the weight loss phase, on average, participants significantly ( p < 0.001) reduced LP-IR score (-12.1 ± 13.5), body weight (-8.9 ± 2.7%), and waist circumference (-7.7 ± 4.1 cm). During the weight maintenance phase, there were no changes in LP-IR score between exercise groups (PA-REC: 4.1 ± 13.6; WM-REC: -2.0 ± 11.2; P = 0.7). The PA-REC group had improvements in LP-IR score from baseline (49.8 ± 24.6 to 36.6 ± 27.6, P < 0.001), yet there were no within-group changes during the weight maintenance phase ( P > 0.05). Conclusion: LP-IR score improved during weight loss in adults with overweight and obesity and were sustained during the weight maintenance phase in the PA-REC group. Aerobic exercise at least at minimum guidelines following CWL can preserve LP-IR score improvements and may indicate a reduced T2DM risk in adults with overweight and obesity.

Background: Glaucoma is a leading cause of vision impairment and permanent blindness. Primary open-angle glaucoma (POAG) is a prominent type of primary glaucoma; however, its cause is difficult to determine. This study aimed to analyze the serum lipid profile of Chinese POAG patients and assess its correlation with intraocular pressure (IOP)., Methods: The study included 1,139, 1,248, and 356 Chinese individuals with POAG, primary angle closure glaucoma (PACG), and controls, respectively. Peripheral whole blood samples were collected at the time of diagnosis. Enzymatic colorimetry was used to determine serum levels of different lipids: high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, cholesterol, and very low-density lipoproteins (VLDL). Additionally, immunoturbidimetry was used to quantify serum levels of apolipoproteins A (APOA), B (APOB), E (APOE), and lipoprotein A [Lp(a)], while intraocular pressure (IOP) was measured in all patients with POAG., Results: After adjusting for age and sex, patients with POAG exhibited elevated serum levels of VLDL, APOA, and APOE but mitigated cholesterol levels compared with the control participants. Significantly lower serum triglyceride, VLDL, and Lp(a) levels were found in patients with PACG than in control participants. Serum cholesterol (P = 0.019; β = -0.75, 95% confidence interval [CI]: -1.38 - -0.12) and HDL levels (P < 0.001; β = -2.91, 95% CI: -4.58 - -1.25) were inversely linked to IOP in patients with POAG, after adjusting for age, sex, and ocular metrics. In addition, serum Lp(a) levels were correlated with the average IOP (P = 0.023; β = -0.0039, 95% CI: -0.0073 - -0.006) and night peak (P = 0.027; β = -0.0061, 95% CI: -0.0113 - -0.0008) in patients with POAG., Conclusions: Significantly different serum lipid and lipoprotein profiles were observed in POAG and PACG patients. This study highlighted the differences in serum lipid and lipoprotein levels among Chinese POAG patients and their relationship with IOP and IOP fluctuation. Serum lipid and lipoprotein profiles should be considered while evaluating glaucoma risk., (© 2024. The Author(s).)

Many studies have reported a relationship between various lipids, such as cholesterol, fatty acids, and lipoproteins, and cardiovascular events. Low-density lipoprotein cholesterol (LDL-C) is often cited as a representative marker. However, there is still room for discussion regarding which markers, among other lipids, should take clinical precedence.This observational study focused on patients without residual stenosis on post-coronary angiography. It was based on blood tests, including lipid profiles at that time, and assessed the association with the subsequent occurrence of major adverse cardiovascular events (MACE, a composite of all-cause mortality, hospitalization due to heart failure, myocardial infarction, stroke, and all revascularizations).Of the 375 patients analyzed, 134 experienced MACE (median follow-up duration: 1031 days). When comparing the MACE and non-MACE groups, significant differences were observed in lipid markers such as non-high-density lipoprotein cholesterol (non-HDL-C) and remnant-like particle cholesterol (RLP-C) (non-HDL-C; P = 0.003, RLP-C; P < 0.001). Furthermore, the area under the curve for RLP-C was 0.656 (95% CI: 0.598-0.714). Improvement in MACE risk discrimination was observed when LDL-C was replaced with non-HDL-C or RLP-C, in addition to atherosclerosis risk factors (non-HDL-C; net reclassification improvement (NRI) = 0.366, 95% CI: 0.159-0.572, RLP-C; NRI = 0.224, 95% CI: 0.016-0.433).It is highly likely that non-HDL-C and RLP-C can serve as significant lipid markers for predicting the occurrence of MACE.

Background: Dyslipidemia has been associated with reduced bone mineral density and osteoporotic fractures, but the relation between lipid and bone metabolism remains poorly understood. Analysing the effects of lipoprotein subclasses on bone turnover may provide valuable insights into this association. We therefore examined whether lipoprotein subclasses, measured by proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy, are associated with bone turnover markers (BTMs) and with the ultrasound-based bone stiffness index., Methods: Data from 1.349 men and 1.123 women, who participated in the population-based Study of Health in Pomerania-TREND were analysed. Serum intact amino-terminal propeptide of type I procollagen (P1NP, bone formation) and carboxy-terminal telopeptide of type I collagen (CTX, bone resorption) concentrations were measured. Associations between the lipoprotein data and the BTMs or the stiffness index were investigated using linear regression models., Results: The triglyceride or cholesterol content in very-low-density lipoprotein and intermediate-density lipoprotein particles was inversely associated with both BTMs, with effect estimates being slightly higher for CTX than for P1NP. The triglyceride content in low-density lipoprotein and high-density lipoprotein particles and the Apo-A2 content in high-density lipoprotein particles was further inversely associated with the BTMs. Associations with the ultrasound-based bone stiffness index were absent., Conclusions: Consistent inverse associations of triglycerides with bone turnover were observed, which argue for a protective effect on bone health, at least in the normal range. Yet, the presented associations did not translate into effects on the ultrasound-based bone stiffness. Further, there was no relevant gain of information by assessing the lipoprotein subclasses. Nevertheless, our study highlights the close relations between lipid and bone metabolism in the general population., (© 2024. The Author(s).)

