Proprotein Convertase Research Articles

Functional and morphological improvement of significant non-culprit coronary artery stenosis by LDL-C reduction with a PCSK9 antibody: Rationale and design of the randomized FITTER trial

Non-culprit coronary artery lesions are commonly present in patients presenting with an acute coronary syndrome (ACS). Additional stenting of non-culprit lesions in addition to the culprit lesion intends to prevent secondary events caused by these lesions. At the same time, multiple trials have demonstrated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing plaque size and changing plaque composition of non-culprit lesions. Whether intensive low-density lipoprotein cholesterol (LDL-C) reduction with PCSK9 inhibitor evolocumab improves non-culprit vessel hemodynamics, reduces the risk of plaque rupture of important non-culprit lesions, and might obviate the need for additional stenting has not been investigated. The “Functional Improvement of non‐infarcT related coronary artery stenosis by Extensive LDL‐C Reduction with a PCSK9 Antibody” (FITTER) trial is a multi-center, randomized, double-blind, placebo-controlled clinical trial for patients presenting with ACS and multivessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) is performed in non-culprit vessels amenable for percutaneous coronary intervention (PCI). Coronary intervention in patients with hemodynamically important non-critical lesions (FFR: 0.67–0.85) is staged after baseline imaging using near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS). Eligible patients are randomized and treated for 12 weeks with either evolocumab or placebo, in addition to high-intensity statin therapy. Follow-up angiography with repeat FFR and IVUS-NIRS is scheduled at 12 weeks. Staged PCI is performed at the operator's discretion.The FITTER trial is the first study to evaluate the effect of maximal LDL-C reduction by the PCSK9 inhibitor evolocumab on invasively measured FFR, plaque size, and plaque composition in hemodynamically important non-culprit lesions, during a treatment period of just 12 weeks after an ACS. Currently, all patients have been included (August 2023) and data analysis is ongoing. Trial registration numberclinicaltrials.gov NCT04141579.

Analysis of furin (FURIN) gene expression in the U-87 MG cell line as a potential target for gene inhibiting therapies in (auto-) immune diseases

Purpose: Furin is a proprotein convertase commonly found in the human body. The enzymatic activity of furin is necessary for the activation of numerous substrates including e.g. hormones and growth factors. Nevertheless, furin is involved in various pathological conditions caused by, among others, chronic inflammation. Therefore furin is considered as a potential target in autoimmune diseases therapy. We performed an experiment in which the expression of FURIN gene in U-87 MG astrocytoma cells was investigated. Additionally, this cell line contains some sequences coding human endogenous retroviruses (HERVs), including ERVW-1 and its receptor- SLC1A5. Deregulation of HERV expression has been observed in some neurodegenerative diseases as well as in inflammatory process. Material and Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) techniques were utilized for analysis. Phorbol 12-myristate 13-acetate (PMA) were used for cell stimulation. Short interfering RNAs (siRNA) were used for gene expression inhibition in U-87 MG cells in vitro. Results: Cell stimulation by PMA strongly increased FURIN expression, simultaneously downregulating ERVW-1 (p<0.01). Moreover addition of PMA significantly stimulates the autocatalytic action of cellular furin itself resulting in the dissociation of its propeptide that was clearly visible in a time-dependent manner. SiRNA-mediated expression inhibition of ERVW-1 and FURIN influenced the mRNA level for SLC1A5 (ASCT2) - primary syncytin-1 receptor, that was significantly lower. FURIN inhibition by siRNA caused strong upregulation of ERVW-1 expression (p<0.01). Conclusion: Our results showed that stimulation by PMA and inhibition expression by siRNA affects the expression of FURIN in U-87 MG astrocytoma cells. Moreover, furin shows a complex relationship on the expression of ERVW-1 and SLC1A5 genes, as well as on the form (precursor or mature) and the amount of the final translation products of the transcripts. The regulation of FURIN may pose a potential therapeutic strategy in the treatment of neurodegenerative diseases caused by autoimmunity.

PCSK1N as a tumor size marker and an ER stress response protein in corticotroph pituitary adenomas.

