Heart failure (HF) is a clinical syndrome characterized by myocardial remodeling, pathological fibrosis, and chronic sterile inflammation. Within the pathophysiological network of HF and its complex comorbidities, neutrophil extracellular traps (NETs) have been identified as key pathological mediators driving tissue damage. This review aims to explore the regulatory mechanisms of NETs in the progression of heart failure (HF) and their cross-organ pathological effects, and to summarize the latest research advances in NET-targeted interventions for the treatment of HF. NETs are reticular structures composed of antimicrobial proteins, such as myeloperoxidase (MPO) and histones, attached to a decondensed DNA scaffold. Under pathological conditions, excessive NET release and impaired clearance trigger inflammatory cascades. Aberrant NETs formation significantly promotes cardiac remodeling and pathological fibrosis by mediating immunothrombosis, inducing cardiomyocyte apoptosis, and activating fibroblasts.NETs serve as a critical pathophysiological link connecting HF to systemic comorbidities. Therapeutic strategies targeting NETs primarily include inhibiting PAD4 or associated signaling axes to block NETs formation, utilizing enzymatic reactions to facilitate NETs clearance, uncovering the novel potential of established clinical agents, and employing nanotechnology-based precision delivery systems. These findings offer new avenues for precision immunotherapy in HF and highlight considerable potential for clinical translation.

ETHNOPHARMACOLOGICAL RELEVANCE:Patients with coronary heart disease (CHD) remain at high risk of major adverse cardiovascular events (MACEs) after percutaneous coronary intervention (PCI). Chinese Patent Medicines (CPMs) have demonstrated therapeutic potential as adjunctive therapies, however, direct comparative evidence regarding their effectiveness is lacking. AIM OF THE STUDY:This network meta-analysis (NMA) aims to systematically evaluate and compare the clinical efficacy and safety of CPMs combined with conventional therapy (CT) in post-PCI management. MATERIALS AND METHODS:A systematic literature search was performed in PubMed, Web of Science, Embase, Cochrane Library, CNKI, CBM, VIP, and Wanfang databases up to December 24, 2024. Randomized controlled trials investigating CPMs in CHD patients following PCI were included. Methodological quality was assessed using the Cochrane Risk of Bias tool. Outcome measures included major adverse cardiovascular events (MACEs), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and nitric oxide (NO) levels. NMA was implemented using STATA 16.0 and R 4.1.2. Odds ratios and standardized mean differences with 95% confidence intervals were calculated for dichotomous and continuous outcomes, respectively. Model selection was guided by heterogeneity assessed using the I2 statistic. Intervention rankings were estimated using the surface under the cumulative ranking curve (SUCRA), with robustness and publication bias evaluated through sensitivity analyses and funnel plots. RESULTS:A total of 84 RCTs involving 10,524 patients and eight CPMs were included. For the primary outcome (MACEs), the SUCRA ranking indicated that Tongxinluo capsules combined with conventional therapy (TXLJN + CT) was the most effective intervention, followed by Shensong Yangxin capsules plus CT (SSYXJN + CT), Shexiang Baoxin pills plus CT (SXBXW + CT), Qili Qiangxin capsules plus CT (QLQXJN + CT), Qishen Yiqi dripping pills plus CT (QSYQDW + CT), Xinyu capsules plus CT (XYJN + CT), Fufang Danshen Dripping Pills plus CT (FFDSDW + CT), and Guanxin Shutong capsules plus CT (GXSTJN + CT), while CT alone ranked last. Correspondingly, the NMA demonstrated that TXLJN + CT was associated with the greatest reduction in LVEDD (SMD -1.01, 95% CI -1.35 to -0.66) and hs-CRP levels (SMD -2.50, 95% CI -3.33 to -1.68). The most significant improvement in LVEF (SMD 1.25, 95% CI 0.85 to 1.64) and NO levels (SMD 1.02, 95% CI 0.73 to 1.29) was observed with QSYQDW + CT. Meanwhile, SXBXW + CT showed the greatest efficacy in reducing NT-proBNP levels (SMD -3.43, 95% CI -4.68 to -2.18). CONCLUSION:CPMs combined with CT may provide clinical benefits in post-PCI management. According to SUCRA rankings, TXLJN + CT ranked first in reducing MACE and in lowering LVEDD and hs-CRP levels. QSYQDW + CT ranked first in improving LVEF and NO levels, while SXBXW + CT showed the highest ranking for reducing NT-proBNP levels. However, larger-scale, high-quality RCTs are needed to validate these findings.

