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.

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.

Statins, but not proprotein convertase subtilisin-kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low-density lipoprotein receptor upregulation.

Hypercholesterolemia is characterized by elevated low-density lipoprotein (LDL)-cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol-lowering with statins or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL-cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high-density lipoprotein (HDL)-cholesterol. Yet, only statins additionally reduced chemerin and high-sensitivity C-reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL2/HDL3 fractions, while >75% was free. Statins lowered both HDL-bound and free chemerin. Pull-down assays revealed that chemerin binds to the HDL-component Apolipoprotein A-I (ApoA-I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL-mediated cholesterol efflux via its chemerin chemokine-like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA-I and inhibits HDL-mediated cholesterol efflux. Statins prevent this by lowering HDL-bound chemerin. Combined with their anti-inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.

Therapeutic Gene Editing in Dyslipidemias.

Dyslipidemia, characterized by abnormal lipid levels in the blood, significantly escalates the risk of atherosclerotic cardiovascular disease and requires effective treatment strategies. While existing therapies can be effective, long-term adherence is often challenging. There has been an interest in developing enduring and more efficient solutions. In this context, gene editing, particularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, emerges as a groundbreaking approach, offering potential long-term control of dyslipidemia by directly modifying gene expression. This review delves into the mechanistic insights of various gene-editing tools. We comprehensively analyze various pre-clinical and clinical studies, evaluating the safety, efficacy, and therapeutic implications of gene editing in dyslipidemia management. Key genetic targets, such as low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (APOC3), and lipoprotein (a) (Lp(a)), known for their pivotal roles in lipid metabolism, are scrutinized. The paper highlights the promising outcomes of gene editing in achieving sustained lipid homeostasis, discusses the challenges and ethical considerations in genome editing, and envisions the future of gene therapy in revolutionizing dyslipidemia treatment and cardiovascular risk reduction.

Preliminary study on the role of human defensins, interleukins and PCSK9 in early and late preeclampsia.

The lack of reliable methods for preeclampsia (PE) early diagnosis limits the opportunities for timely prevention, diagnosis and treatment. This study aims to identify the alterations of biochemical parameters and the immune system activity to build a panel of markers that can support preeclampsia diagnosis. For this study, we recruited 30 pregnant women: 10 healthy pregnant women (CTR); 10 pregnant women with early preeclampsia (EP); 10 pregnant women with late preeclampsia (LP). We evaluated lipid profile and, by gene expression, we assessed PCSK9, IL-2, IL-6, IL-8, IL-10, TNF-α and TGF-ß. Moreover, we evaluated both the serum and gene levels of the defensins HBD-1, HBD-2, HBD-4 and HNP-1. Our results showed an increase in gene expression levels of IL-6 and IL-8 in EP compared to LP (IL-6: median 11.7 vs 3.3, p = 0.005; IL-8: median 634.1 vs 214.1, p = 0.013) and to CTR (IL-6: median 11.7 vs 0.5, p < 0.001; IL-8: median 634.1 vs 225.6, p = 0.012), highlighting a massive activation of immune system in case of more severe preeclampsia. Furthermore, higher serum levels of HBD1 in LP compared to CTR (median: 278.8 vs 67.8, p = 0.005) and to EP (median: 278.8 vs 68.6, p = 0.001) might indicate that the same immune system puts in action protective actions to prevent adverse outcome in these cases. Finally, gene expression levels of PCSK9 decreased significantly in women with EP compared to controls and to LP (median: 0.2 vs 0.9, p = 0.010; median: 0.2 vs 1.2, p = 0.012), causing a decrease in circulating LDL-c necessary for the synthesis of placental hormones.

