Psoriasis is an immune-mediated pro-inflammatory skin condition that is associated with an increase in risk factors for cardiovascular disease, risk of ischemic heart disease, and cardiovascular death. Despite this, traditional modifiable atherosclerotic cardiovascular disease (ASCVD) risk factors are underdiagnosed and undertreated in patients with psoriasis.

At a cellular level, psoriasis and atherosclerosis are driven by a host of shared inflammatory pathways, such as pro-inflammatory cytokines (TNF, IL-6), immune cells, and platelets which act synergistically to drive endothelial damage and atherosclerosis progression.

Optimal prevention of cardiovascular disease in psoriasis centers around modifying known risk factors for the development of ASCVD and emerging data highlight the promise of treating inflammation to further decrease the risk of ASCVD.

Coronary atherosclerosis in patients with diabetes mellitus is the most significant pathophysiological mechanism responsible for ischemic heart disease. Atherosclerosis in diabetes is premature, more diffuse, and more progressive, and it affects more coronary blood vessels compared to non-diabetics. Atherosclerosis begins with endothelial dysfunction, continues with the formation of fatty streaks in the intima of coronary arteries, and ends with the appearance of an atherosclerotic plaque that expands centrifugally and remodels the coronary artery. If the atherosclerotic plaque is injured, a thrombus forms at the site of the damage, which can lead to vessel occlusion and potentially fatal consequences. Diabetes mellitus and atherosclerosis are connected through several pathological pathways. Among the most significant factors that lead to atherosclerosis in diabetics are hyperglycemia, insulin resistance, oxidative stress, dyslipidemia, and chronic inflammation. Chronic inflammation is currently considered one of the most important factors in the development of atherosclerosis. However, to date, no adequate anti-inflammatory therapeutic measures have been found to prevent the progression of the atherosclerotic process, and they remain a subject of ongoing research. In this review, we summarize the most significant pathophysiological mechanisms that link atherosclerosis and diabetes mellitus.

Background: Metabolic syndrome is a complex disorder characterized by the coexistence of multiple risk factors, including dysglycemia, hypertension, dyslipidemia, and visceral obesity. Both metabolic syndrome and diabetes mellitus are closely associated with the onset of microvascular complications such as retinopathy, polyneuropathy, and nephropathy. Methods: This narrative review analyzed 137 studies published up to 2025, retrieved from PubMed and Crossref databases. The objective was to identify and evaluate potential biomarkers that could facilitate the early detection of microvascular complications in patients with metabolic syndrome. Results: Several biomarkers demonstrated a strong correlation with microvascular complications in individuals with metabolic syndrome. These findings suggest their potential role in early diagnosis and risk assessment. Conclusions: The identification of reliable biomarkers may enhance early detection and targeted interventions for microvascular complications in metabolic syndrome. Further research is essential to validate these markers and establish their clinical applicability in routine medical practice.

Anemia of chronic kidney disease is a multifactorial condition secondary to various etiologies, including nutritional deficiencies, chronic inflammation, erythropoietin deficiency or resistance, bone marrow suppression, iron deficiency and adverse drug effects. The major therapeutic intervention for anemia among chronic kidney disease patients is erythropoiesis-stimulating agents. However, a limitation of erythropoiesis-stimulating agents is the risk for thromboembolic events, hypertension, seizures, solid organ malignancies and hyporesponsiveness. A novel interleukin-6 monoclonal antibody, ziltivekimab, has been evaluated for managing anemia in chronic kidney disease patients in pilot clinical trials with promising outcomes, including an improvement in hemoglobin levels and reduction of inflammatory parameters. These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. Furthermore, potentially beneficial effects on serum lipid profile have been reported, leading to the hypothesis of a favorable impact of the drug on atherosclerotic complications. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way.

Atrial fibrillation (AF) is more prevalent in patients with elevated interleukin (IL)-1β levels. Here we show that daily administration of IL-1β for 15 days sensitizes mice to AF, leading to fibrosis, accumulation of β-pleated sheet proteins in the left atrium, and systemic inflammation, resembling the pathophysiological changes observed in patients with AF. IL-1β administration creates a positive feedback loop, dependent on the IL-1 receptor (IL-1R) activity in cardiac resident macrophages. This results in increased caspase-1 maturation in the left atrium and elevated Il1b and Casp1 transcription in atrial macrophages. IL-1β treatment accelerated action potential and Ca2+ restitution in the left atrium, leading to action-potential shortening. This, along with increased caspase-1 maturation and IL-1R signaling, was essential for inducing AF. Lack of IL-1R in macrophages, but not cardiomyocytes, prevented IL-1β-induced AF sensitivity. By depleting recruited macrophages or deleting IL-1R specifically in cardiac resident macrophages, we further demonstrate that IL-1β/IL-1R signaling in these resident macrophages is responsible for increased AF susceptibility. These findings offer insights into the therapeutic potential of targeting IL-1β/IL-1R signaling in patients with AF and emphasize the importance of recognizing different underlying causes in this patient group.

Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.

