Lipoprotein(a) in atherosclerotic cardiovascular disease and proprotein convertase subtilisin/kexin-type 9 inhibitors.

High plasma lipoprotein(a) (Lp(a)) levels increase the cardiovascular risk in populations with atherosclerotic cardiovascular disease (ASCVD). Apolipoprotein (a) [apo(a)], a unique protein component of Lp(a), plays an important role in the pathogenesis of atherosclerosis. Statins, the primary medication in managing ASCVD, lower low-density lipoprotein cholesterol (LDL-C) but concurrently elevate plasma Lp(a) levels, contributing to an increased residual cardiovascular risk. In turn, proprotein convertase subtilisin/kexin-type 9 (PCSK9) inhibitors, a novel class of LDL-C lowering drugs, effectively reduce plasma Lp(a) levels, which is believed to decrease residual cardiovascular risk. However, the mechanism by which PCSK9 inhibitors reduce Lp(a) levels remains unknown. In addition, there are some clinical limitations of PCSK9 inhibitors. Here, we systematically review the past, present, and prospects of studies pertaining to Lp(a), PCSK9 inhibitors, and ASCVD.

Safety and efficacy of PCSK9 inhibitors and effect on coronary plaque phenotype in statin-treated patients following acute coronary syndrome: a systematic review and meta-analysis.

BACKGROUND: Acute coronary syndrome continues to be a significant cardiovascular issue. Statins are commonly acknowledged as medications that reduce LDL-C levels and stabilize plaques. Nevertheless, their efficacy is limited. Presently, PCSK9 inhibitors are suggested to be advantageous in patients who are already receiving statin treatment. The study seeks to assess the safety and effectiveness of PCSK9 inhibitors in individuals who have been treated with statins after experiencing acute coronary syndrome (ACS), as well as investigate the impact on the characteristics of coronary plaque. METHODS: Articles were identified from PubMed, Cochrane Central Register of Controlled Trials, and ProQuest. Our analysis comprised trials and observational studies that compared the plaque phenotype, lipid profile, and safety outcomes between PCSK9 inhibitors and a control group in patients with acute coronary syndrome who were already being treated with statins. The random-effect model was used to measure the pooled effect, which was presented in terms of mean difference, standardized mean difference, and risk ratio. RESULTS: Acquired 12 studies that fulfilled our criteria. The addition of PCSK9 inhibitors ameliorates the plaque phenotype significantly in terms of percent atheroma volume (P = 0.02), total atheroma volume (P < 0.010), fibrous cap thickness (P < 0.00001), lipid arc (P < 0.00001), quantitative flow ratio (P = 0.003), and diameter of stenosis (P = 0.0003) but not in lipid/lesion length (P = 0.17). The administration of PCSK9 inhibitors led to a considerable improvement in all lipid profiles (P < 0.00001). Regarding safety analysis, there is no substantial disparity in the likelihood of non-serious side events (RR 1.21; P = 0.2), however, a significant reduction in the risk of serious adverse effects (RR 0.77; P = 0.04) in the PCSK9 inhibitor group. CONCLUSIONS: The addition of PCSK9 inhibitors compared to statin-only treatment led to a majority of patients experiencing significant benefits in terms of safety and efficacy following ACS.

Enhanced Plaque Stabilization Effects of Alirocumab　- Insights From Artificial Intelligence-Aided Optical Coherence Tomography Analysis of the Alirocumab for Thin-Cap Fibroatheroma in Patients With Coronary Artery Disease Estimated by Optical Coherence Tomography (ALTAIR) Study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors stabilize vulnerable plaque, reducing cardiovascular events. However, manual optical coherence tomography (OCT) analysis of drug efficacy is challenging because of signal attenuation within lipid plaques. METHODS AND RESULTS: Twenty-four patients with thin-cap fibroatheroma were prospectively enrolled and randomized to receive alirocumab (75 mg every 2 weeks) plus rosuvastatin (10 mg/day) or rosuvastatin (10 mg/day) alone. OCT images at baseline and 36 weeks were analyzed manually and with artificial intelligence (AI)-aided software. AI-aided OCT analysis showed significantly greater percentage changes in the alirocumab+rosuvastatin vs. rosuvastatin-alone group in fibrous cap thickness (FCT; median [interquartile range] 212.3% [140.5-253.5%] vs. 88.6% [63.0-119.6%]; P=0.006) and lipid volume (median [interquartile range] -30.8% [-51.8%, -16.6%] vs. -2.1% [-21.6%, 4.3%]; P=0.015). Interobserver reproducibility for changes in minimum FCT and lipid index was relatively low for manual analysis (interobserver intraclass correlation coefficient [ICC] 0.780 and 0.499, respectively), but high for AI-aided analysis (interobserver ICC 0.999 and 1.000, respectively). Agreements between manual and AI-aided OCT analyses of FCT and the lipid index were acceptable (concordance correlation coefficients 0.859 and 0.833, respectively). CONCLUSIONS: AI-aided OCT analysis objectively showed greater plaque stabilization of adding alirocumab to rosuvastatin. Our results highlight the benefits of a fully automated AI-assisted approach for assessing drug efficacy, offering greater objectivity in evaluating serial changes in plaque stability vs. conventional OCT assessment.

Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome.

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Novel insights into the association between genetically proxied inhibition of proprotein convertase subtilisin/kexin type 9 and risk of sarcopenia.

BACKGROUND: The effects of lipid-lowering drugs [including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] on hyperlipidaemia have been established. Some may have treatment effects beyond their reported properties, offering potential opportunities for drug repurposing. Epidemiological studies have reported conflicting findings on the relationship between lipid-lowering medication use and sarcopenia risk. METHODS: We performed a two-sample Mendelian randomization (MR) study to investigate the causal association between the use of genetically proxied lipid-lowering drugs (including statins, ezetimibe, and PCSK9 inhibitors, which use low-density lipoprotein as a biomarker), and sarcopenia risk. The inverse-variance weighting method was used with pleiotropy-robust methods (MR-Egger regression and weighted median) and colocalization as sensitivity analyses. RESULTS: According to the positive control analysis, genetically proxied inhibition in lipid-lowering drug targets was associated with a lower risk of coronary heart disease [PCSK9 (OR, 0.67; 95% CI, 0.61 to 0.72; P = 7.7E-21); 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; OR, 0.68; 95% CI, 0.57 to 0.82; P = 4.6E-05), and Niemann-Pick C1-like 1 (NPC1L1; OR, 0.53; 95% CI, 0.40 to 0.69; P = 3.3E-06)], consistent with drug mechanistic actions and previous trial evidence. Genetically proxied inhibition of PCSK9 (beta, -0.040; 95% CI, -0.068 to -0.012; P = 0.005) and circulating PCSK9 levels (beta, -0.019; 95% CI, -0.033 to -0.005; P = 0.006) were associated with reduced appendicular lean mass (ALM) with concordant estimates in terms of direction and magnitude. Validation analyses using a second instrument for PCSK9 yielded consistent results in terms of direction and magnitude [(PCSK9 to ALM; beta, -0.052; 95% CI, -0.074 to -0.032; P = 7.1E-7); (PCSK9 protein to ALM; beta, -0.060; 95% CI, -0.106 to -0.014; P = 0.010)]. Genetically proxied inhibition of PCSK9 gene expression in the liver may be associated with reduced ALM (beta, -0.013; 95% CI, -0.035 to 0.009; P = 0.25), consistent with the results of PCSK9 drug-target and PCSK9 protein MR analyses, but the magnitude was less precise. No robust association was found between HMGCR inhibition (beta, 0.048; 95% CI, -0.015 to 0.110; P = 0.14) or NPC1L1 (beta, 0.035; 95% CI, -0.074 to 0.144; P = 0.53) inhibition and ALM, and validation and sensitivity MR analyses showed consistent estimates. CONCLUSIONS: This MR study suggested that PCSK9 is involved in sarcopenia pathogenesis and that its inhibition is associated with reduced ALM. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of sarcopenia.

Serum mature and furin-cleaved proprotein convertase subtilisin/kexin type 9 levels and their association with cardiovascular events in statin-treated patients with cardiovascular disease.

BACKGROUND AND AIMS: Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events partly due to measurement methods that cannot distinguish between uncleaved and furin-cleaved forms of PCSK9. METHODS: This is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The primary endpoint was major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In this case-cohort study, serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among 426 participants who developed MACCE (cases) and 1,478 randomly selected participants (sub-cohort). RESULTS: From 1,478 patients in sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of the primary endpoint in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile (hazard ration [HR] 0.809; 95% confidence intervals [CI], 0.541-1.209). Similarly, the HR for the highest to lowest quartiles of furin-cleaved PCSK9 was 0.948 [95% CI, 0.645-1.392] (P = 0.784). Compared to the lowest quartile, neither serum mature nor furin-cleaved PCSK9 levels predicted MACCE. CONCLUSIONS: In a large-scale secondary prevention cohort, serum mature and furin-cleaved PCSK9 levels did not provide useful information for predicting future cardiovascular events in statin-treated patients with stable CAD.

