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Familial hypercholesterolemia (FH), which is traditionally viewed as a monogenic disorder, has significant variability in its phenotypic expression, particularly its physical characteristics. Understanding the relationship between genotype and phenotype is essential for the effective diagnosis and management of this condition, especially in pediatric populations. This study aimed to investigate the correlation between genotype and phenotype in Egyptian children diagnosed with FH. A consecutive sample of 35 Egyptian children diagnosed with FH was recruited for the study. Phenotypic characteristics were comprehensively analyzed and correlated with genetic variants. Next-generation sequencing was employed to identify pathogenic variants in genes associated with FH. Among the 35 cases analyzed, 33 (94.3%) were found to have pathogenic variants in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or PCSK9 genes, with variants in LDLR accounting for approximately 90% of these cases. Zygosity analysis indicated that 63.6% of the children had biallelic pathogenic variants, with 42.4% being homozygous and 21.2% compound heterozygous, whereas the remaining 36.4% were heterozygous. The occurrence of xanthomas, early markers of atherosclerosis, abnormal echocardiographic findings, and elevated levels of total cholesterol and low-density lipoprotein cholesterol were significantly more common in children with homozygous FH. This study revealed a significant correlation between genotype and phenotype in Egyptian children with FH, with homozygous individuals experiencing more severe clinical symptoms. These findings underscore the importance of genetic screening in assessing disease severity and tailoring treatment strategies. Show less

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has expanded from experimental biology to early clinical application, raising the possibility of durable therapies for cardiovascular disease. Because many cardiac conditions are monogenic, they provide clear targets for allele-specific correction or modulation. In hypertrophic cardiomyopathy, preclinical research has shown that base editing of pathogenic MYH7 and MYBPC3 mutations can restore sarcomere function; concurrently, RNA-targeting approaches selectively suppress mutant transcripts. Dilated cardiomyopathy is more heterogeneous: TTN truncations cause haploinsufficiency that can be offset by CRISPR activation, while RBM20 and LMNA mutations require precise correction or interference to restore splicing and nuclear stability. Genome editing is also being tested in familial hypercholesterolemia, where inactivation of PCSK9 using lipid nanoparticle-delivered base editors has now advanced to first-in-human trials, achieving sustained LDL-C lowering. Concurrently, efforts targeting ANGPTL3 and APOB highlight the prospect of multigene modulation of lipid metabolism. In arrhythmic syndromes, patient-derived cardiomyocytes edited at SCN5A and KCNQ1 genes have enabled high-fidelity disease models, while in vivo correction of RYR2 in catecholaminergic polymorphic ventricular tachycardia confirms the viability of editing an arrhythmia substrate. In cardiac regeneration, CRISPR activation of developmental transcription factors has enabled direct reprogramming of fibroblasts into cardiomyocyte-like cells within scar tissue. Even with these advances, delivery remains a bottleneck due to immune responses to viral vectors, limitations in the efficiency of lipid nanoparticles in the heart, and the precision required to target cardiomyocytes or conduction cells, all of which slow progress. Future work will depend as much on technical refinement as on navigating ethical, regulatory, and societal concerns. Show less

Atherogenic dyslipidemia is an important risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes, obesity, and metabolic disorders. Statin therapy, the standard treatment for dyslipidemia management, falls short of controlling the residual risk of adverse cardiovascular events, even with good control of low-density lipoprotein cholesterol (LDL-C). Apolipoprotein B (apoB), in addition to non-high-density lipoprotein cholesterol (non-HDL-C), is considered a better measure of residual risk and a more comprehensive treatment target in atherogenic dyslipidemia. Fibrates in combination with statins represent a proven therapeutic modality for atherogenic dyslipidemia. Fibrates lower triglyceride-rich lipoproteins (TRL), TRL remnants, and small dense LDL particles while increasing HDL-C levels. However, only fenofibrate appears to reduce apoB, whereas gemfibrozil and pemafibrate do not. This leads to a reduction in atherogenic lipids, as measured by a significant decrease in apoB/non-HDL-C levels, and a corresponding reduction in CVD risk. Real-world efficacy studies and CVD outcome trials have shown that fenofibrate may be an option in combination with statins compared to other fibrates and is well tolerated. Additionally, evidence from real-world studies of the fenofibrate-statin combination in patients over a period of up to 20 years has dispelled safety concerns regarding long-term use of fenofibrate. Show less