Introduction Dyslipidemia, especially the elevation of low-density lipoprotein cholesterol (LDL-C), is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Although statins are recommended as a first-line treatment, their long-term application may be limited by adverse reactions and poor adherence in some patients. ZangHongQu(ZHQ) herbal slice is a novel red yeast rice formulation formed by the fermentation of highland barley and red yeast rice bacteria, containing natural Monacolin K and various bioactive components, which has lipid-lowering and metabolic regulatory effects. However, currently, there is a lack of high-quality randomized controlled trials systematically evaluating its efficacy and safety. This study aims to assess the efficacy and safety of ZHQ in treating dyslipidemia. Methods This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. It plans to enroll 240 patients aged 18–75 years with dyslipidemia and LDL-C ≥ 3.4 mmol/L. Participants will be randomly assigned in a 1:1 ratio to either the intervention group receiving ZHQ or the control group receiving placebo. The primary outcome measure is the change in LDL-C levels. Secondary outcomes include other lipid parameters, blood glucose, insulin, uric acid, and homocysteine levels. Safety assessments encompass liver and kidney function, creatine kinase, vital signs, and adverse events monitoring. Assessments will be conducted at baseline, 4 weeks, and 12 weeks after intervention. Discussion This study aims to provide high-quality evidence-based medicine for the efficacy and safety of ZHQ in treating dyslipidemia, and to provide a scientific basis for its potential application in cardiovascular risk management. Clinical Trial Registration and Ethics http://itmctr.ccebtcm.org.cn/ , ITMCTR2025001724. Ethical Review Number: 2025HL-359-01.

Background Myocardial ischemia-reperfusion injury (MIRI) constitutes a significant contributor to the increased incidence of post-ischemic heart failure. The primary mechanisms underlying MIRI involve oxidative stress and mitochondrial calcium overload in reperfused cardiomyocytes. Regulating the homeostasis of the mitochondrial-associated endoplasmic reticulum membranes (MAMs) to improve endoplasmic reticulum-mitochondrial communication is expected to treat MIRI, but there are currently no clear targeted drugs. The Shenfuyixin Granules (SFYX) exhibit capabilities in lowering reactive oxygen species levels, curtailing apoptosis, and improving mitochondrial performance in cardiomyocytes. However, its therapeutic role in MIRI remains unclear. Aim of the study This study aims to clarify the effect of SFYX on mitochondrial calcium overload after MIRI and elucidate its potential mechanism of action. Methods The rat MIRI model was established by short-time ligation of the left anterior descending coronary artery and reperfusion, and SXNI (3.275g/kg, 6.55g/kg, 13.1g/kg) was administered for treatment. Network pharmacology combined with molecular docking has revealed the specific molecular mechanism by which SFYX regulates mitochondrial calcium homeostasis in the myocardium. The improvement effect of SFYX on MIRI was evaluated by western blotting (WB), TUNEL staining, immunofluorescence staining, etc. A hypoxia/reoxygenation (H/R) model of myocardial cells was simultaneously established, MIRI was simulated in vitro, and the mechanism was verified using WB, fluorescent probes, mitochondrial function and other related tests. Results Network pharmacological analysis and molecular docking indicated that SFYX might improve MIRI by reducing mitochondrial calcium overload through the cGMP-PKG signaling pathway and calcium signaling pathway, and the key blood-entering components could stably bind to cGMP and PKG. In vivo experiments confirm that SFYX significantly attenuates myocardial injury associated with MIRI and alleviates levels of oxidative stress and apoptosis through the sGC/PKG pathway. In vitro experiments verify that SFYX regulates MAMs via the sGC/PKG signaling pathway, thereby stabilizing mitochondrial function, alleviating calcium overload and oxidative stress, and ultimately combating MIRI. Conclusion This study suggests that SFYX prophylactic administration can alleviate mitochondrial calcium overload by targeting MAMs through the sGC/PKG signaling axis and has a preventive effect on MIRI. These findings indicate that SFYX may become a potential drug for preventing MIRI in the future.

