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Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention. Show less

ObjectivesTo characterize the rs1042034 allele distribution in Vietnamese adults with untreated hypercholesterolemia and evaluate its impact on baseline lipid profiles and the early lipid-lowering response to rosuvastatin 20 mg.Materials and MethodsIn this cross-sectional exploratory study, 79 adults with low-density lipoprotein cholesterol [LDL-C] ≥ 3.4 mmol/L were enrolled and treated with rosuvastatin 20 mg plus lifestyle advice for 3 months. Genotypes were determined by TaqMan real-time PCR with Sanger sequencing validation. Baseline and 3-month lipid panels (LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol, non-HDL-C, triglycerides) were measured. Between-group comparisons used Kruskal-Wallis/ANOVA as appropriate; analysis of covariance (ANCOVA) models adjusted for baseline values assessed genotype (TT vs. CT + CC) effects on posttreatment lipids. Multivariable linear regression examined age, sex, and body-mass index as predictors; false discovery rate correction was applied.ResultsBaseline lipid concentrations did not differ significantly by genotype (overall LDL-C 4.37 ± 0.62 mmol/L; total cholesterol 6.62 ± 0.77 mmol/L). After three months, LDL-C reductions differed markedly by genotype ( Show less

A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk. Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach. Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk. The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction. Show less

Injectable PCSK9 inhibitors effectively lower LDL-C levels in patients with hypercholesterolemia; however, their high cost and requirement for parenteral administration limit their widespread use. Oral PCSK9 inhibitors have emerged as a convenient alternative. This review and meta-analysis of the literature evaluate the effectiveness and safety of oral PCSK9 inhibitor treatment for adults with hypercholesterolemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing oral PCSK9 inhibitors with placebo. The primary outcome was percentage change in LDL-C, with secondary lipid and safety outcomes. We used Cochrane RoB 2.0 tool to assess risk of bias, and pooled estimates were calculated using a random-effects model. Certainty of evidence was evaluated with GRADE. From 1253 records, 3 trials were included. Participants were mostly men, aged 61-65 years, with elevated baseline LDL-C. Oral PCSK9 inhibitors significantly reduced LDL-C and ApoB in a dose-dependent manner and achieved modest reductions in triglycerides (MD -6.56 mg/dL; 95% CI, -12.30 to -0.83) and total cholesterol (MD -25.25 mg/dL; 95% CI, -30.67 to -19.83). Effects on lipoprotein(a) were inconsistent. Adverse events (RR 1.06; 95% CI, 0.91-1.23) and serious adverse events (RR 1.32; 95% CI, 0.41-4.26) were comparable with placebo. According to our review, oral PCSK9 inhibitors are a promising therapeutic option for treating hypercholesterolemia because of their potent lipid-lowering effects and an overall favorable safety profile. However, more trials are needed to confirm their impact on cardiovascular outcomes. Show less

Familial hypercholesterolemia (FH) markedly increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Despite available therapies, FH remains underdiagnosed and undertreated. The aim of this study is to characterize FH patients and to evaluate treatment response specifically in those with a confirmed pathogenic mutation. We retrospectively analysed 189 adults with clinical suspicion of FH seen at a cardiology department of a Belgian hospital between 2018 and 2024. Clinical, biochemical, and treatment data were retrieved from electronic records, and the Dutch Lipid Clinic Network (DLCN) score was calculated. Genetic testing was performed in 181 patients. Patients were stratified into primary and secondary prevention groups. The cohort comprised 116 patients (61%) in primary prevention and 73 (39%) in secondary prevention; the latter were older, predominantly male, and had more comorbidities. Genetic mutations were identified in 91 patients, most frequently in the LDL receptor gene (74%), followed by the ApoB gene (19%). Twenty-one patients had a DLCN score > 8, of whom four had no detectable pathogenic mutation. In genetically confirmed FH, mean LDL-cholesterol decreased from 267 ± 82 mg/dL at baseline to 100 ± 57 mg/dL at last follow-up, with greater reductions in secondary prevention. PCSK9 inhibitor use increased significantly during follow-up. Nevertheless, only 43% of secondary prevention patients achieved LDL-C < 55 mg/dL, and 24% of primary prevention patients reached < 70 mg/dL. FH lipid management in this real-world cohort achieved substantial LDL-C reductions, but target attainment remained suboptimal. Show less

