A novel mechanism of ferroptosis inhibition-enhanced atherosclerotic plaque stability: YAP1 suppresses vascular smooth muscle cell ferroptosis through GLS1.

Atherosclerosis is a leading cause of cardiovascular diseases (CVDs), often resulting in major adverse cardiovascular events (MACEs), such as myocardial infarction and stroke due to the rupture or erosion of vulnerable plaques. Ferroptosis, an iron-dependent form of cell death, has been implicated in the development of atherosclerosis. Despite its involvement in CVDs, the specific role of ferroptosis in atherosclerotic plaque stability remains unclear. In this study, we confirmed the presence of ferroptosis in unstable atherosclerotic plaques and demonstrated that the ferroptosis inhibitor ferrostatin-1 (Fer-1) stabilizes atherosclerotic plaques in apolipoprotein E knockout (Apoe-/-) mice. Using bioinformatic analysis combining RNA sequencing (RNA-seq) with single-cell RNA sequencing (scRNA-seq), we identified Yes-associated protein 1 (YAP1) as a potential key regulator of ferroptosis in vascular smooth muscle cells (VSMCs) of unstable plaques. In vitro, we found that YAP1 protects against oxidized low-density lipoprotein (oxLDL)-induced ferroptosis in VSMCs. Mechanistically, YAP1 exerts its anti-ferroptosis effects by regulating the expression of glutaminase 1 (GLS1) to promote the synthesis of glutamate (Glu) and glutathione (GSH). These findings establish a novel mechanism where the inhibition of ferroptosis promotes the stabilization of atherosclerotic plaques through the YAP1/GLS1 axis, attenuating VSMC ferroptosis. Thus, targeting the YAP1/GLS1 axis to suppress VSMC ferroptosis may represent a novel strategy for preventing and treating unstable atherosclerotic plaques.

Evolution of a bispecific G-quadruplex-forming circular aptamer to block IL-6/sIL-6R interaction for inflammation inhibition.

IL-6 (interleukin-6) is an essential cytokine that participates in many inflammatory and immune responses, and disrupting the interaction between IL-6 and its receptor sIL-6R (soluble form of IL-6 receptor) represents a promising treatment strategy for inflammation and related diseases. Herein we report the first-ever effort of evolving a bispecific circular aptamer, named CIL-6A6-1, that is capable of binding both IL-6 and sIL-6R with nanomolar affinities and is stable in serum for more than 48 hours. CIL-6A6-1 can effectively block the IL-6/sIL-6R interaction and significantly inhibit cell inflammation. Most importantly, this bispecific aptamer is much more effective than aptamers that bind IL-6 and sIL-6R alone as well as tocilizumab, a commercially available humanized monoclonal antibody against sIL-6R, highlighting the advantage of selecting bispecific circular aptamers as molecular tools for anti-inflammation therapy. Interestingly, CIL-6A6-1 is predicted to adopt a unique structural fold with two G-quadruplex motifs capped by a long single-stranded region, which differs from all known DNA aptamers. This unique structural fold may also contribute to its excellent functionality and high stability in biological complex media. We anticipate that our study will represent a significant step forward towards demonstrating the practical utility of bispecific DNA aptamers for therapeutic applications.

Value of altered methylation patterns of genes RANBP3, LCP2 and GRAP2 in cfDNA in breast cancer diagnosis.

