PCSK9 Research Articles

Background: Monocytes, particularly the proinflammatory intermediate subsets (IM), drive atherosclerosis and predict cardiovascular events. The elevated levels of lipoprotein(a) (Lp(a)) further modulate the monocyte dynamics. However, the impact of lipid-lowering proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) on monocyte distribution in high-risk patients remains unknown. Purpose: We aimed to evaluate the effect of the individual lipoproteins and PCSK9i on monocyte subtypes’ distribution in patients with stable coronary disease and significantly elevated Lp(a) levels. Methods: We included 100 statin-treated patients in stable phase after myocardial infarction and elevated Lp(a) levels. The patients received placebo or PCSK9i every two weeks for 6 months. Biochemical, genetic and cell analysis at baseline and after 6 months were performed. Results: At baseline, the IM levels correlated with total cholesterol (TC) (ρ=-0.202, p =0.044), triglycerides (ρ=-0.324, p <0.001), apoA1 (ρ=0.241, p =0.016), and PCSK9 levels (ρ=-0.282, p =0.006), while PCSK9 levels were additionally associated with the CC-motif chemokine ligand 2 (CCL2) (ρ=0.298, p =0.005), a key monocyte recruitment chemokine. Adding PCSK9i to maximal statin therapy did not significantly alter the distribution of any monocyte subtypes. After treatment with PCSK9i, only an association between IM and Lp(a) levels (ρ=-0.258, p =0.041) remained significant. The number of KIV-2 repeats positively correlated with CCL2 levels (ρ=0.319, p =0.011). Changes in IM levels correlated with changes in TC (ρ=-0.315, p =0.011), low density lipoprotein cholesterol (ρ=-0.279, p =0.026), and apoB concentrations (ρ=-0.400, p =0.001), whereas other associations remained non-significant. Conclusion: In high-risk patients, PCSK9i modulate monocyte-lipoprotein interactions without altering the monocyte subtype distribution. Our data suggest that PCSK9 may express the proinflammatory effects through regulating CCL2, with the CCL2 expression more strongly related to Lp(a) composition than concentration.

Introduction: Dyslipidemia plays a critical role in the progression of chronic allograft vasculopathy (CAV), which is a major cause of long-term graft failure and mortality in heart transplant patients. Proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors have emerged as potent lipid-lowering agents, but their role in managing CAV in this high-risk population remains unclear. Research Question: Do PCSK9 inhibitors improve the lipid profile, stabilize maximal coronary intimal thickness, and affect serum biomarker levels compared to baseline in heart transplant patients with or at risk of chronic allograft vasculopathy? Methods: PubMed, Embase, Cochrane, ClinicalTrials.gov, and WHO ICTRP were searched. All analyses were conducted using RevMan Web, wherein pre- and post-PCSK9 inhibitor parameters were compared. A fixed- or random-effects model was used depending upon the observed heterogeneity. Results: A total of nine studies comprising 240 patients were included. PCSK9 inhibitor therapy led to a statistically significant reduction in total cholesterol (MD=95.96 mg/dL; 95%CI: 73.86, 118.06; P<0.00001) and LDL-C (MD=80.04 mg/dL; 95%CI: 60.90, 99.18; P<0.00001). In contrast, no significant changes were observed in HDL-C (MD= -2.12 mg/dL; 95%CI: -8.64, 4.41; P=0.52) and triglycerides (MD=37.46 mg/dL; 95%CI: -1.77, 76.69; P=0.06). The maximal coronary intimal thickness pre- and post-PCSK9 inhibitor therapy was comparable (MD= -0.03 mm; 95%CI: -0.07, 0.02; P=0.23). Additionally, there were no significant effects on key biomarkers, including N-terminal pro-BNP (SMD=0.80; 95%CI: -1.20, 2.80; P=0.43), glomerular filtration rate (SMD=-0.13; 95%CI: -0.48, 0.21; P=0.45), AST (SMD=0.26; 95%CI: -0.52, 1.05; P=0.51), or creatine kinase (SMD=-0.32; 95%CI: -1.50, 0.86; P=0.60) levels. Conclusions: PCSK9 inhibitors significantly improved lipid parameters, specifically total cholesterol and LDL-C levels, in heart transplant recipients, thereby supporting their role in dyslipidemia management within this high-risk cohort. The comparable pre- and post-therapy maximal coronary intimal thickness may indicate the slowing down of vasculopathy. The absence of significant effects on HDL-C, triglycerides, and non-lipid biomarkers suggests that the benefits are predominantly confined to reducing atherogenic lipoproteins. Further research is needed to evaluate the long-term impact of PCSK9 inhibition on cardiovascular outcomes in these patients.

