心血管科领域文献阅读汇编

Heart failure in the perinatal period remains ambiguous in definition and management despite its recognition as a unique disease state. The true incidence and prevalence of heart failure or left ventricular systolic dysfunction during pregnancy and the postpartum period are unknown, although a prevalence as high as 1% to 2% has been reported in the general adult US population. Assessment of heart failure can be challenging in the pregnant or postpartum state, during which symptoms affecting physical function (eg, dyspnea, exercise intolerance, fatigue, and lower-extremity edema) are prevalent because of physiological changes. Delays in the recognition and diagnosis of heart failure during the perinatal period contribute to adverse maternal outcomes, highlighting the need for evidence-based definitions and thresholds, improved diagnostic criteria to aid disease recognition, and effective screening tools. This scientific statement focuses on heart failure with reduced and mildly reduced ejection fraction in the context of pregnancy and the postpartum period, caused by various forms of cardiomyopathy. It addresses challenges related to recognizing heart failure in obstetric patients, outlines established treatment standards, and underscores potential areas for research. To improve the management of preexisting and de novo heart failure in obstetric patients, standardization of disease definitions, specific therapeutic options, implementation of effective screening tools, and interventions to improve maternal health equity are imperative. Future directions include prioritizing the inclusion of pregnant and postpartum individuals in heart failure studies, implementing interventions that facilitate early disease detection, and ensuring the timely initiation of appropriate therapies with the goal of reducing adverse outcomes associated with perinatal heart failure.

To determine whether weight loss during the initial years following diagnosis of impaired glucose tolerance (IGT) is independently associated with reduced long-term mortality and cardiovascular risk. In the Da Qing Diabetes Prevention Study, 540 adults with IGT were categorized into three groups based on their weight change from baseline to the end of a 6-year lifestyle intervention trial: non-weight loss (n = 200), low weight loss (<5%, n = 163), and high weight loss (≥5%, n = 177). Participants were followed for 34 years to assess all-cause mortality, cardiovascular disease (CVD) mortality, and CVD events. Cox models were used to assess associations. Weight loss during the initial 6 years following IGT diagnosis was associated with reduced long-term risks of CVD events and mortality (P = 0.007-0.015). Compared with participants without weight loss, those with weight loss ≥5% had significantly lower risks of CVD death (hazard ratio [HR] 0.56, 95% CI 0.35-0.89), CVD events (HR 0.71, 95% CI 0.52-0.99), hospitalized heart failure (HR 0.48, 95% CI 0.26-0.88), and all-cause death (HR 0.67, 95% CI 0.48-0.95) after adjusting for age, sex, baseline weight, and other covariates. Furthermore, the high weight loss group showed delays in the median time to all-cause mortality and CVD mortality of 2.1 years and 6.5 years, respectively. Weight loss achieved in the early years after diagnosis of IGT in Chinese adults is associated with substantially lower long-term risks of CVD events and mortality, suggesting the critical importance of early weight management in individuals with prediabetes for improving long-term survival and cardiovascular health.

Advances in therapeutics and interventions have enabled the comprehensive management of patients with heart failure (HF); however, real-world clinical practice remains poorly characterized. This study aimed to evaluate temporal changes in HF management and their impact on patient outcomes. Two large-scale Japanese HF registries were compared: the JROADHF (2013, n = 13 238) and JROADHF-NEXT (2019-21, n = 4016). Propensity score matching (1:1) was performed to compare patient outcomes between cohorts and identify factors associated with outcome improvements. Propensity score matching yielded 2972 patients in each cohort. After matching, guideline-recommended therapy increased for renin-angiotensin system inhibitors (70.9% vs 73.1%), beta-blockers (74.9% vs 80.8%), mineralocorticoid receptor antagonists (54.2% vs 61.1%), cardiac rehabilitation (43.5% vs 88.8%), and nutritional guidance (2.9% vs 56.1%) in the 2013 and 2019-21 cohorts, respectively. The 2019-21 cohort demonstrated 26.7% and 52.1% reductions in 1-year mortality and HF readmission rate (P < .001 for both), respectively, compared with the 2013 cohort. Improved mortality was associated with pharmacotherapy [renin-angiotensin system inhibitors: hazard ratio (HR) .71, 95% confidence interval (CI) .64-.80, P < .001; beta-blockers: HR .85, 95% CI .75-.96, P = .012] and patient education (nutritional guidance: HR .76, 95% CI .64-.89, P = .001). The cohort effect was the strongest predictor of HF readmission (subdistribution HR .49, 95% CI: .43-.57, P < .001). Long-term outcomes of patients with HF improved between 2013 and 2019-21. Guideline-recommended therapy was associated with survival benefit, whereas marked reduction in HF readmission rates coincided with broader changes in post-discharge care and healthcare system.

Pediatric heart failure-related cardiogenic shock carries high morbidity and mortality but is understudied. Improving outcomes in pediatric cardiogenic shock hinges on timely diagnosis and appropriate triage, medical management tailored to the cause and phenotype of cardiogenic shock, and optimal timing of escalation to appropriate mechanical circulatory support. This scientific statement provides a diagnostic framework for the bedside clinician, in addition to proposing a pediatric cardiogenic shock definition and severity staging aligned with systems previously validated in other studies. It outlines the initial approach to diagnosis and stabilization of a child with suspected cardiogenic shock and offers guidance on optimal noninvasive and invasive monitoring strategies to determine clinical trajectory because a significant proportion of children with cardiogenic shock will continue to deteriorate in the first 24 hours. Last, it identifies future directions for the field, including educational interventions for the frontline clinicians seeing these patients, studying the role of a multidisciplinary shock team, evaluating the prognostic and clinical relevance of known and novel biomarkers, and leveraging all these to develop clinical decision tools or algorithms to guide nuanced management of these patients.

Left ventricular structural assessment is fundamental in heart failure (HF). However, the independent prognostic value of left ventricular size beyond its association with ejection fraction remains poorly defined in real-world, large-scale populations. To investigate the association between left ventricular dimension and mortality risk within a large, nationwide cohort with HF. This was a nationwide cohort study using data from the Chinese Cardiovascular Association Database-Heart Failure Center Registry. Patients were enrolled from January 1, 2018, to May 31, 2022. The multicenter study involved 723 centers across 31 provincial-level administrative regions in mainland China. The study included patients hospitalized with HF. Patients were categorized into groups with a small, normal, or large left ventricle (LV) according to American Society of Echocardiography criteria for LV end-diastolic diameter (LVEDD). Data analysis was conducted from March to June 2025. LVEDD measured by echocardiography. The primary and secondary end points were all-cause mortality and cardiovascular mortality, respectively. A total of 273 921 patients (median [IQR] age, 71.0 [62.0-79.0] years; 161 589 male [59.0%]) hospitalized with HF were included in this study. A significant U-shaped association was found between LVEDD and both all-cause and cardiovascular mortality (P for nonlinearity <.001). Both a small LV (adjusted HR [aHR], 1.32; 95% CI, 1.28-1.37; P < .001) and a large LV (aHR, 1.38; 95% CI, 1.35-1.40; P < .001) were independently associated with elevated all-cause mortality. Sex-specific optimal LVEDD thresholds were identified (47 mm for male patients, 43 mm for female patients), with each 1-mm deviation associated with a significant increase in mortality risk. These findings were consistent across prespecified subgroups and were further corroborated by analysis of LVEDD indexed to body surface area and by extensive sensitivity analyses, including competing risk models and complete-case analyses. This large-scale study established that a U-shaped association exists between LVEDD and mortality in HF, suggesting that both abnormally small and abnormally large ventricles signify high risk, likely through distinct mechanisms. These findings support the integration of LV size assessment into routine risk stratification to guide personalized management.

Decidual protein induced by progesterone 1 (DEPP1), also known as DEPP or C10ORF10, was originally identified as a progesterone-induced protein in endometrial stromal cells. Over the past two decades, research has progressively elucidated its involvement in various biological processes such as energy metabolism, redox regulation, and cellular autophagy. Additionally, DEPP1 has been implicated in the pathogenesis of several diseases, including diabetes, atherosclerosis, ischemic cardiomyopathy, breast cancer, and colon cancer. In this review, we systematically summarise the research progress on DEPP1, with particular emphasis on its molecular mechanisms in the crosstalk between oxidative stress and autophagy. Its cellular localization and functional uniqueness are discussed within the context of the classical redox-autophagy regulatory network. Furthermore, key issues in DEPP1 research and its potential translational applications are discussed to provide insights and perspectives for future studies centred on DEPP1.

Liver sinusoidal endothelial cells (LSECs) dysfunction was demonstrated to represent an early and persistent event in chronic heart failure (CHF), preceding congestive hepatopathy and contributing to the pathophysiology of the disease. However, it remains unknown whether classical CHF pharmacotherapy would reverse LSEC defenestration. Herein, we characterised the therapeutic effects of angiotensin-converting enzyme (ACE) inhibitor - perindopril, and sodium-glucose cotransporter 2 (SGLT2) inhibitor - empagliflozin - on the cardiohepatic axis and, in particular, on LSEC defenestration in the murine model of CHF. Untreated 6-month-old Tgαq*44 mice exhibited impaired systolic and diastolic cardiac function, impaired liver perfusion, and LSEC defenestration. Perindopril (2 mg/kg, 8 weeks treatment, 4- to 6-month-old Tgαq*44) significantly improved the left (LV) and right ventricular (RV) systolic function and ameliorated liver perfusion in vivo in Tgαq*44 mice. Perindopril also displayed a pronounced hepatoprotective effect, as evidenced by proteomic analysis of isolated hepatocytes, reduced TBIL, and GGT; however, the number of LSEC fenestrations was unaffected in Tgαq*44 mice treated with perindopril. Empagliflozin (300 mg/kg, 8 weeks treatment, 4- to 6- month-old Tgαq*44) not only significantly improved the LV and RV systolic function and ameliorated liver perfusion, but also improved diastolic cardiac function and significantly reduced defenestration of LSECs. LSEC defenestration was primarily driven by cardiac diastolic dysfunction, not by impaired liver perfusion or hepatocyte function, and was independent of biomarkers of congestive hepatopathy in the murine model of CHF in Tgαq*44 mice. As fully reversed by SGLT2-I, but not by ACE-I, LSEC defenestration arises as a target in the treatment of the cardiohepatic axis in CHF, which is not uniformly improved by CHF pharmacotherapy.

Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TPM1 (tropomyosin 1), a crucial part of the thin filament in cardiomyocytes, has multiple alternative exons. However, the impact of TPM1 alternative splicing (AS) in HFpEF remains unclear. We examined cardiac myofiber disarray in HFpEF using transmission electron microscopy. Nanoindentation was used to detect myocardial compliance. Using genetically engineered (adenovirus-associated virus serotype 9) mouse models and human pluripotent stem cell-derived cardiomyocytes, we investigated the role of TPM1 isoforms and TPM1's upstream SRPK3 (serine/arginine rich protein kinase 3). Subsequently, the underlying mechanisms were investigated using RNA pulldown, mass spectrometry, AS analysis, and other molecular techniques. We identified unique myofilament disorders in HFpEF and observed upregulation of the TPM1b isoform, which skips exon 9a through AS, in both patients with HFpEF and mouse models. Cardiomyocyte-specific overexpression of distinct TPM1 isoforms showed that TPM1b (without exon 9a) exacerbated HFpEF phenotypes in mice and human pluripotent stem cell-derived cardiomyocytes. Furthermore, we found that the splicing kinase SRPK3 mediates the AS of TPM1 exon 9a. Cardiomyocyte-specific overexpression of SRPK3 induced myofiber disarray and diastolic dysfunction, whereas SRPK3 knockdown ameliorated these pathological phenotypes. Supplementation with TPM1 containing exon 9a partially rescued the diastolic dysfunction under conditions of SRPK3 overexpression. Preventive intervention experiments demonstrated that inactivating SRPK3 can alleviate diastolic dysfunction in the HFpEF mouse model. AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3. SRPK3 may represent a novel therapeutic target for HFpEF.

Inflammation and fibrosis can arise as consequences of cardiac injury and further contribute to the progression of heart failure (HF) and arrhythmias. Despite ongoing therapeutic advancements, effective treatments to modulate these pathological processes remain limited. To overcome these limitations, we developed a multifunctional nanotherapeutic system using apoptotic mesenchymal stem cell-derived nanovesicles (ANV) as biocompatible and immunomodulatory delivery platforms for small interfering RNA (siRNA) targeting the adipocyte enhancer binding protein 1 (AEBP1). ANV are constructed via an extrusion method and loaded with AEBP1-targeting siRNA (siAEBP1) through electroporation to form ANV-siAEBP1. The vesicles are then incubated with antibody-conjugated iron oxide magnetic nanoparticles (MNP), forming the ANVP-siAEBP1 complex. For targeted delivery to the injured myocardium, an anti-myosin light chain 3 (MLC3) antibody is incorporated, based on injury-associated MLC3 exposure for localized accumulation of ANVP-siAEBP1 at the injury site. Upon localization, intracellular release of siAEBP1 silences AEBP1 expression, downregulates pro-fibrotic signaling, and mitigates cardiac fibrosis. Simultaneously, the intrinsic anti-inflammatory effects of ANV prevent excessive inflammatory responses. This dual mechanism of action results in synergistic therapeutic effects, significantly attenuating both inflammation and fibrosis with enhanced targeting efficiency. Collectively, this engineered four-in-one nanovesicle platform offers a promising strategy for next-generation precision therapeutics in cardiac injury. STATEMENT OF SIGNIFICANCE: Cardiac injury often leads to heart failure, yet current therapies lack precise targeting and long-term effectiveness. Here, we develop a multifunctional nanocarrier system that enables targeted delivery of siRNA to injured cardiac tissue. This system combines nanoscale engineering with biological functionality, allowing gene regulation that reduces inflammation and fibrosis. By silencing adipocyte enhancer-binding protein 1 (AEBP1) via siRNA, our platform suppresses fibrosis and improves cardiac function in vivo, further supported by the inflammation-regulating properties of the nanovesicle. This work demonstrates how engineered biomaterials can be designed to control cellular responses and disease progression, offering a promising strategy for targeted gene therapy and cardiac repair.

Large-scale perturbation atlases have transformed systems biology, yet no equivalent resource exists for the human heart, where contractile function and transcriptomic state must be measured together. Here, we establish Cardiopedia-Ligand, a comprehensive perturbation-function-transcriptome atlas generated by stimulating human cardiac organoids (hCOs) with 87 ligands targeting 98 cell-membrane receptors expressed in the human heart. We developed an automated high-throughput pipeline enabling individualized contractility measurements and single-organoid mRNA sequencing. We use this pipeline to define both recognized and previously unrecognized functional and transcriptional clusters, including inotropes, endothelin peptides, extracellular matrix regulators, and multiple inflammatory clusters. Clustering analysis, machine learning, and the "fingerprinting" of human heart failure biopsies revealed previously underappreciated similarities between ligands and an interferon-γ signaling signature driving heart failure with preserved ejection fraction (HFpEF). Together, this comprehensive Cardiopedia-Ligand dataset provides a valuable and accessible resource for interrogating cardiac biology and human disease.

Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation. The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFRβ)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization. In a clinically relevant porcine ischemia-reperfusion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFRβ-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.

The prognosis for heart failure (HF) with preserved ejection fraction (HFpEF) remains poor, with treatment evidence and studies at the human cellular level limited. Here, we aimed to model HFpEF-associated diastolic dysfunction in vitro by generating human engineered heart tissues (hEHTs) using human induced pluripotent stem cells and culturing the tissues under high fatty acid and L-NG-nitroarginine methyl ester supplementation. Medium-loaded hEHTs showed a marked reduction in relaxation function while preserving contraction function; secreted high levels of the HF marker, BNP; exhibited abnormal calcium transients; and showed structural and functional features of HF. After treatment with several existing HF drugs, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) improved the decline in relaxation function and contributed to an improvement in the diastolic dysfunction phenotype. This mechanism exhibited an anti-inflammatory effect mediated by the recovery of the eNOS-NO-cGMP-PKG signaling pathway. These findings serve as a basis for elucidating the pathogenesis and mechanisms of improvement in HFpEF.

Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential. We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics. The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C+ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations. The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.

Brain temperature (BT) is a critical physiological indicator closely associated with neurological function and disease progression. However, real-time, noninvasive monitoring of BT remains a challenge due to the limitations of current technologies. Here, we present a novel multimodal framework combining bioheat transfer modeling, deep learning, and computational thermography for accurate BT prediction and imaging. A one-dimensional convolutional neural network was trained on multimodal clinical data, integrating cerebral blood flow, tissue oxygen saturation, and intracranial pressure, achieving a mean absolute error of 0.31°C in BT prediction. The framework incorporates finite element analysis to generate 3D thermographic maps of brain tissue with a spatial resolution of 0.4 mm, validated using MRI-derived data. This approach demonstrated robust performance in predicting localized temperature variations in acute ischemic stroke patients undergoing therapeutic hypothermia, with deviations below 0.45°C. Our findings highlight the potential of this system to enable precise BT monitoring, bridging the gap between computational modeling and clinical neuro-thermometry, and paving the way for advanced diagnostic and therapeutic interventions.

Swallowing disorders are a common complication after stroke, yet current assessment methods rely largely on clinical observation and subjective screening, limiting continuous and objective evaluation. Here, we report a large language model (LLM)-driven throat-wearable sensing system (TWSS) for real-time monitoring of laryngeal activity and quantitative assessment of swallowing function. TWSS consists of a flexible sensing patch and a structured signal sequence-based LLM framework (S3-LLM). The flexible patch integrates a stretchable sensor with a wireless circuit module, enabling conformal attachment to the throat and real-time acquisition of physiological signals. Owing to its dual sensitivity to pressure and strain, the sensor can capture subtle and complex laryngeal movements associated with different physiological activities. S3-LLM converts them into structured signal sequences and combines temporal encoding with parameter-efficient fine-tuning, thereby exploiting the representation and generalization capabilities of LLMs under few-shot conditions. In a clinical validation involving 20 participants, TWSS achieved an accuracy of 92.4% for recognizing normal laryngeal activities and 87.6% for evaluating swallowing function, approximately 20% improvement over conventional models. These results demonstrate that TWSS provides a promising wearable platform for continuous, objective, and quantitative assessment of swallowing disorders and highlights the potential for personalized healthcare.

Development of nanomedicines that can cross blood-brain barrier (BBB) for effective multi-target mitigation of ischemic stroke (IS) is still challenging. Here, we report a hydroxylated poly(amidoamine) dendrimer-based delivery system co-loaded with the immunomodulator fibronectin (FN) protein and the antioxidant neuroprotective drug edaravone (EDV) to tackle IS. We show that generation 5 (G5) poly(amidoamine) dendrimers partially functionalized with phenylboronic acid (PBA) and fully terminated with glycidol hydroxyl groups are able to co-load FN/EDV to form G5.N(Gly)OH-PBA/FN/EDV (GOPFE) nanocomplexes (NCs). The GOPFE exhibits a uniform particle size of 122.2 nm, satisfactory colloidal stability, pH/reactive oxygen species (ROS) dual-sensitive drug release behavior and favorable cytocompatibility. Benefiting from FN-mediated active targeting, the GOPFE can be efficiently internalized by microglia and neuronal cells and can cross BBB to selectively accumulate in cerebral inflammatory lesion due to the abundant dendrimer terminal hydroxyl groups and the FN-derived targeting capability. Mechanistically, the GOPFE effectively suppresses oxygen-glucose deprivation-triggered ROS overproduction, restrains excessive neuroinflammation, and ultimately alleviates neuronal apoptosis. In an IS rat model, the GOPFE preferentially accumulates in ischemic lesion, markedly reduces cerebral infarct volume, facilitates neurological functional recovery, and ameliorates ischemic BBB damage via FN-mediated angiogenesis effect. Moreover, the GOPFE orchestrates inflammatory and immune homeostasis, mitigates neuroinflammatory cascades, and attenuates neuronal damage, thereby executing comprehensive multi-target neuroprotection. Hence, the developed GOPFE NCs may hold a great promise as a targeted therapeutic nanomedicine for IS and other inflammation-related cerebrovascular diseases. STATEMENT OF SIGNIFICANCE: Development of blood-brain barrier (BBB)-crossing nanomedicines for effective multi-target mitigation of ischemic stroke (IS) is still challenging. Herein, we design a hydroxylated phenylboronic acid (PBA)-functionalized PAMAM dendrimer of G5.N(Gly)OH-PBA (GOP) to co-load fibronectin (FN) and edaravone (EDV) for neuroprotection by reducing oxidative stress and modulating the inflammatory microenvironment in IS. The obtained G5.N(Gly)OH-PBA/FN/EDV (GOPFE) nanocomplexes can cross BBB to target inflammatory lesions due to the dendrimer surface hydroxyl groups and FN-mediated recognition. In the tMCAO/R rat model of IS, GOPFE presents desired biosafety and potent synergistic therapeutic efficacy of FN and EDV to markedly reduce cerebral infarct volume, relieve oxidative stress, rescue neurons from apoptosis, promote cerebral angiogenesis, and alleviate excessive neuroinflammation for high-efficiency synergistic therapy of IS.

