apoB Levels Research Articles

Abstract 1009: Elevated Lipoprotein (a) Is Associated With Increased Risk Of Abdominal Aortic Aneurysm.

Introduction: Lipoprotein(a) (Lp(a)) is an apolipoprotein B (ApoB) containing particle that is causally associated with atherosclerotic vascular disease and the target of emerging therapeutics. Recent work has highlighted the role of circulating lipoproteins in abdominal aortic aneurysm (AAA). We sought to triangulate human observational and genetic evidence to evaluate the role of Lp(a) in AAA. Methods: We tested the association between levels of Lp(a) and clinically diagnosed aortic aneurysms while controlling for traditional AAA risk factors and levels of ApoB using logistic regression among 798 individuals with and 384,499 individuals without AAA in the UK biobank (UKB). Multivariable Mendelian randomization (MVMR) was used to test for putatively casual associations between Lp(a) and AAA controlling for ApoB. Genetic instruments for Lp(a) and ApoB were created from genome-wide association studies (GWAS) of Lp(a) and ApoB comprising 335,796 and 418,505 UKB participants, respectively. The instruments were tested against AAA using data from a GWAS of 39,221 individuals with and 1,086,107 without AAA. Results: Elevated Lp(a) levels were associated with an increased risk of AAA (OR 1.04 per 10 nmol/L Lp(a); 95%CI 1.02-1.05; P<0.01). Clinically elevated Lp(a) levels (>150nmol/L) were likewise associated with an increased risk of AAA (OR 1.50; 95%CI 1.17-1.91; P<0.01) when compared to individuals with Lp(a) levels <150nmol/L. MVMR confirmed a significant association between genetically proxied increased Lp(a) and increased genetic liability to AAA (OR 1.13 per SD increased in Lp(a); 95%CI 1.02-1.24; P<0.02). Conclusion: Both observational and genetic casual inference analyses support an association between increased Lp(a) and AAA risk that is independent of ApoB. Mendelian randomization analyses posit a causal relationship. These findings suggest that Lp(a) may be a therapeutic target for AAA and drive the inclusion of AAA as an outcome in clinical trials of Lp(a) antagonists.

Relationships Between the Apolipoprotein Levels and Sarcopenia in Inpatients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.

Apolipoprotein (Apo) may be associated with sarcopenia in elderly inpatients with type 2 diabetes mellitus (T2DM), but fewer studies are available. In this study, we explored the association of ApoA1, ApoB, and ApoB/ApoA1 with sarcopenia and compared the predictive role of Apo indicators for sarcopenia in an elderly T2DM. To investigate the relationships between the Apo and sarcopenia in elderly inpatients with T2DM. This study included 253 inpatients with T2DM (mean age of 70.11±5.44 years, 32.8% male). The inpatients were divided into the sarcopenic group (n = 100) and non-sarcopenic group (n = 153). The associations among the Apo and sarcopenia were assessed using multivariate analyses. Inpatients in the sarcopenia group showed lower ApoA1 levels than those in the non-sarcopenia group (1.25±0.21 vs 1.36±0.20 g/L, P < 0.05) and showed higher ApoB/ApoA1 and ApoB levels than those in the non-sarcopenia group (0.82±0.27 vs 0.69±0.19 g/L, P < 0.05;1.00±0.32 vs 0.93±0.24 g/L, P < 0.05, respectively). After adjusting for age and BMI, the logistic regression model indicated that ApoA1 was a protective factor for elderly inpatients with T2DM sarcopenia.(OR =0.079,95% CI: 0.021~0.306, P < 0.05);ApoB and AopB/AopA1 were risk factors for elderly inpatients with T2DM sarcopenia.(OR =3.578,95% CI:1.318~9.715, P < 0.05;OR =16.440,95% CI:4.437~60.427, P < 0.05, respectively). AopB/AopA1 provided an AUC value of 0.765 in elderly men.(95% CI: 0.665~0.866, P<0.05). ApoA1, AopB, and AopB/AopA1 are associated with sarcopenia in elderly inpatients with T2DM, and AopB/AopA1 may be a potential predictor of sarcopenia in elderly men with T2DM.