Mediation effect of metabolic factors and inflammation on the association of serum uric acid with serum proprotein convertase subtilisin/kexin type 9 levels.

BACKGROUND: The association between serum uric acid (SUA) levels and serum PCSK9 levels has not yet been uncovered. This study aimed to explore the potential link between SUA levels and serum PCSK9 levels and quantify the mediating effect of metabolic factors and inflammation in Chinese adults. Furthermore, assessed whether gender differences modified this association. METHODS: In total, 2624 participants were enrolled and categorized based on their serum UA levels as the hypouricemic (n = 432) and normouricemic group (n = 2192). Stepwise multivariable regression analysis, binary logistic regression analysis and mediation analyses were performed. RESULTS: Participants with hyperuricemia had higher serum PCSK9 levels than those with normouricemia (73.74 ± 30.25 vs 68.55 ± 29.01 ng/ml, P < 0.05), especially in women (69.11 ± 28.84 vs 87.86 ± 27.90 ng/ml, P < 0.001). SUA levels were positively associated with serum PCSK9 levels in all participants (r = 0.06, P < 0.01) and in women (r = 0.22, P < 0.01), but not in men (r = 0.03, P = 0.18). Multiple linear regression and binary logistic regression analyses indicated that serum PCSK9 levels were significantly correlated with SUA levels and hyperuricemia in women. However, when the model was adjusted for triglyceride (TG), the associations of serum PCSK9 levels with SUA levels and hyperuricemia disappeared. In mediation analyses, TG, low-density lipoprotein cholesterol (LDL-C), body mass index(BMI), total cholesterol (TC), white blood cell count and neutrophil count explained 35.08 %, 20.58 %,19.99 %, 14.37 %, 7.10 % and 3.24 % of SUA levels association with serum PCSK9 levels, respectively. CONCLUSION: Serum PCSK9 levels are positively associated with SUA levels in women. Furthermore, this association is partially mediated through metabolic factors and inflammation.

Integrated bioinformatics analysis identifies PCSK9 as a prognosticator correlated with lipid metabolism in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is the most frequent kind of pancreatic cancer (PC). Recent studies suggest that lipid metabolism facilitates tumorigenesis, disease progression, and resistance to therapy by promoting lipid synthesis, accumulation, and breakdown. Thus, exploring the lipid metabolism network could unveil novel therapeutic avenues for early detection, precision medicine, and prognostication in PAAD. This project intends to develop new lipid metabolism-related biomarkers for PAAD diagnosis and investigate the link between important genes and immune cell infiltration (ICI). METHODS: Tissue samples from 20 PAAD patients and 20 healthy controls were obtained. Analysis were focused on the datasets GSE71729 and GSE16515, which include samples of PAAD (n = 161) and those from healthy human tissue (n = 61), derived from the GEO database. Knockdown of PCSK9 on PC cells were conducted by si-RNA and sh-RNA. Migration and cell functional experiments were performed to assess the role of PCSK9 in cell multiplication. Furthermore, a xenograft mouse model was employed to confirm PCSK9's function in vivo. RESULTS: The expression level of Proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly elevated in tissues affected by PAAD when compared to normal tissues. Survival analyses indicated that increased PCSK9 levels are inversely related to overall and disease-free survival (DFS). PCSK9's functional annotation associated it with the cell cycle and metabolism, especially energy metabolism. Examination of ICI data determined that PCSK9 expression demonstrated an unambiguous association with the M0 macrophages, T follicular helper cells (Tfh), gamma delta T cells and activated DC, and an inverse relationship with Monocytes, CD8+ T cells, memory B cells, resting CD4+ memory T cells, activated NK cells and resting DC abundance. PCSK9 expression knockdown has the ability to impede PC cells' migration and proliferation. CONCLUSION: Our study identified PCSK9 as a critical gene in PAAD. Expression levels of PCSK9 varied between PAAD and normal samples. ROC analysis verified PCSK9's strong capacity to differentiate PC from normal samples. Importantly, PCSK9 expression was considerably elevated in PC cell lines and tissues. Furthermore, PCSK9 stimulates the migration and proliferation of tumor cells in vivo and vitro.

Addressing residual risk beyond statin therapy: New targets in the management of dyslipidaemias-A report from the European Society of Cardiology Cardiovascular Round Table.

