Acute coronary syndrome, driven by vulnerable plaque (VP) instability, is a major cause of cardiovascular mortality. Current diagnostic methods for VPs are limited by invasiveness or low specificity, highlighting the need for non-invasive biomarkers. Using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from coronary artery disease (CAD) patients with VPs and controls, we identified circulating T cell-platelet aggregates (TPAs) significantly enriched in VP patients and linked to plaque instability via pro-inflammatory pathways. Through high dimensional weighted gene co-expression network analysis, we discovered TPAs' hub genes and demonstrated their role in plaque destabilization. Furthermore, employing machine learning, including Boruta, least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE), we screened for five blood biomarkers that can serve as diagnostic indicators for VPs. Our study demonstrates that TPAs are critically involved in VPs formation. Furthermore, we identified EPHB6, STAT1, RPL23, IKZF3 and AHCY as potential circulating biomarkers for non-invasive detection of VPs.

BACKGROUND:This study aims to investigate the relationship between risk factors and IRA-related microcirculatory dysfunction, as well as its pharmacological intervention in the context of STEMI treatment using DCB over a two-year period, especially in those with diabetes. METHODS:This retrospective study enrolled 297 consecutive eligible patients diagnosed with STEMI who received DCB treatment from two centers. Clinical and procedure-related parameters were collected. AMR and adverse cardiac events were recorded. RESULTS:Immediately after DCB therapy, IRA-AMR in non-diabetes or good-glycemic control group was significantly smaller than that in diabetes or poor-glycemic control group (p < 0.01). Compared with insulin or dapagliflozin group, IRA-AMR in non-insulin or non-dapagliflozin group was significantly higher (p < 0.01). Univariate and multivariate Cox regression indicated that diabetes was a significant predictor of IRA-INOCA after a 2-year follow-up (p < 0.05). Furthermore, administration of anti-diabetic medications and poor glycemic control post DCB treatment surfaced as significant predictors (p < 0.01). Diabetic patients exhibited a significantly higher incidence of cardiac death along with IRA-INOCA complications compared to their non-diabetic counterparts (p < 0.01). IRA-AMR in diabetic individuals immediately following DCB treatment was significantly lower than those in individuals who experienced inadequate-glycemic management and were readmitted due to IRA-INOCA complications (p < 0.01). The incidence of IRA-INOCA in good-glycemic control, insulin, or dapagliflozin group was significantly lower compared with that in poor-glycemic control, non-insulin, or non-dapagliflozin group (p < 0.05). CONCLUSIONS:This finding highlights the importance of managing glycemic control, especially using insulin or dapagliflozin, in diabetic patients with STEMI after DCB treatment. Such measures may improve long-term cardiovascular outcomes.

Two unique polyphenolic compounds featuring a 6/6/7/6/5 fused skeleton, sotodisoflavanones A and B (1 and 2), and two novel 2-arylbenzofuran dimers shandougenines C and D (3 and 4) were isolated from the roots of Sophora tonkinensis. Their structures were elucidated through spectroscopic analysis and quantum chemical calculations. Compounds 1 and 5-7 showed significant PTP1B inhibition (IC50 = 2.70 ± 0.50, 0.88 ± 0.17, 2.70 ± 0.50, 1.90 ± 0.40 μM, respectively) and enhanced insulin sensitivity by promoting HepG2 cell glucose consumption.

We developed a pharmacophore fusion strategy to design dual-action Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) inhibitors. This involved integrating rhodanine-3-acetic acid with the nitroimidazooxazine/oxazole core of antitubercular nitroimidazoles. The resulting compounds showed potent MptpB inhibition and direct antituberculosis activity. Docking studies indicated a conserved binding mode, with the rhodanine moiety in the P1 pocket and the nitroimidazole core in the P2 pocket. Compound 4 was most promising, exhibiting strong MptpB inhibition (IC50: 0.19 μM), good antituberculosis efficacy (MIC: 1.94 μg/mL), and high selectivity over human PTP1B (345-fold). It also demonstrated excellent metabolic stability, good permeability, acceptable bioavailability in mice, low cytotoxicity, and outperformed Rifampicin and Pretomanid in a macrophage infection model. Mechanistic studies showed that it reversed MptpB-mediated suppression of the macrophage MAPK pathway. This work validates the fusion strategy and identifies a promising lead targeting MptpB for further development.