Non-alcoholic fatty liver disease (NAFLD) is influenced by various factors including diet, genetic predisposition, adipocytokines, oxidative stress and endoplasmic reticulum (ER) stress. In this study, we examined how pre-feeding mice a high-fat diet rich in saturated fatty acids (SFAs) affected various indicators of liver disease after administering tunicamycin (TM), an ER stress inducer. We used 4-wk-old male C57BL/6J mice, dividing them into four groups: a normal diet (C), a high-fat diet (F), a normal diet with TM (CT), and a high-fat diet with TM (FT). After 8 wk of feeding, we administered TM intraperitoneally to the CT and FT groups, followed by an anatomical examination 24 h later. TM administration led to increased triglyceride (TG) and cholesterol accumulation in the liver, while significantly lowering TG, cholesterol, and ApoB levels in the plasma. Although liver TG levels were higher in the CT group compared to the FT group, large lipid droplets were present in all individuals only in the FT group. Classic non-alcoholic steatohepatitis markers, such as neutrophil infiltration and hepatocyte ballooning, were not observed. Additionally, plasma alanine aminotransferase activity and expression levels of ER stress-related proteins were significantly higher in the FT group than in the CT or F groups. These findings indicate that combining a high-fat diet rich in SFAs with TM exacerbates ER stress-induced fatty liver disease. This model may be a valuable tool for preclinical trials aimed at addressing ER stress in early-stage NAFLD. Show less

The Helix Research Network program is a large population genomics initiative that screens an all-comers population of patients for Centers for Disease Control and Prevention Tier 1 genetic conditions, including familial hypercholesterolemia (FH). We evaluated changes in clinical management and low-density lipoprotein cholesterol (LDL-C) levels among patients we identified to have FH. Participants across 9 US health systems provided samples that underwent clinical-grade exome sequencing. Individuals with a positive screening result for a Tier 1 condition were offered no-cost genetic counseling through their health system. Using medication and laboratory testing records, we evaluated changes in patients' lipid-lowering therapies and LDL-C levels. Among 228 602 adults enrolled between 2017 to 2025, 1155 (≈1/198) had a pathogenic FH variant in Following genetic screening, many patients with a pathogenic FH variant experienced improvements in clinical management and LDL-C levels. Electronic health record documentation of the diagnosis code was associated with a greater likelihood of therapeutic modifications, which, in turn, were associated with larger LDL-C reductions. Findings underscore the powerful potential of population genomic screening for supporting optimal lipid management in individuals with FH. Show less

The causal role of LDL in atherosclerotic cardiovascular disease (ASCVD) is well established, but the contribution of HDL has proven more complex. CETP inhibitors were originally developed to increase HDL-cholesterol (HDL-C), but the failure of clinical trials and genetic evidence have changed our understanding of CETP biology. With the development of obicetrapib, a next-generation CETP inhibitor, there has been renewed interest in its therapeutic potential. This review summarizes the latest findings on CETP inhibition and highlights the evolving perspectives from lipid modulation to broader clinical applications. Clinical trials and Mendelian randomisation consistently show that increasing HDL-C alone does not reduce cardiovascular risk, while lowering apoB-containing lipoproteins is associated with benefit. Off-target effects, modest efficacy or insufficient follow-up limited previous CETP inhibitors. Obicetrapib, in contrast, achieves a significant LDL-C and apoB reduction, a marked HDL-C increase and favourable safety. Beyond ASCVD, CETP inhibition may also have an impact on diabetes risk, cognitive function and possibly other conditions, although data are still preliminary. The therapeutic focus has shifted from HDL-C elevation to apoB lowering as the determinant of cardiovascular benefit. Obicetrapib shows promise, with ongoing trials designed to define its role in ASCVD management. Show less