This study aimed to analyze the clinical studies of TCM in treating unstable angina pectoris(UAP)in elderly patients through evidence mapping.The objective was to understand the current status and deficiencies of evidence in this field and to provide directions for future research.A systematic search was conducted across multiple databases,including CNKI,Wanfang,VIP,SinoMed,PubMed,EMbase,Web of Science,and Cochrane Library,covering the period from January 1,2005 to August 31,2025.This search included clinical studies on TCM for the treatment of UAP in elderly patients and aimed to present the distribution characteristics of the evidence in tables and charts.Ultimately,a total of 306 randomized controlled trials(RCTs),6 non-randomized controlled trials(non-RCTs),4 systematic reviews,4 observational studies,and 1 guideline were included.The research interest remained stable over the past seven years,reflecting a trend of low attention.The studies involved 54 types of Chinese patent medicines,with Danhong Injection,Salvia Miltiorrhiza Polyphenol Hydrochloride Injection,and Tongxinluo Capsules comprising the largest proportion.Most studies were single-center with small sample sizes(predominantly between 60-120 cases)and short treatment durations(mostly 2-4 weeks).Outcome indicators primarily focused on symptoms/signs and electrocardiograph(ECG),with less emphasis on prognosis,quality-of-life indicators,and TCM syndromes.The overall quality of literature for RCTs,non-RCTs,and systematic reviews/Meta-analyses was generally low,and the guideline development process lacked standardization,which resulted in an extremely low level of evidence quality.The results indicated that,despite the substantial number of clinical studies on the treatment of UAP in elderly patients with TCM,the level of evidence remained constrained by the quality of the literature.Moving forward,it is essential to conduct more large-scale,multi-center,and long-term clinical trials,standardize systematic reviews,and actively develop a core outcome indicator set that integrates the unique characteristics of TCM.These efforts are crucial for advancing the high-quality development of clinical research on TCM in the treatment of UAP in elderly patients.

Cardiovascular disease (CVD) remains the leading cause of mortality and disability worldwide, characterized by high incidence, morbidity, and mortality. Although guideline-directed medical therapy has improved clinical outcomes and slowed disease progression to some extent, a substantial residual risk persists, and the progression of CVD has not been fundamentally halted. Beyond traditional risk factors such as hypertension, diabetes mellitus, and dyslipidemia, dysregulated inflammatory responses are now recognized as a central driver of CVD initiation, progression, and adverse outcomes. Neutrophil extracellular traps (NETs), as key effectors of innate immunity, contribute to inflammatory cascades through mechanisms including inflammasome activation, modulation of immune responses, and promotion of thrombosis. Accumulating evidence indicates that NETs play a critical role in a spectrum of cardiovascular conditions, including atherosclerosis, myocardial infarction, and heart failure, and are closely associated with poor prognosis. This review systematically summarizes the mechanisms by which NETs mediate inflammatory responses in CVD and discusses their roles across different disease contexts. It further explores the potential of NETs as inflammation-related biomarkers and therapeutic targets, with the aim of providing new insights into inflammation-based strategies for the prevention and treatment of CVD.

IntroductionHeart failure with preserved ejection fraction (HFpEF) is a highly complex clinical syndrome associated with significant morbidity and mortality. Its underlying mechanisms are poorly understood, treatment options are limited, the disease burden on patients is substantial, and clinical outcomes are poor. Previous clinical studies have preliminarily suggested that Shengxian Yixin Granule (SXYX) is an effective herbal formula for the treatment of HFpEF, but it lacks high-quality clinical evidence. This study therefore plans to conduct a randomized controlled trial (RCT) to evaluate the efficacy and safety of SXYX in treating HFpEF, aiming to provide a new therapeutic strategy for this condition.MethodsThis study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. It will be conducted at four Chinese medicine hospitals in China. A total of 148 eligible patients with HFpEF will be enrolled and randomly assigned in a 1:1 ratio to the SXYX group or the placebo group. The SXYX group will receive Shengxian Yixin Granule, while the placebo group will receive a matching placebo. Both groups will receive standard Western medical therapy as background treatment. The treatment duration for all groups is 24 weeks. The primary outcome is the change in peak VO2 (assessed by cardiopulmonary exercise testing) from baseline to 24 weeks. Secondary outcome measures include the change in peak oxygen uptake from baseline to 12 weeks, NT-proBNP, echocardiographic parameters, NYHA functional class, 6-minute walk test distance (6MWT), Traditional Chinese Medicine (TCM) syndrome scale, major symptoms and signs, EQ-5D score, and coagulation function. These outcomes will be used to evaluate the efficacy of SXYX. Routine blood, urine, and stool tests, liver and kidney function tests, electrocardiograms, and adverse events will be used to assess the safety of SXYX. Wearable monitoring devices will be used for out-of-hospital, dynamic, and multidimensional assessment of patients’ exercise tolerance, including heart rate, blood oxygen saturation, step count, and walking distance.DiscussionThis study will evaluate the efficacy and safety of SXYX in treating HFpEF. The findings will provide a scientific basis for the clinical application of SXYX.Clinical Trial Registrationhttps://itmctr.ccebtcm.org.cn, identifier ITMCTR2026000833.

