Cerebral ischemic stroke (CIS) leads to high mortality and disability due to cerebrovascular obstruction. Current therapeutic approaches such as thrombolysis have limitations, and many patients suffer from long-term functional impairments, so new treatment strategies are urgently needed. Both low-intensity pulsed ultrasound (LIPUS) and mesenchymal stem cell-derived exosomes (MSC-EXOs) have demonstrated some therapeutic potential for CIS, but their efficacy is less pronounced when used alone. Therefore, this study aims to evaluate whether the combination of MSC-EXOs and LIPUS exerts an additive effect in the treatment of cerebral ischemic stroke. Adult rats subjected to middle cerebral artery occlusion (MCAO) were randomly assigned to sham, MCAO, MSC-EXO, LIPUS, or combination groups. Outcomes were assessed using the modified Neurological Severity Score (mNSS), corner and Y-maze tests, histological staining (HE and immunofluorescence), transmission electron microscopy (TEM), and quantitative real-time polymerase chain reaction (q-PCR). The combination group showed notable improvements in neurological function, with the highest proportion of cluster of differentiation 31 (CD31)/alpha-smooth muscle actin (α-SMA)/doublecortin (DCX)-positive immunofluorescence area, up-regulation of circular RNA SCMH-1(circSCMH-1), and the best restoration of synaptic ultrastructure. Compared with MSC-EXOs or LIPUS alone, the combined treatment appeared to have an additive effect, supporting neurovascular regeneration and functional recovery after cerebral ischemic stroke.

Pathological thrombosis is a major cause of cardiovascular and cerebrovascular diseases. Current anticoagulants increase bleeding risk by impairing physiological hemostasis. Because coagulation factor XIIa (FXIIa) drives pathological thrombosis but is dispensable for normal hemostasis, inhibiting FXIIa may offer antithrombotic efficacy with reduced bleeding risk. However, the marked flexibility of its active site hampers the discovery of small-molecule inhibitors. Here, we developed an integrated computational workflow to address this challenge and screened a library of approximately 21 million compounds. Four structurally distinct hits (DR1-DR4) were identified. Microsecond-scale molecular dynamics simulations suggested stable binding of all four compounds to FXIIa, and binding free energy calculations suggested that DR1 and DR3 exhibited more favorable binding free energies than the reference inhibitor 1303. These compounds also showed favorable predicted pharmacokinetic properties, providing structurally distinct hits for FXIIa-targeted anticoagulant discovery.

The crystal structure of the FXIIa catalytic domain (PDB ID: 6B74) was prepared in PyMOL 3.1, and missing regions were modeled with MODELLER. To capture active-site flexibility, apo-FXIIa was subjected to three independent 1-µs molecular dynamics simulations, and a representative conformation selected by clustering was used for virtual screening. A hierarchical screening workflow was carried out in DrugFlow using KarmaDock for primary screening, CarsiDock for redocking, and RTMScore for rescoring. Drug-likeness and pharmacokinetic properties were predicted with SwissADME. Selected complexes were simulated in Amber18 using ff19SB for the protein, GAFF2 for ligands, OPC water, and AM1-BCC ligand charges, and trajectories were analyzed with CPPTRAJ in AmberTools. Binding free energies were estimated with MMPBSA.py using the MM/GBSA method, with entropy contributions evaluated by normal mode analysis. Structural visualization was performed with PyMOL and Discovery Studio Visualizer 2016.

Up to 50% of pulmonary embolism (PE) survivors experience long-term functional limitations and reduced quality of life (QoL). Reperfusion strategies can rapidly relieve right-ventricular (RV) dysfunction and prevent clinical deterioration or hemodynamic collapse; however, these approaches have never been evaluated in a randomized trial against anticoagulation alone using patient-centered outcomes.

This study sought to evaluate whether mechanical thrombectomy with anticoagulation improves functional, QoL, and safety outcomes compared with anticoagulation alone in patients with acute intermediate-high risk PE over 90 days.

STORM-PE enrolled 100 PE patients randomized 1:1 to computer-assisted vacuum thrombectomy (CAVT) with anticoagulation or anticoagulation alone across 22 international sites, with RV-to-left-ventricular (RV/LV) ratio change at 48 hours as the primary endpoint. Secondary endpoints included major adverse events within 7 days, functional and QoL outcomes, mortality, and symptomatic PE recurrence through 90 days.