Cardiovascular (CV) disease is the most common cause of death in Europe. Despite proven benefits, use of lipid-lowering therapy remains suboptimal. Treatment goals are often not achieved, even in patients at high risk with atherosclerotic CV disease (ASCVD). The occurrence of CV events in patients on lipid-lowering drugs is defined as "residual risk", and can result from inadequate control of plasma lipids or blood pressure, inflammation, diabetes, and environmental hazards. Assessment of CV risk factors and vascular imaging can aid in the evaluation and management decisions for individual patients. Lifestyle measures remain the primary intervention for lowering CV risk. Where drug therapies are required to reach lipid treatment targets, their effectiveness increases when they are combined with lifestyle measures delivered through formal programs. However, lipid drug dosage and poor adherence to treatment remain major obstacles to event-free survival. This article discusses guideline-supported treatment algorithms beyond statin therapy that can help reduce residual risk in specific patient profiles while also likely resulting in substantial healthcare savings through better patient management and treatment adherence.

Real-world experience of inclisiran prescription at the University of Pennsylvania Health Systems.

Inclisiran is a novel small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that was approved by the US FDA in December 2021. After two doses three months apart, it is administered biannually as a subcutaneous injection and has been shown to lower LDL-C by ∼50 % in clinical trials. Here, we present real-world data on the prescription and administration of inclisiran at the University of Pennsylvania Health Systems. Over a 2-year period, there were 243 patients who were prescribed inclisiran, of whom 153 were approved by insurance and initiated therapy. Approved patients were disproportionately Medicare enrollees and more likely to have a history of ASCVD. Mean post-treatment LDL-C for patients who received at least two doses was 74.7 ± 45.6 mg/dL. For patients new to PCSK9-targeted therapy, a reduction in LDL-C of ∼50 % was observed after initiating inclisiran, supporting clinical trial results. 60 % of patients with ASCVD achieved an LDL-C level of <70 mg/dL after adding inclisiran.

Lipid-Lowering Medications for Managing Dyslipidemia: A Narrative Review.

Dyslipidemia refers to the change in the normal levels of one or more lipid components in the bloodstream, which include triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Dyslipidemia represents a substantial source of danger for cardiovascular disease (CVD). Effectively managing dyslipidemia involves a thorough strategy that includes changing one's lifestyle and using medications that are specifically designed to target the complex processes involved in lipid metabolism. Lipid-lowering treatments play a crucial role in this approach, providing a wide range of medications that are developed to specifically target different components of dyslipidemia. Statins are the main drug among these medications. Other drugs that are used with statin or as monotherapy include fibrates, omega-3 fatty acids (OM3FAs), ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid. Using the PubMed database, we reviewed the literature about dyslipidemia, drugs used for treating dyslipidemia, their efficacy parameters, and common adverse events. We also reviewed the international guidelines for treating dyslipidemia and discussed the future of lipid-lowering medications. More trials and experiments are still required to verify the effectiveness of many lipid-lowering drugs and to know their common adverse events to be able to manage them properly.

Ebronucimab in Chinese patients with hypercholesterolemia---A randomized double-blind placebo-controlled phase 3 trial to evaluate the efficacy and safety of ebronucimab.

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.

The role of proprotein convertase subtilisin/kexin 9 (PCSK9) in macrophage activation: a focus on its LDL receptor-independent mechanisms.

Recent clinical trials demonstrated that proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors reduce cardiovascular events without affecting systemic inflammation in the patients with coronary artery disease, as determined by high sensitivity C-reactive protein (CRP) levels. However, its pro-inflammatory effects in cardiovascular disease in humans and experimental animals beyond the traditional cholesterol receptor-dependent lipid metabolism have also called attention of the scientific community. PCSK9 may target receptors associated with inflammation other than the low-density lipoprotein receptor (LDLR) and members of the LDLR family. Accumulating evidence suggests that PCSK9 promotes macrophage activation not only via lipid-dependent mechanisms, but also lipid-independent and LDLR-dependent or -independent mechanisms. In addition to dyslipidemia, PCSK9 may thus be a potential therapeutic target for various pro-inflammatory diseases.

Genetic association of lipid and lipid-lowering drug target genes with atopic dermatitis: a drug target Mendelian randomization study.

