Background:Ring annuloplasty failure after mitral valve repair frequently occurs after long-term follow up. Valve-in-ring transcatheter mitral valve replacement (TMVR) is an emerging therapeutic option for this high surgical risk condition. While a dual-chamber implantable cardioverter-defibrillator (ICD) is frequently utilized for sudden cardiac death prevention in this population, valve-in-ring TMVR intraprocedural difficulty associated with atrial lead presence is rarely known. Case summary:A 76-year-old male, with history of coronary artery bypass graft surgery and mitral ring annuloplasty experienced recurrence of severe mitral regurgitation. Due to high surgical mortality risk and unsuitable anatomy of mitral valve for transcatheter edge-to-edge repair, this patient underwent mitral valve-in-ring TMVR. Using transvenous-transseptal access, a 26 mm SAPIEN-3 prosthetic valve was delivered to the mitral area. However, as the patient has a history of dual-chamber ICD, a prosthetic valve cannot pass through during delivery, due to atrial lead entanglement. To overcome this difficulty, atrial septum balloon dilatation manoeuvre was done to facilitate valve delivery, which resulted in successful prosthetic valve delivery and deployment at the mitral position with satisfactory results. Discussion:Valve delivery difficulty due to atrial lead entanglement can occur during valve-in-ring TMVR in patients with dual-chamber ICD implantation history. Atrial septum balloon dilatation can be performed to overcome this problem.

Myocardial ischemia-reperfusion injury (MIRI) remains a critical clinical condition with limited preventive and therapeutic strategies, underscoring the need for novel interventions. The gut-heart axis and exosomal crosstalk hold therapeutic promise for cardioprotection, yet the fundamental question of which specific gut cells release the beneficial exosomes is unanswered. This study aimed to elucidate whether ginseng polysaccharides WGPA exert remote cardiac protection by regulating intestinal immune homeostasis, specifically through promoting the release of exosomes from regulatory T cells (Tregs). Using integrated in vivo and in vitro models, we evaluated the protective effects of WGPA against MIRI. The results demonstrated that WGPA pretreatment significantly attenuated myocardial injury and improved cardiac function. Mechanistically, WGPA selectively activated intestinal Tregs and enhanced the release of HSP70-enriched exosomes. These exosomes entered systemic circulation and were delivered to the heart, where surface HSP70 interacted with TLR4 on cardiomyocytes, activating downstream protective signaling pathways and ultimately suppressing cardiomyocyte death and inflammatory responses. Our study reveals for the first time a complete mechanism by which medicinal plant polysaccharides confer cross-organ cardioprotection via the “intestinal Tregs–exosome–heart” axis, providing a novel theoretical basis and a potential intervention strategy for the prevention and treatment of MIRI.

Cognitive impairment affects 30%–80% of patients with heart failure, yet the mechanisms beyond reduced brain blood flow remain poorly defined. Here we show that circulating factors released during heart failure trigger senescence of brain blood-vessel endothelial cells, which in turn drives synaptic loss and cognitive decline through crosstalk between endothelial cells and microglia, the brain’s immune cells. Using a pressure-overload model (transverse aortic constriction) combined with plasma transfer in 8-month-old male mice, we found that elevated circulating TGFβ2 acts on endothelial TGFBR2 and induces the secreted protein SPARC via a non-canonical MEK/ERK–MYC pathway. Endothelial SPARC then activates microglial TLR4, promoting neuroinflammation and abnormal engulfment of synapses. Endothelial deletion of Tgfbr2 or Sparc, and microglial deletion of Tlr4, each preserved synapses and improved cognition, and pharmacological Tlr4 inhibition was protective. These findings define an endothelial–microglia signaling axis and a potential therapeutic target in heart failure-associated cognitive impairment. Cardiac failure is associated with cognitive impairment. Here, the authors show that blood-borne signals can induce brain endothelial cell-release of SPARC, resulting in the activation of microglia, synapse loss, and cognitive decline following transverse aortic constriction in mice.

