Growth Differentiation Factor 15 and Matrix Metalloproteinase 3 in Plasma as Biomarkers for Neuropathy and Nephropathy in Type 1 Diabetes.

Diabetic neuropathy and nephropathy are common complications of type 1 diabetes (T1D). The symptoms are often elusive in the early stages, and available diagnostic methods can be improved using biomarkers. Matrix metalloproteinase 3 (MMP-3) has been identified in the kidneys and is thought to be involved in diabetic nephropathy. Growth differentiation factor 15 (GDF-15) has been suggested to have positive effects in diabetes, but is otherwise associated with adverse effects such as cardiovascular risk, declined kidney function, and neurodegeneration. This study aims to investigate plasma MMP-3 and GDF-15 as systemic biomarkers for diabetic neuropathy and nephropathy in T1D. The study involves patients with childhood-onset T1D (n = 48, age 38 ± 4 years) and a healthy control group (n = 30, age 38 ± 5 years). Neurophysiology tests, evaluations of albuminuria, and measurements of routine biochemical markers were conducted. The neuropathy impairment assessment (NIA) scoring system, where factors such as loss of sensation and weakened reflexes are evaluated, was used to screen for symptoms of neuropathy. MMP-3 and GDF-15 concentrations were determined in heparinized plasma using ELISA kits. In total, 9 patients (19%) had albuminuria, and 25 (52%) had diabetic neuropathy. No significant differences were found in MMP-3 concentrations between the groups. GDF-15 levels were higher in T1D, with median and interquartile range (IQR) of 358 (242) pg/mL in T1D and 295 (59) in controls (p < 0.001). In the merged patient group, a positive correlation was found between MMP-3 and plasma creatinine, a negative correlation was found between MMP-3 and estimated glomerular filtration rate (eGFR; rho = -0.358, p = 0.012), and there was a positive correlation between GDF-15 and NIA (rho = 0.723, p < 0.001) and high-sensitive C-reactive protein (rho = 0.395, p = 0.005). MMP-3 was increased in macroalbuminuria and correlated positively with NIA only in the nine T1D patients with albuminuria (rho = 0.836, p = 0.005). The present study indicates that high MMP-3 is associated with low eGFR, high plasma creatinine, and macroalbuminuria, and that GDF-15 can be a biomarker for diabetic neuropathy in T1D. MMP-3 may be useful as biomarker for neuropathy in T1D with albuminuria.

Physiological Role of Serum Growth Differentiation Factor-15 (GDF-15) Level and Iron Metabolism in Community-Dwelling Older Adults.

Background Anemia is common in older adults and, together with heart failure and chronic kidney disease, forms a vicious cycle, whereas diseases such as chronic inflammation and cancer are associated with the anemia of chronic disease (ACD). Researchers have linked growth differentiation factor-15 (GDF-15) to a variety of conditions such as cardiovascular disease, inflammation, cancer, and kidney disease, and have reported hepcidin as a biomarker for iron regulation in ACD. Therefore, anemia, GDF-15, and hepcidin have significance in aging physiology. Hypothesis GDF-15 and hepcidin play important physiological roles in community-dwelling older adults. This study sought to explore the relationship between these biomarkers and anemia, inflammation, or other health outcomes. Methods This was a prospective study of 73 community-dwelling older adults (six men and 67 women, mean age of 76.3 years). Their serum iron level, percentage transferrin saturation (TSAT), high-sensitivity C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) were measured. Enzyme-linked immunosorbent assays were used to assess their serum GDF-15, ferritin, and hepcidin levels. The participants' grip strength and walking speed were measured. The skeletal muscle mass index (SMI) of each participant was determined by bioelectrical impedance analysis. Results The GDF-15 level was significantly inversely correlated with serum iron, ferritin, and hepcidin levels; percentage TSAT; the eGFR; and gait speed. Serum hepcidin was positively correlated with levels of ferritin, albumin, and hemoglobin. Handgrip strength, SMI, and hs-CRP were not correlated with either GDF-15 or hepcidin levels. After adjusting for age, sex, and body mass index (BMI), multivariate analysis identified the log GDF-15 and serum iron level (log GDF-15: ß=-0.248, iron: ß=0.296) as significant factors determining hemoglobin levels, whose findings have significance due to novel results. Multivariate analysis identified eGFR and levels of hemoglobin and hepcidin as significant factors associated with log GDF-15 (eGFR: ß=-0.406, hemoglobin: ß=-0.269, hepcidin: ß=-0.235). Similarly, ferritin and albumin levels were identified as significant factors associated with hepcidin levels (ferritin: ß=0.590, Alb: ß=0.277). Conclusions Anemia in community-dwelling older adults was determined not only by increasing serum iron levels but also by decreasing GDF-15 levels. Also, the increasing GDF-15 level was determined by a decreasing hepcidin level as well as the presence of anemia and renal dysfunction, and the decreasing hepcidin level was determined by decreasing stored iron and decreasing albumin levels. Serum GDF-15 and hepcidin could potentially inform diagnostic or treatment strategies for anemia or age-related health conditions.

GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

Integrated biomarker profiling for enhanced heart failure management: a comprehensive study on the application of chemiluminescence detection of GDF-15 and multi-index models.

BACKGROUND: Growth differentiation factor 15 (GDF-15) holds promise as a novel marker for heart failure. However, current detection methods fall short of meeting essential clinical requirements. OBJECTIVES: The aim of this investigation was to assess the clinical significance of serum GDF-15 detection through the chemiluminescence method and to enhance its clinical application for predicting and evaluating heart failure in patients. METHODS: A total of 122 patients were included in the study. Serum GDF-15 levels were assessed using the chemiluminescence method and compared with results for NT-proBNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), growth stimulation expressed gene 2 (ST2), high-sensitivity C-reactive protein (hs-CRP), and left ventricular ejection fraction (LVEF). Additionally, we conducted an analysis to evaluate the correlation between these indicators and heart failure events. RESULTS: LVEF, ST2, NT-proBNP, and GDF-15 exhibited significant associations with heart failure. In the multivariate proportional hazard analysis, subsequent to adjusting for the effects of other markers, however, only LVEF and GDF-15 retained their associations with heart failure events. Notably, GDF-15 emerged as the exclusive marker suitable for diagnosing heart failure with preserved ejection fraction. CONCLUSION: The chemiluminescence method proved efficient in the rapid and sensitive detection of GDF-15 in patients with heart failure. Additionally, GDF-15 combined with other markers created a robust multi-index model. This model is valuable for heart failure diagnosis, treatment, and monitoring, with broad clinical applicability.

Growth Differentiation Factor-15 Is Considered a Predictive Biomarker of Long COVID in Non-hospitalized Patients.

Mitochondrial dysfunction is associated with various diseases. Mitochondria plays a regulatory role during infection. The association between mitokines and subsequent COVID progression has not been previously studied. The retrospective cohort study aimed to investigate the potential of serum mitokines as long COVID biomarkers in non-hospitalized patients. Patients with confirmed SARS-CoV-2 infection and blood test reports between January 2021 and April 2023 were included. Patients were categorized into two groups, the recovered and long COVID groups, based on fatigue, decline in focus, and pain. Serum levels of growth differentiation factor 15 (GDF-15) and fibroblast growth factor-21 (FGF-21), which are affected by mitochondrial function, along with inflammatory and vascular endothelium markers, were measured using enzyme-linked immunosorbent assays (ELISA). A receiver operating characteristic curve was used to screen the biomarkers. The threshold value of GDF-15 in the acute phase was 965 pg/mL (sensitivity: 71.4%, specificity: 83.3%), indicating that GDF-15 may be associated with the presence of symptoms three months post onset. No association with inflammatory markers and vascular structures was observed. Therefore, elevated GDF-15 levels in the acute phase may act as a predictive biomarker of long COVID.

Association between plasma growth differentiation factor 15 levels and pre-eclampsia in China.

Background: Growth differentiation factor-15 (GDF-15) is a stress response protein and is related to cardiovascular diseases (CVD). This study aimed to investigate the association between GDF-15 and pre-eclampsia (PE). Method: The study involved 299 pregnant women, out of which 236 had normal pregnancies, while 63 participants had PE. Maternal serum levels of GDF-15 were measured by using enzyme-linked immunosorbent assay kits and then translated into multiple of median (MOM) to avoid the influence of gestational week at blood sampling. Logistic models were performed to estimate the association between GDF-15 MOM and PE, presenting as odd ratios (ORs) and 95% confidence intervals (CIs). Results: MOM of GDF-15 in PE participants was higher compared with controls (1.588 vs. 1.000, p < 0.001). In the logistic model, pregnant women with higher MOM of GDF-15 (>1) had a 4.74-fold (95% CI = 2.23-10.08, p < 0.001) increased risk of PE, adjusted by age, preconceptional body mass index, gravidity, and parity. Conclusions: These results demonstrated that higher levels of serum GDF-15 were associated with PE. GDF-15 may serve as a biomarker for diagnosing PE.

New quasi-Co/Cu-MOF nanozyme coupled with entropy-driven DNA amplification cascades for highly sensitive electrochemical aptamer growth differentiation factor 15 assay.

