Background:Acute coronary syndrome (ACS) poses a serious health risk, and drug-eluting stent (DES) implantation is widely used to improve prognosis. However, the risk of in-stent restenosis (ISR) persists in some patients. The CHG index, a novel metabolic marker, has not been clearly linked to ISR risk in ACS patients undergoing DES-based percutaneous coronary intervention (PCI). Methods:This retrospective study enrolled ACS patients who underwent PCI with successful DES implantation from June 2015 to July 2021 and and underwent coronary angiography at 6 to 24 months after successful DES-based PCI. Patients were stratified into tertiles based on CHG index. Logistic regression analysis models were used to evaluate the independent association between CHG index and ISR. Restricted cubic spline (RCS) models were used to examine potential nonlinear relationships, and subgroup analyses explored possible effect modifiers. Results:A total of 454 patients with ACS were included. In the fully adjusted model, CHG index was positively associated with DES-ISR incidence (per 1-unit increase, odds ratio [OR] = 2.61, 95% confidence interval [CI] 1.28-5.33, P = 0.008). Compared to the lowest tertile, the ORs (95% CI) for the second and third tertiles were 2.33 (1.12-4.85, P = 0.024) and 2.40 (1.05-5.49, P = 0.038), respectively. Furthermore, a linear positive association was observed between CHG index and risk of ISR post-PCI (overall P = 0.016; nonlinear P = 0.118). Conclusion:For ACS patients treated with DES-PCI, a high CHG index was found to be significantly and linearly associated with an increased risk of DES-ISR.

Osteoporosis therapies have become increasingly relevant to cardiovascular medicine because the bone–vascular interface links skeletal remodeling to vascular calcification biology. This narrative review examines whether anti-osteoporosis therapies truly modify coronary biology or risk, or whether the current literature more often reflects heterogeneous vascular end points, indirect coronary inference, and incomplete translation from mechanistic plausibility to clinical outcomes. We summarize the biologic pathways connecting bone remodeling to vascular calcification, including osteogenic transdifferentiation of vascular smooth muscle cells, matrix vesicle-mediated mineralization, the OPG/RANKL axis, and Wnt–sclerostin signaling. We then reassess current evidence for antiresorptive and osteoanabolic therapies while distinguishing coronary-specific data from broader vascular, renal-mineral, pharmacovigilance, and genetic evidence. Bisphosphonates and denosumab remain biologically relevant to vascular calcification, but based on currently available evidence, current studies do not support a reproducible or clinically decisive effect on coronary-specific outcomes. By contrast, romosozumab has sharpened the debate because it combines robust anti-fracture efficacy with unresolved cardiovascular safety questions linked to sclerostin inhibition, whose mechanistic, genetic, and clinical signals are not fully concordant. We further discuss why the literature remains conflicted, emphasizing end point heterogeneity, differences between calcification burden and plaque vulnerability, population-specific mineral stress, and the limitations of fracture trials for coronary inference. Overall, current evidence does not support a uniform cardiovascular class effect of osteoporosis therapies; instead, vascular consequences appear drug-specific, context-dependent, and highly sensitive to phenotype, baseline risk, and time horizon.

BACKGROUND:Pulmonary hypertension that is caused by left heart disease and is associated with heart failure may be driven by sympathetic overactivation leading to increased pulmonary vascular resistance, right ventricular dysfunction, and poor outcomes. Pulmonary-artery denervation may reduce sympathetic activity, although its clinical effects on left heart disease-associated pulmonary hypertension are unknown. METHODS:We conducted a multicenter, randomized trial in China involving patients with pulmonary hypertension associated with left heart disease and heart failure. Patients were randomly assigned in a 1:1 ratio to receive pulmonary-artery denervation plus guideline-directed medical therapy or to receive medical therapy alone. The primary outcome was clinical worsening - a composite of death, heart or lung transplantation, hospitalization for heart failure, outpatient worsening of heart failure, or a decline in the 6-minute walk distance - through the latest follow-up. RESULTS:A total of 264 patients underwent randomization: 134 to receive pulmonary-artery denervation plus medical therapy and 130 to receive medical therapy alone. During a median follow-up of 338 days, the Kaplan-Meier estimated 2-year incidence of clinical worsening was 25.7% in the pulmonary-artery denervation group and 51.5% in the medical-therapy group (hazard ratio, 0.49; 95% confidence interval, 0.30 to 0.82; P = 0.006). Access-site hematomas occurred in two patients in the pulmonary-artery denervation group and in one patient in the medical-therapy group; there were no other procedural complications. Adverse events during follow-up occurred with similar frequency in the two groups. CONCLUSIONS:Among patients with pulmonary hypertension associated with left heart disease and heart failure receiving guideline-directed medical therapy, pulmonary-artery denervation resulted in fewer events of clinical worsening than medical therapy. (Funded by Pulnovo Medical and others; PADN-HF-PH ClinicalTrials.gov number, NCT05824923.).