BACKGROUND: Galactose lectin-3 (Gal-3) has been shown to promote the progression of pulmonary arterial hypertension (PAH), yet the intricate molecular mechanisms are still unclear. METHODS: Primary cultured rat pulmonary arterial smooth muscle cells (PASMCs) and PAH rats were used in this study. Protein phosphorylation and expression levels were identified using Western blotting, while mRNA level was quantified through qRT-PCR. Hemodynamic measurements, hematoxylin-eosin and immunohistochemistry staining were employed to assess the PAH progression. RESULTS: Yes-associated protein 1 (YAP1) mediated Gal-3/toll-like receptor 4 (TLR4)-induced PDZ-binding kinase (PBK) upregulation. Furthermore, polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) mediated Gal-3/TLR4-induced PBK phosphorylation. Activated PBK further phosphorylated protein regulator of cytokinesis 1 (PRC1), which ultimately led to PASMC proliferation. In monocrotaline-induced PAH rat models, inhibition of Gal-3, TLR4, YAP1, CDK1 or silencing of PLK1, PBK, PRC1 attenuated PAH progression. CONCLUSION: Our study presents novel evidence that Gal-3 promotes PASMC proliferation and pulmonary vascular remodeling by activating PBK/PRC1 through the TLR4/YAP1 and TLR4/PLK1/CDK1 signaling pathways, suggesting that this signaling pathway might be a promising target for the treatment of PAH.

BACKGROUND:Patients with multivessel coronary artery disease often receive 12 months of dual antiplatelet therapy (DAPT) after stenting to reduce the risk of ischemic events. Whether extending DAPT beyond 12 months in event-free patients with multivessel disease provides a benefit is uncertain. METHODS:We conducted an open-label, randomized trial at 97 centers in China. Patients 18 to 75 years of age with multivessel coronary artery disease who had no major ischemic or bleeding events while receiving DAPT for 12 months after implantation of a drug-eluting stent were randomly assigned in a 1:1 ratio to receive an additional 12 months of DAPT (clopidogrel plus aspirin) or aspirin monotherapy. The primary efficacy end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary safety end point was clinically relevant or major bleeding (i.e., a bleeding event of Bleeding Academic Research Consortium [BARC] type ≥2; BARC types range from 0 to 5, with higher values indicating greater severity of bleeding). RESULTS:A total of 8250 patients were randomly assigned to receive extended DAPT (4125 patients) or aspirin monotherapy (4125 patients). The median follow-up was 34.3 months. A primary efficacy end-point event occurred in 222 patients in the DAPT group and in 266 patients in the aspirin-monotherapy group (36-month Kaplan-Meier cumulative incidence, 5.8% vs. 6.8%; hazard ratio, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03). Clinically relevant or major bleeding occurred in 51 patients in the DAPT group and in 57 patients in the aspirin-monotherapy group (36-month Kaplan-Meier cumulative incidence, 1.4% vs. 1.5%; hazard ratio, 0.89; 95% CI, 0.61 to 1.30; P = 0.54). CONCLUSIONS:Among patients with multivessel coronary artery disease who were in stable condition 12 months after implantation of a drug-eluting stent, extending DAPT with clopidogrel and aspirin for an additional 12 months led to a lower risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than continuing aspirin alone, without an increased risk of bleeding. (Funded by the National Natural Science Foundation of China and others; DAPT-MVD ClinicalTrials.gov number, NCT04624854.).

Transcatheter aortic valve replacement (TAVR), also known as transcatheter aortic valve implantation (TAVI), is an interventional technology in which an artificial aortic valve is compressed and assembled outside the body, then delivered through a catheter and implanted at the site of the diseased aortic valve, thereby functionally replacing the native valve. Two versions of the Chinese expert consensus on TAVR were issued in China in 2015 and 2020, respectively. To promptly update the field's understanding of TAVR and to promote its broader, more standardized, and higher-quality application in China, an expert panel has developed this new version of the consensus. This consensus includes substantial updates compared with the previous version, covering topics such as the epidemiology of aortic valve disease, recent advances in TAVR research, indications, procedural standards, post-procedural antithrombotic therapy, prevention and management of complications, management of special cases, and future development trends. This consensus integrates international research evidence and references international guidelines to ensure rigor and evidence-based recommendations, while also incorporating domestic research findings and clinical practice in China, thereby enhancing both its forward-looking perspective and practical applicability.

