GDF-15 Levels Research Articles

ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer

ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer

Older patients affected by COVID-19: investigating the existence of biological phenotypes

IntroductionCOVID-19 provides an opportunity to examine biological phenotypes (observable morphological, functional and biological characteristics) in individuals who experience the same acute condition, potentially revealing differences in response to acute external stressors. The aim our study was to investigate biological phenotypes in older patients hospitalized for COVID-19, exploiting a panel of aging biomarkers.MethodsData were gathered from the FRACOVID Project, an observational multicenter study, aimed to evaluate the impact of frailty on health-related outcomes in patients 60 + with COVID-19 in Northern Italy. A hierarchical cluster analysis was run using log-transformed and scaled values of TNF-a, IL-1 beta, IL-6, PAI-1, GDF-15, NT-proBNP, and Cystatin C evaluated at admission.ResultsEighty-one participants (mean age 75.3 years; 60.5% male) were evaluated. Frailty was identified in 42% of the sample and 27.2% were unable to ambulate outdoors. The mean hospital stay was 24.7 days, with an in-hospital mortality rate of 18.5%. Three biological phenotypes were found: (1) ‘inflammatory’, with high inflammatory biomarkers; (2) ‘organ dysfunction’, characterized by elevated cystatin C and NT-proBNP, and lower inflammatory markers; and (3) ‘unspecific’, with lower NT-proBNP and GDF-15 levels, and intermediate concentrations of other biomarkers. The ’organ dysfunction’ phenotype showed the highest mean age and prevalence of frailty, disability, and chronic diseases. The ‘inflammatory‘ phenotype showed the highest burden of respiratory and systemic signs and symptoms of infection.ConclusionBiological phenotypes might be used to identify different clinical and functional phenotypes in individuals affected by COVID-19.

Elevated GDF-15 is associated with stroke severity, myocardial injury and poor clinical outcome in patients after acute ischemic stroke

Abstract Background GDF-15 is emerging as a biomarker of cardiometabolic risk and disease burden. Increased concentrations of circulating GDF-15 are associated with increased mortality in patients with acute coronary syndromes or heart failure. Purpose We aimed to describe relation between GDF-15 elevation with stroke severity, myocardial injury and poor clinical outcome in patients after acute ischemic stroke (AIS). Methods Patients after AIS were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 and 48 hours later to determine the plasma levels of GDF-15 and high-sensitive troponin I (hs-cTnI). Receiver-operating characteristic (ROC) curve analysis was used to determine the diagnostic accuracy and optimal elevation cut-off values of GDF-15 on day 1 for the severity of acute stroke defined by NIHSS score. The optimal cut off in our group was 1776 pg/ml (Sensitivity 0,8, Specificity 0,52). Myocardial injury was defined by fourth universal definition of myocardial infarction using hs-cTnI. Demographic characteristics, clinical data, functional outcome, and all-cause mortality at 1 year were compared between groups according to GDF-15 levels. National Institutes of Health Stroke Scale (NIHSS) at the time of admission and the modified Rankin Scale (mRS) 90 days following the patient’s discharge from the hospital were used to assess stroke severity and clinical outcome. All analyses were performed with SPSS 29.0 (SPSS Inc). Results Between August 2020 and August 2022, 177 patients after AIS were enrolled. Elevated GDF-15 was observed in 71 patients (40,1%). Most common comorbidities included arterial hypertension, dyslipidemia, type 2 DM and atrial fibrillation. In analysis, we observed a connection between elevated GDF-15 with unfavourable outcome evaluated by mRS at 90 days (HR 2.57, 95% CI 1,44 to 4,57, p=0.001) and with all-cause death at 1 year (HR 4.479, 95% CI 1,81 to 11,09, p=0.001). GDF-15 elevation was associated with myocardial injury (Figure 1C). Moreover, individuals with moderate to severe and severe strokes (NIHSS 16-42) displayed higher GDF-15 levels compared to those with minor to moderate stroke (Figure 1D). The Kaplan-Meier survival curve accentuated a significantly elevated all-cause mortality among patients with increased GDF-15 (p < 0.001) (Figure 2). In multivariate regression analysis elevated GDF-15 was associated with atrial fibrillation and high-sensitive troponin I elevation. Conclusion The conclusions drawn suggest that heightened GDF-15 is associated with increased stroke severity, myocardial injury and unfavourable outcome.

Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on mitochondrial-derived peptide-c and on markers of neurohumoral activation

Abstract Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular disease. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on mitochondrial-derived peptide-c (MOTS-c), N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, oxidant and antioxidant biomarkers and cardiovascular function of T2DM patients. Methods A total of 160 T2DM patients were randomized to insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40) or their combination (GLP-1RA+SGLT-2i) (n = 40) as add-on to metformin. We measured at baseline, at 4 and at 12 months of treatment: a) plasma levels of MOTS-c, NT-proBNP and GDF-15, b) thiobarbituric acid reactive substances (TBARS), as an oxidant biomarkers, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), as an antioxidant biomarker, and c) global left ventricular longitudinal strain (GLS) and global work index (GWI) using speckle-tracking imaging. Results Twelve months after treatment, treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c (14.89 ± 11.27 vs. 7.26 ± 4.21 ng/mL, p=0.009, 6.49 ± 3.91 vs. 5.6 ± 3.38 ng/mL, p=0.029, respectively), while treatment with insulin and GLP-1RA had a neutral effect on this biomarker (p > 0.05; Table). GLP-1RA, SGLT-2i and their combination showed a greater reduction of NT-proBNP (-43.1% vs. -54.2% vs. -56.9% vs. -14.7%; Figure) and GDF-15 (-14.8% vs. -15.2% vs. -16.1% vs. -0.9%) than insulin (p < 0.05 for all comparisons), despite the fact that all patient achieved adequate glycemic control. GLP-1RA or GLP-1RA+SGLT-2i provided a remarkable reduction of TBARS and increase of GLS and GWI compared to insulin or SGLT-2i (p < 0.05). In all patients, at 4 and at 12 months, the percentage reduction of NT-proBNP was associated with the improvement of TBARS, GLS and GWI (p < 0.05). The percentage reduction of GDF-15 was correlated with the increase of ABTS and with the improvement of GLS at 4 and 12 months (p < 0.05). In SGLT-2i group, the percentage increase of MOTS-c was related with the percentage reduction of GDF-15 (r = 0.81, p = 0.005) at 12 months. Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cardiac biomarkers in parallel with a greater decrease of oxidative stress than insulin in T2DM. SGLT-2i appears more effective in the improvement of MOTS-c and markers of neurohumoral activation.TableFigure

Integrating aging biomarkers and immune function to predict kidney health: insights from the future of families and child wellbeing study.

Biomarkers of biological aging predict health outcomes more accurately than chronological age. This study examines the relationship between aging biomarkers, immune function, and kidney health using the Future of Families and Child Wellbeing Study Biomarker Dataset. Using Wave 5 (year 9) and Wave 6 (year 15), we examined biomarker data from a total of 4898 individuals. The panel of aging biomarkers, comprised of epigenetic clocks (GrimAge, Horvath), immune function markers (CD8 + T cells, plasmablasts), and metabolic indicators (GDF-15, leptin), was evaluated in depth. We used principal component analysis (PCA) and K-means clustering for subtype identification. A random forest regressor was employed to predict kidney function using Cystatin C levels, and the importance of features was assessed. Three clusters with unique biological age and immune function profiles were identified. Cluster 1 had younger biological age markers. In Cluster 2, both GrimAge and GDF-15 levels were significantly increased, indicating an elevated risk for age-related diseases. According to predictive modeling, GrimAge, Pack Years, and immune function markers had the strongest influence on Cystatin C levels (R2 = 0.856). The incorporation of immune aging markers enhanced the predictive power, emphasizing the importance of immunosenescence in renal health. Aging biomarkers and immune function significantly impact kidney health prediction. The study results call for the utilization of extensive biomarker tests for individualized elderly care and early recognition of kidney deterioration. Clinical practice can be improved by incorporating biological age assessments for the prevention and management of age-related diseases.

Elevated plasma level of arginine and its metabolites at labor among women with preeclampsia: A prospective cohort study.