Pulmonary arterial hypertension (PAH) is increasingly recognized as a metabolically dysregulated and inflammatory vascular disease rather than a purely haemodynamic disorder. Among emerging metabolic pathways, the bile acid-oxysterol axis has gained attention as a potential link between sterol imbalance, endothelial dysfunction, and pulmonary vascular remodeling. This narrative review examines current evidence linking selected bile acid and oxysterol species to PAH phenotypes and discusses their potential mechanistic and translational implications. Human lung tissue studies, circulating metabolomics, and experimental models suggest that selected bile acid intermediates and oxysterol species may carry biological information beyond nonspecific disease severity, although their effects are molecule-specific, receptor-specific, and context-dependent rather than uniform across the entire metabolite class. In particular, recent work implicates disturbed lysosomal sterol trafficking and impaired endothelial lysosomal acidification, including NCOA7-related mechanisms, in generating pro-inflammatory sterol signatures that promote endothelial immunoactivation and worsen experimental PAH. At the same time, the biological origin and interpretation of these metabolites are likely heterogeneous, involving lung-intrinsic sterol remodeling, systemic gut–liver signals, and potential confounding from right-heart failure or congestive hepatopathy. We argue that the bile acid-oxysterol axis should not be viewed as uniformly causal or purely biomarker-like across all patients, but rather as a compartment- and endotype-dependent framework whose interpretation depends on the level of evidence considered. This framework has important implications for biomarker development, therapeutic targeting, and precision trial design, and identifies sterol trafficking and lysosomal homeostasis as promising areas for future investigation.

BACKGROUND:Hyperglycemia is an independent risk factor for colon cancer progression, but its underlying mechanisms remain unclear. Ferroptosis is a form of programmed cell death, yet whether sodium-glucose cotransporter 1 (SGLT1) regulates ferroptosis to affect colon cancer under high glucose has not been reported. This study aims to clarify the mechanism by which SGLT1 regulates the malignant phenotype of colon cancer under high-glucose conditions and explore the therapeutic potential of targeting SGLT1 combined with ferroptosis inducers. METHODS:HT29 and SW480 cells were treated with mmol/L high glucose. Cell proliferation and migration were detected by CCK-8, colony formation and wound-healing assays. Ribonucleic acid sequencing (RNA-seq) screened SGLT1-regulated downstream pathways. Ferroptosis was evaluated by malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), ferrous ions (Fe2+) levels and mitochondrial ultrastructure. Western blot detected nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway proteins. Interventions included ferrostatin-1 (Fer-1), tert-butylhydroquinone (TBHQ) and SLC7A11 overexpression. In vivo antitumor efficacy was assessed in diabetic nude mouse xenografts. RESULTS:High glucose significantly enhanced HT29 and SW480 cell viability, colony formation and migration, with upregulated SGLT1. SGLT1 knockdown reversed these phenotypes, while overexpression aggravated them. RNA-seq showed ferroptosis was the most enriched pathway after SGLT1 knockdown, with downregulated GPX4 and SLC7A11. Only Fer-1 reversed SGLT1 knockdown-induced cell viability decrease (78.5%, P < 0.0001). SGLT1 knockdown increased MDA (3.53/3.40 vs. 2.33 nmol/mL, P < 0.0001), ROS (6.91/7.12 vs. 3.57 a.u., P < 0.01) and Fe2+ (44.50/44.74 vs. 8.54 a.u., P < 0.0001), decreased GSH (35.93/37.04 vs. 46.96 μg/mL, P < 0.0001), and induced mitochondrial atrophy; overexpression had opposite effects. SLC7A11 overexpression restored GPX4 (0.97 vs. 0.40, P = 0.0187) and reversed ferroptosis and growth inhibition. SGLT1 knockdown suppressed Nrf2/HO-1, which was rescued by TBHQ, increasing HO-1 (1.03 vs. 0.62, P = 0.0218), SLC7A11 (0.99 vs. 0.56, P = 0.0303) and GPX4 (1.37 vs. 0.30, P = 0.0065), while concurrently reversing ferroptosis. In vivo, SGLT1 knockdown reduced tumor weight from 264.6 to 36.76 mg (P < 0.0001); mizagliflozin plus erastin achieved 90.69% tumor inhibition (Bliss score 0.087). CONCLUSIONS:High glucose promotes colon cancer cell proliferation and migration by upregulating SGLT1. SGLT1 is a key driver of high glucose-induced colon cancer malignant phenotypes. SGLT1 knockdown inhibits colon cancer mainly by activating ferroptosis, characterized by increased lipid peroxidation, GSH depletion, iron accumulation and mitochondrial atrophy. SGLT1 regulates ferroptosis via the SLC7A11/GPX4 axis. It inhibits ferroptosis by activating Nrf2/HO-1 to upregulate SLC7A11 and GPX4. Targeting SGLT1 enhances colon cancer cell sensitivity to ferroptosis inducers. Combined targeting of SGLT1 and ferroptosis is a novel therapeutic strategy for diabetic colon cancer patients.