Background: The purpose of this study was to investigate the potential of plasma cfDNA methylation patterns in reflecting tumour methylation changes, focusing on three candidate sites, cg02469161, cg11528914, and cg20131654. These sites were selected for verification, with a particular emphasis on their association with breast cancer. Methods: We conducted a comprehensive analysis of 850k whole-methylation sequencing data to identify potential markers for breast cancer detection. Subsequently, we investigated the methylation status of the genes Ran-binding protein 3 (RANBP3), Lymphocyte cytoplasmic protein 2 (LCP2), and GRB2 related adaptor protein 2 (GRAP2), situated at the specified sites, using cancer and canceradjacent tissues from 17 breast cancer patients. We also examined the methylation patterns in different molecular subtypes and pathological grades of breast cancer. Additionally, we compared the methylation levels of these genes in plasma cfDNA to their performance in tissues. Results: Our analysis revealed that RANBP3, LCP2, and GRAP2 genes exhibited significant methylation differences between cancer and cancer-adjacent tissues. In breast cancer, these genes displayed diagnostic efficiencies of 91.0%, 90.6%, and 92.2%, respectively. Notably, RANBP3 showed a tendency towards lower methylation in HR+ breast cancer, and LCP2 methylation was correlated with tumour malignancy. Importantly, the methylation levels of these three genes in plasma cfDNA closely mirrored their tissue counterparts, with diagnostic efficiencies of 83.3%, 83.9%, and 77.6% for RANBP3, LCP2, and GRAP2, respectively. Conclusions: Our findings propose that the genes RANBP3, LCP2, and GRAP2, located at the identified methylation sites, hold significant potential as molecular markers in blood for the supplementary diagnosis of breast cancer. This study lays the groundwork for a more in-depth investigation into the changes in gene methylation patterns in circulating free DNA (cfDNA) for the early detection not only of breast cancer but also for various other types of cancer.

Corrigendum: Tracheal intubation in patients with Pierre Robin sequence: development, application, and clinical value based on a 3-dimensional printed simulator.

[This corrects the article DOI: 10.3389/fphys.2023.1292523.].

A nanomaterial-independent and fluorescent immunoassay based on Eu-micelles for rapid and sensitive detection of fluoroquinolones in chicken.

Fluorescent nanoprobes are widely applied in innovate enzyme-linked immunosorbent assays (ELISA) for detection of fluoroquinolones (FQs) residue in foodstuffs. Nevertheless, the complicated synthesis of nanoprobes hampers their practical applications. Herein, a nanomaterial-independent and fluorescent ELISA for sensitive detection of FQs is developed using the Eu-micelles as signal probe. Non-nanostructured Eu-micelles with high quantum yield and stability are facilely synthesized through the assembly of Eu3+ and ligands. Alkaline phosphatase catalyzes hydrolysis of 4-nitrophenyl phosphate to 4-nitrophenol. The fluorescent Eu-micelles can be readily quenched by 4-nitrophenol via static quenching. The signal generation mechanism integrates well with conventional ELISA systems. The established fluorescent ELISA achieves sensitive detection of FQs with a limit of detection of 0.03 µg/kg. The validation results from LC-MS show that the fluorescent ELISA exhibits good accuracy and recoveries. Our study presents a nanomaterial-independent strategy for developing the rapid immunoassay for FQs, which holds good promise for practical applications.

Transcatheter closure management of mitral paravalvular leakage: A single center experience.

BACKGROUND: Paravalvular leakage (PVL) is a common complication after artificial valve replacement. Transcatheter paravalvular leak closure (PVT), an efficient, safe, and minimally invasive treatment for PVL patients. AIMS: The purpose of this study was to present our experience with transcatheter closure of mitral paravalvular leakage (PVL) after surgical valve replacement in our center. METHODS: A cohort of 81 consecutive patients with mitral PVLs was treated with transcatheter closure between September 2014 and December 2022. We reviewed the demographics, clinical features, therapeutic modalities and follow-up results. The patients' charts were used for retrospective analysis. RESULTS: Eighty-one patients from one center were enrolled in this study. The median age of the patients was 63 ± 11 years. The median LVEF was 51% ± 7%, and the median regurgitation volume was 11.5 ± 10.1 mL. Sealing with occlusion was successful in 70 patients, and the technical success rate was 86.5%. The median regurgitation volume was reduced to 1.95 ± 2.6 mL. The major adverse event was hemolysis, which affected 19 patients, 17 of whom required blood transfusion. Three patients required secondary open surgery due to bleeding. Three patients died during the hospital stay, and all of their deaths were caused by hemolysis-related complications. The median hospital stay was 10.3 ± 6.3 days. During the follow-up period, 2 patients died, and none of their deaths were caused by surgery. The New York Heart Association classification increased in all patients during the 6-month follow-up. CONCLUSION: Transcatheter mitral PVL closure requires complex catheter techniques. However, this technique is minimally invasive and has a shorter hospital stay. Interventional mitral PVL closure is a safe and efficacious technique for high-risk surgical patients with symptomatic paravalvular regurgitation.