Observational studies suggest dyslipidemia as an atopic dermatitis (AD) risk factor and posit that lipid-lowering drugs may influence AD risk, but the causal link remains elusive. Mendelian randomization was applied to elucidate the causal role of serum lipids in AD and assess the therapeutic potential of lipid-lowering drug targets. Genetic variants related to serum lipid traits and lipid-lowering drug targets were sourced from the Global Lipid Genetics Consortium GWAS data. Comprehensive AD data were collated from the UK Biobank, FinnGen, and Biobank Japan. Colocalization, Summary-data-based Mendelian Randomization (SMR), and mediation analyses were utilized to validate the results and pinpoint potential mediators. Among assessed targets, only Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) was significantly linked to a reduced AD risk, corroborated across three separate AD cohorts. No association between serum lipid concentrations or other lipid-lowering drug targets and diminished AD risk was observed. Mediation analysis revealed that beta nerve growth factor (b-NGF) might mediate approximately 12.8% of PCSK9's influence on AD susceptibility. Our findings refute dyslipidemia's role in AD pathogenesis. Among explored lipid-lowering drug targets, PCSK9 stands out as a promising therapeutic agent for AD.

Proprotein convertase subtilisin/kexin type 9 inhibitors in peripheral artery disease: A review of efficacy, safety, and outcomes.

Peripheral artery disease (PAD) is a common condition characterized by atherosclerosis in the peripheral arteries, associated with concomitant coronary and cerebrovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients. This review focuses on the efficacy, safety, and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed. Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events, offering a potential treatment option for PAD patients. Safety evaluations from trials show few adverse events, most of which are injection-site reactions, indicating the overall safety profile of PCSK9 inhibitors. Clinical outcomes show a reduction in cardiovascular events, ischemic strokes, and major adverse limb events. However, despite these positive findings, PCSK9 inhibitors are still underutilized in clinical practice, possibly due to a lack of awareness among care providers and cost concerns. Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.

Established and Emerging Nucleic Acid Therapies for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid-based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH.

Targeting Oxidative Stress in Neurodegenerative Disorders: A Novel Role for PCSK9 Inhibition?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol levels by lysosomal low-density lipoprotein receptor (LDLR) degradation and has recently been associated with the production of neuronal oxidative stress and age-associated cardiovascular dysfunction. Since increased oxidative stress and vascular dysfunction are implicated in the pathology of aging and various neurodegenerative disorders, targeting PCSK9 may offer a promising therapeutic avenue for addressing these conditions. While the precise mechanisms through which PCSK9 contributes to vascular and neuronal oxidative stress in the brain remain elusive, preclinical studies have highlighted a neuroprotective effect linked to PCSK9 inhibition. This inhibition has shown promise in reducing oxidative stress, mitigating neuroinflammation, and alleviating neuropathological changes, thus underscoring the therapeutic potential of this approach in addressing neurodegenerative conditions.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Associated With Recurrence and Survival of Resectable Non-Small Cell Lung Cancer (NSCLC): A Retrospective Study.

INTRODUCTION: Curative lung resection remains the key therapeutic strategy for early-stage non-small cell lung cancer (NSCLC). However, a proportion of patients still experience variable outcomes and eventually develop recurrence or die from their disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a deleterious factor that inhibits tumor cells apoptosis and leads to reduction of lymphocyte infiltration. However, there has been no research on the predicted role of PCSK9 as an immunohistochemical biomarker with survival in resectable NSCLC. METHODS: One hundred sixty-three patients with resectable NSCLC were retrospectively reviewed, and PCSK9 expression of resected NSCLC was analyzed by immunohistochemistry using tissue microarrays. RESULTS: PCSK9 was associated with recurrence (42.1% relapsed in the PCSK9lo group versus 57.9% relapsed in the PCSK9hi group, P = 0.006) and survival status (39.6% dead in PCSK9lo group versus 60.4% dead in PCSK9hi group, P = 0.004) in patients with resectable NSCLC. Moreover, resectable NSCLC patients with higher PCSK9 expression in tumor tissue experienced poorer disease-free survival (median disease-free survival: 10.5 versus 25.2 mo, hazard ratio = 1.620, 95% confidence interval: 1.124-2.334) and overall suvrival (median overall suvrival: 20.0 versus 54.1 mo, hazard ratio = 1.646, 95% confidence interval: 1.101-2.461) compared to those with lower PCSK9 expression. CONCLUSIONS: High PCSK9 expression of tumor was correlated with recurrence and worse survival status of resectable NSCLC in our retrospective study, which indicated that PCSK9 in NSCLC may be an immunohistochemical biomarker of poor prognosis for patients with resectable NSCLC. Further large-scale prospective studies are warranted to establish these results.

Metabolic Changes Induced by Bariatric Surgery May be Mediated by PAI-1 and PCSK9 Crosstalk.

BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.