LDL Particles Research Articles

Mouse Model of Low-density Lipoprotein Desialylation In Vivo.

Atherosclerosis is a chronic disease characterized by the increased infiltration and retention of LDL particles in arterial walls. There are several mechanisms underlying atherogenesis, with the pro-atherogenic modifications of LDL playing a significant role. One such modification of native LDL is desialylation, which is characterized by the removal of terminal sialic acid from ApoB-100 glycans that induces critical changes in the overall functionality of the LDL particle. The aim of this study was to model the desialylation of native LDL in mice, resembling a phenomenon previously observed in atherosclerotic patients. LDL desialylation was induced in C57BL/6J mice via the injection of exogenous neuraminidase. The degree of LDL desialylation and its duration were assessed. The impact of LDL desialylation on blood lipid levels was evaluated. Furthermore, the morphological alterations in the aorta during LDL desialylation in the bloodstream were examined. The control group of C57BL/6J mice received saline injections, while the experimental group underwent a single injection of IgG-conjugated Vibrio cholerae neuraminidase. The LDL sialic acid levels were assessed 1-7 days post-injection using the Warren method and normalized to total protein content measured via the Lowry method. A similar protocol was followed for the subchronic administration of the IgG-neuraminidase conjugate over a 6-week period. The blood lipid profiles were analyzed using commercial kits. The atherosclerotic plaque burden in the mouse aorta was quantified using Oil Red O and hematoxylin-eosin staining. A single administration of 20 mU IgG-neuraminidase conjugate resulted in decreased LDL sialic acid levels for 5 days, gradually recovering by days 6-7. Subchronic administration maintained reduced LDL sialic acid levels for up to 2 months. Notably, sustained LDL desialylation was associated with elevated LDL cholesterol levels. A sustained desialylation of LDL in C57BL/6J mice was achieved through subchronic administration of IgG-conjugated neuraminidase. This study provides an approach for sustained LDL desialylation in mice. Further studies using apolipoprotein E knockout mice and LDL desialylation will reveal the role of this process in the occurrence and development of atherosclerosis.

Ethnic Disparities in the Risk Factors, Morbidity, and Mortality of Cardiovascular Disease in People With Diabetes.

Cardiovascular disease (CVD) is the leading cause of death in people with diabetes. Compared with European Americans, African Americans have more favorable lipid profiles, as indicated by higher high-density lipoprotein cholesterol, lower triglycerides, and less dense low-density lipoprotein particles. The less atherogenic lipid profile translates to lower incidence and prevalence of CVD in African Americans with diabetes, despite higher rates of hypertension and obesity. However, African Americans with CVD experience worse clinical outcomes, including higher mortality, compared with European Americans. This mini-review summarizes the epidemiology, pathophysiology, mechanisms, and management of CVD in people with diabetes, focusing on possible factors underlying the "African American CVD paradox" (lower CVD incidence/prevalence but worse outcomes). Although the reasons for the disparities in CVD outcomes remain to be fully elucidated, we present a critical appraisal of the roles of suboptimal control of risk factors, inequities in care delivery, several biological factors, and psychosocial stress. We identify gaps in current knowledge and propose areas for future investigation.

Metformin-Induced Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition Further Decreases Low-Density Lipoprotein Cholesterol Following Statin Treatment in Patients With Coronary Artery Disease and Without Diabetes.

In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin±ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression. Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019).

Effects of phytosterol supplementation on lipoprotein subfractions and LDL particle quality