Hyperlipidemia(HLP) is a significant independent risk factor for the occurrence and development of cardiovascular and cerebrovascular diseases. Currently, the common clinical lipid-lowering agents include statins(inhibiting HMG-CoA reductase), fibrates(activating PPARα), cholesterol absorption inhibitors(blocking NPC1L1), and PCSK9 inhibitors(preventing LDLR degradation). However, clinical concerns remain about the combination use of multiple drugs, hepatorenal toxicity, and poor adherence to long-term application. The sterol regulatory element-binding protein(SREBP) pathway serves as a master regulator of lipid synthesis, concurrently controlling multiple steps in this process. Targeted intervention of the overactivated SREBP pathway has emerged as a novel research direction for regulating lipid metabolism disturbances, though it remains largely in the preclinical stage of drug research and development. TCM demonstrates multi-target and holistic regulatory advantages in regulating the SREBP pathway. Studies reveal that TCM compounds(Zexie Decoction, Xiangsha Liujunzi Decoction, and so on) and active constituents(berberine, curcumin, and so on) can systematically ameliorate lipid metabolic disturbances by inhibiting SREBP-1c/2 activation and the expression of downstream genes such as FAS, ACC, and HMGCR. This review summarized clinical trials and experimental research in recent years on the mechanisms by which TCM prevents and treats HLP by regulating the SREBP pathway, aiming to provide theoretical basis and new insights for the prevention and treatment of HLP as well as further research.

Myocardial ischemia-reperfusion injury (MIRI) is a key factor affecting the prognosis of myocardial infarction patients. Currently, there remains a lack of specific drugs targeting MIRI, and it is unclear whether Piceatannol-3'-O-β-D-glucopyranoside (PG) improves MIRI through metabolic reprogramming. Therefore, this study takes a clinically oriented approach, using multi-omics technologies to investigate how PG regulates metabolic reprogramming to improve MIRI. The study focuses particularly on PG's regulation of lactate and lactylation. Results indicate that PG enhances LVEF and LVFS, reduces cTnI and CK-MB levels, decreases ROS, lactate, and LDH levels, and increases ATP expression, thereby improving cardiac function. Metabolomics results based on clinical serum samples indicate that PG can reduce lactate and pyruvate levels. The results of research conducted on animal subjects suggest that exogenous lactate supplementation has the capacity to attenuate the cardioprotective effects of PG. PG intervention significantly suppressed the expression of PDK4, MCT1, and ACSL4 proteins while enhancing GPX4 protein expression, inhibiting lipid peroxidation, and improving mitochondrial structure and function. However, the overexpression of PDK4 led to a diminution of the PG-mediated enhancement in MIRI. Overexpression of NDUFS1 K170 lactylation similarly impaired the PG-mediated improvement of MIRI. Therefore, we conclude that PG improves MIRI by inhibiting NDUFS1 K170 lactylation through metabolic reprogramming regulation. The present study provides novel targets and therapeutic agents for MIRI intervention, while also offering fresh insights into the pathogenesis of MIRI.

ObjectiveObstructive sleep apnea (OSA) is a highly prevalent sleep disorder strongly linked to obesity and substantially increases the risk of cardiovascular and metabolic diseases. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and aerobic exercise have shown potential in improving OSA through distinct metabolic and physiological mechanisms. However, direct comparative evidence of their efficacy remains limited. This network meta-analysis aimed to compare the effects of SGLT2 inhibitors, GLP-1 receptor agonists, and aerobic exercise on OSA severity in overweight or obese patients.MethodsWe searched four electronic databases, PubMed, EMBASE, the Cochrane Library, and Web of Science, for articles published before October 31, 2025, without language restrictions. The analysis primarily included randomized controlled trials (RCTs); a limited number of case–control studies were also incorporated due to the scarcity of direct comparative evidence. Primary efficacy outcomes were mean changes in the apnea–hypopnea index (AHI), body mass index (BMI), mean peripheral oxygen saturation (SpO2), and Epworth Sleepiness Scale (ESS) score. The certainty (confidence) of the evidence for every network estimate was appraised with the Confidence in Network Meta-Analysis (CINeMA) framework, which operationalizes the GRADE approach for network meta-analysis.ResultsA total of 15 studies (13 RCTs and 2 case–control studies) involving 1,877 participants were included in the analysis. GLP-1 receptor agonists demonstrated the greatest reduction in AHI compared with placebo (mean difference [MD] = −15.28 events/h; 95% CI, −22.22 to −8.35). They also showed significant benefit versus placebo in lowering BMI (MD = −1.78 kg/m2; 95% CI, −2.15 to −1.41) and improving mean SpO2 (MD = 0.40%; 95% CI, 0.25 to 0.55). Although GLP-1 receptor agonists yielded a statistically significant improvement in ESS score versus placebo (MD = −0.20; 95% CI, −0.26 to −0.14), this effect was an order of magnitude below the 2-point minimal clinically important difference (MCID) for the ESS and is therefore not clinically meaningful. Aerobic exercise ranked highest in surface under the cumulative ranking curve (SUCRA) analysis for this outcome. No network estimate was rated as high certainty. Confidence was moderate for the effect of GLP-1 receptor agonists on BMI, low for their effects on AHI, mean SpO2, and ESS score versus placebo, and very low for all remaining comparisons, mainly because of within-study bias, imprecision, and suspected reporting bias.ConclusionCompared with placebo, GLP-1 receptor agonists reduced AHI and BMI and improved mean SpO2, and ranked highest for these outcomes in the SUCRA analysis. Comparisons between the active interventions, however, were largely non-significant and rested on indirect evidence, and the certainty of the evidence was moderate at best, being low or very low for most comparisons. This treatment hierarchy should therefore be regarded as hypothesis-generating rather than as a basis for firm clinical recommendations. Within these limits, these findings suggest that GLP-1 receptor agonists may offer a promising therapeutic approach for managing OSA in overweight or obese patients with metabolic comorbidities, though this remains to be confirmed in larger, high-quality, head-to-head trials.