The pathological progression of ischemic stroke is driven by a dynamic signaling network mediated by protein-protein interactions (PPI) that involves excitotoxicity, oxidative stress, neuroinflammation, and regulated cell death (RCD), ultimately leading to neurological dysfunctions. Instead of functioning independently, these PPI-driven pathways engage in extensive cross-talk, creating cycles that exacerbate the injury over both space and time. Therapeutic strategies designed to disrupt key nodal PPIs, comprising small molecule inhibitors, peptide mimetics, and chimeras targeting proteolysis (PROTACs), have shown promise. However, clinical translation faces several major challenges, including the structural complexity of PPIs, the efficiency of blood-brain barrier (BBB) penetration, and the adaptive, multifactorial nature of the ischemic cascade. Emerging approaches are now shifting from single-target inhibition to network-level intervention, utilizing artificial intelligence (AI)-guided drug development, multi-target PPI regulators, and context-responsive delivery systems to achieve spatiotemporal precision. Through the integration of multidisciplinary technologies and mechanism-driven innovative designs, PPI-targeted strategies provide a promising approach to reprogramming the ischemic brain for repair, moving beyond traditional neuroprotection to dynamic network medicine.

Ischemia/reperfusion (I/R) injury refers to secondary damage that occurs following ischemic stroke when reperfusion is achieved using thrombolytic agents. The abrupt restoration of blood flow induces excessive production of reactive oxygen species (ROS), inflammatory cytokines, and infiltration of immune cells, resulting in additional tissue injury. Although the anti-inflammatory effects of LpEVs have been researched, their potential as gene delivery vehicles has not been investigated. LpEV, which possesses anti-inflammatory properties and a lipid membrane structure, has the potential to be utilized as a gene delivery vehicle. Our study focuses on whether LpEVs act as delivery vehicles for anti-miRNA-181a oligonucleotides (AMO181a) and exert therapeutic effects on I/R injury. LpEVs were isolated by PEG precipitation method. Physical characterization of LpEVs was performed by dynamic light scattering. In vitro cytokine assays were performed to evaluate the anti-inflammatory effect. For delivery of AMO181a, cholesterol-conjugated AMO181a (AMO181a-chol) was loaded into the LpEVs by hydrophobic interaction. Delivery efficiency of AMO181a was evaluated in Neuro2A cells by flow cytometry. The therapeutic effects of LpEVs and AMO181a were measured in the ischemia/reperfusion animal models. Anti-inflammatory effects of LpEVs were confirmed in the activated macrophages in vitro, reducing pro-inflammatory cytokines. Also, LpEVs decreased the infarct volume in an I/R animal model. Delivery efficiency of AMO181a-chol by LpEVs was higher than that of naked AMO181a-chol and comparable to the AMO181a-chol/polyethylenimine (25 kDa, PEI25k) complex in vitro and in vivo. Furthermore, LpEVs did not induce cytotoxicity. As a result, AMO181a-chol-loaded LpEVs had higher therapeutic effects than controls including LpEV alone, naked AMO181a-chol, and AMO181a-chol/PEI25k. LpEVs may be useful for the treatment of ischemia/reperfusion injury with dual functions of its own anti-inflammatory effects and for delivery of therapeutic oligonucleotides.

Post-stroke depression (PSD) represents a complex neuropsychiatric challenge characterized by persistent neuroinflammation and synaptic dysfunction, yet effective therapeutic interventions are constrained by the blood-brain barrier (BBB) and the lack of specific targets. Using a multidimensional screening strategy for Chaihu-Jia-Longgu-Muli Decoction (CLM), we identified ginsenoside Rd (Rd) as a key blood-absorbed bioactive constituent associated with Epidermal Growth Factor Receptor (EGFR) signaling. To overcome the bioavailability bottleneck, a biomimetic nanodelivery system is engineered by encapsulating Rd into microglia-derived exosomes (Exos@Rd). Based on the reported lesion-homing properties of microglia-derived exosomes, we developed a biomimetic Exos@Rd delivery system. Exosomal loading markedly enhanced the brain accumulation of Rd compared with free Rd. Mechanistically, it is demonstrated that aberrant EGFR activation functions as an upstream regulator of the JAK2/STAT3 cascade in microglia. Exos@Rd effectively suppressed this pathway and promoted anti-inflammatory microglial reprogramming, characterized by a shift from an M1-associated pro-inflammatory state toward an M2-associated anti-inflammatory profile. This microglia-centered anti-inflammatory regulation was accompanied by reduced oxidative stress and restoration of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95) and Synapsin I (SYN1) expression. In a PSD mouse model, Exos@Rd significantly restores cerebral perfusion and alleviates depressive-like behaviors. Collectively, this study elucidates a novel EGFR-driven neuroinflammatory mechanism and presents a bio-inspired strategy for precision CNS drug delivery, offering a promising therapeutic paradigm for PSD.

The brain's microvasculature is essential for oxygen and nutrient delivery; however, the mechanisms underlying cerebral capillary repair following injury remain largely elusive. Here, we identify an unrecognized mechanism through which brain capillary endothelial cells (ECs) autonomously promote capillary remodeling. Using longitudinal two-photon imaging in mice, we demonstrate that following focal endothelial injury and selective loss of a single EC, neighboring ECs extend their plasma membranes toward each other, rapidly re-establishing capillary continuity and blood flow within 24-48 h. This repair process engages vascular endothelial growth factor receptor 2 (VEGFR2) signaling but occurs independently of perivascular or glial cell involvement. Finally, we reveal regional differences in repair efficacy, with hippocampal capillaries exhibiting a slower and less-efficient response compared with those in the cortex. These findings reveal an intrinsic mechanism that safeguards microvascular integrity and suggest that regional vulnerabilities in endothelial repair could shape brain resilience to injury and disease.

Disruption of excitatory/inhibitory (E/I) balance within the basolateral amygdala (BLA) is a critical feature of depressive and anxiety-like states, yet effective circuit-based therapies are lacking. Here, we demonstrate that tactile experience enrichment (TEE)-a noninvasive sensory stimulation-ameliorates depressive- and anxiety-like behaviors in multiple post-stroke depression (PSD) mouse models by engaging a thalamic-amygdala pathway from the reuniens nucleus (Re) to BLA inhibitory neurons (ReExc-BLAInh). Activation of this compensatory circuit re-establishes E/I balance in the BLA through feedforward inhibition of excitatory neurons, thereby bypassing the impaired medial prefrontal cortex-BLA pathway. Both chemogenetic activation of the ReExc-BLAInh pathway and TEE treatment in chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models similarly restore synaptic E/I balance and significantly improve emotional behaviors. These results define a lesion-bypassing circuit mechanism through which tactile input modulates amygdala function in mice and will motivate future studies of translational relevance.

Chagas disease (ChD), a neglected cardiovascular condition, affects 7.5 to 10.5 million people worldwide. Opportunistic screening during routine electrocardiography may allow earlier detection of unrecognized infections, enabling timely antiparasitic therapy or optimized cardiac care. This study prospectively evaluated the feasibility and diagnostic accuracy of an artificial intelligence (AI)-enabled ECG model enriched with 3 epidemiological questions (AI-ECG-EPI model) as an opportunistic screening for ChD in endemic regions of Brazil. We conducted a prospective study embedded in the Telehealth Network of Minas Gerais, Brazil, across 107 municipalities in hyperendemic and endemic regions. From October 2023 to September 2024, adults undergoing routine tele-ECGs were eligible. The primary exposure was the output of the AI-ECG-EPI model: all positive individuals and a 3:1 sample of negative individuals were invited for serology (index test-dependent sampling), the reference standard. Weighted analyses (inverse probability) accounted for this sampling design. Diagnostic metrics included sensitivity, specificity, predictive values, likelihood ratios, area under the receiver operating characteristics curve, and area under the precision recall curve. The AI-ECG-EPI model was compared with both an epidemiological questions model and an AI ECG-only model. Among 75 779 eligible ECGs, the AI-ECG-EPI model was available for 59 154 individuals; 6812 (11.5%) screened positive. A total of 7804 selected were invited for serology, and 3509 completed testing (2517 positive; 992 negative). ChD was confirmed in 36.8% of positive and 9.3% of negative individuals. The weighted prevalence of ChD was 12.2%. Sensitivity was 34.3%, specificity 91.6%, harmonic mean of precision and recall score 0.52, and diagnostic odds ratio 5.69. The AI-ECG-EPI model showed higher discrimination than both the epidemiological questions model and AI ECG-only model (area under the receiver operating characteristics curve, 77.6% versus 70.0% and 64.5%, respectively; P<0.001). Precision recall curves showed higher precision across most recall levels. Exploratory analysis suggested improved risk reclassification (net reclassification improvement, 0.503). Performance was higher in women and in individuals with Chagas cardiomyopathy. In this community-based study, an AI-ECG-EPI model integrated into a public telecardiology network enabled feasible opportunistic screening for ChD in primary care. It showed acceptable diagnostic accuracy, with higher discrimination than epidemiological questions and AI ECG-only models, and identified many previously undiagnosed patients in endemic regions, supporting its potential role in scalable screening strategies. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02646943.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure, especially in the ageing society, but cellular biological mechanism studies are limited by the lack of robust animal models. Vitronectin (VTN), an extracellular matrix (ECM) glycoprotein enriched in amyloid deposits, may contribute to amyloidogenesis, yet its pathogenic role in ATTR-CM remains undefined. Humanized knock-in mice expressing either wild-type (hTTRWT) or V142I mutant transthyretin (hTTRV142I) were generated. Amyloid burden, cardiac structure, and function were assessed by Congo red staining, electron microscopy, echocardiography, and cardiac magnetic resonance. The functional role of VTN and integrin signalling was studied using genetic silencing and pharmacological intervention with low-dose cilengitide. Both hTTRWT and hTTRV142I mice developed age-dependent cardiac amyloidosis with diastolic dysfunction and reduced survival, especially in the hTTRV142I strain. VTN co-localized with TTR fibrils, promoted fibril aggregation, reduced amyloid burden upon its knockdown, and preserved cardiac function. Mechanistically, TTR amyloid suppressed integrin αvβ3/FAK/Akt signalling, leading to marked mitochondrial dysregulation characterized by excessive fission, enhanced mitophagy, and impaired oxidative phosphorylation. Restoration of αvβ3 signalling with cilengitide normalized mitochondrial dynamics, improved bioenergetics, and ameliorated diastolic dysfunction despite persistent amyloid stress. Two reproducible ATTR-CM models that recapitulate the steadily progressive course of human disease were established. Furthermore, VTN actively drives cardiac amyloid deposition, and disruption of integrin αvβ3/FAK/Akt signalling links amyloid-ECM interactions to mitochondrial dysfunction. Therefore, modulation of integrin signalling represents a potential complementary therapeutic strategy in ATTR-CM beyond TTR suppression.