Real-world effectiveness of monoclonal antibody inhibitors of PCSK9 in patients with heterozygous familial hypercholesterolemia: A retrospective cohort study.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is a genetic condition that is associated with a high risk of atherosclerotic cardiovascular disease (ASCVD) due to elevated lipid levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody inhibitors have been shown to reduce low-density lipoprotein cholesterol (LDL-C) substantially. This study aimed to assess the real-world effectiveness of PCSK9 inhibitor therapy among patients with HeFH. METHODS: Retrospective cohort study of patients with probable or definite HeFH on a PCSK9 inhibitor at a specialized lipid clinic between 2015 and 2022. The primary objective was the proportion of patients who attained a ≥50% reduction in LDL-C after 12 months of treatment. RESULTS: In total, 141 patients were screened and 95 were included. Mean age was 63 years, 51% were female, and mean baseline LDL-C level was 4.0 mmol/L (155 mg/dL). A majority of patients (60%) had statin intolerance, and 73% were on ezetimibe. The most common PCSK9 inhibitor was evolocumab (94%). Overall, 74% of patients achieved a ≥50% reduction in LDL-C after 12 months of therapy. Mean LDL-C concentration decreased to 1.7 mmol/L (66 mg/dL) (approximately 59% reduction from baseline) after 12 months of follow-up but increased to 1.9 mmol/L (73 mg/dL) after ≥24 months of follow-up. Similar trends were observed in non-high-density lipoprotein cholesterol and apolipoprotein B. Lipoprotein(a) was significantly reduced by 45% over 12 months. Twelve percent of patients permanently discontinued therapy. Barriers to PCSK9i use were mostly related to cost. CONCLUSIONS: In a real-world cohort of HeFH patients, most of which were intolerant to statins, a high majority were able to achieve a ≥50% reduction in LDL-C after 12 months of PCSK9 inhibitor therapy (mean reduction of approximately 59%), which is similar to clinical trial data of patients with ASCVD. A significant reduction in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were also observed.

Advancing Research on Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Scientometric Analysis.

Atherosclerosis is characterised by the accumulation of fatty deposits and plaque as a result of a continuously high level of low-density lipoprotein cholesterol (LDL-C) in the blood. The primary objective of this research is to assess the current status of knowledge, research endeavours and developmental trajectories about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in correlation with atherosclerosis treatment. Additionally, this study aims to compile bibliometric and scientometric investigations within this domain through rigorous scientometric analysis. Analysing the bibliometric landscape and global research trends associated with PCSK9 inhibitors can contribute valuable insights into comprehending atherosclerosis. This is exemplified by examining publications within the Web of Science Core Collection (WOSCC) database from 2008 to 2022. Citespace was used for frequency, co-occurrence, co-citation, grouping and burst analysis, and Microsoft Excel was used to manage descriptive datasets. Eight hundred eighty-five publications available from WOSCC database between the years 2008 and 2022 were extracted and examined. Over the period, 3,138 collaborating institutions from 87 countries, a staggering 7,750 writers involved and 325 distinct journals published about PCSK9 inhibitors studies. Among authors, Sabatine et al. and the journal The New England Journal of Medicine has had the most significant impact. Lipid-lowering therapy and bempedoic acid are the most prominent topical clusters associated with PCSK9 inhibitors, and the most often used keywords are efficacy, safety and PCSK9 inhibitors. We believe this is the first comprehensive analysis of PCSK9 inhibitors research and publications conducted using Scientometric. These results demonstrate the nascence of PCSK9 inhibitors research. They may encourage a wide range of stakeholders, particularly early career researchers from various disciplines, to work together in the future.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients Following Acute Coronary Syndromes: From Lipid Lowering and Plaque Stabilization to Improved Outcomes.

Lipid lowering, with the use of statins after an acute coronary syndrome (ACS), is a cornerstone, well-established strategy for the secondary prevention of ischemic events in this high-risk cohort. In addition to the positive effect on lipid levels, statins have also been linked to improved atherosclerotic plaque characteristics, such as plaque regression and inflammation reduction, associated with the extent of reduction in LDL-C. The recent emergence of PCSK9 inhibitors for the management of dyslipidemia and the more extensive lipid lowering provided by these agents may provide better prevention for ACS patients when initiated after the ACS event. Several trials have evaluated the immediate post-ACS initiation of PCSK9 inhibitors, which has shown, to date, beneficial results. Furthermore, PCSK9 inhibitors have been linked with positive plaque remodeling and associated mortality benefits, which makes their use in the initial management strategy of such patients appealing. Therefore, in this review, we will analyze the rationale behind immediate lipid lowering after an ACS, report the evidence of PCSK9 inhibition immediately after the ACS event and the available data on plaque stabilization, and discuss treatment algorithms and clinical perspectives for the use of these agents in this clinical setting.

Chronic exposure to E-cigarette aerosols potentiates atherosclerosis in a sex-dependent manner.