A novel dual-target Septin9 methylation assay for improved detection of early-stage colorectal cancer and high-grade intraepithelial neoplasia.

BACKGROUND: Colorectal cancer (CRC) ranks as the third most common malignancies in the world, and periodic examination of the patient is advantageous in reducing the mortality of CRC. The first blood-based Septin9 gene methylation assay which recognized by the US FDA for CRC examination was Epi proColon. However, this assay was not broadly applied in the current clinical guideline because of its relatively lower sensitivity in the detection of early-stage CRC. METHODS: This study aimed at developing a new multiplex Septin9 methylation assay (ColonUSK) which simultaneously evaluates two CpG-rich subregions in the promoter of the Septin9 gene and an internal control in a single reaction. ColonUSK proved increased sensitivity, with a detection limit as low as 12pg of the positive DNA compared with the Septin9 assay targeting one CpG-rich subregion. 1366 subjects were prospectively recruited from four comprehensive hospitals in China in an opportunistic screening study for assessing its value in CRC detection. Blind testing was developed to evaluate ColonUSK in comparison with clinical examination using clinical gold standard such as colonoscopy. RESULTS: The assay demonstrates clinical sensitivity for diagnosing colorectal cancer (CRC) and advanced adenoma at rates of 77.34% and 25.26%, respectively. Furthermore, ColonUSK exhibits a high degree of specificity for non-CRC cases (95.95%) clinically. Significantly, the detection rate of cases in high-grade intraepithelial neoplasia increased to 54.29%. The value for the assay in the Kappa test was 0.76, showing a high degree of consistency between ColonUSK and clinical gold standard. CONCLUSIONS: ColonUSK indicated moderate diagnostic value and could become a non-invasive detection way for CRC. The implementation of the ColonUSK assay has the capacity to markedly enhance CRC screening practices.

IGF-1 inhibits inflammation and accelerates angiogenesis via Ras/PI3K/IKK/NF-κB signaling pathways to promote wound healing.

Exogenous insulin-like growth factor-1 (IGF-1) has been reported to promote wound healing through regulation of vascular endothelial cells (VECs). Despite the existing studies of IGF-1 on VEC and its role in angiogenesis, the mechanisms regarding anti-inflammatory and angiogenetic effects of IGF-1 remain unclear. In this study, we investigated the wound-healing process and the related signaling pathway of IGF-1 using an inflammation model induced by IFN-γ. The results demonstrated that IGF-1 can increase cell proliferation, suppress inflammation in VECs, and promote angiogenesis. In vivo studies further confirmed that IGF-1 can reduce inflammation, enhance vascular regeneration, and improve re-epithelialization and collagen deposition in acute wounds. Importantly, the Ras/PI3K/IKK/NF-κB signaling pathways was identified as the mechanisms through which IGF-1 exerts its anti-inflammatory and pro-angiogenic effects. These findings contribute to the understanding of IGF-1's role in wound healing and may have implications for the development of new wound treatment approaches.

Synergistic ferrate(VI) and chlorine for reclaimed water disinfection: Microbial control and chlorine decay mitigation.