LMNA-related dilated cardiomyopathy (LMNA-DCM) is a progressive genetic disorder characterized by conduction disease, malignant arrhythmias, myocardial fibrosis, and heart failure. Although LMNA mutations have traditionally been associated with cardiomyocyte-intrinsic defects, the mechanisms driving fibrotic remodelling remain incompletely understood. Spatial transcriptomics and integrated single-nuclei multiomics were performed on explanted human LMNA-DCM hearts to define endothelial transcriptional and epigenomic states associated with fibrosis. Patient-specific induced pluripotent stem cell-derived endothelial cells, engineered cardiac organoids, and the LMNAH222P/H222P mouse model were used to investigate RUNX1-mediated endothelial-to-mesenchymal transition (EndoMT). Genetic and pharmacological RUNX1 inhibition strategies were evaluated in vitro and in vivo. Endothelial populations exhibiting EndoMT-associated transcriptional and epigenomic signatures were identified in human LMNA-DCM hearts. LMNA induced pluripotent stem cell-derived endothelial cells demonstrated endothelial dysfunction, mesenchymal gene activation, and epigenetic activation of RUNX1 following loss of LMNA-mediated repression. Genetic RUNX1 deletion restored endothelial identity, reversed EndoMT-associated transcriptional programmes, and normalized chromatin accessibility at endothelial regulatory loci. In multicellular cardiac organoids, endothelial RUNX1 activation impaired endothelial-cardiomyocyte signalling and cardiomyocyte contractile function, whereas endothelial-specific RUNX1 deletion restored endothelial and myocardial function. Pharmacological RUNX1 inhibition with Ro24-7429 similarly improved endothelial and cardiomyocyte function in vitro and reduced myocardial fibrosis while preserving cardiac function in LMNAH222P/H222P mice, including after disease onset. RUNX1-driven EndoMT represents a central mechanism linking LMNA mutations to fibrotic remodelling in LMNA cardiomyopathy. These findings support endothelial transcriptional reprogramming and RUNX1 signalling as potential therapeutic targets in fibrotic cardiomyopathy.

Chronic kidney disease (CKD) is associated with uraemic cardiomyopathy characterised by early metabolic dysfunction. Elevated myocardial intracellular sodium (Naᵢ) has emerged as a driver of cardiometabolic remodelling, however, its role in CKD and therapeutic modulation remains unclear. We investigated whether dual sodium-glucose cotransporter (SGLT)1/2 inhibition with sotagliflozin (SOTA) targets Naᵢ and improves cardiac metabolism in CKD. CKD was induced in male Wistar rats by 5/6 nephrectomy and assessed after 4 weeks. Cardiac phenotype was evaluated using in vivo echocardiography and ex vivo Langendorff perfusion combined with 23Na and 31P NMR spectroscopy. CKD hearts exhibited preserved systolic but impaired diastolic function and a marked elevation in myocardial Naᵢ, identifying Naᵢ overload as an early feature of uraemic cardiomyopathy. Cardiac metabolomic profiling and flux modelling demonstrated widespread suppression of central carbon metabolism, redox imbalance despite preserved PCr/ATP. In silico electrophysiological simulations predicted Naᵢ-driven Ca2+ dysregulation consistent with in vivo diastolic dysfunction. Chronic SOTA treatment (3 weeks, in vivo) normalised myocardial Naᵢ and partially reversed metabolic remodelling. Acute SOTA exposure (20-minute, Langendorff-perfusion) similarly reduced Naᵢ in CKD hearts but not in controls, indicating a direct, disease-selective myocardial effect. Naᵢ normalisation was accompanied by improved redox state and restoration of mitochondrial metabolic flux, without changes in expression of canonical Na + -handling proteins. Myocardial Naᵢ overload emerges as an early and potentially modifiable feature of uraemic cardiomyopathy. Dual SGLT1/2 inhibition with SOTA directly lowers Naᵢ and improves cardiac metabolic homeostasis, supporting Naᵢ as a mechanistically relevant and potentially targetable pathway in CKD-related cardiac remodelling.

In Duchenne muscular dystrophy (DMD), connexin-43 (Cx43) delocalizes from intercalated discs to the lateral membrane of cardiomyocytes, where it forms undocked hemichannels. β-adrenergic stress induces lethal arrhythmias in DMDmdx mice that correlate with increased Cx43 S-nitrosylation and excessive hemichannel opening. Here, we aimed to determine whether S-nitrosylation of Cx43 at cysteine 271 directly contributes to β-adrenergic stress-induced arrhythmias and myocardial injury in DMD. To define the role of Cx43 S-nitrosylation in DMD cardiomyopathy, we generated DMDmdx knock-in mice carrying a cysteine-to-serine substitution at residue 271, a critical S-nitrosylation site involved in NO-dependent Cx43 hemichannel activation (DMDmdx:C271S+/-). Following β-adrenergic stimulation, DMDmdx mice exhibited a higher incidence of arrhythmogenic events and increased triggered activity in isolated cardiomyocytes compared with DMDmdx:C271S+/- mice, which more closely resembled wild-type mice. Optical mapping of isolated hearts showed that DMDmdx mice developed abnormal Ca2+ transients, prolonged action potentials, and episodes of conduction block. These abnormalities were normalized in DMDmdx:C271S+/- mice and attenuated by treatment with the Cx43 hemichannel inhibitor Gap19. Moreover, β-adrenergic stress evoked severe myocardial injury and bradycardia in DMDmdx mice, both of which were significantly attenuated in DMDmdx:C271S+/- mice. Notably, Gap19-treated DMDmdx mice were protected against myocardial injury, further supporting a direct role for Cx43 hemichannels in DMD-associated cardiac damage. These findings reveal, for the first time, a mechanistic link between Cx43 hemichannel activity, arrhythmogenesis, and myocardial injury in DMD. We conclude that S-nitrosylation of Cx43 is a fundamental NO-mediated mechanism driving β-adrenergic stress-induced arrhythmias and myocardial injury in DMDmdx mice through pathological opening of Cx43 hemichannels.

Endoplasmic reticulum (ER) stress is a key driver of diabetic cardiomyopathy (DCM), but its upstream regulators are incompletely defined. The transcription factor DACH1 is genetically linked to diabetes and cardiovascular risk, yet its role in the diabetic heart is unknown. This study aimed to elucidate the function and post-translational regulation of DACH1 in DCM, focusing on its interplay with ER stress. Cardiac function, ER stress, and apoptosis were assessed in db/db mice and high glucose-treated cardiomyocytes. AAV9 was used for cardiac-specific DACH1 overexpression in vivo. SUMOylation and ubiquitination of DACH1 were analyzed via co-immunoprecipitation, mutagenesis, and proteasome inhibition assays. Myocardial DACH1 protein, but not its mRNA, was significantly reduced in experimental DCM. Restoring cardiac DACH1 alleviated dysfunction, ER stress, apoptosis, and fibrosis in diabetic mice. DACH1 stability was associated with SUMOylation at lysines K348, K599, and K631, and TRIM28 facilitated this modification in our experimental system. This modification was reduced under diabetic conditions and was associated with increased ubiquitin-proteasome degradation of DACH1. Enhancing SUMO1 increased DACH1 stability, helped preserve DACH1 nuclear retention, and protected cardiomyocytes from high glucose-induced ER stress and apoptosis. Impaired SUMOylation may contribute to DACH1 depletion in the diabetic heart. SUMOylation-dependent stabilization of DACH1 represents a potential cardioprotective pathway that mitigates diabetic myocardial injury by suppressing ER stress.

Recent studies have revealed heterogeneity among ribosomes. Pathological cardiac hypertrophy is characterized by profound alterations in translation. However, how ribosome heterogeneity contributes to this process remains largely unclear. We used translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins. Cardiomyocyte-specific gene manipulation was achieved through either genetic knockout or adeno-associated virus-mediated overexpression. Pathological cardiac hypertrophy was induced by transverse aortic constriction surgery in vivo and by phenylephrine stimulation in vitro. The cardiomyocyte-specific ribosome proteomics indicated dynamic alterations in ribosome-interacting proteins during pathological hypertrophy. Notably, multiple proteins associated with ribosome stalling were detected in the ribosome-interactome of hypertrophic hearts. Among these, we verified that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) exhibited the most specific ribosome binding in hypertrophic hearts. CDK5RAP3 was upregulated and recruited to ribosomes during pathological hypertrophy. It promoted RPL26 (ribosomal protein L26) UFMylation and ribosome-associated quality control on the mitochondrial surface. In vitro, CDK5RAP3 knockdown exacerbated cardiomyocyte hypertrophy induced by phenylephrine, whereas its overexpression attenuated it. In vivo, cardiomyocyte-specific CDK5RAP3 knockout promoted, while adeno-associated virus-mediated overexpression suppressed pathological cardiac hypertrophy induced by transverse aortic constriction. Mechanistically, ribosome stalling on the mitochondrial surface was exacerbated in hypertrophic hearts of both humans and mice, which was associated with impaired mitochondrial protein import. CDK5RAP3 enhanced ribosome-associated quality control, alleviated ribosome stalling, and restored mitochondrial protein import, thereby improving mitochondrial function. Notably, mitochondrial import of PDP1 was maintained by CDK5RAP3-mediated ribosome-associated quality control. Knockdown of PDK (pyruvate dehydrogenase kinase) 1/2, functional antagonists of PDP1, reversed cardiomyocyte hypertrophy caused by CDK5RAP3 deficiency. This study identifies CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface as a critical protective mechanism that preserves protein import and mitochondrial function during pathological cardiac hypertrophy.

