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[This corrects the article DOI: 10.1371/journal.pone.0303869.].

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels ( p  = 0.0006, CI 95%: 4.12, 13.32) and particle number ( p  = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration ( p  = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity ( p  = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele. Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.

Background The aberrantly increased proliferation and migration of vascular smooth muscle cells (VSMCs) was critically associated with atherosclerosis (AS) progression. MiR-197-3p has been confirmed to regulate various biological processes, such as tumorigenesis; however, whether miR-197-3p is involved with the pathological development of AS remains largely unknown. Methods The serum levels of miR-197-3p in AS patients and healthy donors were determined by polymerase chain reaction (PCR) assay. The transfection efficacies of miR-197-3p mimic or inhibitor in VSMCs were evaluated by PCR assay. The effects of miR-197-3p on VSMC proliferation and migration were determined by EdU cell proliferation and Traswell migration assays. Western blotting was conducted to evaluate the effect of miR-197-3p on WDR5 expression in VSMCs. Results In the present study, we found that the expression of miR-197-3p was decreased in the serum of AS patients compared to healthy donors. Overexpression of miR-197-3p inhibited the proliferation and migration of VSMCs, while silencing miR-197-3p showed opposite effects. Mechanistical study revealed that WD Repeat Domain 5 (WDR5) was a target of miR-197-3p. Moreover, miR-197-3p was downregulated in VSMCs upon IL6 treatment and inhibited IL6-induced proliferation and migration in VSMCs. Conclusions These findings indicate that miR-197-3p could serve as a promising diagnostic marker for AS and that targeting IL6/miR-197-3p/WDR5 axis might be a potential approach to treat AS.

IntroductionThe diagnosis of large vessel occlusion (LVO) with underlying intracranial atherosclerotic disease (ICAD) before endovascular treatment (EVT) continues to be a challenge.AimWe aimed to analyze baseline clinical-radiological variables associated with ICAD-LVO before EVT.MethodsRetrospective study of consecutive patients with stroke treated with EVT from January-2020 to April-2022. We included anterior intracranial LVO (ICA, MCA-M1,2) and analyzed baseline clinico-radiological variables associated with ICAD-LVO. We evaluated the diagnostic value of a multivariate regression model and a weighted scale to diagnose ICAD-LVO before EVT. ICAD-LVO was defined as the presence of angiographic residual stenosis or a trend to re-occlusion during EVT.ResultsOf 338 patients included, 28 patients (8.3%) presented with ICAD-LVO. After adjusting for confounders, absence of atrial fibrillation (OR 10.19, 95%CI 1.12–86.6; p=0.033), lower hypoperfusion intensity ratio (HIR [Tmax>10s/Tmax>6s ratio], OR 0.02, 95%CI 0.00–0.41; p=0.013), presence of symptomatic intracranial artery calcification (IAC, OR 6.94, 95%CI 1.69–28.45, p=0.007), presence of a more proximal occlusion (ICA, MCA-M1: OR 3.16, 95%CI 1.03–9.67; p=0.044) and smoking (OR 3.26, 95%CI 1.21–8.75; p=0.019) were associated with ICAD-LVO. A weighted scale based on the covariates such as HIR (3points), absence of AF (2p), IAC (1p), occlusion location (1p) and smoking (1p) predicted ICAD-LVO with good accuracy (AUC=0.88, 95%CI 0.83–0.94; p<0.001).ConclusionA combination of clinical and radiological variables available before EVT can accurately predict the presence of an ICAD-LVO. The ICAD-Scale could be useful to perform a rapid assessment of underlying etiology and suggest specific pathophysiology-based measures (adjunctive pharmacological treatment, angioplasty and/or intracranial stenting).Disclosure of InterestDr Molina reported receiving personal fees from AstraZeneca for consultant services outside the submitted work. Dr Tomasello reported receiving personal fees from Anaconda Biomed, Balt, Medtronic, Perflow, and Stryker outside the submitted work. Dr Ribo reported receiving personal fees from Anaconda Biomed, AptaTargets, Cerenovus, Medtronic, Methinks, Philips, Sanofi, Stryker, Balt, and Rapid AI outside the submitted work; he has a modest ownership of NoraHealth. The other authors report no conflicts. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Angiopoietin-like 3 (ANGPTL3) inhibits endothelial lipase and lipoprotein lipase. Injection of antisense oligonucleotides targeting ANGPTL3 messenger RNA effects a reduction of atherogenic lipoproteins in humans and mice and a slowing of progression of atherosclerosis in mice.

In a randomized trial involving patients at high cardiovascular risk, the cholesteryl ester transfer protein inhibitor obicetrapib reduced low-density lipoprotein cholesterol levels by 29.9% at 84 days.

