PurposeTo evaluate the efficacy and safety of triple antithrombotic therapy (TT) versus dual antiplatelet therapy (DAPT) for prevention of left ventricular thrombus (LVT) following anterior myocardial infarction.MethodsWe conducted a systematic review and meta-analysis of randomized and observational studies comparing TT (DAPT plus anticoagulation) versus DAPT alone. The primary outcome was LVT formation. Secondary outcomes included all-cause mortality, stroke, systemic embolism, composite thromboembolism, bleeding, and net adverse clinical events (NACE). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. The protocol was registered in PROSPERO (CRD420261343867).ResultsSeven studies (2 randomized, 5 observational), including 2,273 patients (949 TT, 1,324 DAPT), were analyzed. TT was not associated with a reduction in LVT (OR 0.56, 95% CI 0.21-1.49; p=0.25; I²=59%). There was no significant difference in all-cause mortality (OR 0.75, 95% CI 0.27-2.06; p=0.58), ischemic cerebrovascular accidents (OR 1.17, 95% CI 0.20-6.79), systemic embolism (OR 0.69, 95% CI 0.27-1.75), or composite thromboembolism (OR 0.96, 95% CI 0.42-2.19). TT was associated with increased major bleeding (OR 2.82, 95% CI 1.40-5.68; p=0.004) and any bleeding (OR 2.58, 95% CI 1.73-3.85; p<0.001). There was no significant difference in NACE (OR 1.15, 95% CI 0.58-2.29).ConclusionIn anterior myocardial infarction, available evidence did not demonstrate a statistically significant reduction in LVT or thromboembolic events with TT compared with DAPT, while bleeding risk was increased. Given moderate heterogeneity, limited randomized evidence, and potential imaging-related under-detection of LVT, these findings do not support routine prophylactic TT and favor individualized risk-benefit assessment.

Cerebral ischemia impairs neuronal and glial function, ranging from transient synaptic failure to irreversible damage. The effects of ischemia on excitatory synaptic transmission remain incompletely understood. Here, we present a detailed biophysical model, including the first full implementation of the glutamate-glutamine cycle (GG-cycle), which is essential for proper functioning of glutamatergic synapses. We model a presynaptic neuron and an astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath as a proxy for energy supply. The model includes ionic currents with corresponding channels and transporters such as the sodium-potassium ATPase. To model synaptic transmission, we combine calcium-dependent glutamate release, its uptake by the sodium-dependent excitatory amino acid transporters (EAATs), and the GG-cycle, including glutamine synthesis. We simulate ischemia by blocking energy supply completely. This drives the neuron into depolarization block, with pathological ion concentrations and extracellular glutamate accumulation despite disrupted synaptic release. Synaptic transmission failure is not primarily caused by excessive glutamate release or by failure of glutamine synthetase, but mainly results from EAAT dysfunction, driven by the collapse of the sodium gradient. Restoring synaptic transmission is not possible by solely targeting glutamate dynamics but is possible by restoring ion gradients by inhibition of the voltage-gated Na⁺-channel. Our study highlights the critical role of ion homeostasis, in particular the sodium gradient, in failure and recovery of synaptic function and the EAAT during metabolic stress.

The Lancet Diabetes & Endocrinology Commission proposed a new definition for clinical obesity. However, its prognostic value remains unclear.

Clinical obesity was defined using the Commission's criteria in the China Health and Retirement Longitudinal Study (CHARLS), the English Longitudinal Study of Aging (ELSA), and the National Health and Nutrition Examination Survey (NHANES). Prevalence estimation was conducted across four categories based on obesity and organ dysfunction status. Cox proportional hazards models were used to assess associations with clinical outcomes.