Recurrent glioblastoma (rGBM) is a leading brain malignancy with few therapeutic options. Here we present the complete results of a phase 1 trial investigating the safety and efficacy of autologous B7-H3-targeting chimeric antigen receptor T (CAR-T) cell (TX103) therapy for the treatment of rGBM. In this open-label, 3 + 3 dose-escalation trial, patients aged 18-75 years with B7-H3-positive (≥30%) rGBM received intracranial infusion of TX103 at three dose levels (DLs-2 × 107, 6 × 107 and 1.5 × 108 cells per infusion). Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included survival, pharmacokinetics and immunological response. Fifteen patients received a total of 72 intracranial infusions and 13 underwent repeated infusions. TX103 therapy was well tolerated, with no dose-limiting toxicities or MTD identified. Treatment-related adverse events (TRAEs) included low-grade cytokine release syndrome (86.7%), sinus tachycardia (53.3%), vomiting (53.3%), hypertension (53.3%) and elevated intracranial pressure (46.7%). Three grade 3 TRAEs considered serious adverse events occurred (elevated intracranial pressure, epilepsy and depressed consciousness), two at DL3. The 12-month overall survival (OS) rate was 66.7% and median OS was 19.1 months (95% confidence interval = 8.93, not reached) from first infusion. Disease control (stable disease or better) was achieved in 8 of 14 patients with measurable disease, including one complete response sustained through the latest follow-up. Cerebrospinal fluid showed a marked increase in CAR gene copy numbers and cytokine release, with minimal peripheral activity and no cumulative toxicity after repeated infusions. In conclusion, intracranial TX103 infusion demonstrated acceptable safety and encouraging efficacy in rGBM, supporting a future phase 2 evaluation at the RP2D (DL2, 6 × 107 cells per infusion). ClinicalTrials.gov registration: NCT05241392 .

This narrative review aims to critically summarize available data on the association between adult acromegaly and metabolic dysfunction-associated steatotic liver disease (MASLD), with a particular focus on clinical associations and treatment implications. From a pathophysiological perspective, growth hormone (GH) may improve hepatic steatosis, inflammation, and fibrosis by acting directly on hepatocytes and indirectly (through insulin-like growth factor-1) on hepatic stellate cells, thereby inducing their senescence. Nonetheless, GH excess may also favor the development of hepatocellular carcinoma, possibly through mechanisms unrelated to hepatic fibrosis. From a clinical perspective, individuals with acromegaly have low rates of hepatic steatosis and visceral adipose tissue (VAT), but high insulin resistance (IR), which contradicts the generally observed positive association between IR and VAT or hepatic steatosis. By contrast, limited data do not support lower rates of hepatic fibrosis in acromegaly, possibly because GH excess is controlled after diagnosis. From a therapeutic perspective, published evidence, derived mainly from case series, suggests that surgical or pharmacological management of acromegaly increases hepatic steatosis and VAT, despite decreasing IR. However, the long-term effect of acromegaly control on hepatic inflammation and fibrosis remains largely unknown. Acromegaly is associated with IR, type 2 diabetes mellitus, hypertension and cardiovascular disease; however, acromegaly is inversely associated with VAT and MASLD. Further mechanistic and clinical studies are warranted to better elucidate the intriguing association between acromegaly and MASLD.

Binary classification of adverse pregnancy outcomes (APOs) may obscure differences in women's long-term cardiovascular disease (CVD) mortality. CVD mortality was therefore evaluated considering APO sequence and lifetime parity. A total of 1 001 409 women with complete pregnancy histories were identified from the Medical Birth Registry of Norway (1967-2020) and linked to the Norwegian Cause of Death Registry for premature CVD mortality (≤70 years). Pregnancy histories were categorized by lifetime parity (1 vs ≥2) and APO sequence (first vs later) for composite APO, and APO recurrence type (same vs different) for individual APOs-preeclampsia, gestational hypertension, preterm delivery, perinatal loss, small for gestational age, placental abruption-multiparous women without APOs as reference, compared with binary classification (APO presence vs absence). Hazard ratios (HRs) were estimated using Cox proportional hazards models. For composite APOs, women with APOs in first pregnancy and no further pregnancies had the highest CVD mortality [adjusted HR (aHR) 3.30, 95% confidence interval (CI) 2.97-3.66], followed by those with APOs in both first and later pregnancies (aHR 2.41, 95% CI 2.16-2.69). Women with APOs in later pregnancies only (aHR 1.65, 95% CI 1.50-1.81) and women with only one pregnancy without complications (aHR 1.83, 95% CI 1.69-1.97) had moderate CVD mortality. Women with APOs in first pregnancy followed by uncomplicated pregnancies (aHR 1.39, 95% CI 1.27-1.53) had the lowest CVD mortality. Binary classification indicated an overall 1.73-fold higher CVD mortality (95% CI 1.64-1.84). Similar patterns were observed across individual APOs. Considering APO sequence across complete pregnancy histories provides more detailed CVD information than binary classification.

The Cre/loxP recombination system is the main tool for cell type-specific lineage tracing and gene targeting. Currently available smooth muscle cell (SMC)-specific Cre mouse lines show off-target activity outside the SMC lineage and are unable to distinguish among arterial SMCs (ASMCs), venous SMCs, and nonvascular SMCs (NVSMCs). These limitations prevent ASMC- and NVSMC-specific gene targeting, which is required to characterize the role of SMCs in different organs and diseases. To achieve precise manipulation of ASMCs in vivo, we combined alleles for Cspg4-Dre and rox-Stop-containing Acta2-CreER (Acta2-rox-CreER), generating a mouse line with Cre activity exclusively in ASMCs. RNA sequencing of fluorescence-activated cell sorting-isolated ASMCs was used to reveal differences in ASMCs among multiple organs. To specifically target and characterize NVSMCs in different organs, a combination of Chrm2-Dre and Acta2-rox-CreER was used. Disease-specific transcriptional changes of pulmonary ASMCs and NVSMCs were determined in the Sugen 5416/hypoxia model of pulmonary arterial hypertension. Usefulness for functional studies was assessed by inactivation of the genes for the splicing factors RBPMS (RNA-binding protein with multiple splicing) and RBPMS2 (RNA-binding protein with multiple splicing 2) in ASMCs. Intersectional genetic approaches using Cspg4-Dre and Acta2-rox-CreER mouse lines specifically targeted ASMCs within various organs. A combination of Chrm2-Dre with Acta2-rox-CreER achieved specific targeting of NVSMCs. Transcriptomic profiling revealed distinct gene expression signatures in ASMCs of different organs, indicating organ-dependent transcriptional adaptation of ASMCs. Transcriptional differences among NVSMCs were found in the lung, intestine, and bladder. Activation of distinct pathways was uncovered in pulmonary ASMCs and bronchial SMCs after induction of pulmonary arterial hypertension. Inactivation of Rbpms and Rbpms2 in ASMCs increased thickness of the muscular layer in pulmonary arteries, whereas inactivation in all SMCs abolished the contractile phenotype of NVSMCs in the intestine. The successful generation of mouse lines specifically targeting different subtypes of SMCs enhances specificity, allowing distinction between vascular and nonvascular effects of diseased SMCs. The identification of vessel bed-specific gene signatures will pave the way for specific manipulation of SMCs in distinct diseased organs, such as the lung in pulmonary arterial hypertension.

Monoaminergic signaling controls many aspects of human physiology, including autonomic responses, movement, and emotion. The vesicular monoamine transporters (VMAT1 and VMAT2) sequester monoamines into synaptic vesicles within the central and peripheral nervous system. Dysregulation of VMAT function contributes to neuropsychiatric and neurodegenerative disorders, including Parkinson's disease, depression, and psychostimulant substance abuse. Clinically, VMATs are targeted by the inhibitors tetrabenazine and reserpine, used to treat hyperkinetic movement disorders and hypertension, respectively, while amphetamines exploit VMAT2-mediated dopamine efflux to treat ADHD. Emerging VMAT2-selective compounds such as lobeline derivatives and GZ-11610 attenuate psychostimulant reinforcement. Tricyclic antidepressants upregulate VMAT2 function and rescue disease-causing variants, highlighting VMAT2 as a promising therapeutic target. Despite their importance, the molecular mechanisms driving proton-coupled transport, inhibition, and psychostimulant action remain poorly understood. This review summarizes current biochemical, structural, and functional insights into VMATs, highlighting proton coupling, transport kinetics, inhibition mechanisms, unresolved questions, and future research directions.

The optimal timing of adjunctive vasopressin after norepinephrine escalation in septic shock remains uncertain. We emulated a target trial comparing ultra-early vasopressin initiation within 0-3 h with early initiation within > 3-6 h after the norepinephrine infusion rate reached 0.25 μg/kg/min or higher. We emulated a target trial using electronic health record databases (MIMIC-IV 2008-2022 and eICU-CRD 2014-2015). Adults with septic shock who reached the norepinephrine threshold before vasopressin use were eligible. We used the clone-censor-weight method to estimate cumulative incidence curves under the ultra-early and early initiation strategies and compared them via the weighted Cox model. Among 3810 eligible patients, after cloning, 744 clones adhered to the ultra-early strategy and 293 clones adhered to the early strategy. The weighted 28-day mortality risk was 48.1% under the ultra-early strategy and 53.0% under the early strategy (risk difference, - 5.0 percentage points; 95% confidence interval [CI] - 6.8 to - 3.2), with a restricted mean survival time difference of 1.58 days (95% CI 1.21-1.92) and a hazard ratio (HR) of 0.82 (95% CI 0.78-0.85). Ultra-early initiation was associated with lower renal replacement therapy (HR, 0.68; 95% CI 0.63-0.74), continuous renal replacement therapy (HR, 0.61; 95% CI 0.55-0.68), and medically treated arrhythmia (HR, 0.91; 95% CI 0.83-0.99), but not with lower acute kidney injury. Among adults with septic shock whose norepinephrine infusion reached 0.25 μg/kg/min or higher before vasopressin use, vasopressin initiation within 0-3 h was associated with lower 28-day mortality than initiation within > 3-6 h.