Abstract 1022: Microrna-615-3p Decreases Apolipoprotein B Expression In Human Liver Cells And Its Plasma Concentrations Are Inversely Correlated With Plasma Lipid Levels

Plasma lipids are mainly carried in apolipoprotein B (apoB) containing lipoproteins. High levels of these lipoproteins are associated with several metabolic diseases and lowering their plasma levels is associated with reduced incidence of atherosclerotic cardiovascular disease. MicroRNAs (miRs) are small non-coding RNAs that reduce protein expression of their target genes and are potential therapeutic agents. Here, we identified a novel miR-615-3p that interacts with human 3′-UTR of apoB mRNA, induces post-transcriptional mRNA degradation, and reduces cellular and secreted apoB100 in human hepatoma Huh-7 cells. Reducing cellular miR-615-3p levels by CRISPR-sgRNA increased cellular and secreted apoB100 indicating endogenous miR regulates apoB expression. Furthermore, we found that obese subjects have lower levels of miR-615-3p than healthy individuals. Moreover, there was a significant negative correlation between miR-615-3p and plasma lipids and apoB levels. These studies indicate that miR-615-3p negatively regulates apoB and its plasma levels could serve as a biomarker for obesity and possibly other metabolic diseases.

Proteomic Signatures of Coronary Artery Disease and Hypercholesterolemia

Background: Coronary artery disease (CAD) is the most common type of cardiovascular disease (CVD), it causes narrowing of the blood vessel lumen due to atherosclerotic plaque formation. Atherosclerosis, is strongly influenced by hypercholesterolemia (HC). Proteomics offers advantages over traditional studies that focus on individual biomarkers. This method provides a holistic view by examining the entire proteomic spectrum in a biological sample, making it an indispensable asset for spotting potential novel protein biomarkers directly linked to atherosclerosis occurrence, progression, and complications such as plaque instability or rupture. Methods: Slow Off-rate Modified Aptamer (SOMAmer)-based protein array was used to quantify proteins. Our cross-sectional study involved healthy controls (n=45), and patients diagnosed with HC (n=51) or CAD (n=32). Proteome data was analyzed using multiple statistical methods. Results: The orthogonal partial least square discriminant analysis (OPLS-DA) revealed a clear separation of the 3 study groups based on two principal components, with R2X= 0.267, R2Y= 0.9, and Q2= 0.28, indicating distinct protein alterations between groups. A total of 1,305 proteins were analyzed and 156 of them in CAD vs control, 140 of them in HC vs control, and 326 of the proteins in CAD vs HC comparisons, were significantly differentially expressed with a p-value&lt;0.05. Among those, q-value&lt;0.05 were determined. As a result, in CAD patients, 2 proteins exhibited significantly differential expressions compared to healthy controls. In contrast, HC patients had 15 significantly altered proteins compared to controls. Furthermore, a comparison between CAD and HC patients revealed 87 significantly regulated proteins. The receiver operating characteristic (ROC) was performed on proteins with distinct expressions ( q&lt;0.05) in pairwise group comparisons. The AUC was calculated to identify potential biomarker candidates for the disease groups. In the CAD vs. control analysis, both significant proteins (PCSK9, SDF-1) exhibited an AUC of 0.75. In the comparison between HC and control groups, out of 15 significantly altered proteins, 7 had an AUC of 0.75 or higher (LRP1B, Apo E, QORL1, Apo E3, Apo B, Transferrin, MMP-3). Among the 87 proteins significantly differentially expressed in CAD versus HC, 59 had an AUC ≥ 0.75. Sixteen of these proteins had an AUC ≥ 0.80. Conclusion: Distinct protein patterns associated with each condition were identified. CAD patients showed a significant increase in the cholesterol-metabolizing protein PCSK9 and varying levels of the angiogenesis-related protein SDF-1. Several other proteins (LRP1B, VAV, CSRP3, HSP 60, and TAK1-TAB1) also exhibited unique expressions in disease groups, suggesting potential roles in atherosclerosis development. Moreover, a statistically significant correlation between SDF-1, ApoB levels, and LDL levels was found in CAD patients but not in healthy controls. This discovery phase cohort study unveils potential biomarkers for atherosclerosis within the HC context. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 2048: Pla2g12b Is Critical For Intestinal Lipid Absorption In Mice