Silent corticotroph adenoma (SCA) exhibits more tumor aggressiveness features than functioning adenomas (FCA). We aimed to investigate PCSK1N expression in CA and examine if ER stress-induced responses affect cell survival in a corticotroph tumor cell model. Clinical and imaging characteristics were recorded in 33 patients with FCA (20 women, 11 macroadenomas) and 18 SCA (8 women, all macroadenomas). Gene expression of proopiomelanocortin (POMC), T-box transcription factor 19(TBX19)/TPIT, proprotein convertase subtilisin/kexin type 1(PCSK1)/PC1/3, and its inhibitor PCSK1N, was measured by RT-qPCR in adenoma tissue.Mouse pituitary corticotroph tumor (AtT-20) cells were treated with tanespimycin (17-AAG), a HSP90 chaperone inhibitor, to induce ER stress, followed by gene and protein analyses. POMC, TPIT, and PCSK1 expression were higher, whereas PCSK1N was lower in FCA compared to SCA. PCSK1N correlated with POMC (rs= -0.514, p <0.001), TPIT (rs= -0.386, p = 0.005), PCSK1 (rs= -0.3691, p = 0.008), and tumor largest diameter (rs= 0.645, p <0.001), in all CA. Induction of ER stress by 17-AAG in AtT-20 cells led to a decrease of POMC and an increase of PCSK1N gene expression at 24h. Moreover, a downregulation of cell cycle, apoptosis, and senescence pathways, and alterations in cell adhesion and cytoskeleton were observed at the protein level. PCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins.

Lipids and Inflammation: Novel Molecular Targets and Therapeutic Implications.

Atherosclerotic cardiovascular disease represents the most common cause of death worldwide. Altered cholesterol metabolism and inflammation are major cardiovascular risk factors that underpin atherosclerotic plaque growth and destabilization. While initial evidence considered dyslipidemia and inflammation as independent atherogenic actors, growing evidence has revealed that several molecular mechanisms implicated in cholesterol metabolism participate in multiple inflammatory signalling pathways. In particular, proprotein convertase subtilisin/kexin type 9, adenosine monophosphate-activated protein kinase pathway, oxidized low-density lipoproteins, and lipoprotein (a) have been demonstrated to share concurrent atherogenic and inflammatory properties. Novel lipid-lowering therapies targeting these molecular pathways have been implemented. Mechanistic and clinical studies have addressed their hypolipidemic potential and explored their role in atherosclerosis-related vascular inflammation, and ongoing randomized clinical trials are investigating their prognostic role. The purpose of this review was to dive into the signalling pathways linking cholesterol metabolism and inflammation and outline the current evidence on the anti-inflammatory activities of the novel lipid-lowering drugs.

Endocrinopathy due to proproteinkovertase 1/3 deficiency: primary enteropathy, diabetes insipidus, secondary hypothyroidism

Proprotein convertase 1/3 (PC1/3) deficiency is an autosomal recessive disease caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK 1)gene, associated with severe malabsorptive diarrhea, obesity and some endocrine abnormalities. Proprotein convertase 1/3 is acalcium-dependent serine endoprotease involved in the proteolytic processing of various prohormones (peptide hormones in enteroendocrine cells that are necessary for the absorption of nutrients and is also expressed in the arcuate and paraventricular nuclei of the hypothalamus, in the beta cells of the pancreas) in their bioactive forms. The onset of the disease in the neonatal period of life is characterized by aclinical picture of severe malabsorption diarrhea, accompanied by developmental delays, and requires long-term parenteral nutrition. As the disease progresses, additional endocrine abnormalities develop, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, hypothyroidism, and obesity. We conducted aprospective observation of apatient with agenetic disease due to proprotein convertase 1/3 deficiency confirmed during follow-up. The patient was examined and treated at the State Novosibirsk Regional Clinical Hospital in Novosibirsk for 11 months, with repeated (3-fold) hospitalizations. Purpose: to demonstrate the features of the onset and course of the disease, as well as the difficulties in verifying the clinical diagnosis of an ultra-rare genetic disease from the category of endocrinopathies, the complexity of medical support and therapy. Apeculiarity of this case is the fact that the identified mutation in the gene was not previously registered in control Russian samples of the genetic mutation of proprotein convertase 1/3 deficiency, as well as apreviously undescribed variant of the nucleotide sequence in exon 4 of the PCSK1 gene in aheterozygous state and was not registered in control samples gnomAD and RUSeq. Proprotein convertase 1/3 deficiency is adisease that is amultidisciplinary problem, since etiopathogenetic therapy has not yet been developed. The disease has achronic course with constant relapses of intestinal syndrome, is difficult to manage with symptomatic treatments and, as it progresses, has ahigh risk of developing additional endocrinopathies and death. All of the above emphasizes the need for early diagnosis and selection of rational replacement and accompanying therapy to save the lives of patients.

