Hyperuricemia is characterized by abnormally elevated serum uric acid (UA) levels. Persistent hyperuricemia not only triggers gout but also causes damage to the kidneys and cardiovascular system. Therefore, utilizing non-invasive diagnostic methods for early and continuous monitoring is crucial for preventing disease progression. Herein, we reported a portable wireless electrochemical sensing platform constructed from SA-Pt/rGO/MOF catalysts prepared via photochemical deposition of platinum single atoms (Pt SAs) on reduced graphene oxide/metal-organic framework (rGO/MOF) composites. The designed single-atom catalysts (SACs) exhibited exceptional electrocatalytic activity toward UA oxidation, and the fabricated sensing platform demonstrated a broad linear detection range (1-1000 μM) and relatively low detection limit (1.12 μM), with excellent selectivity and reproducibility. To enhance direct biofluid analysis, we designed a hydrophilic surface-modified microfluidic device for enhanced collection efficiency. Building upon this device, the integrated wireless microfluidic electrochemical platform enabled quantitative UA analysis and correlation studies in serum and saliva from 10 hyperuricemia patients and 10 healthy volunteers, demonstrating promising clinical utility. This work not only extended SACs applications to ultrasensitive biomarker detection but also provided a feasible strategy for developing next-generation non-invasive point-of-care testing (POCT) devices.

Heart failure (HF) and cancer are leading causes of global morbidity and mortality that share a significant bidirectional relationship. Epidemiologic studies reveal that cancer patients and survivors face a substantially elevated risk of HF, largely driven by cardiotoxic systemic therapies including chemotherapy, targeted therapy, immunotherapy and radiation therapy. Conversely, individuals with HF have a markedly increased incidence of cancer. This interconnection is underpinned by age and shared modifiable risk factors, including smoking, hypertension, diabetes and obesity, as well as common pathophysiological mechanisms such as chronic inflammation, neurohormonal activation, oxidative stress and dysregulated angiogenesis. Clonal haematopoiesis of indeterminate potential has emerged as a novel biological link, promoting both maladaptive cardiac remodelling and tumourigenesis. Clinically, the coexistence of HF and cancer creates complex management challenges, as each condition worsens the prognosis of the other and limits therapeutic options. In addition to providing a broad overview of the topic, this review incorporates three aspects that are underexplored in existing cardio-oncology literature-management of advanced metastatic cancer in patients with HF, use of advanced HF therapies in patients with cancer and disparities in cardio-oncology care and clinical trial representation. Effective management of patients with HF and cancer requires a multidisciplinary cardio-oncology approach that incorporates rigorous risk stratification, early detection using serial cardiac biomarkers and imaging and personalised management tailored to cancer treatment. Irrespective, cancer patients with HF have a poor prognosis. It is necessary to balance oncological efficacy with cardiovascular safety while providing a clear definition of the goals of care. Early integration of palliative and rehabilitative care can significantly improve patient quality of life and outcomes. Nevertheless, effective novel treatment strategies have significantly improved the overall survivorship for patients with cancer and/or HF.