BACKGROUND: The monitoring of concentration variation of the newly developed growth differentiation factor 15 (GDF15) biomarker in human serum is of great significance for diagnosing cardiovascular diseases. Current methods for the detection of the GDF15 protein mainly are based on antibody-assisted immunoassays, which encounter the limitations in terms of sensitivity, complexity and costs. The development of simple and sensitive biosensors for GDF15 can therefore facilitate the diagnosis of cardiovascular diseases. RESULTS: A new bimetallic quasi-Cu/Co-MOF nanozyme with high catalytic performance for electrochemical reduction of H2O2 is synthesized via simple one-step precipitation and low-temperature calcination method. Such nanozymes are further employed as amplification tags and coupled with cyclic entropy-driven DNA signal enhancement strategies to construct ultrasensitive aptamer-based biosensor for detecting GDF15 in human serums. GDF15 molecules associate with two aptamers and release the ssDNA trigger sequences via target-binding induced displacement reaction. These ssDNAs subsequently initiate cyclic DNA-fueled strand displacement and catalytic hairpin assembly (CHA) reaction cascades for confining many quasi-Cu/Co-MOF nanozymes on sensor electrode, which yield drastically amplified H2O2 reduction current for detecting GDF15 down to 0.12 pg mL-1 with a dynamic range of 0.5 pg mL-1 to 20 ng mL-1. The electrochemical aptasensor also presents good reproducibility and selectivity and exhibits the capability to detect GDF15 in diluent serums. SIGNIFICANCE: Our aptamer-based GDF15 protein electrochemical assay clearly outperforms current existing antibody-based methods and the quasi-Cu/Co-MOF nanozyme/entropy-driven cascaded signal amplification means can be used as a universal strategy for sensitive monitoring of different biomolecular markers for diverse applications.

Exploration of treatment strategies and susceptibility gene of postoperative nausea and vomiting in breast cancer patients: a randomised controlled trial.

BACKGROUND: A history of severe nausea and vomiting during pregnancy (SNVP) is a risk factor for postoperative nausea and vomiting (PONV). This study aimed to explore potentially effective treatment strategies and potential genetic factors underlying SNVP risk-related PONV. METHODS: A total of 140 female patients undergoing breast cancer surgery were assigned to either the study group (70 with SNVP) or the control group (70 with mild to moderate nausea and vomiting during pregnancy (MNVP)). Patients in each group were randomly assigned to two different treatment subgroups and received either ondansetron plus dexamethasone (OD) or OD + TEAS (ODT) (transcutaneous electrical acupoint stimulation, TEAS). Blood samples were collected from patients before induction (D0) and 24 h (D1) after surgery for growth differentiation factor 15 (GDF-15) evaluation. The primary outcome was the incidence of PONV within 36 h. The secondary outcome was the serum GDF-15 level. RESULTS: The incidence of PONV in the SNVP group was significantly higher than that in the MNVP group within 24 h (P < 0.005). In the SNVP group, ODT-treated patients had less PONV than those in the OD-treated group during the 6-12 h (P = 0.033) and 12-24 h (P = 0.008) intervals, while within 6 h, there were fewer vomiting cases in the ODT-treated group (SNVP-ODT vs. SNVP-OD, 7/33 vs. 19/35, P = 0.005). The preoperative GDF-15 serum levels in patients with SNVP were significantly higher (P = 0.004). Moreover, higher preoperative GDF-15 serum levels correlated with a higher incidence of PONV (P = 0.043). CONCLUSIONS: TEAS showed significant effect on PONV treatment in patients with SNVP. A higher serum GDF-15 level was associated with a history of SNVP, as well as a higher risk of PONV.

Effect of Acute Nutritional Ketosis on Circulating Levels of Growth Differentiation Factor 15: Findings from a Cross-Over Randomised Controlled Trial.

Exogenous supplementation with ketone beverages has been shown to reduce plasma glucose levels during acute nutritional ketosis. It remains to be investigated whether growth differentiation factor 15 (GDF-15)-an anorexigenic hormone-is involved in this process. The aim was to investigate the effect of a ketone ester beverage delivering ß-hydroxybutyrate (KEßHB) on plasma levels of GDF-15, as well as assess the influence of eating behaviour on it. The study was a randomised controlled trial (registered at clinicaltrials.gov as NCT03889210). Individuals were given a KEßHB beverage or placebo in a cross-over fashion. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 min after ingestion. Eating behaviour was assessed using the three-factor eating questionnaire. GDF-15 levels were not significantly different (p = 0.503) after the KEßHB beverage compared with the placebo. This finding remained consistent across the cognitive restraint, emotional eating, and uncontrolled eating domains. Changes in the anorexigenic hormone GDF-15, irrespective of eating behaviour, do not appear to play a major role in the glucose-lowering effect of exogenous ketones.

GDF15 ameliorates sepsis-induced lung injury via AMPK-mediated inhibition of glycolysis in alveolar macrophage.