This study aimed to explore whether Tongmai Yangxin Pills(TMYX) can improve cardiac arrhythmia in rats after ischemia-reperfusion(I/R) by inhibiting inflammation and apoptosis through the advanced glycation end products(AGE)-receptor for AGE(RAGE) signaling pathway. This study employed the Langendorff isolated heart perfusion system for electrophysiological mapping to determine the safe concentration range of TMYX. Subsequently, network pharmacology was utilized to predict the potential targets and key signaling pathways of TMYX against cardiac arrhythmia. Finally, the in vivo I/R cardiac arrhythmia model in rats was established through left anterior descending coronary artery ligation for verification. In the in vitro experiment, the control group and the TMYX group were used to explore the safe concentration of TMYX, and the I/R group and the TMYX group were used to observe the incidence of cardiac arrhythmia. The animals for the in vivo experiment were randomly divided into the control, I/R, low/high-dose TMYX, metoprolol, and RAGE inhibitor FPS-ZM1 groups, and corresponding interventions were given. During the experiment, cardiac arrhythmia was monitored by electrocardiograms, and cardiac function was evaluated by echocardiograms. The myocardial infarction area was observed by triphenyltetrazolium chloride(TTC) staining, aggregation of inflammatory cells was observed by hematoxylin-eosin(HE) staining, and cell apoptosis was detected by TUNEL staining. The levels of inflammatory factors were determined by enzyme-linked immunosorbent assay(ELISA). Network pharmacology was used to find the potential targets and key signaling pathways of TMYX, and the changes in the expression levels of related proteins were detected by Western blot. When the dose did not exceed the clinical equivalent dose(5 mg·mL~(-1)), TMYX had little effect on the electrophysiological parameters of isolated hearts of rats. TMYX could significantly improve the cardiac arrhythmia induced by I/R injury in in vivo and isolated hearts, reduce the incidence and duration of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation, and improve left ventricular systolic function. TMYX treatment could reduce the myocardial infarction area, attenuate the aggregation of inflammatory cells in myocardial tissue, lower the level of cell apoptosis, and down-regulate the abnormal increase in the expression of serum interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). At the same time, it was observed that TMYX treatment could inhibit the activation of the AGE-RAGE signaling pathway in I/R myocardial tissue and the changes in the protein expression of B-cell lymphoma-2(Bcl-2) and Bcl-2 associated X protein(Bax). This study, through the integration of experimental strategies, has for the first time confirmed TMYX may inhibit the activation of the AGE-RAGE signaling pathway in I/R myocardial tissue of rats, thereby reducing inflammation and apoptosis, and ultimately improving I/R cardiac arrhythmia.

This multicenter observational analysis, based on prospectively collected data from a 1-year disease-management cohort, assessed secondary prevention status at enrollment and 1-year unplanned readmission among 2,896 patients with cardiovascular and cerebrovascular diseases in China. Patients included 1,061 with stable angina (CAD), 427 with myocardial infarction (MI), 1,141 with cerebral infarction (CI), and 267 with intracerebral hemorrhage (ICH), recruited from three regions between August 2020 and March 2021. Data on demographics, Traditional Chinese Medicine (TCM) syndromes, and medications were analyzed. Logistic regression was used to examine factors associated with blood pressure, lipid, and glucose target achievement, as well as 1-year readmission. Among 2,698 patients with available target-control data, the blood pressure target-achievement rate was 45.4

