Growth Differentiation Factor Research Articles

The interaction of ambient ozone and personal temperature variability on blood markers of inflammation, oxidative stress, coagulation, endothelial function, and stress hormones

The interaction between ozone and temperature on cardiovascular biomarkers has not been thoroughly examined. A panel study was conducted among 40 college students with four equal interval follow-ups in Hefei, Anhui Province, China between August and October 2021. Real-time concentrations of ozone were collected from a nearby monitoring device. Temperature variability parameters included diurnal temperature range (DTR), the standard-deviation of temperature (SDT), and temperature variability (TV). A set of cardiovascular biomarkers were measured, including markers of inflammation (Granulocyte-macrophage colony-stimulating factor, GM-CSF and serum amyloid A, SAA), coagulation (D-dimer and ADAMTS13), oxidative stress (Myeloperoxidase, MPO and Growth differentiation factor-15, GDF-15), endothelial function (vascular endothelial growth factor A, VEGFA), and stress hormone (5-hydroxytryptamine, 5-HT). Linear mixed-effect models were conducted to analyze the associations between ozone, temperature variability, and all blood markers. The results showed significant associations among ozone, DTR, SDT, TV, and blood markers, suggesting harmful effects on markers. For instance, a 10-μg/m3 increase in ozone at lag 2d was associated with higher levels of SAA by 19.65% (95%CI: 13.70, 25.60), VEGFA by 10.90% (95%CI: 4.57, 17.22), GDF-15 by 5.33% (95%CI: 0.59, 10.06), and GM-CSF by 2.52% (95%CI: 1.70, 3.34), but 13.09% lower D-dimer (95%CI: 6.99, 19.19). We also found statistically significant interaction between ozone and TV exposures for GM-CSF and SAA. This study shows that ambient ozone and personal TV exposures may independently have acute effects on markers of inflammation, oxidative stress, coagulation, endothelial function, and neuroendocrine stress response. Simultaneous exposure to these factors may also lead to interactive effects on inflammation markers. These findings offer valuable insights for developing comprehensive strategies in cardiovascular disease control and prevention.

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.

DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

BackgroundPlasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification.ResultsIn the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, PFDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2 range of 5.7–12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population.ConclusionsEpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

Novel insights into the pleiotropic health effects of growth differentiation factor 11 gained from genome-wide association studies in population biobanks

BackgroundGrowth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β (TGF-β) superfamily that has gained considerable attention over the last decade for its observed ability to reverse age-related deterioration of multiple tissues, including the heart. Yet as many researchers have struggled to confirm the cardioprotective and anti-aging effects of GDF11, the topic has grown increasingly controversial, and the field has reached an impasse. We postulated that a clearer understanding of GDF11 could be gained by investigating its health effects at the population level.Methods and resultsWe employed a comprehensive strategy to interrogate results from genome-wide association studies in population Biobanks. Interestingly, phenome-wide association studies (PheWAS) of GDF11 tissue-specific cis-eQTLs revealed associations with asthma, immune function, lung function, and thyroid phenotypes. Furthermore, PheWAS of GDF11 genetic variants confirmed these results, revealing similar associations with asthma, immune function, lung function, and thyroid health. To complement these findings, we mined results from transcriptome-wide association studies, which uncovered associations between predicted tissue-specific GDF11 expression and the same health effects identified from PheWAS analyses.ConclusionsIn this study, we report novel relationships between GDF11 and disease, namely asthma and hypothyroidism, in contrast to its formerly assumed role as a rejuvenating factor in basic aging and cardiovascular health. We propose that these associations are mediated through the involvement of GDF11 in inflammatory signaling pathways. Taken together, these findings provide new insights into the health effects of GDF11 at the population level and warrant future studies investigating the role of GDF11 in these specific health conditions.

Hypothesis paper: GDF15 demonstrated promising potential in Cancer diagnosis and correlated with cardiac biomarkers

BackgroundCardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction).MethodsAnalysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG).ResultsGDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort.ConclusionGDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

Evaluation of some nonroutine cardiac biomarkers among adults and children with beta-thalassemia major.