Phytosterols are natural components of plant-based foods used as supplements because of their known cholesterol-lowering effect. However, their effects on lipoprotein subfractions and the quality of the LDL particle have not been studied in greater detail. We aimed to evaluate the effects of phytosterols supplements on lipids, lipoproteins subfractions, and on the quality of LDL. A prospective, pilot-type, open label, cross-over study, randomized 23 males in primary prevention of hypercholesterolemia to receive diet or diet plus phytosterol (2.6 g in 2 doses, with meals) for 12 weeks, when treatments were switched for another 12 weeks. Lipoprotein subfractions were analyzed by electrophoresis in polyacrylamide gel (Lipoprint System®). The Sampson equation estimated the small and dense (sd) and large and buoyant (lb) LDL subfractions from the lipid profile. Quality of LDL particle was analyzed by Z-scan and UV–vis spectroscopy. Primary outcome was the comparison of diet vs. diet plus phytosterols. Secondary outcomes assessed differences between baseline, diet and diet plus phytosterol. Non-parametric statistics were performed with p < 0.05. There was a trend to reduction on HDL-7 (p = 0.05) in diet plus phytosterol arm, with no effects on the quality of LDL particles. Heatmap showed strong correlations (ρ > 0.7) between particle size by different methods with both interventions. Diet plus phytosterol reduced TC, increased HDL-c, and reduced IDL-B, whereas diet increased HDL7, and reduced IDL-B vs. baseline (p < 0.05, for all). Phytosterol supplementation demonstrated small beneficial effects on HDL-7 subfraction, compared with diet alone, without effects on the quality of LDL particles.This trial is registered in Clinical Trials (NCT06127732) and can be accessed at https://clinicaltrials.gov.

Low-density lipoprotein particle profiles compared with standard lipids measurements in the association with asymptomatic intracranial artery stenosis

The Shiga Epidemiological Study of Subclinical Atherosclerosis was conducted in Kusatsu City, Shiga, Japan, from 2006 to 2008. Participants were measured for LDL-p through nuclear magnetic resonance technology. 740 men participated in follow-up and underwent 1.5 T brain magnetic resonance angiography from 2012 to 2015. Participants were categorized as no-ICAS, and ICAS consisted of mild-ICAS (1 to < 50%) and severe-ICAS (≥ 50%) in any of the arteries examined. After exclusion criteria, 711 men left for analysis, we used multiple logistic regression to examine the association between lipid profiles and ICAS prevalence. Among the study participants, 205 individuals (28.8%) had ICAS, while 144 individuals (20.3%) demonstrated discordance between LDL-c and LDL-p levels. The discordance “low LDL-c–high LDL-p” group had the highest ICAS risk with an adjusted OR (95% CI) of 2.78 (1.55–5.00) in the reference of the concordance “low LDL-c–low LDL-p” group. This was followed by the concordance “high LDL-c–high LDL-p” group of 2.56 (1.69–3.85) and the discordance “high LDL-c–low LDL-p” group of 2.40 (1.29–4.46). These findings suggest that evaluating LDL-p levels alongside LDL-c may aid in identifying adults at a higher risk for ICAS.

Discovery of potent small-molecule inhibitors of lipoprotein(a) formation

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3–7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7–8. We identify compounds that bind to apo(a) KIV7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).

Obesity and Sex as Determinants of Atherogenic Risk Associated with High-Density (HDL) and Low-Density Lipoprotein (LDL) Subfractions in Adolescents: A Population-based Study Based on Health Survey of Sao Paulo

