25-Hydroxycholesterol inhibits Hantavirus infection by reprogramming cholesterol metabolism.

Hantavirus causes two types of acute diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. It is a major health concern due to its high mortality and lack of effective treatment. Type I interferon treatment has been suggested to be effective against hantavirus when treated in advance. Interferons induce multiple interferon-stimulated genes (ISGs), whose products are highly effective at resisting and controlling viruses. A product of ISGs, the enzyme cholesterol 25-hydroxylase (CH25H), catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25HC). 25HC can inhibit multiple enveloped-virus infections, but the mechanism is largely unknown, and whether 25HC plays an important role in regulating hantavirus remains unexplored. In this study, we show that Hantaan virus (HTNV), the prototype hantavirus, induced CH25H gene in infected cells. Overexpression of CH25H and treatment with 25HC, inhibited HTNV infection, possibly by lowering 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase, HMGCR), which inhibits cholesterol biosynthesis. In addition, cholesterol-lowering drugs such as HMGCR-targeting statins have potent hantavirus inhibitory effects. Our results indicate that 25HC and some statins are potential antiviral agents effective against hantavirus infections. This study provides evidence that targeting cholesterol metabolism is promising in developing specific hantavirus antivirals and indicates the possibility of repurposing FDA-approved cholesterol-lowering drug, statins for treating hantavirus infection.

The molecular basis of the anticancer effect of statins.

Statins, widely used cardiovascular drugs that lower cholesterol by inhibiting HMG-CoA reductase, have been increasingly recognized for their potential anticancer properties. This study elucidates the underlying mechanism, revealing that statins exploit Synthetic Lethality, a principle where the co-occurrence of two non-lethal events leads to cell death. Our computational analysis of approximately 37,000 SL pairs identified statins as potential drugs targeting genes involved in SL pairs with metastatic genes. In vitro validation on various cancer cell lines confirmed the anticancer efficacy of statins. This data-driven drug repurposing strategy provides a molecular basis for the anticancer effects of statins, offering translational opportunities in oncology.

The Efficacy of Medical Interventions for Free-Floating Thrombus in Cerebrovascular Events: A Systematic Review.

Although free-floating thrombus (FFT) poses a significant risk of stroke or transient ischemic attack (TIA), optimal management strategies are uncertain. To determine the state-of-the-art of medical interventions for FFT, we conducted a systematic review of the efficacy of various medical interventions and factors influencing FFT resolution and recurrence. A comprehensive search of Embase, PubMed, and ScienceDirect identified 61 studies encompassing 179 patients with FFT-related stroke or TIA treated with anticoagulants, antiplatelets, or their combinations. Primary outcomes assessed were stroke recurrence and thrombus resolution. Statistical analyses (Fisher's exact test, chi-square test, Mann-Whitney test, and Kruskal-Wallis test) utilized significance set at p < 0.05. Over a median follow-up of 7 months, thrombus resolution occurred in 65% of patients, while 11.2% experienced recurrence, primarily as TIAs. Cardioembolism was significantly less common in resolved cases (p = 0.025). Combination therapy (antiplatelets, anticoagulants, and statins) significantly enhanced clot resolution (OR 11.4; 95% CI 1.436-91.91; p = 0.021) compared to monotherapies. Ulcerated plaque was a significant predictor of recurrence (OR 8.2; 95% CI 1.02-66.07; p = 0.048). These findings underscore the superiority of combination therapy in FFT management and highlight the need for targeted interventions in patients with ulcerated plaques to mitigate recurrence risk.

The Association between Statin Use and Reduced Migraine Likelihood: A Comprehensive Analysis of Migraine Subtypes and Statin Types in a Nationwide Korean Cohort.