Single-atom nanozymes (SANs), characterized by tunable electronic properties and optimized atomic utilization efficiency, have attracted considerable attention for biomedical applications. Despite significant progress, their catalytic performance remains inferior to that of natural enzymes, largely attributable to symmetric coordination and an electronic structure. Herein, we successfully engineer a bromine (Br) doping copper (Cu)-based SAN with asymmetric coordination (Cu-BrN3/SAN@M), which exhibits higher catalytic performances compared to its symmetric counterpart, Cu-N4/SAN@M. The high electronegativity of Br causes a slight elongation of the Cu-N bonds in Cu-BrN3/SAN@M, optimizing the adsorption and desorption of oxygen intermediates, thereby markedly enhancing catalytic activity. Density functional theory (DFT) calculations state that asymmetric coordination in the Cu-BrN3/SAN@M configuration strengthens the activation of structural electrons and shifts the d-band center of Cu atoms closer to the Fermi level. This facilitates the adsorption and activation of hydrogen peroxide, hydroxyl radicals, and superoxide anions, confirming their enhanced capability for reactive oxygen species elimination. Experimental results indicate that Cu-BrN3/SAN@M preserves cardiomyocyte viability and functional connectivity by scavenging excess reactive oxygen species (ROS) , reprogramming proinflammatory M1 macrophages toward the reparative M2 phenotype, and amplifying regulatory T cell activity. Collectively, these effects enable robust modulation of the inflammatory microenvironment and restoration of immune homeostasis in an acute myocardial infarction model.

BACKGROUND:Myocardial infarction (MI) remains a leading cause of cardiovascular mortality. While ketone bodies show cardioprotective potential, their role in regulating cardiomyocyte autophagy post-MI is unclear. METHODS:A rat MI model was established and treated with 1,3-butanediol (1,3-BD, 10 mg/100 g/day), a ketone precursor. Cardiac structure and function were assessed alongside autophagy and apoptosis levels. In vitro, hypoxia-induced cardiomyocytes were treated with β-hydroxybutyrate (β-HB) and phosphatidylinositol 3-kinase (PI3K) inhibitor. Mechanisms were explored via transcriptomics/metabolomics and validated by immunoblotting. RESULTS:1,3-BD treatment for 4 weeks significantly elevated serum β-HB, improved cardiac structure and function,and reduced cardiomyocyte apoptosis in MI rats, a finding corroborated in vitro where β-HB attenuated hypoxia-induced apoptosis in primary neonatal rat cardiomyocytes. The number of autophagic vesicles and LC3 fluorescence intensity in the infarct border zone decreased in the MI group compared with the control group, whereas 1,3-BD significantly increased autophagy levels in cardiomyocytes. In vitro, both β-HB and the PI3K inhibitor increased autophagy. However, the combination did not have an additional effect on regulating autophagy. Multi-omics analysis revealed 1,3-BD enriched the autophagy and PI3K-Akt-FOXO3 pathways. MI activated PI3K-Akt signaling and suppressed FOXO3, downregulating autophagy proteins (Atg7, Atg13, Beclin1, ULK1, LC3II/LC3I). 1,3-BD intervention reversed these changes. CONCLUSION:1,3-BD improves post-MI cardiac remodeling by inhibiting cardiomyocyte apoptosis and enhancing autophagy, the latter mediated via suppression of the PI3K/Akt/FOXO3 pathway. Ketone supplementation represents a promising strategy against ischemic cardiomyopathy.