BACKGROUND AND OBJECTIVES: Implantable cardioverter defibrillator (ICD) therapy is indicated following a myocardial infarction (MI) to curtail the risk of sudden cardiac death (SCD) in patients who are classified as high-risk, defined by a left ventricular ejection fraction (LVEF) ≤35%. The understanding of risk in patients with ischaemic injury who do not meet these criteria is limited. This study aims to assess the burden of SCD in patients' post-MI with LVEF 36-50%. METHODS: Articles reporting mortality and SCD outcomes for participants with LVEF 36-50% post-MI without additional risk stratification or intervention were included. Medline, Embase and Cochrane databases were searched from index entries until the present. Data were synthesised using a random-effects model. Competing risk adjusted number needed to treat (NNT) for ICD implantation was calculated. This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: 7435 records were identified, five studies with 9345 patients were included. The pooled annual rate of SCD in patients with LVEF 36-50% post-MI was 1.74% (95% CI 1.02 to 2.95); a higher annual rate of 6.34% was observed for LVEF≤35% (p=0.03) while a lower yearly rate of 0.55% was observed for LVEF >50% (p=0.02). The proportion of mortality due to SCD was similar across all LVEF strata (p=0.79). Very high between-study heterogeneity was observed (I=89.9% for SCD and I=96.8% for all-cause mortality). During exploratory modelling, the primary prevention ICD NNT for patients with LVEF 36-50% was 19 when applying the MADIT-II ICD treatment effect (HR 0.33, 95% CI 0.20 to 0.53) and extrapolation to a 5-year device lifespan. CONCLUSION: This is the first meta-analysis reviewing post-MI patients with LVEF 36-50%. These findings highlight a clinically relevant unmet need for patients who carry a substantial burden of SCD despite being outside current ICD eligibility criteria. Further study is needed to improve risk stratification within this population and determine whether suitable intervention is beneficial. PROSPERO REGISTRATION NUMBER: CRD42024551830.

BACKGROUND: The role of blood pressure (BP) lowering in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) remains uncertain, and it is unclear to what extent the existing benefits of therapies are mediated by BP reduction. METHODS AND RESULTS: A systematic review and meta-analysis of randomised clinical trials was conducted, comparing any BP lowering treatment to placebo, usual care or another drug class in patients with HFmrEF/HFpEF. The primary endpoint was a composite of cardiovascular death and HF hospitalisation. Data were pooled using a random effects meta-analysis and meta-regression with inverse variance weighting expressed as a risk ratio (RR) and its 95% CI. 18 studies were identified totalling 39 452 patients. Pharmacological BP lowering led to a significant reduction in the primary composite endpoint (RR 0.86, 95% CI 0.83 to 0.89; p≤0.001), but there were significant differences between drug classes (p value=0.018), with evidence of benefit with sodium-glucose cotransporter 2 inhibitor, mineralocorticoid receptor antagonist, angiotensin-receptor neprilysin inhibitor and glucagon-like peptide-1 receptor agonists but not other drug classes. Meta-regressions found no significant association between the degree of BP reduction and treatment effects (coefficient slope=-0.0125, p=0.304). Similarly, pharmacological BP lowering was associated with a reduction in HF hospitalisations (RR 0.83, 95% CI 0.79 to 0.86; p≤0.001), but treatment effects were not related to degree of BP reduction (coefficient slope=-0.0121, p=0.528). CONCLUSION: In patients with HFmrEF/HFpEF, there was no significant association between pharmacological BP lowering and clinical outcomes, suggesting that BP lowering alone is unlikely to explain all the benefits observed with the use of recently established HF therapies. PROSPERO REGISTRATION NUMBER: CRD42025631539.

Cardiac myxoma is the most common primary cardiac tumor and typically arises in the left atrium. Large, mobile myxomas may prolapse through the mitral valve and produce functional mitral stenosis with secondary pulmonary hypertension. We report a 57-year-old woman with cardiovascular risk factors (hypercholesterolemia and obesity) who presented with New York Heart Association class III dyspnea and palpitations. First-line transthoracic echocardiography revealed a giant, mobile left atrial mass (4.7 x 4.8 cm) attached to the basal third of the interatrial septum, prolapsing into the left ventricle and producing a mean transmitral gradient of 16 mmHg with severe pulmonary hypertension (estimated pulmonary artery systolic pressure approximately 80 mmHg). Preoperative coronary computed tomography (CT) angiography, performed to exclude significant coronary artery disease given her cardiovascular risk factors and to characterize the intracardiac mass non-invasively, confirmed the mass and showed coronary atheromatosis without significant stenosis. The mass was surgically resected within two weeks of diagnosis via a minimally invasive thoracoscopic approach, decided in a multidisciplinary heart team meeting, with femoro-femoral cannulation, without preoperative anticoagulation; activity restriction and close clinical monitoring were maintained while awaiting surgery. The postoperative course was uncomplicated, with early extubation and rapid mobilization. At one-month follow-up, the transmitral gradient and pulmonary artery pressures had normalized, with a stable, mild residual mitral regurgitation and complete symptom resolution. Histopathological examination showed a well-circumscribed, non-encapsulated, smooth-surfaced proliferation of spindle-to-stellate cells within an abundant myxoid stroma, without atypia, mitoses, or necrosis; immunohistochemistry was positive for calretinin, confirming the diagnosis of myxoma. This case illustrates the diagnostic and hemodynamic impact of a giant left atrial myxoma and the feasibility of a minimally invasive thoracoscopic resection in a carefully selected patient.