Despite growing interest in the preventive effects of statins, as lipid-lowering agents, on migraine attacks, comprehensive nationwide studies comparing migraine likelihood between statin users and controls are lacking. Our nested case-control study within the Korean National Health Insurance Service-Health Screening Cohort (2002-2019) investigated this association using 38,957 migraine patients and 155,828 controls, considering migraine subtypes (with/without aura) and statin types (lipophilic vs. hydrophilic). Using propensity score matching and adjusting for confounders, statin use was linked to reduced migraine likelihood overall (odds ratio (OR) 0.93), particularly for migraines with aura (OR 0.75) and without aura (OR 0.94). Lipophilic statins were effective for both subtypes, while hydrophilic statins mainly reduced the likelihood of migraines without aura. Subgroup analyses showed consistent benefits across demographics, but varied effectiveness based on weight, smoking, alcohol use, hemoglobin levels, and dyslipidemia history. In summary, this nationwide cohort study suggests that statin use may reduce migraine likelihood among Korean adults across diverse demographics and clinical profiles, but varied effectiveness based on certain lifestyle and comorbidity factors underscores the importance of considering individual patient profiles when assessing the potential benefits of statin therapy for migraine prevention.

Lipid control and stroke risk in atrial fibrillation patients treated with direct oral anticoagulants and statins.

INTRODUCTION: The risk of ischemic stroke and intracerebral hemorrhage (ICH) with intensive lipid control by statins among patients with atrial fibrillation (AF) who require direct oral anticoagulants (DOAC) is unclear. We aimed to determine the risks of ischemic stroke and ICH in AF patients treated with DOAC and statins. PATIENTS AND METHODS: In a population-based retrospective cohort study, we identified AF patients concurrently on DOAC and statins from 2015 to 2021 in Hong Kong. Primary outcome was ischemic stroke. Secondary outcomes were ICH and death. We correlated study outcomes with low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) as time-varying, continuous variables with restricted cubic spline. In secondary analyses, the risks of study outcomes with statin intensity (low, moderate, high) were determined by multivariable time-dependent marginal structural Cox models. RESULTS: We identified 32,752 AF patients co-prescribed with DOAC and statins. Lower LDL-C (p < 0.001) and higher HDL-C (p < 0.001) levels were associated with lower risk of ischemic stroke but not significantly associated with ICH. LDL-C of <1.8 mmol/L (70 mg/dL) was not associated with mortality (19.6% vs 18.4%, difference 1.2% [95% CI -0.35 to 2.13]). High-intensity statin was associated with a lower risk of ischemic stroke compared with low-intensity statin (weighted Cox-specific hazard ratio [95% CI]: 0.82 [0.67-0.99], p = 0.040) independent of LDL-C levels. Similar associations were found in 11,444 AF patients with a history of ischemic stroke. DISCUSSION AND CONCLUSION: Intensive lipid control by high-intensity statins was associated with a lower risk of ischemic stroke in AF patients who required DOACs and did not appear to increase the risk of ICH.

Role of gut microbiota and metabolomics in the lipid-lowering efficacy of statins among Chinese patients with coronary heart disease and hypercholesterolemia.

Background: Statins, being the primary pharmacological intervention for hypercholesterolemia, exhibit a notable degree of interpatient variability in their effectiveness, which may be associated with gut microbiota. This study sought to identify the biomarkers for evaluating differences in statin efficacy. Methods: A quasi case-control study was conducted among participants with hypercholesterolemia and coronary heart disease taking rosuvastatin essential. According to the level of low density lipoprotein cholesterol (LDL-C), participants was divided into the "Up to standard" (US) group and the "Below standard" (BS) group. 16S rDNA sequencing and untargeted metabolomics were applied to detected the information of gut microbiota and related metabolites. Results: A total of 8 US and 8 BS group matched by age and sex were included in the final analysis. 16S rDNA sequencing results indicated that the characteristic strains of the US group were f-Eubacterium_coprostanoligenes and g-Papillibacter, while the characteristic flora of the BS group were o-C0119, g-Pseudolabrys, s-Dyella-Marensis and f-Xanthobacaceae. Metabolomic results suggested that the levels of chenodeoxycholic acid-3-ß-D-glucuronide, 1-methylnicotinamide and acetoacetate in stool samples of the US group were significantly higher than those of the BS group. By identifying the differentially abundant bacterial taxa, the gut microbiota could modulate the efficacy of statins through producing enzymes involved in cholesterol metabolism. Conclusions: The findings suggest that the difference in statin efficacy may be related to gut microbiota strains that can produce short-chain fatty acids and secondary bile acids and affect the efficacy of statins by regulating the activities of cholesterol metabolite-related proteins. Metabolites related to short-chain fatty acids and secondary bile acids in the gut are expected to be biomarkers indicating the efficacy of statins.