We previously showed that Pla2g12bhlb218/hlb218 (Pla2g12bmt/mt) mice injected with viruses expressing mutant PCSK9, fed a western diet had significantly lower plasma lipids and fewer atherosclerotic plaques. Here, we aimed to explain mechanisms for resistance to hyperlipidemia and atherosclerosis in these mice. We performed studies in 3-month-old male and female chow fed Pla2g12bmt/mt and control mice. Dual x-ray absorptiometry did not reveal any significant differences in body weight, fat weight and fat percentage in Pla2g12bmt/mt mice compared to controls. Moreover, there were no significant differences in energy expenditure and food intake between mutant and control mice. However, these mice had significantly lower levels of plasma glucose, insulin, triglyceride, cholesterol, HDL-c, LDL-c, apoB48, and apoB100. In oral fat tolerance test Pla2g12bmt/mt mice showed significant defects in triglyceride absorption. Furthermore, these mice excreted more fecal triglyceride, but not cholesterol. Oil Red O, H &amp; E staining, transmission electron microscopy, and quantifications of lipids in the duodenum indicated accumulation of large lipid droplets and dilated endoplasmic reticulum. These studies suggest that Pla2g12bmt/mt mice have significant defect in intestinal fat absorption. These defects were not due to reductions in apoB and MTP expression. RNA-Seq analysis of duodenal samples revealed upregulation of glycerolipid metabolism, arachidonic acid metabolism, oxidative phosphorylation, and thermogenesis. These pathways were likely upregulated to increase cellular catabolism and oxidation of accumulated lipids. Down upregulated pathways were related to pancreatic secretion, protein digestion and absorption. Despite severe defects in fat absorption, these mice maintain normal growth and physiology. These mice may serve as model to understand metabolism in hypolipidemia disorders associated with significant defects in lipid absorption such as abetalipoproteinemia and hypobetalipoproteinemia.

The role of BMI, serum lipid profile molecules and their derivative indexes in colorectal polyps.

To investigate the role of body mass index (BMI), serum lipid profile molecules and their derivative indexes in colorectal polyps. A total of 352 individuals who underwent colonoscopy at our center were included in this retrospective analysis. Of these, 247 patients without evident abnormalities (control group), while 105 patients diagnosed with colorectal polyps (patient group). Serum lipid profile molecules and their derivative indexes were then compared between the two groups. The patient group exhibited significantly higher levels of total cholesterol (TC) and apolipoprotein B (ApoB) compared to the control group (p<0.05). In males, the patient group displayed elevated levels of ApoB and ApoB/ApoA1 ratio compared to the control group (p<0.05). Additionally, the triglycerides (TG) and TG/high-density lipoprotein-cholesterol (HDL-C) ratios were significantly higher in the multiple polyps group than in the single polyp group (p<0.05). Furthermore, the HDL-C and HDL-C/ApoA1 ratio levels were higher in the adenomatous polyp group when compared to the non-adenomatous polyp group (p<0.05). Multiple logistic regression analysis indicated that total cholesterol (TC), TG, low-density lipoprotein-cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio and LDL-C/HDL-C ratio were risk factors for the occurrence of colorectal polyps (p<0.05). ROC curve analyses revealed that TC, ApoB, and ApoB/ApoA1 ratio were associated with colorectal polyps. No significant difference in BMI between the two groups (p>0.05). The incidence and progression of colorectal polyps are linked to serum lipid molecules and their derivative indexes. Dyslipidemia may increase the risk of colorectal polyps, potentially leading to colorectal cancer (CRC).

Roles of Single Nucleotide Polymorphisms of C3 Gene in Patients with Coronary Artery Disease.