Current pharmacological strategies for delaying the progression of calcific aortic valve disease (CAVD) remain inadequate. This study used Mendelian randomization (MR) analysis to identify a significant association between the plasma protein Contactin-2 (CNTN2) and CAVD. Transcriptomic and in vivo/in vitro experiments further validated these findings. An MR study was conducted to evaluate the exposure-outcome relationship between plasma proteins and CAVD. Transcriptomic profiling identified differentially expressed genes and also analyzed pathways related to the osteogenic differentiation phenotype of human primary aortic valve interstitial cells (hVICs), which further validated the MR analysis. Western blotting, Alizarin Red staining and immunohistochemistry were used to validate the MR result in hVICs and patients with CAVD. Furthermore, adenovirus-mediated CNTN2 overexpression in hVICs was performed to elucidate the role in the osteogenic phenotype. MR analysis demonstrated a significant causal association between CNTN2 and CAVD. Colocalization analysis indicated that CNTN2 shares genetic loci with CAVD. Gene Ontology (GO) analyses revealed that CNTN2 was downregulated in hVICs with an osteogenic phenotype. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that CNTN2 is enriched in pathways associated with the osteogenic phenotype. Immunoblotting further confirmed that CNTN2 protein expression was reduced in osteogenically induced hVICs and in clinical specimens obtained from patients with CAVD. Additionally, overexpression of CNTN2 significantly inhibited the osteogenic phenotype of hVICs. CNTN2 has a significant causal relationship with CAVD and contributes to protection during aortic valve calcification. These findings could provide new insights and therapeutic targets for the prevention and treatment of CAVD.

Doxorubicin (DOX) cardiotoxicity involves dysregulated autophagy, yet the role of ACE2 in this process remains unclear. We aimed to determine if ACE2 protects against DOX-induced injury by modulating the AMPK/mTOR-autophagy axis. DOX-induced cardiotoxicity was established in mice and primary cardiomyocytes. The effects of modulating ACE2 and mTOR signaling were investigated using the agonist Diminazene Aceturate (DIZE), inhibitor MLN-4760, activator MHY1485 (MHY), and inhibitor Rapamycin (Rapa). Cardiac injury, apoptosis, autophagy, and key molecules in the RAS and AMPK/mTOR pathways were evaluated. DOX induced cardiac dysfunction, apoptosis, and excessive autophagy, accompanied by ACE2 downregulation, AMPK activation, and mTOR inhibition. ACE2 activation via DIZE reversed these pathologies both in vivo and in vitro. Mechanistically, the cardioprotective effects of DIZE were mimicked by mTOR activation and, importantly, abolished by mTOR inhibition with Rapamycin. Our findings demonstrate that ACE2 protects against DOX-induced cardiotoxicity by suppressing excessive autophagy. This effect is causally dependent on its ability to inhibit AMPK and activate mTOR signaling. Thus, targeting the ACE2-mTOR axis represents a promising therapeutic strategy to mitigate DOX cardiotoxicity.