INTRODUCTION: Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects. METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes ( = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST. RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44;  < 0.001). DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.

BACKGROUND: Atrial fibrillation (AF) is the most prevalent sustained arrhythmia and is associated with significant morbidity and mortality. Data on AF in hospitalized patients in the Middle East are limited. METHODS: We analyzed 536 hospitalized patients with nonvalvular AF from the Jordan atrial fibrillation (JoFib) registry. A prospective multicenter study of 2020 patients enrolled between May 2019 and December 2020. Patients were stratified into new-onset atrial fibrillation (NOAF) and previously diagnosed AF, and their clinical characteristics and in-hospital outcomes were compared. RESULTS: The cohort had a mean age of 70.2 ± 14.1 years, and 48.7% were male. The most common comorbidities were hypertension (77.6%), diabetes (52.1%), and heart failure (31.3%). NOAF patients were significantly younger and more likely to be smokers, whereas those with prior AF had more comorbidities and larger left atrial size. Overall, in-hospital mortality was 6.7% but was significantly higher in NOAF patients. CONCLUSIONS: Hospitalized patients with NOAF are younger, more often smokers, and face higher in-hospital mortality compared with chronic AF, underscoring the need for early recognition and risk factor modification to prevent hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03917992.

Health anxiety poses unique challenges in long-term conditions requiring symptom monitoring to prevent deterioration. In ACHD, the nature of health anxiety is poorly understood, and treatment must support health management without reinforcing anxiety. This case demonstrates reduced heart-focused anxiety and health anxiety in a 25-year-old female with ACHD following CBT.

Heart transplantation remains the gold standard treatment for end-stage heart failure. However, the persistent shortage of donor organs continues to limit the number of procedures performed worldwide. Several strategies have been developed to expand the donor pool, including the reuse of a previously transplanted cardiac graft, which represents a rare alternative. We report the first case of cardiac graft reuse performed in France, and the ninth case described worldwide. A 61-year-old man with end-stage dilated cardiomyopathy and cardiogenic shock underwent urgent heart transplantation using a graft that had been previously transplanted into another recipient, who subsequently developed brain death. Pretransplant evaluation confirmed preserved graft function, allowing for retransplantation. The postoperative course was initially complicated by vasoplegic shock but evolved favorably. At the 3-year follow-up, the patient remained in a good functional status with preserved cardiac function.

Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment-related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress-response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer-cardiovascular interface. We analyze how the ubiquitin-proteasome system, autophagy-lysosome pathway, endoplasmic reticulum stress-induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy-induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio-oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.

Simultaneous heart-kidney transplantation is a viable and effective treatment option for patients with congenital heart disease and advanced chronic kidney disease when both conditions threaten survival.