Cardiac injury caused by iron overload is the leading cause of mortality and morbidity in patients with beta-thalassemia, owing to frequent blood transfusion, increased iron overload, and blood hemolysis. This research aimed to assess several novel cardiac biomarkers in the blood samples of children and adult patients with beta-thalassemia major (βTM), along with their respective control groups. These biomarkers included endothelin 1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), growth differentiation factor-15 (GDF-15), and renalase (RNLS). This case-control study was done on 46 patients with βTM (23 children <18 years, and 23 adults ≥18 years) from the Genetic Hematology Center in Thi-Qar province, Iraq, and 42 comparable controls in 2 groups (21 for each group) in the period from February to April 2023. Levels of ET-1, NT-proBNP, ANP, GDF-15, RNLS, and ferritin were higher in the children and adults with βTM than in the control subjects. Elevations of the novel cardiac biomarkers ET-1, NT-proBNP, ANP, GDF-15, and RNLS in the sera of children and adult patients with βTM when compared with comparable control subjects confirm that the majority of patients with βTM are at risk of cardiac and cardiovascular complications even when there are no obvious symptoms, especially in children, which gives suitable predictive biomarkers.

Increased serum carboxylesterase-1 levels are associated with metabolic dysfunction associated steatotic liver disease and metabolic syndrome in children with obesity

BackgroundCarboxylesterase 1(CES1) is expressed mainly in the liver and adipose tissue and is highly hypothesized to play an essential role in metabolism. Our study aimed to investigate the association between CES1 and metabolic syndrome (MetS) and metabolic dysfunction associated steatotic liver disease (MASLD) in children with obesity in China.MethodsThis study included 72 children with obesity aged 6-13years (including 25(35%) diagnosed as MetS and 36(50%) diagnosed as MASLD). All subjects were measured in anthropometry, serum level of biochemical parameters related to obesity, circumstance levels of insulin-like growth factor1, adipokines (adiponectin, leptin and growth differentiation factor 15) and CES1.ResultsHigher serum CES1 level were found in the MetS group (P = 0.004) and the MASLD group (P < 0.001) of children with obesity. Serum CES1 levels were positively correlated with alanine aminotransferase, aspartate aminotransferase, triglyceride, cholesterol, low-density lipoprotein cholesterol, GDF15, Leptin and negatively correlated with high-density lipoprotein cholesterol, adiponectin and IGF1. We also found a multivariable logistic regression analysis of MASLD and MetS predicted by CES1 significantly (MASLD P < 0.01, MetS P < 0.05). The combination of CES1, sex, age and BMI Z-score showed a sensitivity and specificity of 92.7% for the identification of MASLD and 78.6% for the identification of MetS. The cutoff for CES1 of MASLD is 56.30 ng/mL and of MetS is 97.79 ng/mL.ConclusionsCES1 is associated with an increasing risk of MetS and MASLD and can be established as a biomarker for metabolic syndrome and MASLD of children with obesity.

Effects of combination of melatonin and L-carnitine on in vitro maturation in mouse oocytes: An experimental study.

Melatonin and L-carnitine are free radical scavengers with antiapoptotic and antioxidant properties that improve oocyte development. This study aimed to find the possible effect of combining 2 antioxidant agents of melatonin and L-carnitine on oocyte morphology, maturation, apoptosis, and expression of bone morphogenetic protein 15 (BMP-15) and growth differentiation factor 9 (GDF-9) genes in a mice model. To overstimulation, 60 female NMRI mice were injected intraperitoneally using mare serum gonadotropin. On day 2 post-injection, 70 cumulus-oocyte complexes were collected from each mouse. The collected oocytes randomly were then divided into 4 groups including, the control, melatonin, L-carnitine, and melatonin + L-carnitine groups. The morphology and maturation rate of the oocytes was evaluated using a light microscope. Apoptosis was identified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and the expression of BMP-15 and growth and differentiation factor GDF-9 genes was also evaluated by real-time polymerase chain reaction. Oocyte diameter significantly was increased in combination treatment of L-carnitine and melatonin compared to other groups (p 0.05). L-carnitine group showed the highest mean percentage of oocyte cytoplasmic pattern. Results of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling indicated that the lowest apoptosis rate belonged to the melatonin + L-carnitine group. Moreover, the combination groups showed the highest number of oocytes and maturation rate. The BMP-15 and GDF-9 genes were significantly upregulated in all treatment groups compared to the control group. Our results suggested a combination of melatonin + L-carnitine administration as a more effective choice for in vitro promotion of oocyte maturation.