Preeclampsia complicates 3-5% of all pregnancies and is associated with higher levels of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines. Dimethylarginines are inhibitors of nitric oxide, which is a uterine smooth muscles relaxant. Women with hypertensive disorders experience a shorter labor duration compared to normotensive women. However, very little is known about the possible biochemical mechanisms behind differences in labor duration. In this study we aimed to investigate if women with preeclampsia had higher levels of arginines (ADMA, SDMA and L-arginine) at labor than controls, and also investigate the association between arginines and labor duration. The study was based on data from the Swedish, Uppsala County population-based, prospective cohort BASIC, between 2009 and 2018. Arginines were analyzed by Ultra-High Performance Liquid Chromatography using plasma samples taken at labor from women with preeclampsia (n=47) and normotensive pregnancy (n=90). We also analyzed inflammation markers CRP, TNF-R1, TNF-R2 and GDF-15. Women with preeclampsia had higher levels of ADMA (p<0.001), SDMA (p<0.001), L-arginine (p<0.001), TNF-R1 (p<0.001), TNF-R2 (p=0.03) and GDF-15 (p<0.01) compared to controls. Further, ADMA and SDMA, not inflammation markers, were negatively correlated to labor duration in preeclampsia. No correlations were observed when comparing arginines and inflammation markers. Among women with preeclampsia, our novel findings of higher level of arigines, negative correlation of arginines to duration of labor and absence of correlation of arginines to inflammation markers might support the theory that it is not inflammation but arginines which could be associated with shorter duration of labor in preeclampsia.

Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction

GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.

Growth Differentiation Factor 15 during pregnancy and postpartum as captured in blood, cerebrospinal fluid and placenta: A cohort study on associations with maternal mental health

IntroductionGrowth Differentiation Factor 15 (GDF15) increases substantially during pregnancy and is primarily produced by the placenta. Elevated levels of GDF15 have been associated with mental health problems in non-perinatal populations, higher corticosterone levels, and decreased estrogen receptor activity. However, the role of GDF15 in mental health during the perinatal transition remains unknown. This longitudinal study is the first to evaluate pregnancy levels of GDF15 in cerebrospinal fluid (cGDF15), plasma (pGDF15) and placenta GDF15 mRNA, along with mapping plasma GDF15 (pGDF15) level changes from late pregnancy to early postpartum. Moreover, we aimed to evaluate the association between pregnancy cGDF15 levels and cortisol early postpartum, evaluate the association between pregnancy cGDF15 levels and mental health in pregnancy and postpartum, and evaluate the association between pGDF15 and estrogens and high-sensitivity C-reactive protein (CRP). MethodsWe included data from 95 women scheduled for a planned cesarean section and obtained cerebrospinal fluid (CSF) and plasma levels of GDF15. We quantified GDF15 mRNA levels in placenta biopsies. Estrogens, high-sensitivity CRP, and mental health measures were further collected on the day or one day before the cesarean section. At five weeks postpartum, mental health measures and saliva samples for cortisol analyses were collected. Correlation analyses for GDF15 in CSF, plasma, and placenta mRNA were performed, along with association analyses for pregnancy cGDF15, Cortisol Awakening Response, and mental health outcomes. ResultsWe demonstrated a strong correlation between cGDF15 and pGDF15 (r=0.52; p<0.001) and found that both cGDF15 and pGDF15 correlated with placenta GDF15 mRNA*placental weight (r=0.62, p<0.001 and r=0.44, p=0.008, respectively). During late pregnancy, both estradiol (E2) and estriol (E3) were significantly associated with pGDF15 levels (E2: p=0.002; E3: p(corrected)<0.001). Finally, we found that cGDF15 levels were not associated with self-reported mental well-being or the Cortisol Awakening Response or absolute cortisol at awakening postpartum. ConclusionThis novel study points to the unique hormonal landscape during the perinatal transition and the specific role of GDF15 in pregnancy, which appears uncoupled with perinatal mental health and cortisol outcomes. Our data also strongly imply that the overall amount of circulating GDF15 in late pregnancy is closely related to placenta size.