Machine learning-based prediction model for the efficacy and safety of statins.

Objective: The appropriate use of statins plays a vital role in reducing the risk of atherosclerotic cardiovascular disease (ASCVD). However, due to changes in diet and lifestyle, there has been a significant increase in the number of individuals with high cholesterol levels. Therefore, it is crucial to ensure the rational use of statins. Adverse reactions associated with statins, including liver enzyme abnormalities and statin-associated muscle symptoms (SAMS), have impacted their widespread utilization. In this study, we aimed to develop a predictive model for statin efficacy and safety based on real-world clinical data using machine learning techniques. Methods: We employed various data preprocessing techniques, such as improved random forest imputation and Borderline SMOTE oversampling, to handle the dataset. Boruta method was utilized for feature selection, and the dataset was divided into training and testing sets in a 7:3 ratio. Five algorithms, including logistic regression, naive Bayes, decision tree, random forest, and gradient boosting decision tree, were used to construct the predictive models. Ten-fold cross-validation and bootstrapping sampling were performed for internal and external validation. Additionally, SHAP (SHapley Additive exPlanations) was employed for feature interpretability. Ultimately, an accessible web-based platform for predicting statin efficacy and safety was established based on the optimal predictive model. Results: The random forest algorithm exhibited the best performance among the five algorithms. The predictive models for LDL-C target attainment (AUC = 0.883, Accuracy = 0.868, Precision = 0.858, Recall = 0.863, F1 = 0.860, AUPRC = 0.906, MCC = 0.761), liver enzyme abnormalities (AUC = 0.964, Accuracy = 0.964, Precision = 0.967, Recall = 0.963, F1 = 0.965, AUPRC = 0.978, MCC = 0.938), and muscle pain/Creatine kinase (CK) abnormalities (AUC = 0.981, Accuracy = 0.980, Precision = 0.987, Recall = 0.975, F1 = 0.981, AUPRC = 0.987, MCC = 0.965) demonstrated favorable performance. The most important features of LDL-C target attainment prediction model was cerebral infarction, TG, PLT and HDL. The most important features of liver enzyme abnormalities model was CRP, CK and number of oral medications. Similarly, AST, ALT, PLT and number of oral medications were found to be important features for muscle pain/CK abnormalities. Based on the best-performing predictive model, a user-friendly web application was designed and implemented. Conclusion: This study presented a machine learning-based predictive model for statin efficacy and safety. The platform developed can assist in guiding statin therapy decisions and optimizing treatment strategies. Further research and application of the model are warranted to improve the utilization of statin therapy.

Research advances in the therapy of metabolic syndrome.

Metabolic syndrome refers to the pathological state of metabolic disorder of protein, fat, carbohydrate, and other substances in the human body. It is a syndrome composed of a group of complex metabolic disorders, whose pathogenesis includes multiple genetic and acquired entities falling under the category of insulin resistance and chronic low-grade inflammationand. It is a risk factor for increased prevalence and mortality from diabetes and cardiovascular disease. Cardiovascular diseases are the predominant cause of morbidity and mortality globally, thus it is imperative to investigate the impact of metabolic syndrome on alleviating this substantial disease burden. Despite the increasing number of scientists dedicating themselves to researching metabolic syndrome in recent decades, numerous aspects of this condition remain incompletely understood, leaving many questions unanswered. In this review, we present an epidemiological analysis of MetS, explore both traditional and novel pathogenesis, examine the pathophysiological repercussions of metabolic syndrome, summarize research advances, and elucidate the mechanisms underlying corresponding treatment approaches.

Exploiting the anti-fibrotic effects of statins on thoracic aortic aneurysm progression: results from a meta-analysis and experimental data.

