Sepsis-induced acute liver injury (SALI) is a severe complication with high mortality, largely driven by excessive reactive oxygen species (ROS) and uncontrolled inflammation. The heart is also frequently affected in sepsis, manifesting as cardiomyopathy and arrhythmias. Sepsis can also precipitate heart failure and myocardial infarction. However, targeted therapies that simultaneously address oxidative stress and inflammatory organ damage remain lacking. Tanshinone IIA (Tan) exhibits potent antioxidant and anti-inflammatory activities, but its poor water solubility and low bioavailability limit clinical translation. Herein, we develop a mannosamine-modified PLGA-PEG nanoparticle encapsulating tanshinone IIA (Tan-NPs) via a double-emulsion solvent evaporation method for targeted delivery to liver macrophages. The nanoparticles display uniform spherical morphology (105.3 nm), narrow size distribution (PDI < 0.2), favorable negative zeta potential, and excellent colloidal stability in physiological media. Tan-NPs achieve efficient lysosomal escape, potently scavenge intracellular ROS, restore mitochondrial membrane potential, and reduce apoptosis in LPS-stimulated RAW264.7 macrophages. They significantly suppress the secretion of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and shift macrophage polarization from the M1 to the anti-inflammatory M2 phenotype. Following intravenous injection into mice with LPS-induced sepsis-associated acute liver injury, Tan-NPs preferentially accumulate in the liver via mannose receptor-mediated active targeting, dramatically ameliorate hepatic histopathological damage, and reduce both oxidative stress and NF-κB activation. Importantly, the nanoparticles exhibit excellent biocompatibility with no overt cytotoxicity or hemolysis. Collectively, Tan-NPs show potential as a targeted nanomedicine for the treatment of sepsis-induced acute liver injury, with potential applicability to other ROS-driven inflammatory diseases.

Predicting the improvement of functional mitral regurgitation (FMR) to medical therapy is an important, yet overlooked, clinical issue. The objective of the study was to evaluate whether echocardiographic assessment of left ventricular (LV) mechanoenergetic parameters and of LV volumes is associated with improvement of FMR in HFrEF patients after optimization of pharmacological therapy.

The study included 662 patients with chronic HFrEF prospectively enrolled in a multicenter, open-label registry before starting sacubitril/valsartan. Echocardiography was performed at baseline and repeated at 6-12 months. A simplified, non-invasive echocardiographic P/V loop model was used, based on brachial arterial pressure and transthoracic two-dimensional Doppler echocardiographic data.

Patients with FMR improvement showed greater gains in LV function and mechanoenergetics. In the subgroup of 279 patients with moderate/severe FMR, age, ventricular efficiency (VE) and LV end-diastolic volume index (LVEDVi) were independently associated with FMR improvement in the primary model. Individual discrimination was modest. In a post-hoc sensitivity analysis adding baseline E/e', VE was no longer significant (OR 1.11; p = 0.491), whereas E/e' was independently associated with FMR improvement (model AUC 0.704 to 0.762).

The combined assessment of echocardiography-derived VE and LVEDVi was associated with FMR improvement in the primary model; however, VE was no longer independently associated after additional adjustment for baseline E/e'. FMR improvement was closely associated with LV reverse remodeling, although a causal direction cannot be established from this observational study.

Orforglipron is an oral, non-peptide GLP-1 receptor agonist. While some peptide GLP-1 receptor agonists have established cardiovascular benefit, the cardiovascular safety of non-peptide GLP-1 receptor agonists has not been studied. This study aimed to compare the effect of orforglipron with insulin glargine on the incidence of major adverse cardiovascular events in individuals with type 2 diabetes and obesity or overweight who are at increased risk for cardiovascular events.

This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories. Adults with type 2 diabetes at increased cardiovascular risk with glycated haemoglobin (HbA_1c) concentrations between 7·0% and 10·5% (53-91 mmol/mol) and a BMI of 25 kg/m² or more, treated with up to three glucose-lowering medications (metformin, a sulfonylurea, and/or an SGLT2 inhibitor), were randomly assigned (1:1) to oral orforglipron maximum tolerated dose (up to 36 mg capsule [equivalent to 17·2 mg tablet]) or injectable titrated insulin glargine, each administered once daily. All participants had established cardiovascular or chronic kidney disease. The primary outcome was time to occurrence of four-component major adverse cardiovascular events (MACE-4), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. Non-inferiority of orforglipron to insulin glargine was declared if the upper limit of the two-sided 95% CI for the hazard ratio (HR; orforglipron vs insulin glargine) was less than 1·8. The primary endpoint and other safety endpoints were assessed in all participants who took at least one dose of assigned treatment using all datapoints from baseline until withdrawal or study completion, regardless of treatment adherence. This trial was registered on ClinicalTrials.gov (NCT05803421) and is completed.