Trends and Prospects of Low-Density Lipoprotein Cholesterol in Stroke: A Bibliometric Analysis.

Management of low-density lipoprotein cholesterol (LDL-C) in stroke is a crucial component of cardiovascular disease care. Recent years have seen substantial progress in understanding and managing LDL-C in the context of stroke. This study utilized bibliometric methods to analyze and synthesize trends in this area over the past decade, incorporating 2,841 publications from the Web of Science database. The analyses included trend topic analysis, co-authorship analysis, and co-citation analysis. The findings indicate that research had predominantly concentrated on epidemiological studies related to pharmacological management strategies. Future research is expected to continue exploring lipid-lowering therapies, including both established treatments like statins and newer drugs such as proprotein convertase subtilisin-kexin type 9 inhibitors. Assessing residual cholesterol and employing Mendelian randomization techniques may become potential research hotspots. The New England Journal of Medicine is the most globally influential journal, while Circulation holds the most influence within the field, and Atherosclerosis ranks as the most prolific. International collaboration in this research area was strong between the USA and England, followed by the USA and China. However, collaboration between productive institutions in the USA and China remains limited, highlighting the need to strengthen partnerships between these institutions to further advance the field.

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

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. 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. 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. 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 PCSK9 is a novel serological biomarker for the diagnosis and prognosis of pancreatic cancer.

Although CA19-9 is an essential blood biomarker of pancreatic cancer (PC), its sensitivity and specificity are limited for early detection. We analyzed the serum proprotein convertase subtilisin/kexin type 9 (sPCSK9) in PC patients, benign disease groups (BDG), and healthy controls (HC) by ELISA. Consistently, sPCSK9 was considerably lower in PC patients than in HC (Z = -2.546, P < 0.05), and sPCSK9 in PC patients was statistically significantly higher than in BDG (Z = -5.457, P < 0.001). sPCSK9 was linked to the invasion of lymph nodes (χ2 = 6.846, P < 0.01). According to ROC curves, combining sPCSK9 with CA19-9 could potentially enhance the diagnostic capability of CA19-9 in early-stage PC patients. Furthermore, the low sPCSK9 group (n = 41) exhibited statistically significantly prolonged overall survival compared to the high sPCSK9 group (n = 15), with median survival times of 27 months (95% CI [17.59-36.41]) and 11 months (95% CI [7.21-14.79]), respectively (P = 0.022). The diagnostic performance of CA19-9 for early-stage PC patients could be improved by combining sPCSK9 with CA19-9. Moreover, the higher sPCSK9 group has a significantly shorter overall survival rate.

Use and effectiveness of PCSK-9 inhibitors in heart diseases: A review.

Proprotein Convertase Subtilisin/Kexin type-9 (PCSK-9) inhibitors have recently used in the management of different cardiac complications. Several clinical trials demonstrated their effectiveness in patients with hypercholesterolemia. However, the effectiveness of these medications in patients with heart diseases is still controversial. To review and summarize the clinical trials pertaining to the use and effectiveness of PCSK-9 inhibitors in heart diseases and to discuss the pharmacotherapy of these agents. A review was conducted of all clinical trials with PCSK-9 inhibitors for heart diseases registered at ClinicalTrials.gov since inception up to and including January 19th, 2024. These trials were retrieved. Data from these trials were extracted manually, categorized and analyzed. The number of identified clinical trials was 25,371. After screening and excluding irrelevant studies, 12 studies met the search criteria. The majority of these studies were conducted in the US. The total number of patients in these studies was 27,700. Alirocumab and Evolocumab were the most frequently used PCSK-9 inhibitors. This review identified only a few clinical trials on PCSK-9 inhibitors in heart disease patients. Therefore, it is recommended to conduct more randomized controlled clinical trials on PCSK-9 inhibitors in this patient population.