BACKGROUND: While PDZ-LIM domain-containing protein (PDLIM2) suppresses lung cancer, its clinical significance and therapeutic potential remain to be fully explored. METHODS: Next-generation sequencing and immunohistochemistry of programmed death ligand 1 (PD-L1) were performed on lung adenocarcinoma (LUAD) tissues from 15,765 patients. PDLIM2 gene therapy was tested in syngeneic LUAD mouse models using intravenous nano-complexed plasmid DNA, alone or with chemoimmunotherapy. RESULTS: PDLIM2-high tumors were more common in primary/local biopsies versus metastatic samples (73.1% vs 53.0%; p < 0.001). High PDLIM2 expression was linked to lower mutation rates in RB1, TP53, SMARCA4, STK11, and KEAP1, but increased EGFR mutations (all p < 0.01). PDLIM2-high tumors also showed increased immune cell infiltration, T cell-inflamed scores, and PD-L1 positivity (all p < 0.008). High PDLIM2 was associated with improved survival (24.1 vs 18.1 months; p < 0.001, HR = 0.84) and remained prognostic in multivariate analysis (HR = 0.88, 95% CI 0.83-0.93), as well as with longer pembrolizumab time, especially with platinum-based therapy (p = 0.012, HR = 0.867). In two LUAD mouse models, nanoPDLIM2 improved median overall survival versus chemoimmunotherapy alone (10-12.5 vs 8-9 days; N = 8; p = 0.0001, 0.0003). CONCLUSION: PDLIM2 is a promising prognostic biomarker in LUAD linked to immune-receptive tumors. Preclinically, PDLIM2-based therapy enhances chemoimmunotherapy efficacy, though its predictive role warrants further evaluation.

Patients with type 2 diabetes mellitus (T2DM) have elevated risk for aortic stenosis (AS). The impact of diabetes on prognosis and clinical progression in AS is not well documented. In this study we try to assess if patients with T2DM and AS have faster clinical progression compared to patients without diabetes. By linkage of nationwide Swedish registries, we identified 16,116 T2DM and AS individuals (cases) and compared them with 31,066 matched comparators (AS without diabetes) from general population concerning clinical progression, defined as progression from AS diagnosis to hospitalization for heart failure, aortic valve replacement, mortality, and composite outcome of these endpoints. Kaplan-Meier curves were used to compare outcomes between cases and comparators and Cox proportional hazards analyses to account for confounders. AS individuals (total 47,182, 16,116 cases and 31,066 comparators) had mean age 71 years. The cases were younger, men predominated (58% versus 53%) and had more comorbidities. During follow-up, cases had faster clinical progression- 11% higher hazard for valve replacement (95% CI 1.04-1.18), 14% higher hazard for heart failure hospitalization (95% CI 1.03-1.26) and 4% higher hazard for composite outcome (95% CI 1.01-1.08), but with no mortality excess (HR1.00, 95%CI 0.97-1.05). Preexisting T2DM seems to be linked to moderately more rapid clinical progression in AS.

To externally validate the RSNA 2020 challenge 2-place deep-learning (DL) algorithm for detecting pulmonary embolism (PE) on computed tomography pulmonary angiography (CTPA) scans with additional focus on subsegmental-only PEs (SSPE). Between 2015 and 2022 1,038 CTPAs were retrospectively enrolled. An experienced radiologist (> five years) labelled CTPAs for the presence, location (central, lobar and segmental, subsegmental-only) and side (right-sided, left-sided, bilateral) of PE. The DL model was tested for its ability to predict these labels by analyzing accuracy, sensitivity, specificity and area under the receiver operating characteristic curve (AUROC) using different model outcome probabilities for each analysis. Overall, 136 central, 375 peripheral PEs (303 lobar and segmental PEs, 72 SSPEs), and 527 patients without any PE were analyzed. The model correctly predicted the presence of any PE in 921/1,038 patients (88.7%), yielding a sensitivity of 0.80, specificity of 0.97 and AUROC of 0.94. No central PE was missed, whereas 100/375 (26.7%) peripheral PEs remained undetected. Using the corresponding model output probability, the central PE status was correctly identified in 999/1,038 (96.2%) patients, while peripheral PE was correctly identified in 785/1,038 (75.6%) patients. This corresponded to sensitivities of 0.94 and 0.77, specificities of 0.97 and 0.75, and AUROC values of 0.99 and 0.74, respectively. The model performed better in detecting right-sided compared to left-sided PEs (AUROC: right- vs. left-sided: 0.95 and 0.92, p < 0.05). SSPE status was correctly predicted in 796/1,038 (76.7%) patients, yielding a sensitivity of 0.94, a specificity of 0.22, and an AUROC of 0.48, respectively. The model demonstrated high performance in detecting any PE, performing best on central and slightly lower on lobar and segmental PE. Predicting the presence of SSPEs was difficult, likely due to the model not being explicitly trained for this subtype.