Aims: Thoracic aortic aneurysm (TAA) that progress to acute aortic dissection is often fatal and there is no pharmacological treatment that can reduce TAA progression. We aim to evaluate statins' effects on TAA growth rate and outcomes using a meta-analysis approach. Methods and results: A detailed search related to the effects of statins on TAA was conducted according to PRISMA guidelines. The analyses of statins' effects on TAA growth rate were performed on 4 studies (n = 1850), while the impact on outcomes was evaluated on 3 studies (n = 2,867). Patients under statin treatment showed a reduced TAA growth rate (difference in means = -0.36 cm/year; 95%CI: -0.64, -0.08; p = 0.013) when compared to controls, patients not taking statins. Regarding the outcomes (death, dissection, or rupture of the aorta, and the need for operative repair), statins exhibited a protective effect reducing the number of events (log odds ratio = -0.56; 95%CI: -1.06, -0.05; p = 0.030). In vitro, the anti-fibrotic effect of atorvastatin was tested on vascular smooth muscle cells (VMSC) isolated from patients with TAA. Our results highlighted that, in transforming growth factor beta 1 (TGF-ß1) pro-fibrotic condition, VSMC expressed a significant lower amount of collagen type I alpha 1 chain (COL1A1) when treated with atorvastatin (untreated = +2.66 ± 0.23 fold-change vs. treated = +1.63 ± 0.09 fold-change; p = 0.014). Conclusion: Statins show a protective effect on TAA growth rate and adverse outcomes in patients with TAA, possibly via their anti-fibrotic properties on VSMC. Given the current lack of effective drug treatments for TAA, we believe our findings highlight the need for more in-depth research to explore the potential benefits of statins in this context.

Association of statins with peak oxygen consumption in 4,941 adults: A cross-sectional study.

Background and aims: Cardiovascular disease remains a leading cause of mortality, with statins widely used to reduce its risk. Despite extensive research, the nuanced impact of statin therapy on cardiorespiratory fitness, particularly the reduction in peak oxygen consumption (VO2), is still an open question. This study aims to contribute fresh insights to the ongoing discussion, highlighting the unresolved nature of this clinical matter. Methods: We retrospectively analyzed maximal cardiopulmonary exercise test (CPET) in male and female participants over 18 years of age who were under statins treatment. They were categorized as physically active or inactive according to self-report of physical activity. From 33,804 CPET, 4,941 participants (76 % men, age 42 ± 13 years; and 24 % women, age 41 ± 13 years) were included in the study. Results: The multivariate linear regression model showed that statins were associated with a significant reduction in VO2 peak (-4.2 [-4.8, -3.5] mL/kg/min, p < 0.01) after adjusting for age, sex, use of beta-blockers, antiarrhythmics, presence of diabetes, and weekly level of physical activity. This reduction in VO2 peak was attenuated in participants with higher weekly physical activity volume (150 to 300 min/week: 3.2 [2.7; 3.7] mL/kg/min; 301 to 600 min/week: 4.5 [3.7; 5.3] mL/kg/min; and > 600 min/week: 6.9 [5.4; 8.4] mL/kg/min, all p < 0.01). Conclusions: Statin use is associated with a lower VO2 peak in adults. However, this adverse effect appears to be mitigated by engaging in regular physical activity (>150 min/week). Future research should explore the mechanisms behind this interaction and identify optimal exercise regimens for individuals on statin therapy.

Aspirin but not statins is inversely related to gastric cancer with a duration-risk effect: Results from the Stomach Cancer Pooling Project Consortium.

BACKGROUND: Aspirin and statins have been suggested to have potential chemopreventive effects against gastric cancer (GC), although the results of previous studies have been inconsistent. This study therefore aimed to investigate the association between the use of aspirin and statins and GC. METHODS: A pooled analysis of seven case-control studies within the Stomach Cancer Pooling Project, including 3220 cases and 9752 controls, was conducted. Two-stage modeling analyses were used to estimate the association between aspirin and statin use and GC after adjusting for potential confounders. RESULTS: The pooled odds ratio (OR) of GC for aspirin users versus nonusers was 0.72 (95% confidence interval [CI], 0.54-0.95). The protective effect of aspirin appeared stronger in individuals without a GC family history (OR, 0.60; 95% CI, 0.37-0.95), albeit with borderline heterogeneity between those with and without a family history (p = .064). The OR of GC decreased with increasing duration of aspirin use, with an OR of 0.41 (95% CI, 0.18-0.95) for durations of ≥15 years. An inverse, nonsignificant association with the risk of GC was observed for the use of statins alone (OR, 0.79; 95% CI, 0.52-1.18). CONCLUSIONS: These findings suggest that aspirin use, particularly long-term use, is associated with a reduced risk of GC, whereas a similar association was not observed with statins, possibly because of the low frequency of use.