This post hoc analysis assessed the durability of tirzepatide for primary cardiovascular disease (CVD) prevention in obesity, based on predicted CVD risk, in the SURMOUNT-1 (SM-1) 3-year study. SM-1 was a phase 3, double-blind, randomised trial where individuals with obesity/overweight and prediabetes received tirzepatide (5, 10, 15 mg) or placebo for 176 weeks. Predicted 10-year CVD risk was calculated using the Framingham Heart Study (FHS) equation. The use of the FHS equation to predict treatment effect (model-derived hazard ratio, HR) was examined for consistency with the observed cardiovascular events in the REWIND trial. In SM-1, 2,539 participants were randomised, 1,032 of those had prediabetes, 976 did not have pre-existing CVD, and 962 participants had baseline and at least one post-baseline predicted CVD risk score for this post hoc analysis. For these participants, receiving tirzepatide 15 mg was associated with a reduction in the predicted 10-year CVD risk at week 72 (absolute risk reduction, (ARR) -1.92%), while placebo was associated with increased risk (absolute risk increase, (ARI) 1.10%) (p < 0.001; HR = 0.73). At week 176, tirzepatide-treated participants had a predicted risk reduction (ARR -1.31%) while predicted risk in placebo increased (ARI 3.84%) from baseline (p < 0.001; HR = 0.62).To test the predictability of FHS risk equations for treatment effect, REWIND data suggested that the HR for dulaglutide vs placebo based on risk prediction is consistent with the HR based on observed cardiovascular events (HR 0.83 and 0.85, respectively). These findings suggest that tirzepatide was associated with a lower predicted 10-year CVD risk vs placebo with long-term (3 years) treatment in individuals with obesity/overweight and prediabetes. The risk equation's predictive performance for treatment effect was supported by observed CVD events in the REWIND trial. The potential benefit of tirzepatide for primary CVD prevention needs to be confirmed in event-based cardiovascular outcomes trials such as SURMOUNT-MMO.

Bruton's tyrosine kinase inhibitors (BTK-I) affect platelet function, increasing bleeding risk, and are also associated with hypertension and atrial fibrillation. This study aimed to assess the risk of incident non-fatal ischaemic major adverse cardiovascular events (MACE) associated with BTK-I exposure through a systematic review and meta-analysis of randomized controlled trials (RCTs). ClinicalTrials.gov, EudraCT, MEDLINE, and Cochrane CENTRAL were systematically searched to identify Phase 3 RCTs of BTK-I (ibrutinib, acalabrutinib, zanubrutinib) reporting non-fatal ischaemic MACE up to 19 December 2024. The primary outcome was the summary risk of incident non-fatal ischaemic MACE (defined as a partial MACE composite of myocardial ischaemic syndromes and ischaemic stroke/transient ischaemic attack) associated with BTK-I exposure vs controls in adults with B-cell malignancies. A random-effects meta-analysis for binary outcomes was performed using the Mantel-Haenszel method, with between-study heterogeneity estimated using the DerSimonian-Laird estimator, to derive pooled risk ratios with their 95% confidence intervals. Seventeen Phase 3 RCTs including 6799 patients were analysed (55.5% BTK-I arms). Most patients received ibrutinib (77.2%), followed by acalabrutinib (13.5%) and zanubrutinib (9.3%). BTK-I exposure was associated with an increased risk of non-fatal ischaemic MACE (risk ratio 1.66, 95% confidence interval 1.09-2.53, P = .02), with substantial heterogeneity (I2 = 70%). Based on adverse-event reporting from Phase 3 RCTs that does not permit adjustment for competing risks, BTK-I exposure is associated with an increased risk of non-fatal ischaemic MACE. PROSPERO, International Prospective Register of Systematic Reviews; registration number: CRD420251241020.

The human brain exhibits a complex and hierarchical organization that supports efficient information integration across local and global scales. Accurately characterizing such topological organization from neuroimaging data remains challenging. Conventional graph neural networks (GNNs) effectively capture local dependencies through neighborhood aggregation but often overlook higher-order topological structures that reflect the brain's small-world organization. Although Transformer architectures enable global dependency modeling, their high computational cost limits scalability for large connected brain networks. To address these challenges, we propose a Topology-Constrained Graph Transformer Network (TC-GTN) that explicitly integrates brain network topology into graph learning. TC-GTN combines two complementary modules: a cycle-constrained graph convolution, which captures localized edge aggregation and models modular brain organization, and an MST-guided Transformer, which constrains global attention along minimum spanning tree (MST) pathways to efficiently model long-range dependencies while reducing redundant communication. Moreover, we introduce cycle-based edge positional encodings (CEPE) that provide a topological coordinate system for distinguishing edges with similar local structures but different cycle-level contexts. We evaluate TC-GTN on both structural and functional brain networks, extracted from diffusion-weighted imaging (DWI) and functional MRI (fMRI) respectively, using large-scale datasets, including UK Biobank (38557 participants; 18100 females/20457 males; age 40-70 years) and ABCD (7684 participants; 3782 females/3902 males; age 9-10 years). Experiments on sex classification and brain-age estimation demonstrate that TC-GTN consistently outperforms state-of-the-art graph network approaches, achieving superior accuracy, interpretability, and generalizability. Clinical significance analysis further demonstrates that the model accurately characterizes neuroanatomical divergence across pathological states. Using the brain age gap (BAG) as a biomarker, systemic accelerated aging is identified in multiple sclerosis and dementia, alongside heterogeneous structural alterations in stroke and Parkinson's disease. Our code is available at https://github.com/bieqa/TC-GTN.

To determine whether soluble urokinase plasminogen activator receptor (suPAR) is modified by randomized diabetes and revascularization strategies in patients with type 2 diabetes and coronary artery disease and whether combined suPAR and hs-CRP classification refines residual cardiovascular risk stratification. In this ancillary analysis of Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D), we measured plasma suPAR and hs-CRP at baseline (n = 2,277) and 1 year (landmark cohort, n = 1,978). The primary outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Associations were assessed using sequentially adjusted Cox models. Over 1 year, suPAR was not reduced by diabetes (insulin sensitizing vs. insulin provision) or cardiac (revascularization vs. medical therapy) treatment strategies (median 2.96-3.15 ng/mL; all-treatment arm P ≥ 0.75), while hs-CRP declined substantially (median 2.07-1.30 mg/L). suPAR independently predicted the composite outcome (adjusted hazard ratio [HR] 1.40 per SD; 95% CI 1.27-1.55), unattenuated after hs-CRP adjustment. In an exploratory analysis, suPAR modified the diabetes treatment effect (P-interaction = 0.005), with insulin provision associated with worse outcomes in the highest suPAR tertile (HR 1.33; 95% CI 1.03-1.72). Baseline suPAR predicted risk in participants whose hs-CRP normalized (HR 1.45; 95% CI 1.04-2.03). Joint classification revealed a threefold gradient in event rates (7.1% to 21.6%), with elevated suPAR conferring excess risk even after hs-CRP normalization. Over 1 year, suPAR was unmodified by diabetes or revascularization strategies in BARI 2D despite intensive guideline-directed medical optimization, in contrast to hs-CRP, which declined substantially. Combined suPAR and hs-CRP classification produced a graded risk hierarchy that hs-CRP normalization alone did not resolve.

In patients on long-term oral anticoagulation (OAC), the optimal antithrombotic strategy in the setting of concomitant chronic coronary syndrome (CCS) remains unclear. We therefore performed a systematic review and meta-analysis of randomized controlled trials comparing OAC monotherapy versus OAC plus single antiplatelet therapy (combination therapy) in patients with CCS and any indication for long-term OAC.. We systematically searched PubMed/MEDLINE and Embase through February 2026 to identify trials randomizing CCS patients with an indication for long-term OAC to OAC monotherapy vs. combination therapy. Net adverse clinical events (NACE) were defined as primary composite endpoint. Key secondary outcomes included major adverse cardiovascular events (MACE), major bleeding, and major or clinically relevant non-major bleeding. Hazard ratios (HRs) were pooled using Bayesian random-effects models. Six (6) randomized trials met the inclusion criteria. Five (5) contributed to quantitative synthesis of primary and main secondary outcome measures (5,777 participants). OAC monotherapy significantly reduced NACE (HR 0.61, 95% CrI 0.43-0.85), major bleeding (HR 0.47, 95% CrI 0.30-0.71) and major or clinically relevant non-major bleeding (HR 0.47, 95% CrI 0.31-0.66) compared to combination therapy. No significant differences were observed for MACE (HR 0.83, 95% CrI 0.60-1.18), cardiovascular death (HR 0.70, 95% CrI 0.44-1.13), all-cause death, unplanned revascularisation, myocardial infarction and ischemic stroke. Prespecified subgroup analyses for NACE and MACE outcomes detected a signal of lower risk of MACE with direct oral anticoagulant monotherapy compared to monotherapy with vitamin K antagonists (p=0.02). In CCS patients on OAC, OAC monotherapy reduces bleeding events compared to combination therapy, without clear evidence of a concomitant increase in ischemic risk.

Recent European and American dyslipidemia guideline updates mark a relevant shift in preventive cardiology. The 2025 ESC/EAS focused update and the 2026 ACC/AHA guideline share the same biological premise: low-density lipoprotein cholesterol and other apolipoprotein B-containing lipoproteins are causal drivers of atherosclerotic cardiovascular disease, and cardiovascular benefit depends on earlier, deeper, and sustained reduction of atherogenic burden. Their main differences lie in how prevention is organized in clinical practice. The European framework places greater emphasis on the explicit linkage between risk categories, predefined low-density lipoprotein cholesterol goals, and treatment escalation. The American framework gives greater operational weight to lifetime risk, coronary artery calcium, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), treatment burden, and shared decision-making more directly into treatment selection. These differences influence patient classification, treatment intensity, and incorporation of non-statin therapies, particularly in borderline-risk primary prevention, subclinical atherosclerosis, and patients requiring combination therapy beyond statins. At the same time, both documents converge on key principles: reduced tolerance for prolonged exposure to atherogenic lipoproteins, broader use of combination lipid-lowering therapy, earlier intensification after acute coronary syndromes and in very high-risk settings, and selective use of biomarkers and imaging to refine prevention. Together, they offer complementary models of contemporary lipid management.

In the relationship between periodontitis and coronary heart disease (CHD), the mechanistic role of subclinical atherosclerosis remains incompletely understood. This study examines whether subclinical atherosclerosis mediates the periodontitis-incident CHD association; how a specific periodontitis phenotype modifies subclinical coronary atherosclerosis; and whether periodontitis is associated with epicardial adipose tissue (EAT) attenuation as a marker of inflammation. Data from the Swedish CArdioPulmonary bioImage Study (SCAPIS) were linked to national registers for dental data and CHD incidence. Coronary atherosclerosis was quantified using coronary artery calcium scores (CACS) and segment involvement scores (SIS). EAT characteristics were derived from non-contrast cardiac computed tomography. Associations between severe periodontitis and incident CHD events were examined using multivariable regression models, and mediation by CACS and SIS was explored. Among 29 056 SCAPIS participants, severe periodontitis was present in 6% (n = 1809) and was associated with severe CACS [≥301, odds ratio (OR) 1.69, 95% confidence interval (CI) 1.39-2.06] and severe SIS (>4 segments, OR 1.40, 95% CI 1.17-1.67), with the strongest associations among individuals without concomitant dental caries. Moreover, periodontitis was associated with lower EAT attenuation (β = -0.27 HU, 95% CI -0.48 to -0.05) and a 42% higher risk of incident CHD events (hazard ratio 1.42, 95% CI 1.03-1.97), which was partially mediated by coronary atherosclerosis. Severe periodontitis is positively associated with subclinical coronary atherosclerosis, EAT alterations reflecting inflammatory activity, and CHD event incidence. These results position periodontitis as a marker of increased coronary risk, warranting targeted cardiovascular risk assessment.