Background: The accurate measurement of blood lipids and lipoproteins is crucial for the clinical management of atherosclerotic disease risk. Despite progress in standardization, there are still significant variations in pre-analytical requirements, methods, nomenclature, and reporting work flows., Content: The guidance document aims to improve standardization of clinical lipid testing work flows. It provides recommendations for the components of the lipid panel, fasting requirements, reporting of results, and specific recommendations for non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (apo B), point-of-care lipid testing, and LDL subfraction testing., Summary: Lipid panels should always report non-HDL-C and LDL-C calculations if possible. Fasting is not routinely required except in specific cases. Modern equations should be utilized for LDL-C calculation. These equations allow for LDL-C reporting at elevated concentrations of triglycerides and obviate the need for direct measured LDL-C in most cases., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: Studies have consistently demonstrated associations between ultra-processed food and drink (UPFD) consumption and non-communicable diseases. However, there is a lack of data investigating relationships between UPFD intake and intermediate cardiometabolic disease markers. In this study we explored UPFD associations with lipoprotein subclasses., Methods: This was a cross-sectional study of 1986 middle-to older-aged men and women randomly selected from a large primary care centre. The percentage contribution of UPFDs to total energy intake was calculated for each participant using the NOVA classification. Lipoprotein particle subclass concentrations and size were determined using nuclear magnetic resonance spectroscopy. Correlation and multivariate-adjusted linear regression analyses were performed to examine UPFD intake relationships with lipoprotein subclasses., Results: In fully adjusted regression models, higher UPFD consumption was associated with reduced high-density lipoprotein (HDL) cholesterol concentrations (β = -0.024, p = 0.001), large low-density lipoprotein (LDL) levels (β = -18.645, p = 0.002), total and medium HDL concentrations (β = -0.328, p = 0.012; β = -0.510, p < 0.001), smaller LDL and HDL size (β = -0.026, p = 0.023; β = -0.023, p = 0.024), and increased medium very low-density lipoprotein levels (β = 0.053, p = 0.022), small LDL and HDL concentrations (β = 20.358, p = 0.02; β = 0.336, p = 0.011), and higher lipoprotein insulin resistance scores (β = 0.048, p = 0.012), reflecting greater lipoprotein-related insulin resistance., Conclusions: Findings from this research suggest that increased intake of UPFDs is associated with a more pro-atherogenic, insulin-resistant metabolic profile in middle-to older-aged adults which may be a potential mechanism underlying reported associations between UPFD consumption and chronic disease risk and mortality., Competing Interests: Conflict of interest No competing interests exist., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Blood is a two-component system with two levels of hierarchy: the macrosystem of blood formed elements and the dispersed system of blood nanoparticles. Biological nanoparticles are the key participants in communication between the irradiated and non-irradiated cells and inducers of the non-targeted effects of ionizing radiation. The work aimed at studying by atomic force microscopy the structural, mechanical, and electrical properties of exosomes and lipoproteins (LDL/VLDL) isolated from rat blood after its exposure to X-rays in vitro., Materials and Methods: The whole blood of Wistar rats fed with a high-fat diet was irradiated with X-rays (1 and 100 Gy) in vitro. The structural and mechanical properties (the elastic modulus and nonspecific adhesion force) of exosome and lipoprotein isolates from the blood by ultracentrifugation method were studied using Bruker Bioscope Resolve atomic force microscope in PF QNM mode, their electric properties (the zeta-potential) was measured by electrophoretic mobility., Results: Lipoproteins isolated from non-irradiated blood were softer (Me(LQ; UQ): 7.8(4.9;12.1) MPa) compared to blood nanoparticles of its exosome fraction (34.8(22.6;44.9) MPa) containing both exosomes and non-membrane nanoparticles. X-ray blood irradiation with a dose of 1 Gy significantly weakened the elastic properties of lipoproteins. Exposure of the blood to 100 Gy X-rays made lipoproteins stiffer and their nonspecific adhesive properties stronger. The radiation effects on the mechanical parameters of exosomes and non-membrane nanoparticles in exosome fractions differed. The significant radiation-induced change in electric properties of the studied nanoparticles was detected only for lipoproteins in the blood irradiated with 1 Gy X-rays. The low-dose radiation-induced changes in zeta-potential and increase in lipoprotein size with the appearance of a soft thick surface layer indicate the formation of the modified lipoproteins covered with a corona from macromolecules of irradiated blood., Conclusion: Our data obtained using the nanomechanical mapping mode of AFM are the first evidence of the significant radiation-induced changes in the structural and mechanical properties of the dispersed system of blood nanoparticles after the X-ray irradiation of the blood., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cardiovascular disease is one of the leading causes of death worldwide. Evidence suggests that alterations in the gut microbiome could play a role in cardiovascular diseases, including heart failure. The purpose of this study was to evaluate the effect of synbiotics on serum paraoxonase 1(PON1), soluble CD163/soluble TNF-like weak inducer of apoptosis (sCD163/sTWEAK), and lipid profile, which are involved in heart failure in patients with chronic heart failure. In this triple-blind randomized clinical trial, 90 eligible patients were included in the study. They were randomly assigned to receive one capsule (500 mg) of synbiotics or a placebo daily for ten weeks. Serum PON1, sCD163/sTWEAK, and lipid profiles were measured at the beginning and end of the study. The data were analyzed by SPSS 24, and the p-value < 0.05 was considered statistically significant. Among 90 patients who met the inclusion criteria, 80 completed the study. The primary outcomes showed a small effect on sTWEAK, with an adjusted standard mean difference (SMD) of 0.2. However, no significant changes were observed in sCD163/sTWEAK (SMD: 0.16). Secondary outcomes indicated no changes in PON1, total cholesterol (TC), or LDL-C levels. However, there was an increase in HDL-C levels (adjusted SMD: 0.46, 95% CI: 0.02-0.91) and a decrease in TG and TC/HDL levels (adjusted SMD: - 0.5 and - 0.3, respectively) in the synbiotic group. A favorable effect of synbiotics on sTWEAK, HDL, TG, and TC/HDL of patients with heart failure was observed, but no statistically significant effect was found on sCD163/sTWEAK, PON1, LDL, and TC factors., (© 2024. The Author(s).)