Between May 1, 2023, and Sept 5, 2024, 2749 participants were randomly assigned (1371 to orforglipron and 1378 to insulin glargine). 1032 (38%) participants were female and 1717 (62·5%) male. 2362 (85·9%) participants had established cardiovascular disease and 1033 (37·6%) had chronic kidney disease. Mean baseline age, HbA_1c, and BMI were 63·1 years (SD 9·9), 8·2% (1·0), and 33 kg/m² (6·2), respectively. Over a median follow-up of 2 years, the primary outcome occurred in 57 (4·2%) of 1358 orforglipron participants and 67 (5·0%) of 1343 insulin glargine participants, showing non-inferiority to insulin glargine for MACE-4 (HR 0·84; 95% CI 0·59-1·20; p<0·0001 for non-inferiority). Gastrointestinal adverse events were reported in 851 (62·1%) of 1371 orforglipron participants and 193 (14·2%) of 1355 insulin glargine participants; clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL]) occurred in 93 (6·8%) of 1371 orforglipron participants and 260 (19·2%) of 1355 insulin glargine participants. 62 deaths were reported during the study: 19 (1·4%) of 1371 participants receiving orforglipron and 43 (3·2%) of 1355 participants receiving insulin glargine; all deaths except one (in the insulin glargine group) were deemed unrelated to treatment.

In people with type 2 diabetes at increased cardiovascular risk, the cardiovascular safety of orforglipron was confirmed by demonstrating non-inferiority to insulin glargine for MACE-4. Gastrointestinal adverse events were the most frequent adverse event and most common reason for orforglipron treatment discontinuation with orforglipron, while clinically significant hypoglycaemia occurred less frequently with orforglipron than with insulin glargine. These findings support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk.

Eli Lilly and Company.

Marfan syndrome (MFS) is a genetic fibrillin disorder causing cardiac, ocular, and musculoskeletal pathology; it is not well reported on in dogs, with minimal descriptions of antemortem diagnosis.

Use whole-genome sequencing (WGS) to diagnose a dog with suspected MFS to guide prognostication and potential treatment.

A client-owned, 10-month-old Golden Retriever presented with signs of possible connective tissue disorder. Blood and DNA samples from a non-affected German Shepherd-Beagle mix and 160 unrelated Golden Retrievers were used as controls.

Physical examination, blood collection, and radiography were performed on the dog while at the hospital. Whole-genome sequencing was performed on DNA from the affected dog. Genetic analysis focused on single-nucleotide variants, small insertion-deletions, and structural variants to detect potential disease-causing genetic variants in the genome, prioritizing candidate genes. Polymerase chain reaction amplification and Sanger sequencing of a suspected region were carried out to confirm presence of the candidate pathogenic variant.

The dog was presented for cardiology consultation and had clinical signs of cardiac enlargement, pneumothorax, and joint hypermobility. After genetic analysis, a 3618 base pair deletion encompassing exon 24 of the FBN1 gene on 1 allele was detected (NC_049251.1:g.14998228_15001846del), likely causing an in-frame deletion in the coding sequence.

Physical and complementary examination findings are suggestive of MFS and associated with a causal deletion variant.

Human Pregnancy-related Cardiovascular Diseases (CVDs) are unique and difficult to study because of many unknown, potentially harmful effects of medical interventions on the fetus. Because of that, there are only sparse data and mechanisms available, which could provide recommendations with strong evidence for physicians.

To assess the efficacy of the European Society of Cardiology (ESC) 2025 Guidelines for the management of cardiovascular disease and Pregnancy (Pregnancy-GL-2025), we used a previously developed mathematical analytic method.

A total of 208 Recommendations and Evidence were analyzed, of which 161 Recommendations concern certain CVD. To assess the efficacy, the Certainty/Uncertainty ratio and the Certainty Index (CI, ranging from -1 to +1) were calculated.