Background A novel computational angiographic microcirculatory resistance (AMR) derived from a single angiographic view presents a feasible alternative to the pressure wire‐based index of microcirculatory resistance. However, its prognostic significance in patients undergoing percutaneous coronary intervention (PCI) remains insufficiently established. Methods This is a post hoc analysis of 3404 patients undergoing PCI from the FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients With Coronary Artery Disease) trial. Pre‐ and post‐PCI AMR were measured in target vessels, with percentage change in AMR before and after PCI calculated as (100×[post‐PCI AMR−pre‐PCI AMR]/pre‐PCI AMR). The primary model used was the log‐rank test, and the proportional hazards model was also used to assess the association between AMR and the 3‐year risk of major adverse cardiac events, defined as a composite of all‐cause death, myocardial infarction, or ischemia‐driven revascularization. Results Patients with percentage change in AMR before and after PCI ≥85 (23.7%) versus <85 (76.3%) had comparable baseline characteristics but received more and longer stents per patient. Overall major adverse cardiac events risk was similar between groups (14.8% versus 12.4%; hazard ratio [HR], 1.18 [0.95–1.45]; log‐rank P=0.064). However, in patients with post‐PCI AMR ≥250, percentage change in AMR before and after PCI ≥85 showed a significant increase in the major adverse cardiac events risk (16.3% versus 10.8%; HR, 1.52 [1.14–2.04]), contrasting with no difference when post‐PCI AMR <250 (12.3% versus 13.4%; HR, 0.89 [0.63–1.25]; Pinteraction=0.019). Conclusions In patients undergoing PCI from the FAVOR III China population, significant AMR elevation (percentage change in AMR before and after PCI ≥85) in target vessels alone did not predict outcomes, but in the subgroup with post‐PCI AMR ≥250 it identified patients at increased 3‐year cardiovascular risk. REGISTRATION https://www.clinicaltrials.gov; Unique identifier: NCT03656848.

BACKGROUND:The prognostic utility of residual pressure wire-based physiological assessment after percutaneous coronary intervention (PCI) has been demonstrated. OBJECTIVES:The aim of this study was to investigate the prognostic value of the residual global Murray law-based angiographic quantitative flow ratio (μQFR) in an acute coronary syndrome (ACS) population. METHODS:In this post hoc analysis from the FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients With Coronary Artery Disease) trial, off-line μQFR was computed for 3 major coronary arteries. Residual global μQFR was calculated as the sum of postprocedural μQFR values for treated vessels and preprocedural values for nontreated vessels. ACS patients (including those with ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina) were categorized into high-risk (less than or equal to the cutoff value) and low-risk (greater than the cutoff value) groups according to residual global μQFR. The primary endpoint was 3-year major adverse cardiac events (MACE), the composite of all-cause death, myocardial infarction, or ischemia-driven revascularization. RESULTS:Among 2,428 ACS patients, 2,241 (92.3%) had analyzable μQFR, with a cutoff value of 2.71. High-risk patients (n = 407 [18.2%]) had a greater incidence of 3-year MACE (21.2% vs 10.4%; adjusted HR [aHR]: 1.53; 95% CI: 1.10-2.13; P = 0.01) and MACE excluding periprocedural myocardial infarction (16.2% vs 7.8%; aHR: 1.72; 95% CI: 1.17-2.53; P = 0.006) compared with the low-risk group. The prognostic effect of residual global μQFR was consistent across QFR- and angiography-guided subgroups (P for interaction = 0.35). Patients with low residual ischemia derived the best outcomes after QFR-guided PCI (MACE 8.8% vs 11.9% for angiography-guided PCI; HR: 0.73; 95% CI: 0.55-0.97). CONCLUSIONS:Residual global μQFR is a robust angiographic index for post-PCI ischemia burden and long-term risk stratification. In patients with ACS, QFR-guided PCI achieving low residual global ischemia was associated with the most favorable 3-year prognosis.