For all patients, median time from randomization to last follow-up visit was 91.0 days [Q1-Q3: 80.5-100.0]. At 90 days, 66.0% (31/47) of CAVT and 64.2% (34/53) of anticoagulation patients completed the 6-min walk test. The CAVT arm exhibited a longer 6-min walk distance compared with anticoagulation alone (478.7 ± 159.5 m vs 368.0 ± 127.8 m, P = 0.003). More CAVT than anticoagulation patients were NYHA Functional Class I (97.4% [37/38] vs 75.6% [34/45], P = 0.005) at 90 days. Dyspnea and QoL scores were comparable between groups, with no differences between arms for all-cause mortality, PE-related mortality, and symptomatic PE recurrence within 90 days.

In STORM-PE, CAVT with anticoagulation resulted in improved functional outcomes at 90 days compared with anticoagulation alone, with equivalent safety rates. This trial supports CAVT as an effective and safe reperfusion strategy for intermediate-high risk PE.

https://clinicaltrials.gov Unique Identifier: NCT05684796.

As more adults with atrial septal defect (ASD) survive into older age and undergo atrial fibrillation (AF) ablation, evidence to guide post-ablation risk stratification remains limited.

To evaluate long-term outcomes after the first AF ablation across ASD management states compared with an intact interatrial septum.

This real-world cohort study included 27 675 patients undergoing their first AF ablation, classified by interatrial septal status as intact septum (n = 27 134), unrepaired ASD (n = 232), percutaneous closure (n = 119), or surgical repair (n = 190). Three pairwise comparisons with an intact septum were constructed. Propensity score overlap weighting was used to balance baseline characteristics, and Cox proportional hazards models were used to assess outcomes. The primary outcome was atrial arrhythmia recurrence after the 3-month blanking period; the secondary outcome was a composite cardiovascular outcome.

Compared with an intact septum, unrepaired ASD was associated with a higher recurrence risk (hazard ratio [HR], 1.27; 95% CI, 1.07-1.51; p = 0.006), with excess risk mainly observed between 3 months and 1 year after ablation. Surgical repair was also associated with higher recurrence risk (HR, 1.21; 95% CI, 1.01-1.46; p = 0.038), with differences emerging beyond 1 year. Percutaneous closure was not associated with increased recurrence risk (HR, 1.07; 95% CI, 0.83-1.38; p = 0.589). Composite cardiovascular outcomes did not differ significantly across groups.

ASD management status identified distinct temporal patterns of atrial arrhythmia recurrence after AF ablation, suggesting that ASD should not be treated as a single binary condition in post-ablation risk assessment.

AIM: To evaluate the potential neuroprotective effect of felbamate in a rat model of spinal cord ischemia-reperfusion injury. MATERIAL and METHODS: Twenty-one male Wistar albino rats were randomly assigned to three groups (n=7 each): control, ischemia, and felbamate-treated. Transient spinal cord ischemia was induced by abdominal aortic occlusion for 20 minutes, followed by reperfusion. Felbamate was administered via a nasogastric tube immediately after reperfusion at a dose of 20 mg/kg. Twenty-four hours after surgery, tissue caspase-3 levels were measured using an enzyme-linked immunosorbent assay, spinal cord sections were evaluated histopathologically using a semiquantitative composite injury score, and neurological function was assessed using the modified Tarlov scoring system. RESULTS: Tissue caspase-3 levels differed significantly across the three groups (ANOVA, F=205.19, p.

Acute myocarditis is an inflammatory disorder of the myocardium that can lead to severe cardiac dysfunction, arising from a broad spectrum of infectious and noninfectious etiologies. Ankylosing spondylitis, which primarily affects the axial skeleton, can involve the heart due to its systemic inflammatory nature, occasionally resulting in severe complications such as myocarditis.

We report an unusual case of acute myocarditis in a 49-year-old male with ankylosing spondylitis presenting with chest pain and systemic inflammatory symptoms. Diagnostic workup using the 2018 Lake Louise Criteria among cardiac MRI confirmed myocarditis in the absence of coronary artery disease or infectious etiology. The patient also demonstrated extraarticular manifestations with pulmonary and ocular involvement, consistent with an active ankylosing spondylitis flare. Management combined beta blockers, physical activity restriction, and re-introduction of anti-TNF alpha therapy, leading to both clinical and biological improvement.