Dyslipidemias in multiple sclerosis

PurposeTo investigate the frequency of dyslipidemia phenotypes in multiple sclerosis and to assess the associations with lipoprotein particle size distributions. MethodsThis cross-sectional study included 203 healthy controls (HC), 221 relapsing-remitting MS (RRMS), and 126 progressive MS (PMS). A lipid profile with total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B levels were measured. Low density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol, large buoyant LDL-C and small dense LDL-C were calculated using the Sampson-NIH equations method. Dyslipidemia phenotypes were categorized by their nonHDL-C and triglyceride values. The diameters and concentrations of triglyceride-rich lipoprotein particles (TRLP), LDL particles (LDLP), and HDL particles (HDLP) were measured with proton NMR lipoprotein profiling. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels were obtained using immunoassay. ResultsThe frequencies of normolipidemia, and various dyslipidemia phenotypes were similar in HC, RRMS, and PMS. The size of the TRLP, very large TRLP, large TRLP, and small LDLP concentrations had a decreasing pattern of HC>RR>PMS. The lowest tertile of EDSS was associated with higher concentrations of HDLP and small HDLP in PMS. PCSK9 was associated with concentration of HDL particles, primarily via its effects on the concentration of small HDL particles. ConclusionsThere were no differences in the frequency of dyslipidemias in MS compared to healthy controls. Higher HDLP concentrations are associated with lower disability in PMS.

PCSK9 Inhibitors and Anthracyclines: The Future of Cardioprotection in Cardio-Oncology.

The field of cardio-oncology is an expanding frontier within cardiovascular medicine, and the need for evidence-based guidelines is apparent. One of the emerging focuses within cardio-oncology is the concomitant use of medications for cardioprotection in the setting of chemotherapy regimens that have known cardiovascular toxicity. While clinical trials focusing on cardioprotection during chemotherapy are sparse, an inaugural trial exploring the prophylactic potential of Sodium-Glucose Cotransporter-2 inhibitors (SGLT2is) for anthracycline (ANT)-induced cardiotoxicity has recently commenced. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, though less studied in this oncology demographic, have exhibited promise in preclinical studies for conferring cardiac protection during non-ischemic toxic insults. While primarily used to reduce low-density lipoprotein, PCSK9 inhibitors exhibit pleiotropic effects, including the attenuation of inflammation, reactive oxygen species, and endothelial dysfunction. In ANT-induced cardiotoxicity, these same processes are accelerated, resulting in premature termination of treatment, chronic cardiovascular sequelae, heart failure, and/or death. This review serves a dual purpose: firstly, to provide a concise overview of the mechanisms implicated in ANT-induced cardiotoxicity, and, finally, to summarize the existing preclinical data supporting the theoretical possibility of the cardioprotective effects of PCSK9 inhibition in ANT-induced cardiotoxicity.

Organosulfur Compounds, S-Allyl-L-Cysteine and S-Ethyl-L-Cysteine, Target PCSK-9/LDL-R-Axis to Ameliorate Cardiovascular, Hepatic, and Metabolic Changes in High Carbohydrate and High Fat Diet-Induced Metabolic Syndrome in Rats.

