Search Results (3,731)

Background/Objectives: Cardiovascular disease increases with ageing and remains the leading cause of death worldwide. Cellular senescence contributes to cardiac dysfunction in the older population by secreting the senescence-associated secretory phenotype (SASP). Cardiac injury models induced by surgery have been shown to induce senescence in young adult rodents. However, surgical models are complex and associated with high mortality. Methods: We established a rat model of injury and senescence using isoproterenol (ISO). Male SD rats received ISO (100 mg/kg) for five days, then hearts were collected on days 10 and 28 after the first ISO dose. Results: ISO administration caused cardiac injury, manifested by inflammatory infiltration, fibrosis, and increased cardiomyocyte cross-sectional area. Cardiac injury was accompanied by an increase in the senescence markers SA-β-gal, p16 and p21, and DNA damage marker γH2AX. Moreover, the mRNA levels of p21 increased on day 10, along with several SASP factors, whereas the mRNA levels of p16 increased on day 28. Fibrosis, hypertrophy, and senescence persisted until day 28, indicating long-lasting cardiac remodeling and senescent cell accumulation. Conclusions: These findings suggest that ISO can provide a simple, cost-effective platform for studying senescence and cardiac injury. This model facilitates the study of timing, dosage, mechanisms and efficacy of senolytic interventions and may contribute to the development of senescence-targeted therapies. Full article

Coronary artery vasospasm (CAV) is a transient, reversible constriction of the epicardial coronary arteries that reduces coronary blood flow and may cause myocardial ischemia. Despite its clinical significance, CAV remains underdiagnosed and can present as chest pain, acute coronary syndrome, malignant arrhythmias or sudden cardiac death. Vasospasm may occur in both angiographically normal coronary arteries and at sites of pre-existing atherosclerotic stenosis. The pathophysiology of CAV is multifactorial and involves vascular smooth muscle cells (VSMCs) hyperreactivity, endothelial dysfunction, chronic inflammation and autonomic dysregulation. VSMCs contraction is mediated by phosphorylation of the myosin light chain (MLC) through calcium (Ca²⁺)/calmodulin-dependent myosin light chain kinase (MLCK), while relaxation is regulated by myosin light chain phosphatase (MLCP). Increased intracellular Ca²⁺ levels and enhanced Ca²⁺ sensitivity contribute to excessive vasoconstriction. Rho-kinase (ROCK) plays a pivotal role in sustained vasospasm by inhibiting MLCP, thereby promoting prolonged smooth muscle contraction. Endothelial dysfunction contributes to CAV by disrupting normal vascular tone regulation, largely as a result of decreased nitric oxide (NO) mediated vasodilation. Chronic low-grade inflammation and oxidative stress exacerbate both endothelial dysfunction and VSMCs contraction. Understanding these molecular mechanisms is essential for identifying novel therapeutic targets. Emerging treatment strategies, including ROCK inhibitors, endothelin receptor antagonists and anti-inflammatory agents, may improve outcomes in patients with refractory CAV. Full article

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance. Full article

Exercise is one of the safe and effective methods to improve obesity and its complications, but the mechanism has not been fully elucidated. Sestrin2 (SESN2) is a stress-induced protein that protects cells from stress damage. The role and mechanism of SESN2 in the improvement of obesity-induced cardiac dysfunction by exercise are still unclear. Male C57BL/6J mice were used to prepare a high-fat diet-induced obesity mouse model and conducted aerobic exercise training. After training, echocardiography was used to evaluate the cardiac function of mice, and HE and Masson staining were used to assess the extent of cardiac damage. Cell experiments were conducted using the H9C2 cell line derived from embryonic rat hearts, with the intervention of palmitic acid ester and exogenous SESN2. We detected indicators related to myocardial cell damage, fibrosis, inflammation, and oxidative stress, as well as the activation level of the AMPK-PGC-1α signaling pathway. The results showed that aerobic exercise significantly inhibited myocardial fibrosis, inflammation, oxidative stress, and cell damage in HFD mice, upregulated cardiac SESN2 expression, and activated the AMPK-PGC-1α signaling pathway. Cell experiments have found that exogenous SESN2 pretreatment alleviates palmitate-induced injury, inflammation, and oxidative stress in H9C2 cardiomyocytes, and activates the AMPK-PGC-1α signaling pathway. This indicates that aerobic exercise significantly upregulates the expression of SESN2 and activates the AMPK-PGC-1α signaling pathway, which is potentially involved in alleviating myocardial inflammation, oxidative stress, cardiac fibrosis and cardiac dysfunction in HFD mice. Full article