BACKGROUND:Rest-activity rhythm (RAR) is a fundamental biomarker of age-related circadian system deterioration. However, the long-term effect of RAR patterns on mortality in older adults remains unclear. METHODS:This study analysed data from National Health and Nutrition Examination Survey 2011-2014. The RAR parameters were derived from wrist accelerometers, and four patterns were identified through clustering analysis using Gaussian mixture models. Cox models were used to compare the hazard ratio (HR) and 95% confidence interval (CI) of mortality among participants with different RAR parameters and patterns. RESULTS:This study included 1710 participants aged ≥60 years. The median follow-up duration was 6.67 years. In total, 269 all-cause deaths and 77 cardiovascular deaths occurred during follow-up period. Four RAR patterns were identified: 'morning-type', 'earlier-type', 'delayed-type', and 'evening-type'. Compared to 'morning-type', 'evening-type' was associated with higher risks of cardiovascular (HR: 12.16, 95% CI: 4.02-36.82) and all-cause mortality (HR: 3.31, 95% CI: 1.91-5.72). Higher interdaily stability was associated with lower risks of cardiovascular (HR: 0.67, 95% CI: 0.55-0.81), and all-cause mortality (HR: 0.86, 95% CI: 0.74-1.00). Higher relative amplitude was associated with lower risks of cardiovascular (HR: 0.61, 95% CI: 0.49-0.75), and all-cause mortality (HR: 0.70, 95% CI: 0.60-0.81). Conversely, higher intradaily variability was associated with increased risk of cardiovascular (HR: 1.30, 95% CI: 1.15-1.46) and all-cause mortality (HR: 1.19, 95% CI: 1.10-1.30). CONCLUSIONS:RAR patterns and parameters were significantly associated with cardiovascular and all-cause mortality in older adults. Early identification and intervention for adverse RAR patterns may help improve long-term health outcomes.

Despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, many patients remain at high risk of cardiovascular events due to elevated triglyceride-rich lipoproteins and remnants. Angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for addressing this residual risk. As a liver-secreted regulator of lipoprotein metabolism, ANGPTL3 influences triglycerides, LDL-C, and high-density lipoprotein cholesterol through inhibition of lipoprotein lipase and endothelial lipase. Human genetic studies and pharmacologic interventions consistently show that ANGPTL3 inhibition improves lipid profiles and lowers apolipoprotein B–containing lipoproteins, independent of LDL receptor function. This review integrates biological, genetic, and clinical evidence, and provides an overview of novel ANGPTL3-targeted therapies, offering new perspectives for cardiovascular prevention and lipid management.

Background The impact of estimated pulse wave velocity (ePWV) on the prognosis of cardiovascular-kidney-metabolic (CKM) syndrome has not been explored. This study investigated the association between ePWV and mortality and its predictive performance in individuals with CKM syndrome. Methods This population-based prospective study of 9,416 American participants used ordinal logistic regression to assess the association between ePWV and CKM syndrome severity. Cox regression was applied to evaluate the relationship between ePWV and all-cause and cardiovascular mortality at different CKM stages, as well as their interaction effects on mortality. To evaluate the predictive performance, the area under the curve (AUC) was calculated, and the predictive capabilities of the combined model incorporating both CKM syndrome and ePWV were compared with CKM syndrome alone. Furthermore, various machine learning models were developed for prediction. Results ePWV was found to be significantly associated with the severity of CKM syndrome, with a common odds ratio (cOR) of 1.73 [95% confidence interval (CI): 1.68-1.77] per 1 m/s increase in ePWV. Moreover, ePWV demonstrated a significant association with both all-cause and cardiovascular mortality. Specifically, the hazard ratios (HR) per 1 m/s increase in ePWV were: 1.60 [95% CI: 1.51-1.69] for all-cause mortality in participants with early-stage CKM, 1.29 [95% CI: 1.23-1.35] for all-cause mortality in participants with advanced-stage CKM, 1.84 [95% CI: 1.63-2.08] for cardiovascular mortality in participants with early-stage CKM, and 1.23 [95% CI: 1.13-1.34] for cardiovascular mortality in participants with advanced-stage CKM. A notable interaction effect between ePWV and CKM syndrome was observed for both all-cause and cardiovascular mortality (P for interaction < 0.001). ePWV significantly enhanced the predictive performance of CKM syndrome for all-cause and cardiovascular mortality [the net reclassification improvement (NRI) across different time points ranged from 0.25 to 0.382 for all-cause mortality and from 0.005 to 0.431 for cardiovascular mortality]. Furthermore, the combination of ePWV and CKM syndrome demonstrated strong predictive power in most models (time-dependent AUC > 0.7). Conclusion ePWV serves as a critical indicator for both the severity and the mortality risk among individuals with CKM syndrome. ePWV significantly enhanced the accuracy of mortality risk prediction of CKM syndrome.