Acute myocarditis represents a rare yet severe cardiac manifestation of ankylosing spondylitis, requiring a high clinical suspicion to prevent heart failure and dilated cardiomyopathy.

In-hospital cardiac arrest (IHCA) is an acute event associated with high mortality. Although survival has improved in high-income countries, contemporary multicenter data from low- and middle-income countries remain scarce, limiting global benchmarking and the identification of system-level opportunities for improvement.

This cohort study used data from the BASIC-IHCA (Baseline Investigation of In-Hospital Cardiac Arrest) registry. Adult patients (≥18 years) who experienced IHCA and received cardiopulmonary resuscitation between July 1, 2019, and December 31, 2020, at 37 hospitals across 29 provinces in China were included. The primary outcome was survival to 30 days or hospital discharge. Secondary outcomes included return of spontaneous circulation, 6- and 12-month survival, and favorable neurological outcome (Cerebral Performance Category score 1-2). Process measures focused on the timeliness of resuscitation response and the implementation of postresuscitation interventions.

Among 17 602 patients (median age, 66 years; 65.5% male), the annual incidence of adult IHCA was 4.1 per 1000 admissions. Cardiac etiology was identified in 6569 (37.3%) patients, and 2380 (13.5%) presented with initial shockable rhythm. Among all patients, 16 872 (95.9%) received cardiopulmonary resuscitation within 1 minute; timely defibrillation or epinephrine was achieved in 71.4% and 84.4% of patients with initial shockable and nonshockable rhythms, respectively. Sustained return of spontaneous circulation was achieved in 6200 (35.2%) patients, of whom 222 (3.6%) received temperature control therapy and 320 (5.2%) underwent coronary angiography. Overall, 1610 (9.1%) patients survived to 30 days or discharge, with 1241 (7.1%) having a favorable neurological outcome. At 12 months, 1075 (6.1%) patients remained alive, and 986 (5.6%) had a favorable neurological outcome.

This multicenter registry highlights a substantial burden of IHCA in China, with markedly low survival rates. Despite prompt initial resuscitation, critical gaps persist in postresuscitation care. Systemic and cultural factors, including the infrequent use of do not attempt cardiopulmonary resuscitation orders, may further contribute to survival disparities. These findings suggest several system-level opportunities to improve IHCA outcomes, including structured response systems, optimized critical care resource allocation, and greater integration of advanced care planning.

Cardiometabolic diseases (CMDs) often manifest in the form of cardiometabolic multimorbidity. Traditional risk assessment methods that rely on single biomarkers fail to adequately characterise the heterogeneity among patients across various subtypes. This study seeks to utilise routine biomarkers to identify clinical subtypes with unique characteristics, thereby improving risk assessment.

We included 337 334 UK Biobank participants without type 2 diabetes (T2D), ischaemic heart disease (IHD) or stroke at baseline. Multi-task Deep LASSO selected 12 variables for K-means clustering. Multi-state Cox models assessed transitions to first cardiometabolic disease (FCMD), cardiometabolic multimorbidity (CMM) and death. Analyses of 251 plasma metabolic measures and circulating proteins characterised molecular correlates; metabolite panels were evaluated in held-out testing.

Four risk-informed phenotypes were identified: metabolically healthy (MH), older cardio-renal-metabolic (OCRM), lean hypercholesterolaemia (LHC) and early-onset metabolic syndrome (EO-MetS). During a median follow-up of approximately 13 years, OCRM showed the highest FCMD and FCMD-to-CMM risks. In primary models, OCRM and EO-MetS showed strong T2D associations, whereas LHC showed stronger relative associations with IHD and stroke than with T2D. Age adjustment attenuated several OCRM and LHC associations, particularly with IHD and stroke; T2D associations remained largely unchanged. Phenotypes exhibited differing metabolic profiles, and exploratory decomposition showed statistical overlap with phenotype-outcome associations without establishing causality. Protein enrichment highlighted complement/coagulation and vascular-remodelling processes. Metabolite panels modestly improved discrimination beyond full clinical models, increasing the 10-year CMM area under the receiver operating characteristic curve from 0.834 to 0.848; phenotype membership added little further improvement.