Genetic regulation of ovulation rate and multiple births.

Ovulation rate in many mammalian species is controlled to regulate the numbers of offspring and maximise reproductive success. Pathways that regulate ovulation rate still respond to genetic and environmental factors and show considerable variation within and between species. Genetic segregation, positional cloning, and association studies have discovered numerous mutations and genetic risk factors that contribute to this variation. Notable among the discoveries has been the role of mutations in bone morphogenetic protein 15 (BMP15 ), growth differentiation factor 9 (GDF9 ) and bone morphogenetic protein receptor type 1B (BMPR1B ) from the intra-ovarian signalling pathway contributing to the evidence that signalling from the oocyte is the key driver in follicle regulation rather than circulating gonadotrophin concentrations. Multiple variants in different domains of BMP15 and GDF9 result in partial or complete loss of function of the proteins providing insights into their functional roles and differential regulation contributing to species differences in ovulation rate. Early success encouraged many more studies in prolific strains of sheep, cattle and goats providing a valuable catalogue of genetic variants of large effect increasing ovulation rate and litter size. More recently, genetic association studies are beginning to identify genetic risk factors with smaller effects. Most genes implicated are from pathways with defined roles in regulation of the ovarian function. However, some genomic regions suggest regulation by novel genes. Continuing genetic and related functional studies will add further to our understanding of the detailed regulation of ovulation rate and litter size with implications for health and animal production systems.

Heart Failure Risk Assessment Using Biomarkers in Patients With Atrial Fibrillation: Analysis From COMBINE-AF

BackgroundHeart failure (HF) is common among patients with atrial fibrillation (AF), and accurate risk assessment is clinically important. ObjectivesThe goal of this study was to investigate the incremental prognostic performance of N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor (GDF)-15 for HF risk stratification in patients with AF. MethodsIndividual patient data from 3 large randomized trials comparing direct oral anticoagulants (DOACs) with warfarin (ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48], and RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy]) from the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) cohort were pooled; all patients with available biomarkers at baseline were included. The composite endpoint was hospitalization for HF (HHF) or cardiovascular death (CVD), and secondary endpoints were HHF and HF-related death. Cox regression was used, adjusting for clinical factors, and interbiomarker correlation was addressed using weighted quantile sum regression analysis. ResultsIn 32,041 patients, higher biomarker values were associated with a graded increase in absolute risk for CVD/HHF, HHF, and HF-related death. Adjusting for clinical variables and all biomarkers, NT-proBNP (HR per 1 SD: 1.68; 95% CI: 1.59-1.77), hs-cTnT (HR: 1.39; 95% CI: 1.33-1.44), and GDF-15 (HR: 1.20; 95% CI: 1.15-1.25) were significantly associated with CVD/HHF. The discrimination of the clinical model improved significantly upon addition of the biomarkers (c-index: 0.70 [95% CI: 0.69-0.71] to 0.77 [95% CI: 0.76-0.78]; likelihood ratio test, P < 0.001). Using weighted quantile sum regression analysis, the contribution to risk assessment was similar for NT-proBNP and hs-cTnT for CVD/HHF (38% and 41%, respectively); GDF-15 provided a statistically significant but lesser contribution to risk assessment. Results were similar for HHF and HF-related death, individually, and across key subgroups of patients based on a history of HF, AF pattern, and reduced or preserved left ventricular ejection fraction. ConclusionsNT-proBNP, hs-cTnT, and GDF-15 contributed significantly and independently to the risk stratification for HF endpoints in patients with AF, with hs-cTnT being as important as NT-proBNP for HF risk stratification. Our findings support a possible future use of these biomarkers to distinguish patients with AF at low or high risk for HF.