Chlorination is the most widely used disinfection technology due to its simplicity and continuous disinfection ability. However, the drawbacks of disinfection by-products and chlorine-resistant bacteria have gained increasing attention. Nowadays, ferrate (Fe(VI)) is a multifunctional and environmentally friendly agent which has great potential in wastewater reclamation and reuse. This study investigated synergistic Fe(VI) and chlorine technology for reclaimed water disinfection in terms of microbial control and chlorine decay mitigation. Specifically, synergistic disinfection significantly improved the inactivation efficiency on total coliform, Escherichia coli and heterotrophic bacteria compared to sole chlorination. Synergistic disinfection also exhibited superior performance on controlling the relative abundance of chlorine-resistant bacteria and pathogenic bacteria. In addition, the decay rate of residual chlorine was relatively lower after Fe(VI) pretreatment, which was beneficial for microbial control during the reclaimed water distribution process. Technical and economic analyses revealed that synergistic Fe(VI) and chlorine disinfection was suitable and feasible. Results of this study are believed to provide useful information and alternative options on the optimization of reclaimed water disinfection.

Salvage surgery and conversion surgery for patients with non-small cell lung cancer: A narrative review.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. With the development of screening, patient selection and treatment strategies, patients' survival outcomes and living quality significantly improved. However, some patients still have local recurrence or residual tumors after receiving definitive therapies. Salvage surgery has been regarded as an effective option for recurrent or residual NSCLC, but its effectiveness remains undetermined. Furthermore, conversion surgery is a special type of salvage surgery for tumors converted from "initially unresectable" to "potentially resectable" status due to a favorable response to systemic treatments. Although conversion surgery is a promising curative procedure for advanced NSCLC, its concept and clinical value remain unfamiliar to clinicians. In this narrative review, we provided an overview of the safety and efficacy of salvage surgery, especially salvage surgery after sublobar resection in early-stage NSCLC. More importantly, we highlighted the concept and value of conversion surgery after systemic treatment in advanced NSCLC to gain some insights into its role in the treatment of lung cancer.

Esketamine mitigates mechanical ventilation-induced lung injury in chronic obstructive pulmonary disease rats via inhibition of the MAPK/NF-κB signaling pathway and reduction of oxidative stress.

PURPOSE: To investigate esketamine's impact on inflammation and oxidative stress in ventilated chronic obstructive pulmonary disease (COPD) rats, examining its regulatory mechanisms. METHODS: Rats were divided into four groups: control group (Con), COPD model group (M), COPD model with saline treatment group (M+S), and COPD model with esketamine treatment group (M+K), with 12 rats in each group. After two months, all rats underwent anesthesia and mechanical ventilation. Group M+K received 5 mg/kg esketamine intravenously, while Group M+S received the same volume of saline. Lung tissues were collected for analysis two hours later, including airway peak pressure, wet-to-dry(W/D) ratio, lung permeability index(LPI), hematoxylin and eosin(H&E) staining, and transmission electron microscopy(TEM). Tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), interleukin-8(IL-8), and interleukin-10(IL-10) levels were determined by enzyme-linked immunosorbent assay(ELISA); phosphorylated Nuclear Factor Kappa B(p-NF-κB), mitogen-activated protein kinase 14(p38), phosphorylated p38 (p-p38), c-Jun N-terminal kinase(JNK), and phosphorylated JNK (p-JNK) expressions by Western blotting and immunohistochemistry; and malondialdehyde(MDA), myeloperoxidase(MPO), and superoxide dismutase(SOD) levels were also measured by corresponding biochemical assays. RESULTS: Lung specimens from groups M, M+S, and M+K manifested hallmark histopathological features of COPD. Compared with group Con, group M displayed increased peak airway pressure, W/D ratio, and LPI. In group M+K, compared with group M, esketamine significantly reduced the W/D ratio, LPI, and concentrations of pro-inflammatory cytokines TNF-α, IL-6, and IL-8 while concurrently elevating IL-10 levels. Furthermore, the treatment attenuated the activation of the NF-κB and MAPK pathways, indicated by decreased levels of p-NF-κB, p-p38, and p-JNK.Additionally, compared to group M, group M+K showed decreased MDA and MPO levels and increased SOD levels in lung tissue. CONCLUSION: Esketamine attenuates mechanical ventilation-induced lung injury in COPD rat models by inhibiting the MAPK/NF-κB signaling pathway and reducing oxidative stress.