Current therapies for diabetes and atherosclerotic cardiovascular diseases (ACVDs) mainly target metabolic risk factors, but often fall short in addressing systemic inflammation, a key driver of disease onset and progression. Advances in our understanding of the biology of neutrophils, the cells that are principally involved in inflammatory situations, have highlighted their pivotal role in cardiometabolic diseases. Yet, neutrophils can reprogram their immune-metabolic functions based on the energetic substrates available, thus influencing both tissue homeostasis and the resolution of inflammation. In this review, we examine the effects of canonical therapies for cardiometabolic diseases on the key molecular pathways through which neutrophils respond to inflammatory stimuli. In addition, we explore potential synergies between these established therapeutic approaches and the anti-inflammatory therapies being evaluated for repurposing in the treatment of cardiometabolic diseases.

The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD).

Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines.

A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (β, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (β, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (β, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (β, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (β, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (β, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc.

Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Sterile inflammation has been increasingly recognized as a hallmark of non-infectious kidney diseases. Induction of pro-inflammatory cytokines in injured kidney tissue promotes infiltration of immune cells serving to clear cell debris and facilitate tissue repair. However, excessive or prolonged inflammatory response has been associated with immune-mediated tissue damage, nephron loss, and development of renal fibrosis. Interleukin 6 (IL-6) is a cytokine with pleiotropic effects including a major role in inflammation. IL-6 signals either via membrane-bound (classic signaling) or soluble receptor forms (trans-signaling) thus affecting distinct cell types and eliciting various metabolic, cytoprotective, or pro-inflammatory reactions. Antibodies neutralizing IL-6 or its receptor have been developed for therapy of autoimmune and chronic non-renal inflammatory diseases. Small molecule inhibitors of Janus kinases acting downstream of the IL-6 receptor, as well as recombinant soluble glycoprotein 130 variants suppressing the IL-6 trans-signaling add to the available therapeutic options. Animal data and accumulating clinical experience strongly suggest that suppression of IL-6 signaling pathways bears therapeutic potential in acute and chronic kidney diseases. The present work analyses the renoprotective potential of clinically relevant IL-6 signaling inhibitors in acute kidney injury, chronic kidney disease, and kidney transplantation with focus on current achievements and future prospects.

This study aims to investigate how the impact of preoperative sarcopenia and inflammatory markers for laryngeal cancer patients and develop a new scoring system to predict their prognosis.

Patients who underwent laryngectomy for laryngeal cancer (LC) from December 2015 to December 2020 at the Second Affiliated Hospital of Fujian Medical University were included. Independent prognostic factors were determined using univariate and multivariate analyses. A new scoring system (SFAR) was established based on FAR and preoperative sarcopenia, and statistically analyzed.

198 cases included in this study that met the admission criteria. Multivariate analysis shown that preoperative sarcopenia, pTNM stage, and FAR were independent prognostic factors for laryngeal cancer. Based on these three indicators, we developed the SFAR scoring system. Multivariate analysis showed that SFAR was an independent predictor of laryngeal cancer (p < 0.001). SFAR was then incorporated into a prognostic model that included T-stage and N-stage, and a column-line graph was generated to accurately predict its survival.

Systemic inflammation and sarcopenia are significantly associated with postoperative prognosis in laryngeal cancer. A new scoring system (SFAR) had implications for improving the prognosis of patients undergoing surgery for laryngeal cancer.

Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events.

The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD.

The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set.

RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events.

Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence.

We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I² = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I² = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I² = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I² = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I² = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I² = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I² = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I² = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I² = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I² = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I² = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I² = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I² = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I² = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I² = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I² = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I² = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I² = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I² = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I² = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I² = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I² = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I² = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I² = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I² = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I² = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting.

This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.

In this review, we aimed to summarize the different aspects of the field of cardio-rheumatology, the role of the cardio-rheumatologist, and future research in the field.

Cardio-rheumatology is an emerging subspecialty within cardiology that focuses on addressing the intricate relationship between systemic inflammation and cardiovascular diseases. It involves understanding the cardiovascular impact of immune-mediated inflammatory diseases on the heart and vascular system. A cardio-rheumatologist's role is multifaceted. First, they should understand the cardiac manifestations of rheumatological diseases. They should also be knowledgeable about the different immunotherapies available and side effects. Additionally, they should know how to utilize imaging modalities, either for diagnosis, prognosis, or treatment monitoring. This field is constantly evolving with new research on both treatment and imaging of the effects of inflammation on the cardiovascular system.

Adding intensive low-density lipoprotein cholesterol (LDL-C)-lowering agents or colchicine to statin has been shown to result in additional cardiovascular benefits for patients with atherosclerotic cardiovascular diseases (ASCVD). We aimed to compare the efficacy and safety of these supplementary agents in patients with ASCVD receiving statin.

We performed a systematic review and frequentist network meta-analysis of randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death, and all-cause mortality, respectively. The safety endpoints were treatment discontinuation and non-cardiovascular death. We obtained estimates for efficacy outcomes and safety endpoints and presented these estimates as risk ratio (RR) with 95% confidence intervals. We ranked the comparative efficacy and safety of all drugs with P-scores.

Seventeen trials totaling 85,823 participants treated with colchicine (5926 participants), intensive LDL-C lowering (37,854 participants) via proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor or ATP citrate lyase (ACL) inhibitor, or statin alone (42,043 participants) were included. Colchicine was associated with a greater reduction in the risk of MACE (RR 0.72, 0.69-0.91), stroke (RR 0.55, 0.33-0.92), and coronary revascularization (RR 0.73, 0.60-0.90) compared with NPC1L1 inhibitor, and it provided a larger reduction in the risk of MACE (RR 0.79, 0.69-0.91) compared to PCSK9 inhibitor. However, colchicine was associated with increased risk of non-cardiovascular death compared with NPC1L1 inhibitor (RR 1.48, 1.04-2.10) and PCSK9 inhibitor (RR 1.57, 1.08-2.27). Although no regimen prolonged survival, colchicine had worse performance on non-cardiovascular death and all-cause mortality.

In patients with ASCVD receiving statin, colchicine seems to be more effective than intensive LDL-C-lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor for cardiovascular prevention. However, using colchicine as an alternative to intensive LDL-C-lowering therapy may need to be weighed against the cardiovascular benefits and the potential harms of higher non-cardiovascular death.

PROSPERO Identifier: CRD42023441385.

The neutrophil-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) are emerging inflammatory markers related to cardiovascular outcomes. This study investigated their relationships with cardiovascular disease (CVD) and mortality among individuals with prediabetes or diabetes and assessed their predictive roles.

A cohort of 6871 individuals with diabetes or prediabetes from the NHANES (2001-2018) was included. Weighted multivariate logistic regression models assessed NLR and SII associations with CVD risk, while survey-weighted Cox proportional hazards models evaluated their links to mortality. The predictive accuracy of the biomarkers for mortality was quantified by receiver-operating characteristic (ROC) curve analysis.

Individuals in the higher NLR and SII groups exhibited a high incidence of CVD. A total of 1146 deaths occurred throughout an average follow-up duration of 191 months, of which 382 were caused by CVD. Participants with higher NLR markedly increased the risk of all-cause (HR = 1.82) and cardiovascular mortality (HR = 2.07). A similar result was observed in the higher SII group. RCS analysis identified a linear correlation between NLR and CVD risk and mortality (p > 0.05), while SII showed a nonlinear correlation (p < 0.05). ROC results demonstrated that NLR exhibited a higher predictive ability in mortality than SII.

Elevated levels of NLR and SII correlated with an increased risk of CVD and both all-cause and cardiovascular mortality in individuals with diabetes or prediabetes. The NLR appears to be particularly valuable for assessing risk and predicting outcomes in these patients.

The triglyceride-glucose (TyG) index is linked to both the development and progression of diabetes, while obesity remains a significant risk factor for this disease. However, the relationship between the TyG index and overweight or obese diabetes remains unclear.

This study was a cross-sectional analysis of data from 40,633 participants with body mass index (BMI) ≥ 24 kg/m2 who were screened from January 2018 to December 2023 at Henan Provincial People's Hospital. Participants were divided into groups of overweight or obese individuals with diabetes and those without diabetes according to the diabetes diagnostic criteria. The TyG index, the dependent variable, was determined using the equation ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. We explored the association between TyG index and diabetes in overweight or obese individuals through multivariate logistic regression, subgroup analysis, generalized additive models, smoothed curve fitting, and analysis of threshold effects.

Patients who were overweight or obese and had diabetes had higher TyG index levels than those without diabetes. After adjusting for confounders, our findings indicated a significant association between the TyG index and the risk of diabetes in overweight or obese individuals [odds ratio (OR) = 7.38, 95% confidence interval (CI): 6.98-7.81]. There was a J-shaped nonlinear association between TyG index and diabetes. When TyG index was > 4.46, the risk of diabetes increased sharply. Notably, a high baseline TyG index (Q4 group) correlated with a notably greater risk of diabetes than did the Q1 group, with an OR of 22.72 (95% CI: 20.52-25.16). Subgroup analysis revealed that the association between TyG and diabetes was stronger in females than in males (OR = 7.57, 95% CI: 6.76-8.48,), more significant in individuals with a BMI of 24-28 kg/m2 than in those with a BMI ≥ 28 kg/m2 (OR = 8.40, 95% CI: 7.83-9.02), and increased with age (OR = 8.15, 95% CI: 7.25-9.17) (all P for interaction < 0.001).

Among overweight or obese individuals, a higher TyG index is associated with an elevated risk of diabetes, especially when TyG is > 4.46. Furthermore, factors such as sex, age, and BMI significantly influence the risk of diabetes in overweight or obese individuals. Specifically, older women with a BMI of 24-28 kg/m2 are at a greater risk of diabetes under similar TyG index conditions.

Today, diabetes mellitus (DM) is one of the leading causes of morbidity and mortality globally.In this grim context, while our current armamentarium of anti-diabetic agents is vast and increasingly available, glycemic control in a significant proportion of these patients continues to remain sub-optimal.This necessitates the exploration of other potential cellular pathways and targets to effectively manage this notorious disease and its numerous complications. Inflammatory responses are thought to be implicated in the decline of pancreatic beta-cell function, with interleukin-1 beta (IL-1β) playing an important role in these pathways. Canakinumab, a human monoclonal anti-IL-1β antibody, operates by reducing inflammation, potentially safeguarding or enhancing pancreatic beta-cell function. This systematic review aims to study the safety and efficacy of canakinumab in the prevention and control of type 2 diabetes mellitus (T2DM) and its complications. This study was conducted in accordance with the PRISMA 2020 Guidelines. PubMed including MEDLINE, Google Scholar and Cochrane Library were used as information sources and randomized clinical trials and retrospective observational studies evaluating patients with T2DM or impaired glucose tolerance with/without complications receiving canakinumab, compared with placebo or standard therapy and reporting about glycemic indicators including hemoglobin A1C (HbA1C) or blood sugar levels (BSL) or insulin levels and/or inflammatory indicators including high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6) were included. Non-randomized clinical trials, animal studies, review articles, case reports, case series, studies not in the English language and those evaluating type 1 DM were excluded. In total, 271 studies were identified to be included in this study. Subsequently, 27 were found to be duplicate records and were eliminated. Manual screening of title/abstract of 244 records was done which found 207 to be ineligible and 37 studies were shortlisted. These were retrieved and full-text screening was undertaken which resulted in the exclusion of 28 reports due to the following reasons: ineligible study design (17), studies evaluating type 1 DM (three), studies evaluating anakinra (one), trial being canceled (three) and duplicate studies (four). Subsequently, a total of nine studies were included in the final review. All studies were included post quality appraisal. We found that canakinumab had a modest but mostly non-significant effect on glycemic parameters including HbA1C, while having a consistently significant reduction in systemic inflammatory parameters like hsCRP and IL-6. Additionally, it was found to have a significant reduction in incident major adverse cardiovascular events (MACE). Canakinumab was also found to be safe and well-tolerated in all patient populations. Although canakinumab did not reduce incident T2DM, an exploration of alternative pathways and targets implicated in the pathogenesis of this disease process is warranted for the prevention and control of T2DM.

Statins are currently widely used in the prevention of coronary artery disease (CAD) primarily for lipid-lowering with a potential anti-inflammatory effect. However, it is not clear if their potential anti-inflammatory effects are mediated through the interleukin 6 (IL-6) signaling pathway.

Using the Mendelian randomization (MR) approach followed by multivariable MR analyses, we examined the extent to which the effects of statins on CAD might be mediated through the IL-6 signaling pathway.

Our observations showed that HMG-CoA reductase, using LDL levels as a proxy, had a significant effect on upstream IL-6 (βMR = 0.47, P-IVW = 0.01) and nominally significant effects on IL-6RA (βMR = 0.22, P-IVW = 0.047) and APOB (βMR = 0.82, P-IVW = 1.8 × 10-33). While the IL-6 signaling cascade (IL-6RA βMR = -0.06, P-IVW = 3.45 × 10-20 and IL-6 βMR = -0.03, P-IVW = 0.09) and the anti-inflammatory effect of HMG-CoA reductase (βMR = -0.31, P-IVW = 0.01) was found to influence the risk of CAD, the multivariable MR (MVMR) model indicated that the anti-inflammatory effect of HMG-CoA reductase is not likely to be mediated through the IL-6 signaling cascade, including APOB and IL-6RA (MVMRβ = 0.23, P = 0.688).

Our findings suggest that statins may use inflammatory mechanisms independent of the IL-6 signaling pathway to prevent CAD. This result could potentially affect the definition of the target population for statin use.

National guidelines define psoriasis as a risk enhancer for cardiovascular disease and recommend increased monitoring and more intense management of cardiovascular risk factors in these patients, who face an increased burden of cardiovascular disease morbidity and mortality. Screening for modifiable cardiovascular risk factors, including blood pressure, weight, cholesterol, glucose, and smoking, can be efficiently incorporated into routine dermatology clinical practice. Partnerships with primary care providers and preventive cardiologists are essential to improving management of cardiovascular risk in patients with psoriasis.

Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1β (IL-1β) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1β production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.

Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are several types of CVDs like stroke, endothelial dysfunction, thrombosis, atherosclerosis, plaque instability and heart failure. Identification of a new drug for heart disease takes longer duration and its safety efficacy test takes even longer duration of research and approval. This chapter explores drug repurposing, nano-therapy, and plant-based treatments for managing CVDs from existing drugs which saves time and safety issues with testing new drugs. Existing drugs like statins, ACE inhibitor, warfarin, beta blockers, aspirin and metformin have been found to be useful in treating cardiac disease. For better drug delivery, nano therapy is opening new avenues for cardiac research by targeting interleukin (IL), TNF and other proteins by proteome interactome analysis. Nanoparticles enable precise delivery to atherosclerotic plaques, inflammation areas, and damaged cardiac tissues. Advancements in nano therapeutic agents, such as drug-eluting stents and drug-loaded nanoparticles are transforming CVDs management. Plant-based treatments, containing phytochemicals from Botanical sources, have potential cardiovascular benefits. These phytochemicals can mitigate risk factors associated with CVDs. The integration of these strategies opens new avenues for personalized, effective, and minimally invasive cardiovascular care. Altogether, traditional drugs, phytochemicals along with nanoparticles can revolutionize the future cardiac health care by identifying their signaling pathway, mechanism and interactome analysis.

Vaccination is one of medicine's greatest achievements; however, its full potential is hampered by considerable variation in efficacy across populations and geographical regions. For example, attenuated malaria vaccines in high-income countries confer almost 100% protection, whereas in low-income regions these same vaccines achieve only 20-50% protection. This trend is also observed for other vaccines, such as bacillus Calmette-Guérin (BCG), rotavirus and yellow fever vaccines, in terms of either immunogenicity or efficacy. Multiple environmental factors affect vaccine responses, including pathogen exposure, microbiota composition and dietary nutrients. However, there has been variable success with interventions that target these individual factors, highlighting the need for a better understanding of their downstream immunological mechanisms to develop new ways of modulating vaccine responses. Here, we review the immunological factors that underlie geographical variation in vaccine responses. Through the identification of causal pathways that link environmental influences to vaccine responsiveness, it might become possible to devise modulatory compounds that can complement vaccines for better outcomes in regions where they are needed most.

The rapid advancements in genome-scale (omics) techniques has created significant opportunities to investigate complex disease mechanisms in tissues and cells. Nevertheless, interpreting -omics data can be challenging, and pathway enrichment analysis is a frequently used method to identify candidate molecular pathways that drive gene expression changes. With a growing number of -omics studies dedicated to atherosclerosis, there has been a significant increase in studies and hypotheses relying on enrichment analysis. This brief review discusses the benefits and limitations of pathway enrichment analysis within atherosclerosis research. We highlight the challenges of identifying complex biological processes, such as cell phenotypic switching, within -omics data. Additionally, we emphasize the need for more comprehensive and curated gene sets that reflect the biological complexity of atherosclerosis. Pathway enrichment analysis is a valuable tool for gaining insights into the molecular mechanisms of atherosclerosis. Nevertheless, it is crucial to remain aware of the intrinsic limitations of this approach. By addressing these weaknesses, enrichment analysis in atherosclerosis can lead to breakthroughs in identifying the mechanisms of disease progresses, the identification of key driver genes, and consequently, advance personalized patient care.

Adiposity and elevated inflammation are two hallmarks of hyperglycemia. However, it is unknown whether clustering of elevated inflammation and adiposity interact act on diabetogenesis and lead to a greater risk for incident type 2 diabetes (T2D).

Adiposity was indicated by body mass index, waist circumference and ultrasonography-measured fatty liver degrees. Elevated inflammation was indicated as high-sensitivity C-reactive protein levels ≥ 2 mg/L. Time-to-event survival analyses were conducted to investigate the joint effect of adiposity and inflammation on incident T2D on both multiplicative and additive scales.

Among 82,172 non-diabetic participants from a prospective cohort in China, 14,278 T2D occurred over a median follow-up of 11 years. In the multivariable-adjusted model, elevated inflammation [1.12 (1.08‒1.16)] and adiposity [1.76 (1.69‒1.83) for overweight/obesity, 1.49 (1.44‒1.55) for central obesity, and 2.02 (1.95‒2.09) for fatty liver] were significantly associated with incident diabetes. Higher adiposity-associated risks and incidence rates of diabetes were observed with elevated inflammation. When studying the joint effect, the adjusted HRs were 1.77 (1.69‒1.85) for overweight/obesity, 1.14 (1.06‒1.23) for elevated inflammation, and 2.08 (1.97‒2.19) for their joint effect, with a relative excess risk due to interaction of 0.17 (0.05‒0.28). The attributable proportions were 71.30% for overweight/obesity, 12.96% for elevated inflammation, and 15.74% for their interaction. Similar results were observed when adiposity was assessed as waist circumference or fatty liver.

Adiposity and elevated inflammation synergically lead to greater risks of incident diabetes than addition of each individual exposure. Strategies simultaneously targeting both risks should produce more benefits for diabetes prevention than through initiatives directed at each separate risk.

A high fibrinogen-to-albumin ratio (FAR), a novel inflammatory marker, is considered to be a prognostic marker in vascular diseases. However, the association of FAR with large artery atherosclerosis (LAA) stroke is still unknown. This study was conducted to evaluate the association between FAR levels and clinical outcomes in patients with acute LAA stroke.

A total of 809 patients within 72 hours of LAA stroke were included and followed up to 1 year. FAR was calculated as fibrinogen (g/L)/albumin (g/L). The associations of FAR with clinical outcomes were assessed by multivariate Cox regression or logistic regression analysis. Clinical outcomes included stroke recurrence, all-cause death, poor functional outcome (modified Rankin Scale score 3-6), and dependence (modified Rankin Scale score 3-5). Among the 809 patients with acute LAA stroke, the median FAR was 0.075 (interquartile range, 0.064-0.087). At 1 year, 103 (12.7%) patients had stroke recurrence, 105 (13.0%) had poor functional outcome, 76 (9.8%) had dependence, and 29 (3.6%) had died. After adjusting for all confounding risk factors, a high FAR level was associated with stroke recurrence (hazard ratio, 2.57 [95% CI, 1.32-5.02]), poor functional outcome (odds ratio, 3.30 [95% CI, 1.57-6.94]), and dependence (odds ratio, 3.49 [95% CI, 1.49-8.19]).

A high FAR level was associated with an increased risk of stroke recurrence, poor functional outcome, and dependence in patients with acute LAA stroke.

Atherosclerosis (AS) is a prevalent cardiovascular disease that greatly increases mortality in the aging population and imposes a heavy burden on global healthcare systems. The purpose of this study is to examine the research structure and current trends of monoclonal antibodies (mAbs) against AS from a bibliometric perspective, since the development of these drugs is currently booming. This study collected articles and reviews on mAbs against AS from the Web of Science Core Collection, spanning from 2003 to 2022. Biblioshiny was utilized to analyze and visualize the characteristics of countries, regions, authors, institutions, and journals included in this collection. We used VOS viewer to illustrate the frequency of country co-occurrence, and CiteSpace to visualize co-cited reference, keywords co-occurrence, keywords citation bursts, keywords clustering and timeline plots. The study included 1325 publications, with the United States emerging as a leading contributor to the field. ATHEROSCLEROSIS, CIRCULATION and ARTERIOSCLEROSISTHROMBOSIS AND VASCULAR BIOLOGY are core journals that publish high-quality literature on the latest advances in the field. Noteworthy authors with numerous high-quality publications include Witztum JL and Tsimikas S. Currently, lipid metabolism and inflammation are the main research areas of interest in this field. The mAbs against AS is an evolving field, and ongoing research continues to advance our understanding. This paper provides a comprehensive overview of the current state of knowledge in this area, highlighting two primary research directions: inflammation and lipid metabolism. Additionally, the paper identifies emerging research hotspots, which will provide researchers with useful insights to guide future investigations and anticipate research directions.

Rapid endothelialization of cardiovascular materials can enhance the vascular remodeling performance. In this work, we developed a strategy for amyloid-like protein-assembly-mediated interfacial engineering to functionalize a biomimetic nanoparticle coating (BMC). Various groups (e.g., hydroxyl and carboxyl) on the BMC are responsible for chelating Zn2+ ions at the stent interface, similar to the glutathione peroxidase-like enzymes found in vivo. This design could reproduce the release of therapeutic nitric oxide gas (NO) and an aligned microenvironment nearly identical with that of natural vessels. In a rabbit abdominal aorta model, BMC-coated stents promoted vascular healing through rapid endothelialization and the inhibition of intimal hyperplasia in the placement sites at 4, 12, and 24 weeks. Additionally, better anticoagulant activity and immunomodulation in the BMC stents were also confirmed, and vascular healing was mainly dependent on cell signaling through the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) cascade. Overall, a metal-polypeptide-coated stent was developed on the basis of its detailed molecular mechanism of action in vascular remodeling.

The objective of the study was to report the efficacy and safety of canakinumab treatment in Japanese patients with systemic juvenile idiopathic arthritis (sJIA) over a 48-week study period.

Patients were administered canakinumab 4 mg/kg (maximum dose 300 mg) every 4 weeks, with no dose adjustments. The key outcome measures included adapted American College of Rheumatology paediatric (aACR pedi) 30/50/70/90/100 response, proportion of patients with inactive disease, and corticosteroid (CS) tapering.

In total, 16/19 (84.2%) patients received canakinumab for ≥96 weeks reaching end-of-study (EOS) visit without premature discontinuation. Regardless of the level of joint involvement at baseline, high aACR pedi responses were observed throughout the study; at the EOS, aACR pedi 90/100 response rates were 84.2%/63.2%, respectively. The proportion of patients who successfully tapered CSs at EOS was 66.7% (12/18), of which 10 patients were steroid-free. The most common adverse events were infections (238.3 events/100 patient-years). Serious adverse events were observed in 52.6%. The event (n=1) adjudicated as possible macrophage activation syndrome was preceded by sJIA flare. No deaths were reported.

Canakinumab treatment resulted in a sustained treatment response in sJIA patients over 48 weeks and was associated with CS tapering in majority of patients. No new safety findings were reported.

The aim was to investigate the association of monocyte heterogeneity and presence of circulating endothelial cells with the severity of coronary atherosclerosis in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). We recruited 62 patients with CAD, including 22 patients with DM2. The severity of atherosclerosis was evaluated using Gensini Score. Numbers of classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14+CD16++) monocyte subsets; circulating endothelial progenitor cells; and the presence of circulating endothelial cells were evaluated. Counts and frequencies of intermediate monocytes, but not glycaemia parameters, were associated with the severity of atherosclerosis in diabetic CAD patients (rs = 0.689; p = 0.001 and rs = 0.632; p = 0.002, respectively). Frequency of Tie2+ cells was lower in classical than in non-classical monocytes in CAD patients (p = 0.007), while in patients with association of CAD and T2DM, differences between Tie2+ monocytes subsets disappeared (p = 0.080). Circulating endothelial cells were determined in 100% of CAD+T2DM patients, and counts of CD14++CD16+ monocytes and concentration of TGF-β predicted the presence of circulating endothelial cells (sensitivity 92.3%; specificity 90.9%; AUC = 0.930). Thus, intermediate monocytes represent one of the key determinants of the appearance of circulating endothelial cells in all the patients with CAD, but are associated with the severity of atherosclerosis only in patients with association of CAD and T2DM.

SSc-ILD (scleroderma associated interstitial lung disease) is a complex rheumatic disease characterized in part by immune dysregulation leading to the progressive fibrotic replacement of normal lung architecture. Because improved treatment options are sorely needed, additional study of the fibroproliferative mechanisms mediating this disease has the potential to accelerate development of novel therapies. The contribution of innate immunity is an emerging area of investigation in SSc-ILD as recent work has demonstrated the mechanistic and clinical significance of the NLRP3 inflammasome and its associated cytokines of TNFα (tumor necrosis factor alpha), IL-1β (interleukin-1 beta), and IL-18 in this disease. In this review, we will highlight novel pathophysiologic insights afforded by these studies and the potential of leveraging this complex biology for clinical benefit.

Women with hypertensive disorders of pregnancy (HDP) have a significantly higher risk of developing cardiovascular diseases later in life. The stratification of this risk using biomarkers during pregnancy can help to identify these women and apply early prevention.

We aimed to determine proinflammatory cytokines and angiogenic markers, echocardiographic parameter changes after delivery and predict early cardiovascular disease risk in women with arterial hypertension and its complications during pregnancy.

We conducted a literature search using the PubMed database for the last ten years. A total of 17 articles were included to our study and full text reviewed.

Four out of six studies found higher postpartum Interleukin-6 (IL-6) levels in women with HDP. IL-6 correlated positively with waist circumference, body mass index, and triglycerides, and negatively with high density lipoproteins (HDL). Two out of four studies found higher postpartum tumor necrosis factor alpha (TNF-α) levels in women with HDP but later concentration equalizes. One out of eight studies found higher placental growth factor (PlGF) and two out of eight found more elevated soluble fms-like tyrosine kinase-1 (sFlt-1) in women with HDP. With decreasing PlGF and increasing sFlt-1, common carotid artery intima and media thickness, aortic root diameter, left atrial diameter, left ventricle mass, systolic, diastolic, and mean blood pressure increased, whereas HDL decreased. One out of four studies found higher sFlt-1/PlGF.

IL-6 remains significantly higher after delivery. Few studies found higher TNF-α, sFlt-1, PlGF and their ratio postpartum. All studies found a correlation between angiogenic factors, IL-6, and cardiovascular disease risk factors.

Venous thromboembolism (VTE) remains a major health burden despite anticoagulation advances, suggesting incomplete management of pathogenic mechanisms. The NLRP3 (NACHT-, LRR- and pyrin domain-containing protein 3) inflammasome, interleukin (IL)-1, and pyroptosis are emerging contributors to the inflammatory pathogenesis of VTE. Inflammasome pathway activation occurs in patients with VTE. In preclinical models, inflammasome signaling blockade reduces venous thrombogenesis and vascular injury, suggesting that this therapeutic approach may potentially maximize anticoagulation benefits, protecting from VTE occurrence, recurrence, and ensuing post-thrombotic syndrome. The nonselective NLRP3 inhibitor colchicine and the anti-IL-1β agent canakinumab reduce atherothrombosis without increasing bleeding. Rosuvastatin reduces primary venous thrombotic events at least in part through lipid-lowering independent mechanisms, paving the way to targeted anti-inflammatory strategies in VTE. This review outlines recent preclinical and clinical evidence supporting a role for inflammasome pathway activation in venous thrombosis, and discusses the, yet unexplored, therapeutic potential of modulating inflammasome signaling to prevent and manage VTE.

Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus, tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote pro-inflammatory pathways also contributing to pro-coagulability and a prothrombotic state. In addition, changes in the extracellular matrix composition lead to (peri-)vascular remodelling and alterations of the vessel wall, e.g., aneurysm formation. Moreover, progressive fibrosis leads to reduced tissue perfusion due to loss of functional capillaries. The present review aims at discussing the molecular and clinical effects of inflammatory processes on the micro- and macrovasculature with a focus on peripheral artery disease.

Over the years, it has been found that colchicine offers substantial benefits in secondary prevention in patients with coronary artery disease (CAD). We studied the effects of colchicine timing because there are no guidelines about when to provide it during the perioperative period for patients with CAD.

Up to January 1, 2023, seven electronic literature databases were screened (including three English databases and four Chinese databases). Randomized controlled trials included only treatment with colchicine in the perioperative period of CAD. The Cochrane Evaluation Tool was used to judge the risk of bias in research. Statistical analysis was performed by Stata 16.0 software.

We evaluated twelve studies that found colchicine to be effective in decreasing the occurrence of major adverse cardiac events (MACEs) (p < 0.00001), but it also raised the rate of adverse events (p = 0.001). Subgroup analysis showed the same benefit in lowering the incidence of MACE with continuous administration of a total daily dose of 0.5 mg postoperatively while minimizing drug-related side effects in the patients (p = 0.03). When it comes to preventing surgical stroke occurrences, postoperative administration is more effective (p = 0.006). While the effect of simultaneous preoperative and postoperative administration was marginally greater than other periods in reducing postoperative hs-CRP levels (p = 0.02).

Colchicine, a traditional anti-inflammatory drug, also reduces the risk of MACE by reducing inflammation after PCI. Administration at different periods had no significant effect on decreasing the occurrence of MACE, but when administered postoperatively, we advise continuous administration with a total daily dose of 0.5 mg to obtain the same benefit while minimizing the drug's side effects. Postoperative administration is the better measure to prevent postoperative stroke events. Due to the effective anti-inflammatory effect of colchicine, we recommend its use as early as possible in the perioperative period and its continued use at low doses in the postoperative period.

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=316751, identifier CRD42022316751.

Anti-hypertensive drugs can improve vascular endothelial function. However, the mechanism remains to be elucidated.

This study sought to investigate mechanisms of anti-hypertensive drugs on improvement of vascular endothelial function in patients with essential hypertension.

Forty-five patients (mean age 58.5 ± 11.2 years) with uncontrolled essential hypertension were randomly assigned to receive olmesartan, an angiotensin II type 1 receptor blocker (ARB) (N = 23), or amlodipine, a calcium channel blocker (CCB) (N = 22), for 6 months. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR) within the carotid arteries using 18F-fluorodeoxyglucose-positron emission tomography combined with computed tomography.

There were no significant differences of baseline clinical data between the ARB and CCB groups. Both anti-hypertensive drugs comparably lowered blood pressure and increased %FMD. TBR values were reduced by olmesartan (P < .001), while blood pressure variability was decreased by amlodipine (P = .004). Changes in %FMD from baseline (Δ%FMD) were inversely associated with ΔTBR in the olmesartan group (r = - .606, P = .003) and with Δsystolic blood pressure variability in the amlodipine group (r = - .434, P = .039).

Our study indicated that olmesartan and amlodipine could improve endothelial function in patients with essential hypertension in different manners, suppression of vascular inflammation, and decrease in blood pressure variability, respectively.

Atherosclerosis is a progressive disease that develops in areas of disturbed flow (d-flow). Progressive atherosclerosis is characterized by bulky plaques rich in mesenchymal cells and high-grade inflammation that can rupture leading to sudden cardiac death or acute myocardial infarction. In response to d-flow, endothelial cells acquire a mesenchymal phenotype through endothelial-to-mesenchymal transition (EndMT). However, the signaling intermediaries that link d-flow to EndMT are incompletely understood.

In this study we found that in human atherosclerosis, cells expressing SNAI1 (Snail 1, EndMT transcription factor) were highly expressed within the endothelial cell (EC) layer and in the pre-necrotic areas in unstable lesions, whereas stable lesions did not show any SNAI1 positive cells, suggesting a role for EndMT in lesion instability. The interleukin-1 (IL-1), which signals through the type-I IL-1 receptor (IL-1R1), has been implicated in plaque instability and linked to EndMT formation in vitro. Interestingly, we observed an association between SNAI1 and IL-1R1 within ECs in the unstable lesions. To establish the causal relationship between EndMT and IL-1R1 expression, we next examined IL-1R1 levels in our Cre-lox endothelial-specific lineage tracing mice. IL-1R1 and Snail1 were highly expressed in ECs under atheroprone compared to athero-protective areas, and oscillatory shear stress (OSS) increased IL-1R1 protein and mRNA levels in vitro. Exposure of ECs to OSS resulted in loss of their EC markers and higher induction of EndMT markers. By contrast, genetic silencing of IL-1R1 significantly reduced the expression of EndMT markers and Snail1 nuclear translocation, suggesting a direct role for IL-1R1 in d-flow-induced EndMT. In vivo, re-analysis of scRNA-seq datasets in carotid artery exposed to d-flow confirmed the IL-1R1 upregulation among EndMT population, and in our partial carotid ligation model of d-flow, endothelial cell specific IL-1R1 KO significantly reduced SNAI1 expression.

Global inhibition of IL-1 signaling in atherosclerosis as a therapeutic target has recently been tested in the completed CANTOS trial, with promising results. However, the data on IL-1R1 signaling in different vascular cell-types are inconsistent. Herein, we show endothelial IL-1R1 as a novel mechanosensitive receptor that couples d-flow to IL-1 signaling in EndMT.