This study explored the effect of a moderate (90 g/d) low-carbohydrate diet (LCD) in type 2 diabetes patients over 18 months. Ninety-two poorly controlled type 2 diabetes patients aged 20-80 years with HbA1c ≥7.5% (58 mmol/mol) in the previous three months were randomly assigned to a 90 g/d LCD r traditional diabetic diet (TDD). The primary outcomes were glycaemic control status and change in medication effect score (MES). The secondary outcomes were lipid profiles, small, dense low-density lipoprotein (sdLDL), serum creatinine, microalbuminuria and carotid intima-media thickness (IMT). A total of 85 (92.4%) patients completed 18 months of the trial. At the end of the study, the LCD and TDD group consumed 88.0±29.9 g and 151.1±29.8 g of carbohydrates, respectively (p < 0.05). The 18-month mean change from baseline was statistically significant for the HbA1c (-1.6±0.3 vs. -1.0±0.3%), 2-h glucose (-94.4±20.8 vs. -18.7±25.7 mg/dl), MES (-0.42±0.32 vs. -0.05±0.24), weight (-2.8±1.8 vs. -0.7±0.7 kg), waist circumference (-5.7±2.7 vs. -1.9±1.4 cm), hip circumference (-6.1±1.8 vs. -2.9±1.7 cm) and blood pressure (-8.3±4.6/-5.0±3 vs. 1.6±0.5/2.5±1.6 mmHg) between the LCD and TDD groups (p<0.05). The 18-month mean change from baseline was not significantly different in lipid profiles, sdLDL, serum creatinine, microalbuminuria, alanine aminotransferase (ALT) and carotid IMT between the groups. A moderate (90 g/d) LCD showed better glycaemic control with decreasing MES, lowering blood pressure, decreasing weight, waist and hip circumference without adverse effects on lipid profiles, sdLDL, serum creatinine, microalbuminuria, ALT and carotid IMT than TDD for type 2 diabetic patients.

Emerging evidence has spurred a considerable evolution of concepts relating to atherosclerosis, and has called into question many previous notions. Here I review this evidence, and discuss its implications for understanding of atherosclerosis. The risk of developing atherosclerosis is no longer concentrated in Western countries, and it is instead involved in the majority of deaths worldwide. Atherosclerosis now affects younger people, and more women and individuals from a diverse range of ethnic backgrounds, than was formerly the case. The risk factor profile has shifted as levels of low-density lipoprotein (LDL) cholesterol, blood pressure and smoking have decreased. Recent research has challenged the protective effects of high-density lipoprotein, and now focuses on triglyceride-rich lipoproteins in addition to low-density lipoprotein as causal in atherosclerosis. Non-traditional drivers of atherosclerosis—such as disturbed sleep, physical inactivity, the microbiome, air pollution and environmental stress—have also gained attention. Inflammatory pathways and leukocytes link traditional and emerging risk factors alike to the altered behaviour of arterial wall cells. Probing the pathogenesis of atherosclerosis has highlighted the role of the bone marrow: somatic mutations in stem cells can cause clonal haematopoiesis, which represents a previously unrecognized but common and potent age-related contributor to the risk of developing cardiovascular disease. Characterizations of the mechanisms that underpin thrombotic complications of atherosclerosis have evolved beyond the ‘vulnerable plaque’ concept. These advances in our understanding of the biology of atherosclerosis have opened avenues to therapeutic interventions that promise to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases. This Review discusses recent research that has transformed our understanding of the biology of atherosclerosis, and examines its implications for the treatment of atherosclerotic cardiovascular disease.

Background Previous studies reported the prognostic value of the atherogenic index of plasma (AIP) in the course of atherosclerosis and other cardiovascular diseases (CVDs). Still, the predictive utility of the AIP is unknown among patients with type 2 diabetes mellitus (T2DM). Methods This was a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which randomized 10,251 patients with long-lasting T2DM. ROC curve analysis was used to determine an optimal threshold for AIP, and the study population was divided into high and low AIP groups. Univariable and multivariable Cox proportional hazards regression analyses were used to determine the association between AIP and primary (major adverse cardiovascular events [MACEs], including nonfatal myocardial infarction, nonfatal stroke, and/or death from cardiovascular causes) and secondary outcomes (all-cause mortality). Stratified analyses were performed to control for the confounding factors. Results AIP was an independent risk factor for the prognosis of T2DM (HR = 1.309; 95% CI 1.084–1.581; P  = 0.005). The threshold for AIP was determined to be 0.34 in the study population. After adjustments for confounding factors, multivariable analysis showed that AIP was associated with the risk of MACEs (Model 1: HR = 1.333, 95% CI 1.205–1.474, P  < 0.001; Model 2: HR = 1.171, 95% CI 1.030–1.333, P  = 0.016; Model 3: HR = 1.194, 95% CI 1.049–1.360, P  = 0.007), all-cause mortality (Model 1: HR = 1.184, 95% CI 1.077–1.303, P  < 0.001), cardiovascular death (Model 1: HR = 1.422, 95% CI 1.201–1.683, P  < 0.001; Model 3: HR = 1.264, 95% CI 1.015–1.573, P  = 0.036), and nonfatal myocardial infarction (Model 1: HR = 1.447, 95% CI 1.255–1.669, P  < 0.001; Model 2: HR = 1.252, 95% CI 1.045–1.499, P  = 0.015; Model 3: HR = 1.284, 95% CI 1.071–1.539, P  = 0.007). Subgroup stratified analyses showed that AIP might interact with sex, a classical risk factor of cardiovascular events. Conclusions This study showed that AIP might be a strong biomarker that could be used to predict the risk of cardiovascular events in patients with T2DM. Trial registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620.