Rapid segmentation of computed tomography angiography images of the aortic valve: the efficacy and clinical value of a deep learning algorithm.

Objectives: The goal of this study was to explore the reliability and clinical value of fast, accurate automatic segmentation of the aortic root based on a deep learning tool compared with computed tomography angiography. Methods: A deep learning tool for automatic 3-dimensional aortic root reconstruction, the CVPILOT system (TAVIMercy Data Technology Ltd., Nanjing, China), was trained and tested using computed tomography angiography scans collected from 183 patients undergoing transcatheter aortic valve replacement from January 2021 to December 2022. The quality of the reconstructed models was assessed using validation data sets and evaluated clinically by experts. Results: The segmentation of the ascending aorta and the left ventricle attained Dice similarity coefficients (DSC) of 0.9806/0.9711 and 0.9603/0.9643 for the training and validation sets, respectively. The leaflets had a DSC of 0.8049/0.7931, and the calcification had a DSC of 0.8814/0.8630. After 6 months of application, the system modeling time was reduced to 19.83 s. Conclusion: For patients undergoing transcatheter aortic valve replacement, the CVPILOT system facilitates clinical workflow. The reliable evaluation quality of the platform indicates broad clinical application prospects in the future.

Phlorizin from Lithocarpus litseifolius [Hance] Chun ameliorates FFA-induced insulin resistance by regulating AMPK/PI3K/AKT signaling pathway.

BACKGROUND: Insulin resistance (IR) is the central pathophysiological feature in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia. As the main active ingredient in Lithocarpus litseifolius [Hance] Chun, previous studies have shown that phlorizin (PHZ) can reduce insulin resistance in the liver. However, the effect of phlorizin on attenuating hepatic insulin resistance has not been fully investigated, and whether this effect is related to AMPK remains unclear. PURPOSE: The present study aimed to further investigate the effect of phlorizin on attenuating insulin resistance and the potential action mechanism. METHODS: Free fatty acids (FFA) were used to induce insulin resistance in HepG2 cells. The effects of phlorizin and FFA on cell viability were detected by MTT analysis. Glucose consumption, glycogen synthesis, intracellular malondialdehyde (MDA), superoxide dismutase (SOD), total cholesterol (TC), and triglyceride (TG) contents were quantified after phlorizin treatment. Glucose uptake and reactive oxygen species (ROS) levels in HepG2 cells were assayed by flow cytometry. Potential targets and signaling pathways for attenuating insulin resistance by phlorizin were predicted by network pharmacological analysis. Moreover, the expression levels of proteins related to the AMPK/PI3K/AKT signaling pathway were detected by western blot. RESULTS: Insulin resistance was successfully induced in HepG2 cells by co-treatment of 1 mM sodium oleate (OA) and 0.5 mM sodium palmitate (PA) for 24 h. Treatment with phlorizin promoted glucose consumption, glucose uptake, and glycogen synthesis and inhibited gluconeogenesis in IR-HepG2 cells. In addition, phlorizin inhibited oxidative stress and lipid accumulation in IR-HepG2 cells. Network pharmacological analysis showed that AKT1 was the active target of phlorizin, and the PI3K/AKT signaling pathway may be the potential action mechanism of phlorizin. Furthermore, western blot results showed that phlorizin ameliorated FFA-induced insulin resistance by activating the AMPK/PI3K/AKT signaling pathway. CONCLUSION: Phlorizin inhibited oxidative stress and lipid accumulation in IR-HepG2 cells and ameliorated hepatic insulin resistance by activating the AMPK/PI3K/AKT signaling pathway. Our study proved that phlorizin played a role in alleviating hepatic insulin resistance by activating AMPK, which provided experimental evidence for the use of phlorizin as a potential drug to improve insulin resistance.