This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the C3 gene locus and the risk of coronary artery disease (CAD) as well as lipid levels in the Chinese population, and to further explore the interactions between SNPs and environmental factors that may be associated with CAD risk. A case-control study was conducted to investigate the association between CAD and C3 gene polymorphisms in a hospital setting. The study consisted of 944 CAD patients with a mean age of 55.97 10.182 years and 897 non-CAD controls with a mean age of 55.94 9.162 years. There were 565 males and 288 females in the CAD group and 583 males and 314 females in the control group. TagSNPs in the C3 gene were identified by employing the improved multiplex ligation detection reaction (iMLDR) technique, and multifactor dimensionality reduction (MDR) analysis was utilized to investigate the C3 gene-environment and gene-gene interactions in relation to the risk of CAD. Results of the polymorphism study indicated that the CC genotype of rs7257062 was more frequent in the CAD group compared to the control group (10.9% vs 7.7%), with a statistically significant difference (p = 0.009). Moreover, the TT and CC + CT genotype groups of rs7257062 in the CAD subgroup showed a significant difference in terms of serum triglyceride levels (2.326 1.889 vs 2.059 1.447, p = 0.019). Analysis of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (ApoA), and apolipoprotein B (ApoB) levels revealed no significant differences between the TT and CC + CT genotypes. Furthermore, no significant differences in serum lipid levels were observed between genotypes of the other SNPs. Multivariable logistic analysis, controlling for gender, age, body mass index (BMI), triglycerides (TG), TC, HDL-C, LDL-C, ApoA and ApoB, demonstrated that rs7257062 was still an independent risk factor of CAD (OR = 1.499, 95% CI: 1.036-2.168, p = 0.032). MDR analysis revealed that the rs7257062 interacted significantly with environmental factors such as smoking, diabetes, hypertension, BMI, and TG (p 0.05). The rs7257062 variation of the C3 gene could be linked to both lipid balance and the risk of CAD. It is conceivable that the interplay between C3 polymorphisms and environmental elements could account for the etiology of CAD.

Contactin 5 and Apolipoproteins Interplay in Alzheimer's Disease.

Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10-8), D (p = 1.86×10-4), E (p = 2.92×10-9), J (p = 2.65×10-9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p < 0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.

Lp(a) Levels in Relatives of Patients with Acute Coronary Syndrome and Elevated Lp(a): HER(a) Study.

Background: Lipoprotein(a) [Lp(a)] is a proatherogenic particle associated with increased cardiovascular risk. It is mainly genetically determined; so, the aim of our study is to evaluate the levels of Lp(a) in the relatives of a prospective cohort of patients who have suffered from an acute coronary syndrome (ACS) with Lp(a) ≥ 50 mg/dL. Methods: We conducted a multicenter prospective study, in which consecutive patients who had suffered from an ACS and presented Lp(a) ≥ 50 mg/dL and their first-degree relatives were included. Results: We included 413 subjects, of which 56.4% were relatives of the patients. Family history of early ischemic heart disease was present in 57.5%, and only 20.6% were receiving statin treatment. The family cohort was younger (37.5 vs. 59.1 years; p < 0.001), and 4% had ischemic heart disease and fewer cardiovascular risk factors. Mean Lp(a) levels were 64.9 mg/dL, 59.4% had levels ≥ 50 mg/dL, and 16.1% had levels ≥ 100 mg/dL. When comparing the patients with respect to their relatives, the mean level of Lp(a) was lower but without significant differences regarding the levels of LDLc, ApoB, and non-HDL. However, relatives with Lp(a) ≥ 50 mg/dL, had values similar to the group of patients with ACS (96.8 vs. 103.8 mg/dL; p = 0.18). No differences were found in Lp(a) levels in relatives based on the other lipid parameters. Conclusions: Overall, 59.4% of the first-degree relatives of patients who suffered from an ACS with Lp(a) ≥ 50 mg/dL also had elevated levels. Relatives with elevated Lp(a) had similar levels as patients.

Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia

Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains. To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG. The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 centers across the US, Europe, New Zealand, Australia, and Canada from May 31, 2021, to August 31, 2023. Eligible patients had fasting triglyceride levels in the range of 500 to 4000 mg/dL (to convert to millimoles per liter, multiply by 0.0113) while receiving stable lipid-lowering treatment. Participants received 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo on day 1 and at week 12 and were followed up through week 48. The primary end point evaluated the placebo-subtracted difference in means of percentage triglyceride change at week 24. Mixed-model repeated measures were used for statistical modeling. Of 229 patients, 226 (mean [SD] age, 55 [11] years; 176 male [78%]) were included in the primary analysis. Baseline mean (SD) triglyceride level was 897 (625) mg/dL and plasma APOC3 level was 32 (16) mg/dL. Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose. Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) level, which was significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001). However, apolipoprotein B (ApoB) levels did not increase, and non-high-density lipoprotein cholesterol (HDL-C) levels decreased significantly at all doses, with a placebo-adjusted change of -20% at the highest dose. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death. In this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute pancreatitis risk in most participants. Other triglyceride-related lipoprotein parameters improved. An increase in LDL-C level was observed but with no change in ApoB level and a decrease in non-HDL-C level. The safety profile was generally favorable at all doses. Additional studies will be required to determine whether plozasiran favorably modulates the risk of sHTG-associated complications. ClinicalTrials.gov Identifier: NCT04720534.

Changes in metabolic hormones and trace elements in CSF in active smokers indicate oxidative damage to brain cells.

This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism. A total of 156 adult men were included, comprising active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, as well as the trace elements iron and zinc in CSF, were assessed. Compared to nonsmokers, active smokers showed higher BMI, and elevated CSF levels of FGF21, Zn, and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers. These data relate smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize metabolic hormones such as adiponectin, ghrelin, leptin, or orexin A in the brain, by disrupting mitochondrial function and causing oxidative stress in the neurons.

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.

Abstract P185: Plasma Lipidome Signature of Visceral Fat Reveals Heterogenous Cardiometabolic Risk Profiles

Background: Excessive visceral fat is associated with metabolic alterations and is a causal risk factor for CVD. The plasma lipidome is altered in obesity and lipidome signatures of BMI and obesity have been identified. However, few studies have examined the plasma lipidome in relation to visceral fat. Methods: Plasma lipids were measured using the C8-positive LC-MS method in 671 participants from the HERITAGE Family Study (56% Female, 35% Black, 35 yrs). Visceral fat was measured using CT scans. Linear mixed models were used to test the associations of 193 known plasma lipids with visceral fat adjusting for age, sex, race, and BMI. A FDR&lt;5% was used to determine significance. Results: In individual models, 156 lipid species were significantly associated with visceral fat, with 109 species associated after additional adjustment for BMI ( Fig 1 ). The top positively associated lipids were triglycerides, while cholesterol esters showed the strongest inverse associations with visceral fat. A LASSO regression model retained 73 lipids and explained 78.5% of the variance in visceral fat. Delta visceral fat was calculated as the difference between predicted (from LASSO) and measured visceral fat. Examining quartiles of delta visceral fat showed that discordance between predicted and actual visceral fat was associated with differing cardiometabolic profiles independent of age, sex, race, visceral fat, and BMI. Individuals with higher delta visceral fat (Q4, overpredicted) had significantly (p&lt;1.0x10 -04 ) higher levels of TG, apoB, total cholesterol, LDL-C, and fasting insulin and lower levels of large HDL particles and LPL activity compared to those with lower delta visceral fat (Q1, underpredicted). Conclusions: The plasma lipidome is widely associated with visceral fat levels. A lipidome-based visceral fat score may provide additional information over measured visceral fat for assessment of cardiometabolic health. Further studies are needed to test and validate the clinical utility of such lipidome-based scores.

Efficacy and Safety of PSCK9 Inhibitors on Patients with Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

PCSK9 MaB (Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor) may reduce the occurrence of major adverse cardiovascular events (MACEs) in patients diagnosed with acute coronary syndrome (ACS). In this meta-analysis, we conducted a thorough compilation of evidence from established clinical studies to evaluate PCSK9 MaB's capacity to control blood lipid levels and prevent MACEs in ACS patients. We conducted searches on Pubmed, Embase, the Cochrane Library, and Web of Science to identify relevant articles. Data from ACS patients were extracted using a standardized format for aggregating data. We calculated the risk ratio (RR) for MACE and assessed changes in blood lipid parameters. All statistical analyses were performed using RevMan. 11 articles representing 5 trials were included in our systematic review and meta-analysis. When compared to a placebo, PCSK9 MaB significantly reduced the risk of MACEs ( = 0%, p = 0.63, RR [95% CI] = 0.88 [0.81, 0.97], p 0.01) and the recurrence rate of ACS ( = 45%, p = 0.18, RR [95% CI] = 0.89 [0.83, 0.95], p 0.01). Additionally, PCSK9 MaB notably reduced low-density lipoprotein cholesterol (LDL-C) levels (SMD [95% CI] = -2.12 [-2.32, -1.92], p 0.01) and Apolipoprotein B (ApoB) levels (SMD [95% CI] = -1.83 [-2.48, -1.18], p 0.01). Importantly, there were no significant differences in adverse reactions between the PCSK9 MaB group and the control group. PCSK9 MaB, whether used as a standalone treatment or in combination with other therapies, can effectively inhibit PCSK9. It substantially lowers key blood lipid parameters, including low-density lipoprotein (LDL), ApoB, and triglycerides, all without giving rise to notable safety concerns.