The APOE p.(Leu167del) variant has been identified as a rare cause of autosomal dominant hypercholesterolemia. A comprehensive phenotypic profile of carriers remains undefined, and its frequency has not been systematically studied. To characterize the phenotypic differences between p.(Leu167del) carriers among individuals with primary hypercholesterolemia and those with familial hypercholesterolemia (FH), and to estimate the variant's frequency in different populations. Phenotypic differences were assessed from the Lipid Unit cohort of the Hospital Universitario Miguel Servet (HUMS, n = 6489). The allele frequency of the p.(Leu167del) variant was estimated using data from the HUMS and Aragon Workers Health Study (AWHS, n = 5678), a cohort of working adults, and international cohorts: GnomAD (n ≈ 807,162), TOPMed (n ≈ 180,000), 100 K Genomes Project (n ≈ 85,000). To characterize the profile of carriers, data from the HUMS cohort and a systematic review of the published literature were also used. Carriers showed significantly higher high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and non-HDL cholesterol and lower lipoprotein(a) [Lp(a)] concentrations compared to noncarriers with primary hypercholesterolemia. In comparison with FH patients carrying LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) variants, carriers displayed higher triglycerides and HDL cholesterol but lower LDL cholesterol and Lp(a). The APOE p.(Leu167del) frequency is approximately 1 in 12,000 individuals in the general population and about 2.5% of FH. The study confirmed the association of APOE p.(Leu167del) with hypercholesterolemia but with lower LDL cholesterol than subjects with FH. These findings support p.(Leu167del) as a cause of FH and its inclusion in the genetic screening for FH, particularly in Caucasian populations. Show less

Apolipoprotein B-containing triglyceride-rich lipoproteins (TRLs) -chylomicrons, very low-density lipoproteins (VLDL), their remnants, and intermediate-density lipoproteins (IDL) - are recognised as key contributors to atherosclerotic cardiovascular disease (ASCVD). On a per particle basis, genetic and clinical evidence indicates that TRL/remnants exhibit a greater atherogenic potential than LDL and evidence points to this being mediated by enhanced arterial wall retention of TRLs, the pro-inflammatory actions of their constituent apolipoproteins and cargo of cholesterol and bioactive lipids, and their capacity to induce endothelial dysfunction. Despite the strong association between plasma triglyceride levels and ASCVD, TRL-lowering trials have produced inconsistent, often negative results. The answer to this conundrum, as explored here, likely lies in the complexity of TRL structure, composition and metabolism, and in the dynamic influence that TRLs have on the properties of LDL, the most abundant atherogenic lipoprotein. The substantial heterogeneity in the TRL/remnant/IDL spectrum means that these particles present a wide range of potentially pathogenic factors to the artery wall in the form of major and minor lipids and a variety of surface apolipoproteins. Significant gaps exist in our knowledge: how are TRL remodelled during their lifetime in the bloodstream to become cholesterol-enriched lipoproteins; which are the most relevant TRL subspecies or TRL constituents, that initiate and progress the formation of atherosclerotic lesions; and what are the prime targets for effective intervention. Critical to the design of future triglyceride-lowering prevention trials will be the development of superior biomarkers of TRL/remnant atherogenicity and the development of a precision medicine approach to ASCVD prevention. Show less

Residual cardiovascular risk remains substantial despite widespread adoption of intensive lipid-lowering strategies-statins, PCSK9 inhibitors, and RNA-based agents-that achieve very low LDL-C and apoB levels. Over the past three years, converging epidemiologic and mechanistic evidence has highlighted emotional stress-including anger, grief, anxiety, and chronic psychosocial strain-as a biologically active determinant of atherosclerotic disease and a frequent trigger of acute events. We propose the Emotion-Lipid Synergy Model, in which lipid burden establishes the atherothrombotic substrate while emotion-driven autonomic and vascular perturbations amplify endothelial dysfunction, microvascular constriction, inflammation, and thrombogenicity-thereby widening the residual-risk gap even when lipid targets are met. From this perspective, prevention should evolve toward precision psychocardiology: systematically screening for distress and stress reactivity; leveraging wearables to detect high-risk emotional states; and delivering timely, scalable, just-in-time behavioral interventions alongside guideline-directed lipid management. Particular attention is warranted for women and patients with angina and no obstructive coronary disease, who appear disproportionately susceptible to mental-stress ischemia. We outline a research agenda-flagship outcomes trials, mechanistic studies, and multimodal phenotyping-and discuss implementation pathways that integrate emotion metrics into cardiac rehabilitation and routine care. Integrating emotion assessment and modulation with lipid control offers a pragmatic route to reduce residual risk and advance equitable, personalized cardiovascular prevention. Show less