Differentiated cells such as the plastic vascular smooth muscle cells (SMCs) could continue to develop after birth, mediated by continuously expanded enhancer network. However, it still remains unclear whether the adult enhancer network expansion follows a pre-designed path as seen during embryonic development, and how enhancers are selected for activation? Here, through systemic tracking of chromatin behaviors within vascular SMCs both in vivo and in vitro, we identified multiple collections of active enhancers exhibiting distinct behavioral patterns. Detailed epigenetic profiling further revealed these differentially behaved active enhancers were in distinct maturation states, characterized by varied sequential accumulation states for H3K4me1, H2A.Z and H3K27ac. H2A.Z was further found to recognize H3K4me1 and mediate initial H3K27ac modification that became stabilized later. This hit-and-stabilize process continued on new enhancer regions in vascular SMCs, but not in quiescent cardiomyocytes that also lacked H2A.Z accumulation. Further comparative study of human aortas at different ages also confirmed that new enhancer activation in adult non-restrictively followed a pre-designed path and reflected transformation history of vascular SMCs. Therefore, this newly clarified enhancer activation process would not only provide a new perspective for more accurately assessing the transformation history of aortic tissue, but also help to better understand the adult cell development in general.

Pressure overload-induced vascular remodeling is a complex physiological response that can result in detrimental cardiovascular diseases. Ubiquitination plays a critical role in this process; however, the role and specific mechanism of deubiquitinating enzyme USP13 in vascular remodeling remain poorly understood. Male C57BL/6J mice were subjected to pressure overload via transverse aortic constriction to investigate USP13’s effects in arterial remodeling. Primary vascular smooth muscle cells (VSMCs) were employed to investigate the role of USP13 on VSMC phenotype transition and potential mechanism. Mechanical stretch increased USP13 protein levels in vascular tissues while downregulating Acta2. Similarly, in both rat and human aortic VSMCs, PDGF-BB treatment significantly raised USP13 mRNA and protein levels. Notably, USP13 overexpression worsened arterial wall thickening in TAC mice and decreased Acta2 levels, whereas Spautin-1 treatment had a protective effect. At the cellular level, knocking down USP13 mitigated PDGF-BB-induced VSMC proliferation, as indicated by lower PCNA levels and reduced EdU (+) cell counts. Additionally, USP13 overexpression enhanced VSMC migration, demonstrated by scratch and transwell experiments. USP13 also aggravated PDGF-BB-induced downregulation of ACTA2 and Transgelin while promoting OST elevation. Mechanistically, USP13 interacted with Beclin-1, facilitating its deubiquitination and promoting autophagic flux, as shown by increased LC3 II/I ratios and decreased p62 levels. Moreover, BHLHE40 was explored as a new transcription factor of USP13, and BHLHE40 can regulate VSMCs proliferation and migration by transcriptionally activating USP13. In conclusion, our findings elucidate the role of USP13 in vascular remodeling under pressure overload, suggesting that targeting USP13 may offer therapeutic potential for pathological vascular disorders.

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

Acute myocardial infarction (AMI) is a leading global cause of death with a sudden onset, which necessitates rapid and accurate diagnosis for effective treatment. However, existing detection methods for emergency scenarios (e.g., ambulances) suffer from limited sensitivity and high cost, hindering their widespread application. To address this unmet clinical need, we developed a rapid and highly sensitive immunoassay platform based on surface-enhanced resonance Raman scattering (SERRS) for the quantitative detection of cardiac troponin T (cTnT), the gold-standard biomarker for AMI. This platform exhibits several advances. First, an antibody-oriented engineering strategy combined with core-shell SERRS nanotag synthesis fully exposes the antibody Fab regions to improve antigen-binding efficiency while reducing the nanotag cost by up to 75%. Meanwhile, selection of the resonance Raman reporter IR-808, which matches the 785 nm laser excitation wavelength, significantly enhances the detection signal intensity and sensitivity. Integrating these advantages with the classic sandwich immunoassay structure, the assay achieves a remarkable limit of detection of 0.24 pg/mL within only 7 min. Furthermore, systematic optimization of the incubation buffer (including pH value, surfactants, and blocking agents) effectively minimizes nonspecific adsorption, enabling 100% accurate differentiation between cTnT-positive and negative human serum samples. Collectively, this sensitive, rapid, and cost-effective platform demonstrates great potential for AMI point-of-care testing and prognosis monitoring.