8073 Association Between Serum GDF15 Level And Metabolic Parameters in Severely Obese Men Undergoing Weight Loss From Lifestyle Intervention

Abstract Disclosure: S. Bathina: None. V. Fuenmayor Lopez: None. M. Prado: None. G. Colleluori: None. D.T. Villareal: None. R.C. Villareal: None. Background: Growth Differentiation factor (GDF-15), member of TGF-β superfamily was identified as marker of aging, frailty, and metabolic disorders. Several clinical studies demonstrated an association between GDF15 with obesity and cardiovascular disease. However, information on the changes in GDF15 and its relationship to changes in metabolic and body composition parameters in the population of severely obese subjects undergoing weight loss (WL) remains lacking. Objective: The objective of this study is to evaluate the influence of WL on serum GDF15 level and its relationship to glucometabolic parameters in severely obese hypogonadal men. Method: Data from 116 severely obese (BMI ≥35 kg/m2) hypogonadal men participating in an ongoing clinical trial of WL from lifestyle intervention±anastrozole, aged 35-65 years old (NCT03490513) were analyzed. Hemoglobin A1C (A1C) was measured by HPLC, lipid profile by colorimetric method (except LDL was calculated), testosterone (T) and estradiol (E2) LC-MS and GDF-15 by ELISA. Body composition was measured by DXA. Results: The mean age of the participants was 51.4±7.6 years with mean BMI 41.8 ±5.4 kg/m2. At baseline, serum GDF15 positively correlated with age (r=0.25, p=0.01), fasting blood glucose (r=0.29, p=0.004) and A1C (r=0.39, p&amp;lt;0.001) but no correlation was found for lipid parameters and with T and E2. GDF15 was negatively correlated with total lean mass (r= -0.23, p=0.03), appendicular lean mass (r= -0.30, p=0.02), and fat-free mass (r= -0.22, p=0.03), but positively correlated with visceral adipose tissue volume (r=0.22, p=0.03). Average WL was 4.2±4.7% and 5.8±8.5% at 6months (6M) and 12 months (12M), respectively. Overall GDF15 levels increased by 9.4±84.7% at 6M and 18.4±128.0% at 12M. At 12M, changes in GDF15 levels positively correlated with changes in A1C (r= 0.26, p&amp;lt;0.05), and negatively with changes in total cholesterol ( r= -0.30, p=0.05), Triglycerides (r= -0.35, p=0.02) and E2 (r=-0.31, p=0.028). For LDL cholesterol changes, a negative correlation with GDF15 changes was observed at 6M (r= -0.27, p=0.047). There was no correlation between changes in GDF15 with changes in body weight and changes in body composition parameters. A comparison for those with significant WL (≥5%) vs. those with less WL showed that at 6M, GFD15 levels were reduced among those with WL of ≥5% (-19.5±42.3%) vs &amp;lt;5% (+19.8±93.9%), p=0.07, and at 12M (≥5% (-29.5±38.7) vs &amp;lt;5% (+0.61±69%), p&amp;lt;0.1). Conclusion: We demonstrated that changes in serum GDF15 in severely obese men undergoing WL was associated with alteration in cardiometabolic parameters. Our results show a new perspective on the potential role of GDF15 in cardiometabolic disorders associated with severe obesity. Aside from GDF15 used as a biomarker for health, it may also be used as target for drug development in modifying potential cardiometabolic complications in severe obesity. Presentation: 6/1/2024

CD151 identifies an NK cell subset that is enriched in COVID-19 patients and correlates with disease severity

Severe coronavirus disease 2019 (COVID-19) often leads to acute respiratory distress syndrome and multi-organ dysfunction, driven by a dysregulated immune response, including a cytokine storm with elevated proinflammatory cytokine levels. Natural killer (NK) cells are part of the innate immune system with a fundamental role in the defense against viral infections. However, during COVID-19 acute infection, they exhibit an altered phenotype and impaired functionality contributing to the immunopathogenesis of the disease. In this work, we have studied a cohort of patients with COVID-19 (ranging from mild to severe) by analyzing IL-15, TGF-β, PlGF and GDF-15 plasma levels and performing multiparametric flow cytometry studies. Our results revealed that severe COVID-19 patients exhibited high levels of IL-15, PlGF and GDF-15, along with an enrichment of anNK cell subset expressing the CD151 tetraspanin, which correlated with IL-15 plasma levels and disease severity. In patients, these CD151+ NK cells displayed a more activated phenotype characterized by an increased expression of HLA-DR, CD38 and granzyme B, a distinct receptor repertoire, with lower levels of CD160 and CD31 and higher levels of CD55 and, remarkably, a higher expression of tissue-resident markers CD103 and the NK cell decidual marker CD9. Last of all, in individuals with severe disease, we identified an expansion of a CD151brightCD9+ NK cell subset, suggesting that these cells play a specific role in COVID-19. Altogether, our findings suggest that CD151+ NK cells may have a relevant role in COVID-19 immunopathogenesis.