Background:Transcatheter edge-to-edge repair (TEER) has become an effective alternative for treating degenerative mitral regurgitation (DMR) in patients at high surgical risk. The SQ-Kyrin-M TEER system (SQ-Kyrin-M system) is a novel TEER device developed in China. This study aimed to evaluate the feasibility, safety, and 12-month clinical efficacy of the SQ-Kyrin-M system in patients with high-risk degenerative mitral regurgitation. Methods:In this prospective, multicenter, single-arm study (ClinicalTrials.gov: NCT06467110), 120 patients with symptomatic DMR (grade ≥3+) had the device implanted. The primary endpoint was the clinical success rate at 12 months. Secondary endpoints included technical, device, and procedural success rate; New York Heart Association (NYHA) class improvement; Kansas City Cardiomyopathy Questionnaire (KCCQ) score change; and mitral regurgitation (MR) reduction. Safety endpoints encompassed all-cause mortality, cardiovascular mortality, and major adverse event rate. Results:A total of 120 patients received the TEER procedure across 25 participating sites in China; the mean age was 71.9 years, and the mean Society of Thoracic Surgeons (STS) risk score was 9.3. At 12 months, the Kaplan-Meier estimates were 82.5% for clinical success, 7.6% for all-cause mortality, and 10.8% for major adverse events; MR ≤2+ and MR ≤1+ were achieved in 91.7 and 70.4% of the patients, respectively; 88.9% of patients were in NYHA class I or II; and KCCQ score had improved by 18.9 points. Favorable left ventricular remodeling was observed with sustained reductions in left ventricular end-diastolic and end-systolic volumes. Conclusions:This study demonstrates that the SQ-Kyrin-M system is a safe and effective therapeutic option for DMR patients.

Low-dose colchicine has re-emerged as a pragmatic anti-inflammatory strategy to address residual atherothrombotic risk in coronary artery disease, with randomized evidence showing fewer recurrent ischemic events when therapy is maintained over months to years on top of contemporary lipid-lowering and antithrombotic treatment. Yet clinical signals are not uniform across settings: benefit has been most consistent in chronic coronary disease, whereas findings in post-myocardial infarction and periprocedural settings remain more heterogeneous. In particular, CLEAR-SYNERGY complicates any simple chronic-versus-acute dichotomy, even though the overall long-term evidence base for low-dose colchicine remains supportive. We synthesize mechanistic and clinical data to propose a “time-window” framework that reconciles these observations. Colchicine rapidly dampens microtubule-dependent neutrophil activation, NET formation, and NLRP3 inflammasome signaling, but translation into fewer clinical events likely requires sustained exposure sufficient to modify plaque inflammation and vulnerability—processes that evolve more slowly than cath lab risk, which is compressed into hours and driven by thrombus burden, distal embolization, and microvascular injury already strongly influenced by procedural factors and potent background therapies. Clinically, the evidence supports colchicine as a long-horizon adjunct for secondary prevention in selected patients, with proactive management of early gastrointestinal intolerance and careful attention to drug–drug interactions to maximize persistence. Remaining priorities include precision selection, better discrimination between transient post-infarction inflammatory activation and persistent residual inflammatory risk, optimal timing and duration, and biomarker-guided implementation strategies.