Metabolic syndrome (MetS) is an ever-evolving set of diseases that poses a serious health risk in many countries worldwide. Existing evidence illustrates that individuals with MetS have a 30%-40% higher chance of acquiring type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or both. This study was undertaken to uncover the regulatory role of natural organosulfur compounds (OSCs), S-allyl-L-cysteine (SAC), and S-ethyl-L-cysteine (SEC), in targeting high carbohydrate high fat (HCHF)-diet-induced MetS-associated risk management. Our findings suggested that SAC and SEC ameliorated HCHF-diet-induced diabetic profiles, plasma lipid and lipoprotein level, liver function, oxidative-stress, inflammatory cytokines, and chemokines including monocyte chemoattractant protein-1 (MCP-1), lipid peroxidation, plasma proprotein convertase subtilisin/kexin type-9 (PCSK-9), and high-sensitivity C-reactive protein (hs-CRP). Moreover, the assessment of the hepatic mRNA expression of the key genes involved in cholesterol homeostasis depicted that SAC and SEC downregulated the PCSK-9 mRNA expression via targeting the expression of HNF-1α, a transcriptional activator of PCSK-9. On the other hand, the LDL-receptor (LDL-R) expression was upregulated through the activation of its transcriptional regulator sterol regulatory element binding protein-2 (SREBP-2). In addition, the activity and the mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme-A reductases (HMG-R) and peroxisome proliferator-activated receptors (PPARs) were also improved by the treatment of SAC and SEC. We concluded that SAC and SEC can protect against MetS via improving the lipid and lipoprotein content, glycemic indices, hepatic function, targeting the inflammatory cascades, and oxidative imbalance, regulation of the mRNA expression of PCSK-9, LDL-R, SREBP-2, HNF-1α, PPARs, and inflammatory biomarkers.

O75 INHIBITION OF PCSK9/NFAT AMELIORATES CARDIAC DYSMETABOLISM AND FIBROSIS IN EXPERIMENTAL RAT MODEL OF PCOS BY REDUCING ATHEROGENIC LIPID AND IMPROVING INSULIN SENSITIVITY

Background: Polycystic ovarian syndrome (PCOS) remains an independent risk factor of cardiovascular disease (CVD), particularly in women of child-bearing age, and contributes to global increase in the prevalence/incidence of cardiovascular mortality and morbidity in women. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce residual CVD risk. Similarly, Nuclear factor of activated T cells (NFAT) is a transcription factor that is implicated in cardiac fibrosis. However, the role of PCSK9/NFAT in PCOS-associated cardiometabolic syndrome is not clear. Short chain fatty acids (SCFAs) play a multifaceted regulatory role in metabolic health. The present study therefore investigated the role of PCSK9/NFAT in cardiometabolic syndrome associated with experimental PCOS, and the therapeutic potential of SCFAs, especially butyrate. Material and Methods: Eight-week-old female Wistar rats were allotted into four groups (n=5). Polycystic ovarian syndrome was induced by administering letrozole (1 mg/kg p.o.) once daily for 21 days, thereafter the animals were treated with 200 mg/kg (oral gavage) of sodium butyrate for six weeks. Gene expression, biochemical parameters and cardiac/ovarian morphology were evaluated with appropriate methods. Results: Rats with PCOS showed androgen excess, multiple ovarian cysts and reduced insulin sensitivity. The rats in addition displayed atherogenic dyslipidemia (triglyceride/HDLc, TC/HDLc and LDLc), hypercorticosteronemia and elevated cardiac triglyceride, inflammatory biomarkers (NF-kappaB and TNF-alpha), caspase-6, 4-hydroxynonenal, inflammasome (NLRP3), fibrosis and depleted antioxidant defense (NrF2 and glutathione) as well as increased expression of PCSK9 and NFAT when compared to the control rats. Nevertheless, these systemic and morphological alterations were ameliorated following treatment with sodium butyrate. Conclusion: The present results collectively demonstrate cardiac dysmetabolism, inflammation, fibrosis as well as apoptosis in experimental PCOS rat model, which are driven by elevated expression of PCSK9/NFAT. The results further suggest that SCFAs, butyrate alleviates cardiometabolic syndrome and its attendant cardiomorbidity by suppression of PCSK9/NFAT. The present data provide a preclinical insight to prevention and management of CVD in PCOS individuals.