Background: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles., Materials and Methods: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS)., Results: Within- and between-run precisions were 1.4-11.1 % and 2.2-14.1 %, respectively, while the accuracies were all 86.3 ∼ 121.9 % with the correlation coefficients (r 2 ) > 0.988 for all the sterols. In the patients (four girls and two boys, 6.5 ± 2.8 years), sitosterol levels were significantly increased, with an optimal cut-off value of 2.5 µg/mL distinguishing them from ninety-three age-matched healthy children. A cut-off value of 31.9 µg/mL differentiated the patients from six ABCG5/ABCG8 heterozygous carriers. In addition, the molecular ratios of sitosterol to cholesterol, desmosterol, and 7-dehydrocholesterol provided excellent cut-off values of 26.3, 67.6, and 21.6, respectively, to distinguish patients from both healthy controls and heterozygous carriers., Conclusions: The novel DBS-based GC-MS profiling of free sterols accurately identified patients with sitosterolemia, with a performance comparable to that of a serum assay. The DBS profiling could be more feasible method in clinical practice as well as population screening programs, and it can provide diagnostic cut-off values for individual plant sterols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The capacity of high-density lipoprotein cholesterol (HDL) to acquire free cholesterol (FC) from triglyceride-rich lipoproteins during lipoprotein lipase-dependent lipolysis in a process of reverse remnant cholesterol transport, has been proposed as a key biological function of HDL particles that underlies the U-shaped relationship between HDLcholesterol and cardiovascular diseases. Although reverse remnant cholesterol transport has been evaluated in a fasting state, it has never been explored under nonfasting conditions., Methods and Results: FC transfer was evaluated in healthy men (n=78) before and throughout the postprandial phase up to 8 hours after consumption of a test meal. Postprandially, the capacity of HDL to acquire FC increased progressively, reaching a maximal mean value of 98.5%±22.5% 6 hours after meal intake ( P <0.05). Analysis of the study population according to tertiles of postprandial variation of FC transfer identified subjects exhibiting reduced capacity of HDL to acquire FC (tertile 1), those for whom the capacity of HDL to acquire FC remained unchanged (tertile 2), and subjects characterized by an enhanced FC transfer during the postprandial phase (tertile 3). Across the tertiles, we found an inverse relationship between the maximal postprandial change in FC transfer to HDL and the degree of postprandial triglyceride response., Conclusions: Healthy individuals exhibiting exacerbated postprandial triglyceride response and reduced HDL cholesterol levels feature reduced FC transfer to HDL during the postprandial state. These data suggest that to normalize postprandial triglyceride response, 2 conditions need to be fulfilled: notably elevated FC transfer to HDL in the postprandial phase and increased levels of acceptor HDL particles.

Cardiovascular diseases (CVDs) represent the leading cause of mortality worldwide, despite the significant advancements that have been made in terms of primary and secondary prevention strategies over the past decades [...].

Macrophages in atherosclerotic lesions exhibit a spectrum of behaviours or phenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs), its correlation with MDM lipid content, and relation to blood lipoprotein densities are not well understood. Of particular interest is the balance between low density lipoproteins (LDL) and high density lipoproteins (HDL), which carry bad and good cholesterol respectively. To address these issues, we have developed a mathematical model for early atherosclerosis in which the MDM population is structured by phenotype and lipid content. The model admits a simpler, closed subsystem whose analysis shows how lesion composition becomes more pathological as the blood density of LDL increases relative to the HDL capacity. We use asymptotic analysis to derive a power-law relationship between MDM phenotype and lipid content at steady-state. This relationship enables us to understand why, for example, lipid-laden MDMs have a more inflammatory phenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDL capacity. We show further that the MDM phenotype distribution always attains a local maximum, while the lipid content distribution may be unimodal, adopt a quasi-uniform profile or decrease monotonically. Pathological lesions exhibit a local maximum in both the phenotype and lipid content MDM distributions, with the maximum at an inflammatory phenotype and near the lipid content capacity respectively. These results illustrate how macrophage heterogeneity arises in early atherosclerosis and provide a framework for future model validation through comparison with single-cell RNA sequencing data., (© 2024. The Author(s).)

Globally, burns are a significant cause of injury that can cause substantial acute trauma as well as lead to increased incidence of chronic comorbidity and disease. To date, research has primarily focused on the systemic response to severe injury, with little in the literature reported on the impact of nonsevere injuries (<15% total burn surface area; TBSA). To elucidate the metabolic consequences of a nonsevere burn injury, longitudinal plasma was collected from adults ( n = 35) who presented at hospital with a nonsevere burn injury at admission, and at 6 week follow up. A cross-sectional baseline sample was also collected from nonburn control participants ( n = 14). Samples underwent multiplatform metabolic phenotyping using 1 H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry to quantify 112 lipoprotein and glycoprotein signatures and 852 lipid species from across 20 subclasses. Multivariate data modeling (orthogonal projections to latent structures-discriminate analysis; OPLS-DA) revealed alterations in lipoprotein and lipid metabolism when comparing the baseline control to hospital admission samples, with the phenotypic signature found to be sustained at follow up. Univariate (Mann-Whitney U) testing and OPLS-DA indicated specific increases in GlycB ( p -value < 1.0e -4 ), low density lipoprotein-2 subfractions (variable importance in projection score; VIP > 6.83e -1 ) and monoacyglyceride (20:4) ( p -value < 1.0e -4 ) and decreases in circulating anti-inflammatory high-density lipoprotein-4 subfractions (VIP > 7.75e -1 ), phosphatidylcholines, phosphatidylglycerols, phosphatidylinositols, and phosphatidylserines. The results indicate a persistent systemic metabolic phenotype that occurs even in cases of a nonsevere burn injury. The phenotype is indicative of an acute inflammatory profile that continues to be sustained postinjury, suggesting an impact on systems health beyond the site of injury. The phenotypes contained metabolic signatures consistent with chronic inflammatory states reported to have an elevated incidence postburn injury. Such phenotypic signatures may provide patient stratification opportunities, to identify individual responses to injury, personalize intervention strategies, and improve acute care, reducing the risk of chronic comorbidity.