Background: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have been shown to effectively lower low-density lipoprotein cholesterol (LDL-C) and reduce the risk of cardiovascular events. However, despite these benefits, some patients are unable to continue PCSK9 inhibitor therapy due to financial or other non-medical reasons. Clinical evidence regarding outcomes following discontinuation of PCSK9 inhibitors remains limited. Purpose: This study aims to investigate patients who were unable to continue PCSK9 inhibitor therapy, with particular emphasis on those who discontinued treatment due to financial or other non-medical reasons. The primary objective is to evaluate the impact of therapy discontinuation on the incidence of major adverse cardiovascular events (MACE). Methods: This study included 201 Japanese patients with coronary artery disease who received PCSK9 inhibitor therapy between July 2016 and December 2023. Clinical outcomes were compared between patients who continued therapy and those who discontinued. The primary endpoint was MACE, defined as a composite of all-cause mortality, coronary revascularization, target lesion revascularization (TLR), fatal or non-fatal myocardial infarction (MI), and hospitalization for heart failure. Results: Among the 201 patients (median age: 69 years; interquartile range [IQR]: 59–75; 73% male), the median follow-up duration was 4.7 years (IQR: 2.2–6.4). At one year, the median LDL-C was 42 mg/dL, with 82% achieving LDL-C <70 mg/dL. During follow-up, 111 patients (55.2%) continued therapy, while 90 (44.8%) discontinued. Among those who discontinued, 33% cited financial difficulties, 23% clinical stability, and 21% patient preference. Multivariate Cox regression analysis showed that those who discontinued therapy had a significantly higher incidence of MACE compared to those who continued (hazard ratio: 1.76; 95% confidence interval: 1.03–3.02; p=0.039). Conclusions: Discontinuation of PCSK9 inhibitors—particularly for financial or other non-medical reasons—is associated with an increased risk of MACE. These findings underscore the need for strategies to support long-term adherence and address socioeconomic barriers to therapy continuation. This insight has important implications for clinical decision-making and healthcare policy.

Introduction: Ischemic heart disease (IHD) remains a leading global cause of morbidity and mortality despite advances in therapies. Lowering low-density lipoprotein cholesterol (LDL-C) is critical in reducing cardiovascular risk. Statins are usually the first-line agents, but many patients either fail to reach LDL-C targets or remain at residual risk. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors effectively lower LDL-C and provide cardiovascular benefits in high-risk patients. This meta-analysis assessed both the efficacy and safety of PCSK9 inhibitors used in conjunction with statins in patients with IHD, with a focus on efficacy and safety endpoints. Methods: We systematically searched PubMed, Cochrane Library, and ClinicalTrials.gov through May 2025 for randomized controlled trials (RCTs) comparing PCSK9 inhibitors plus statins vs. placebo with or without statins in patients with IHD. Three reviewers independently extracted data. Efficacy outcomes included LDL-C at 30 days; ischemic stroke; heart failure hospitalization; unstable angina; neurocognitive events; all-cause mortality; myocardial infarction (MI) and coronary revascularization. Safety outcomes included injection site and allergic reactions. Pooled risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Means and standard deviations were estimated from medians/IQRs by Wan’s method. Study quality was assessed using Cochrane RoB 2.0. Assessment of publication bias was not feasible due to fewer than 10 included studies. Results: In this meta-analysis, five RCTs were included. Combination therapy significantly reduced total cholesterol at 30 days (MD =–49.21 mg/dl; 95% CI; –90.68 to –7.74; p = 0.02) coronary revascularization (RR = 0.84; 95% CI: 0.76–0.93; p = 0.0008), MI (RR 0.76; 95% CI; 0.62-0.93; p= 0.007) and increased the risk of injection site reactions (RR=1.36; 95% CI: 1.16–1.59; p = 0.0001). Sensitivity analyses were conducted to address heterogeneity. No significant differences were observed for all-cause mortality, stroke, heart failure, neurocognitive events, or allergic reactions. Conclusion: In patients with IHD, the addition of PCSK9 inhibitors to statin therapy improved lipid levels and reduced coronary revascularization with a favorable safety profile. These findings support their use in select high-risk populations who remain inadequately managed on statins alone.