Routine biomarker-derived subtypes showed distinct cardiometabolic trajectories and multi-omic profiles. These risk-informed phenotypes support exploratory description of cardiometabolic heterogeneity, pending external validation.

Randomized evidence comparing conduction system pacing (CSP) and biventricular pacing (BVP) following atrioventricular node ablation in patients with refractory atrial fibrillation (AF) and heart failure (HF) remains limited. This study evaluated whether CSP with left bundle branch area pacing is non-inferior to BVP in patients undergoing atrioventricular node ablation.

CONDUCT-AF was an investigator-initiated, multicentre, randomized trial conducted across 10 European centres. Patients with refractory AF, HF with left ventricular ejection fraction (LVEF) < 50%, narrow QRS duration (≤120 ms), and N-terminal pro-B-type natriuretic peptide > 600 ng/L were randomized 1:1 to CSP or BVP. The primary endpoint was the change in LVEF after 6 months, assessed by an independent core laboratory. Secondary endpoints included echocardiographic, clinical, and procedural outcomes. Analyses followed the intention-to-treat principle.

Eighty-two patients were randomized (mean age 72 ± 7 years, 46% male). At 6 months, LVEF improved similarly in CSP {from 36% [95% confidence interval (CI) 33-39] to 46% [95% CI 44-49]; P < .001} and BVP group [from 34% (95% CI 31-36) to 46% (95% CI 43-49); P < .001]. The between-group difference was .4% (95% CI -3.1-3.8; P = .002 for non-inferiority). Changes in left ventricular volumes, clinical parameters, and composite endpoint of worsening HF or cardiovascular death were comparable between groups. Paced QRS [mean difference -14 ms (95% CI -19 to -9; P < .001)] and procedural and fluoroscopy times were significantly shorter with CSP compared with BVP.

In HF patients with refractory AF undergoing atrioventricular node ablation, CSP with left bundle branch area pacing was non-inferior to BVP for LVEF improvement at 6 months, providing comparable clinical outcomes and a favourable procedural profile.

Neonatal hypoxic-ischemic brain damage (HIBD) is the leading cause of neonatal death and long-term neurological dysfunction. Dexmedetomidine (DEX) has been shown to have neuroprotective effects, but its mechanisms in HIBD remain incompletely understood. This study aimed to explore whether DEX inhibits neuroinflammation and pyroptosis via activating adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) axis, thereby reducing HIBD. A HIBD model was established. Histological staining observed the pathological changes and neuronal survival. Primary cortical neurons were cultured to establish an oxygen-glucose deprivation/reoxygenation (OGD/R) model. DEX was used for intervene, and siAMPK was transfected to knock down AMPK expression. Inflammatory and oxidative stress indicators within brain tissue and neuronal cells were measured using enzyme-linked immunosorbent assay (ELISA) and biochemical kits. The AMPK/SIRT1 pathway and pyroptosis protein expressions were evaluated using fluorescence staining and Western blot. DEX dose-dependently reduced cerebral infarction volume, improved cerebral cortex pathological damage, enhanced neuronal nuclei (NeuN) positive neurons, decreased interleukin (IL)-6 and malondialdehyde (MDA) contents, enhanced superoxide dismutase (SOD) activity, and inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)/cleaved Caspase-1 double positive cells and N-terminal domain of Gasdermin D (GSDMD-N) protein expressions. DEX significantly upregulated p-AMPK and SIRT1 expression, whereas the AMPK inhibitor Compound C reversed the neuroprotective effect of DEX. In vitro experiments confirmed that DEX increased neuronal cell viability, reduced lactate dehydrogenase (LDH) release and propidium iodide (PI)-positive cell rate, reduced oxidative stress, and inhibited inflammatory factor release and pyroptosis-related protein expression. AMPK knockdown significantly reversed this axis activation by DEX and attenuated the neuroprotective effect of DEX. In conclusion, DEX improved neurological function in HIBD rats via the activating AMPK/SIRT1 pathway, reducing neuroinflammation and inhibiting neuronal pyroptosis.