Background Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) is associated with fewer clinical events than angiography-guided PCI. Whether the use of IVUS guidance improves the outcomes as compared with angiography guidance in patients with complex coronary bifurcation lesion undergoing double kissing (DK) crush is uncertain. Objectives This study aimed to investigate the treatment effect of IVUS-guided PCI, as compared with angiography-guided PCI, in patients with complex bifurcation lesions. Methods We conducted a multicenter, randomized, open-label trial at 24 centers in China. Patients with clinical indications for PCI and a complex bifurcation lesion based on DEFINITION (Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary Intervention Using Drug-Eluting Stents) criteria (particularly side branch lesion length ≥10 mm) from coronary angiography were randomly assigned in a 1:1 ratio to IVUS-guided PCI or angiography-guided PCI. The primary endpoint was a composite of target vessel failure, defined as cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization at 1 year after randomization. Results We assigned 555 patients to IVUS-guided PCI (n = 277) or angiography-guided PCI (n = 278). A total of 124 patients (44.8%) in the IVUS-guided PCI group and 122 (43.9%) in the angiography-guided PCI group had a bifurcation lesion involving the left main coronary artery. DK crush was used in 96.8% of patients. At 1 year, a primary endpoint event occurred in 17 patients (6.1%) in the IVUS-guided PCI group and in 41 patients (14.7%) in the angiography-guided PCI group (HR: 0.40; 95% CI: 0.23-0.71; P = 0.002), driven mainly by reductions in target vessel myocardial infarction or target vessel revascularization. Conclusions In the present randomized trial comparing IVUS-guided vs angiography-guided PCI for complex coronary bifurcation lesions treated with the 2-stent DK crush technique, the benefits of IVUS-guided PCI at 1 year was achieved largely through achievement of IVUS-defined optimization targets rather than IVUS use alone. (IVUS-guided DK Crush Stenting Technique for Patients With Complex Bifurcation Lesions [DKCRUSH VIII]; NCT03770650)

Background Complete revascularization (CR) has been shown to reduce the risk of adverse cardiovascular events compared with culprit-only revascularization (COR) in acute ST-segment elevation myocardial infarction (STEMI) patients with multi-vessel disease (MVD). However, the optimal timing of staged complete revascularization (SCR) after primary percutaneous coronary intervention (PCI) remains unclear. Trial design The STAGED trial is an investigator-initiated, multicenter, randomized study involving 37 sites, aiming to include 1,586 acute STEMI patients with MVD undergoing successful primary PCI of the culprit lesion followed by SCR. Eligible patients will be assigned to two groups based on the timing of SCR: early-staged PCI and delayed-staged PCI. The primary endpoint is major adverse cardiac event (MACE), including cardiovascular death, myocardial infarction, or ischemia-driven revascularization for both culprit and non-culprit vessels at 12 months since the randomization. The secondary endpoint is individual components of primary endpoint, all-cause death, heart failure-related rehospitalization, stroke, contrast-induced nephropathy, and radiation exposure dose . Follow-up will be conducted through clinic visits or telephone interviews at 1, 3, and 12 months after the index procedure. Conclusion The STAGED trial is the first randomized controlled study specifically designed to evaluate the clinical efficacy and safety of different timing strategies for SCR in acute STEMI patients with MVD. Trial registration clinicaltrials.gov, NCT04918030.