Background:In the treatment of coronary calcification by rotational atherectomy (ROTA), guidewire bias is often considered to lead to procedure-associated coronary dissections or perforations. However, the actual meaning of guidewire bias is unclear, though it usually refers to the cross-sectional location of the intravascular imaging (IVI) catheter in the coronary artery. This study tentatively explores the quantitative criteria in optical coherence tomography (OCT) imaging of guidewire bias, which may cause ROTA-induced coronary dissection. Methods:A total of 21 patients with severe calcified coronary lesions who underwent ROTA treatment were enrolled in our study. OCT successfully detected these patients pre-ROTA and post-ROTA. All observed coronary segments were analyzed cross-sectionally at every 1-mm interval after manual coregistration of pre-ROTA and post-ROTA OCT images. ROTA-related coronary dissection was the primary endpoint. Results:A total of 388 OCT cross-sectional images were effectively measured and analyzed to assess the distribution and characteristics of plaque and OCT catheter location pre-ROTA, as well as the presence or absence of coronary dissections post-ROTA after manual coregistration. According to the receiver operating characteristic (ROC) analysis, the distance from the center of OCT catheter to the media at the bias direction (Dcmb) (area under the curve (AUC): 1.000, p < 0.001, 95% confidence intervals (CI): 0.999-1.000) and the touch angle (AUC: 0.988, p < 0.001, 95%CI: 0.968 to 1.000) were strongly correlated with ROTA-related coronary dissection, with the corresponding cutoff values of 0.720 mm and 98.2° respectively. Conclusion:Dcmb and touch angle detected by OCT are two valuable and convenient independent predictors of ROTA-related coronary intimal dissections caused by guidewire bias.

Urate transporter 1 (URAT1) is a clinically validated therapeutic target for hyperuricemia and gout. To obtain structurally novel URAT1 inhibitors, a series of benzomorpholine derivatives were designed by adopting a pharmacophore guided molecular hybridization strategy. Most compounds potently inhibit the human URAT1 in HEK293 cells, and the most active compound 7 exhibited an IC50 of 0.72 μM, which was much more potent than Lesinurad and comparable to Benzbromarone. The possible interaction mode of compound 7 with URAT1 was revealed by molecular modeling. Cell viability assays indicated that compound 7 was less cytotoxic than Benzbromarone in Hep-G2 cells. The urate-lowering effects of compounds 1 and 7 were confirmed in two different hyperuricemia mouse models, and no obvious toxicity was observed in the treated mice. The results provide new chemical prototypes for urate-lowering drug discovery targeting URAT1.

Objective Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer. Herein, we probed into the role of E3 ubiquitin protein ligase family member 1 (HERC1) in promoting ferroptosis and inhibiting LUAD cell proliferation by regulating RAF proto-oncogene serine/threonine-protein kinase (C-RAF). Methods In cultured human normal lung epithelial cells and non-small cell lung adenocarcinoma cell lines, HERC1 expression was determined by RT-qPCR and Western blot tests. PC-9 and Calu-3 cells were transfected with oe-HERC1, oe-C-RAF or their negative controls. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and Fe2+ levels were assessed by biochemical assays. Cell viability, death, and proliferation were evaluated by CCK-8, LDH and colony formation assays, followed by assessments of HERC1-C-RAF interaction, C-RAF ubiquitin level, and C-RAF protein stability. Results HERC1 was poorly expressed in LUAD cells. HERC1 promoted LUAD cell ferroptosis and repressed their proliferation and migration, corresponding to reduced levels of system xc-, GPX4, and GSH, as well as elevated levels of ROS, MDA, Fe2+, and ACSL4. LUAD cells overexpressing HERC1 displayed decreased C-RAF protein level, HERC1-C-RAF interaction, elevated C-RAF ubiquitin level, and accelerated C-RAF protein degradation, indicating that HERC1 facilitated C-RAF ubiquitin degradation and attenuated C-RAF protein stability via interaction with C-RAF. C-RAF overexpression partially abrogated the regulatory impact of HERC1 on LUAD cell ferroptosis and proliferation. Conclusion HERC1 expedites C-RAF ubiquitin degradation by interacting with C-RAF, which consequently promotes ferroptosis, thereby inhibiting LUAD cell proliferation.