BACKGROUND: The potential cardiac toxicity of glutamate is debated and has been suggested by some epidemiological and experimental studies. To our knowledge, none investigated the links between both naturally occurring and food additive glutamate and cardiovascular disease (CVD) risk. OBJECTIVE: Our objective was to assess the associations between intakes of total, food additive and naturally occurring glutamate, and the risk of CVD, including cerebrovascular (CVA) and coronary heart (CHD) diseases, in a large population-based study. METHODS: Participants (n= 108,932, NutriNet-Santé prospective cohort, 2009-2023, France, mean age=42.4y (SD=14.5), 79.3% females) completed repeated 24h-dietary records (mean = 21 (SD=18), up to 84), including brands of industrial food consumed. Exposure to food additive glutamate was evaluated through multiple composition databases and ad-hoc laboratory assays in food matrices. Associations between time-dependent continuous exposures to total, naturally occurring and food additive glutamate and risk of CVD, CVA, and CHD were investigated using multivariable Cox models. RESULTS: During follow-up (median=7.92y), 2397 CVD, 1113 CVA, and 1284 CHD cases were diagnosed. Higher intakes of food additive glutamate (Hazard Ratio=1.05, 95%Confidence Interval (1.01, 1.09), p-value=0.02), naturally occurring glutamic acid (HR=1.13(1.03, 1.25), p-value=0.009), and total glutamate (HR=1.15(1.05, 1.26), p-value=0.004) were associated with higher risks of CHD. For CVD, corresponding HRs were 1.03(1.00, 1.06; p-value=0.07), 1.09(1.01, 1.18; p-value=0.02) and 1.10(1.02, 1.18; p-value=0.01). No association was detected for CVA (all p-values≥0.5). Residual confounding cannot be entirely ruled out, and causality cannot be established based on this single observational study. CONCLUSIONS: This large prospective study showed positive linear associations between higher glutamate intakes and increased risks of CVD. In particular, food additive glutamate, naturally occurring glutamic acid, and total glutamate intakes were all associated with higher CHD risk. This adds to previous experimental data showing a role of glutamate in regulating heart functioning at physiological doses, while also suggesting heart rate dysfunction at higher exposures. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335644.

Angiogenesis is critical for post-ischemic tissue repair. Although miR-485-5p is highly expressed in vascular tissues and RGS4 regulates angiogenesis, their specific roles under hypoxia remain largely unknown. This study aimed to elucidate these functions and underlying mechanisms. Using a CoCl₂-induced hypoxic model in HUVECs, we observed that hypoxia significantly downregulated miR-485-5p expression while concurrently upregulating RGS4 mRNA levels. Notably, either inhibition of RGS4 or overexpression of miR-485-5p markedly enhanced HUVEC proliferation, migration, and tube formation. A luciferase reporter assay further confirmed that miR-485-5p directly targets RGS4. In addition, miR-485-5p overexpression or RGS4 inhibition increased the phosphorylation levels of VEGFR-2, AKT, and ERK1/2. Through co-immunoprecipitation assays, we revealed for the first time a direct interaction between RGS4 and VEGFR-2, which suppresses VEGF signaling and consequently impairs angiogenesis. Conversely, overexpression of RGS4 reversed the pro-angiogenic effects of miR-485-5p, as evidenced by reduced VEGFR-2/AKT/ERK1/2 phosphorylation and decreased proliferation, migration, and tube formation in HUVECs. These findings indicate that miR-485-5p promotes angiogenesis by downregulating RGS4. Consistent with these in vitro results, experiments in vivo using a rat hindlimb ischemia model confirmed that inhibition of RGS4 via si-RGS4 or overexpression of miR-485-5p via agomir-miR-485-5p markedly improved blood perfusion recovery, enhanced vascular angiogenesis, and increased VEGFR-2/AKT/ERK1/2 phosphorylation. Collectively, our study demonstrates that the miR-485-5p/RGS4 axis promotes hypoxia-induced angiogenesis by relieving RGS4-mediated inhibition of VEGFR-2/AKT/ERK1/2 signaling, thereby providing a strong rationale for targeting miR-485-5p as a possible treatment approach for lower extremity arterial disease.