Atrial fibroblast activation is a central cellular event driving atrial fibrotic remodeling, which plays a critical role in the initiation and maintenance of atrial fibrillation (AF). Our previous studies have identified the intermediate-conductance Ca2+-activated potassium channel KCa3.1 as a key mediator of reactive atrial fibrosis. However, the upstream mechanisms regulating its expression under pro-fibrotic stimulation remain incompletely defined. The present study aimed to investigate whether NADPH oxidase (NOX)-derived reactive oxygen species (ROS) regulate KCa3.1 expression and function in atrial fibroblasts. Primary rat atrial fibroblasts were stimulated with angiotensin II (Ang II). Ang II markedly increased intracellular ROS generation through AT1 receptor-dependent activation of NOX. Pharmacological inhibition with Diphenyleneiodonium (DPI) or CRISPR-mediated deletion of NOX2 or NOX4 significantly suppressed Ang II-induced upregulation of KCa3.1 expression and channel activity. Exposure to hydrogen peroxide (H2O2) alone was sufficient to enhance KCa3.1 expression and TRAM-34-sensitive currents. Functionally, pharmacological blockade or genetic deletion of KCa3.1 markedly attenuated ROS-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, ROS activated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of either pathway suppressed KCa3.1 promoter activity and expression. Collectively, these findings identify a NOX-ROS-JNK/ERK-KCa3.1 signaling axis that drives atrial fibroblast activation and may represent a potential therapeutic target in oxidative stress-associated atrial remodeling.

Since the publication of the 2021 Asian Pacific Society of Cardiology (APSC) consensus statements on the use of MitraClip for mitral regurgitation (MR), other transcatheter edge-to-edge repair (TEER) devices have been introduced for the treatment of both tricuspid regurgitation (TR) and MR. Hence, the APSC developed these consensus recommendations, with general cardiologists and internal medicine specialists practicing cardiology as the intended readers, to update the recommendations on the appropriate use of TEER in patients with TR or MR. The APSC expert panel reviewed and appraised the available evidence using the GRADE system. Consensus recommendations were developed and put to an online vote. Consensus was reached when at least 80% of votes for a given recommendation were in support of ‘agree’ or ‘neutral’, The resulting 16 statements provide guidance for clinical practitioners in the region on the evaluation and management of patients with TR or MR in the Asia-Pacific region who are being considered for TEER therapy.

Background: Acacetin, a naturally occurring flavone present in various plants, is known as a promising drug candidate for cardiovascular disorders. Our previous study demonstrated that acacetin ameliorates atherosclerosis through endothelial cell protection; however, its pharmacological effects on vascular smooth muscle cells (VSMCs) remain unexplored. This study investigates the therapeutic potential of acacetin against lysophosphatidylcholine (LysoPC)-induced VSMC injury and elucidates the underlying molecular mechanisms. Methods and Results: Multiple biochemical techniques were employed in the present study. The results showed that acacetin significantly attenuated LysoPC-induced apoptosis and reactive oxygen species (ROS) generation in cultured VSMCs. Western blot analysis revealed that the cytoprotection of acacetin was associated with upregulated expression of antioxidant defense proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), NADPH quinone oxidoreductase 1 (NQO-1), and superoxide dismutase 1 (SOD1). Nrf2 silencing completely abolished these protective effects. Mechanistically, siRNA-silencing of Sirtuin 1 (Sirt1) abrogated acacetin-induced modulation of the Nrf2/Keap1/p62 signaling. In vivo validation using aortic tissues from high-fat-diet-fed ApoE-/- mice confirmed that acacetin effectively suppressed VSMC apoptosis and ROS overproduction associated with restoring the downregulated Sirt1 expression levels. Conclusions: These findings establish a novel mechanistic paradigm wherein acacetin confers protection against LysoPC-induced VSMC apoptosis and oxidative stress through Sirt1-dependent activation of the Nrf2/p62 signaling pathway, suggesting that acacetin is a promising therapeutic drug candidate for atherosclerotic plaque stabilization.