GLP-1 RAs are effective in treating obesity; however, they typically result in significant loss of skeletal muscle mass. Real-world evidence to inform systematic guidelines and clinical implementation for preserving skeletal muscle mass and reducing cardiometabolic risk with lifestyle modifications on GLP-1 RAs remains limited. This study evaluated the effectiveness of the TouchCare Method, a lifestyle intervention incorporating nutrition and exercise with GLP-1 RAs, for improving body composition and cardiometabolic risk. A retrospective chart review included patients enrolled in Bucks Health and Wellness between February 2024 and September 2025, for at least 12 month ( Patients adherent to the TouchCare Method for 12 months were included in the final analysis ( The TouchCare Method may improve GLP-1 RA treatment outcomes by providing comprehensive structured lifestyle interventions supporting clinically significant weight loss while preserving skeletal muscle mass and improving cardiometabolic risk factors. Show less

Cardiovascular diseases are the leading cause of death globally. Consequently, metabolomics studies have in recent years aimed at identifying relevant biomarkers, yet no studies have been performed in twin populations, which reduce confounding due to genetic and environmental factors. We included 11,217 twins (age at intake, 47-94 years (mean = 65)) from the Swedish Twin Registry, holding data on 173 nuclear magnetic resonance metabolomic biomarkers and nationwide register-based data on diagnoses of ischemic stroke, ischemic heart disease, myocardial infarction, angina pectoris, and coronary artery disease. Only incident cases (i.e., exclusively holding diagnosis after blood sampling) were included for statistical analyses, which were performed at the individual level and the twin-pair level by Cox regression analyses. Lastly, biomarkers significant in both analyses were inspected, hence conditioning on the twin pair design. Fifty-one biomarkers were found to be associated with myocardial infarction after correction for multiple testing, all showing a hazard ratio above 1. LASSO regression analysis of these biomarkers identified four biomarkers, all related to ApoB lipoprotein biology, potentially reflecting a pro-atherogenic effect. Investigation of biomarkers with p-values < 0.05 identified 20 biomarkers for ischemic heart disease, all showing hazard ratios below 1 and primarily related to ApoA1 lipoprotein biology, potentially reflecting an anti-atherogenic effect. Lastly, three biomarkers, i.e., acetoacetate, bOHbutyrate, and isoleucine, were found for ischemic stroke, all showing a hazard ratio above 1. Taken together, different biomarkers associated with the disease phenotypes indicate that their molecular profiles are different, despite their common basis. The ApoB stands out as a promising biomarker for myocardial infarction. Show less

MN-001 (tipelukast), a compound with lipid-modulating and anti-inflammatory properties, and its active metabolite MN-002, have been suggested to influence cholesterol metabolism. This study aimed to investigate whether MN-001 and MN-002 enhance cholesterol efflux via ABCA1 and ABCG1, thereby reducing foam cell formation. We also evaluated cholesterol efflux capacity in patients with diabetes before and after MN-001 administration. Cholesterol efflux was assessed in THP-1 macrophages treated with MN-001 and MN-002 in the presence of ApoA-I or HDL. ABCA1 and ABCG1 expression were evaluated using western blot and qPCR analyses. A 12-week observational study in patients with diabetes evaluated the cholesterol efflux capacity using ApoB-depleted serum and radiolabeled J774.1 macrophages. Molecular docking simulations were conducted to explore MN-002 binding affinities, aiming to identify potential target proteins and elucidate the molecular mechanisms underlying their effects on cholesterol metabolism. MN-002 enhanced ABCA1-mediated cholesterol efflux and upregulated ABCA1 expression independently of PKA. It also increased ABCG1 expression; however, neither MN-001 nor MN-002 influenced HDL-mediated efflux. MN-001 showed no significant improvement in cholesterol efflux capacity (p = 0.6507) in patients with diabetes. Molecular docking simulations indicated that MN-002 may bind to PPAR-alpha, suggesting a potential mechanism for its effects. MN-002 offers a novel therapeutic approach for atherosclerosis by upregulating ABCA1 and ABCG1 expression and enhancing ApoA-I-mediated cholesterol efflux. Further studies are required to clarify the underlying mechanisms and assess their clinical potential in atherosclerosis and metabolic disorders. Show less

Most patients with heterozygous familial hypercholesterolemia fail to achieve adequate low-density lipoprotein (LDL) cholesterol lowering. Here we carried out a randomized trial to test the safety and efficacy of obicetrapib, a highly selective cholesteryl ester transfer protein inhibitor that lowers LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia and an LDL cholesterol level ≥70 mg dl Show less