Background: Worldwide, obesity in adolescents is an epidemiological concern. Overweight and obesity are associated with comorbidities in adult life, such as increased risk of hypertension and other non-communicable diseases. This study investigated possible differences between traditional lipid markers and Low-Density Lipoprotein (LDL) and High-Density Lipoprotein (HDL) subfractions in a population-wide representative sample of Brazilian adolescents. Methods: The individuals included in the study comprise a subsample of the 2015 Health Survey of São Paulo (ISA-Capital 2015). LDL and HDL particle sizes were determined by the Lipoprint® System (Quantimetrix Corporation). Results: 272 Brazilian adolescents with a mean age of 15.2 ± 2.2 years, of which 47.8% (n = 130) are boys. Analysis of LDL subfractions showed an increase in LDL 2 content in girls (5.7% vs. 5.1%; p = 0.047). This result was associated with a higher content of large LDL in girls (17.8% vs. 13.5%; p &lt; 0.001) and a significant, lower content of small LDL (1.7% vs. 3.4%; p = 0.002). When obesity was considered, we observed that regardless of being overweight, girls had higher large and small LDL than boys. However, when a large to small LDL ratio was calculated, girls with no excess weight had higher values than boys with no excess weight (10.6 vs. 9.3; p = 0.038), and these had lower LDL ratio than overweight boys (9.3 vs. 13.5; p = 0.016). On the other hand, boys had higher HDL 2 content than girls (8.9% vs. 8.0%; p = 0.017), which was associated with increased large HDL values in boys (1.9% vs. 1.7%; p = 0.047). Regression analysis was performed according to gender, the sum of very low-density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) C + IDL B subfractions was adjusted for age and body mass index (BMI), showing that girls had lower atherogenic lipid profile (β = 0.987; CI = 0.977-0.998; p = 0.017) than boys. When the regression analysis was performed according to BMI, large LDL in adolescents with no excess weight presented a lower atherogenic lipid profile (β = 1.040; CI = 1.000-1.082; p = 0.049), adjusted for age and sex, than overweight adolescents. Conclusion: Regardless of excess weight, girls showed a cardioprotective profile more associated with a favorable distribution of LDL subfractions than boys, reinforcing the relevance of evaluating qualitative aspects of lipoproteins in addition to the traditional cholesterol content.

Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial

ObjectivesTo determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. MethodsIndividuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS. ResultsIndividuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21–1.53), factor 3 (OR:1.75, 95 %CI:1.53–2.02) and factor 4 (OR:1.49; 95 %CI:1.32–1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77–0.97) and factor 5 (OR:0.74, 95 %CI:0.65–0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82–61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14–9.29) and HDL (OR:0.35, 95 %CI:0.13–0.72) were confirmed. ConclusionsLarge TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS.

Obicetrapib on top of maximally tolerated lipid‐modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a) and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

Acoustic Delivery of Plasma Low-Density Lipoprotein into Liver via ApoB100-Targeted Microbubbles Inhibits Atherosclerotic Plaque Growth.

Atherosclerosis is the main risk factor for cardiovascular disease, which accounts for the majority of mortality worldwide. A significantly increased plasma level of low-density lipoprotein cholesterol (LDL-C), surrounded by a monolayer of phospholipids, free cholesterol, and one apolipoprotein B-100 (ApoB-100) in the blood, plays the most significant role in driving the development of atherosclerosis. Commercially available cholesterol-lowering drugs are not sufficient for preventing recurrent cardiovascular events. Developing alternative strategies to decrease the plasma cholesterol levels is desirable. Herein, we develop an approach for reducing LDL-C levels using gas-filled microbubbles (MBs) that were coated with anti-ApoB100 antibodies. These targeted MBApoB100 could selectively capture LDL particles in the bloodstream through forming LDL-MBApoB100 complexes and transport them to the liver for degradation. Further immunofluorescence staining and lipidomic analyses showed that these LDL-MBApoB100 complexes may be taken up by Kupffer cells and delivered to liver cells and bile acids, greatly inhibiting atherosclerotic plaque growth. More importantly, ultrasound irradiation of these LDL-MBApoB100 complexes that accumulated in the liver may induce acoustic cavitation effects, significantly enhancing the delivery of LDL into liver cells and accelerating their degradation. Our study provides a strategy for decreasing LDL-C levels and inhibiting the progression of atherosclerosis.

Linkage of the CETP’S activity to LDL subclasses and particle size in patients with OSA

Linkage of the CETP’S activity to LDL subclasses and particle size in patients with OSA

Cardiovascular risk assessment in inflammatory bowel disease with metabolic dysfunction-associated steatotic liver disease