ETHNOPHARMACOLOGICAL RELEVANCE:Zhigancao Decoction (ZGCT), also known as Fumai Decoction, is a classical traditional Chinese medicine formula recorded in Shanghan Lun and has long been used for the treatment of "palpitations" and "irregular pulse," corresponding to arrhythmias in modern medicine. Although ZGCT has shown beneficial effects against cardiac arrhythmias, its absorbed bioactive constituents and the underlying mechanisms involved in ischemic heart failure (IHF)-related ventricular arrhythmias (VAs) remain unclear. AIM OF THE STUDY:This study aimed to characterize the chemical profile of ZGCT and identify its circulating and cardiac constituents using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), to identify key pathways through transcriptomic analysis, and evaluate the effects of ZGCT on IHF-related VAs in rats while exploring the potential involvement of myocardial fibrosis and TGF-β/Smad signaling. MATERIALS AND METHODS:UPLC-Q-TOF-MS was employed to characterize the chemical constituents of ZGCT extract and to identify its absorbed components in rat serum and myocardial tissue after administration, thereby defining its in vivo bioactive basis. RNA sequencing (RNA-seq)-based transcriptomic profiling was then performed on myocardial tissues from the control, model, and ZGCT-treated groups to identify differentially expressed genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to screen candidate signaling pathways underlying ZGCT activity. In addition, a rat model of IHF was established by permanent ligation of the left anterior descending coronary artery. Rats were randomly assigned to the control, model, low-, medium-, and high-dose ZGCT, metoprolol, SB-431542(a selective TGF-β receptor type I inhibitor), and SB-431542 plus ZGCT groups. Cardiac function was evaluated by echocardiography; ventricular arrhythmia susceptibility, conduction velocity, and electrical conduction dispersion were assessed by burst pacing and multichannel electrical mapping; infarct size and myocardial fibrosis were determined by 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), and Masson's trichrome staining; and the expression of TGF-β1, phosphorylated Smad3 (p-Smad3), Smad7, and matrix metalloproteinase 2 (MMP2) was measured by Western blotting and RT-qPCR. RESULTS:UPLC-Q-TOF-MS identified 113 constituents in the ZGCT extract in vitro, of which 80 were detected in serum and 53 were distributed in myocardial tissue after administration. Transcriptomic analysis revealed that ZGCT predominantly regulated the extracellular matrix (ECM)-receptor interaction and TGF-β signaling pathways, with the TGF-β pathway emerging as a putative key target. In IHF rats, ZGCT significantly improved cardiac function and reduced both the incidence and duration of ventricular arrhythmias. Multichannel electrical mapping further demonstrated that ZGCT reversed IHF-induced slowing of conduction velocity and increased conduction dispersion. Mechanistically, ZGCT downregulated the expression of TGF-β1, p-Smad3, and MMP2, while upregulating Smad7. SB-431542 elicited anti-fibrotic and pathway-related molecular changes comparable to those of ZGCT, further supporting a role for TGF-β/Smad signaling in the anti-fibrotic effects of ZGCT. CONCLUSIONS:ZGCT reduced ventricular arrhythmia susceptibility and improved conduction abnormalities in IHF rats in association with attenuation of myocardial fibrosis and modulation of transforming growth factor-β/Smad-related signaling. However, these findings were obtained from a single batch of ZGCT, and further multi-batch validation is required to confirm its chemical consistency and pharmacological reproducibility.

Heart failure (HF) is a terminal cardiovascular syndrome related to systemic hypoxia. Hypoxia is considered a fundamental pathophysiological process, and the resulting tissue response depends on the severity and duration of exposure. Hypoxia-inducible factors (HIFs) promote adaptation to hypoxic conditions by regulating the expression of multiple hypoxia-responsive genes. Its short-term activation during acute hypoxia exerts cardioprotective effects, whereas chronic activation induces pathological hypertrophy, depending on the disease context. Therefore, HIF-mediated hypoxic responses in HF may involve hierarchical adaptations to hypoxia. This review discusses the role of HIFs in the physiology and pathology of HF, focusing on metabolic remodeling, angiogenesis, cardiac inflammation, and circadian influences, as well as their potential effects on myocardial performance. Furthermore, the therapeutic potential of HIF-targeting compounds in HF treatment will be reviewed. Overall, whether targeting HIF-induced changes in HF is an effective strategy remains to be established; thus, research in this field is urgently needed.