Lipoproteins are essential for lipid transport in all bilaterians. A single Apolipoprotein B (ApoB) molecule is the inseparable structural scaffold of each ApoB-containing lipoprotein (B-lps), which are responsible for transporting lipids to peripheral tissues. The cellular mechanisms that regulate ApoB and B-lp production, secretion, transport, and degradation remain to be fully defined. In humans, elevated levels of vascular B-lps play a causative role in cardiovascular disease. Previously, we have detailed that human B-lp biology is remarkably conserved in the zebrafish using an Show less

Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in APOB, much less frequently Angiopoietin-like 3 gene (ANGPTL3). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in ANGPTL3 cosegregated with HBL in a family. The aim of the present study was to assess in vitro the functionality of this variant and to establish its causality in this family. Targeted next-generation sequencing was performed in the proband to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score (PRS All 8 HBL subjects had PRS This study shows that the novel ANGPTL3-p.H343R variant decreases ANGPTL3 secretion in vitro and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition. Show less

Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less

Lipoprotein(a) [Lp(a)] is an LDL-like particle, which is synthesized and assembled in the liver, and whose plasma levels are strongly associated with, and considered to be causative of, atherosclerotic cardiovascular disease (ASCVD). Several promising pharmacological therapies that directly target Lp(a) are under development. We discuss the role of Lp(a) in ASCVD, describe the pharmacodynamics, pharmacokinetics, and metabolism of muvalaplin, an oral Lp(a) inhibitor, as well as reporting on the findings of the phase II KRAKEN trial in adults at high cardiovascular risk with elevated Lp(a). Muvalaplin is the first oral small molecule inhibitor of Lp(a) formation for the treatment of elevated Lp(a). In KRAKEN, muvalaplin significantly reduced Lp(a) levels in high-risk patients by up to 70% and 85.5% by traditional and novel isoform-insensitive intact assays, respectively. Safety and tolerability studies reported to date are promising, with minimal effect on plasminogen activity that was independent of dose. In terms of patient convenience and adherence, the oral dosing of muvalaplin may confer practical advantages over injectable Lp(a)-lowering therapies. The results of the MOVE-Lp(a) phase III trial, which is evaluating the effect of muvalaplin on cardiovascular outcomes in high-risk patients with elevated Lp(a), are eagerly awaited. Show less

End-stage renal disease (ESRD) is associated with high morbidity and mortality. Identifying patients with stage 4 chronic kidney disease (CKD) at risk of short-term progression to ESRD remains challenging. Accurate prediction can improve advanced care planning and patient outcomes. This study aimed to develop and validate a machine learning (ML) model for predicting progression within 25 weeks (approximately six months) of ESRD in patients with stage 4 CKD. Electronic health records (EHRs) of patients with stage 4 CKD were analyzed. Nine ML models including Ridge regression (Ridge), random forest (RF), and eXtreme Gradient Boosting (XGBoost) were used to predict short-term progression to ESRD within 25 weeks. The models were trained and externally validated using the data of 346 and 105 patients. Of the 451 patients with stage 4 CKD, 219 developed ESRD. Among the evaluated models, XGBoost demonstrated the best overall performance. In the internal validation, it achieved an area under the curve (AUC) of 0.93, an accuracy of 0.90, and an F1 score of 0.89. In the external validation, XGBoost maintained the highest AUC (0.85), accuracy (0.79), and F1 score (0.79), along with the highest average precision (0.89) and a low log-loss (0.48), indicating strong discriminative ability and good generalizability. The top predictive features included high-density lipoprotein cholesterol, Alb, Cys C, ApoB, FGB, Bun, Neutrophil, and Total cholesterol. This study demonstrated the feasibility of ML for assessing ESRD prognosis based on easily accessible clinical features. XGBoost demonstrated superior performance in both internal and external validation, suggesting its potential for future patient screening. Show less