The prevalence of clinical obesity was 2.50% (CHARLS), 6.18% (ELSA), and 9.08% (NHANES), respectively. Overall, older adults and men had lower prevalence, while older men in NHANES showed higher prevalence. Compared with non-obesity without dysfunctions, clinical obesity and non-obesity with dysfunctions showed higher risks of cardiovascular outcomes. Compared with preclinical obesity, clinical obesity elevated cardiovascular risk in CHARLS (HR = 2.49, 95% CI: 1.32-4.70) and ELSA (HR = 1.80, 95% CI: 1.02-3.17) and increased all-cause (HR = 1.88, 95% CI: 1.23-2.87) and cardiovascular (HR = 3.11, 95% CI: 1.49-6.50) mortality risk in NHANES.

The prevalence of clinical obesity varied by age, sex, and country. Overall, the prevalence was lower among older adults and men. Clinical obesity was associated with increased cardiovascular event risk across cohorts and increased all-cause mortality risk in NHANES, highlighting its value for risk stratification.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global morbidity and mortality, but its genetic architecture remains incompletely understood. This study aims to uncover novel genetic insights into ASCVD through multivariate genomic analysis and molecular structure predictions.

We analysed genomic data from over 3.8 million individuals across various ASCVD phenotypes, including coronary heart disease, stroke, transient ischemic attack, peripheral artery disease and abdominal aortic aneurysm. Advanced tools such as Genomic Structural Equation Modeling, fine-mapping, FUSION, FOCUS and other functional annotation methods were applied to identify causal single nucleotide polymorphisms associated with ASCVD. Protein structural analysis was performed using AlphaFold3, and AI-driven thermodynamic analysis (ThermoMPNN) assessed the stability and functional consequences of mutations.

Our analysis revealed 347 genome-wide significant variants linked to ASCVD, distributed across 213 loci. Ninety of these variants were not identified in any of the five input GWAS datasets. Upon cross‑referencing with large‑scale external GWAS, 19 of the 90 variants showed no prior association with any cardiovascular or metabolic trait, 15 were previously reported only in risk factor GWAS, and 56 had been reported in direct ASCVD endpoint GWAS. The latter group includes the DCLRE1B rs11552449 missense mutation. Nevertheless, AI‑based structural and thermodynamic analyses revealed that this mutation (H61Y) disrupts DCLRE1B protein stability, increases conformational flexibility, and alters solvent‑accessible surface area-mechanistic insights that have not been previously described.

This study provides a hypothesis‑generating genetic landscape of ASCVD, unveiling novel variants and their molecular impacts. These findings enhance our understanding of ASCVD mechanisms and may offer potential avenues pending experimental validation and targeted therapies in cardiovascular disease.

MiR-146b-5p, a disease-responsive miRNA with circulatory stability, has been implicated in multiple pathologies, but its role in acute myocardial infarction (AMI) remains unexplored. The objective of this study was to explore the role of miR-146b-5p in AMI.

Serum from 103 AMI patients and 95 healthy controls was analyzed via qRT-PCR to quantify miR-146b-5p/PRKAR2A expression, with ROC curves evaluating diagnostic performance and correlation analyses linking miR-146b-5p levels to clinical indicators of AMI severity. Prognostic associations were systematically assessed using Kaplan-Meier curves and COX regression models. In vitro ox-LDL-induced HCAEC injury models employed CCK-8 assays, flow cytometry, Caspase-3 activity measurements, ELISA, and oxidative stress assays to elucidate cellular mechanisms. Dual-luciferase reporter and Western blot assays assessed the relation between miR-146b-5p and PRKAR2A.

Upregulated miR-146b-5p expression was observed in AMI compared with the HC group, showing diagnostic value and correlation with hs-CRP, CK-MB, cTnI, LVEF, and Killip grade. Higher miR-146b-5p expression predicted poor prognosis of AMI. In ox-LDL-induced HCAECs, miR-146b-5p inhibition reduced apoptosis, inflammation (IL-1β, TNF-α), and endothelial dysfunction marker levels (ET-1, vWF), while promoting proliferation. PRKAR2A was downregulated in ox-LDL and confirmed as a miR-146b-5p target, with its knockdown reversing the protective effects of miR-146b-5p inhibition on ox-LDL-induced HCAEC injury.