Objective:Ischemic heart failure (IHF) is a multifaceted syndrome associated with significant mortality and high hospitalization rates globally. Yiqi Huoxue prescription (YQHX) has been incorporated into clinical practice, showing significant therapeutic efficacy. However, to date, the pharmacological mechanisms remain vague. We combined multi-omics, machine learning, and molecular docking strategies to elucidate the mechanisms by which YQHX protects against IHF. Methods:Clinically, the efficacy and safety of YQHX in improving cardiac function in IHF patients were observed. Transcriptomic, proteomic, and targeted metabolomic analyses were performed on serum samples from IHF patients and healthy individuals before and after YQHX intervention. Multi-omics association analysis integrating machine learning identified the potential mechanisms underlying YQHX's effects. Key ingredient-targets interactions were validated in vitro experiments. Results:After 12 weeks of treatment, YQHX significantly decreased N-terminal pro-B-type natriuretic peptide (NT-proBNP) (MD, -1180.28; 95% CI: -2107.23 to -253.32), enhanced left ventricular ejection fraction (LVEF) (MD, 4.78; 95% CI: 2.23 to 7.32), and improved 6-minute walk distance (6MWD). No serious adverse events were observed during the study. Multi-omics integration analysis revealed that platelet activation NET formation, HIF-1 signaling pathway, TCA cycle, and glycolysis are indispensable pathways for the treatment of IHF. Machine learning has identified H3-3A, HMGB1, SOD2, ACTG1, PGAM1, FGA, LDHA, FN1, VWF, and ACO2 as critical molecular targets of YQHX treatment. Clinical research further demonstrated that YQHX treatment beneficially modulates energy metabolism, improves coagulation system functions, and ameliorates inflammatory responses in IHF. Molecular docking revealed that astragaloside I/III/IV, isoastragaloside I/II, paeoniflorin, and hydroxysafflor yellow A are likely active compounds contributing to YQHX's therapeutic effects, and these findings were further validated through in vitro experiments. Conclusion:YQHX combats IHF via multi-target and multi-pathway mechanisms, including energy metabolism reprogramming, coagulation system enhancement, and immune-inflammatory response modulation, positioning it as a potential therapeutic strategy for IHF.

Background:Heart failure (HF) secondary to acute myocardial infarction (AMI) remains a public health concern. Peripheral blood mononuclear cells (PBMCs) are the essential initiators of heart failure after myocardial infarction (HFpAMI). We aimed to identify PBMCs-related critical genes as diagnostic biomarkers for HFpAMI and analyze the immune infiltration patterns. Methods:Differential expression genes (DEGs) from PBMCs microarray data of AMI with or without HF were identified. Functional enrichment analysis was used to explore the biological roles of DEGs. Subsequently, candidate biomarkers were identified using machine learning and the MCODE plugin, with ROC used to describe the accuracy. CIBERSORT was utilized to investigate immune infiltration. Multi-level validation of our findings was conducted, including RNA-seq profiling of the external cohort, RT-qPCR, and flow cytometry analyses on PBMCs samples. Results:In the comparison between 30 HFpAMI and 34 non-HF samples, 27 DEGs were identified. Functional enrichment analysis suggested that DEGs may be involved in the pathological process of HFpAMI by participating in immune-inflammatory response. Employing machine learning and MCODE assessment, we identified three robust potential biomarkers (CLU, FOS, and CXCL8). Immunological analysis revealed a marked increase in neutrophils and decrease in CD4T cells. In the external validation cohort, RNA-seq analysis demonstrated consistent upregulation of CLU, FOS, and CXCL8 in HFpAMI compared to non-HF controls. RT-qPCR and flow cytometry further corroborated these expression trends and their correlations with neutrophil infiltration, CD4T cells and M2 macrophage concentration reductio, aligning with bioinformatics predictions. ROC analysis validated the diagnostic efficacy of these biomarkers, with CLU exhibiting the highest AUC (0.833, 95% CI: 0.679-0.988), followed by FOS (0.809, 95% CI: 0.64-0.977) and CXCL8 (0.802, 95% CI: 0.635-0.970). Conclusions:Significantly upregulated DEGs, including CLU, FOS, and CXCL8, might be served as novel diagnostic biomarkers for HFpAMI, and dysregulated immune infiltration hinted possible the immune system intervention point in the setting of HFpAMI.

Atherosclerosis, a chronic inflammatory disorder and leading cause of cardiovascular disease, is characterized by macrophage-derived inflammation and foam cell formation. Emerging evidence suggests that metabolic reprogramming of macrophages represents a promising therapeutic approach for atherosclerosis management. In this study, the therapeutic potential of wogonin, a bioactive flavonoid isolated from Scutellaria baicalensis, in modulating macrophage metabolism and attenuating atherogenesis is investigated. Wogonin reduces lesion size and plaque vulnerability, accompanied by a reduction in foam cell formation and inflammation. Mechanistically, wogonin reprogrammes macrophage metabolism from glycolysis to fatty acid oxidation (FAO) by activating the PPARα-CPT1α pathway and acts as a mitochondrial protector by activating PPARα. Wogonin also promotes the KLF11 expression and KLF11 knockout exacerbated atherosclerosis and abolishes the inhibitory effect of wogonin on glycolysis and atherosclerosis. KLF11 forms a transcriptional complex with PPARα and YAP1, serving both as a brake on PPARα-YAP1-mediated glycolysis and a transcriptional activator of ABCA1/G1. Collectively, wogonin reprograms macrophage metabolism from glycolysis to FAO through activation of the PPARα-KLF11-YAP1 pathway, thereby reducing inflammation and foam cell formation, ultimately attenuating atherogenesis.