To establish a short-term high-fat/high-cholesterol (HFHC) diet-induced Metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model, and evaluate the effects of rapamycin (RaPa) and chloroquine (CQ) on this model to explore their therapeutic potential and side effects. An early MASLD mouse model was constructed via short-term HFHC diet feeding. Model mice were intraperitoneally injected with RaPa or CQ. Drug effects were analyzed on body weight, liver weight, lipid metabolism-related genes (APOB, FASN, PLIN2), inflammatory factors (IL-6, IL-10), and fibrosis markers (LOX, Col-1α-1, CCL2, TGFβ1, PDGFRβ, α-SMA) at mRNA and protein levels. RaPa ameliorated body weight and liver weight in early MASLD mice, downregulated FASN and PLIN2 expression, upregulated IL-10 mRNA levels, and alleviated hepatic steatosis, but induced metabolic disorders such as Insulin resistance and hyperlipidemia. In contrast, CQ promoted FASN and PLIN2 expression, exacerbated hepatic steatosis, reduced IL-10 mRNA levels, and upregulated fibrosis-related markers (LOX, TGFβ1, PDGFRβ, α-SMA) at both mRNA and protein levels, thereby driving MASLD progression to liver fibrosis. Notably, CQ improved metabolic abnormalities in model mice, including obesity, hyperlipidemia, and Insulin resistance. RaPa and CQ exhibit dual effects on early MASLD: RaPa alleviates hepatic steatosis but exacerbates metabolic disorders, whereas CQ improves metabolic abnormalities but accelerates liver fibrosis. This paradox highlights the need to balance metabolic regulation and liver injury prevention in MASLD treatment, providing critical experimental insights for targeted drug development. Show less

Atherosclerosis is a chronic inflammatory condition that remains a major global cause of cardiovascular morbidity and death. Circular RNAs (circRNAs), emerging as key regulators of biological processes, have been linked to atherosclerosis because of their functions in inflammation, lipid metabolism, and plaque stability. This review explores the biogenesis and cellular functions of circRNAs, highlighting specific circRNAs, such as circANRIL, circHIPK, and circRSF1, which influence atherosclerosis progressions and development. CRISPR-Cas technology, specifically Cas9 and Cas13, has transformed the way atherosclerosis is studied and potentially treated. Targeting PCSK9, LDLR, and APOB to modify lipid metabolism, including lowering LDL cholesterol and repairing mutations in familial hypercholesterolemia, has been made possible using CRISPR-Cas9 in atherosclerosis models. In parallel, CRISPR-Cas13 offers a novel approach for RNA-level intervention by selectively editing circRNAs, providing a dynamic approach to regulate atherosclerosis-related pathways. In order to convert these findings into therapeutic treatments, future research should focus on elucidating the mechanics of circRNA, which in turn determines CRISPR-Cas13, and designing specific delivery systems. This review paper demonstrates the revolutionary promise of circRNA research and CRISPR innovation in the treatment of atherosclerosis and underscores the need for extensive preclinical validation to bridge the gap towards clinical use. Show less

Mania, a core feature of bipolar disorder, is characterized by impulsivity, hyperactivity, and mood disturbances. Impulsivity has been linked to lipid metabolism, particularly cholesterol and apolipoproteins. This study investigates the relationship between lipid profile, apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), and impulsivity in first-episode mania patients. A case-control study was conducted at Sriram Chandra Bhanja (SCB) Medical College, Cuttack, involving 60 patients with first-episode mania and 60 age-matched healthy controls. Lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), ApoA1, and ApoB, were measured. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Independent samples t-tests and Pearson's correlation were used for statistical analysis. Mania patients had significantly lower TC (156.58 ± 14.00 mg/dL vs. 175.93 ± 23.59 mg/dL, p < 0.001), LDL (75.00 ± 9.24 mg/dL vs. 83.58 ± 16.86 mg/dL, p = 0.001), and TG (74.03 ± 11.94 mg/dL vs. 96.43 ± 29.48 mg/dL, p < 0.001) compared to controls. ApoB levels were higher in mania patients (795.95 ± 725.44 mg/dL vs. 549.53 ± 796.67 mg/dL, p = 0.079), though not statistically significant. BIS-11 scores negatively correlated with cholesterol levels, particularly TC and LDL, suggesting an association between hypercholesterolemia and increased impulsivity. Lower cholesterol levels, particularly LDL, are significantly associated with impulsivity in first-episode mania patients. These findings highlight the potential role of lipid metabolism in psychiatric disorders and suggest lipid monitoring in high-risk individuals. Show less