Cardiovascular disease and cancer remain the leading causes of death worldwide. Although numerous cancer therapies have improved survival rates, they also increase the risk of cardiomyopathy, heart failure, and arrhythmias. These cardiovascular complications can limit treatment options and adversely affect the long-term quality of life of cancer survivors. Ca_V1.3, an L-type calcium channel encoded by CACNA1D, emerges as a central molecular mediator linking cardiovascular disease and cancer. It regulates calcium entry into cardiomyocytes and contributes to sinoatrial pacemaking and atrioventricular conduction. It also contributes to proliferation, migration, and therapy resistance in several cancers. Chemotherapy-induced oxidative stress, inflammatory signaling, hypoxia, and transcriptional changes can modulate the expression, gating, splicing, and trafficking of Ca_V1.3 channels. All these changes destabilize diastolic depolarization and impair conduction, thereby promoting arrhythmias in cancer patients. This review focuses on Ca_V1.3 biology in cardio-oncology, along with the mechanisms of chemotherapy-induced cardiotoxicity. It outlines the role of Ca_V1.3 as a key mediator linking cancer therapies to subsequent nodal dysfunction and increased arrhythmia susceptibility. It also expands on how patient-specific induced pluripotent stem cell-derived cardiomyocytes can model Ca_V1.3 dysregulation as well as support the development of targeted therapies. We propose that Ca_V1.3 represents a mechanistic bridge linking cancer therapy, calcium signaling, and cardiac electrophysiology, and that elucidating its pathophysiology may guide the design of targeted strategies in cardio-oncology. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is strongly associated with atrial structural remodeling driven by activated cardiac fibroblasts. Autophagy has been implicated in AF-related atrial remodeling; however, the non-coding RNA mechanisms that govern autophagic activation in atrial fibroblasts under rapid electrical stress remain poorly understood. Methods: Human cardiac fibroblasts from adult atria (HCF-aa) were subjected to rapid electrical stimulation (RES) at 0.5 V/cm and 10 Hz. Expression levels of exosomal metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), cytoplasmic miR-204-5p, and microtubule-associated protein light chain 3B (LC3B) were measured using quantitative real-time PCR and Western blot analyses. Luciferase reporter assays were performed to confirm direct molecular interactions. The functional roles of MALAT1 siRNA, miR-204-5p mimics/antagomirs, rapamycin, and 3-methyladenine (3-MA) on LC3B expression and autophagic activation were assessed by Western blot and immunofluorescence confocal microscopy for LC3B puncta formation. Results: RES significantly induced exosomal MALAT1 expression in a voltage- and time-dependent manner, peaking at 2 h post-stimulation, while cytoplasmic MALAT1 levels remained unchanged. Cytoplasmic miR-204-5p exhibited an initial transient rise followed by a significant decline at 2 h, inversely correlating with peak MALAT1 levels. LC3B mRNA and protein expression subsequently increased, peaking at 6 and 16 h, respectively. Luciferase reporter assays confirmed that miR-204-5p directly binds both the MALAT1 transcript and the 3′-UTR of LC3B mRNA. MALAT1 knockdown augmented miR-204-5p levels and suppressed LC3B expression, while miR-204-5p overexpression attenuated RES-induced LC3B upregulation and LC3B puncta accumulation. Conversely, miR-204-5p inhibition further enhanced autophagic activation, as evidenced by increased LC3B puncta density. Conclusions: In HCF-aa subjected to RES, MALAT1 functions intracellularly as a competing endogenous RNA to putatively sequester miR-204-5p, thereby de-repressing LC3B expression and promoting autophagic activation. Concurrent exosomal secretion of MALAT1 may additionally serve as a paracrine signal to neighboring cells, though this requires future conditioned-media transfer experiments to confirm. Full article