Background and aimsInflammatory bowel disease (IBD) has been reported to increase the risk of early atherosclerosis even in young patients. Moreover, metabolic dysfunction-associated steatotic liver disease (MASLD), which has been linked to IBD, is a well-recognized but underdiagnosis entity related to cardiovascular risk. We analyze the impact of MASLD in IBD patients’ cardiovascular risk through both advanced lipoprotein profile sorted by nuclear magnetic resonance spectroscopy, and carotid artery intima-media thickness (CIMT). MethodsCross-sectional cohort study which involves 941 IBD adult outpatients. Of them, 50 patients with IBD who met criteria for MASLD and 50 with IBD without MASLD, matched by sex and age were included. Alterations in CIMT were evaluated considering abnormal measures above the 75th percentile adjusted for sex and age. Specific advanced lipoprotein profile was also carried out. ResultsMost of the patients had an abnormal CIMT (58%). MASLD (OR=5.05, CI 95%=1.71–14.92) and female sex (OR=3.32, CI 95%=1.03–10) were significantly associated with CIMT alterations. Dense LDL particles (with high cholesterol composition in general cohort (OR=3.62, 95% CI=1.07–12.19) and high triglycerides density in young subgroup (OR=6.25, 95% CI=1.04–50) but not total LDL cholesterol were associated with CIMT alterations. ConclusionsMASLD and female sex are associated with early atherosclerosis in IBD patients. Dense LDL particle in combination with vascular imaging findings should be evaluated as non-invasive tools in the management of cardiovascular risk in IBD patients.

Effects of portable pedal machines at work on lipoprotein subfraction profile in sedentary workers – the REMOVE study

BackgroundSedentary behaviour at work is a major cause of atherosclerosis, particularly in tertiary workers. However, no studies have ever assessed the effect of active workstation on lipoprotein subfraction profile. This study aimed to evaluate the effect of 12-week portable pedal machines (PPMs) on lipoprotein subfraction profile among healthy sedentary workers.MethodsHealthy administrative workers were randomized into an intervention group using PPMs for 12 weeks or a control group using normal-desk. Lipoprotein subfractions were assessed using Lipoprint® electrophoresis. Main outcomes were explored using mixed models with sensitivity analyses (four models).ResultsWe included 40 participants (43.7 ± 8.6 years old, 100% women, BMI 23.8 ± 3.4 kg/m2; sedentary time at work 7.7 ± 1.8 h/day). Groups did not differ at baseline in any outcomes. 32 participants finished the trial. Changes in lipoprotein subfractions were especially marked for LDL profile. There was an interaction time x group for all parameters related to LDL and their subfractions: total LDL-cholesterol (p = 0.012), LDL particle size (p = 0.027), large LDL subfractions 1 and 2 (p = 0.001), and small dense LDL subfractions 3 to 7 (p = 0.046), using the crude model. The interaction reflects difference in the direction of changes between groups. The LDL particle size significantly increased in the intervention group (from 271.9 ± 2.5 at t0 to 272.8 ± 1.9 Ångström at t1, p = 0.037) while it did not change in the control group (272.5 ± 1.7 at t0 to 271.8 ± 1.5Å at t1, p = 0.52). All interactions were constantly significant whatever the models. Influencing variables were mainly stress at work that was associated with an increase in total LDL-cholesterol (coefficient 3.15, 95CI 0.20 to 6.11 mg/dl, p = 0.038), and BMI that was associated with Large-LDL, Large-HDL, IDL-C and triglycerides.ConclusionsLipoprotein profile was improved after a 12-week PPMs intervention at work in healthy administrative workers. Changes were mainly showed for LDL and LDL subfractions. Lipoprotein profile was worsened by stress at work, BMI and age.Trial registrationNCT04153214.

Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes.

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.

MicroRNA-mediated Regulation of LDL Receptor: Biological and Pharmacological Implications.

One of the main causes of atherosclerosis is a disruption in cellular cholesterol hemostasis. The low-density lipoprotein receptor (LDLR) is an important factor in maintaining cholesterol homeostasis by the receptor-mediated endocytosis of LDL particles. Defective hepatic LDLR activity and uptake of LDL particles lead to elevated blood levels of low-density lipoprotein cholesterol (LDL-C), which is associated with a higher risk of atherosclerotic cardiovascular disease. LDLR expression can be affected by microRNAs (miRNAs). Some miRNAs, like miR-148a, miR-185, miR-224, miR-520, miR-128-1, miR-27a/b, miR-130b, and miR-301 seem to be important post-transcriptional regulators of LDLR related genes. These findings indicate the critical role of miRNAs in regulating LDL metabolism. The aim of this review was to provide insight into the miRNAs involved in LDLR activity and their potential roles in the treatment of cardiovascular disease.

Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 modulate bile acids and cholesterol metabolism in humans.

Probiotics with high bile salt hydrolase (BSH) activity have shown to promote cardiovascular health. However, their mechanism(s) of action remain poorly understood. Here, we performed a pilot exploratory study to investigate effects of a 4-week intervention with escalating doses of a BSH-active formula containing Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 on bile acid (BA), lipid profile, and lipoprotein function. Healthy overweight individuals were included in this study. The probiotic intake was associated with a progressive decrease of conjugated BAs in serum, due to the reduction of tauro- and glyco-conjugated forms. Plasma levels of fibroblast growth factor-19 were significantly reduced and correlated with BA changes. The probiotic induced significant changes in serum lipids, with reduction in non-HDL cholesterol (non-HDLc) and LDL cholesterol (LDLc) levels. The largest decrease was evidenced in the subgroup with higher baseline LDLc levels (LDLc > 130 mg/dL). Fasting levels of circulating apolipoprotein(Apo) B100 and ApoB48 were significantly reduced. Importantly, the decrease in non-HDLc levels was associated with a significant reduction in small LDL particles. Functional testing indicated that LDL particles had a significantly lower susceptibility to oxidation, while HDL particles gained antioxidant capacity after the probiotic intake. The microbiota profile in faeces collected at the end of the study was enriched with members of class Desulfovibrio, a taurine-consuming bacteria, likely because of the increase in free taurine in the gut due to the BSH activity of the probiotic. The intervention with L. plantarum strains induces beneficial effects on BA signature and lipoprotein profile. It reduces ApoB and small LDL levels and LDL susceptibility to oxidation and increases HDL antioxidant capacity. These metabolic profile changes suggest increased protection against atherosclerotic disease.

VLDL and LDL Subfractions Enhance the Risk Stratification of Individuals Who Underwent Epstein-Barr Virus-Based Screening for Nasopharyngeal Carcinoma: A Multicenter Cohort Study.

Serological tests for Epstein-Barr virus (EBV) antibodies have been widely conducted for the screening of nasopharyngeal carcinoma (NPC) in endemic areas. Further risk stratification of NPC can be achieved through plasma lipoprotein and metabolic profiles. A total of 297 NPC patients and 149 EBV-positive participants are enrolled from the NCT03919552 and NCT05682703 cohorts for plasma nuclear magnetic resonance (NMR) metabolomic analysis. Small, dense very low density lipoprotein particles (VLDL-5) and large, buoyant low density lipoprotein particles (LDL-1) are found to be closely associated with nasopharyngeal carcinogenesis. Herein, an NMR-based risk score (NRS), which combines lipoprotein subfractions and metabolic biomarkers relevant to NPC, is developed and well validated within a multicenter cohort. Combining the median cutoff value of the NRS (N50) with that of the serological test for EBV antibodies, the risk stratification model achieves a satisfactory performance in which the area under the curve (AUC) is 0.841 (95% confidence interval: 0.811-0.871), and the positive predictive value (PPV) reaches 70.08% in the combined cohort. These findings not only suggest that VLDL-5 and LDL-1 particles can serve as novel risk factors for NPC but also indicate that the NRS has significant potential in personalized risk prediction for NPC.

Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study.

Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010). In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

Abstract P180: Navigating Lipid Discrepancies: Implications for Cardiovascular Risk With LDL, Non-HDL, LDL-P, and ApoB

Background: Lipid discordance, characterized by conflicting results among various lipid measures used in cardiovascular risk assessment, has been a subject of interest and concern. Previous comparisons of LDL-C and non-HDL-C with ApoB and LDL particle numbers as cardiovascular risk predictors have shown conflicting results, partly because they were treated as independent variables. This study aimed to examine the extent of lipid discordance and its implications for risk assessment. Methods: A cross-sectional study involving 106 individuals with lipid panels was conducted, and LDL cholesterol (LDL-C), non-HDL cholesterol (non-HDL-C), LDL particle number (LDL-P), and Apolipoprotein B (ApoB) were measured using standardized methods. Lipid discordance was defined as disagreement in risk categorization between different measures based on established cut-off values. Prior studies have described three different approaches to identify discordance such as quintiles, percentiles or the median, and all have demonstrated similar clinical results. Our analysis utilized the percentile method. Results: The results revealed a substantial level of lipid discordance, with 91.5% of individuals having at least one discordance among the four lipid measures. Most prevalent was the discordance between LDL-C and LDL-P, observed in 70.75% of individuals, with an average discordance of approximately 45.03% for LDL-P. Additionally, 20.75% of individuals displayed discordance between LDL-C and ApoB, averaging about 17.07%. The remaining 8.49% showed relative concordance. Conclusion: Our study highlights significant lipid discordance among various measures, impacting cardiovascular risk assessment. Increased ApoB or LDL particle numbers elevate risk, even with stable LDL-C and non-HDL-C. Conversely, low ApoB or LDL particles and elevated LDL-C or non-HDL-C indicate lower risk. We stress the limitations of population-based lipid management and advocate personalized strategies based on the most discordant lipid measure, improving accuracy and outcomes. Individualized risk assessment and tailored interventions are crucial.

Abstract MP60: A Randomized Placebo-Controlled Trial of Pitavastatin Calcium to Treat Combined Dyslipidemia of Obesity in Adolescents - The Pediatric Heart Network Dyslipidemia of Obesity Intervention in Teens (Do It!) Trial

Background: Combined dyslipidemia of obesity (CDO) is prevalent in ~20% of youth and characterized by high numbers of atherogenic small LDL (sLDL) particles associated with stiffer arteries. The safety and impact of statin therapy is not known. Methods: A 2-year masked trial of pitavastatin calcium 4 mg/day versus placebo for participants ages 10-19 years with body mass index (BMI) ≥85 th %ile and CDO defined as non-HDL-C ≥120 mg/dL and either low HDL-C or high triglyceride (TG):HDL-C ratio. The primary outcome was change in carotid-femoral pulse wave velocity (PWV) and carotid measures assessed at baseline, 6, 12, 18, and 24 months. Secondary outcomes included safety and lipid measures. Results: Across 18 sites, 59 participants were randomized to pitavastatin and 60 to placebo. Demographic (mean age 13.5±1.2 yrs; 55% males), anthropomorphic (BMI %ile 98±3; waist/height ratio 0.66±0.08), lipid (non-HDL-C 167±29 mg/dL, LDL-C 127±25 mg/dL, HDL-C 37±7 mg/dL, TG/HDL ratio 6.4±4.7, sLDL number 866±419 nmol/L), vascular (PWV 5.0±0.7 m/sec) and safety measures were similar at baseline between groups. There were 28 early terminations (11 pitavastatin, 17 placebo). Significant reductions with pitavastatin versus placebo were noted in non-HDL-C (median -25% vs +3% at 6 months, p&lt;0.001), LDL-C (-29% vs +7%, p&lt;0.001), and apolipoprotein B (-26% vs 0%, p&lt;0.001). An early reduction relative to placebo in sLDL particle number was not sustained (FIGURE A), and there were no significant changes or trends for PWV (FIGURE B) or carotid measures in either group. There was one serious adverse event (placebo), and no significant differences in liver enzymes, muscle toxicity, glucose homeostasis, or somatic growth, including adiposity. Conclusions: Over 2 years, treatment of CDO in adolescents with pitavastatin calcium resulted in significant improvement in dyslipidemia with no safety concerns. No change in PWV in either group may be due to lower-than-expected baseline PWV, insufficient magnitude of impact on CDO, or lack of change in adiposity.