The "obesity paradox" suggests lower cardiovascular risk at higher body mass index (BMI) after myocardial infarction (MI), but whether it reflects true protection or methodological bias is unclear. From the nationwide SWEDEHEART registry, patients hospitalised with MI from 2010-2021 were included. BMI at admission was modelled both as a continuous variable using restricted cubic splines and categorised into 6 groups, with 20 to <25 kg/m2 as reference. The primary outcome was major adverse cardiovascular events (MACE), a composite of recurrent MI, stroke, heart failure hospitalisation, or cardiovascular death. Cox regression models estimated the BMI associated with lowest risk and HRs for categorical BMI groups. Adjustments included sociodemographic factors, smoking, and comorbidities not attributed to obesity. Mediation analyses assessed the roles of diabetes, hypertension, and prior cardiovascular disease. In 173 617 patients, the mean age was 71.0 years, 66.7% were men, and mean BMI was 27.1 kg/m2. During a median follow-up of 3.3 years, 36.5% experienced MACE. BMI had a U-shaped association with MACE, with the lowest risk at BMI 25.1 kg/m2. The adjusted HR (95% CI) for MACE was 0.99 (0.97-1.01) for overweight and 1.17 (1.14-1.20) for obesity class I, increasing across higher obesity classes. Excess risk was largely mediated by diabetes, hypertension, and prior cardiovascular disease. Obesity was associated with increased risk of MACE, partly mediated by obesity-related risk factors. The findings suggest that previously reported "obesity paradoxes" may reflect differences in confounder adjustment, handling of mediators, patient populations, and survivor bias.

Cardiomyocytes exhibit marked susceptibility to ferroptosis after myocardial infarction (MI), rendering ferroptosis inhibition a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is recognized as a core driver of ferroptosis, the potential role of mitochondrial DNA transcription in regulating cardiomyocyte ferroptosis remains unexplored. To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in cardiomyocyte ferroptosis, we integrated RNA sequencing and single-nucleus RNA sequencing data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 (αβ-hydrolase domain-containing protein 11) in cardiomyocyte ferroptosis and cardiac repair after MI, we used loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, nontargeted lipidomics, site-specific mutagenesis, molecular docking, coimmunoprecipitation, native gel electrophoresis, proximity ligation assay, methylation-specific polymerase chain reaction, and chromatin immunoprecipitation assay. We found that cardiac ferroptosis peaked at day 7 after MI and was enriched in peri-infarct cardiomyocytes. Mitochondrial dysfunction was a key driver of cardiomyocyte ferroptosis after MI, and the lipid enzyme ABHD11 was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts, and its transcription was repressed by DNMT1 (DNA methyltransferase 1)-mediated promoter hypermethylation. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated cardiomyocyte ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Mechanistically, independent of its canonical enzymatic activities, ABHD11 acted as a mitochondrial DNA transcription coactivator by enhancing the TEFM (mitochondrial transcription elongation factor)-POLRMT (mitochondrial RNA polymerase) interaction. This promoted mitochondrial DNA transcription, restored mitochondrial function, and reduced reactive oxygen species/PUFA-PLs (polyunsaturated fatty acid-containing glycerophospholipids)-driven lipid peroxidation and 4-hydroxynonenal generation. The reduction in 4-hydroxynonenal stabilized YY1 (Yin Yang 1), which subsequently regulated key ferroptosis-driving genes governing iron deposition, reactive oxygen species production, and polyunsaturated fatty acid lipids accumulation, further inhibiting lipid peroxidation and ferroptosis, and ultimately promoting cardiac recovery after MI. This study revealed that ABHD11-mediated mitochondrial DNA transcription attenuated cardiomyocyte ferroptosis after MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.

Whether direct oral anticoagulants (DOACs) are a safe and effective alternative to warfarin in patients with atrial fibrillation and mitral stenosis (AF-MS) remains controversial. To evaluate the effectiveness and safety of DOACs versus warfarin in patients with AF-MS. Observational cohort study using target trial emulation. Population-wide insurance claims data in Taiwan. Patients diagnosed with AF-MS and prescribed either DOACs or warfarin between 1 January 2011 and 31 December 2021 were included in the study. DOACs or warfarin. Absolute risk differences (RDs) and risk ratios (RRs) at 1 year and 5 years of follow-up for ischemic stroke, systemic embolism, composite stroke, myocardial infarction (MI), intracranial hemorrhage, gastrointestinal bleeding, bleeding at other critical sites, and all-cause death. Compared with warfarin, DOACs were associated with an increased risk for ischemic stroke (RD, 4.97 percentage points [95% CI, 1.27 to 8.57 percentage points]; RR, 1.22 [CI, 1.05 to 1.41]) and composite stroke (RD, 5.56 percentage points [CI, 1.77 to 8.97 percentage points]; RR, 1.23 [CI, 1.07 to 1.42]) and a decreased risk for MI (RD, -1.61 percentage points [CI, -3.17 to -0.03 percentage points]; RR, 0.61 [CI, 0.37 to 0.99]) at the 1-year follow-up. Rivaroxaban increased the risk for ischemic stroke during both short- and long-term follow-up periods. The 2 groups did not differ in risks for bleeding or all-cause death. Limited sample size, lack of detailed information on MS severity, and lack of international normalized ratio measurements. In Asian patients with AF-MS, DOACs were associated with an increased 1-year risk for stroke but a decreased risk for MI compared with warfarin. Research Grants Council of Hong Kong.

This prespecified AZALEA-TIMI 71 analysis showed that prior oral anticoagulation (OAC) experience indicates bleeding risk in atrial fibrillation. The factor XI inhibitor abelacimab reduced bleeding regardless of prior OAC experience, with potentially greater absolute benefit among OAC-naïve patients. This trial was registered at www.ClinicalTrials.gov as NCT04755283.

The coexistence of moderate mitral regurgitation (MR) and severe tricuspid regurgitation (TR) is common, yet evidence guiding optimal management remains limited. Transcatheter edge-to-edge repair (TEER) of both valves-performed either sequentially or in combination-has emerged as a potential therapeutic strategy. This study aimed to assess the prognostic impact of moderate MR in patients undergoing tricuspid TEER (T-TEER) for severe TR and to evaluate whether concomitant mitral TEER (M-TEER) improves clinical outcomes. Data from the EuroTR registry (2016-25) were analysed, including patients with severe TR treated with T-TEER. Outcomes were compared between patients with untreated moderate MR and those who underwent concomitant M-TEER using propensity score matching (PSM). The primary endpoint was all-cause mortality at 2 years. Secondary endpoints included New York Heart Association (NYHA) class, 6 min walk distance (6MWD), TR severity, and heart failure rehospitalizations. Among 3100 patients, 30% had moderate MR, which was associated with higher 2-year mortality (23% vs 37%, p<0.0001). After PSM, 217 matched patients treated with concomitant M-TEER had greater TR reduction (-1.9 vs -1.6 grades, P = .001), better NYHA improvement, and increased 6MWD at follow-up. Survival was higher in the combined treatment group (87% vs 76% at 1 year; 81% vs 70% at 2 years, P = .005). In a multivariable analysis, moderate MR predicted increased mortality [hazard ratio (HR) 1.81, P = .005), while combined M-TEER predicted better survival (HR 0.46, P < .0001). Moderate MR predicts impaired prognosis in patients undergoing T-TEER for treatment of severe TR. Concomitant M-TEER is associated with improved survival and functional outcomes in this population with multivalve disease. These findings are hypothesis-generating and need to be tested in a dedicated randomized controlled trial.

Tricuspid regurgitation (TR) is a common yet historically neglected condition associated with poor outcomes. Traditionally managed conservatively, TR has recently gained renewed attention, thanks to advances in surgical and transcatheter interventions. Selecting the optimal therapy, however, requires an integrated and systematic approach considering TR aetiology, stage of the disease, comorbidities, operative risk, and anatomical feasibility. This review describes a standardized stepwise work-up for patients with TR from the referral centre to the expert heart valve centre (HVC). It provides practical algorithms and structured protocols covering clinical and biological assessment, multimodality imaging (echocardiography, computed tomography, cardiac magnetic resonance), and invasive haemodynamic evaluation. The document highlights the importance of multidisciplinary collaboration, involving imagers, heart failure specialists, interventional cardiologists, electrophysiologists, and surgeons, in line with the new recommendations of the 2025 ESC/EACTS Guidelines for the Management of Valvular Heart Disease. By harmonizing diagnostic standards and promoting a structured approach to patient assessment within HVCs, this review aims to facilitate timely referral and ensure consistent evaluation and management of patients with this complex and often underestimated condition.

To investigate the effect of long-term beta-blocker therapy on physical activity (PA) level after myocardial infarction (MI) in patients without heart failure. The BETAMI trial, randomised patients hospitalised with a MI without heart failure (LVEF ≥40%) to beta-blocker or no beta-blocker. In this pre-planned sub-study PA level was assessed by guideline-recommended PA level (≥30 minutes moderate activity ≥5 days/week) or not and self-reported hours/week with light to moderate and vigorous PA. Between-group differences in PA from baseline before randomisation to 18-months were estimated by linear mixed models. Exploratory analysis assessed treatment effects on a composite of all-cause mortality and major adverse cardiovascular events using Cox proportional hazards model. Of the 2867 randomised patients, 2185 (76%) responded to the PA questions and were included in this analysis. Mean age was 62.5 (SD 10.1) years, 20.6% were women. No differences in guideline-recommended PA level or mean hours of light to moderate and vigorous PA were reported between the beta-blocker and non-beta-blocker group at baseline or during 18-months follow-up. At 12-month follow-up, 37.0% in the beta-blocker group and 36.7% in the no beta-blocker group reported guideline-recommended PA level (OR 0.97, 95% CI 0.69-1.37). Exploratory, hypothesis-generating analyses did not demonstrate a statistically significant interaction (p for interaction = 0.06) between treatment assignment and baseline PA level for recurrent clinical events. Beta-blocker therapy did not result in a change in PA level in post-MI patients without heart failure during the 18 months follow-up.