Ferroptosis related CPT1A and GDF15 gene polymorphisms are risk factors for lung adenocarcinoma: A case-control study

BackgroundFerroptosis is not only a consequence of inflammation, but also a dynamic process. Recent bioinformatics analysis suggests that ferroptosis related genes might be associated with lung adenocarcinoma (LUAD). CPT1A and GDF15 are critical for the process of ferroptosis and development of inflammation; however, little study focused on the mutation level of these genes in patients with LUAD. MethodsThe candidate SNPs in CPT1A and GDF15 were genotyped in 320 pairs of LUAD patients and controls using Mass ARRAY platform. Moreover, the different expression of CPT1A and GDF15 in LUAD cases and healthy controls were validated by qRT-PCR and ELISA. ResultsThe rs80356779 G > A, rs3019594 C > T, rs888663 T > G and rs4808793 G > C all exhibited an increased risk of the disease (p < 0.05). Moreover, the rs80356779-GA, rs3019594-TT, rs888663-TG and rs4808793-CC genotypes were all related to different levels of increase in LUAD risk (p < 0.05). Genetic model results showed that rs80356779 G > A, rs888663 T > G and rs4808793 G > C were associated with LUAD susceptibility under dominant and additive models (p < 0.05), while rs3019594 C > T was correlated with an elevated risk of the disease in all three models (p < 0.05). Additionally, patients with rs80356779 G > A and rs3019594 C > T exhibited lower expression and serum concentration of CPT1A compared with wile types, and patients with rs888663 T > G and rs4808793 G > C exhibited higher serum and expression level of GDF15. ConclusionThe results provided new clues for the role of ferroptosis in LUAD and new potential targets for screening of susceptible population.

Elevated cerebrospinal fluid neuronal injury biomarkers within 24 hours of onset in infection-triggered acute encephalopathy compared to complex febrile seizures

ObjectiveThis study aimed to measure and compare cerebrospinal fluid neuronal injury biomarkers in the acute phase of complex febrile seizure (CFS) and infection-triggered acute encephalopathy (AE). Furthermore, we determined the pathogenesis of AE with biphasic seizures and late reduced diffusion (AESD). MethodsPediatric patients with febrile status epilepticus who visited Hyogo Prefectural Kobe Children's Hospital from November 1, 2016, to December 31, 2022, and whose cerebrospinal fluid samples were collected within 24 h of neurological symptom onset were included. Patients were classified as having CFS or infection-triggered AE according to their definitions. Patients with AE were further categorized into AESD or unclassified AE. Cerebrospinal fluid biomarkers (neuron-specific enolase, growth differentiation factor 15 [GDF-15], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein, and tau protein were measured and compared among the groups. ResultsTotal of 63 patients (45 with CFS and 18 with AE) were included. Among the AE patients, nine were classified as having AESD and nine as having unclassified AE. S100B levels were significantly higher in patients with AESD than in patients with CFS (485 pg/ml vs. 175.3 pg/ml) and were even higher in patients with AESD and neurological sequelae (702.4 pg/ml). GDF-15 levels were significantly elevated in patients with AE compared to patients with CFS (85.8 pg/ml vs. 23.6 pg/ml). ConclusionsThe elevation of S100B suggests that activated astrocytes may be closely associated with the early pathology of AESD. Elevated GDF-15 levels in infection-triggered AE suggest the activation of defense mechanisms caused by stronger neurological injury.

Prognostic Value of Circulating Fibrosis Biomarkers in Dilated Cardiomyopathy (DCM): Insights into Clinical Outcomes.