In total, the Pregnancy-GL-2025 showed 64.4% of the Class I and III Recommendations (CVDs, 62.7%). The ESC Pregnancy-GL-2025 includes mostly Evidence C (89.4%) and showed 78.8% Certainty (CI = 0.58). Although it includes only a few higher-quality Evidence, these are related to the Class I Recommendations, resulting in a high level of Certainty.

The mathematical analysis of the ESC Pregnancy-GL-2025 showed that it has several helpful Recommendations, yet they are supported primarily by Evidence C. However, because of a few higher-quality evidence related to Class I Recommendations, the overall efficacy of the guideline was relatively high. In addition, the mathematical analysis used instead of frequency analyses does not imply a lower efficacy of a guideline. Thus, we propose that this type of evaluation of guidelines, as a complementary quantitative approach to describing guidelines' recommendations, can facilitate the development of new guidelines.

Cardiovascular stents are life-saving interventions for occlusive vascular diseases, yet current designs such as drug-eluting stents suppress restenosis via universal antiproliferation, inevitably impairing endothelial regeneration and raising the risk of late thrombosis. Here, we introduce a bioinspired endothelial-selective peptide self-assembling nanofibrous coating (ECSP-SANC) that integrates extracellular matrix (ECM)-mimetic β-sheet nanofibrous topography with REDV (Arg-Glu-Asp-Val)-mediated endothelial recognition cues to create a regenerative stent interface. ECSP-SANC forms a highly hydrated three-dimensional nanofibrous network that recapitulates key architectural features of native ECM while displaying accessible REDV motifs to preferentially promote endothelial cell adhesion, migration, proliferation, and functional maturation. In parallel, the coating suppresses smooth muscle cell overgrowth and synthetic phenotypic switching, thereby conferring an endothelial competitive advantage on the stent surface. The hydrated nanofibrous interface also minimizes platelet adhesion and inflammatory responses, contributing to improved hemocompatibility and local immune regulation. In a rabbit iliac artery implantation model, ECSP-SANC-functionalized stents accelerated re-endothelialization, suppressed neointimal hyperplasia, and effectively prevented restenosis. This approach demonstrates that precise integration of endothelial-selective biochemical signals with ECM-mimetic architecture can orchestrate vascular repair beyond conventional antiproliferative strategies. ECSP-SANC represents a versatile, next-generation platform for regenerative stent coatings, offering a blueprint for cardiovascular therapies that harmonize anti-restenotic efficacy with rapid endothelial recovery.

The Shenqi Fuzheng (SQ) formula, made from Codonopsis Radix (Dangshen, DS) and Astragali Radix (Huangqi, HQ), has been used in Traditional Chinese Medicine (TCM) and exhibits cardio-protective effects against acute myocardial infarction (AMI). However, the molecular basis of DS-HQ synergy remains unclear. Here, we combined RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) to explore their synergistic mechanisms. Transcriptomic analyses showed that SQ influenced the AMI network more effectively than either herb alone. ScRNA-seq analysis revealed that these synergistic effects involve both direct and indirect pro-angiogenic pathways. The combination treatment enhanced pro-angiogenic responses in microvascular endothelial subpopulations and promoted angiogenesis in the border zone. It also enhanced the anti-inflammatory role of a specific reparative macrophage subset and stimulated vascular endothelial growth factor A (VEGFA) secretion from these cells, supporting the VEGFA-VEGFR signaling between macrophages and microvascular endothelial cells. This coordinated regulation provides a plausible mechanistic explanation for the reduced infarct size and improved cardiac outcomes seen in vivo, highlighting the therapeutic value of TCM.