Research on the influencing factors of adult learners' intent to use online education platforms based on expectation confirmation theory.

This study addresses the understanding gap concerning the factors that influence the continuous learning intention of adult learners on online education platforms. The uniqueness and significance of this study stem from its dual focus on both platform features, such as service quality, and course features, including perceived interactivity and added value, aspects often overlooked in previous research. Rooted in Expectation Confirmation Theory, the study constructs a comprehensive model to shed light on the complex interplay of these factors. Empirical evidence collected from a survey of 1592 adult learners robustly validates the effectiveness of this model. The findings of the study reveal that platform service quality, perceived interactivity, and perceived added value significantly amplify adult learners' expectation confirmation and perceived usefulness. These elements subsequently enhance learner satisfaction, fostering their ongoing intention to use online education platforms. These insights offer practical guidance for online education providers, emphasizing the necessity to enhance platform service quality and course features to meet adult learners' expectations and perceived usefulness. The study provides valuable perspectives for devising strategies to boost user satisfaction and stimulate continuous usage intention among adult learners in the intensely competitive online education market. This study enriches the literature by uncovering the relationships among platform features, course features, expectation confirmation, perceived usefulness, and continuous usage intention. By proposing a comprehensive model, this study provides a novel theoretical basis for understanding how platform and course features impact adult learners' ongoing intention to use online education platforms, thereby aiding the evolution and refinement of relevant theories.

Postoperative rehabilitation and quality of life evaluation for transoral endoscopic thyroidectomy vestibular approach.

There are no targeted rehabilitation training modalities and assessment tools for patients after transoral endoscopic thyroidectomy vestibular approach (TOETVA). Herein, we develop a new assessment questionnaire and rehabilitation training modality and evaluate its safety and effectiveness. The THYCA-QoL-TOETVA questionnaire was compiled, and reliability and validity analyses were performed. Patients were divided into the new rehabilitation training group (N) or the conventional rehabilitation training group (C), and 1:1 propensity score matching (PSM) was performed after administering questionnaires to patients in both groups. Cervical range of motion (CROM) data were also measured and collected for statistical analysis. The questionnaire used in this study showed good expert authority, coordination, internal consistency, and questionnaire reliability. A total of 476 patients were included after PSM, and the questionnaire results showed that recovery and quality of life were better in the N group than in the C group (124.55 ± 8.171 vs. 122.94 ± 8.366, p = 0.026). Analysis of cervical spine mobility showed that rehabilitation was better in the N group compared to the C group at postoperative one month (flexion: 1.762°, extension: 4.720°, left lateral bending: 3.912°, right lateral bending: 4.061°, left axial rotation: 5.180°, right axial rotation: 5.199°, p value all of these < 0.001), and at postoperative three months (flexion: 2.866°, extension: 2.904°, left lateral bending: 3.927°, right lateral bending: 3.330°, left axial rotation: 4.395°, right axial rotation: 3.992°, p value all of these < 0.001). The THYCA-QoL-TOETVA provides an appropriate and effective tool for measuring the postoperative quality of life of TOETVA patients. This new rehabilitation training can effectively alleviate the problem of limited neck movement and improve the quality of life of patients after TOETVA surgery.Trial registration: ChiCTR2300069097.

The Improvement and Related Mechanism of Microecologics on the Sports Performance and Post-Exercise Recovery of Athletes: A Narrative Review.

The diversity and functionality of gut microbiota may play a crucial role in the function of human motor-related systems. In addition to traditional nutritional supplements, there is growing interest in microecologics due to their potential to enhance sports performance and facilitate post-exercise recovery by modulating the gut microecological environment. However, there is a lack of relevant reviews on this topic. This review provides a comprehensive overview of studies investigating the effects of various types of microecologics, such as probiotics, prebiotics, synbiotics, and postbiotics, on enhancing sports performance and facilitating post-exercise recovery by regulating energy metabolism, mitigating oxidative-stress-induced damage, modulating immune responses, and attenuating bone loss. Although further investigations are warranted to elucidate the underlying mechanisms through which microecologics exert their effects. In summary, this study aims to provide scientific evidence for the future development of microecologics in athletics.