Moyamoya disease (MMD) is caused by abnormal vascular development. Guanylate cyclase soluble subunit alpha-1 (GUCY1A3) gene variation is verified as a crucial susceptible gene in MMD. In this study, we investigated the impact of GUCY1A3 on angiogenesis. GUCY1A3-knockout (KO) models were established using CRISPR/Cas9 technology in zebrafishes and mice. Blood vessel distribution in GUCY1A3-KO zebrafishes and retinal angiogenesis in postnatal GUCY1A3-KO mice were analyzed. Anti-angiogenic behaviors, including cell proliferation, migration, and apoptosis, and changes in hypoxia-inducible factor-1α (HIF-1α) distribution were examined in GUCY1A3-knockdown (KD) mice brain microvascular endothelial cells (BMECs). GUCY1A3-KO significantly decreased intracranial central artery development in zebrafishes, delayed retinal vascularization in mice, reduced retinal vascular endothelial growth factor A (VEGFA) expression in mice, and abolished expression of the GUCY1A3-encoded protein, α1 subunit of soluble guanylate cyclase. GUCY1A3-KD significantly decreased cell proliferation (flow cytometry analysis) and migration (wound-healing and Transwell assays), but increased apoptosis (hypoxia-induced apoptosis assay) in the BMECs. Immunofluorescence of HIF-1α revealed that nuclear translocation and protein expression were significantly reduced in the GUCY1A3-KD BMECs. These findings indicated that decreased expression of GUCY1A3 resulted in anti-angiogenic activity through inhibiting VEGFA and HIF-1α expression and nuclear translocation, inhibiting endothelial cell proliferation and migration, and promoting endothelial cell apoptosis.

Myocardial infarction (MI), a primary contributor to mortality from cardiovascular diseases, continues to pose a significant challenge in clinical treatment. In this study, our objective was to investigate the cardioprotective effects of paeonol (PAE) on mice with MI, and to delve into the precise mechanisms underlying these effects. We developed the MI model by ligating the left anterior descending artery in mice and replicated this model in vitro by stimulating H9C2 cells with levarterenol (LN). Cardiac function, infarct size, cardiomyocyte size, apoptosis, and mitochondrial structure were evaluated through echocardiography, Masson's trichrome staining, WGA staining, TUNEL assay, and electron microscopy, respectively. Colorimetry, Western blotting, flow cytometry, RT-PCR, and the dual-luciferase reporter assay were employed to explore the underlying mechanisms. Compared with the model group, PAE significantly ameliorated cardiac dysfunction and hypertrophy, diminished infarct size, cardiomyocyte hypertrophy, and apoptosis, mitigated mitochondrial structural damage, lowered levels of malondialdehyde and NOX2, reduced ROS production, and NOX activity, while enhancing the activities of T-SOD, GSH-PX, and mitochondrial complexes I-V in mice with MI or H9C2 cells subjected to LN intervention. Ultimately, PAE was found to negatively regulate the transcription of NOX2 mRNA in H9C2 cells, partly through inhibition of phospho-STAT3-Y705 protein expression. These results imply that PAE's transcriptional inhibition of NOX2 mRNA expression primarily confers a cardioprotective effect, mitigating myocardial remodelling following MI by improving oxidative stress and mitochondrial dysfunction. This indicates that PAE holds therapeutic promise for the treatment of patients post-MI.