Dilated cardiomyopathy (DCM) involves myocardial remodeling, characterized by significant fibrosis and extracellular matrix expansion. These changes impair heart function, increasing the risk of heart failure and sudden cardiac death. This study investigates the prognostic value of circulating fibrosis biomarkers as a less invasive method in DCM patients. Plasma samples from 185 patients with confirmed DCM were analyzed to measure 13 circulating biomarkers using Luminex bead-based multiplex assays and ELISA. The prognostic value of these biomarkers was evaluated concerning heart failure-associated events and all-cause mortality. Elevated MMP-2 levels (>1519.3 ng/mL) were linked to older age, higher diabetes prevalence, lower HDL, increased NT-proBNP and hs-TnT levels, and severe systolic dysfunction. High TIMP-1 levels (>124.9 ng/mL) correlated with elevated NT-proBNP, more atrial fibrillation, reduced exercise capacity, and larger right ventricles. Increased GDF-15 levels (>1213.9 ng/mL) were associated with older age, systemic inflammation, renal impairment, and poor exercise performance. Elevated OPN levels (>81.7 ng/mL) were linked to higher serum creatinine and NT-proBNP levels. Over a median follow-up of 32.4 months, higher levels of these biomarkers predicted worse outcomes, including increased risks of heart failure-related events and mortality. Circulating fibrosis biomarkers, particularly MMP-2, TIMP-1, GDF-15, and OPN, are valuable prognostic tools in DCM. They reflect the severity of myocardial remodeling and systemic disease burden, aiding in risk stratification and therapeutic intervention. Integrating these biomarkers into clinical practice could improve DCM management and patient prognosis.

Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study.

Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable. To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients. In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed. Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning+1 point for male sex, smoking, and age of ≥60 years and+2 points for atherosclerotic disease, yielding a bootstrapped C-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a C-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death. Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this first-of-its-kind risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.

Abstract P194: Metabolic effects of GDF15 and Activin A on trophoblasts

Preeclampsia (PE), a pregnancy-related complication, is a major cause of maternal and fetal morbidity and mortality. The pathophysiology is not fully elucidated. Activin A and GDF15 are part of the TGFβ superfamily and markers for trophoblast differentiation. Both are senescence associated secretory phenotype (SASP) factors that have been associated with cardiovascular disease. Mitochondrial dysfunction is associated with SASP and both have been described in PE. Serum levels of GDF15 and Activin A, were elevated in the maternal blood prior to the onset of PE and found to be elevated in placental tissue of women with PE. BeWo cells were metabolically reprogrammed to a physiological glucose-environment by cultivating them for 10-15 passages in a cell culture medium with 5.5 mM glucose as opposed to the standard high-glucose environment at 17.1mM. Next, BeWo cells were differentiated into multinucleated syncytiotrophoblasts with Forskolin, and with DMSO as solvent control to model cytotrophoblasts. Subsequently, these two trophoblast differentiation states were treated with GDF15 (20 ng/ml) and Activin A (20ng/ml) and the cell metabolic profile was analyzed. Additionally, a single cell human trophoblast organoid transcriptomics dataset from Shannon et al. was investigated for expression patterns of GDF15 and INHBA (Activin A) together with the overall metabolic profile of trophoblast cells. Treating BeWo cells with Activin A and GDF15 leads to an increase in mitochondrial activity, shown by elevated ATP levels in syncytiotrophoblast and an increase in mitochondrial membrane potential in cytotrophoblasts. Additionally, the oxygen consumption rate is significantly higher in syncytiotrophoblasts after Activin A and GDF15 treatment. In human trophoblast organoids, syncytiotrophoblasts showed the lowest metabolic activity measured by the expression of genes related to glycolysis and mitochondrial respiratory chain. Furthermore, GDF15 and INHBA (Activin A) were strongly expressed in syncytiotrophoblasts. Together, Activin A and GDF15 stimulation increases the metabolic activity in BeWo cells. As preeclampsia is associated with mitochondrial dysfunction as well as with senescence, our data indicate a potential role of Activin A and GDF15 in preeclampsia development.

Plasma proteomics identifies proteins and pathways associated with incident depression in 46,165 adults