The utility of emerging lipid markers-apolipoprotein B (apoB) and lipoprotein(a) (Lp[a])-for improving atherosclerotic cardiovascular disease (ASCVD) risk assessment beyond traditional lipid measures remains uncertain, particularly in young adults. To evaluate associations of traditional and emerging lipid markers with ASCVD and assess the incremental value of emerging markers beyond established risk models. This prospective cohort study included adults aged 18 years or older without cardiovascular disease from 3 US cohort studies (Coronary Artery Risk Development in Young Adults, the Framingham Heart Study Offspring, and the Multi-Ethnic Study of Atherosclerosis [MESA]). Data were analyzed from April to June 2025. Lipid markers, including low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, total-to-HDL cholesterol ratio, apoB, and Lp(a). Hazard ratios (HRs) for incident ASCVD per-SD increase in lipid marker levels, estimated using Cox proportional hazards regression models adjusted for demographic and clinical factors, and model performance metrics (Harrell concordance index [C-index], net reclassification improvement [NRI], and mean calibration) comparing models including the risk estimated by the Predicting Risk of Cardiovascular Disease Events (PREVENT) base equations against models that additionally included each lipid marker. Among 10 519 participants (mean [SD] age, 48.3 [15.7] years; 53.0% female), 1103 ASCVD events occurred during a median follow-up of 21.3 (IQR, 16.5-26.0) years. ApoB was positively associated with ASCVD events, especially in younger adults aged 18 to 39 years (adjusted HR [AHR] per-SD increase, 1.53; 95% CI, 1.30-1.79) vs those aged 40 years or older (AHR, 1.13; 95% CI, 1.06-1.20) (P < .001 for interaction). Lp(a) as a continuous variable was associated with a marginal increase in ASCVD in adults aged 40 years or older (AHR, 1.07; 95% CI, 1.00-1.16) but not in younger adults (AHR, 1.02; 95% CI, 0.87-1.19) (P = .61 for interaction). When dichotomized (>50 vs ≤50 mg/dL), Lp(a) was associated with ASCVD in adults aged 40 years or older (AHR range, 1.36; 95% CI, 1.13-1.64) but not in younger adults (AHR, 0.98; 95% CI, 0.66-1.45) (P = .42 for interaction). Adding apoB to 10-year ASCVD risk estimated by the PREVENT base equations was associated with improved risk reclassification in younger adults (continuous NRI, 0.67; 95% CI, 0.23-1.09) but not in those aged 40 years or older (continuous NRI, 0.16; 95% CI, -0.05 to 0.27). ApoB was also associated with improved 30-year risk reclassification in younger adults (continuous NRI, 0.47; 95% CI, 0.02-0.84). Dichotomized Lp(a), but not continuous Lp(a), was associated with improved 10-year NRI only in MESA (0.13; 95% CI, 0.03-0.24). In this cohort study of 10 519 adults, adding apoB to PREVENT-estimated ASCVD risks was associated with improved risk reclassification, particularly in younger adults. However, the clinical importance of these modest improvements remains uncertain. Show less

Alzheimer's disease (AD) involves proteostasis dysregulation causing protein misfolding, but whether these structural changes manifest as plasma conformational biomarkers remains unclear. We profiled plasma protein structures from 520 participants including individuals with AD, individuals with mild cognitive impairment (MCI) and healthy controls. Using mass spectrometry and machine learning, we systematically characterized the structural proteome changes associated with ApoE variations and neuropsychiatric symptoms to identify AD-specific signatures. We developed a diagnostic panel using peptides from C1QA, CLUS and ApoB representing AD-associated structural changes. This three-marker panel achieved 83.44% accuracy in three-way classification (healthy versus MCI versus AD). Binary classification yielded area under the receiver operating characteristic curves of 0.9343 for healthy versus MCI and 0.9325 for MCI versus AD. Longitudinal samples were classified with 86.0% accuracy. This multi-marker panel based on plasma protein structural alterations represents a promising diagnostic approach that may enhance early AD detection and provide insights for clinical trials, improving therapeutic outcomes. Show less

Apolipoprotein B (apoB) is essential for lipoprotein assembly and secretion and plays a central role in the development of cardiovascular disease and metabolic dysfunction-associated steatotic liver disease. Although apoB protein degradation during very-low-density lipoprotein maturation has been extensively studied, the regulation of A forward genetic screen in randomly mutagenized mice identified HELZ2 (helicase with zinc finger 2) as a critical regulator of lipid metabolism. The metabolic effects of HELZ2 mutations or deficiency were evaluated in mice maintained on a chow diet or a high-fat diet. We also used a doxycycline-inducible, liver-specific HELZ2 overexpression model to test the sufficiency of hepatocyte We discovered a unique gain-of-function mutation in HELZ2 (L1833P, called HELZ2 is a key regulator of Show less