Introduction: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective adjunct therapy for reducing low-density lipoprotein cholesterol (LDL-C) in patients with hyperlipidemia. Current approved PCSK9 inhibitors are injectable therapies. Laroprovstat (AZD0780) is an oral, small molecule PCSK9 inhibitor in development to lower LDL-C in patients with hyperlipidemia. Methods: In this Phase 1 study, the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) properties of laroprovstat were assessed in participants with LDL-C ≥100 mg/dL and ≤190 mg/dL (NCT05384262). Participants were first treated with rosuvastatin 20 mg for three weeks followed by randomization to laroprovstat 1 mg, 30 mg or placebo administered once daily for 28 days. The change from baseline following the rosuvastatin run-in to end of treatment was measured for LDL-C and clinically commonly assessed lipid parameters. Furthermore, a broad panel of apolipoproteins was analyzed with a mass spectrometry-based proteomics method, ApoEdge™. Results: Laroprovstat was well tolerated with no safety findings of concern. Laroprovstat 30mg accumulated following multiple dosing with ratios of 2.837 for AUC and 2.765 for Cmax . However, there was no evidence of time-dependent PK following 30 mg laroprovstat plus rosuvastatin with a geometric mean ratio (90% CI) of AUCinf Day 1 compared to AUCtau Day 8 of 0.9500 (0.8260, 1.0926). When dosed following a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 mg and 30 mg reduced LDL-C by 29% (95% CI: 38, 18) and 51% (95% CI: 58, 44). Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 mg and 30 mg, respectively. Numerical reductions in total cholesterol, non-HDL-C, and ApoB were also observed with laroprovstat treatment. Decreased levels of ApoB, ApoE, and Apo(a) were also detected with the ApoEdge™ method. Conclusions: In treatment-naïve hypercholesterolemic patients, rosuvastatin combined with laroprovstat led to nearly 80% LDL-C reduction and was well-tolerated in this Phase 1 study. These data support further development of laroprovstat as the first oral small molecule PCSK9 inhibitor.