BACKGROUND:Lingguizhugan decoction (LGZG), a typical Chinese herbal formula, has remarkable clinical effects for treating pulmonary hypertension (PH) with unclear ingredients and mechanisms. This study aimed to evaluate the efficacy of LGZG and the mechanism of its active ingredients in treating PH. METHODS:The PH patient phenotype was characterized by transcriptomic assay of peripheral blood mononuclear cells (PBMCs) and multiplex cytokine profiling of serum. The active ingredients of LGZG were identified by UPLC-Q-TOF-MS. The monocrotaline (MCT)-induced PH model was performed to evaluate the effects of LGZG and its active ingredients in vivo. The interleukin-33 (IL-33)-induced RAW264.7 cells and the mouse pulmonary artery smooth muscle cells (mPASMCs) were applied to explored phenotype and mechanism of the active ingredients of LGZG by immunofluorescence, western blotting and RT-qPCR in vitro. RESULTS:Inflammatory receptor activity in PBMCs and serum interleukin-6 (IL-6) levels were elevated in PH patients. Porinic acid B, cinnamic acid, atractylenolide I and glycyrrhizin (PCAG) were characterized and combined to treat the PH, And the IL-33/Growth stimulation expressed gene 2 (ST2) pathway may be the potential mechanism by transcriptomic analysis of lung tissues. Both in vivo and in vitro experiments confirmed that PCAG inhibited the IL-33/ST2 pathway, reduced macrophage polarization, and suppressed IL-6 secretion. Moreover, ST2 overexpression in macrophages attenuated the inhibitory effect of PCAG. Using a co-culture system of macrophages and mPASMCs, we demonstrated that PCAG reduced mPASMCs phenotypic switching by suppressing macrophage-derived IL-6 secretion. CONCLUSION:The active ingredient of LGZG, PCAG, inhibits the progression of PH by preventing macrophage polarization and IL-6 secretion through the IL-33/ST2 pathway.

BackgroundIschemic heart failure (IHF) is one of the leading causes of death worldwide. In traditional Chinese medicine, blood stasis syndrome (BSS) is regarded as a core pathological feature of IHF. This study aims to clarify the main biological characteristics and underlying mechanisms of BSS in IHF.MethodsUsing an integrated multi-omics strategy combining transcriptomics, proteomics, and targeted metabolomics, we systematically analyzed the molecular characteristics of BSS in patients with IHF from multiple perspectives. By integrating multi-omics data and correlating them with clinical parameters, we identified a core molecular network associated with BSS. Key targets within this network were further validated using iPRM and RT-qPCR. ROC curve analysis and responses to pharmacological intervention were employed to confirm the diagnostic and therapeutic potential of these core molecular targets.ResultsA total of 435 differentially expressed genes, 176 differentially abundant proteins, and 40 differentially altered metabolites related to IHF with BSS were identified. Multi-omics analysis highlighted the involvement of the complement and coagulation cascade and B cell receptor signaling pathway. Moreover, targeted metabolomics suggested that metabolic pathways associated with BSS involve glycine, arginine, tryptophan metabolism, and fatty acid biosynthesis. Integrated multi-omics correlation analysis identified CD79A, CD79B, CD19, CD22, CR2, F2, F8, F9, C3, FN1, 5-hydroxyindolacetic acid, and 4-acetamidobutanoate as core molecular features, with significant correlations observed between these molecules and clinical indicators. iPRM and RT-qPCR validation confirmed that the expression trends of these core molecules are consistent with the sequencing results. Furthermore, cross-validation with Yiqi Huoxue formula intervention identified F2, F8, F9, and FN1 as four diagnostic and therapeutic targets for BSS.ConclusionThis multi-omics analysis reveals that immune dysregulation, inflammation, and impaired coagulation function are central to BSS in IHF. Key pathways involved include the complement and coagulation cascade as well as B-cell receptor signaling, with F2, F8, F9, and FN1 identified as potential diagnostic and therapeutic targets. These findings provide new molecular insights into BSS in IHF.