Transforming hypercholesterolemia management: Spotlight on PCSK9 peptide vaccines

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a therapeutic target for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). Two recent studies published by Fang etal.1 and Zhang etal.2 in Cell Reports Medicine and Cell Reports, respectively, show the efficacy of peptide vaccines in eliciting an antibody response against PCSK9 and reducing plasma cholesterol levels.

Ferritin-based disruptor nanoparticles: A novel strategy to enhance LDL cholesterol clearance via multivalent inhibition of PCSK9-LDL receptor interaction.

Hypercholesterolemia, characterized by elevated low-density lipoprotein (LDL) cholesterol levels, is a significant risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol metabolism by regulating LDL receptor degradation, making it a therapeutic target for mitigating hypercholesterolemia-associated risks. In this context, we aimed to engineer human H ferritin as a scaffold to present 24 copies of a PCSK9-targeting domain. The rationale behind this protein nanoparticle design was to disrupt the PCSK9-LDL receptor interaction, thereby attenuating the PCSK9-mediated impairment of LDL cholesterol clearance. The N-terminal sequence of human H ferritin was engineered to incorporate a 13-amino acid linear peptide (Pep2-8), which was previously identified as the smallest PCSK9 inhibitor. Exploiting the quaternary structure of ferritin, engineered nanoparticles were designed to display 24 copies of the targeting peptide on their surface, enabling a multivalent binding effect. Extensive biochemical characterization confirmed precise control over nanoparticle size and morphology, alongside robust PCSK9-binding affinity (KD in the high picomolar range). Subsequent efficacy assessments employing the HepG2 liver cell line demonstrated the ability of engineered ferritin's ability to disrupt PCSK9-LDL receptor interaction, thereby promoting LDL receptor recycling on cell surfaces and consequently enhancing LDL uptake. Our findings highlight the potential of ferritin-based platforms as versatile tools for targeting PCSK9 in the management of hypercholesterolemia. This study not only contributes to the advancement of ferritin-based therapeutics but also offers valuable insights into novel strategies for treating cardiovascular diseases.

Efficacy of Traditional Anti-lipidemic Drugs in Lowering Lipoprotein(a) Levels: A Systematic Review.

Lipoprotein(a), or Lp(a), was identified in the early 1960.Its role as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) became widely recognized by the late 20th century, regardless of other traditional risk markers such as low-density lipoproteins and high-density lipoproteins. This study aimed to systematically review available literature and compare the efficacy of different lipid-lowering drugs, both approved for clinical use and currently undergoing trials, in lowering Lp(a) levels. A comprehensive search of medical databases including PubMed, PubMed Central (PMC), Medline, ScienceDirect, Cochrane Library, and Google Scholar was conducted to identify relevant studies. A total of 29 research papers met the inclusion criteria, focusing on the impact of various lipid-lowering drugs on Lp(a) concentration in patients with significantly elevated baseline Lp(a) levels. Plasma Lp(a) levels exceeding 30 mg/dL are associated with a higher risk of ASCVD, including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and increased all-cause mortality. Most commonly used lipid-lowering agents, such as statins, fibrates, ezetimibe, and nutraceuticals like coenzyme Q10 (CoQ10), showed no significant effect on Lp(a) plasma levels. However, Lp(a) apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were found to effectively reduce plasma Lp(a) concentrations. Emerging therapies targeting apolipoprotein(a) RNA, including anti-sense oligonucleotides (ASO) and small interfering RNA (siRNA), significantly reduced Lp(a) levels in Phase 2 trials. While several lipid-lowering agents have minimal impact on Lp(a) levels, therapies like Lp(a) apheresis, PCSK-9 inhibitors, and novel RNA-targeting drugs show promise in effectively reducing Lp(a) concentrations. However, whether these reductions translate into decreased cardiovascular events remains to be determined.