Proteomic alterations preceding the onset of depression offer valuable insights into its development and potential interventions. Leveraging data from 46,165 UK Biobank participants and 2920 plasma proteins profiled at baseline, we conducted a longitudinal analysis with a median follow-up of 14.5 years to explore the relationship between plasma proteins and incident depression. Linear regression was then used to assess associations between depression-related proteins and brain structures, genetic factors, and stress-related events. Our analysis identified 157 proteins associated with incident depression (P <1.71 × 10−5), including novel associations with proteins such as GAST, PLAUR, LRRN1, BCAN, and ITGA11. Notably, higher expression levels of GDF15 (P = 6.18 × 10−26) and PLAUR (P = 2.88 × 10−14) were linked to an increased risk of depression, whereas higher levels of LRRN1 (P = 4.28 × 10−11) and ITGA11 (P = 3.68 × 10−9) were associated with a decreased risk. Dysregulation of the 157 proteins is correlated with brain regions implicated in depression, including the hippocampus and middle temporal gyrus. Additionally, these protein alterations were strongly correlated with stress-related events, including self-harm events, adult, and childhood trauma. Biological pathway enrichment analysis highlighted the critical roles of the immune response. EGFR and TNF emerged as key proteins in the protein–protein interaction network. BTN3A2, newly linked to incident depression (P = 4.35 × 10−10), was confirmed as a causal factor through Mendelian randomization analysis. In summary, our research identified the proteomic signatures associated with the onset of depression, highlighting its potential for early intervention and tailored therapeutic avenues.

The soluble ST2 level predicts risk of atrial fibrillation recurrences in long-term period after radiofrequency ablation

Background and objectives:The hypothesis of the study was the assumption that the serum levels of soluble ST2 (sST2) and growth differentiation factor (GDF-15) can be predictors of atrial fibrillation (AF) recurrence in long-term period after primary radiofrequency catheter ablation (RFA).MethodsOf the 165 patients included in the prospective follow-up, the final analysis included 131 patients whose follow-up duration reached 18 months after the end of the blanking period (3 months after RFA). The median age of patients was 59.0 (50.0; 64.0) years, and 80 (61%) were men. Paroxysmal AF was present in 103 (79%) and persistent AF in 28 (21%) patients. All patients underwent transthoracic and transesophageal echocardiography, and electroanatomic mapping was used to assess the area of low-voltage zones (LVZ). sST2 and GDF-15 levels were determined by ELISA using GDF-15/MIC-1 analytical kits (BioVender, Czech Republic) and Presage ST2 (Critical Diagnostics, USA) before RFA. After RFA, patients had regular follow-up visits at 3-6-9-12-18 months with 12-lead ECG or Holter ECG monitoring and with clinical evaluation. The primary endpoint was the occurrence of the first symptomatic AF recurrence (AFr) lasting > 30 s, recorded on an ECG or during daily ECG monitoring, after a blanking period.ResultsAt the 18-month follow-up, 47 patients (35.9%) had AFr. The groups with and without AFr didn`t differ in the LVZ area. The medians of NT-proBNP, GDF-15 and sST2 also didn`t differ significantly between the groups, but in patients with AFr, the proportion of those with sST2 ≥ 36 ng/ml (the border of the lower and middle terziles) was higher (p = 0.03). According to the one-factor Cox regression analysis, AFr were associated with four factors: AF history ≥ 1 year, early AFr (during the blanking period), left atrial appendage flow velocity (LAAFV) < 54 cm/sec and sST2 ≥ 36 ng/ml. In the multivariate Cox analysis two independent predictors of AFr were obtained: sST2 ≥ 36 ng/ml (HR = 3.8; 95% CI 1.5–9.8, p = 0.006) and LAAFV < 54 сm/sec (HR = 1.96; 95% CI 1.01–3.82, p = 0.048).ConclusionsSerum sST2 level with a cut-off value of 36 ng/ml or more can be used as a predictor of AF recurrence in the long-term period after primary RFA.

Association of biomarkers and Barthel Index with occurrence of age-related adverse health outcomes in individuals with diabetes.

The clinical significance of age-related biomarkers in patients with diabetes has not been fully elucidated. In this study, we aimed to establish models to predict the progression of aging in patients with diabetes using biomarkers. This single-center, retrospective cohort study included 115 Japanese patients with diabetes aged ≥60 years. Age-related adverse health outcomes were defined as emergency hospitalization, any increase in the level of nursing care certification, admission to a nursing home or death. The associations of age-related biomarker levels (adiponectin, growth differentiation factor 15 [GDF15], C-X-C motif chemokine ligand 9 and apelin) and clinical indicators with age-related adverse health outcomes were evaluated. Factors that predominantly influenced the occurrence of age-related adverse health outcomes were explored using the Cox proportional hazards model. The mean age of the 115 participants was 73 years, 50.6% were men, the mean body mass index and hemoglobin A1c level were 25.3 kg/m2 and 9.79%, respectively. There were 26 age-related adverse health outcomes during the study period (median 1.93, range 0-4.65 years). In a model combining clinical indicators and biomarkers, including the Barthel Index, GDF15 and adiponectin, the occurrence of age-related adverse health outcomes was found to be significantly associated with GDF15 and Barthel Index. The group with both GDF15 and adiponectin levels higher than the median proved to be significantly higher than the group with both lower. The measurement of GDF15 and adiponectin levels and the Barthel Index might be useful for predicting age-related adverse health outcomes in patients with diabetes.