Background: Recaticimab, a humanized monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) with a novel YTE mutation, prolongs its half-life by enhancing neonatal Fc receptor (FcRn) binding, making it the longest-acting anti-PCSK9 antibody. Approved for dyslipidemia management, its clinical performance concerning immunogenicity is still under study. Aims: To explore the impact of immunogenicity on the efficacy and safety of recaticimab in patients with dyslipidemia. Methods: The pooled analysis was conducted using data from 3 phase III trials (REMAIN 1-3) and 1 phase Ib/II trial (NCT03944109). Patients with primary hypercholesterolemia (non-familial and heterozygous) and mixed hyperlipemia were randomized to receive subcutaneous recaticimab at doses of 150 mg every 4 weeks (Q4W), 300 mg Q8W, 450 mg Q12W, or matching placebo. Anti-drug antibodies (ADAs) were measured over time, with ADA-positive samples tested for neutralizing antibodies (Nabs). Efficacy outcome (the percent change in low-density lipoprotein cholesterol [LDL-C] from baseline at Week 12 (Q4W and Q12W groups), and Week 16 (Q8W group), and safety outcome were evaluated by ADA and Nab status. Results: Among 1034 patients who received recaticimab, 146 (14.1%) tested positive for treatment-emergent ADA (ADA + ), and 33 (3.2%) for Nab (Nab + ). In the placebo group (n=507), 10 (2.0%) were ADA + , and none were Nab + . In recaticimab-treated patients, LDL-C reductions from baseline at Week 12/16 were comparable across ADA - , ADA + , Nab + patients for all dosing regimens (Figure 1). The incidence of treatment-related adverse events (TRAEs) was 22.8% (202 of 885) in ADA - patients, 29.5% (43 of 146) in ADA + patients, and 42.4% (14 of 33) in Nab + patients. Injection site reactions were the most common TRAE: 2.8% (25 of 885) in ADA - , 10.3% (15 of 146) in ADA + , and 18.2% (6 of 33) in Nab + patients. All TRAEs in the ADA + and Nab + groups were mild to moderate, with no serious TRAEs reported. Conclusions: The incidence of ADAs (14.1%) and Nabs (3.2%) following recaticimab treatment did not impact efficacy. ADA + and Nab + patients had a higher incidence of self-resolving injection site reactions compared to ADA - patients. These findings support the clinical use of recaticimab for lipid-lowering therapy, regardless of immunogenicity status.

Background: The low-density lipoprotein receptor (LDLR) in the liver plays a crucial role in clearing low-density lipoprotein cholesterol (LDL-C) from the bloodstream. Under atherogenic conditions, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), secreted by the liver, binds to LDLR on hepatocytes, preventing its recycling and enhancing its lysosomal degradation. Epsins, a family of ubiquitin-binding endocytic adaptors, are key regulators of atherogenesis. We aimed to determine whether and how liver epsins contribute to PCSK9-mediated LDLR endocytosis and degradation, thereby impairing LDL-C clearance and accelerating atherosclerosis. Methods: We utilized single-cell RNA sequencing (scRNA-seq), along with molecular, cellular, and biochemical analyses, to investigate the role of liver epsins in PCSK9-mediated LDLR degradation. Liver-specific epsin knockout (Liver-DKO) atherosclerotic models were generated in ApoE -/- and PCSK9-AAV8-induced atheroprone mice fed on a Western diet. Additionally, we explored the therapeutic potential of nanoparticle-encapsulated siRNAs targeting epsins 1 and 2 in ApoE -/- mice with established atherosclerosis. Results: Western diet (WD)-induced atherosclerosis was significantly attenuated in ApoE -/- /Liver-DKO mice compared with ApoE -/- controls, as well as in PCSK9-AAV8-induced Liver-DKO mice compared with PCSK9-AAV8-induced wild-type (WT) mice accompanied by reductions in blood cholesterol and triglyceride levels. Mechanistically, hepatocyte-derived scRNA-seq data analysis revealed increased pathways of LDL particle clearance in WD-fed ApoE -/- /Liver-DKO mice compared with WD-fed ApoE -/- controls, correlating with decreased plasma LDL-C levels. The absence of liver epsins led to an upregulation of LDLR protein expression in hepatocytes. We further demonstrated that epsins bind LDLR via the ubiquitin-interacting motif (UIM), enabling PCSK9-mediated LDLR degradation. Depleting epsins abolished this degradation, thereby preventing atheroma progression. Lastly, targeting liver epsins with nanoparticle-encapsulated epsins siRNAs effectively ameliorates dyslipidemia and inhibits atherosclerosis progression. Conclusions: Liver epsins drive atherogenesis by promoting PCSK9-mediated LDLR degradation, elevating circulating LDL-C levels and heightening lesional inflammation. Targeting epsins in the liver represents a promising therapeutic strategy to mitigate atherosclerosis by preserving LDLR and enhancing LDL-C clearance in the liver.