The therapeutic effects of different combination therapies containing cholesteryl ester transfer protein (CETP) inhibitors vary. Evidence from head-to-head comparisons is scarce and inconsistent. This study aimed to evaluate the impact of CETP inhibitor-based combination therapy on lipid levels and explore its adverse events (AEs). Randomized controlled trials (RCTs) were retrieved from PubMed, Embase, Cochrane Library, and Web of Science up to August 30, 2025. Thirteen RCTs were analyzed through STATA 14.0. This systematic review and network meta-analysis of 13 studies (9248 participants) evaluated CETP inhibitor-based combination therapies. For HDL-C elevation, obicetrapib + ezetimibe + statin ranked highest (SUCRA = 95.1%). Evacetrapib + statin achieved reduction in LDL-C (SUCRA = 94.3%). Obicetrapib + ezetimibe + statin excelled in reducing TC (SUCRA = 100.0%) and TG (SUCRA = 99.9%). Obicetrapib + statin was most effective for ApoAI increase (SUCRA = 100.0%), while obicetrapib + ezetimibe + statin best reduced ApoB (SUCRA = 100.0%). Regarding safety, obicetrapib + statin had the optimal profile for all grade AEs (SUCRA = 19.2%) and severe AEs (SUCRA = 22.5%), conversely, evacetrapib + statin had the worst profile (SUCRA = 83.1% and 66.3%, respectively). Our meta-analysis demonstrated that CETP inhibitor combination therapies offer distinct lipid-modulating benefits and safety profiles. The obicetrapib + ezetimibe + statin triple therapy showed superior comprehensive efficacy, while obicetrapib + statin exhibited the optimal safety. Evacetrapib + statin provided potent LDL-C reduction but had the poorest safety. These findings facilitate personalized treatment selection for dyslipidemia management. PROSPERO CRD420251145396 ( https://www.crd.york.ac.uk/prospero/ ). Show less

Dyslipidemia is a universal finding in nephrotic syndrome with relapse, but there are limited data on its prevalence in disease remission. Primary objectives of the study were to identify dyslipidemia and analyze the profile of serum apolipoproteins and lipoprotein(a) in children with nephrotic syndrome in disease remission. This cross-sectional study included children (2-18 years) with nephrotic syndrome. A detailed history was elicited, and an examination was performed; blood investigations included glycosylated hemoglobin, serum albumin, kidney function tests (KFT), fasting lipid profile, serum apolipoprotein A-1 (ApoA-1), apolipoprotein B (ApoB), and lipoprotein(a), and a spot urine for urine protein-to-creatinine ratio. The median age (IQR) of 92 enrolled children (male 65; female 27) was 8 (6-11) years. Forty-seven had steroid-sensitive nephrotic syndrome (SSNS), 29 had steroid-resistant nephrotic syndrome (SRNS) in disease remission, and 16 were in relapse and included for comparison. Dyslipidemia was seen in 39.5%, with a prevalence of 32% in SSNS, 51.7% in SRNS during remission, and 100% in children in relapse, using conventional markers. ApoB/ApoA-1 ratio ≥0.6 was seen in 14.2% and 29.6% of children with SSNS and SRNS, respectively, while a ratio ≥0.8 was seen in only 5.2% of those in remission. The median values of the ApoB/ApoA-1 ratio in remission and relapse were 0.5 (0.4-0.6) and 0.85 (0.62-1.33), respectively. ApoB, ApoA-1, and ApoB/ApoA-1 showed sensitivities of 63.3%, 40%, and 13.3%, and specificities of 82.6%, 80.4%, and 100%, respectively, for the diagnosis of dyslipidemia, and receiver operator characteristic analysis showed area under the curve of 0.704, 056, and 0.65, respectively. Identification of dyslipidemia using conventional parameters may lead to overdiagnosis in nephrotic syndrome during disease remission; the ApoB/ApoA-1 ratio appears to be a better marker. Show less

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health. Show less

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Lipid biomarkers, including direct low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), and apolipoprotein A1 (ApoA1), are essential tools for cardiovascular risk assessment. Monitoring patient-derived median values over time may provide insights into population health and analytical performance. This study provides a descriptive analysis of population-level lipid results spanning nearly two decades. While trends in patient medians may support quality assurance, these data do not constitute a validated approach to risk prediction or definitive analytical monitoring due to the absence of outcome and treatment information. We retrospectively analyzed routine clinical laboratory data from Uppsala University Hospital, Sweden, covering January 2006-December 2024. A total of 890,948 LDL-C, 867,446 HDL-C, 64,787 ApoB, and 65,500 ApoA1 results were included. Measurements were performed on Abbott Architect systems until 2021, after which assays were transferred to Roche Cobas Pro platforms. Statistical analyses included trend evaluation, variability assessment, and seasonal pattern analysis. Women had modestly higher LDL-C and HDL-C levels compared to men, while ApoB values were similar between sexes. ApoA1 was notably higher in women. Over the 19-year period, median LDL-C declined from 3.18 to 2.62 mmol/L, consistent with improved lipid management. HDL-C remained stable (1.36-1.45 mmol/L), while ApoB and ApoA1 concentrations showed minimal change. Variability was highest for LDL-C (median CV 6.4%) and lowest for ApoA1 (median CV 2.6%). Seasonal variation was negligible across all analytes. Testing volumes increased substantially for LDL-C and HDL-C, whereas ApoB and ApoA1 requests peaked around 2010 and later declined. Long-term monitoring of median patient values demonstrates declining LDL-C, stable HDL-C, and consistent ApoB/ApoA1 ratios with minimal seasonal effects. These findings highlight the potential utility of patient medians as supplementary quality indicators and for population-level lipid surveillance. Show less