The effects of acute aerobic exercise on appetite-regulating parameters and energy intake in males with obesity.

To investigate the effects of moderate-intensity aerobic exercise on appetite control parameters, appetite perceptions, and energy intake in sedentary males with obesity. Eleven males with obesity (body fat percentage 36.5 ± 2.5%, body mass index 35.3 ± 4.2 kg/m2, V̇O2peak 29 ± 3.1 mL·kg-1·min-1) completed two experimental sessions: (1) no exercise (CTRL) and (2) 60 min of moderate-intensity cycling exercise at 60% V̇O2peak (MICT) in a crossover design. Blood analysis included growth differentiation factor 15 (GDF-15), total ghrelin, peptide tyrosine tyrosine3-36 (PYY3-36), total glucagon-like peptide-1 (GLP-1), insulin, and glucose, as well as subjective appetite perceptions were measured in specific intervals. A standard breakfast at 0 h and an ad libitum meal postexercise was provided. GDF-15 (95% confidence interval [CI]: [2.48-27.28] ng/L, p = 0.021) increased immediately following MICT compared to CTRL. However, there were no differences for PYY3-36 (p = 0.480, ), total ghrelin (p = 0.646, ), and total GLP-1 (p = 0.451, ) between sessions. Appetite perceptions (95% CI: [(-20.38)-(-6.16)] mm, p = 0.001) were suppressed following MICT though energy intake was not different between the sessions (95% CI: [(-1904.9)-928.1] kJ, p = 0.480). Sixty minutes of MICT increased GDF-15 while suppressing appetite perceptions in individuals with obesity. There was no energy compensation postexercise.

Growth differentiation factor 9 activates the TGF-β pathway in follicle atresia of Muscovy ducks

Muscovy ducks' high broodiness hinders industry growth. Studying broodiness regulation contributes to the theoretical foundation for enhancing reproductive performance in Muscovy ducks. Experiment 1, a total of 18 Muscovy ducks were divided into 2 groups: Laying group (LO) and Broody group (BO). To collect ovaries for morphological and transcriptome analysis. Experiment 2, Primary Muscovy ducks granulosa cells (GC) were isolated and treated with or without GDF9 at appropriate concentrations as indicated. Experiment 3, GC were treated with or without GDF9 in the presence or absence of a receptor inhibitor. The cell viability, cell apoptosis rate and levels of TGF-β pathway were determined. In vivo, there was a gradual disappearance of follicles in the ovaries and accompanied by follicle atrophy and a concentration of cytoplasm in BO group. The transcriptome expression profile revealed a total of 1,185 up-regulated differentially expressed transcripts (DEs) and 1,258 down-regulated DEs in the BO group compared to the LO group. The up-regulated differentially expressed GDF9 is involved in regulating the TGF-β pathway, which is among the top 10 pathways identified through the KEGG pathway analysis (P < 0.05). Additionally, the fluorescence intensity of apoptosis is primarily observed in the granulosa layers of the ovary. Compared to the LO group, the mRNA level of TGF-β pathway and the protein of GDF9 and p-Smad2/3 were increased in ovary of the BO group (P < 0.05). In vitro, GDF9 supplementation demonstrated does-related promotion of GC (P < 0.01). Compared to CTRL group, 12 ng/mL GDF9 supplementation to GC increased the rate of cell apoptosis, the mRNA and protein expression of TGF-β pathway and the apoptosis-related genes. Pretreatment of GC with GDF9-receptor inhibitor largely abrogated the negative function of GDF9 treatment (P < 0.05). In summary, granulosa cell apoptosis leading to follicle atresia in broodiness of Muscovy ducks is associated with GDF9 activation of the TGF-β pathway. This discovery lays a solid foundation for understanding duck follicular development and enhancing egg production in Muscovy ducks.