Background/Objectives: Only substantial quantities of xeno-free human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) (hiPSC-CMs) with stable quality and structural and functional maturity can meet the demand for cardiac cell therapy. The use of xeno-free microcarriers can significantly increase cell yield. Co-culturing with hematopoietic stem cells (HSCs) simulates the environment in vivo and has a necessary impact on the development of CMs. However, no microcarrier-based protocol for xeno-free hiPSC-CM culture has yet been established, and the effects of HSCs on CM development and their underlying mechanisms remain unclear. Therefore, this study aims to investigate these issues. Methods: We used a xeno-free microcarrier (plastic) culture system coated by a defined xeno-free matrix (MatriClone) to expand hiPSCs and hiPSC-CMs with human hematopoietic stem cells (hHSCs). Using RNA sequencing (RNA-seq), cytokine assay, and various cellular molecular techniques, we investigated the role of hHSCs in cardiac differentiation and maturation, and underlying mechanisms. Results: hiPSCs were evenly distributed on the surface of plastic coated with 1 μg/cm² MatriClone (MatriClone-Plastic), increasing and sustaining pluripotency marker levels. Directed differentiation of hiPSCs on 1 μg/cm² MatriClone-Plastic induced a larger number of CMs, and the level of cardiac differentiation was also significantly improved. When hHSCs were co-cultured with cells at the cardiac progenitor cell stage, results from electron microscopy, electrophysiology, and qPCR showed that hiPSC-CMs significantly promoted cardiac structural and functional maturation. The co-cultured hHSCs released multiple cytokines that were changed dynamically at different time points, and that were highly likely to activate the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway to promote cardiac development and maturation. Conclusions: hHSCs can efficiently promote differentiation and maturation of xeno-free hiPSC-CMs on MatriClone-Plastic via the EGFR/MAPK/ERK signaling pathway. Full article

Background/Objectives: Myocardial microcirculatory dysfunction is a critical pathological feature of cardiovascular diseases, closely associated with inflammation, oxidative stress, and excessive neutrophil activation. Neutrophil extracellular traps (NETs) serve as crucial mediators of myocardial microvascular inflammatory injury. Dalbergia odorifera volatile oil (DOVO) demonstrates anti-inflammatory and antioxidant properties; however, its protective role against myocardial microcirculatory damage and its regulatory effect on NET formation remain inadequately characterized. This study investigates the protective effects of DOVO on myocardial microcirculatory disturbances and elucidates the underlying mechanisms related to NETs. Methods: A rat model of myocardial microcirculatory dysfunction was established through polyethylene microsphere injection, and an in vitro neutrophil inflammation model was generated using differentiated HL-60 cells. DOVO was administered at various doses both in vivo and in vitro, and hemodynamics, inflammatory cytokines, oxidative stress, and NET-related markers, including MPO and CitH3, were analyzed. Results: DOVO dose-dependently ameliorated microcirculatory impairment, hemodynamic disorders, inflammation, and oxidative stress in rats, significantly suppressing NET formation. In differentiated HL-60 cells, DOVO similarly reduced inflammatory gene expression and inhibited LPS-induced NETs production by downregulating MPO and CitH3. Conclusions: DOVO suggests a protective effect against myocardial microcirculatory injury by inhibiting oxidative stress, inflammatory responses, and subsequent NET formation. These findings elucidate a novel mechanism by which DOVO alleviates microcirculation-related cardiac damage and provide a theoretical basis for its application in cardiovascular injury. Full article