Cholestasis in primary biliary cholangitis (PBC) induces delta bilirubin and lipoprotein-X (LpX), complicating biochemical interpretation. Comparative wet/dry chemistry analyses, total cholesterol (TC)/apolipoprotein B (Apo B) ratio calculation, and clinical-laboratory integration were utilized. Delta bilirubin (87.4 µmol/L) masked true bilirubin levels, while LpX falsely elevated LDL-cholesterol (LDL-C) (23.98 mmol/L) and induced pseudohyponatremia (Na⁺: 135 → 142 mmol/L). Integrated methodologies and clinician-laboratory collaboration are essential to mitigate diagnostic pitfalls in PBC. Show less

Olezarsen (Tryngolza) is a next-generation, N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide that selectively inhibits hepatic ApoC-III, a key regulator of triglyceride metabolism. By inhibiting ApoC-III, olezarsen increases triglyceride clearance through both lipoprotein lipase (LPL)-dependent and -independent pathways. In the Phase 3 BALANCE trial, olezarsen reduced fasting triglycerides by approximately 60% at 12 months in patients with familial chylomicronemia syndrome (FCS), with a marked decrease in pancreatitis events versus placebo. Consistent triglyceride reductions (around 50%) were also observed in moderate and severe hypertriglyceridemia, along with improvements in ApoB-containing lipoproteins and high-density lipoprotein (HDL) profiles. In completed trials, olezarsen demonstrated a favorable safety profile, with most adverse events limited to mild injection-site reactions and no clinically significant thrombocytopenia. Ongoing Phase 3 trials (ESSENCE, CORE, and CORE2) will further define its role in cardiovascular risk reduction and pancreatitis prevention in broader hypertriglyceridemic populations. Olezarsen represents a precision medicine advance, offering effective triglyceride lowering with improved tolerability compared with earlier antisense therapies. Show less

To assess the predictive ability of baseline serum apolipoprotein B (ApoB) and the ratio of ApoB to apolipoprotein A1 (ApoB/ApoA1 ratio) for dyslipidemia risk in patients receiving second-generation antipsychotics (SGAs). Medical records of patients hospitalized between March 2019 and March 2025 were retrospectively reviewed. The optimal cut-off points for baseline serum ApoB levels and the ApoB/ApoA1 ratio were identified using a maximally selected log-rank statistic analysis. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs). The Kaplan-Meier method with Log rank testing was used to compare the cumulative incidence of dyslipidemia between groups defined by these cut-off points. Of 311 enrolled patients, 33 (10.6%) lacking baseline ApoA1 measurements were excluded from ApoB/ApoA1 ratio analyses. The optimal cut-off points were 0.70 g/L for baseline ApoB and 0.45 for the ApoB/ApoA1 ratio. Multivariable Cox proportional hazards models, fully adjusted for covariates, demonstrated significantly elevated dyslipidemia risk for patients exceeding these thresholds vs low-risk groups: adjusted HR 2.98 (95% CI: 2.05-4.32, p < 0.001) for high ApoB and 3.17 (95% CI: 1.62-6.22, p = 0.001) for high ApoB/ApoA1 ratio. Continuous analysis showed each 0.1 g/L ApoB increase conferred a 34% higher risk (adjusted HR 1.34, 95% CI: 1.21-1.48, p < 0.001), while each 0.1-unit ApoB/ApoA1 ratio increase conferred a 20% higher risk (adjusted HR 1.20, 95% CI: 1.10-1.30, p < 0.001). Kaplan-Meier curves confirmed significantly higher cumulative dyslipidemia incidence in high vs low groups for both markers (Log rank test, both p < 0.001). Baseline serum ApoB levels and the ApoB/ApoA1 ratio are valuable risk markers for dyslipidemia in patients treated with SGAs. Show less