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05212428. Show less

Apolipoprotein B48 (ApoB48) may be an indicator of residual cardiovascular risk beyond conventional lipid measures. However, its performance for detecting coronary artery disease (CAD), alone and in combination with the ankle-brachial index (ABI), remains to be investigated. This cross-sectional study (358 patients; 299 and 59 with and without CAD, respectively) assessed the value of ApoB48 (cutoff: ≥4.5 μg/mL) and ABI (cutoff: <0.9) in detecting CAD. Subgroup analyses were performed for patients with diabetes mellitus, hypertension, dyslipidemia, and low levels of low-density lipoprotein-cholesterol (LDL-C) (<100 mg/dL). Baseline characteristics, including lipid profiles and biomarker levels, were compared between patients with and without CAD. Patients with CAD exhibited significantly higher ApoB48 levels compared to those without (5.1 ± 3.2 vs. 4.0 ± 2.2 μg/mL, respectively, p = 0.001); there were no significant differences in ABI values. The sensitivity and specificity of ABI alone for CAD were 16.7% and 81.4%, respectively, while those for ApoB48 alone were 48.2% and 61.0%, respectively. Combining both markers improved sensitivity to 55.5%, though specificity declined to 47.5%. Subgroup analyses revealed that ApoB48 maintained superior sensitivity across groups with diabetes, hypertension, dyslipidemia, and low levels of LDL-C. Lipid parameters (LDL-C, non-high density lipoprotein-cholesterol, and triglycerides) showed minimal discriminatory power between patients with and without CAD. ApoB48 demonstrates superior sensitivity for CAD detection compared to ABI, particularly in high-risk patients. While combining ApoB48 and ABI enhances sensitivity, it compromises specificity, suggesting the need for balanced diagnostic strategies. ApoB48 may be a valuable marker of residual cardiovascular risk, particularly in patients with well-controlled LDL-C or comorbid metabolic conditions. Show less

Emerging lipid-lowering therapies, such as Plozasiran, target apolipoprotein C-III (APOC-III) by inhibiting its hepatic production at the mRNA level, presenting a novel approach to lipid regulation. However, the safety and efficacy of plozasiran have yet to be fully established. We searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL register of trials for studies comparing plozasiran to placebo in patients with dyslipidemic disorders. The primary outcomes were percentage changes from baseline in triglyceride (TG) and APOC-III levels at 24 weeks and the end of the study. Secondary outcomes included changes in other lipid parameters and safety outcomes at 24 weeks and the end of the study. A protocol was registered to PROSPERO under registration number [CRD420251026605]. Four studies encompassing 1,514 participants were included in our meta-analysis. Plozasiran significantly improved TGs, APOC-III, non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels at both 24 weeks and study completion. Subgroup analyses based on dose and regimen revealed consistent findings. Quarterly administration of plozasiran at 10 mg, 25 mg, and 50 mg resulted in significant reductions in TGs, APOC-III, non-HDL-C, and HDL-C at both 24 weeks and study completion. For ApoB, all three doses produced significant reductions at 24 weeks; however, only the 25 mg and 50 mg quarterly regimens sustained these reductions through the end of the study. Regarding safety, patients receiving plozasiran experienced a higher incidence of any adverse events, headache, and mild rises in HbA1C levels. Subgroup analysis revealed a dose-dependent pattern for certain safety outcomes. While Plozasiran shows strong potential as a therapeutic option for severe dyslipidemic conditions, further studies are needed to compare its efficacy and safety with currently available treatments and, more importantly, evaluate its impact on clinical outcomes for implementation in clinical practice. Show less