Dietary Patterns, Gut Microbiota and Sports Performance in Athletes: A Narrative Review.

The intestinal tract of humans harbors a dynamic and complex bacterial community known as the gut microbiota, which plays a crucial role in regulating functions such as metabolism and immunity in the human body. Numerous studies conducted in recent decades have also highlighted the significant potential of the gut microbiota in promoting human health. It is widely recognized that training and nutrition strategies are pivotal factors that allow athletes to achieve optimal performance. Consequently, there has been an increasing focus on whether training and dietary patterns influence sports performance through their impact on the gut microbiota. In this review, we aim to present the concept and primary functions of the gut microbiota, explore the relationship between exercise and the gut microbiota, and specifically examine the popular dietary patterns associated with athletes' sports performance while considering their interaction with the gut microbiota. Finally, we discuss the potential mechanisms by which dietary patterns affect sports performance from a nutritional perspective, aiming to elucidate the intricate interplay among dietary patterns, the gut microbiota, and sports performance. We have found that the precise application of specific dietary patterns (ketogenic diet, plant-based diet, high-protein diet, Mediterranean diet, and high intake of carbohydrate) can improve vascular function and reduce the risk of illness in health promotion, etc., as well as promoting recovery and controlling weight with regard to improving sports performance, etc. In conclusion, although it can be inferred that certain aspects of an athlete's ability may benefit from specific dietary patterns mediated by the gut microbiota to some extent, further high-quality clinical studies are warranted to substantiate these claims and elucidate the underlying mechanisms.

Correction to: Unveiling the next generation of MRI contrast agents: current insights and perspectives on ferumoxytol-enhanced MRI.

[This corrects the article DOI: 10.1093/nsr/nwae057.].

Benefits and Risks of Antihyperlipidemic Medication in Adults with Different Low-Density Lipoprotein Cholesterol Based on the Number Needed to Treat.

PURPOSE: The objective of this investigation is to examine the benefits and potential risks of these drugs in individuals by varying baseline low-density lipoprotein cholesterol (LDL-C) values, utilizing the concept of the number needed to treat (NNT). METHODS: We extensively searched electronic databases, such as PubMed, EMBASE, Cochrane, and Web of Science, up to 6 August 2023. Baseline LDL-C values were stratified into four categories: < 100, 100-129, 130-159, and ≥ 160 mg/dL. Risk ratios (RRs) and NNT values were computed. RESULTS: This analysis incorporated data from 46 randomized controlled trials (RCTs), encompassing a total of 237,870 participants. The meta-regression analysis demonstrated an incremental diminishing risk of major adverse cardiovascular events (MACE) with increasing baseline LDL-C values. Statins exhibited a significant reduction in MACE [number needed to treat to benefit (NNTB) 31, 95% confidence interval (CI) 25-37], but this effect was observed only in individuals with baseline LDL-C values of 100 mg/dL or higher. Ezetimibe and PCSK9 inhibitors also were effective in reducing MACE (NNTB 18, 95% CI 11-41, and NNTB 18, 95% CI 16-24). Notably, the safety outcomes of statins and ezetimibe did not reach statistical significance, while the incidence of injection-site reactions with PCSK9 inhibitors was statistically significant [number needed to treat to harm (NNTH) 41, 95% CI 80-26]. CONCLUSION: Statins, ezetimibe, and PCSK9 inhibitors demonstrated a substantial capacity to reduce MACE, particularly among individuals whose baseline LDL-C values were relatively higher. The NNT visually demonstrates the gradient between baseline LDL-C and cardiovascular disease (CVD) risk. SYSTEMATIC REVIEW REGISTRATION: Registration: PROSPERO identifier number: CRD42023458630.