Familial dyslipidemia (FD), particularly familial hypercholesterolemia (FH), is a major contributor to premature cardiovascular disease (CVD), especially in regions with high consanguinity and underutilized genetic screening, such as Egypt. This study aimed to assess clinical, biochemical, and genetic factors that differentiate FD patients with and without CVD, and to develop a composite risk score for individualized stratification. A cross-sectional study was conducted on 60 Egyptian patients aged 15-25 years with genetically confirmed FD, equally divided based on CVD status. All participants underwent detailed clinical assessment, lipid profiling, and targeted next-generation sequencing of LDLR, APOB, and PCSK9 genes. Missense variants were evaluated using SIFT, PolyPhen-2, CADD, and ΔΔG stability scores, and classified according to ACMG criteria. Compared to non-CVD patients, those with CVD had significantly higher triglyceride levels (median: 356.5 vs. 236.5 mg/dL; p < 0.001) and a higher frequency of heterozygous pathogenic LDLR variants (30.0% vs. 3.3%; p = 0.006), while homozygous variants were more common in non-CVD patients (26.7% vs. 0%; p = 0.002). Deleterious missense variants were notably more frequent in the CVD group (56.7% vs. 10.0%; p < 0.001). A 10-variable composite risk score integrating clinical, lipid, and bioinformatic predictors effectively distinguished high- and moderate-risk cases (AUC = 0.742; p = 0.022), with 89.5% sensitivity and 81.8% negative predictive value. The study highlights the importance of combining clinical and genomic data for early risk stratification and introduces a pragmatic tool for identifying high-risk youth in resource-limited, consanguineous populations. Show less

Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive impairment, increased adverse cardiac events, and even death. This study aimed to investigate the correlation between plasma lipid levels and the characteristics of atherosclerotic plaques in adult patients with type 2 diabetes mellitus. A retrospective analysis was conducted on adult patients with type 2 mellitus who were hospitalized in the Department of Endocrinology at Affiliated Hospital of Hebei University between January 2017 and December 2021.Patients were categorized into two groups based on arterial ultrasound results. Statistical analyses were performed to compare plasma lipid levels and plaque characteristics across the groups. 1) Statistically significant differences were observed among the two groups in terms of gender, hypertension, age, duration of diabetes mellitus, plaque location, triglycerides (TG),total cholesterol (TC), Apolipoprotein A1 (Apo A1),very-low-density lipoprotein (VLDL), VLDL/apolipoprotein B(ApoB), high-density lipoprotein cholesterol (HDL)/ApoA1 ( In clinical practice, the characteristics of atherosclerotic plaques and lipid profiles should be jointly evaluated to guide targeted treatment and effectively reduce the risk of atherosclerotic cardiovascular disease. Show less

Ischemic stroke is frequently associated with symptomatic intracranial atherosclerotic stenosis (sICAS), is a leading cause of global disability and mortality. Current guidelines recommend dual antiplatelet and intensive statin therapies. Proprotein convertase subtilisin 9/kexin type 9 (PCSK9) inhibitors have emerged as a potent lipid-lowering therapy, potentially influenced by genetic variations, particularly in the CYP2C19 gene. This study at Xuzhou Central Hospital from January 2021 to December 2023 included 151 patients divided into a statin group (n = 73) and a PCSK9 inhibitor (PCSK9i) group (n = 78). It evaluated lipid profiles, inflammatory markers, neurological function, and clinical outcomes over a 180-day follow-up period, with additional analysis stratified by CYP2C19 genotype. The PCSK9i group demonstrated significant improvements in lipid parameters compared to the statin group, including greater reductions in low-density lipoprotein cholesterol (LDL-C) (p = 0.008), total cholesterol (TC) (p < 0.001), and triacylglycerols (TAG) (p = 0.041), along with apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) (both p < 0.001). Inflammatory markers, particularly interleukin-6 (IL-6), significantly reduced in the PCSK9i group (p < 0.001). In the PCSK9i group, CYP2C19 rapid metabolizers achieved greater reductions in LDL-C (p = 0.021), ApoB (p = 0.003), and IL-6 levels (p = 0.041) compared to slow metabolizers. Post-treatment modified Rankin Scale (mRS) scores were significantly lower in rapid metabolizers compared to slow metabolizers (p = 0.018), though clinical events occurred infrequently in both subgroups. This study demonstrates that PCSK9 inhibitor therapy combined with statins provides enhanced lipid-lowering and anti-inflammatory effects compared to statin monotherapy in sICAS patients. While the CYP2C19 genotype may influence specific treatment responses, particularly lipid parameters, its impact on clinical outcomes requires further investigation. Show less