Introduction: Primary dyslipidemias represent a heterogeneous group of inherited disorders characterized by abnormal plasma levels of lipoproteins. Among them, familial hypercholesterolemia (FH) is the most prevalent and clinically significant condition due to its strong association with premature atherosclerotic cardiovascular disease (CVD). FH is most commonly caused by pathogenic variants in the LDLR , APOB , or PCSK9 genes, which lead to impaired clearance of low-density lipoprotein cholesterol (LDL-C) from the bloodstream and result in markedly elevated LDL-C levels from birth. Early identification and treatment are crucial to reduce morbidity and mortality. Despite this, FH remains widely underdiagnosed and undertreated. Research Question: In response to this public health challenge, in 2015 we established the LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network) registry, a collaborative nationwide initiative designed to enhance the clinical and molecular diagnosis of genetic dyslipidemias in Italy, with a primary focus on FH. Methods: The LIPIGEN is an observational, multicenter, retrospective and prospective study. To date, it involves 64 specialized lipid clinics distributed throughout Italy ( Figure ). Patients with suspected FH are primarily identified on a clinical basis, considering LDL-C levels, signs of long-term exposure to hypercholesterolemia (as xanthomas), personal anamnesis of premature cardiovascular events and family history of hypercholesterolemia or CVD. These patients are then referred for genetic testing to screen for pathogenic variants in the relevant candidate genes. The biochemical and clinical data are collected and entered into a centralized database. Results: To date, data from more than 11,800 individuals with a clinical diagnosis of FH have been recorded in the LIPIGEN database. Genetic testing has been performed in 78% of these individuals. Among them, a pathogenic or likely pathogenic variant was identified in 67% of cases, confirming the high diagnostic yield of targeted genetic analysis in this population. The most frequently mutated gene was LDLR , which is consistent with global epidemiologic data. Conclusion: The creation and implementation of the LIPIGEN network represents a significant advancement in the landscape of dyslipidemia care in Italy. By promoting standardized clinical evaluation and widespread access to genetic testing, the LIPIGEN facilitates earlier diagnosis and better-targeted therapy for individuals with FH.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulator of cholesterol homeostasis, yet the shallow PCSK9-LDLR interface has hindered small-molecule inhibitor development. Using mixed-solvent molecular dynamics (MSMD) simulations with six diverse probes, we identified a novel cryptic allosteric pocket within the C-terminal domain (CTD), ∼60 Å from the LDLR-binding site. Pocket opening was facilitated by the disruption of key salt bridges, notably R580-E612, and observed across all probe conditions. Network-based correlation analyses revealed communication pathways linking this CTD pocket to the LDLR-binding interface with functionally important residues such as H574 and V610 involved. These results uncover a previously uncharacterized druggable allosteric site in PCSK9 and provide mechanistic insight into long-range allosteric modulation. The findings lay a foundation for the rational design of next-generation PCSK9 inhibitors, offering new opportunities for hypercholesterolemia therapy.

Liver-targeted siRNA delivery via artificial red blood cells to lower LDL-C.

Sex-dependent behavioral responses and phenotypic traits of Pcsk9 knockout mice in anxiety- and depression-like paradigms.

Background Few percutaneous coronary intervention (PCI) patients achieve low-density lipoprotein cholesterol (LDL-C) targets with statins alone. While proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively diminish LDL-C levels, their combined use with statins for reducing major adverse cardiovascular events (MACE) and improving lipid profiles post-PCI requires further validation. This study seeks to appraise the therapeutic impact of PCSK9 inhibitors combined with statins on MACE and blood lipids in patients following PCI. Methods Randomized controlled trials (RCTs) and cohort studies as of February 2025 in the PubMed, Embase, Cochrane Library, and Web of Science databases were identified. Regarding the risk of bias evaluation, Cochrane ROB 2.0 was employed for RCTs. Moreover, cohort studies were appraised by means of the Newcastle-Ottawa Scale. In terms of heterogeneity, it was appraised by means of the I 2 statistics. The relative risk (RR) and 95% confidence interval (CI) for dichotomous variables, along with the weighted mean difference (WMD), standardized mean difference (SMD), and their respective 95% CIs for continuous variables. Results The meta-analysis included 17 studies, including 9 RCTs and 8 cohort studies, involving 5,607 subjects. The meta-analysis revealed that, against the statin group, the combination therapy group displayed a notable decline in MACE incidence (RR: 0.61; 95% CI: 0.50–0.75; p < 0.001; I 2 = 0.0%). Meanwhile, the combination therapy group demonstrated greater LDL-C reduction vs. statin monotherapy (SMD: −1.29; 95% CI: −1.70 to −0.87). Moreover, The combination therapy group achieved significantly higher LDL-C ≤ 1.4 mmol/L attainment rates vs. statin monotherapy (RR: 5.83; 95% CI: 5.20–6.55). Conclusion PCSK9 inhibitors combined with statins significantly reduces MACE incidence, improves lipid profiles in post-PCI patients compared to statin monotherapy. Systematic Review Registration https://www.crd.york.ac.uk/ , identifier (CRD420250650716).