Plasma 25-hydroxyvitamin D [25(OH)D] deficiency and elevated homocysteine (Hcy) levels are both well-established risk factors for cardiovascular disease (CVD). However, the relationship between 25(OH)D and Hcy remains unclear. This study aimed to investigate the associations between plasma 25(OH)D concentrations and serum Hcy levels, as well as the odds of hyperhomocysteinemia (HHcy), in Chinese adults. Based on baseline data from the China Precision Nutrition and Health KAP Real-World Study, this cross-sectional study used multivariable linear and logistic regression models to evaluate the associations of plasma 25(OH)D concentrations with serum Hcy and HHcy, respectively. Restricted cubic spline analyses were performed to evaluate nonlinear dose-response relationships. HHcy was primarily defined as serum Hcy ≥ 10 µmol/L, and sensitivity analyses were conducted using the conventional threshold of ≥ 15 µmol/L. After multivariable adjustment, plasma 25(OH)D concentrations showed a nonlinear association with serum Hcy. Compared with participants in Q4 (24.3–28.2 ng/mL), those in Q1-Q3 and Q5 had serum Hcy concentrations that were each 0.16 µmol/L higher. Restricted cubic spline analysis identified an estimated inflection point of 27.2 ng/mL for serum Hcy. When HHcy was defined as Hcy ≥ 10 µmol/L, participants in Q1-Q3 and Q5 had 11% and 10% higher odds of HHcy, respectively, than those in Q4. Although the spline curve suggested a change in direction around 26.1 ng/mL, the nonlinear test was not statistically significant (P for nonlinearity = 0.298). In sensitivity analyses using the conventional HHcy threshold of ≥ 15 µmol/L, participants in Q1-Q3 and Q5 had 20% and 17% higher odds of HHcy, respectively. The restricted cubic spline analysis showed a nonlinear association, with an estimated inflection point of 25.6 ng/mL. Plasma 25(OH)D concentrations were nonlinearly associated with serum Hcy in this Chinese adult population. Participants with intermediate plasma 25(OH)D concentrations showed comparatively lower Hcy concentrations and lower odds of HHcy in categorical analyses. In sensitivity analyses using the conventional HHcy threshold of ≥ 15 µmol/L, a nonlinear association was observed, whereas the formal test for nonlinearity was not statistically significant for the primary HHcy definition of ≥ 10 µmol/L. Given the cross-sectional design, these findings should be interpreted cautiously and require confirmation in prospective studies.

Sensitization to common foods is typically considered clinically irrelevant in individuals without symptomatic food allergies. However, recent studies found an association between IgE specific to the mammalian oligosaccharide galactose-α-1,3-galactose and cardiovascular disease (CVD). The aims of this study are to determine whether common food sensitization is associated with early vascular aging (EVA) and to examine whether healthier lifestyle behaviors modifies the association in individuals without CVD. This was a cross-sectional, population-based study of 2788 American participants aged 30 years or older without cardiovascular disease. Total and specific IgE levels for common foods were measured. EVA was defined based on the 10th percentile of the difference between chronological age (CA) and vascular age (VA). Logistic regression models were employed to assess the associations between food sensitization and EVA, and whether healthy lifestyle modified the association. Poisson regression models, ordinal logistic regression models, and linear regressions were performed as sensitivity analysis. Sensitization to at least one food allergen associated with an increased risk of EVA (odds ratio [OR] 1.91 [95

AIMS:Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid accumulation and inflammation. Macrophage phenotypic transformation plays a critical role in AS progression. Aryl hydrocarbon receptor (AhR) has been proved to regulate the phenotype of macrophages. This study investigates the role and molecular mechanism of AhR activation by its endogenous ligand, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) attenuates AS. MATERIALS AND METHODS:We employed Western blotting to analyze the expression of AhR, NF-κB, and lipocalin-2 (LCN2). Flow cytometry and immunofluorescence staining were used to assess the phenotype of macrophages. Plaque progression was evaluated using pathological staining. Transcriptome sequencing was utilized to explore the potential mechanism by which AhR promotes macrophage phenotypic transformation. CUT&Tag-qPCR and lentivirus infection confirmed that the AhR/NF-κB/LCN2 pathway regulates macrophage polarization. KEY FINDINGS:Activation of AhR by ITE reduced plaque area and inhibited lipid deposition. ITE significantly increased the number of M2-like macrophages both in vivo and in vitro. Transcriptome sequencing identified LCN2 as a key target for AhR-mediated macrophage M2-like polarization. Furthermore, AhR activation suppressed the NF-κB/LCN2 pathway. SIGNIFICANCE:Our findings reveal that AhR promotes the macrophages to exhibit M2-like characteristics to attenuate AS by inhibiting the NF-κB/LCN2 pathway. These results suggest that AhR may serve as a novel therapeutic target for AS.