Despite widespread use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, substantial atherosclerotic cardiovascular disease risk persists, especially in people with heterozygous familial hypercholesterolemia or elevated lipoprotein(a) [Lp(a)] levels. Cholesteryl ester transfer protein (CETP) inhibitors block the transfer of hydrophobic cholesteryl esters from high-density lipoprotein to apolipoprotein B (apoB)-containing particles. This process raises high-density lipoprotein-C and lowers low-density lipoprotein-C, apoB, and Lp(a) levels. The first-generation of CETP inhibitors was limited by toxicity, neutral outcomes, or unfavorable pharmacokinetics. Obicetrapib is a next-generation amphipathic CETP inhibitor that selectively targets both CETP's hydrophobic and hydrophilic tunnels. It reduces low-density lipoprotein-C by about 30-51%, apoB by 20-33%, and Lp(a) by 30-57% without causing tissue accumulation or toxicity. Phase 3 trials (BROOKLYN, BROADWAY, TANDEM) show that obicetrapib is effective when added to maximized therapy, with a safety profile similar to placebo. Its consistent reduction of Lp(a) addresses an important unmet need. In addition to lowering atherogenic lipoproteins, early data suggest potential for neuroprotection, such as reductions in p-tau217 seen among APOE4 carriers. A 2025 pooled analysis offers initial evidence that major adverse cardiovascular events are reduced, as studied in the ongoing PREVAIL outcomes trial. This review covers CETP biology and tunnel mechanics, outcomes from earlier CETP inhibitor studies, obicetrapib's pharmacology, and current efficacy and safety data, and will clarify its potential place in lipid management today. Show less

Patients with chronic kidney disease frequently exhibit abnormalities in their lipid metabolism. Confounding factors in observational studies often obscure the causal relationship between these 2 diseases. This study investigated the causal relationships between genetically predicted levels of 6 key lipid parameters (total cholesterol (TC), triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB)) and circulating kidney injury molecule 1 (KIM-1) levels, using a comprehensive bidirectional Mendelian randomization (MR) analysis. Using genome-wide association study data, the primary analysis used the inverse-variance weighted (IVW) method, supported by MR-Egger regression and a weighted median estimator. Sensitivity analyses including heterogeneity, pleiotropy tests, leave-one-out, and reverse causality analyses were conducted. The IVW model revealed the following: TG (odds ratio (OR): 1.1843, 95% confidence interval (CI): 1.1178-1.2547, P = 9.5894e-09), TC (OR: 1.1096, 95% CI: 1.0178-1.2095, P = .0182), and ApoA1 (OR: 1.1820, 95% CI: 1.0741-1.3007, P = .0007) were found to have significant causal relationships with KIM-1, a biomarker of kidney tubular injury, and may be risk factors for renal tubular injury; No significant causal associations were observed between high-density lipoprotein cholesterol (HDL-C), (P = .2929), LDL-C (P = .2178), ApoB (P = .1836), and KIM-1; Horizontal pleiotropy was detected for ApoA1 (P = .0208). However, sensitivity analyses confirmed the robustness of the results after the removal of outliers; significant heterogeneity was observed across all lipid parameters (Cochran Q P < .05), which necessitated the use of random-effects IVW models; and reverse causality analyses (MR-Egger intercept P > .05, Steiger filtering) confirmed no evidence of reverse causation between lipid profiles and KIM-1. TG, HDL-C, and ApoA1 levels may be risk factors for renal tubular injury. However, no significant causal relationships were observed between HDL-C, LDL-C, and ApoB levels and renal tubular injury. To further explore the underlying mechanisms of the associations between TG, HDL-C, ApoA1, and KIM-1 and to inform lipid management strategies in tubulopathy-related conditions. Show less

Mercury (Hg) is a widespread environmental pollutant with known neurotoxic and cardiometabolic effects, and its influence on lipid metabolism during childhood remains insufficiently understood. Mitochondrial dysfunction is proposed as a potential mechanism linking Hg exposure to metabolic disruption. Mitochondrial DNA copy number (mtDNA-CN) is regarded as an indicator of mitochondrial biogenesis and functional capacity, where lower levels generally suggest mitochondrial damage or dysfunction. In contrast, ribosomal DNA (rDNA) and relative telomere length (RTL) reflect genomic stability and cellular aging. This study investigated the associations between blood Hg levels and serum lipid profiles in children and adolescents and assessed the mediating roles of mtDNA-CN, rDNA, and RTL. A cross-sectional study was performed among 352 children and adolescents aged 6–17 years in eastern China. Blood Hg levels were determined using inductively coupled plasma mass spectrometry (ICP-MS), and serum lipid markers, namely total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were assessed along with the genomic indicators such as mtDNA-CN, rDNA, and RTL. Multivariable linear regression and mediation analyses were conducted. Higher Hg levels were significantly related with increased TC (β = 0.144, Hg exposure in children and adolescents is linked to an atherogenic lipid profile, potentially through mitochondrial dysfunction. MtDNA-CN appears to be a sensitive molecular mediator of Hg-induced lipid disturbances, which highlights the relevance of mitochondrial health in early-life environmental epidemiology and cardiovascular risk prevention. The findings support early prevention strategies and environmentally focused health policies that reduce toxicant exposure and thus promote long-term cardiometabolic health in young populations. Show less