Effects of bempedoic acid on markers of inflammation and Lp(a).

To study the effect of bempedoic acid on markers of inflammation and lipoprotein (a) to help determine if the drug would be useful to treat patients with elevated cardiovascular risks and residual cardiovascular risk despite optimal low-density lipoprotein cholesterol (LDL-C) levels. Bempedoic acid is found to cause significant reduction in LDL-C and high-sensitivity C-reactive protein (hs-CRP) in various randomized clinical trials. Multiple meta-analyses have also found that bempedoic acid therapy leads to reduction in non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC) and apolipoprotein B (ApoB) levels. However, it has minimal effect on lipoprotein (a) (Lp(a)) level. Bempedoic acid is a new lipid-lowering agent that inhibits enzyme ATP-citrate lyase in the cholesterol biosynthesis pathway. Major risk of cardiovascular events and its associated morbidity and mortality are proportional to LDL-C and inflammatory markers levels. It was found that bempedoic acid significantly lowers LDL-C, hs-CRP and other inflammatory markers levels. This drug could potentially be used in patients with elevated cardiovascular risk, in patients with residual cardiovascular risk despite attaining LDL-C goal and in statin intolerant patients.

Causality of the gut microbiome and atherosclerosis-related lipids: a bidirectional Mendelian Randomization study

AimsRecent studies have indicated an association between intestinal flora and lipids. However, observational studies cannot indicate causality. In this study, we aimed to investigate the potentially causal relationships between the intestinal flora and blood lipids.MethodsWe performed a bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between intestinal flora and blood lipids. Summary statistics of genome-wide association studies (GWASs) for the 211 intestinal flora and blood lipid traits (n = 5) were obtained from public datasets. Five recognized MR methods were applied to assess the causal relationship with lipids, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates.ResultsThe results indicated a potential causal association between 19 intestinal flora and dyslipidemia in humans. Genus Ruminococcaceae, Christensenellaceae, Parasutterella, Terrisporobacter, Parabacteroides, Class Erysipelotrichia, Family Erysipelotrichaceae, and order Erysipelotrichales were associated with higher dyslipidemia, whereas genus Oscillospira, Peptococcus, Ruminococcaceae UCG010, Ruminococcaceae UCG011, Dorea, and Family Desulfovibrionaceae were associated with lower dyslipidemia. After using the Bonferroni method for multiple testing correction, Only Desulfovibrionaceae [Estimate = -0.0418, 95% confidence interval [CI]: 0.9362–0.9826, P = 0.0007] exhibited stable and significant negative associations with ApoB levels. The inverse MR analysis did not find a significant causal effect of lipids on the intestinal flora. Additionally, no significant heterogeneity or horizontal pleiotropy for IVs was observed in the analysis.ConclusionThe study suggested a causal relationship between intestinal flora and dyslipidemia. These findings will provide a meaningful reference to discover dyslipidemia for intervention to address the problems in the clinic.

Associations between birth weight and adult apolipoproteins: The LifeGene cohort.

Early life factors may predict cardiovascular disease (CVD), but the pathways are still unclear. There is emerging evidence of an association of early life factors with apolipoproteins, which are linked to CVD. The study objective was to assess the associations between birth variables and adult apolipoproteins (apoA1 and apoB, and their ratio) in a population-based cohort. The LifeGene Study is a prospective cohort comprising index participants randomly sampled from the general population. Blood samples were collected between 2009 and 2016. In this sub-study, we used birth variables, obtained from a national registry for all participants born 1973 or later, including birth weight and gestational age, while adult CVD risk factors included age, sex, body mass index (BMI), lipids, and smoking history. We employed univariate and multivariate general linear regression to explore associations between birth variables, lipid levels and other adult CVD risk factors. The outcomes included non-fasting apoA1 and apoB and their ratio, as well as total cholesterol and triglycerides. A total of 10,093 participants with both birth information and lipoprotein levels at screening were included. Of these, nearly 42.5% were men (n = 4292) and 57.5% were women (n = 5801). The mean (standard deviation) age of men was 30.2 (5.7) years, and for women 28.9 (5.8) years. There was an increase of 0.022 g/L in apoA1 levels per 1 kg increase in birth weight (p = 0.005) after adjusting for age, sex, BMI, gestational age, and smoking history. Similarly, there was a decrease of 0.023 g/L in apoB levels per 1 kg increase in birth weight (p<0.001) after adjusting for the same variables. There were inverse associations of birth weight with the apoB/apoA1 ratio. No independent association was found with total cholesterol, but with triglyceride levels (ẞ-coefficient (95% Confidence Interval); -0.067 (-0.114, -0.021); p-value 0.005). Lower birth weight was associated with an adverse adult apolipoprotein pattern, i.e., a higher apoB/apoA1 ratio, indicating increased risk of future CVD manifestations. The study highlights the need of preconception care and pregnancy interventions that aim at improving maternal and child outcomes with long-term impacts for prevention of cardiovascular disease by influencing lipid levels.

Association of apolipoprotein levels with all-cause and cardiovascular mortality.

Research has shown that apolipoproteins (Apos) are potential indicators of heart health and death. We investigated the associations of Apo levels with all-cause and cardiovascular mortality. We systematically searched the Cochrane Library, PubMed, and Web of Science for English language studies up to 28 November 2022. We used Stata 17.0 to summarize the estimated effects with 95% confidence intervals (CIs). We also conducted subgroup analyses according to study location, year of publication, individual age, follow-up years, and sample size. Moreover, we performed a sensitivity analysis to evaluate bias in our study. This study included 23 studies with 152 854 individuals in total. The level of ApoA was negatively related to cardiovascular mortality [odds ratio (OR) = 0.69, 95% CI = 0.52-0.93]. An increased ratio of ApoB/A1 was a risk factor for cardiovascular mortality (OR = 2.13, 95% CI = 1.48-3.07) and all-cause mortality (OR = 2.05, 95% CI = 1.52-2.77). The level of ApoB was positively related to cardiovascular mortality (OR = 1.12, 95% CI = 0.85-1.47), but the difference was not statistically significant. However, the associations between ApoB or ApoA1 and all-cause mortality were not obvious. Our subgroup analyses showed that the location, year of publication, individual age, and follow-up years of the studies affected the heterogeneity of our study to varying degrees. The sensitivity analysis showed that our results were almost robust, apart from excluding the article by Nomikos (OR = 0.77, 95% CI = 0.65-0.92) and Zeng (OR = 0.77, 95% CI = 0.65-0.91), when investigating the relationship between ApoA1 and all-cause mortality. In this study, we found that Apo levels were linked to cardiovascular and all-cause mortality. Our study strengthens the evidence on the association between the level of Apos and cardiac health and may provide ideas for regulating the level of Apos to promote public health.

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Contribution of ApoB-100/SORT1-Mediated Immune Microenvironment in Regulating Oxidative Stress, Inflammation, and Ferroptosis After Spinal Cord Injury.

This study aims to explore the impacts of ApoB-100/SORT1-mediated immune microenvironment during acute spinal cord injury (SCI), and to investigate the potential mechanism. CB57BL/6 mice underwent moderate thoracic contusion injury to establish the SCI animal model, and received ApoB-100 lentivirus injection to interfere ApoB-100 level. Functional recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) score and footprint analysis. Transmission electron microscopy was applied to observe the ultrastructure of the injured spinal cord tissue. Hematoxylin-eosin (HE) staining and Perls staining were conducted to assess histological changes and iron deposition. Biochemical factor and cytokines were detected using their commercial kits. M1/M2 macrophage markers were detected by immunofluorescence assay in vivo and by flow cytometry in vitro. HT22 neurons were simulated by lipopolysaccharide (LPS), followed by incubation with polarized macrophage medium to simulate the immune microenvironment of injured spinal cord in vitro. The local immune microenvironment is changed in SCI mice, accompanied with the occurrence of oxidative stress and the elevation of both M1 and M2 macrophages. Knockdown of ApoB-100 ameliorates oxidative stress and lipid disorder, and inhibits inflammation and ferroptosis in SCI mice. Importantly, knockdown of ApoB-100 can partly restrict M1 macrophages but does not change M2 macrophage proportion in SCI mice. Further, M1 macrophages are observed to attenuate the inflammatory response, oxidative stress, and ferroptosis levels of LPS-induced HT22 cells, which is further strengthened by SORT1 knockdown. Blockage of ApoB-100/SORT1-mediated immune microenvironment plays a protective role against SCI via inhibiting oxidative stress, inflammation, lipid disorders, and ferroptosis, providing novel insights of the targeted therapy of SCI.