Upregulated miR-146b-5p, which correlated with AMI severity, demonstrated diagnostic and prognostic potential for AMI. It promoted AMI progression by aggravating endothelial injury under ox-LDL induction through suppressing PRKAR2A.

Both obesity and oxidative stress are closely linked to leukocyte telomere length (LTL) shortening, yet the specific mediating role of total bilirubin in this association remains insufficiently explored. This study aimed to quantify the extent to which total bilirubin, a potent endogenous antioxidant, mediates the association between obesity and LTL.

We analyzed data from 6,717 adults participating in the National Health and Nutrition Examination Survey 1999-2002. Causal mediation analysis with 1,000 bootstrap iterations was employed to investigate the mediating effect of serum total bilirubin on the association between body mass index (BMI) and LTL.

In the fully adjusted model, BMI was significantly and inversely associated with LTL, with a total effect of -3.532 base pairs (bp) per 1-unit increase in BMI (95% confidence interval [CI]: -6.225 to -1.178; P = 0.002). Serum total bilirubin significantly mediated this association (average causal mediation effect = -0.446 bp; 95% CI: -0.726 to -0.237; P < 0.001). The estimated proportion of the association explained by bilirubin was 13.2% (95% CI: 5.5% to 41.2%; P = 0.002). A series of sensitivity analyses confirmed the robustness and stability of these mediation findings.

Total bilirubin serves as a significant statistical mediator in the relationship between obesity and LTL shortening. However, given the cross-sectional design of this study, further longitudinal investigations are required to confirm these associations and establish causality.

Fabry disease (FD) is a rare inborn error of metabolism in which absent or deficient activity of α-galactosidase A leads to lysosomal dysfunction and globotriaosylceramide accumulation in different organs, including the heart. FD is characterized by a broad clinical spectrum, but Fabry cardiomyopathy represents the leading cause of morbidity and mortality. Electrocardiogram (ECG), echocardiography, and cardiac magnetic resonance (CMR) imaging are the cornerstones to suspect and diagnose cardiac involvement and to monitor it. Cardiac biomarkers such as troponin and N-terminal pro-B-type natriuretic peptide are also used to ascertain the degree of cardiac involvement. However, definitive data are lacking on how to plan the follow-up of patients with or without cardiac involvement, when to initiate specific therapy, and when to switch from one treatment to another. Current proposals suggest initiating treatment when there is evidence of left ventricular hypertrophy but before fibrosis develops.

Ten experts on FD met in Milan on March 8, 2024. The panel of experts was selected based on their expertise and contribution to the literature on FD. The group deliberated on appropriate parameters for cardiac assessment at diagnosis and during follow-up. The panel discussed developing a multiparametric cardiac assessment system (including ECG, laboratory biomarkers, echocardiographic and CMR parameters) to be used in clinical practice to guide management and monitor treatment response. The authors defined the requirements of such a system and advocate for the research needed to build and validate it. The experts also proposed a multiparametric clinical pathway for cardiac assessment, treatment initiation, and follow-up, designed to support routine clinical decisions. This was intended as general guidance, acknowledging that clinicians should tailor management to the individual patient's specific characteristics - a principle of particular importance in rare diseases such as FD, where organ involvement and treatment response can differ substantially among individuals.

Since cardiovascular disease is a leading cause of death in FD, an agreed staging system for evaluating cardiac progression is urgently needed. Further research should be carried out to confirm the criteria of a cardiac assessment system, evaluate its prognostic and predictive validity, and ensure its reliability and reproducibility.

The systemic immune-inflammation index (SII) is considered a promising inflammatory index for predicting adverse outcomes in cardiovascular diseases. However, its prognostic value in patients undergoing heart valve surgery remains unclear. This study aimed to investigate the predictive significance of preoperative SII for early postoperative complications and 30-day mortality.

This was a retrospective, single-center cohort study conducted at the National Cardiovascular Center Harapan Kita in Jakarta, Indonesia, a tertiary cardiac surgery referral hospital. It included adults (> 18 years) who underwent elective aortic, mitral, or combined valve surgery between January 2020 and December 2024. After applying exclusion criteria, 1347 patients were stratified by SII into low (< 551 × 10³/mm³, n = 927) and high (≥ 551 × 10³/mm³, n = 420) groups.