LBA82 Efficacy and safety of ponsegromab, a first-in-class, monoclonal antibody inhibitor of growth differentiation factor 15, in patients with cancer cachexia: A randomized, placebo-controlled, phase II study

LBA82 Efficacy and safety of ponsegromab, a first-in-class, monoclonal antibody inhibitor of growth differentiation factor 15, in patients with cancer cachexia: A randomized, placebo-controlled, phase II study

Epicardial adipose tissue and muscle distribution affect outcomes in very old patients after transcatheter aortic valve replacement.

To analyse the relevance of body composition and blood markers for long-term outcomes in very old patients after transcatheter aortic valve replacement (TAVR). A total of 403 very old patients were characterized with regard to subcutaneous, visceral, and epicardial fat, psoas muscle area, plasma growth differentiation factor 15 (GDF-15), and leptin. Cohorts grouped by body mass index (BMI) were analysed for long-term outcomes. Patients underwent transapical and transfemoral TAVR (similar 30-day/1-year survival). Body mass index >35 kg/m2 showed increased 2- and 3-year mortality compared with BMI 25-34.9 kg/m2 but not compared with BMI <25 kg/m2. Fat areas correlated positively to BMI (epicardial: R 2 = 0.05, P < 0.01; visceral: R 2 = 0.20, P < 0.001; subcutaneous: R 2 = 0.13, P < 0.001). Increased epicardial or visceral but not subcutaneous fat area resulted in higher long-term mortality. Patients with high BMI (1781.3 mm2 ± 75.8, P < 0.05) and lean patients (1729.4 ± 52.8, P < 0.01) showed lower psoas muscle area compared with those with mildly elevated BMI (2055.2 ± 91.7). Reduced psoas muscle area and increased visceral fat and epicardial fat areas were independent predictors of long-term mortality. The levels of serum GDF-15 were the highest in BMI >40 kg/m2 (2793.5 pg/mL ± 123.2) vs. BMI <25 kg/m2 (2017.6 pg/mL ±130.8), BMI 25-30 kg/m2 (1881.8 pg/mL ±127.4), or BMI 30-35 kg/m2 (2054.2 pg/mL ±124.1, all P < 0.05). Increased GDF-15 level predicted mortality (2587 pg/mL, area under the receiver operating characteristic curve 0.94). Serum leptin level increased with BMI without predictive value for long-term mortality. Morbidly visceral and epicardial fat accumulation, reduction in muscle area, and GDF-15 increase are strong predictors of adverse outcomes in very old patients post-TAVR.

Temporal trajectory and left ventricular ejection fraction association of eight circulating biomarkers in first acute myocardial infarction patients: a 12-month prospective cohort study.

Our study aimed to explore the temporal trajectory of eight circulating biomarkers, measured serially over 12 months, in a prospective observational cohort of patients with acute myocardial infarction (AMI) and to investigate the association between these biomarkers and left ventricular ejection fraction (LVEF) during follow-up assessments. We enrolled 155 patients admitted for a first AMI requiring percutaneous coronary intervention (PCI). Baseline characteristics, laboratory test results, and cardiac ultrasound examinations were collected at pre-PCI (H0), immediately post-PCI (H24), at discharge (D3), and at 6 months (M6) and 12 months (M12) post-PCI. Blood samples were analysed for established and emerging biomarkers described in left ventricular dysfunction: soluble suppression of tumorigenicity 2 (sST2), interleukin-6 (IL-6), osteopontin, angiopoietin-2, insulin-like growth factor-binding protein 2 (IGFBP-2), growth differentiation factor 15 (GDF-15), hepcidin, and galectin-3. Values at H24, D3, M6, and M12 were compared with value at H0. Three kinetic profiles were identified, with six biomarkers peaking during the acute MI phase. Crude relationships between clinical variables and the peak values (highest observed between H0 and D3) of each biomarker were studied. Peak levels of sST2, IL-6, osteopontin, and angiopoietin-2 demonstrated significant correlations with both baseline and follow-up LVEF values. The assessment of the temporal trajectories of these biomarkers and their associations with LVEF suggests that sST2, IL-6, osteopontin, and angiopoietin-2 hold significant promise as companion biomarkers. These biomarkers may improve the identification of patients at risk for developing impaired LVEF following AMI, thereby enabling more targeted and effective management strategies.