Objective:This study aimed to investigate the relationship between serum vitamin D (Vit D) levels and the risk of mortality among adults with H-type hypertension, a subtype of hypertension characterized by elevated homocysteine (Hcy) levels. Methods:This retrospective analysis utilized NHANES 2001 to 2006 to examine associations of Vit D and Hcy with mortality in hypertensive adults overall (n=5459), followed by targeted analyses in H-type hypertension (n=2276). The primary endpoints of the study were all-cause mortality and cardiovascular disease mortality, with follow-up through 2019. Weighted multivariable Cox models, mediation analyses, restricted cubic splines, and machine-learning validation were conducted. Results:In the overall hypertensive cohort, H-type hypertension had lower Vit D and higher mortality than non-H-type. Higher Vit D was inversely associated with mortality. Joint risk analysis showed greater risk reduction with Vit D>50 nmol/L and Hcy<10 μmol/L than with either factor alone. Hcy was a mediating factor in the relationship between Vit D and mortality. In H-type hypertension, Vit D showed a linear inverse association with mortality. Vit D was identified as an important variable through LASSO regression for feature selection. Five machine learning models were constructed, and three of them performed well in predicting mortality. Among Vit D-deficient individuals with H-type hypertension, engagement in moderate to vigorous activity was associated with a reduced risk of mortality. Conclusion:Higher serum Vit D levels linked to lower mortality risk in hypertension patients, including H-type hypertension, with significantly higher risk in severe deficiency (<25 nmol/L).

Background Early prediction of heart failure (HF) after acute myocardial infarction (AMI) is essential for personalized treatment. We aimed to use interpretable machine learning (ML) methods to develop a risk prediction model for HF in AMI patients.MethodsWe retrospectively included patients initially with AMI who received percutaneous coronary intervention (PCI) in our hospital from November 2016 to February 2020. The primary endpoint was the occurrence of HF within 3 years after operation. For developing a predictive model for HF risk in AMI patients, the least absolute shrinkage and selection operator (LASSO) Regression was used to feature selection, and four ML algorithms including Random Forest (RF), Extreme Gradient Boost (XGBoost), Support Vector Machine (SVM), and Logistic Regression (LR) were employed to develop the model on the training set. The performance evaluation of the prediction model was carried out on the training set and the testing set, utilizing metrics including AUC (Area under the receiver operating characteristic curve), calibration plot, and decision curve analysis (DCA). In addition, we used the Shapley Additive Explanations (SHAP) value to determine the importance of the selected features and interpret the optimal model.ResultsA total of 1220 AMI patients were included and 244 (20%) patients developed HF during follow-up. Among the four evaluated ML models, the XGBoost model exhibited exceptional accuracy, with an AUC value of 0.922. The SHAP method showed that left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LVDs) and lactate dehydrogenase (LDH) were identified as the three most important characteristics to predict HF risk in AMI patients. Individual risk assessment was performed using SHAP plots and waterfall plot analysis.ConclusionsOur research demonstrates the potential of ML methods in the early prediction of HF risk in AMI patients. Furthermore, it enhances the interpretability of the XGBoost model through SHAP analysis to guide clinical decision-making.

BACKGROUND:Post-infarction metabolism changes, inflammatory responses, and fibrosis are crucial contributors to adverse cardiac remodeling. 2-(1'H-indole-3'‑carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), the aryl hydrocarbon receptor (AHR) ligand, has demonstrated effective AHR activation, yet its impact and mechanisms in myocardial infarction (MI) remain unclear. METHODS:The MI model was established by ligating left anterior coronary artery, and ITE was administered for 4 weeks. Echocardiography and hemodynamic monitoring were used to assess cardiac structure and function. Hematoxylin-eosin and Masson's trichrome were used to examine morphology and collagen deposition. Transmission electron microscopy was employed to examine mitochondrial morphology. The transcriptome and metabolome were used to screen for key targets and pathways. Hypoxic neonatal rat cardiomyocytes and fibroblasts models combined with adenoviral AHR knockdown were used to verify key targets and pathways. RESULTS:ITE intervention significantly improved cardiac structure and function, mitochondrial morphology, fibrosis and inflammation in MI rats. Multi-omics revealed that differentially expressed genes and metabolites were enriched in glucose metabolism related pathways and identified a key target, HK2. Compared to MI group, ITE significantly improved the expression of key enzymes in glucose metabolism after MI. In vitro, AHR activation by ITE and tapinarof significantly ameliorated hypoxia-induced abnormalities in HK2, CISY, OGDH, fibrosis, and inflammatory markers, while hexokinase inhibitor eliminated the beneficial effects of ITE. Moreover, AHR knockdown impairs glucose metabolism and promotes inflammation and fibrosis. CONCLUSION:The AHR activation by ITE mitigates inflammation and fibrosis, improves cardiac structure and function by promoting HK2 and glucose metabolism after MI.