Statins for the prevention of cardiovascular events associated with avian influenza: the COVID-19 pandemic as a reference.

There is growing concern that the severe respiratory disease in birds (avian influenza or 'bird flu') caused by the H5N1 influenza virus, might potentially spread more widely to humans and cause a pandemic. Here we discuss clinical issues related to human infections by the highly pathogenic H5N1 subtype of the avian influenza A virus and make a clinical comparison with recent information obtained from studies of SARS-CoV-2 infection. Firstly, we consider the potential increase in cardiovascular events in humans infected with the H5N1 virus. Like SARS-CoV-2 infection, H5N1 infection may result in endothelial dysfunction and the associated procoagulant and prothrombotic state, and via this mechanism, the infection can potentially increase cardiovascular morbidity, especially in vulnerable individuals with pre-existing cardiovascular disease. Secondly, we discuss the potential beneficial role of statin use, both in the prophylaxis and the treatment of individuals with influenza A(H5N1), as was found favorable for the treatment of COVID-19 caused by SARS-CoV-2 infection.

There is a concern that avian influenza caused by the highly pathogenic avian influenza A(H5N1) virus might potentially spread more widely to humans and result in a pandemicH5N1 infection may result in endothelial dysfunction and via this mechanism, it can potentially increase cardiovascular morbidity and mortality as has occurred with SARS-CoV-2 infection.There is a potential advantage of the use of statins to reduce cardiovascular morbidity and mortality in patients with avian influenza A(H5N1), as has been found in patients suffering from COVID-19.

Evidence of an effect of statins on lesions originating from dental infection. A retrospective clinical investigation.

BACKGROUND: Apical periodontitis (AP) is an inflammatory dental disease caused by bacterial infections of the endodontic system. The correlation between AP and cardiovascular diseases. (CVD) has been consistently investigated. Statins are a class of drugs that are used to treat hypercholesterolemia and prevent atherosclerotic vascular diseases. They have other beneficial pleiotropic effects such as anti-inflammatory, antithrombotic, and antioxidant activities. The aim of this study was to evaluate the oral health status and prevalence of AP in patients treated with statins (Group S) in comparison with untreated patients (Group C) to understand whether the anti-inflammatory action of these drugs can influence the prevalence of AP. METHODS: The records of seventy-nine patients (43 men and 36 women, mean age 68 ± 11 years, 1716 teeth) treated with statins and referred to the University clinic for dental evaluation were reviewed. Seventy patients free from systemic diseases and without therapy (39 men and 31 women, mean age 62 ± 9 years, 1720 teeth) constituted the control group. All subjects underwent complete oral, dental, and radiographic examinations to determine the presence and severity of AP. Periapical index (PAI) and decayed, missed, and filled teeth (DMFT) scores were obtained. RESULTS: AP was significantly less common in Group S (22,8%) than in Group C (50%) (P < 0.05). Furthermore, the mean value of the qualitative rank of the severity of AP (PAI score) was higher in Group C than in Group S (P ≤ 0.05). CONCLUSIONS: Our results suggest that statins can attenuate the prevalence of AP, which is associated to CVD.

Rosuvastatin ameliorates chemically induced acute lung injury in rats by targeting ferroptosis, heat shock protein B1, and inflammation.