High preoperative SII was significantly associated with acute kidney injury (AKI) (p = 0.002), prolonged mechanical ventilation (p = 0.039), extended total hospital length of stay (LOS-H) (p = 0.004), and 30-day mortality (p = 0.026). Multivariate logistic regression identified SII (OR 2.169; 95% CI 1.600-2.941; p < 0.001) as independent predictor of adverse postoperative outcomes. When analyzed as a continuous variable, preoperative SII remained independently associated with adverse postoperative outcomes (adjusted OR per 100-unit increase 1.196; 95% CI 1.148-1.245; p < 0.001). Subgroup analysis revealed the highest predictive value in patients undergoing aortic valve surgery, with an area under the curve (AUC) of 0.797 (95% CI 0.728-0.866).

Elevated preoperative SII is independently associated with an increased risk of early postoperative complications and 30-day mortality in patients undergoing heart valve surgery. As a simple and cost-effective inflammatory index, SII may aid in preoperative risk stratification and support more personalized perioperative care.

Thromboinflammation is the pathological hallmark of diverse cardiovascular and inflammatory disorders. Platelets are the key effector cells linking thrombosis and inflammation and are known to express Toll-like receptors (TLRs) including TLR4. High mobility group box 1 protein (HMGB1) initiates a thromboinflammatory cascade by functioning as a primary ligand for platelet TLR4. Despite its central role in thromboinflammatory responses, HMGB1-TLR4 axis remains an unmet clinical need. In this study, we explored therapeutic potential of Low-molecular-weight Fucoidan (LMF) in modulating HMGB1-TLR4-driven thromboinflammation. It was found that LMF interacted with HMGB1 and interrupted HMGB1-dependent TLR4-mediated pro-inflammatory signaling. By targeting HMGB1, LMF profoundly suppressed early TLR4-driven platelet outside-in signaling events, encompassing intracellular calcium mobilization, Akt-upregulation and subsequent αIIbβ3 activation. This early signaling interception was manifested as functional deficit including impaired activation, reduced platelet aggregation and thrombus consolidation under shear conditions. Importantly, LMF disrupted HMGB1-driven platelet-leukocyte crosstalk as evident through reduced formation of neutrophil-extracellular traps. Further, LMF administration conferred cerebrovascular protection in mice by limiting HMGB1-driven thrombus growth, accompanied by marked reduction in cerebral infarction and systemic inflammation as reflected by decreased circulating IL-6 concentration. These findings demonstrate that LMF restrains HMGB1-dependent TLR4-driven thrombosis and vascular inflammation and could be a promising therapeutic intervention for thromboinflammatory disorders.

Adolescents in China face intensifying mental health challenges as extraordinary academic pressures rooted in cultural expectations for high achievement. While government-led initiatives provide multilevel formal support structures, critical gaps remain in understanding adolescents' perceptions of both formal and informal social support adequacy across different phases of mental health problems. This study applied qualitative thematic analysis to semi-structured interview data collected in Anhui Province. Participants included 17 adolescents aged 10-19 years and one 25-year-old whose mental health concerns originated in adolescence (age 15), with 15 family members jointly interviewed alongside them. Four themes characterized participants' narratives: the early manifestation phase, marked by multilevel barriers to timely mental health intervention, including insufficient parental response, a lack of systematic school-based prevention and stigma among adolescents; the problem escalation phase, characterized by insufficient policy implementation and a demand-execution gap, reflected in barriers to formal support access, insurance issues and disruptions in peer support; the treatment-recovery phase, multi-dimensional support gaps involving medicalization path dependence, limited inter-institutional coordination and inadequate follow-up support for families; and participants' visions for ideal collaborative support systems. The findings underscore the critical need to strengthen formal support systems for adolescents, which not only shape the identification of mental health needs and resource access but also play a crucial role in fostering adolescents' psychological development through informal networks such as families and peers.