Cholecystectomy alters lipid profiles and is associated with the risk of major adverse cardiac and cerebrovascular events (MACCE), yet the results are ambiguous. To assess the causal effects of cholecystectomy on blood lipid levels and risks of MACCE, we performed Mendelian randomization (MR) aiming to reduce confounding. We used genetic data on gallbladder removal, lipid levels, and MACCE from public databases. MR analysis estimated causal effects using genetic variants as instruments. Enrichment analysis identified relevant metabolic pathways, while multivariable MR evaluated specific lipid subtypes. Expression Quantitative Trait Loci MR pinpointed key genes, with cellular distribution insights from single-cell sequencing. Cholecystectomy was associated with delayed onset of angina, coronary heart disease, heart failure, myocardial infarction, and stroke. The ApoB/ApoA1 ratio was a key mediator, and the LPL gene influenced lipid-related cardiovascular risk. Cholecystectomy may reduce cardiovascular risks by lowering the ApoB/ApoA1 ratio, which highlights the role of lipid regulation in mitigating cardiovascular risk post-cholecystectomy. Show less

Biochemical items play a significant role in clinical decision-making, so this study aims to evaluate the performance of different biochemical platforms. We collected 1,524 serum samples that were centrifuged, and plasma was analyzed for HDL-C, LDL-C, Apo A1, Apo B, PA, and Fs-CRP with the Mindray BS2000M and Roche Cobas 8000 platforms. The results were evaluated by a non-parametric two-related sample test, Passing-Bablok regression analysis, Weighted Least Square analysis (WLS), and Bland-Altman analysis according to CLSI EP09-A3, EP5-A2, and EP15-A3. Between the two systems, there were statistically significant differences in the average bias of LDL-C, Apo A1, Apo B, PA, and Fs-CRP ( These findings suggest that the two platforms have good correlation and consistency in high-concentration medical decision levels in HDL-C, LDL-C, Apo A1, Apo B, and Fs-CRP, and all levels of PA in the two platforms are interchangeable and can replace each other. Show less

Women diagnosed with PCOS exhibit a high prevalence of obstructive sleep apnea (OSA). This study aims to assess risk factors of OSA among patients with PCOS. This retrospective study included 126 patients with PCOS who were categorized into an OSA group (n = 30) and a non-OSA group (n = 96) according to the apnea-hypopnea index (AHI). A control group comprised 72 patients without PCOS who presented during the same period for infertility due to fallopian tube, pelvic, or male factors. Patients with PCOS A multivariate logistic regression model was used to analyze independent risk factors for OSA in the PCOS group. Patients with PCOS had significantly higher AHI values and elevated values for various physical indicators, including body mass index (BMI) and neck, waist, and hip circumferences; prolactin (PRL); fasting plasma glucose (FPG); insulin (FINS); triglycerides (TG); homeostasis model assessment of insulin resistance (HOMA-IR); 2-hour postprandial glucose (2-hPG) and insulin (2-hINS); AHI; and oxygen desaturation index (ODI). Conversely, levels of high-density lipoprotein cholesterol (HDL-C) and lowest oxygen saturation (LSaO OSA in PCOS patients is linked to metabolic indicators. High neck circumference and BMI levels were independent risk factors, highlighting the need for OSA in routine PCOS screening, particularly in the context of metabolic dysregulation. Show less

Dipeptidyl peptidase-4 inhibitors (DPP-4i) serve as an incretin-based hypoglycemic class for the treatment of type 2 diabetes (T2D). DPP-4i have been reported to produce a pleiotropic effect on lipid profiles in addition to regulation of glucose homeostasis. The aim of this systematic review and meta-analysis was to quantitatively evaluate the impact of DPP-4i on lipid parameters in patients with T2D. PubMed, Embase, and The Cochrane Library were systematically searched for randomized controlled trials. Trials were identified if changes in lipid parameters, including low-density-lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), high-density-lipoprotein cholesterol (HDL-C), non-HDL-C, and apolipoprotein B (ApoB) were reported. A total of 95 publications were identified. DPP-4i significantly reduced levels of LDL-C (-3.48 mg/dL; 95% CI, -4.77 to -2.20; I2 = 70%, P < .00001), TC (-2.59 mg/dL; 95% CI, -3.88 to -1.29; I2 = 73%, P < .0001), TG (-5.39 mg/dL; 95% CI, -8.04 to -2.75; I2 = 77%, P < .0001), and non-HDL-C (-6.27 mg/dL; 95% CI, -10.94 to -1.60; I2 = 53%, P = .008). No significant effect was found on HDL-C (-0.32 mg/dL; 95% CI, -1.19 to 0.55; I2 = 97%, P = .47) and ApoB (-0.88 mg/dL; 95% CI, -3.36 to 1.60; I2 = 36%, P = .49) during DPP-4i treatment. DDP-4i significantly improved lipid parameters including LDL-C, TC, TG, and non-HDL-C in patients with T2D. This underscores the potential cardiovascular benefits of DPP-4i and their role in improving diabetes-related outcomes. PROSPERO registration no. CRD42020175999. Show less