Acute lung injury (ALI) is a life-threatening condition characterized by respiratory failure. Rosuvastatin (RSV) is an antihypercholesterolemic agent with antioxidant properties. The current study aimed to investigate RSV novel therapeutic impact on ALI with emphasis on oxidative stress, inflammation, and heat shock protein B1 (HSPB1). Male albino rats (N = 30) were divided into five groups. Normal control (NC) group: rats received normal saline 2 mL/kg P.O daily. Lipopolysaccharides (LPS) group: rats received LPS (3 mg/kg intraperitoneally once). RSV group: rats received RSV (2 mg/kg P.O daily). LPS + RSV group: rats received RSV as in group 3 and on the 7th day rats received LPS as group 2. LPS + Dexamethasone (DX): rats received DX (2 mg/kg P.O, daily for one week) and on the 7th day rats received LPS as group 2. At the end of experiment (one week), lung tissue was used to determine HSPB1, high mobility group box 1 (HMGB1) using ELISA. IL-6, nuclear factor-2 (Nrf2), haem Oxygenase-1 (HO-1) protein levels were assessed using immunohistochemistry. GSH, catalase, MDA, NO, albumin and urea are assessed by colorimetry. The results revealed that RSV treatment resolved histopathological changes in lung tissue induced by LPS. Compared to LPS group, LPS + RSV group showed significant decrease in urea, NO, MDA, HMGB1, IL-6 and HO-1 level compared to LPS-treated rats. Conversely, RSV treatment significantly increased HSPB1, Nrf2, albumin, GSH, and CAT levels compared to LPS rats. RSV is effective for amelioration of ALI and thus can be used as adjuvant therapy for ALI.

Incidence of prostate, colorectal and male breast cancers in relation with statins and testosterone replacement therapy: SEER-Medicare 2007-2015.

INTRODUCTION: Statins and testosterone replacement therapy (TTh) have been inconsistently associated with a reduced risk of hormone-related cancers (HRCs, prostate [PCa], colorectal [CRC], and male breast cancers [BrCa]). Yet, the joint association of statins and TTh with the incidence of these cancers, and whether these associations vary by race, remains poorly understood. The objective of this retrospective cohort study is to examine the independent and joint effects of pre-diagnostic use of statins and TTh on the risk of HRCs, including PCa, CRC, and male BrCa. MATERIALS: and Methods: In 105,690 men (≥65 yrs) identified using the SEER-Medicare 2007-2015 data, we identified 82,578 White and 10,256 Black men. Pre-diagnostic prescription of statins and TTh was ascertained for this analysis and categorized into four groups (Neither users, statins alone, TTh alone and Dual users). Multivariable Time-varying Cox proportional hazards and Accelerated Failure Time (AFT) models were performed. RESULTS: We found inverse joint associations of statins and TTh with incident HRCs before (aHR: 0.39; 95 % CI: 0.35-0.44) and after 3 years of follow-up (aHR: 0.74; 95 % CI: 0.67-0.82). This included a lower risk for advanced stage HRC (only <3 years follow-up). Similar joint associations were identified with incident PCa, aggressive PCa, incident CRC, and its specific right- and left-sided CRC (only <3 years follow-up). In general, the inverse associations persisted among White (mainly <3 years follow-up) and Black men (high-grade HRC and <3 years follow-up). Findings from the AFT analysis were similar. DISCUSSION: Pre-diagnostic use of statins and TTh were, independently and jointly, associated with reduced risks of HRC and specific cancer sites at three years of follow-up overall, and among White and Black men. Greatest associations of HRCs risk reduction were observed among dual users (statins plus TTh). Further studies are needed to validate these findings, including larger samples of Black men, and male BrCa sites.

Evaluation of infectious diseases physicians' attitudes to dyslipidemia management in PLWH.