The German Lipoprotein Apheresis Registry-Summary of the eleventh annual report

BackgroundIn 2012, the German Lipoprotein Apheresis Registry (GLAR) was launched. Real-world data on lipoprotein apheresis (LA) treatment are now available for a time period of 11 years. All patients received the maximally tolerated lipid-lowering therapy, which included statins, ezetimibe, bempedoic acid, and either proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies or antisense therapy. Methods and ResultsDuring the time period from 2012 to 2022, 92 German apheresis centers collected retrospective and prospective observational data of a total of 2,301 patients undergoing regular lipoprotein apheresis (LA) treatment of hypercholesterolemia or/and Lp(a)-hyperlipoproteinemia suffering from progressive atherosclerotic cardiovascular disease (ASCVD), with complete data sets of 1.125 patients, who were the subject of this analysis. More than 61,500 LA sessions are documented in the database. In 2022, all patients treated with LA demonstrated a significant immediate median reduction rate of LDL-C (68.8 %) and Lp(a) (72.9 %). Patient data were analyzed for the incidence rate of major coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y-1) and prospectively up to eleven years on LA treatment (y+1 to y+11). During the first two years of LA treatment (y+1 and y+2), a MACE reduction of 73 % was observed and continued to be low during y+3 to y+11, when all LA patients were analyzed. LA patients with only increased Lp(a) levels (Lp(a) ≥ 60 mg/dl (≥120 nmol/l) and an LDL-C < 100 mg/dl (<2.6 mmol/l)) had a higher MACE reduction (85 %; n = 443) in the first two years of LA treatment compared to LA patients with only increased LDL-C-levels (LDL-C ≥ 100 mg/dl (≥2.6 mmol/l); Lp(a) < 60 mg/dl (<120 nmol/l)) (53 %; n = 171). Adverse events of LA remained low (about 5 %) over the eleven years and mainly represented puncture problems (1.0 %). No side effects resulted in termination of LA therapy. ConclusionsThe current analysis of GLAR data indicates that regular LA leads to very low incidence rates of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive ASCVD, and maximally tolerated lipid-lowering medication, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Additionally, LA was safe with a low rate of adverse effects over an 11-year period. The number of enrolled patients and the duration of observation establish GLAR as the largest LA registry worldwide.

LIpid Response to Statins ± Ezetimibe In Mumbai (LIRIM): A Cross-sectional Observational Study.

India has the highest burden of cardiovascular disease (CVD) among developing nations. Data from international studies show significant underimplementation of recommended aggressive lipid-lowering strategies for achieving low-density lipoprotein cholesterol (LDL-C) goals, especially after percutaneous coronary intervention (PCI), a pattern also observed in India. Moreover, ethnic variation in response to statin therapy has prompted clinicians to adopt lower doses of statin therapy in Asians to achieve comparable LDL-C lowering. To document the dose of statin ± ezetimibe required to achieve the European Society of Cardiology (ESC) goals of LDL-C <55 mg/dL in Indian patients with established atherosclerotic cardiovascular disease (ASCVD). This retrospective single-center, cross-sectional, observational, all-comers study in Mumbai evaluated the dose of atorvastatin (A)/rosuvastatin (R) ± ezetimibe (E) treatment at which patients with established ASCVD (n = 542), irrespective of their baseline level, achieved LDL-C goals (<55 mg/dL). Those with LDL-C levels >55 mg/dL on current therapy were switched to R 40 mg ± E 10 mg daily. The final data set (n = 340) included those who achieved LDL-C goals at the initial visit and those at follow-up. The primary and secondary outcomes assessed the impact of R 40 mg ± E 10 mg (R40 ± E10) on LDL-C (<55 mg/dL) and non-high-density lipoprotein cholesterol [non-HDL-C (<85 mg/dL)] goal achievement, respectively. At the end of follow-up, LDL-C <55 mg/dL was observed in 42.16% of patients (n = 113) with R40 and in another 43.28% (n = 116) with R40 + E10. A few patients (n = 39; 14.6%) achieved this goal with other dosages. Similarly, non-HDL-C <85 mg/dL was observed in 39.3% of patients (n = 107) with R40 and in another 47.4% of patients (n = 129) with R40 + E10. Overall, around 20% of patients were unable to achieve their LDL-C and non-HDL-C goals despite being on high-intensity statin ± E therapy. In the first report of its kind in India, this study showed that suboptimal LDL-C goal achievement occurred in around 20% of high-risk ASCVD patients on dual therapy. This indicates that clinicians should consider the addition of other therapies [e.g., bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and inclisiran] to mitigate the residual risk. Several more trials are needed to determine the most suitable treatment regimen for this population.