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, with prevalence increasing due to aging and risk factors like obesity and hypertension. The retina, rich in microvasculature, provides a unique opportunity to investigate microvascular dysfunction linked to CVDs and other systemic vascular diseases. This study used a multifaceted approach to assess the genetic correlation and causal relationship between retinal characteristics and CVDs. Linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) analyses were conducted using genome-wide association study (GWAS) data from the UK Biobank and FinnGen datasets. A cross-sectional study was also conducted to validate the findings, collecting optical coherence tomography (OCT) images from 124 eyes (89 with CVDs and 35 healthy controls). A prediction model is based on least absolute shrinkage and selection operator (LASSO) regression to assess the risk of CVD. Using LDSC and two-sample MR, we found genetic evidence consistent with a causal effect whereby genetically proxied thinner retinal nerve fiber layer (RNFL) was associated with higher risks of hypertension and myocardial infarction (MI), while genetically proxied thicker photoreceptor inner segment/outer segment (PR-IS/OS) was associated with coronary heart disease and MI (false discovery rate [FDR] thresholds as reported). Genetically proxied thinner retinal pigment epithelium (RPE) showed an inverse association with stroke risk. Several circulating biomarkers-including lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB-exhibited MR evidence of association with multiple CVDs. In a cross-sectional cohort, retinal layer differences and their relationships with lipids were directionally consistent with the genetic findings. Retinal structural traits measured by OCT-particularly RNFL, PR-IS/OS, and RPE thickness-are best interpreted as non-invasive markers that reflect systemic vascular biology. Our MR analyses support shared etiologic pathways between retinal microstructure and CVDs rather than implying that retinal damage clinically causes cardiovascular events. Findings warrant validation in larger and more diverse populations and should not be considered definitive proof of causality. Show less

Emerging evidence suggests that ApoB outperforms LDL-C in predicting cardiovascular risk, especially in cases of discordance with the two. However, the specific type and composition of lipoprotein particles in this situation remain unclear. 375,544 individuals were enrolled from the UK Biobank without baseline cardiovascular disease, not on lipid-lowering therapy, and with available lipid nuclear magnetic resonance (NMR) data. Based on whether the absolute difference in baseline percentile of LDL-C and ApoB level was over 10 units, participants were categorized into concordant, discordantly high ApoB, and discordantly low ApoB group. The primary endpoint was major adverse cardiovascular events (MACE). Cox regression analysis showed the risk of MACE was increased in the discordantly high ApoB group (HR, 1.11; 95% CI, 1.06-1.15) and reduced in the discordantly low ApoB group (HR, 0.87; 95% CI, 0.83-0.93). Similar trends were observed in the NMR data. Compared to the other two groups, the discordantly high ApoB group exhibited the highest concentrations of VLDL-C, VLDL-CE, and VLDL particles. However, the CE content per LDL, IDL, and VLDL particle was lower in this group. Mediation analysis showed that VLDL particles and triglycerides mediated 25.5% and 26.6% of the MACE risk, respectively, in the discordantly high ApoB group (both P < 0.001). ApoB is a more comprehensive marker of cardiovascular risk than LDL-C. The higher cardiovascular risk in discordantly high ApoB individuals was partly mediated by VLDL; however, no conclusive evidence indicated that VLDL provides additional prognostic value beyond triglyceride measurements alone. Show less