Two racemic pairs of new stilbenoid dimers, (+/-)-heterosmilaxones A (1) and B (2), with unique 6/6/6 and 6/5/7 tricyclic core systems, respectively, were isolated from the rhizomes of Heterosmilax yunnanensis. Their structures were elucidated through comprehensive spectroscopic analyses, quantum chemical calculations and X-ray diffraction crystallography. Compound (+)-1, initially reported as syagrusin A with a 1,4,4a,9a-tetrahydrofluoren-9-one skeleton, is now revised to a new structure characteristic with a benzo bicyclo[3.3.1] nonene scaffold. And compound 2 bears an unprecedented carbon skeleton with four continuous chiral centers in the central benzo bicyclo[4.2.1]nonene motif. Biogenetically, both 1 and 2 were proposed to derive from 3,3 ',4,5,5 '-pentahydroxy stilbene and could be generated through key inverse-electron-demand [4 + 2] and [5 + 2] cycloadditions, respectively. Interestingly, both (+/-)-1 and (+/-)-2 showed significant inhibition against alpha-glucosidase. (+/-)-1 and its pure enantiomers could modulate protein tyrosine phosphatase-1B (PTP1B) enzyme activities and increased glucose consumption in HepG2 cells in a dose-dependent manner. (c) 2025 Published by Elsevier B.V .on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

The predictors and clinical outcomes of Percutaneous Coronary Intervention in patients with suspected coronary heart disease with COmorbid major DEpressive disorder (PCI CODE) study employs a prospective, multidisciplinary, observational design to evaluate clinical outcomes post-percutaneous coronary intervention (PCI) between coronary heart disease (CHD) patients with or without major depressive disorder (MDD). This study is registered with ClinicalTrials.gov (NCT03852082). During enrollment, all consecutive individuals aged ≥18 years who are clinically suspected of CHD and scheduled for coronary angiography at Nanjing First Hospital are our observational cohort. After completing the self-rated Patient Health Questionnaire, undergoing a clinical MDD diagnosis by a psychiatrist when indicated, and having CHD confirmed by interventional cardiologists, participants in the PCI arm are stratified into 2 groups: CHD patients with MDD and CHD patients without MDD. The primary composite endpoint is the 1-year and 5-year incidence of major adverse cardiac events including all-cause death, non-fatal myocardial infarction, and any coronary revascularization. The secondary endpoints comprise individual events, including all-cause death, cardiovascular death, non-fatal myocardial infarction, any coronary revascularization, stent thrombosis, in-stent restenosis, cardiac-related rehospitalization, non-cardiac-related rehospitalization, or stroke. The PCI CODE study, which hypothesizes that certain biomarker combinations may correlate with a higher incidence of major adverse cardiac events at 1 and 5 years post-PCI, seeks to identify the key determinants that lead to poorer prognoses following PCI in patients with CHD and comorbid MDD compared to those without MDD.

BACKGROUND:The association between lipoprotein(a) [Lp(a)] levels and progression of non-culprit atherosclerosis (NSA) in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI) is unknown. METHODS:This study enrolled 177 patients with ACS who underwent OCT-guided PCI and follow-up OCT examinations of non-culprit lesions between 2013 and 2018. Lesion characteristics including fibrous tissue, calcium, lipid, and macrophage content were assessed using quantitative plaque analysis. High Lp(a) levels were defined as Lp(a) ≥ 30 mg/dL. The association between Lp(a) levels and NSA progression was investigated using linear effect models adjusted for clinical risk factors. A discordance analysis was also performed. RESULTS:At 1-year follow-up, individuals with Lp(a) levels ≥ 30 mg/dL had increased total atheroma volume and lipid component, and higher incidence of thin-cap fibroatheroma (TCFA) (p = 0.021; p = 0.006; p = 0.025, respectively). After adjusted, multivariable linear regression model revealed an association between Lp(a) and plaque progression in NSA (7.22 for each 1 SD increase, 95% CI: 0.96-13.48; p = 0.025) and increased lipid component (3.60 for each 1 SD increase, 95% CI: 0.63-6.56; p = 0.019). Discordance analyses showed that individuals with discordantly low Lp(a) levels had the lightest plaque progression and increase in lipid plaque burden (17.34 [10.22, 28.21] vs. 28.73 [14.88, 45.88] versus 25.73 [13.85, 45.70], p = 0.017). CONCLUSION:Among patients with ACS, elevated Lp(a) levels were related to the progression of coronary plaques in non-culprit lesions, including increased total atheroma volume and lipid component, and a higher prevalence of TCFA at follow-up.