Type 2 diabetes mellitus (T2DM) is a major driver of chronic kidney disease and cardiovascular morbidity worldwide. Extracellular vesicles (EVs), particularly exosomes, carry microRNAs (miRNAs) that reflect the pathophysiological state of their parent cells and represent promising non-invasive biomarkers. This review comprehensively examines the diagnostic and mechanistic roles of EV-derived miRNAs in diabetic nephropathy (DN) and cardiovascular diseases (CVDs) associated with T2DM. A PRISMA-guided literature search of PubMed, Scopus, Web of Science, and Embase identified 847 articles published between January 2020 and June 2026, of which 156 studies met the inclusion criteria. Several urinary exosomal miRNAs demonstrated significant diagnostic performance for DN, including miR-4534 (AUC = 0.786), miR-136-5p (sensitivity 72.2%, specificity 78.4%), and miR-142-3p. A meta-analysis of circulating miRNAs in diabetic kidney disease reported a pooled AUC of 0.79. In the cardiovascular setting, exosomal miR-155-5p (AUC = 0.901), miR-15a-3p (AUC = 0.874), and a four-miRNA panel (miR-433-3p/let-7b/miR-30-5p/miR-122-5p; AUC = 0.833) demonstrated strong diagnostic performance for ischemic heart disease and carotid atherosclerosis in T2DM. Mechanistically, key EV-associated miRNAs, including miR-21, miR-192, and the anti-fibrotic miR-29 family, participate in fibrosis, inflammation, oxidative stress, endothelial dysfunction, and cardiac remodeling pathways. EV-derived miRNAs therefore represent highly promising non-invasive biomarkers for the early diagnosis and monitoring of diabetic renal and cardiovascular complications. However, clinical translation requires standardized EV isolation and miRNA detection protocols, together with validation in large multicenter prospective cohorts. This review highlights the considerable diagnostic and translational potential of EV-derived miRNAs for precision medicine and liquid biopsy applications in T2DM complications. Full article

Autoimmune myocarditis frequently progresses to inflammatory cardiomyopathy through dysregulated immune–stromal interactions. This study employs single-nuclei RNA-sequencing (snRNA-seq) to profile 46,233 cardiac nuclei from the experimental autoimmune myocarditis (EAM) mouse model at four timepoints: day 0 (healthy), day 14 (inflammation), day 21 (acute inflammation), and day 40 (late cardiac remodelling). Single-nuclei RNA profiling identified 18 transcriptionally distinct cell populations. Global cell–cell communication analysis revealed a dramatic peak of intercellular signalling at day 14 (5907 interactions), with fibroblast subpopulations and macrophages as dominant hubs, followed by partial resolution at day 21 (2264 interactions) and renewed remodelling at day 40 (4862 interactions). Subclustering of the macrophage compartment identified five subpopulations: Mac-TLF, Mac-MHCII, Mac-rMHCII, Mac-ResL, and Classical Monocytes. Tissue-resident macrophages (Mac-TLF, CCR2-) dominated at healthy state (~55%) but were rapidly depleted at day 14, coinciding with a dramatic influx of recruited CCR2⁺ macrophages (Mac-rMHCII), which expanded to over 70% of the compartment and maintained dominance through day 40. At inflammation (day 14), the expanded Mac-rMHCII subpopulation displayed a strongly pro-inflammatory signature (Il1b, Stat2, Parp14, Apoe), and the overall macrophage compartment was enriched for cytokine response, Fc-gamma receptor, and Notch signalling pathways, while downregulating homeostatic and mitochondrial metabolic programmes, potentially contributing to impaired efferocytosis and cardiomyocyte dysfunction. Macrophage-centred communication networks expanded markedly at day 14 (1047 interactions), with resting fibroblasts (FB-R) as the primary signalling partner, driving pro-inflammatory stromal activation marked by upregulation of Ccl2, Ccl7, and Csf2. Intra-macrophage subcluster communication also intensified at this timepoint (447 interactions). These findings delineate the temporal and functional heterogeneity of cardiac macrophages during EAM progression and identify key immune–stromal interactions driving pathological cardiac remodelling. The coexistence of pro-inflammatory and transitional reparative macrophage subsets highlights the limitations of broad immunosuppression and supports precision strategies targeting CCR2-mediated recruitment, the SPP1 signalling axis, and macrophage–fibroblast crosstalk as therapeutic avenues in myocarditis and its progression. Full article