BACKGROUND: Awareness of dysphagia and its clinical implications is increasing, yet its occurrence and impact among patients in Departments of Pulmonary Medicine remain underexplored. This study aims to assess the occurrence of dysphagia using standardized screening tools and describe the findings across patient subgroups. METHODS: Over six months, patients aged 65 or older-or those under 65 with dysphagia risk factors-admitted to the Department of Pulmonary Medicine were screened using the Four-Question Test (4QT) and a 30 mL water swallow test. Those who screened positive were referred to a full clinical swallow assessment. RESULTS: Of the 945 patients admitted to the Departments of Pulmonary Medicine, 800 met the inclusion criteria, and 679 were screened for dysphagia. Screening was incomplete for 121 patients due to early discharge, time constraints, or limited project awareness during the initial phase. Overall, 160 patients (17%) screened positive for dysphagia risk and were referred for further swallow assessment. Among these, 74 (46%) had previously been diagnosed with dysphagia. Ultimately, 118 patients underwent further assessment, with dysphagia confirmed in 111 (94%). A positive screening test was identified in 21% of patients admitted with pulmonary diseases. In comparison, 32% of patients admitted with other medical conditions, including those with a working or admission diagnosis of cardiovascular disease, non-pulmonary infections, or cancer, screened positive. CONCLUSION: Dysphagia is common yet underdiagnosed in Departments of Pulmonary Medicine, regardless of the admission diagnosis. This study demonstrates that simple bedside screening can effectively identify patients at risk of dysphagia. Systematic screening at admission may enable earlier detection and intervention for dysphagia in a hospital setting.

Biallelic titin truncation variants (TTNtvs) are linked to severe cardiac and skeletal muscle diseases, due to unclear mechanisms. Using induced pluripotent stem cell-derived cardiomyocytes from a biallelic TTNtv patient with dilated cardiomyopathy, we investigated sarcomere structure/function. Only the longest of the TTNtvs was detected as protein, and this nearly full-length titin was incorporated into the sarcomere. Subtle structural alterations occurred, with shortened A-bands observed in a subset of sarcomeres. Resulting reduction and imbalance of force development was linked to lowered contractility, and many sarcomeres being stretched by their neighbors. Thus, inefficient sarcomere assembly and interaction promotes cardiomyopathy in biallelic TTNtv.

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.

We conducted a population-based study examining the associations of diabetes duration and prior cardiovascular disease (CVD) with subsequent cardiovascular events. We demonstrate that diabetes-even if ≥ 10 years in duration-now confers an increased risk of cardiovascular events that is relatively lower than that of prior CVD.