Postoperative atrial fibrillation (POAF) is strongly linked to mitochondrial oxidative stress, yet the upstream post-translational mechanisms that couple redox imbalance to atrial vulnerability remain unclear. We investigated atrial lysine 2-hydroxyisobutyrylation (Khib) remodeling and tested whether site-specific Khib regulates mitochondrial energy-redox signaling in POAF. Quantitative Khib proteomics was performed in right atrial appendage tissue from coronary artery bypass grafting patients. Differentially modified proteins were analyzed by functional enrichment and protein-interaction networks. Mitochondrial transcription factor A (TFAM) K76 Khib was validated by immunoprecipitation and western blotting. Site-directed mutagenesis in atrial cardiomyocytes was combined with measurements of cytochrome c oxidase (COX) activity, ATP, mitochondrial reactive oxygen species (mtROS), and AMPK phosphorylation, together with structural modeling and ultrastructural analysis. POAF atria exhibited extensive Khib remodeling enriched in mitochondrial metabolism, contractile regulation, and stress-response networks. Khib at TFAM Lys76 was markedly increased in POAF. Enhanced K76 modification impaired COX activity and ATP production, reduced AMPK phosphorylation, and increased mtROS accumulation. In silico structural modeling predicted that K76 Khib would weaken the interaction between TFAM and mtDNA. Electron microscopy demonstrated mitochondrial swelling and cristae disruption in POAF atria. These findings identify coordinated bioenergetic failure and oxidative stress downstream of aberrant TFAM K76 modification. TFAM K76 Khib affects a TFAM-COX/ATP/ROS-AMPK axis that couples mitochondrial bioenergetic dysfunction and redox imbalance in POAF. This Khib-induced alteration of the energy-redox pathway provides a mechanistic framework and a potential biomarker and therapeutic target for POAF.

Acute cervical spinal cord injury (cSCI) disrupts supraspinal autonomic cardiovascular control. Heart rate variability (HRV), assessed using linear and nonlinear methods, provides a sensitive index of cardiovascular autonomic regulation.

To evaluate linear and nonlinear HRV parameters associated with autonomic cardiovascular dysregulation in acute cSCI.

This monocentric prospective study included 500 patients with traumatic or non-traumatic acute cSCI and 200 age- and sex-matched healthy controls. All participants underwent 24-hour Holter ECG monitoring. Time- and frequency-domain indices and nonlinear metrics, including Poincaré plot analysis, entropy, detrended fluctuation analysis, and recurrence quantification analysis, were calculated. Predictive modeling used logistic regression, random forest, gradient boosting, and support vector machine algorithms with cross-validation.

Both cSCI groups showed significantly reduced HRV amplitude and altered autonomic cardiovascular regulation. Nonlinear indices demonstrated reduced entropy, altered fractal scaling, and decreased recurrence dynamics. Female patients showed relatively preserved nonlinear HRV parameters. Models combining linear and nonlinear features discriminated autonomic dysfunction better than models using conventional HRV metrics alone.

Combined linear and nonlinear HRV analysis provides complementary characterization of autonomic cardiovascular dysregulation following acute cSCI.

Israel's nationwide mental health reform (July 1, 2015) transferred responsibility and funding for mental healthcare from the Ministry of Health to Israel's four Health Maintenance Organizations (HMOs), aiming to improve access and availability, integrate mental health into general care, and shift delivery toward community-based models. Using electronic health records and administrative data from all four HMOs and the Ministry of Health, we assessed longitudinal trends in mental health service utilization from 2012 to 2019 among continuously insured Israeli residents with any recorded mental health diagnosis, mental health-related service contact, or psychotropic medication dispensing (31% of the national population). Outcomes included annual community-based mental health visits in HMO clinics, outpatient psychiatric visits in hospital clinics, mental health-related emergency department (ED) visits, psychiatric hospitalizations, and psychiatric medication dispensed. Post-reform changes were examined using Poisson regression adjusted for age, sex, social group, and socioeconomic status. Post-reform, community-based visits increased fourfold and hospital outpatient visits increased 3.3-fold. Psychiatric medication dispensing rose by 56% (psychostimulants + 87%; antidepressants + 60%). ED visits without admission increased by 40% while admission rates remained stable; total hospitalizations increased by 10%. Women had higher outpatient and medication use, whereas men had higher ED and inpatient use. Adjusted models indicated a 16% post-reform increase in service utilization (P < .0001). During 2015-2019, we analyzed 265,286 mental health-related ED visits; 77% occurred in psychiatric-hospital EDs and 23% in general-hospital EDs, and most visits did not result in hospitalization (78% in general hospitals; 67% in psychiatric hospitals). Overall, Israel's reform was associated with system-wide expansion and a shift toward community-based care, alongside rising non-admission ED presentations, warranting further research on pathways, clinical need, and follow-up, and on strengthening accessible community-based urgent and crisis alternatives to ED care.