Proprotein Convertase Subtilisin-Kexin type 9 (PCSK9) is a key regulator of lipid metabolism, binding to the low-density lipoprotein receptor (LDLR) on the cell surface and preventing its recycling, thereby reducing clearance of LDL cholesterol (LDLc) from the circulation. For this reason, it constitutes an alternative therapeutic target for the control of hypercholesterolaemia, with the development of monoclonal antibodies against PCSK9 occurring within twelve years of the protein's discovery. Recent research has also suggested an inflammatory role played by PCSK9, with elevated plasma levels identified in critical illnesses such as sepsis and Acute Respiratory Distress Syndrome, where PCSK9 is thought to reduce bacterial endotoxin clearance and may exacerbate inflammation. Further work is required in order to clarify the exact role played by PCSK9 in extra-hepatic tissues, and the potential benefits of its pharmacological inhibition.

Obesity is a multifactorial condition projected to affect over half of the global population by 2035, posing significant clinical and socioeconomic challenges. Traditional metrics such as body mass index lack precision in predicting individual risk, disease progression, and therapeutic response due to the heterogeneous nature of obesity. Advances in omics technologies such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics have enabled the identification of molecular subtypes and candidate biomarkers that offer deeper insights into obesity pathophysiology. Genomic studies have revealed hundreds of loci associated with obesity related traits, while polygenic risk scores offer modest improvements in early risk prediction. Epigenomic profiling, particularly deoxy ribose nucleic acid (DNA) methylation signatures such as those at carnitine palmitoyl transferase 1A (CPT1A) and hypoxia inducible factor 3 subunit alpha (HIF3A), has uncovered modifiable pathways linked to adiposity and metabolic dysfunction. These findings are increasingly being integrated with other omics layers to improve stratification and therapeutic targeting. Metabolomic subtypes, including ceramide driven insulin resistance and branched chain amino acid (BCAA) dominant dysregulation, have shown potential in guiding treatment selection, such as sodium glucose cotransporter 2 (SGLT2) inhibitors or glucagon like peptide-1 (GLP-1) agonists. Proteomic markers like proprotein convertase subtilisin/kexin type 9 (PCSK9) and retinol binding protein 4 (RBP4) are being evaluated for cardiovascular risk stratification independent of body mass index (BMI). Integrative multiomics frameworks and AI driven models are beginning to bridge molecular data with clinical phenotypes, enabling patient stratification and risk modeling. However, most findings remain in research grade environments, and clinical translation is limited by cohort diversity, data harmonization challenges, and the lack of standardized validation protocols. This review synthesizes evidence from single and multiomics studies, highlights emerging biomarkers and molecular subtypes, and discusses the potential of omics guided frameworks to inform precision obesity care.