Background and Aims: Lipoprotein(a) [Lp(a)] is a causal, genetically determined cardiovascular risk factor. Limited evidence suggests that dietary unsaturated fat may increase serum Lp(a) concentration by 10-15 %. Linoleic acid may increase Lp(a) concentration through its endogenous conversion to arachidonic acid, a process regulated by the fatty acid desaturase (FADS) gene cluster. We aimed to compare the Lp(a) and other lipoprotein trait-modulating effects of dietary alpha-linolenic (ALA) and linoleic acids (LA). Additionally, we examined whether FADS1 rs174550 genotype modifies Lp(a) responses., Methods: A genotype-based randomized trial was performed in 118 men homozygous for FADS1 rs174550 SNP (TT or CC). After a 4-week run-in period, the participants were randomized to 8-week intervention diets enriched with either Camelina sativa oil (ALA diet) or sunflower oil (LA diet) 30-50 mL/day based on their BMI. Serum lipid profile was measured at baseline and at the end of the intervention., Results: ALA diet lowered serum Lp(a) concentration by 7.3 % (p = 0.003) and LA diet by 9.5 % (p < 0.001) (p = 0.089 for between-diet difference). Both diets led to greater absolute decreases in individuals with higher baseline Lp(a) concentration (p < 0.001). Concentrations of LDL cholesterol (LDL-C), non-HDL-C, remnant-C, and apolipoprotein B were lowered more by the ALA diet (p < 0.01). Lipid or lipoprotein responses were not modified by the FADS1 rs174550 genotype., Conclusions: A considerable increase in either dietary ALA or LA from vegetable oils has a similar Lp(a)-lowering effect, whereas ALA may lower other major atherogenic lipids and lipoproteins to a greater extent than LA. Genetic differences in endogenous PUFA conversion may not influence serum Lp(a) concentration., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R 2  = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies., (© 2024. The Author(s).)

Context: Cottonseed oil (CSO) is higher in polyunsaturated fatty acids (PUFA) and saturated fatty acids (SFAs) than many liquid plant oils., Objectives: To conduct a systematic review of randomized controlled trials (RCTs) examining effects of CSO on markers of lipid metabolism and evaluate lipid and lipoprotein effects of incorporating CSO into a healthy dietary pattern using regression equations., Data Sources: A systematic search was conducted for RCTs comparing CSO with a non-CSO comparator in any population., Data Analyses: The Katan regression equation was used to predict lipid/lipoprotein changes when incorporating CSO into a US-style healthy eating pattern at 25 to 100% of the total oil allowance (ie, 27 g/2000 kcal) compared with average American intake (NHANES 2017 to 2020 pre-COVID pandemic)., Results: In total, 3 eligible publications (n = 2 trials), with 58 participants that provided 44% and 30% of total energy as CSO, were included. Fasting low-density lipoprotein cholesterol (LDL-C; ≈ -7.7 mg/dL) and triglycerides (≈ -7.5 mg/dL) were lower after 5 days of a CSO-enriched diet vs olive oil (OO). In a 56-day trial, CSO lowered total cholesterol (TC; ≈ -14.8 mg/dL), LDL-C (≈ -14.0 mg/dL), and non-high-density lipoprotein cholesterol (≈ -14.2 mg/dL) vs OO. Postprandially, angiopoietin-like protein-3, -4, and -8 concentrations decreased with CSO and increased with OO intake. Compared with average American intake, a healthy eating pattern with 27 g of CSO was estimated to lower TC (-8.1 mg/dL) and LDL-C (-7.3 mg/dL) levels, with minimal reduction in high-density lipoprotein cholesterol (-1.1 mg/dL). Compared with the healthy eating pattern, incorporating 27 g of CSO was predicted to increase TC and LDL-C levels by 2.4 mg/dL., Conclusion: Limited high-quality research suggests CSO may improve lipid/lipoprotein levels compared with OO. Cholesterol predictive equations suggest CSO can be incorporated into a healthy dietary pattern without significantly affecting lipids/lipoproteins., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Objective: To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy., Methods: After retrospectively screening the data of 742 patients between January 2007 and July 2020, 50 patients aged 13 to 39 years with Enneking stage II disease were included in the study. Serum lipid levels, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein-α [Lp(a)], and apolipoprotein A1, B, and E (ApoA1, ApoB, and ApoE), and clinicopathological characteristics were collected before and after neoadjuvant chemotherapy., Results: The mean levels of TC, TG, and ApoB were significantly increased following neoadjuvant chemotherapy (16%, 38%, and 20%, respectively, vs. pretreatment values; P<0.01). The mean levels of LDL-C and ApoE were also 19% and 16% higher, respectively (P<0.05). No correlation was found between the pretreatment lipid profile and the histologic response to chemotherapy. An increase in Lp(a) was strongly correlated with the Ki-67 index (R=0.31, P=0.023). Moreover, a trend toward longer disease-free survival (DFS) was observed in patients with decreased TG and increased LDL-C following chemotherapy, although this difference was not statistically significant (P=0.23 and P=0.24, respectively)., Conclusion: Significant elevations in serum lipids were observed after neoadjuvant chemotherapy in patients with localized osteosarcoma. There was no prognostic significance of pretreatment serum lipid levels on histologic response to neoadjuvant chemotherapy. The scale of increase in serum Lp(a) might have a potential prognostic role in osteosarcoma. Patients with increased LDL-C or reduced TG after chemotherapy seem to exhibit a trend toward favorable DFS., (© 2024. Huazhong University of Science and Technology.)