Rotational atherectomy (RA) is an effective, mature, and specific treatment for calcified lesions. However, the incidence of RA-related myocardial injury remains high and has not been adequately addressed. To assess the safety and efficacy of low-temperature RA-flush solution versus room-temperature RA-flush solution during RA. A total of 132 patients with moderate-to-severe calcified lesions who underwent RA were randomly assigned to the low-temperature RA-flush solution group or the room-temperature RA-flush solution group. The primary endpoint was RA-related myocardial injury, defined as any increase in myocardial biomarkers within 72 h after percutaneous coronary intervention (PCI). Secondary endpoints included RA-related myocardial infarction (MI), RA-related transient slow/no flow, or transient coronary spasm. A total of 78 patients (59.1%) had increased cardiac troponin I (cTnI) levels, and 60 patients (45.5%) had increased creatine kinase isoenzyme (CK-MB) levels after PCI. The number of patients with myocardial injury (primary endpoint), defined as elevated cTnI (47.0% vs. 71.2%, p = 0.005) or elevated CK-MB (28.8% vs. 62.1%, p < 0.001), was significantly lower in the low temperature group than in the room temperature group. The number of patients with RA-related transient slow/no flow (6.1% vs. 34.8%, p < 0.001) and transient coronary spasm (9.1% vs. 25.8%, p = 0.012) (secondary endpoints) was significantly lower in the low temperature group than in the room temperature group; no significant difference in the incidence of RA-related MI was observed between the two groups. Compared with room-temperature RA-flush solution, low-temperature RA-flush solution is associated with reduced RA-related myocardial injury in patients treated with RA.Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03701230; first submitted registration date: 09/10/2018.

Aims:The IVUS-ACS trial demonstrated that intravascular ultrasound (IVUS) guidance reduces target-vessel failure (TVF) in patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Whether this benefit applies to all ACS patients across the spectrum of risk is unknown. We sought to develop a new risk score for 1-year TVF after PCI in ACS and determine whether IVUS guidance compared with angiography guidance improves outcomes in both high- and low-risk patients. Methods and results:From the angiography-guided group of the IVUS-ACS trial (n = 1743), the TVF-ACS risk score was developed using the least absolute shrinkage and selection operator method in a derivation group (n = 1288), and its robustness was assessed in an internal validation group (n = 455). External validation was then performed separately in the IVUS-XPL and ULTIMATE trials. Outcomes in high- and low-risk patients randomized to IVUS guidance vs. angiography guidance were then examined. Ten readily available clinical, laboratory, and angiographic variables were selected for inclusion in the TVF-ACS risk score. A cut-off value of 15.64 discriminated angiography-guided PCI patients at high-risk vs. low risk [area under the curve (AUC) 0.715, 95% confidence interval (CI) 0.653-0.777]. The AUC was similar in the validation group [0.709 (95% CI 0.630-0.788)]. High-risk patients exhibited a higher 1-year rate of TVF compared with low-risk patients [19.8 vs. 5.7%, hazard ratio (HR) 3.81, 95% CI 2.06-7.02, P = 0.00002]. Among 3486 randomized patients, IVUS guidance compared with angiography guidance reduced 1-year TVF in high-risk patients (6.9 vs. 17.6%; HR 0.38, 95% CI 0.24-0.59) with a lesser effect in low-risk patients (3.2 vs. 4.3%; HR 0.75, 95% CI 0.51-1.11; P interaction = 0.02). External validation in the IVUS-XPL and ULTIMATE trials confirmed these benefits but with consistent effects in high- and low-risk patients (P interactions = 0.49 and 0.92, respectively). Conclusion:The TVF-ACS risk score reliably stratifies ACS patients undergoing PCI into high- and low-risk groups. The benefits of IVUS guidance during PCI are most pronounced in high-risk ACS patients, although all ACS patients are likely to benefit.