Down syndrome (DS) is a widespread chromosomal disorder primarily associated with cognitive impairment and progressive neurodegenerative changes. Clinically, age 50 years is considered a pivotal turning point in the health trajectory of individuals with DS. Before this age, they primarily face developmental challenges including significant cognitive deficits and difficulties in social interaction. However, as they age, they increasingly exhibit more severe neurodegenerative changes, including Alzheimer’s disease (AD)-like cognitive decline and dementia symptoms. This study aimed to dissect intricate gene expression patterns in key neuronal cell types within the DS cerebral cortex and to examine how these patterns evolve with age. We conducted a detailed gene expression analysis of key neuronal cells, including inhibitory neurons, excitatory neurons, microglia, and oligodendrocyte progenitor cells, in individuals with DS. Additionally, the bioinformatics tool NeuronChat was employed to investigate the intercellular communication networks in the DS brain. Individuals with DS were divided into younger and older groups, with age 50 years as the boundary. Through comparative analysis, our findings indicated that aging in DS is associated with exacerbated neuronal dysfunction, decreased energy metabolism in microglia, and increased neurodegenerative traits in oligodendrocyte progenitor cells. Notably, compared to the control group, the DS brain showed increased complexity in cellular communication networks, reflecting an effort to maintain adaptability during syndrome progression. However, this increased complexity does not translate into effective signal transmission, suggesting significant disruptions in the function and structure of the neural network. This study provides a deeper understanding of cell function abnormalities and signal transmission irregularities in DS. By integrating single-cell and systemic network analyses, we revealed complex pathophysiological mechanisms, laying a foundational framework for developing new treatment methods. Our comprehensive analysis emphasizes the necessity for targeted strategies to address the multifaceted nature of DS pathogenesis and improve treatment outcomes.

Cardiometabolic multimorbidity (CMM) poses a severe global health burden. Effective prediction requires biomarkers capturing its complex pathophysiology, integrating inflammation, insulin resistance (IR), and central obesity. The C-reactive protein-triglycerides-glucose index-waist to height ratio (CTI-WHtR) is a composite index synthesizing these three pathways, but its longitudinal association with CMM risk remains unestablished. This prospective analysis utilized data from the China Health and Retirement Longitudinal Study (CHARLS). Cohort 1 (n = 8,875), free of CMM at baseline (2011), was established to assess the association between baseline CTI-WHtR and incident CMM. Cohort 2 (n = 5,807), a sub-cohort of longitudinal analysis, was analyzed to evaluate the impact of cumulative CTI-WHtR (cuCTI-WHtR) exposure (up to 2015) on CMM risk. The primary outcome was new-onset CMM (≥ 2 of diabetes, heart disease, or stroke). Cox proportional hazards models, restricted cubic splines, threshold analysis, and ROC curves were employed. During the follow-up period, 873 and 490 incident CMM cases occurred in Cohort 1 and Cohort 2, respectively. After multiple adjustment, participants in the highest quartile of baseline CTI-WHtR had a 2.85-fold (95

Rationale:Heart failure (HF) is increasingly recognized as a systemic disorder that extends beyond the heart and affects neurovascular tissues, including the retina. However, the mechanisms by which circulating factors from HF trigger retinal neuroinflammation remain unclear. Methods:HF was induced in adult mice by transverse aortic constriction (TAC). Retinal structure and function were evaluated using optical coherence tomography (OCT) and electroretinography (ERG). Parabiosis and plasma transfer experiments were performed to assess the role of circulating factors. Endothelial senescence, microglial activation, and inflammatory signaling were analyzed using immunofluorescence, qPCR, and molecular assays. The functional relevance of TGFβ2 and microglia was tested using anti-TGFβ2 antibody administration and microglial depletion with PLX5622 treatment. Results:TAC mice exhibited pronounced retinal thinning, diminished electroretinography (ERG) amplitudes, and reduced vascular density. Exposure of healthy mice to HF plasma reproduced these abnormalities, indicating that circulating mediators drive retinal injuries. TGFβ2 levels were markedly elevated in the plasma of both patients with HF and TAC mice. Mechanistically, TGFβ2 activated the pSMAD2/EP300 pathway in retinal endothelial cells, promoting H3K9 acetylation, P21 induction, and endothelial cell senescence. Senescent endothelial cells release proinflammatory factors that activate retinal microglia, leading to hypertrophic morphology, enhanced synaptic phagocytosis, and upregulation of cytokines such as IL1β, TNFα, and IL6. Neutralization of TGFβ2 or microglial depletion markedly reduced inflammation, preserved the retinal architecture, and restored visual function. Conclusions:Elevated TGFβ2 levels in heart failure drive retinal endothelial epigenetic senescence, which secondarily activates microglia and induces neuroinflammation. Endothelial-specific disruption of TGFβ2 signaling is sufficient to protect the retina independently of primary cardiac recovery. Targeting the TGFβ2-endothelial-microglia axis may represent a promising therapeutic strategy for preventing retinal neurovascular degeneration associated with systemic cardiac disease.