Background:  Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers., Methods:  We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis., Results:  All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis., Conclusion:  TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Aims: To assess if advanced characterization of serum glycoprotein and lipoprotein profile, measured by proton nuclear magnetic resonance spectroscopy ( 1 H-NMRS) improves a predictive clinical model of cardioautonomic neuropathy (CAN) in subjects with type 1 diabetes (T1D)., Methods: Cross-sectional study (ClinicalTrials.gov Identifier: NCT04950634). CAN was diagnosed using Ewing's score. Advanced characterization of macromolecular complexes including glycoprotein and lipoprotein profiles in serum samples were measured by 1 H-NMRS. We addressed the relationships between these biomarkers and CAN using correlation and regression analyses. Diagnostic performance was assessed by analyzing their areas under the receiver operating characteristic curves (AUC ROC )., Results: Three hundred and twenty-three patients were included (46% female, mean age and duration of diabetes of 41 ± 13 years and 19 ± 11 years, respectively). The overall prevalence of CAN was 28% [95% confidence interval (95%CI): 23; 33]. Glycoproteins such as N-acetylglucosamine/galactosamine and sialic acid showed strong correlations with inflammatory markers such as high-sensitive C-reactive protein, fibrinogen, IL-10, IL-6, and TNF-α. On the contrary, we did not find any association between the former and CAN. A stepwise binary logistic regression model (R 2  = 0.078; P = 0.003) retained intermediate-density lipoprotein-triglycerides (IDL-TG) [β:0.082 (95%CI: 0.005; 0.160); P = 0.039], high-density lipoprotein-triglycerides (HDL-TGL)/HDL-Cholesterol [β:3.633 (95%CI: 0.873; 6.394); P = 0.010], and large-HDL particle number [β: 3.710 (95%CI: 0.677; 6.744); P = 0.001] as statistically significant determinants of CAN. Adding these lipoprotein particles to a clinical prediction model of CAN that included age, duration of diabetes, and A 1c enhanced its diagnostic performance, improving AUC ROC from 0.546 (95%CI: 0.404; 0.688) to 0.728 (95%CI: 0.616; 0.840)., Conclusions: When added to clinical variables, 1 H-NMRS-lipoprotein particle profiles may be helpful to identify those patients with T1D at risk of CAN., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background and Aims: Lipoprotein particle concentrations and size are associated with increased risk for atherosclerosis and premature cardiovascular disease. Certain dietary behaviours may be cardioprotective and public health strategies are needed to guide consumers' dietary choices and help prevent diet-related disease. The Food Standards Agency nutrient profiling system (FSAm-NPS) constitutes the basis of the five-colour front-of-pack Nutri-Score labelling system. No study has examined FSAm-NPS index associations with a wide range of lipoprotein particle subclasses., Methods: This was a cross-sectional study of 2006 middle-to older-aged men and women randomly selected from a large primary care centre. Individual participant FSAm-NPS dietary scores were derived from validated food frequency questionnaires. Lipoprotein particle subclass concentrations and size were determined using nuclear magnetic resonance spectroscopy. Multivariate-adjusted linear regression analyses were performed to examine FSAm-NPS relationships with lipoprotein particle subclasses., Results: In fully adjusted models which accounted for multiple testing, higher FSAm-NPS scores, indicating poorer dietary quality, were positively associated with intermediate-density lipoprotein (β = 0.096, p = 0.005) and small high-density lipoprotein (HDL) (β = 0.492, p = 0.006) concentrations, a lipoprotein insulin resistance score (β = 0.063, p = 0.02), reflecting greater lipoprotein-related insulin resistance, and inversely associated with HDL size (β = -0.030, p = 0.045)., Conclusions: A higher FSAm-NPS score is associated with a less favourable lipoprotein particle subclass profile in middle-to older-aged adults which may be a potential mechanism underlying reported health benefits of a healthy diet according to Nutri-Score rating., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters., (© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Pathogenic variants in PLIN1 -encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1 -related FPL., Methods: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1 -mutated FPL and 3 controls., Results: Patients with PLIN1 -mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P =0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P <0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P =0.006). Compared with controls, patients with PLIN1 -related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P =0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P =0.005). VLDL-apoB100 production was not different between patients with PLIN1 -related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1 -related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 ( P =0.031) and IDL-apoB100 ( P =0.031). Plasma LPL mass was significantly lower in patients with PLIN1 -related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P <0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass., Conclusions: We show that hypertriglyceridemia associated with PLIN1 -related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass., Competing Interests: None.

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.

Background: Metabolic syndrome (MetS) is a cluster of medical conditions and risk factors correlating with insulin resistance that increase the risk of developing cardiometabolic health problems. The specific criteria for diagnosing MetS vary among different medical organizations but are typically based on the evaluation of abdominal obesity, high blood pressure, hyperglycemia, and dyslipidemia. A unique, quantitative and independent estimation of the risk of MetS based only on quantitative biomarkers is highly desirable for the comparison between patients and to study the individual progression of the disease in a quantitative manner., Methods: We used NMR-based metabolomics on a large cohort of donors (n = 21,323; 37.5% female) to investigate the diagnostic value of serum or serum combined with urine to estimate the MetS risk. Specifically, we have determined 41 circulating metabolites and 112 lipoprotein classes and subclasses in serum samples and this information has been integrated with metabolic profiles extracted from urine samples., Results: We have developed MetSCORE, a metabolic model of MetS that combines serum lipoprotein and metabolite information. MetSCORE discriminate patients with MetS (independently identified using the WHO criterium) from general population, with an AUROC of 0.94 (95% CI 0.920-0.952, p < 0.001). MetSCORE is also able to discriminate the intermediate phenotypes, identifying the early risk of MetS in a quantitative way and ranking individuals according to their risk of undergoing MetS (for general population) or according to the severity of the syndrome (for MetS patients)., Conclusions: We believe that MetSCORE may be an insightful tool for early intervention and lifestyle modifications, potentially preventing the aggravation of metabolic syndrome., (© 2024. The Author(s).)