Many cancers evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes MHC-I degradation and is elevated in glioma. Evolocumab is a clinically approved PCSK9 inhibitor which restores MHC-I expression in pre-clinical cancer models. However, monoclonal antibodies have limited blood brain/tumor barrier penetrance (BBB/BTB). We conducted a window-of-opportunity trial, evaluating evolocumab’s BBB/BTB penetrance and biological effect (PesKE; NCT04937413). Patients with newly diagnosed or recurrent glioma undergoing a clinically indicated biopsy or resection were enrolled (n = 32, M: 16, F: 16; control average age: 51.85, evolocumab: 53). Intervention participants (n = 6) received a single subcutaneous evolocumab dose pre-procedure, of which 4 provided research tissue. No significant adverse events were observed. Evolocumab was detected in all analyzed intervention tissue, with an average tumor: blood ratio of 0.0222 (SD ± 0.0190), akin to other monoclonals. Evolocumab quantitation was 4.44× greater in contrast-enhancing (mean 0.0068 fmol/mcg (SD ± 0.001)) vs non-contrast enhancing cases (mean 0.0015 fmol/mcg (SD ± 0.0004)). Proteomic analysis found positive trends between evolocumab and MHC-I subtypes (HLA-A-C, E-G), with a significant positive correlation with HLA-H (R2 = 0.9584, p = 0.021*). Tumor tissue with higher evolocumab titers demonstrated increased surface MHC-I and CD8+ T cell infiltration. Increased CD8+TNF, FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue and untreated controls. Pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other monoclonal antibodies. Increased tumoral evolocumab/PCSK9i may enhance tumoral MHC-I/effector CD8+ infiltration. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-21064-9.

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.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism, vascular inflammation, plaque formation, atherosclerosis, and renal injury. This study aimed to investigate the level of serum PCSK9 and its association with clinical characteristics and particularly major adverse cardiovascular event (MACE) risk in hemodialysis patients. A Sum of 177 hemodialysis patients and 50 healthy subjects was included in this study. Serum PCSK9 level was determined by enzyme-linked immunosorbent assay. MaCE information is collected in hemodialysis patients with a median follow-up period of 15.8months. PCSK9 level was 179.0 [interquartile range (IQR): 106.9-297.7]ng/mL in hemodialysis patients, which was higher than that of 121.0 (IQR: 76.1-185.1)ng/mL in healthy subjects (P < 0.001). PCSK9 level was positively correlated with age (r = 0.202, P = 0.007), total cholesterol (TC) (r = 0.235, P = 0.002), and low-density lipoprotein cholesterol (LDL-C) (r = 0.271, P < 0.001) in hemodialysis patients. 18.1% of hemodialysis patients experienced MACE during the follow-up; PCSK9 level was 287.8 (IQR: 167.3-441.3)ng/mL in cases that experienced MaCE, which was higher than that of 163.3 (IQR: 98.4-277.0)ng/mL in those who did not (P < 0.001). Receiver operator characteristic curve revealed that PCSK9 level could estimate MaCE risk with area under the curve at 0.719, and the best cutoff threshold was 163.5ng/mL. After adjustment by four models involving different types of parameters, PCSK9 level and PCSK9 > 163.5ng/mL independently predicted a higher MACE risk. Serum PCSK9 level correlates with age, TC, and LDL-C, and predicts a higher MACE risk in hemodialysis patients, indicating its potency as a prognostic biomarker.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) plays a crucial role in pathophysiologic processes leading to limb and cardiovascular complications in diabetes, including cholesterol homeostasis, inflammation, and endothelial oxidative stress. This study examined the association between PCSK9 levels and major adverse limb events (MALEs) in patients with type 2 diabetes mellitus (T2DM) and chronic limb-threatening ischemia (CLTI) after endovascular revascularization.This prospective cohort study included 147 T2DM patients with peripheral artery disease undergoing endovascular revascularization for CLTI. Clinical assessments, including PCSK9 blood levels, were performed, and patients were followed for 12 months to monitor MALEs. Logistic regression and ROC curve analyses assessed the relationship between PCSK9 and MALEs.During follow-up, 53 patients experienced MALEs. These patients were younger and had more severe peripheral artery disease. PCSK9 levels were significantly higher in those with MALEs (410.5 ng/mL) versus those without (360.6 ng/mL). ROC analysis showed that adding PCSK9 to cardiovascular risk factors improved MALE prediction. PCSK9 levels and Rutherford 4 category were independent risk factors for MALEs.Elevated PCSK9 levels are strongly associated with increased MALE risk in T2DM patients and may influence age of presentation and disease severity in CLTI. These findings highlight PCSK9 as a potential predictive biomarker and therapeutic target for vascular complications.