Despite being designed for smoking cessation, e-cigarettes and their variety of flavors have become increasingly attractive to teens and young adults. This trend has fueled concerns regarding the potential role of e-cigarettes in advancing chronic diseases, notably those affecting the cardiovascular system. E-cigarettes contain a mixture of metals and chemical compounds, some of which have been implicated in cardiovascular diseases like atherosclerosis. Our laboratory has optimized in vivo exposure regimens to mimic human vaping patterns. Using these established protocols in an inducible (AAV-PCSK9) hyperlipidemic mouse model, this study tests the hypothesis that a chronic exposure to e-cigarette aerosols will increase atherosclerotic plaques. The exposures were conducted using the SCIREQ InExpose™ nose-only inhalation system and STLTH or Vuse products for 16 weeks. We observed that only male mice exposed to STLTH or Vuse aerosols had significantly increased plasma total cholesterol, triglycerides, and LDL cholesterol levels compared to mice exposed to system air. Moreover, these male mice also had a significant increase in aortic and sinus plaque area. Male mice exposed to e-cigarette aerosol had a significant reduction in weight gain over the exposure period. Our data indicate that e-cigarette use in young hyperlipidemic male mice increases atherosclerosis in the absence of significant pulmonary and systemic inflammation. These results underscore the need for extensive research to unravel the long-term health effects of e-cigarettes.

PCSK9 inhibitors on the management of primary and secondary cardiovascular prevention.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have represented an important change in the management of hypercholesterolemia, although, until now, they have barely been used. Without PCSK9i, many patients with atherosclerotic cardiovascular disease (CVD) or those at very high risk do not reach their therapeutic LDLc objectives. OBJECTIVE: The analysis aimed to examine the clinical and biochemical characteristics of subjects receiving PCSK9i treatment in the Dyslipidemia Registry of the Spanish Atherosclerosis Society. METHODS: All consecutive subjects aged ≥ 18 years from different Lipid Units included in the Dyslipidemia Registry of the SEA were analyzed. Inclusion criteria consisted of unrelated patients aged ≥ 18 at the time of inclusion with hypercholesterolemia (LDL-C ≥ 130 mg/dL or non-HDL-C ≥ 160 mg/dL after the exclusion of secondary causes) who were studied for at least two years after inclusion. Participants' baseline and final visit clinical and biochemical characteristics were analyzed based on whether they were on primary or secondary prevention and whether they were taking PCSK9i at the end of follow-up. RESULTS: Eight hundred twenty-nine patients were analyzed, 7014 patients in primary prevention and 1281 in secondary prevention at baseline. 4127 subjects completed the required follow-up for the final analysis. The median follow-up duration was 7 years (IQR 3.0-10.0). Five hundred patients (12.1%) were taking PCSK9i at the end of the follow-up. The percentage of PCSK9i use reached 35.6% (n = 201) and 8.7% (n = 318) in subjects with and without CVD, respectively. Subjects on PCSK9i and oral lipid-lowering agents with and without CVD achieved LDLc reductions of 80.3% and 75.1%, respectively, concerning concentrations without lipid-lowering drugs. Factors associated with PCSK9i use included increasing age, LDLc without lipid-lowering drugs and the Dutch Lipid Clinic Network (DLCN) score. However, hypertension, diabetes, smoking, and LDLc after oral lipid-lowering drugs were not independent factors associated with PCSK9i prescription. In subjects with CVD, the use of PCSK9i was higher in men than in women (an odds ratio of 1.613, P = 0.048). CONCLUSIONS: Approximately one-third of CVD patients received PCSK9i at the end of follow-up. The use of PCSK9i was more focused on baseline LDLc concentrations rather than on CVD risk. Women received less PCSK9i in secondary prevention compared to men.

Drug interactions in cardiology: focus on statins and their combination with other lipid-lowering drugs.