The contribution of circulating group 3 innate lymphoid cells (ILC3s) to lipid dysregulation has remained poorly defined, and the mechanisms through which washed microbiota transplantation (WMT) improves lipid metabolism require further clarification. Peripheral ILC subsets and plasma IL-22 were assessed in hyperlipidemia patients and healthy controls. The lipid-lowering effects of WMT were evaluated in a prospective cohort without lipid-lowering medications. Gut microbial and plasma metabolite profiles before and after WMT were analyzed. A hyperlipidemic mouse model was used to determine whether healthy microbiota promote hepatic ILC3 homing via integrin α4. Hyperlipidemia was characterized by reduced circulating ILC3s, integrin α4 Hyperlipidemia is associated with depletion of circulating ILC3s and reduced IL-22. Restoration of ILC3 subsets and enhancement of integrin α4-dependent hepatic homing are achieved after WMT, accompanying improvements in lipid metabolism. Show less

Traditional lipid parameters like low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol (TC) are commonly used in evaluating cardiovascular risk. Recently, emerging biomarkers such as apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) are proposed to provide improved accuracy in assessing atherosclerotic risk. This study examined the association between conventional and novel lipid parameters and plaque burden in statin-naïve acute coronary syndrome (ACS) patients. We enrolled 81 statin-naïve patients with ACS. Each underwent both standard and extended lipid profiling. Coronary angiograms were evaluated using the Gensini score to quantify plaque burden. All participants were followed for 28 days to monitor for major adverse cardiac events (MACE). The average age was 51 years, with males comprising 77%. The ST-segment elevation myocardial infarction (STEMI) was observed in 58% of cases, non-ST-segment elevation myocardial infarction (NSTEMI) in 31%, and unstable angina in 11%. There was a significant correlation between the Gensini score and TC/HDL ratio ( The ratios of TC/HDL, LDL/HDL, and ApoB levels were positively associated with coronary plaque burden. While conventional lipid parameters continue to serve well in cardiovascular risk assessment (CRA), ApoB presents a promising standalone marker for identifying atherogenic risk and may serve as a practical alternative in clinical practice. Show less

Cardiovascular disease (CVD) remains a major global health concern and a leading cause of morbidity and mortality worldwide. Early-diagnosis and prompt medical attention are crucial in managing and reducing overall impact on health-and-wellbeing, necessitating the development of innovative diagnostics, which transcend traditional methodologies. Raman spectroscopy uniquely provides molecular fingerprinting and structural information, offering insights into biochemical composition. Integration of Raman spectroscopy with advanced machine learning is established as a powerful clinical adjunct for point-of-care detection of CVDs. A non-invasive, label-free spectroscopic platform coupled with neural network algorithm, 'SKiNET' has been developed to accurately detect the biomolecular changes within plasma of CVD versus healthy cohorts, enabling rapid diagnosis and longer-term monitoring, where the real-time capabilities provide dynamic assessment of progression, aligning treatment strategies with evolving states. CVD has been detected and classified via SKiNET with 88.6 %-accuracy, 92.9 %-specificity and 85.1 %-sensitivity and with 83.8 %-accuracy. The hybrid RS-SKiNET bio-molecularly specific detection signposted a comprehensive panel of CVD-indicative biomarkers, including SIL-6, IL-9, LpA, ApoB, PCSK9 and NT-ProBNP, offering important insights into disease mechanisms and risk-stratification. This multidimensional technique holds potential for improved patient-and-healthcare management for CVDs, laying the platform toward high-throughput biomolecular profiling of CVD-indicative macromolecular biomarkers, particularly vital for widespread point-of-care diagnostics and monitoring. Show less

Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, characterised by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth, which confers a substantially increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Pathogenic variants primarily occur in the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (ApoB), low-density lipoprotein receptor adaptor protein 1 (LDLRAP1), or proprotein convertase subtilisin/kexin type 9 (PCSK9). Early diagnosis, based on clinical criteria, family history, and genetic testing, is imperative to promptly initiate aggressive therapeutic strategies. Standard treatment involves lifestyle modifications and high-intensity pharmacotherapy, primarily with statins, often in combination with ezetimibe. For patients who do not achieve their therapeutic goals or are intolerant, PCSK9 inhibitors represent a significant evolution in the treatment paradigm. In this article, we present a case of homozygous familial hypercholesterolaemia. Show less