Very short-term effects of a single dose of a proprotein convertase subtilisin/kexin 9 inhibitor before percutaneous coronary intervention: A single-arm study

Background and aimsThe short-term (within 6 weeks) effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on lipid plaques have not been adequately evaluated. We aimed to investigate whether a single dose of a PCSK9 inhibitor before percutaneous coronary intervention (PCI) could reduce the abundance of lipid-core plaques identified via near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) at target lesions within a very short period. MethodsThis prospective, single-arm, single-center interventional study enrolled 27 consecutive patients with coronary artery disease. These patients underwent NIRS-IVUS during coronary angiography and repeat NIRS-IVUS during PCI performed between 2 and 6 weeks after the single-dose administration of 420 mg evolocumab. Changes in lesion lipid-core burden index (LCBI) and maximal LCBI over any 4-mm segment (max-LCBI4mm) were assessed using NIRS at the target lesions, along with lipid profile. ResultsThe max-LCBI4mm significantly decreased from 387 before PCSK9 inhibitor administration to 315 after its administration (interquartile range [IQR]: 268–572 and 221–488, respectively; p = 0.02) within a very short period. The lesion LCBI also decreased from 161 to 117 (IQR: 105–263 and 65–226, respectively; p = 0.02). No significant changes were observed in the minimum lumen area and diameter. After PCSK9 inhibitor administration, low-density lipoprotein (LDL) cholesterol (p < 0.001), lipoprotein(a) (p = 0.001), and malondialdehyde-modified LDL (p < 0.001) levels decreased compared with those before its administration. ConclusionsA single dose of the PCSK9 inhibitor administered before PCI reduced the abundance of lipid-core plaques identified via NIRS-IVUS at target lesions within a very short period of 2–6 weeks.

Causal effects of lipid-lowering drugs on inflammatory skin diseases: Evidence from drug target Mendelian randomisation.

Clinical research has revealed that inflammatory skin diseases are associated with dyslipidaemia. Modulating lipids is also a rising potential treatment option. However, there is heterogeneity in the existing evidence and a lack of large-scale clinical trials. Observational research is prone to bias, making it difficult to determine causality. This study aimed to evaluate the causal association between lipid-lowering drugs and inflammatory skin diseases. A drug target Mendelian randomisation (MR) analysis was conducted. Genetic targets of lipid-lowering drugs, including proprotein convertase subtilis kexin 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, were screened. Common inflammatory skin diseases, including psoriasis, allergic urticaria, rosacea, atopic dermatitis, systemic sclerosis and seborrhoeic dermatitis, were considered as outcomes. Gene-predicted inhibition of PCSK9 was causally associated with a decreased risk of psoriasis (ORIVW [95%CI] = 0.600 [0.474-0.761], p = 2.48 × 10-5) and atopic dermatitis (ORIVW [95%CI] = 0.781 [0.633-0.964], p = 2.17 × 10-2). Gene-predicted inhibition of HMGCR decreased the risk of seborrhoeic dermatitis (ORIVW [95%CI] = 0.407 [0.168-0.984], p = 4.61 × 10-2) but increased the risk of allergic urticaria (ORIVW [95%CI] = 3.421 [1.374-8.520], p = 8.24 × 10-3) and rosacea (ORIVW [95%CI] = 3.132 [1.260-7.786], p = 1.40 × 10-2). Among all causal associations, only PCSK9 inhibition demonstrated a robust causal effect on psoriasis after a more rigorous Bonferroni test (p < 4.17 × 10-3, which is 0.05/12). Modulating lipids via PCSK9 inhibition may offer potential therapeutic targets for psoriasis and atopic dermatitis. Given the potential cutaneous side effects associated with HMGCR inhibitors, PCSK9 inhibitors could be considered viable alternatives in lipid-lowering medication.