Regulation of Energy and Glucose Homeostasis by the Nucleus of the Solitary Tract and the Area Postrema.

The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes.

Correlation of Immunomodulatory Cytokines with Tumor Volume and Cerebrospinal Fluid in Vestibular Schwannoma Patients.

Sporadic vestibular schwannomas (VSs) often exhibit slow or negligible growth. Nevertheless, some VSs increase significantly in volume within a few months or grow continuously. Recent evidence indicates a role of inflammation in promoting VS growth. Therefore, our study aimed to identify cytokines, which are associated with larger VSs. The expression of different cytokines in VS tumor samples and VS primary cultures was investigated. Additionally, the concentration of cytokines in cell culture supernatants of VS primary cultures and cerebrospinal fluid (CSF) of VS patients and healthy controls were determined. Correlation analysis of cytokine levels with tumor volume, growth rate, Koos grade, age, and hearing was examined with Spearman's-rank test. The mRNA expression of CC-chemokine ligand (CCL) 18, growth differentiation factor (GDF) 15, and interferon regulatory factor 4 correlated positively with tumor volume. Moreover, the amount of GDF15 in the cell culture supernatant of primary cells correlated positively with tumor volume. The concentrations of the cytokines CCL2, CCL5, and CCL18 and transforming growth factor beta (TGFB) 1 in the CSF of the patients were significantly different from those in the CSF controls. Inhibition of immune cell infiltration could be a putative approach to prevent and control VS growth.

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 ventricular-arterial coupling with biomarkers involved in heart failure pathophysiology-the STANISLAS cohort.

Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals. In the forth visit of the STANISLAS family cohort, involving 1309 participants (mean age 48 ± 14 years; 48% male) from parent and children generations, we analysed the association of 32 HF-related proteins with non-invasively assessed VAC using pulse wave velocity (PWV)/global longitudinal strain (GLS) and arterial elastance (Ea)/ventricular end-systolic elastance (Ees). Among the 32 tested proteins, fatty acid-binding protein adipocyte 4, interleukin-6, growth differentiation factor 15, matrix metalloproteinase (MMP)-1, and MMP-9 and adrenomedullin were positively associated with PWV/GLS whereas transforming growth factor beta receptor type 3, MMP-2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were negatively associated. In multivariable models, only MMP-2 and NT-proBNP were significantly and inversely associated with PWV/GLS in the whole population and in the parent generation. Higher levels of NT-proBNP were also negatively associated with Ea/Ees in the whole cohort but this association did not persist in the parent subgroup. Elevated MMP-2 and NT-proBNP levels correlate with better VAC (lower PWV/GLS), possibly indicating a compensatory cardiovascular response to regulate left ventricular pressure amidst cardiac remodelling and overload.

Growth Differentiation Factor -15 (GDF-15) Levels in Diabetic Conditions: Animal Model

Diabetes mellitus (DM) is a disease characterized by increased blood sugar levels, consisting of Diabetes Mellitus type I (DMT1) and Diabetes Mellitus type II (DMT2). Chronic increases in blood glucose levels will cause oxidative stress through the accumulation of Reactive Oxygen Species (ROS). Oxidative stress will induce the secretion of pro- and anti-inflammatory mediators, including Growth Differentiation Factor-15 (GDF-15). GDF-15 levels can be used to predict the risk and progression of DM disease. In exploring diabetes, several studies were carried out on experimental animal models of diabetes, both T1DM and 2DMT models. This research is an experimental study with a Pre and Post-Test Control Group Design approach using rat animals divided into four groups (I=Control group; II=Alloxan group; III=Streptozotocin group and IV=Streptozotocin and high fat diet group) with the aim of to see the levels of Growth Differentiation Factor-15 (GDF-15) in diabetic animal model. Based on this research, there was an increase in levels of Growth Differentiation Factor-15 (GDF-15) before and after diabetic animal model in the Streptozotocin group P value 0.010; and Streptozotocin with a High Fat Diet group with P value of 0.043 (significance value P &lt; 0.05).