INTRODUCTION: Statins are the primary therapeutic approach for treating hypercholesterolemia in hyperlipidemic high cardiovascular-risk patients, as stated by the recent European and American guidelines. However, in some patients, statin treatment is not sufficient to achieve the recommended plasma LDL-C levels, and the addition of a second hypolipidemic drug becomes mandatory. Concomitant administration of multiple medications may increase the risk of adverse events, potentially leading to statin-associated muscle or liver symptoms and non-adherence or discontinuation of statin therapy, such as in women. The addition of a second hypolipidemic drug (such as ezetimibe, anti-PCSK9 monoclonal antibodies, bempedoic acid, and inclisiran) may lead to drug-drug interactions (DDIs). The evaluation of the different pharmacokinetic profiles may improve and personalize the treatment. AREAS COVERED: We aimed to give an update on the potential DDIs between statins and other hypolipidemic drugs currently used to treat high-risk hyperlipidemic patients. EXPERT OPINION: It is fundamental to understand the risk associated with DDIs to manage better the addition of a concomitant hyperlipidemic drug to a statin-treated patient. Many health agencies have published specific guidelines for assessing DDIs, but these mainly apply to in vitro studies. New predictive approaches are being proposed and may help evaluate and manage DDIs.

PCSK9 inhibitor effectively alleviated cognitive dysfunction in a type 2 diabetes mellitus rat model.

Background: The incidence of diabetes-associated cognitive dysfunction (DACD) is increasing; however, few clinical intervention measures are available for the prevention and treatment of this disease. Research has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, particularly SBC-115076, have a protective effect against various neurodegenerative diseases. However, their role in DACD remains unknown. In this study, we aimed to explore the impact of PCSK9 inhibitors on DACD. Methods: Male Sprague-Dawley (SD) rats were used to establish an animal model of type 2 diabetes mellitus (T2DM). The rats were randomly divided into three groups: the Control group (Control, healthy rats, n = 8), the Model group (Model, rats with T2DM, n = 8), and the PCSK9 inhibitor-treated group (Treat, T2DM rats treated with PCSK9 inhibitors, n = 8). To assess the spatial learning and memory of the rats in each group, the Morris water maze (MWM) test was conducted. Hematoxylin-eosin staining and Nissl staining procedures were performed to assess the structural characteristics and functional status of the neurons of rats from each group. Transmission electron microscopy was used to examine the morphology and structure of the hippocampal neurons. Determine serum PCSK9 and lipid metabolism indicators in each group of rats. Use qRT-PCR to detect the expression levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) in the hippocampal tissues of each group of rats. Western blot was used to detect the expression of PCSK9 and low-density lipoprotein receptor (LDLR) in the hippocampal tissues of rats. In addition, a 4D label-free quantitative proteomics approach was used to analyse protein expression in rat hippocampal tissues. The expression of selected proteins in hippocampal tissues was verified by parallel reaction monitoring (PRM) and immunohistochemistry (IHC). Results: The results showed that the PCSK9 inhibitor alleviated cognitive dysfunction in T2DM rats. PCSK9 inhibitors can reduce PCSK9, total cholesterol (TC), and low-density lipoprotein (LDL) levels in the serum of T2DM rats. Meanwhile, it was found that PCSK9 inhibitors can reduce the expression of PCSK9, IL-1ß, IL-6, and TNF-α in the hippocampal tissues of T2DM rats, while increasing the expression of LDLR. Thirteen potential target proteins for the action of PCSK9 inhibitors on DACD rats were identified. PRM and IHC revealed that PCSK9 inhibitors effectively counteracted the downregulation of transthyretin in DACD rats. Conclusion: This study uncovered the target proteins and specific mechanisms of PCSK9 inhibitors in DACD, providing an experimental basis for the clinical application of PCSK9 inhibitors for the potential treatment of DACD.

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.

Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing.

Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O2._) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O2._ production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.

The clinical relevance of the reversal of coronary atherosclerotic plaque.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death globally despite advances in preventive therapies. Understanding of the initiation and progression of atherosclerosis, the interplay between lipoproteins, endothelial dysfunction, inflammation, and immune responses is critical to treating this disease. The development of vulnerable coronary plaques prone to thrombosis, can lead to acute coronary syndromes, for these reasons, the potential plaque stabilization and regression through pharmacological interventions, particularly lipid-lowering agents like statins and PCSK9 inhibitors is crucial. The imaging techniques such as intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) play a key role in assessing plaque composition and guiding interventional therapeutic strategies. Clinical evidence supports the efficacy of intensive lipid-lowering therapy in inducing plaque regression, with studies demonstrating reductions in plaque volume and improvements in plaque morphology assessed by IVUS, OCT and NIRS. While pharmacological interventions show promise in promoting plaque regression and stabilization, their impact on long-term cardiovascular events requires further investigation. Multimodality imaging and comprehensive outcome trials are proposed as essential tools for elucidating the relationship between plaque modification and clinical benefit in coronary atherosclerosis. The stabilization or regression of atherosclerotic plaque might serve as the phenomenon linking the reduction in LDL-C levels to the decrease in cardiovascular events. Overall, this review emphasizes the ongoing efforts to advance our understanding of ASCVD pathophysiology and optimize therapeutic approaches for improving patient outcomes.

Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy.

T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.

Clinical Impact of Lipoprotein (a) and Cumulative Low-Density Lipoprotein Cholesterol Exposure on Coronary Artery Disease in Patients with Heterozygous Familial Hypercholesterolemia.

AIMS: Elevated lipoprotein (a) (Lp[a]), predominantly determined by genetic variability, causes atherosclerotic cardiovascular disease (ASCVD), particularly in patients with familial hypercholesterolemia (FH). We aimed to elucidate the clinical impact of Lp(a) and cumulative exposure to low-density lipoprotein cholesterol (LDL-C) on CAD in patients with FH. METHODS: One hundred forty-seven patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) were retrospectively investigated. Patients were divided into 2 groups according to the presence of CAD. Their clinical characteristics and lipid profiles were evaluated. RESULTS: There were no significant differences in untreated LDL-C levels between the 2 groups (p=0.4), whereas the cumulative exposure to LDL-C and Lp(a) concentration were significantly higher in patients with CAD (11956 vs. 8824 mg-year/dL, p＜0.01; 40 vs. 14 mg/dL, p＜0.001, respectively). A receiver operating characteristic (ROC) curve analysis demonstrated that the cutoff values of Lp(a) and cumulative LDL-C exposure to predict CAD in patients with FH were 28 mg/dL (AUC 0.71) and 10600 mg-year/dL (AUC 0.77), respectively. A multivariate analysis revealed that cumulative LDL-C exposure ≥ 10600 mg-year/dL (p＜0.0001) and Lp(a) level ≥ 28 mg/dL (p＜0.001) were independent predictors of CAD. Notably, the risk of CAD remarkably increased to 85.7% with smoking, Lp(a) ≥ 28 mg/dL, and cumulative LDL-C exposure ≥ 10600 mg-year/dL (odds ratio: 46.5, 95%CI: 5.3-411.4, p＜0.001). CONCLUSIONS: This study demonstrated an additive effect of Lp(a) and cumulative LDL-C exposure on CAD in patients with HeFH. Interaction with traditional risk factors, particularly smoking and cumulative LDL-C exposure, enormously enhances the cardiovascular risk in this population.

A Medical Claims Database Study of Factors Associated with Medication Adherence and Treatment Persistence in Patients Receiving PCSK9 Monoclonal Antibodies.

AIM: To investigate medication adherence and treatment persistence in patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) in Japan. METHODS: Using an anonymized claims database from January 2015 to December 2021, data on adult patients at high risk for atherosclerotic cardiovascular disease or with a history of coronary artery disease (CAD) who had at least 1 prescription for PCSK9-mAbs were retrieved. RESULTS: In total, 276 patients were analyzed. The cumulative treatment persistence rate after 1 year was 67.0%. A multivariate analysis revealed that better adherence to oral low-density lipoprotein cholesterol (LDL-C)-lowering therapy in the year before starting PCSK9-mAbs (adjusted odds ratio [OR] 2.16) and a history of CAD for secondary prevention (adjusted OR 2.44) were associated with better adherence to PCSK9-mAbs in the first year. Better adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (adjusted OR 2.32) and a history of CAD for secondary prevention (adjusted OR 3.03) were also associated with a lower rate of discontinuation of PCSK9-mAbs. Age, sex, comorbidity, number of tablets taken daily (all medications), and number of hospital or clinic visits in the year prior to starting PCSK9-mAbs did not affect the persistence rate or adherence to PCSK9-mAbs in the multivariate analyses. CONCLUSION: Better adherence to oral LDL-C-lowering therapy and secondary prevention were identified as factors associated with better medication adherence and treatment persistence in patients receiving PCSK9-mAbs within the first year.

Monoclonal Anti-PCSK9 Antibodies: Real-World Data.

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines' recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines' recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines' recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients.