Sirtuin 1 (SIRT1) regulates CD4+ T cell differentiation, particularly Th17 and Th9 subsets, in various autoimmune and inflammatory diseases, but its role in viral myocarditis (VMC) remains poorly understood. In this study, using a coxsackievirus B3 (CVB3)-induced VMC mouse model, we initially found that Sirt1 mRNA levels in CD4+ T cells peaked at day 7 post-infection, coinciding with maximal myocardial inflammation and Th17/Th9 transcription factors Rorc/Spi1 mRNA levels. Pharmacological inhibition of SIRT1 using EX527 attenuated cardiac inflammation and CVB3 viral load by downregulating SIRT1 expression in CD4+ T cells, leading to decreased Th17 proportions and increased Th9 cell infiltration in both cardiac tissue and spleen of VMC mice. In vitro, EX527 effectively suppressed the mouse CD4+ T cell activation and proliferation, directly inhibiting Th17 cell differentiation while promoting Th9 cell differentiation, and this shift in Th17/Th9 differentiation was also observed in human blood CD4+ T cells. While reduced glycolysis in CD4+ T cells was linked to EX527, a notable reduction in Pyruvate kinase M2 (PKM2) prompted the discovery of a non-metabolic mechanism. Mechanistically, EX527 specifically inhibited PKM2 nuclear translocation and the direct PKM2-STAT3 interaction, resulting in decreased p-STAT3/RORγt and increased p-STAT5/PU.1 levels downstream, while Foxp3 expression remained unchanged. These effects were reversed by SAICAR, an agonist of PKM2 nuclear translocation. Collectively, SIRT1 contributes to the Th17/Th9 imbalance in VMC through PKM2/STAT3/STAT5 signaling pathways, highlighting its potential as a novel therapeutic target.

Trained immunity refers to a functional reprogramming of the innate immune system that enhances its ability to respond to secondary stimuli. Monocytes and macrophages are central effectors of innate immunity with broad therapeutic relevance. Their capacity to acquire trained immunity enhances host defense and shapes immune homeostasis through epigenetic, metabolic, and functional changes. Unlike previous reviews that primarily focus on molecular mechanisms or vaccine-induced training, this review emphasizes the distinct roles of monocyte/macrophage-mediated trained immunity, originating from both central and peripheral sources. We further discuss how nanomaterials can be harnessed to precisely modulate this process, offering new opportunities for infection control, tumor immunotherapy, and the regulation of chronic inflammatory diseases. This dual-perspective framework provides a foundation for translating trained immunity into targeted clinical interventions.

BackgroundThe heterogeneous subtypes in dilated cardiomyopathy (DCM) are poorly characterized, thus posing challenges to risk stratification. This study aimed to establish a DCM subtype framework based on metabolic and immunoinflammatory factors.MethodsDCM subtypes were identified using unsupervised clustering based on the expression patterns of metabolism-related genes in the left ventricular myocardium of 89 DCM patients. By comparing metabolic pathways, clinical characteristics, immune cell infiltration, inflammatory responses, and immunotherapy efficacy between the subtypes, key metabolic genes were identified through correlation analysis and validated at both bulk and single-cell levels. The alterations in gene expression were verified using the DCM mouse model. Molecular docking was performed to assess the binding affinity between the target protein and potential therapeutic small molecules.ResultsTwo subtypes were identified; subtypes 1 and 2 were characterized by increased amino acid metabolism and decreased glucose and energy-related metabolisms, respectively. Subtype 2 displayed worse left ventricular structure and function, higher levels of immune and inflammatory activity, and a more favorable response to immunotherapy. The integrative analysis identified DHRS7C as a key regulator of glucose/energy metabolism; its expression was inversely correlated with left ventricular impairment. The DCM mice showed downregulated DHRS7C expression, which positively correlated with cardiac dysfunction. Additionally, molecular docking identified 17beta-estradiol as a potential therapeutic agent targeting DHRS7C.ConclusionsThis study suggested two heterogeneous DCM subtypes with different metabolic and immunoinflammatory profiles. Furthermore, DHRS7C was inversely correlated with DCM indices and could be targeted by 17beta-estradiol.

Coronary artery disease (CAD) is a major public health concern, necessitating accurate risk factor identification. However, existing methods often suffer from feature preference bias and insufficient multidimensional evaluation, limiting their reliability. To address this, we propose a novel two-stage mechanism integrating multiple cross-filtering and binary cuckoo search (BCS). In the first stage, features are evaluated from three perspectives—relevance (chi-square test), information richness (mutual information), and distance (Fisher score)—to eliminate low-importance features and reduce bias. In the second stage, a random forest classifier optimizes feature selection via BCS, using classification accuracy as the objective function. Empirical analysis on the UCI CAD dataset demonstrates that our method achieves an accuracy of 89%, precision of 0.87, recall of 0.91, F1-score of 0.89, and AUC of 0.93. These values outperform existing homogeneous models (Method II, Method III, Method IV) by at least 3.49%, 3.57%, 3.41%, 3.49%, and 3.33%, respectively. The results highlight superior computational efficiency and predictive performance, making the mechanism a valuable tool for CAD risk assessment.

BACKGROUND:Identification of significant coronary artery stenosis (CAS) in patients with chronic coronary syndromes (CCS) is crucial for clinical management. Myocardial work (MW) is a new noninvasive method reflecting myocardial metabolism and has been applied in myocardial ischemia. We aimed to explore the value of global MW during vasodilator stress echocardiography in detecting significant CAS. METHODS:Patients with angina or equivalent symptoms underwent coronary angiography and vasodilator stress echocardiography. Significant CAS was defined as ≥70% luminal stenosis in one or more major epicardial vessels or ≥50% in the left main coronary. Global MW was analyzed by speckle-tracking echocardiography with blood pressure. The diagnostic performance of MW parameters in detecting significant CAS was evaluated. RESULTS:One hundred forty-six patients were enrolled into the study, and 67 patients had significant CAS. Coronary flow velocity reserve (CFVR), global longitudinal strain (GLS), global MW index (MWI), and global MW efficiency (MWE) were significantly lower in the significant CAS group than those in the non-significant group both at rest and peak stress (p < 0.001 for CFVR, GLS, MWE; p < 0.01 for MWI). Logistic regression analyses showed that CFVR and peak MWE effectively predicted significant CAS. Peak MWE outperformed other parameters with the highest area under the curve (AUC) of 0.820. Furthermore, the model integrating CFVR and peak MWE (AUC = 0.886) was much better than CFVR or peak MWE alone. CONCLUSIONS:Peak MWE combined with CVFR might be a reliable method of noninvasively screening significant CAS in patients with CCS before invasive angiography.

OBJECTIVE:Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. METHODS:The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. RESULTS:At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all P<0.0001). Furthermore-these changes, coupled with improvements in LVEF, NT-proBNP and New York Heart Association (NYHA) functional classification, excluding the LVEDd in the QLQX group, were greater than those in the placebo group (all P<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. CONCLUSION:QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.

[This corrects the article DOI: 10.3389/fimmu.2016.00409.].

Studies have shown that Sacubitril/valsartan (Sac/Val) can reduce myocardial inflammation in myocarditis mice, in addition to its the recommended treatment of heart failure. However, the underlying mechanisms of Sac/Val in myocarditis remain unclear. C-type natriuretic peptide (CNP), one of the targeting natriuretic peptides of Sac/Val, was recently reported to exert cardio-protective and anti-inflammatory effects in cardiovascular systems. Here, we focused on circulating levels of CNP in patients with acute myocarditis (AMC) and whether Sac/Val modulates inflammation by targeting CNP in experimental autoimmune myocarditis (EAM) mice as well as LPS-induced RAW 264.7 cells and bone marrow derived macrophages (BMDMs) models. Circulating CNP levels were higher in AMC patients compared to healthy controls, and these levels positively correlated with the elevated inflammatory cytokines IL-6 and monocyte count. In EAM mice, Sac/Val alleviated myocardial inflammation while augmenting circulating CNP levels rather than BNP and ANP, accompanied by reduction in intracardial M1 macrophage infiltration and expression of inflammatory cytokines IL-1β, TNF-α, and IL-6. Furthermore, Sac/Val inhibited CNP degradation and directly blunted M1 macrophage polarization in LPS-induced RAW 264.7 cells and BMDMs. Mechanistically, the effects might be mediated by the NPR-C/cAMP/JNK/c-Jun signaling pathway apart from NPR-B/cGMP/NF-κB pathway. In conclusion, Sac/Val exerts a protective effect in myocarditis by increasing CNP concentration and inhibiting M1 macrophages polarization.

OBJECTIVE:The macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE) is a severe and life-threatening complication. Early diagnosis of MAS is particularly challenging. In this study, machine learning models and diagnostic scoring card were developed to aid in clinical decision-making using clinical characteristics. METHODS:We retrospectively collected clinical data from 188 patients with either SLE or the MAS secondary to SLE. 13 significant clinical predictor variables were filtered out using the Least Absolute Shrinkage and Selection Operator (LASSO). These variables were subsequently utilized as inputs in five machine learning models. The performance of the models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), F1 score, and F2 score. To enhance clinical usability, we developed a diagnostic scoring card based on logistic regression (LR) analysis and Chi-Square binning, establishing probability thresholds and stratification for the card. Additionally, this study collected data from four other domestic hospitals for external validation. RESULTS:Among all the machine learning models, the LR model demonstrates the highest level of performance in internal validation, achieving a ROC-AUC of 0.998, an F1 score of 0.96, and an F2 score of 0.952. The score card we constructed identifies the probability threshold at a score of 49, achieving a ROC-AUC of 0.994 and an F2 score of 0.936. The score results were categorized into five groups based on diagnostic probability: extremely low (below 5%), low (5-25%), normal (25-75%), high (75-95%), and extremely high (above 95%). During external validation, the performance evaluation revealed that the Support Vector Machine (SVM) model outperformed other models with an AUC value of 0.947, and the scorecard model has an AUC of 0.915. Additionally, we have established an online assessment system for early identification of MAS secondary to SLE. CONCLUSION:Machine learning models can significantly improve the diagnostic accuracy of MAS secondary to SLE, and the diagnostic scorecard model can facilitate personalized probabilistic predictions of disease occurrence in clinical environments.

BACKGROUND:Allopurinol, a xanthine inhibitor that lowers uric acid concentration, has been proven to reduce inflammation and oxidative stress in patients with cardiovascular disease. However, it is unknown whether these beneficial effects translate into favorable plaque modification in acute coronary syndromes (ACS). This study aimed to investigate whether allopurinol could improve coronary plaque stabilization using coronary computed tomography angiography (CCTA). METHODS:This was a prospective, single-center, randomized, double-blind clinical trial began in March 2019. A total of 162 ACS patients aged 18-80 years with a blood level of high-sensitivity C-reactive protein (hsCRP) ​> ​2 ​mg/L were included. The subjects were randomly assigned in a 1:1 ratio to receive either allopurinol sustained-release capsules (at a dose of 0.25 ​g once daily) or placebo for 12 months. The plaque analysis was performed at CCTA. The primary efficacy endpoint was the change in low-attenuation plaque volume (LAPV) from baseline to the 12-month follow-up. RESULTS:Among 162 patients, 54 in allopurinol group and 51 in placebo group completed the study. The median follow-up duration was 14 months in both groups. Compared with placebo, allopurinol therapy did not significantly alter LAPV (-13.4 ​± ​3.7 ​% vs. -17.8 ​± ​3.6 ​%, p ​= ​0.390), intermediate attenuation plaque volume (-16.1 ​± ​3.0 ​% vs. -16.2 ​± ​2.9 ​%, p ​= ​0.992), dense calcified plaque volume (12.2 ​± ​13.7 ​% vs. 9.7 ​± ​13.0 ​%, p ​= ​0.894), total atheroma volume (-15.2 ​± ​3.2 ​% vs. -16.4 ​± ​3.1 ​%, p ​= ​0.785), remodeling index (2.0 ​± ​3.9 ​% vs. 5.4 ​± ​3.8 ​%, p ​= ​0.536) or hsCRP levels (-73.6 [-91.6-17.9] % vs. -81.2 [-95.4-47.7] %, p ​= ​0.286). CONCLUSIONS:Our findings suggest that allopurinol does not improve atherosclerotic plaque stability or inflammation in ACS.

The tumour microenvironment (TME) is critical for the initiation, progression, and metastasis of tumours, and cancer-associated fibroblasts (CAFs) are the most dominant cells and have attracted interest as targets for cancer therapy among the stromal components within the TME. Currently, most of the identified CAF subpopulations are believed to exhibit suppressive effects on antitumour immunity. However, accumulating evidence indicates the presence of immunostimulatory CAF subpopulations, which play an important role in the maintenance and amplification of antitumour immunity, in the TME. Undoubtedly, these findings provide novel insights into CAF heterogeneity. Herein, we focus on summarizing CAF subpopulations that promote antitumour immunity, the surface markers of these populations, and possible immunostimulatory mechanisms in the context of recent advances in research on CAF subpopulations. In addition, we discuss the possibility of new therapies targeting CAF subpopulations and conclude with a brief description of some prospective avenues for CAF research.

Podoplanin (PDPN), a small mucin-like glycoprotein, was recently found to promote the generation of cardiac ectopic lymphoid follicles and anti-heart autoantibodies (AHA) in viral myocarditis (VMC) mice. Herein, we investigated the blood PDPN expression and its potential clinical value in VMC patients. Overall, 40 VMC patients were enrolled among 112 hospitalized patients with suspected myocarditis. Their serum PDPN levels were higher than those in controlled acute myocardial infarction (AMI) patients (n = 40) and healthy individuals (n = 30) (both p < 0.01) and positively correlated with CRP, IL-17, and IL-4 (all p < 0.01). Elevation of serum PDPN discriminated VMC from AMI (OR = 4.061, p < 0.01) and PDPN addition to the basic model (age, CRP, and peak cTNI) increased AUC values (from 0.822 to 0.933, p = 0.04). Additionally, the serum levels of PDPN ligand CCL21 were also increased and correlated with PDPN (R = 0.59, p < 0.01) in VMC patients, accompanied by AHA production. Moreover, the anti-MHC antibody was closely related to PDPN levels (R = 0.53, p < 0.01), and antiMHC-positive patients with VMC displayed higher percentages of CD4(+)IL-17A(+)PDPN(+)T cells and CD19(+)CCR7(+)B cells (both p < 0.05). Noticeably, VMC patients complicated by ventricular arrhythmias (27.50%) presented with AHA production and higher PDPN levels (p < 0.05). Finally, we screened out and verified that miR-182-5p directly targeted PDPN and negatively regulated its expression (all p < 0.01). These data suggested that blood PDPN might be a novel inflammation-associated biomarker for the early diagnosis of VMC and may contribute to AHA production by binding CCL-21 to recruit Th17 and B cells, which were regulated by miR-182-5p.

Left ventricular noncompaction (LVNC) is a heterogeneous disorder with unclear genetic causes. The arhGEF18 gene is a guanine nucleotide exchange factor related to the Rho pathway and a possible predisposing gene for LVNC. In this study, a mouse model of arhGEF18 gene conditional knockout (cKO) in cardiomyocytes was established using the Cre-LoxP system to provide an animal model for the genetic study of LVNC. ArhGEF18 cKO mice were obtained by crossing arhGEF18f/+/myh6-Cre+ and arhGEF18f/f mice. The mRNA and protein expression levels of arhGEF18 in different tissues were verified. The myocardial cytoskeleton and polar protein expression, the survival rate, cardiac function, and cardiac histology of model mice were determined. ArhGEF18 cKO mice were successfully established. ArhGEF18 was confirmed to be specifically knocked out in the myocardial tissue of arhGEF18f/f/myh6-Cre+ mice at the mRNA and protein levels, and the knockout rate was approximately 75%. The relative expression levels of cytoskeleton and cell polarity proteins such as α/β-tubulin, Scribble, Crb2, and PAR3 in the cKO group were significantly lower than those in the control group (p < 0.05). During monitoring, the survival rate, cardiac systolic function, and myocardial structure of arhGEF18f/f/myh6-Cre+ mice were not significantly different from those of control mice. A mouse model of cardiomyocyte arhGEF18 gene cKO was successfully established, and it was confirmed that knocking out arhGEF18 changed cytoskeleton and cell polar protein expression levels in the myocardium. However, there was no obvious LVNC phenotype in the constructed arhGEF18 cKO mice.

心力衰竭（心衰）是大多数心血管疾病进展的终末阶段。针对目前中国心衰流行、诊治欠规范等问题，积极构建心衰防控体系并推进分级诊疗制度实施，具有重要的意义。自2015年和2018年相继成立湖北省心血管内科医疗质量控制中心和湖北省心衰中心联盟以来，加入医院分别是212家和106家，湖北省心衰诊疗防控体系基本建立。通过开展基层医疗培训与继续教育、推行心衰常态化质控工作、推广心衰健康教育等举措，湖北省心衰住院诊疗质量得到持续改进。未来需努力实现区域更高质量和更广覆盖的心衰防控体系建设。

Aim We aimed to evaluate clinical characteristics and 1-year outcomes in hospitalized patients with heart failure with preserved ejection fraction (HFpEF) from China. Factors associated with outcomes (hospitalization for HF [HHF] and cardiovascular [CV] death) were assessed. Method and results Data were from the China Cardiovascular Association (CCA) Database-HF Center Registry. Between January 2017 and June 2021, 41 708 hospitalized HFpEF patients with 1-year follow-up from 481 CCA Database-HF Center certified secondary and tertiary hospitals across overall 31 provinces of mainland China were included in this study. Of study participants (mean age 72.2 years, 49.3% female), 18.2% had HHF in prior 1 year and 55.8% had New York Heart Association class III/IV. Median left ventricular ejection fraction was 59%. Ischaemia (26.6%), infection (14.4%) and arrhythmia (10.5%) were the three most common precipitating factors for index HHF. Nearly 67.4% had >= 3 comorbidities. Hypertension (65.2%), coronary heart disease (60.3%) and atrial fibrillation (41.2%) were the three most common comorbidities. Device and medication therapy non-compliance with current HF guideline recommendation was observed. The 1-year rate of clinical outcomes was 16.4%, the 1-year rate of HHF was 13.6% and CV death was 3.1%. Factors associated with clinical outcomes included HHF in prior 1 year, serum level of sodium <135 mmol/L and N-terminal pro-B-type natriuretic peptide >1800 pg/ml. Conclusion Patients with HFpEF from China were characterized by high comorbid burden and high 1-year risk of HHF and CV death. Immediate efforts are needed to improve HFpEF management in China

钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂已成为治疗心力衰竭（心衰）的新兴药物,但其作用机制尚不清楚。健康人心肌细胞仅表达SGLT1,SGLT2定位在肾脏近曲小管和心外膜脂肪组织（EAT）,在疾病状态下高表达。舒张性心衰患者发生EAT堆积,EAT高表达SGLT2和分泌脂肪细胞因子,介导心肌纤维化和心肌肥厚;心肌细胞高表达SGLT1介导细胞内Na + 超载。基于SGLT2/1在心脏和肾脏的分布,我们推测SGLT2抑制剂治疗心衰的潜在作用机制主要涉及心脏血流动力学和心脏代谢重构,EAT-SGLT2可能是心脏代谢重构防治的重要靶点。

The development of dilated cardiomyopathy (DCM) is accompanied by a series of metabolic disorders, resulting in myocardial remodeling or exacerbation, while the mechanism remains not completely clear. This study was to find out the key metabolism-related genes involved in the onset of DCM, providing new insight into the pathogenesis of this disease. The datasets of GSE57338, GSE116250, and GSE5406 associated with hearts of patients with DCM were downloaded from the Gene Expression Omnibus database. GSE57338 was analyzed to screen out metabolism-related differentially expressed genes (DEGs), while GSE116250 and GSE5406 were utilized to verify the optimal genes through R software. Support vector machine recursive feature elimination algorithm and least absolute shrinkage and selection operator algorithm were used to determine key genes. Finally, 6 of 39 metabolism-related DEGs were screened out and identified as the optimal genes. After quantitative reverse-transcription polymerase chain reaction (qRT-PCR) validation performed on the samples drawn from the left ventricles of human hearts, it showed that only the expression of oxoglutarate dehydrogenase-like (OGDHL) increased while PLA2G2 decreased significantly in patients with DCM compared with non-failing donors, respectively. Furthermore, the higher OGDHL protein expression, except the change of PLA2G2, was also found in DCM hearts, and its mRNA expression was negatively correlated with myocardial Masson's scores (r = -0.84, P = 0.009) and left ventricular end-diastolic diameter (LVEDd; r = -0.82, P = 0.014), which might be regulated by miR-3925-5p through further bioinformatics prediction and qRT-PCR verification. The data then suggested that the metabolism-related gene OGDHL was associated with myocardial fibrosis of DCM and probably a biomarker for myocardial remodeling in patients with DCM.

Myocarditis is an inflammatory cardiovascular disease which contributes to dilated cardiomyopathy (DCM) and heart failure. Canagliflozin (CANA) exerts anti-inflammatory and cardioprotective effects in heart failure besides its hypoglycemic effect. However, the role of CANA in myocarditis has not been elucidated. In this work, CANA treatment markedly alleviated cardiac inflammation and improved cardiac function in experimental autoimmune myocarditis (EAM) mice induced by α-myosin-heavy chain peptides. The expressions of NLRP3 inflammasome complexes (NLRP3, ASC, and Caspase-1) and their downstream molecules (IL-1β, IL-18) were significantly downregulated by CANA, accompanied with reduced Th17 cell infiltration in hearts. Furthermore, Bax/Bcl-2 ratio, Cleaved Caspase-3 protein level and the percentage of TUNEL-positive myocardial cells, which usually indicated apoptosis, were reduced by CANA treatment. These findings suggest CANA could be a valuable medication for myocarditis treatment.

目的:探讨免疫吸附疗法应用于扩张型心肌病（DCM）患者的有效性和安全性。方法:本研究在国内首次报道免疫吸附疗法成功应用于1例DCM患者，并通过荟萃分析系统性评价免疫吸附疗法在DCM患者中的有效性与安全性。荟萃分析中，我们检索PubMed、Embase、Web of Science-MEDLINE、Cochrane Library、CENTRAL和ClinicalTrials.gov等数据库，查找2000年1月1日—2021年11月26日以英文发表的免疫吸附疗法治疗DCM的临床研究。应用Stata MP Version 15.0和GraphPad Prism Version 7.0软件进行荟萃分析和统计分析。结果:该例DCM患者接受单疗程的免疫吸附治疗后，在18个月随访期间，N末端脑钠肽原下降，左室射血分数增加以及左室舒张末期内径减低。荟萃分析最终纳入11篇文献，包括313例DCM患者，其中免疫吸附组167例，对照组146例，平均随访时间为3～30个月。与对照组相比，免疫吸附组DCM患者NYHA心功能分级得到明显改善（P＜0.000 1）,伴左室射血分数升高（WMD=6.70,95%CI:5.28～8.12）和左室舒张末期内径减低（WMD=-3.65,95%CI:-4.12～-3.19）。免疫吸附组患者未见感染、大出血、肾功能恶化等严重并发症的报道。结论:免疫吸附疗法可明显改善DCM患者的心功能和逆转心脏重构。