Background: Endometriosis is a poorly understood disease that affects up to 196 million women worldwide and imposes high costs in terms of economic burden and quality of life of women. Traits of circulating lipids have been related to the onset and progression of endometriosis in previous observational studies but the results have remained contradictory., Methods: We performed univariable and multivariable Mendelian randomization (MR) analyses using instrument variables to genetically predict the associations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides, and apolipoprotein (apo) A-I and B from the UK Biobank with endometriosis (consisting of 8288 cases and 68 969 controls from the FinnGen consortium). The inverse-variance weighted (IVW) method was used as the primary estimate, whereas MR-Egger and weighted median were conducted as complements to the IVW model., Results: Increased levels of triglycerides were associated with higher risk of endometriosis and endometriosis of the pelvic peritoneum in the univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, triglycerides still retained a robust effect. Decreased levels of apoA-I and HDL cholesterol were associated with increased risk of endometriosis and endometriosis of the pelvic peritoneum in univariable MR analyses. After mutual adjustment, HDL cholesterol retained a robust effect whereas the association for apoA-I was attenuated., Conclusions: This is the first MR-based evidence to suggest that triglycerides and HDL cholesterol are the predominant traits that account for the aetiological relationship of lipoprotein lipids with risk of endometriosis, in particular endometriosis of the pelvic peritoneum. Further well-designed randomized controlled trials are needed to address these results., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The current first-line treatment for atherosclerotic cardiovascular disease (ASCVD) involves the reduction of a patient's low-density lipoprotein cholesterol (LDL-C) levels through the use of lipid-lowering drugs. However, even when other risk factors such as hypertension and diabetes are effectively managed, there remains a residual cardiovascular risk in these patients despite achieving target LDL-C levels with statins and new lipid-lowering medications. This risk was previously believed to be associated with lipid components other than LDL, such as triglycerides. However, recent studies have unveiled the crucial role of remnant cholesterol (RC) in atherosclerosis, not just triglycerides. The metabolized product of triglyceride-rich lipoproteins is referred to as triglyceride-rich remnant lipoprotein particles, and its cholesterol component is known as RC. Numerous pieces of evidence from epidemiological investigations and genetic studies demonstrate that RC plays a significant role in predicting the incidence of ASCVD. As a novel marker for atherosclerosis prediction, when LDL-C is appropriately controlled, RC should be prioritized for attention and intervention among individuals at high risk of ASCVD. Therefore, reducing RC levels through the use of various lipid-lowering drugs may yield long-term benefits. Nevertheless, routine testing of RC in clinical practice remains controversial, necessitating further research on the treatment of elevated RC levels to evaluate the advantages of reducing RC in patients at high risk of ASCVD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Historically, lipids and lipoproteins were measured in the fasting state for cardiovascular risk prediction; however, since 2009 use of nonfasting lipid profiles has increased substantially worldwide. For patients, nonfasting lipid profiles are convenient and avoid any risk of hypoglycemia. For laboratories, blood sampling in the morning and extra visits for patients who have not fasted are avoided. For patients, clinicians, hospitals, and society, nonfasting sampling allows same-day visits with first blood sampling followed by a short wait for test results before clinical consultation. Therefore, nonfasting compared to fasting lipid profiles will save money and time and may improve patient compliance with cardiovascular prevention programs., Content: We report on the progression of endorsement and implementation of nonfasting lipid profiles for cardiovascular risk prediction worldwide and summarize the recommendations from major medical societies and health authorities in different countries. We also describe practical advantages and disadvantages for using nonfasting lipid profiles. Further, we include a description of why fasting has been the standard historically, the barriers against implementation of nonfasting lipid profiles, and finally we suggest the optimal content of a nonfasting lipid profile., Summary: Lipid, lipoprotein, and apolipoprotein concentrations vary minimally in response to normal food intake and nonfasting lipid profiles are equal or superior to fasting profiles for cardiovascular risk prediction. Major guidelines and consensus statements in Europe, the United States, Canada, Brazil, Japan, India, and Australia now endorse use of nonfasting lipid profiles in some or all patients; however, there are still gaps in endorsement and implementation of nonfasting lipid profiles worldwide., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: The serum lipid level is strongly associated with atherosclerosis. However, research on the relationship between lipid-derived indices and acute ischemic stroke (AIS) occurrence in hemodialysis populations is limited. This study aimed to explore the predictive value of lipid-derived indices, including atherogenic index of plasma (AIP), Non- high density lipoprotein cholesterol (Non-HDL-C), Non-HDL-C/HDL-C, and lipoprotein combine index (LCI) in clinical practice for the occurrence and prognosis of AIS in hemodialysis patients., Methods: A total of 451 patients undergoing maintenance hemodialysis were screened and 350 were enrolled in this study. The lipid parameters exhibit a progressive increase across the tertiles, with values rising from Q1 through Q3. Enrolled patients were divided into three groups (Q1, Q2, and Q3) based on tertiles of AIP, Non-HDL-C, Non-HDL-C/HDL-C, and LCI values. Kaplan-Meier curves were performed to investigate the association between the AIP, Non-HDL-C, Non-HDL-C/HDL-C, LCI and AIS-free survival in hemodialysis patients. Chi-square analysis was used to explore the association between the AIP, Non-HDL-C, Non-HDL-C/HDL-C, LCI and AIS outcomes in hemodialysis patients. AIS outcomes were assessed using the modified Rankin Scale (mRS)., Results: Kaplan-Meier analysis revealed that the AIS-free survival rates were significantly higher in the Q1 group compared to Q2 and Q3 groups for AIP, Non-HDL-C, Non-HDL-C/HDL-C, and LCI. Log rank tests showed statistically significant differences between the Q1 group and the Q2 and Q3 groups (p < 0.05 for all). The proportion of patients with a good outcome mRS was higher in the Q1 group compared to the Q2-Q3 groups (AIP: 0.818 vs 0.792; Non- HDL-C: 0.866 vs 0.767; Non- HDL-C/HDL-C: 0.867 vs 0.767; LCI: 0.938 vs 0.750)., Conclusion: The four lipid-derived parameters are effective predictors of AIS in patients undergoing hemodialysis, and AIP has a strongest correlation with the risk of AIS. Hemodialysis patients with elevated levels of the four lipid-derived indices had a higher incidence of AIS and poorer functional outcomes compared to those with lower levels. Our conclusions may require confirmation by further research in the future., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Ma et al.)