BackgroundOur previous study has demonstrated the preventive effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on early neurological deterioration (END) in patients with acute non-cardiogenic ischemic stroke. Here, we performed a post hoc subgroup analysis to investigate whether the large artery atherosclerosis (LAA) subtype contributed to the clinical outcomes.MethodsAccording to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, patients were divided into LAA and small vessel occlusion (SVO) subgroups. In each subgroup, patients were further subdivided into combination therapy of evolocumab and atorvastatin (PI group) and atorvastatin monotherapy (AT group). The primary outcome was END within 7 days, defined as a ≥ 2-point National Institutes of Health Stroke Scale (NIHSS) score increase or NIHSS motor score ≥ 1-point compared with baseline.ResultsA total of 272 patients were included: 186 were categorized into the LAA subtype (93 in the PI group and 93 in the AT group) and 86 into the SVO subtype (43 in the PI group and 43 in the AT group). Compared with AT group, the primary analyses showed a significantly lower incidence of END with PI group in the LAA subtype (14.0% versus 28.0%; RR, 0.45; 95% CI, 0.26 to 0.80; p = 0.006), but not in the SVO subtype (11.6% versus 16.3%; RR, 0.77; 95% CI, 0.26 to 2.33; p = 0.649). Similar results were observed in terms of favorable functional Outcome at 90 days, combination therapy of evolocumab and atorvastatin was significantly associated with a high proportion of modified Rankin Scale scores of 0–2 at 90 days in the LAA group (81.7% versus 61.3%; RR, 1.39; 95% CI, 1.18 to 1.65; p < 0.001), but not in the SVO subtype (86.0% versus 74.4%; RR, 1.16; 95% CI, 0.95 to 1.42; p = 0.157). Other outcomes were similar between the two treatment groups in patients with LAA or SVO subtypes.ConclusionsAmong patients with LAA subtype stroke, combination therapy of evolocumab and atorvastatin may be superior to atorvastatin monotherapy regarding preventing END.Trial registrationhttp://www.chictr.org.cn. Identifier: ChicTR2200059445. Date of registration: 29 April 2022.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12883-025-04434-8.

Venous thromboembolism (VTE) remains a major cause of preventable morbidity and mortality. Prophylaxis with anticoagulation is limited by bleeding risk, contraindications, and patient-specific factors. Interest has therefore grown in alternative or adjunctive nonanticoagulant strategies that can mitigate thrombotic risk without increasing bleeding complications. Aspirin has demonstrated efficacy in both primary and secondary prevention of VTE. Most studies and trials have been undertaken in an orthopaedic population but with favorable safety profile. Statins have been shown to reduce VTE incidence without increased bleeding in several trials. Metformin appears to reduce prothrombotic mechanisms in type 2 diabetes. Observational studies have suggested its use to lower VTE risk. However, randomized data are lacking. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to reduce weight, improve metabolic control, and possess anti-inflammatory effects. Evidence suggests GLP-1 RAs may reduce VTE risk. However, findings are inconsistent across observational and trial-based analyses. Other emerging alternatives include hydroxychloroquine, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (post hoc analyses of cardiovascular trials suggesting lower VTE rates potentially via lipoprotein (a) reduction), sodium-glucose cotransporter-2 inhibitors (overall neutral in meta-analyses of randomized control trials with some real-world evidence vs. comparators), and renin-angiotensin-aldosterone system modulators (mixed observational data and no trial-proven benefit). Uncertainties remain regarding optimal patient selection, duration of prophylaxis, and their role in combination with standard anticoagulation across these drug classes. Further studies/trials are warranted to define the efficacy, safety, and guideline positioning of these agents in diverse patient populations.