OBJECTIVES: Dyslipidemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). ASCVD prevalence among people living with HIV (PLWH) is twice that of the general population. This study aimed to evaluate the infectious diseases (ID) physicians' attitudes on dyslipidemia management in PLWH. METHODS: This observational, cross-sectional study was conducted as online survey among ID physicians between November 2023 and February 2024. An e-mail with the survey link, title and purpose of the study was sent to physicians through the local ID societies. The survey included questions about physicians' demographic characteristics and their attitudes toward treating dyslipidemia in PLWH. RESULTS: A total of 242 physicians responded to the survey, of whom 59.9% (n = 145) were ID specialists and 40.1% (n = 97) were ID residents. Forty-one percent (n = 100) of physicians reported that they did not follow a guideline, and 26% of physicians reported that they did not use a cardiovascular risk calculator in their clinical practice. Specialists (69%) were more likely than residents (43.3%) to follow clinical guidelines for dyslipidemia management (p < 0.001). Seventy-two percent (n = 174) of physicians doubted the need to treat dyslipidemia, and 73% (n = 177) of physicians were affected by the patient skepticism. Workload and lack of time were identified by 68.6% of physicians as barriers to implementing dyslipidemia guideline recommendations. CONCLUSION: A considerable number of Turkish ID physicians did not prefer using clinical guidelines for dyslipidemia and ASCVD risk calculators. Statin prescribing of physicians was influenced by workload, lack of time, patient skepticism, and lack of knowledge. Training ID physicians in primary prevention of ASCVD and management of dyslipidemia in PLWH is paramount.

KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment.

BACKGROUND: The KCNJ16 gene has been associated with a novel kidney tubulopathy phenotype, viz. disturbed acid-base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistic links between Kir5.1 and tubulopathy, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advanced in vitro human kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the tubulopathy and potential therapeutic interventions. METHODS: We used CRISPR/Cas9 to generate KCNJ16 mutant (KCNJ16+/- and KCNJ16-/-) cell lines from healthy human induced pluripotent stem cells (iPSC) KCNJ16 control (KCNJ16WT). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air-liquid interface. RESULTS: KCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated that KCNJ16-/- organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition in KCNJ16-/- kidney organoids. CONCLUSIONS: Mature kidney organoids represent a relevant in vitro model for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney.

Prognostic impact of high-intensity lipid-lowering therapy under-prescription after acute myocardial infarction in women.

AIMS: Women are less likely to receive lipid-lowering therapy (LLT) after acute myocardial infarction (AMI). We analysed whether this under-prescription currently persists and has an impact on long-term outcomes. METHODS AND RESULTS: The FAST-MI programme consists of nationwide registries including all patients admitted for AMI ≤ 48 h from onset over a 1 month period in 2005, 2010, and 2015, with long-term follow-up. This analysis focused on high-intensity LLT (atorvastatin ≥ 40 mg or equivalent, or any combination of statin and ezetimibe) in women and men. Women accounted for 28% (N = 3547) of the 12 659 patients. At discharge, high-intensity LLT was significantly less prescribed in women [54 vs. 68% in men, P < 0.001, adjusted odds ratio (OR) 0.78(95% confidence interval (CI) 0.71-0.87)], a trend that did not improve over time: 2005, 25 vs. 35% (P = 0.14); 2010, 66 vs. 79% (P < 0.001); 2015, 67 vs. 79.5% (P = 0.001). In contrast, female sex was not associated with a lack of other recommended treatments at discharge: beta-blockers [adjusted OR 0.98(95% CI 0.88-1.10), P = 0.78], or renin-angiotensin blockers [adjusted OR 0.94(95% CI 0.85-1.03), P = 0.18]. High-intensity LLT at discharge was significantly associated with improved 5 year survival and infarct- and stroke-free survival in women [adjusted hazard ratios (HR) 0.74(95% CI 0.64-0.86), P < 0.001 and adjusted HR: 0.81(95% CI: 0.74-0.89); P < 0.001, respectively]. Similar results were found using a propensity score-matched analysis [HR for 5 year survival in women with high-intensity LLT: 0.82(95% CI 0.70-0.98), P = 0.03]. CONCLUSION: Women suffer from a bias regarding the prescription of high-intensity LLT after AMI, which did not attenuate between 2005 and 2015, with potential consequences on both survival and risk of cardiovascular events.

Lipid-lowering therapy (LLT) is under-prescribed in women after acute myocardial infarction (AMI). Whether this difference persists over time and influences long-term outcomes is unclear. Women still suffer from insufficient prescription of high-intensity LLT at discharge after an AMI, even in the most recent years of the study, with a 5 year survival significantly reduced in women who did not receive high-dose LLT Propensity score matched analysis showed similar results on survival and cardiovascular events.

Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer.

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.