Prognostic and therapeutic monitoring value of plasma and urinary cytokine profile in primary membranous nephropathy: the STARMEN trial cohort

Abstract Background and hypothesis Primary membranous nephropathy (PMN) is usually caused by anti-PLA2R autoantibodies. There are different therapeutic options according to baseline risk. Novel biomarkers are needed to optimize risk stratification, and predict and monitor the response to therapy, as proteinuria responses may be delayed. We hypothesized that plasma or urinary cytokines may provide insight into the course and response to therapy in PMN. Methods Overall, 192 data-points from 34 participants in the STARMEN trial, randomized to tacrolimus-rituximab (TAC-RTX) or corticosteroids-cyclophosphamide (GC-CYC), were analyzed for plasma and urine cytokines using a highly sensitive chemiluminescence immunoassay providing a high-throughput multiplex analysis. Results Baseline (pretreatment) urinary CXCL13 predicted the therapeutic response to TAC-RTX. Cytokine levels evolved over the course of therapy. The levels of nine plasma and six urinary cytokines correlated with analytical parameters of kidney damage and disease activity, such as proteinuria, eGFR and circulating anti-PLA2R levels. The correlation with these parameters was most consistent for plasma and urinary GDF15, plasma TNF-α and urinary TWEAK. Decreasing plasma GDF15 levels were associated to response to GC-CYC. Four clusters of cytokines were associated to different stages of response to therapy in the full cohort, with the less inflammatory cluster associated to remission. Conclusion In conclusion, PMN displayed characteristic plasma and urine cytokine patterns that evolved over time as patients responded to therapy. Baseline urinary CXCL13 concentration could be a prognostic marker of response to TAC-RTX.

GDF-15 and the risk of bleeding in patients with stable CAD receiving multicomponent antithrombotic therapy: the results of the prospective REGATA register

To evaluate the prognostic value of GDF-15 in relation the development of bleeding and events in stable CAD patients, receiving combined antithrombotic therapy. The data was obtained from the prospective registry REGATA, 343 CAD patients (249 males), median age 68 [IQR 62; 75] years) were enrolled. Patients with sinus rhythm and concomitant PAD received acetylsalicylic acid in combination with rivaroxaban 2.5 mg bid (31.8%) or clopidogrel (24.8%). Other 43.4% with concomitant atrial fibrillation (AF) received direct oral anticoagulants in combination with antiplatelet therapy after elective percutaneous coronary interventions. Median follow-up was 12 months [IQR 9.0; 18.0]. The safety end point was major and clinically relevant bleedings (type 2-5) according to the BARC classification. Plasma samples for GDF-15 identification were taken at the inclusion and analyzed using ELISA assay. Frequency of BARC 2-5 bleedings was 16% (BARC 2 - 46; BARC 3 - 9; BARC 4-5 - 0), median GDF-15 level was 1185.0 pg/ml [850.0; 1680.0]. In patients with AF and concomitant MFA, the level of GDF-15 was significantly higher than in the subgroups of patients with only AF or MFA (p=0.0022). According to the quintile analysis, GDF-15 values in the top three quintiles of distribution (cut-off value >943 pg/ml) were associated with higher frequency of bleeding events: 23.2% versus 5.1%; p=0.0001. The multivariable logistic regression model demonstrated that bleeding events were independently associated with GDF-15 level>943 pg/ml (OR 2.65, 95% CI 1.11-6.30; p=0.0275), AF (OR 2.61, 95% CI 1.41-4.83; p=0.0023) and chronic kidney disease (OR 1.92, 95% CI 1.03-3.60; p=0.0401). Clinical factors determining the risk of bleeding events also determined a GDF-15 elevation. Assessment of GDF-15 level may improve bleeding risk stratification in CAD patients with concomitant AF and/or PAD receiving combined antithrombotic therapy.