Circular RNAs have emerged as important regulators of gene expression in cardiovascular disease, expanding the current understanding of the molecular mechanisms that underlie cardiac remodeling and dysfunction. Initially regarded as byproducts of aberrant splicing, circRNAs are now recognized as stable, abundant, and functionally versatile molecules with marked tissue specificity and diverse modes of action. In the cardiovascular system, circRNAs are generated through tightly regulated back-splicing mechanisms and act through multiple molecular pathways, including microRNA sequestration, protein scaffolding, modulation of transcription and splicing, regulation of mitochondrial and metabolic homeostasis, and in some cases, peptide translation. These properties position circRNAs as regulatory hubs that connect molecular interactions to functional cellular outcomes. Across a broad range of cardiovascular conditions, including heart failure, myocardial ischemia, fibrosis, arrhythmias, cardiotoxicity, and cardiorenal syndrome, circRNAs have been implicated in processes such as hypertrophy, inflammation, cell death, extracellular matrix remodeling, and regenerative responses. Beyond their mechanistic relevance, circRNAs also hold preclinical relevance as circulating biomarkers and therapeutic targets owing to their stability in biofluids and their capacity to modulate disease-relevant networks. Nevertheless, major challenges remain, including incomplete functional validation, methodological heterogeneity, annotation inconsistencies, and barriers to clinical translation. In this review, we synthesize the current knowledge on circRNA biogenesis, molecular function, disease-specific roles, biomarker potential, and therapeutic applications and discuss the conceptual and technical advances required to move the field from descriptive association toward mechanistic and clinical impact. Full article

Erdheim–Chester Disease (ECD) constitutes a rare and clinically heterogeneous non-Langerhans cell histiocytosis, characterized by the systemic infiltration of tissues by foamy, lipid-laden histiocytes. These cells typically exhibit an immunophenotypic profile positive for CD68 and negative for CD1a. The disease’s multifaceted presentation, which can span from isolated bone lesions to fulminant multi-organ failure, frequently results in considerable diagnostic delay. In this case-based review, we describe the case of a 58-year-old who presented with a primary complaint of exertional dyspnoea and fatigue. The initial diagnostic evaluation revealed a hemodynamically significant circumferential pericardial effusion and imaging findings suggestive of aortitis. Clinical presentation of ECD depends on the organs and tissues involved, and may range from bone pain to neurological symptoms, endocrine dysfunction, and cardiac involvement. Cardiovascular involvement occurs in at least 40% of ECD patients, although it is frequently underdiagnosed. Cardiac ECD is heterogeneous and may mimic many alternative aetiologies. The infiltration of the right atrioventricular sulcus, right atrial walls, or interatrial septum is one of the most typical cardiac manifestations of ECD. Recognition of pseudo-tumour intra-atrial mass, pericardial involvement, as well as the circumferential encasement of the entire aorta, the so-called coated aorta, are other frequent findings. Diagnosis often requires a multimodal approach, in particular when cardiac symptoms represent the onset of clinical manifestation of ECD. The combined use of computed tomography, fluorodeoxyglucose positron emission tomography, dedicated cardiac and abdominal magnetic resonance imaging, and X-ray of long bones can collectively reveal a constellation of findings diagnostic of ECD. Full article