BACKGROUND: Extramammary Paget disease (EMPD) involving the genital and anogenital region is difficult to manage when lesions are extensive, chronic, or located across functionally sensitive sites. In older patients with diabetes, cardiovascular disease, or advanced local involvement, wide excision may lead to considerable perioperative burden, delayed healing, and anatomical impairment. OBJECTIVE: To describe the short-term clinical outcomes and symptom relief associated with aminolevulinic acid photodynamic therapy (ALA-PDT) in older patients with extensive EMPD who were unsuitable for disfiguring surgery or declined surgical treatment. METHODS: We retrospectively reviewed three histologically confirmed EMPD cases affecting the mons pubis, penile root or foreskin, scrotum, inguinal region, and adjacent proximal thigh. All patients received lesion preparation by debridement followed by topical 10% ALA-PDT using a standardized illumination regimen. RESULTS: At the 3-month evaluation, erosive and exudative areas had re-epithelialized, and nodular lesions showed marked reduction or flattening. Pruritus and local pain improved rapidly and had resolved within 2 weeks after treatment initiation. Mild transient erythema was the only treatment-related reaction. No clinically apparent regrowth or progression was observed during the 12-month clinical and dermoscopic follow-up. CONCLUSION: In this small retrospective series, ALA-PDT was associated with short-term clinical control and palliative benefit in older patients with extensive genital EMPD, while preserving genital anatomy without creating large surgical defects. These preliminary findings support further evaluation of optimized PDT-based conservative strategies for difficult-to-treat EMPD.

Diabetic cardiovascular disease remains the leading cause of mortality in patients with diabetes, underscoring the urgent need for effective therapeutic strategies to improve clinical outcomes and prevent major adverse cardiovascular events in this high-risk population. Metformin, a widely prescribed antihyperglycemic agent, not only lowers blood glucose levels but also modulates multiple intracellular signaling pathways, thereby exerting pleiotropic effects. The present study aimed to evaluate the cardioprotective effects of metformin and elucidate its underlying molecular mechanisms in myocardial ischemia-reperfusion injury. Accordingly, we established in vivo diabetic models and in vitro hyperglycemic conditions to assess the effects of metformin on myocardial tissue in diabetes. The results demonstrated that metformin treatment significantly ameliorated cardiac dysfunction and attenuated myocardial morphological abnormalities in diabetic rats subjected to ischemia-reperfusion, and concurrently improved cardiomyocyte viability under hyperglycemic conditions. Moreover, metformin enhanced autophagy, promoted mitophagic activity, and restored mitochondrial homeostasis-effects that were further validated using compound C in cultured cardiomyocytes under hyperglycemic conditions. Collectively, these findings indicate that metformin confers cardioprotection against myocardial ischemia-reperfusion injury (MIRI) through activation of AMP-activated protein kinase (AMPK) and its downstream signaling cascades, thereby regulating mitophagic processes.

Primary graft dysfunction (PGD), the most extensively studied phenotype within the evolving spectrum of early graft dysfunction (EGD), remains the leading cause of early mortality after heart transplantation and continues to limit broader utilization of marginal donor organs. Despite advances in donor preservation strategies and perioperative management, the mechanisms underlying PGD remain incompletely understood. Traditionally, PGD has been conceptualized as a manifestation of ischemia-reperfusion injury (IRI) leading to early graft contractile failure. Accumulating evidence suggests that impaired metabolic recovery may represent one important mechanistic layer of multifactorial PGD, characterized by incomplete restoration of mitochondrial energetics and substrate utilization after IRI. Advances in metabolomics have enabled comprehensive profiling of circulating and perfusate metabolites, providing new insights into myocardial energy metabolism during transplantation and identifying candidate biomarkers of PGD. Notably, recent studies suggest that plasma metabolomic signatures may help identify recipients at increased risk of severe PGD, while metabolomic profiling during ex situ organ perfusion reveals the dynamic changes in myocardial fuel utilization that correlate with markers of graft injury. In parallel, machine perfusion technologies provide a unique platform for dynamic metabolic assessment of donor organs before implantation. Metabolic characterization of PGD may improve donor assessment, preservation strategies, and post-transplant monitoring, although clinical implementation will require prospective validation, standardized workflows, and clinically actionable thresholds. In this review, we summarize emerging evidence linking mitochondrial dysfunction and impaired metabolic recovery to PGD and propose a conceptual framework, informed by transplant metabolomic studies, to support graft assessment, preservation, perfusion, and transplantation.