Background: Phospholipid transfer protein (PLTP) transfers surface phospholipids between lipoproteins and as such plays a role in lipoprotein metabolism, but with unclear effects on coronary artery disease (CAD) risk. We aimed to investigate the associations of genetically-influenced PLTP activity with 1-H nuclear magnetic resonance ( 1 H-NMR) metabolomic measures and with CAD. Furthermore, using factorial Mendelian randomization (MR), we examined the potential additional effect of genetically-influenced PLTP activity on CAD risk on top of genetically-influenced low-density lipoprotein-cholesterol (LDL-C) lowering., Methods: Using data from UK Biobank, genetic scores for PLTP activity and LDL-C were calculated and dichotomised based on the median, generating four groups with combinations of high/low PLTP activity and high/low LDL-C levels for the factorial MR. Linear and logistic regressions were performed on 168 metabolomic measures (N = 58,514) and CAD (N = 318,734, N-cases=37,552), respectively, with results expressed as β coefficients (in standard deviation units) or odds ratios (ORs) and 95% confidence interval (CI)., Results: Irrespective of the genetically-influenced LDL-C, genetically-influenced low PLTP activity was associated with a higher high-density lipoprotein (HDL) particle concentration (β [95% CI]: 0.03 [0.01, 0.05]), smaller HDL size (-0.14 [-0.15, -0.12]) and higher triglyceride (TG) concentration (0.04 [0.02, 0.05]), but not with CAD (OR 0.99 [0.97, 1.02]). In factorial MR analyses, genetically-influenced low PLTP activity and genetically-influenced low LDL-C had independent associations with metabolomic measures, and genetically-influenced low PLTP activity did not show an additional effect on CAD risk., Conclusions: Low PLTP activity associates with higher HDL particle concentration, smaller HDL particle size and higher TG concentration, but no association with CAD risk was observed., Competing Interests: Declarations of Competing Interest None., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: I declare no competing interests.