Growth differentiation factor 15 (GDF15) levels are associated with increased mortality and rehospitalisation in heart failure (HF) patients. Whether GDF15 is causally involved in the pathobiology of HF remains largely unknown. Using the transverse aortic constriction (TAC) mouse model, we investigated the role of GDF15 in pressure overload-induced HF. Following TAC, circulating GDF15 levels increased significantly. Compared to wild type (WT) littermates, genetically deficient Gdf15^-/- mice developed more pronounced adverse cardiac remodelling one week after TAC, characterised by increased cardiac volumes and impaired myocardial global deformation. This further aggravated into severe HF in Gdf15^-/- mice over 42 days follow-up. Cardiac remodelling in Gdf15^-/- was accompanied by enhanced perivascular fibrosis and increased co-localization of fibroblast- and endothelial-specific markers in the cardiac endothelium of Gdf15^-/- mice, suggestive of endothelial plasticity and Endothelial-to-Mesenchymal transition (EndMT)-like changes. To further explore potential endothelial mechanisms underlying these observations, we performed complementary in vitro experiments in GDF15 knockdown endothelial cells. GDF15 deficiency impaired barrier function and enhanced Activin A-induced mesenchymal marker expression, consistent with increased endothelial phenotypic modulation. Together, these findings demonstrate that the loss of GDF15 aggravates pressure overload-induced heart failure, hallmarked by perivascular fibrosis and signs of endothelial dysfunction. Our data further support a potential protective role for GDF15 in maintaining endothelial integrity during cardiac stress. Full article

Background: Postoperative hyperbilirubinemia is a serious complication after cardiac surgery and has been associated with increased perioperative morbidity and mortality. However, data specifically addressing patients undergoing redo valve surgery remain limited. This study aimed to determine the incidence and risk factors of postoperative hyperbilirubinemia after redo valve surgery, and evaluate its association with early postoperative outcomes. Methods: We retrospectively reviewed 259 adult patients who underwent elective redo valve surgery under cardiopulmonary bypass (CPB) between March 2018 and July 2024. Postoperative hyperbilirubinemia was defined as a serum total bilirubin level > 3 mg/dL at any time after surgery. Patients were divided into a hyperbilirubinemia group and a non-hyperbilirubinemia group. Perioperative variables were compared between groups. Univariable and multivariable logistic regression analyses were performed to identify risk factors for postoperative hyperbilirubinemia. Postoperative complications and in-hospital mortality were also compared. Results: Postoperative hyperbilirubinemia occurred in 101 of 259 patients (39.0%). Compared with patients without hyperbilirubinemia, those with hyperbilirubinemia had longer mechanical ventilation and intensive care unit stay, and higher rates of pneumonia, reintubation, tracheostomy, continuous renal replacement therapy, and in-hospital mortality. Univariable logistic regression showed that higher EuroSCORE II, higher preoperative total bilirubin and direct bilirubin levels, lower hemoglobin and platelet count, pulmonary hypertension, anemia, longer operative time, CPB duration, and aortic cross-clamp time, lower nasopharyngeal temperature, greater intraoperative blood loss, larger red blood cell and plasma transfusion volumes, and concomitant surgery on all three valves were associated with postoperative hyperbilirubinemia. Multivariable analysis identified elevated preoperative direct bilirubin, prolonged CPB duration, and more plasma transfusion as independent risk factors. Receiver operating characteristic analysis showed that peak postoperative total bilirubin had moderate prognostic discrimination for in-hospital mortality, with an optimal cut-off value of 3.95 mg/dL (AUC 0.756, sensitivity 66.7%, specificity 80.2%, p = 0.003). Conclusions: Postoperative hyperbilirubinemia is common after redo valve surgery and is associated with worse early postoperative outcomes and higher in-hospital mortality. In this setting, postoperative bilirubin elevation should be interpreted primarily as a prognostic marker of perioperative stress and hepatic vulnerability rather than a direct causal driver of adverse outcomes. Elevated preoperative direct bilirubin, prolonged CPB duration, and greater plasma transfusion were independently associated with the development of postoperative hyperbilirubinemia in this high-risk population. Full article