Risk prediction is fundamental to pulmonary hypertension (PH) guideline-based care, yet pediatric-specific risk prediction models remain limited, relying primarily on single predictors, expert opinion, or application of adult models to children. The authors developed and externally validated a data-driven 1-year risk prediction model for pediatric PH. Pediatric patients with PH (n=345; World Symposium on Pulmonary Hypertension groups 1 and 3) enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014-2020; 50.4% male; median age, 4.9 years [interquartile range, 1.9-10.3]) were split into training (80%) and test cohorts (20%). The Dutch National Registry for Pulmonary Hypertension in Childhood (n=155 [1993-2020]) and the Spanish Registry of Pediatric Pulmonary Hypertension (n=327 [2009-2023]) were used for external validation. From 176 variables, BorutaSHAP feature selection with random forest identified 16 predictors for a 1-year outcome of time to death, transplant, Potts shunt, or atrial septostomy, modeled using extreme gradient boosting. Performance was assessed with the area under the receiver operating characteristic curve, confusion matrices, calibration, and Kaplan-Meier event-free survival. The final model achieved an area under the receiver operating characteristic curve of 0.90 (0.79-0.97) and 99% (96%-99%) negative predictive value in testing, dividing participants into 3 groups with strong outcome discrimination. External validation showed an area under the receiver operating characteristic curve of 0.76 (Dutch National Registry for Pulmonary Hypertension in Childhood, 0.70-0.81) and 0.77 (Spanish Registry of Pediatric Pulmonary Hypertension, 0.73-0.82) with negative predictive values of 93% (93%-97%) and 96% (93%-97%), respectively. Kaplan-Meier analysis significantly differentiated outcomes by risk group. This multicenter, validated model provides good 1-year risk prediction in pediatric PH across World Symposium on Pulmonary Hypertension groups 1 and 3, providing a robust tool for clinical risk stratification to guide therapy and addressing a gap in pediatric PH care.

To improve survival of patients at risk of sudden cardiac death, subcutaneous implantable cardioverter defibrillators (S-ICDs) require optimal implant positioning for effective shocks. Defibrillation (DF) testing is recommended but carries serious risks. The PRAETORIAN score predicts defibrillation outcomes on the basis of chest X-ray. The PRAETORIAN-DFT (Prospective Randomized Comparative Trial of Subcutaneous Implantable Cardioverter Defibrillator Implantation With and Without Defibrillation Testing) trial evaluated whether omission of DF testing guided by the PRAETORIAN score is noninferior for first-shock efficacy. In this multinational trial, S-ICD patients from 37 centers were randomized to DF testing or no DF testing. In the No-DF testing group, the PRAETORIAN score was evaluated before discharge. The primary end point was failed first shock for spontaneous ventricular arrhythmias, as a surrogate for defibrillation success, tested for noninferiority with a 3% absolute risk margin. Secondary end points included mortality, potential DF testing-related complications, and S-ICD revisions. The included 965 patients (No-DF testing, n=483; DF testing, n=482) were followed for a median of 41 months. Failed first shock for spontaneous ventricular arrhythmia occurred in 1.7% of the No-DF testing group versus 2.3% of the DF testing group (-0.6% [95% CI, -2.6 to 1.4], P<0.001). There were no significant differences in all-cause mortality (hazard ratio [HR], 0.9 [95% CI, 0.6-1.4]) or arrhythmic death (HR, 0.4 [95% CI, 0.04-3.4]). Potential DF testing-related complications occurred in 1.7% in the DF testing group. Postoperative S-ICD revisions due to inadequate positioning were identical between groups (n=2 each). PRAETORIAN score-guided omission of DF testing after S-ICD implantation did not increase the risk of failed first shocks for spontaneous ventricular arrhythmias and reduced procedural risk without increasing S-ICD revisions. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03495297.

To investigate the results of cardiac screening, prevalence of cardiac diseases and subsequent health outcomes among elite female football players in the UK. Between 2000 and 2024, 3121 elite female football players underwent the English Football Association (FA) cardiac screening programme, comprising a health questionnaire, 12-lead ECG and echocardiogram. The FA registry was interrogated for screening findings, subsequent testing, diagnosis and cardiac morbidity or mortality, including sudden cardiac arrest and death (SCA/SCD). Sex-based comparisons were performed in 2680 females screened between 2017 and 2024, matched 1:2 by age, ethnicity and screening period to 5360 male players screened through the same programme. Female athletes were 19.8±5.4 years old, and the majority (87%) were White. Among 3121 female football players, 193 (6.2%) had an abnormal screening result requiring further evaluation; positive health questionnaires were present in 321 (10.3%), of which two (0.6%) athletes were true-positive for major cardiac conditions. Abnormal ECGs were present in 77 (2.5%), of which four (5.2%) were true positives. Major cardiac conditions were diagnosed in six (0.2%), including four with long QT syndrome, one with Wolff-Parkinson-White syndrome and one with bicuspid aortic valve with moderate to severe aortic regurgitation. No female had cardiomyopathy diagnosed at baseline; however, one (0.03%) was diagnosed with arrhythmogenic cardiomyopathy 18 months later. During 19 193 person-years of follow-up, no female experienced SCA/SCD. In matched analysis, major cardiac conditions were diagnosed in five females (0.2%) and 29 males (0.5%; p=0.027), with higher estimated screening expenditure per major diagnosis in females (£146 809 vs £51 888). Cardiovascular screening in elite female football players identified a low prevalence of major cardiac conditions, predominantly electrical disorders, with no cardiomyopathy diagnosed at baseline and no SCA/SCD during follow-up. As female participation in elite sport continues to grow, these findings support the need for sex-appropriate interpretation and adequate budgeting for pre-participation cardiovascular evaluation.

Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.

Arrhythmia is one of the leading causes of mortality and lacks diagnostic and therapeutic options. Electrical activity at the cellular level is difficult to use as a basis for evaluating drug effects on cardiac rhythm. Cardiac organoids, as organized and functional cell clusters, offer significant advantages as models for the pathophysiological mechanisms of arrhythmia or as drug screening platforms. Here, we applied a standardized set of electrophysiological techniques to integrate electrophysiological activity of cardiac organoids, including multielectrode array (MEA), calcium signal optical mapping and patch clamp analysis. We first established cardiac organoids containing cardiomyocyte and endothelial cell components through hiPSC (human induced pluripotent stem cell) induction. Then by this electrophysiological detection protocol, we found that the characteristics of electrical activity and calcium transient signal of cardiac organoids under E-4031, cisapride or ATX-II induction were more similar to cardiac tissue rather than to cardiomyocytes cultured in vitro. Finally, the patch clamp analysis revealed the existence of subpopulations of ventricular-like cardiomyocytes with different electrical activity phenotypes in cardiac organoids, which aligns with the theoretical basis for cardiac rhythm formation. Our findings systematically validated the tissue-like characteristics of cardiac organoids and can be applied to the testing of molecules' effects on cardiac rhythm, thereby screening for novel antiarrhythmic drugs.

Conduction disturbances and permanent pacemaker implantation remain the most common complications after transcatheter aortic valve implantation. The strongest predictors of conduction abnormalities and subsequent permanent pacemaker implantation after transcatheter aortic valve implantation include pre-existing right bundle branch block, a short membranous interventricular septum, deep transcatheter heart valve implantation, and valve type. Importantly, both new permanent pacemaker implantation and new left bundle branch block after transcatheter aortic valve implantation are associated with increased mortality and heart failure hospitalizations. As transcatheter aortic valve indications expand to lower risk and younger populations, with longer life expectancy, strategies to minimize the risk of conduction disturbances and optimize their detection and management become increasingly crucial. Refined transcatheter heart valve implantation techniques may be associated with a reduction in rhythm disturbances after transcatheter aortic valve implantation and anti-inflammatory treatments are under investigation. Ongoing trials are investigating the impact of beta-blocker withdrawal to prevent conduction abnormalities, electrophysiology studies for risk stratification, and conduction system pacing to prevent adverse cardiac remodelling. This review aims to provide an overview of the incidence, pathophysiology, and consequences of conduction disturbances after transcatheter aortic valve implantation, discuss preventive strategies, highlight the relevant ongoing studies, and provide an evidence-based framework for the management of this important clinical issue.

Over the past decades, the approach to cardiomyopathies has deeply evolved. It has progressively transitioned from one predominantly based on clinical evaluation and conventional imaging towards an integrated and multidimensional approach that incorporates advanced imaging techniques, tissue characterization, and comprehensive genetic testing. In this perspective, the current classification of cardiomyopathies, from the European Society of Cardiology, has introduced the new entity of non-dilated left ventricular cardiomyopathy (NDLVC) that encompasses a spectrum of diseases from hypokinetic non-dilated forms [formerly called dilated cardiomyopathies (DCMs)] to non-hypokinetic non-dilated forms, characterized by left ventricular scar (previously called arrhythmogenic cardiomyopathies). However, the pivotal principle of the new classification is that the phenotype should be considered the starting point of a dynamic diagnostic pathway rather than its ultimate definition. Contemporary evaluation of patients with DCM and NDLVC requires a longitudinal and integrative perspective in which clinical features, imaging markers, and molecular data converge to refine disease characterization. Stated that, several aspects warrant further refinement. Arrhythmic risk stratification of DCM and NDLVC remains incompletely delineated, reflecting the complex and heterogeneous nature of the underlying arrhythmogenic substrate and its variable expression across different stages of the diseases. In addition, a proportion of patients remain genetically elusive despite extensive testing, underscoring the need for deeper molecular insights. At the same time, the expanding recognition of genotype-positive/phenotype-negative individuals introduces clinical scenarios that are not yet fully delineated, particularly with regard to surveillance strategies and preventive decision-making. This review paper aims to provide a structured and evidence-informed framework to guide personalized management of DCM and NDLVC, starting from the phenotype towards precision medicine.

Despite many advances in the last 75 years in the fight against cardiovascular disease mortality, it remains the leading cause of death worldwide. Despite improved therapeutic approaches, cardiovascular disease remains the leading cause of death worldwide. Mounting evidence suggests that restricting food intake to a limited period in the day or extending periods of fasting may be a lifestyle intervention that reduces progression of cardiovascular disease. Various protocols for time-restricted feeding paradigms suggest significant benefits throughout the cardiovascular system. Despite some limitations to their use, the general mechanisms is thought to revolve around circadian alignment of cellular and organ function with behavioral and environmental patterns. Here we review recent evidence in a rapidly expanding field that strives to understand how timing of food intake regulates circadian physiology of cardiovascular systems focusing on heart, vascular, and neuroendocrine physiology. We review both preclinical and clinical reports showing how timed feeding may alter organ function in both health and disease.