Purpose: In Familial Hypercholesterolemia (FH), female atherosclerotic cardiovascular disease occurs 20 years earlier than in women without FH. The aim of this study is to describe the differences in lipoprotein apheresis (LA), a last therapeutic option, in terms of efficacy, safety and clinical outcomes between the two sexes., Materials and Methods: Sex related differences were analysed in 31 subjects in on LA treatment with FH and not achieving LDL-cholesterol and/or Lp(a) target values on maximum lipid-lowering therapies. Moreover, sex related differences in time to major cardiovascular event (MACE) was investigated in 68 subjects, with at least one year of follow-up., Results: Among the 31 patients currently undergoing LA treatment who did not achieve LDL-cholesterol and/or Lp(a) target values, no differences in comorbidity were recorded despite a worse pre-LA treatment lipid profile (LDL-C 77 ± 60 mg/dl in males vs. 128 ± 105 mg/dl in females; p 0.025) and a longer mean inter-apheresis interval (17 ± 4 days in males vs. 19 ± 5 days in females; p 0.012) reported in females compared to males. Additionally, in comparison with men, it was found that the time between the first cardiovascular event and the beginning of LA, as well as the age at the beginning of LA, were significantly higher in females than in males (p 0.027 and 0.007, respectively)., Conclusions: Sex differences in FH subjects not only affect the diagnosis and treatment but also influence varied responses to the treatment itself., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with schizophrenia show a disproportionally increased risk of cardiovascular disease. Hypertriglyceridemia is prevalent in this population; however, how this relates to levels of remnant cholesterol, triglyceride (TG)-rich lipoprotein (TRL) particle size and composition, TG turnover, and apolipoprotein (apo) and angiopoietin-like protein (ANGPTL) concentrations is unknown. Fasting levels of cholesterol (total [TC], LDL-C, HDL-C, non-HDL-C and remnant cholesterol) and TG were determined in 110 patients diagnosed with schizophrenia, and 46 healthy controls. TRL particle size, concentration and composition, and β-hydroxybutyrate (TG turnover marker) were assessed by NMR. Levels of apoCII, apoCIII, apoE, ANGPTL3, ANGPTL4, and ANGPTL8 were measured by ELISA, and apoCII, apoCIII and apoE were further evaluated in HDL and non-HDL fractions. Patients with schizophrenia had significantly elevated TG, TG:apoB ratio, non-HDL-C, remnant cholesterol, non-HDL-apoCII and non-HDL-apoCIII, and HDL-apoE (all P < 0.05), lower HDL-C and apoA-I (all P < 0.001), and comparable apoB, TC, TC:apoB ratio, LDL-C, β-hydroxybutyrate, ANGPTL3, ANGPTL4 and ANGPTL8 to healthy controls. Patients had a 12.0- and 2.5-fold increase in the concentration of large and medium TRL particles respectively, but similar cholesterol:TG ratio within each particle. Plasma TG, remnant cholesterol, and large and medium TRL particle concentrations correlated strongly with apoCII, apoCIII, and apoE in the non-HDL fraction, and with apoCIII and apoE in the HDL fraction in patients with schizophrenia. Differences in TG, HDL-C, TRL particle concentrations, apoCIII, and apoE persisted after adjustment for conventional risk factors. These results are consistent with impaired TRL lipolysis and clearance in patients with schizophrenia which may be responsive to targeting apoCIII., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: L.K. has participated in clinical trials sponsored by Amgen and Novartis; he has given lectures and received consulting fees from Seqiris (CSL), Amgen and Novartis. D.S. has participated in clinical trials sponsored by NHMRC Clinical Trials Centre; he has received support from Arrowhead Pharmaceuticals for previous publications; he has received grants/contracts sponsored by Regeneron Pharmaceuticals, Ionis Pharmaceuticals, Arrowhead Pharmaceuticals, Amgen and Novartis; he has given lectures and received consulting fees from Amgen and Novartis; he has received contributions from Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence., Methods: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis., Findings: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037)., Interpretation: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life., Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health., Competing Interests: Declaration of interests BAH received a research grant from Silence Therapeutics. GKH reports research grants from the Klinkerpad fonds, and part-time employment at Novo Nordisk (Søborg, Denmark) since April, 2019. GKH is shareholder of Novo Nordisk. DJB reports clinical trial fees paid to their institution from LIB Therapeutics, Novartis, Silence Therapeutics, and IONIS; speaker fees from Amgen, Sanofi, Organon, MSD, Amryt, and Novartis; and consulting fees from Amryt. ALC has received research grants or support from Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi Regeneron, and served as a consultant for or received honoraria from Akcea, Amarin, Amgen, Daiichi Sankyo, Esperion Therapeutics, Ionis, Kowa, Medco, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, Sanofi, and The Corpus. MC reports institutional support for the conduction of clinical trials from Regeneron Pharmaceuticals and Regenxbio, and consulting fees from Amryt Pharma. AG received grants and personal fees from Amgen, Sanofi–Regeneron, Mylan Viatris, MSD, Akcea Therapeutics, Amryt, Servier, Novartis, and Ultragenyx. FJR reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics. KKR reports grants from Amgen, Sanofi–Regeneron, Pfizer, Merck Sharp & Dohme, Daiichi Sankyo, and Ultragenyx; consulting fees from AstraZeneca, Kowa, Novartis, Sanofi, Amgen, Eli Lilly, Algorithm, Boehringer Ingelheim, Novo Nordisk, Silence Therapeutics, Bayer, Esperion, Daiichi Sankyo, Abbott, New Amsterdam, SCRIBE, CRISPR, VAXXINITY, EMENDOBIO, Cargene, Viatris, Amarin, Nodthera, and Resverlogix; honoraria for lectures from AstraZeneca, Novartis, Sanofi, Amgen, Algorithm, Boehringer Ingelheim, Novo Nordisk, Esperion, Daiichi Sankyo, and Amarin; and stock options in New Amsterdam, PEMI 31, and SCRIBE. HS reports research grants from Amgen, MSD, Synageva, Amryt, Alexion, and Akcea; consulting fees from Amgen, Alexion, Daiichi-Sankyo, Novartis, Pfizer, and Akcea; and speaker fees from Amgen, Daiichi-Sankyo, Sanofi, and Akcea. AW reports research grants from Amgen, Esperion, Novartis, Regeneron, Sanofi, Silence Therapeutics, and Ultragenyx; consulting fees from Chiesi and Novartis; and speaker fees from Algorithm, Sanofi, and Ultragenyx. All other authors declare no competing interests. The declaration of interests of individual collaborators are listed in the appendix (p 27)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Higher total serum cholesterol is associated with lower mortality in heart failure. Evaluating associations between lipoprotein subfractions and mortality among people with heart failure may provide insights into this observation., Methods: We prospectively enrolled a community cohort of people with heart failure from 2003 to 2012 and assessed vital status through 2021. Plasma collected at enrollment was used to measure lipoprotein subfractions via nuclear magnetic resonance spectroscopy. A composite score of 6 lipoprotein subfractions was generated using the lipoprotein insulin resistance index (LP-IR) algorithm. Using covariate-adjusted proportional hazards regression models, we evaluated associations between LP-IR score and all-cause mortality., Results: Among 1382 patients with heart failure (median follow-up 13.9 years), a one-standard-deviation (SD) increment in LP-IR score was associated with lower mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.97-0.99). Among LP-IR parameters, mean high-density lipoprotein (HDL) particle size was significantly associated with lower mortality (HR per 1-SD decrement in mean HDL particle size = 0.83; 95% CI, 0.78-0.89), suggesting that the inverse association between LP-IR score and mortality may be driven by smaller mean HDL particle size., Conclusions: LP-IR score was inversely associated with mortality among patients with heart failure and may be driven by smaller HDL particle size., (Published by Elsevier Inc.)

Coagulopathy, microvascular alterations and concomitant organ dysfunctions are hallmarks of sepsis. Attempts to attenuate coagulation activation with an inhibitor of tissue factor (TF), i.e. tissue factor pathway inhibitor (TFPI), revealed no survival benefit in a heterogenous group of sepsis patients, but a potential survival benefit in patients with an international normalized ratio (INR) < 1.2. Since an increased TF/TFPI ratio determines the procoagulant activity specifically on microvascular endothelial cells in vitro, we investigated whether TF/TFPI ratio in blood is associated with INR alterations, organ dysfunctions, disseminated intravascular coagulation (DIC) and outcome in septic shock. Twenty-nine healthy controls (HC) and 89 patients with septic shock admitted to a tertiary ICU were analyzed. TF and TFPI in blood was analyzed and related to organ dysfunctions, DIC and mortality. Patients with septic shock had 1.6-fold higher levels of TF and 2.9-fold higher levels of TFPI than HC. TF/TFPI ratio was lower in septic shock compared to HC (0.003 (0.002-0.005) vs. 0.006 (0.005-0.008), p < 0.001). Non-survivors had higher TFPI levels compared to survivors (43038 (29354-54023) vs. 28041 (21675-46582) pg/ml, p = 0.011). High TFPI levels were associated with acute kidney injury, liver dysfunction, DIC and disease severity. There was a positive association between TF/TFPI ratio and troponin T (b = 0.531 (0.309-0.754), p < 0.001). A high TF/TFPI ratio is exclusively associated with myocardial injury but not with other organ dysfunctions. Systemic TFPI levels seem to reflect disease severity. These findings point towards a pathophysiologic role of TF/TFPI in sepsis-induced myocardial injury., (© 2024. The Author(s).)