Growth differentiation factor 15 (GDF15) as a stress response cytokine is involved in the development and progression of several diseases associated with metabolic disorders. However, the regulatory role and the underlying mechanisms of GDF15 in sepsis remain poorly defined. Our study analyzed the levels of GDF15 and its correlations with the clinical prognosis of patients with sepsis. In vivo and in vitro models of sepsis were applied to elucidate the role and mechanisms of GDF15 in sepsis-associated lung injury. We observed strong correlations of plasma GDF15 levels with the levels of C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), and lactate as well as Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. In the mouse model of lipopolysaccharide-induced sepsis, recombinant GDF15 inhibited the proinflammatory responses and alleviated lung tissue injury. In addition, GDF15 decreased the levels of cytokines produced by alveolar macrophages (AMs). The anti-inflammatory effect of glycolysis inhibitor 2-DG on AMs during sepsis was mediated by GDF15 via inducing the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) and the expression of activating transcription factor 4 (ATF4). Furthermore, we explored the mechanism underlying the beneficial effects of GDF15 and found that GDF15 inhibited glycolysis and mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) signaling via promoting AMPK phosphorylation. This study demonstrated that GDF15 inhibited glycolysis and NF-κB/MAPKs signaling via activating AMP-activated protein kinase (AMPK), thereby alleviating the inflammatory responses of AMs and sepsis-associated lung injury. Our findings provided new insights into novel therapeutic strategies for treating sepsis.

Is There a Role for Growth and Differentiation Factor-15 in B-Cell Lymphoproliferative Neoplasms?

Growth and differentiation factor-15 (GDF-15) correlates with worse outcome of many tumours and any cause mortality. Data about its role in lymphoproliferative neoplasms (LPN) are scarce. Our research aimed to reveal the correlation between GDF-15 and standard laboratory parameters of LPN activity, and to get insight into the possible value of this cytokine assessment in lymphoma patients. Prospective research included 40 patients treated for aggressive or indolent LPN, and 31 with indolent LPN on "watch and wait" regimen. Analyses were performed before and after treatment in treated patients and on two separate occasions in the "watch and wait" group. ELISA technique with R&D assays according to the manufacturer manual, from stored sera at - 70 °C was used for GDF-15 level measurement. Statistical analyses were performed by IBM SPSS Statistics 22 using descriptive and inferential statistics. As appropriate, differences between groups were assessed by two tailed t-test, Mann-Whitney or x2 test. Spearman Rank Order Correlation was done to correlate GDF-15 with standard laboratory markers of disease activity. All tests are two-tailed with significance level p < 0. 05. GDF-15 (p = 0.028) and fibrinogen (p = 0.001) concentrations increased after treatment in indolent lymphoma patients while ß2 microglobulin decreased (p < 0.001). GDF-15 positively correlated with ß2microglobulin before (p < 0.001) and after (p = 0.031) therapy. There were no differences in any of the aforementioned parameters in the "watch and wait" group during observation. A positive correlation between GDF-15 and ß2 microglobulin in patients with indolent LPN who need treatment suggests potential value in risk assessment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01695-6.

Determination of systemic inflammatory biomarkers in multiple sclerosis.

Background: Multiple sclerosis (MS) is one of the most common demyelinating diseases of the central nervous system. We aimed to investigate serum and cerebrospinal fluid levels of different laboratory inflammatory biomarkers in patients with MS. Methods: A total of 120 subjects participated in the study, 60 of whom were diagnosed with MS, 30 with the final diagnosis of non-inflammatory diseases of the central nervous system (CNS), and 30 healthy subjects representing the control group. Regarding the progression of radiological findings after 2 years from the initial diagnosis, the MS group was divided into stationary radiological findings (n=30) and radiologically proven disease progression (n=30). In all patients, we analyzed levels of laboratory inflammatory biomarkers: C reactive protein (CRP), Neutrophil-to-lymphocyte ratio (NLR), Growth differentiation factor 15 (GDF15) in serum samples, and neurofilaments (NFs) in cerebrospinal fluid (CSF). NFs and GDF15 were analyzed initially, while CRP and NLR values were analyzed initially and after two years. Results: We found statistically lower GDF15 values and initial CRP values in the MS group regarding the group with non-inflammatory diseases of the CNS (p<0.0001). On the other side, we determined a significant elevation of laboratory markers CRP and NLR, initially and after a two-year period, in the MS subgroup with the progression of magnetic resonance imaging (MRI) findings (p<0.0001 and p=0.050, respectively). Also, we found a positive correlation between CRP and NFs (r=0.243, p=0.04), as well as a positive correlation between CRP and GDF15 in patients with MS (r=0.769, p<0.0001). Conclusions: We found a significant elevation of laboratory markers of systemic inflammation, CRP, and NLR in MS patients who developed disease progression based on MRI findings. There is a need for further studies to validate current parameters to be considered as useful markers of MS activity and disability.

Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. CONCLUSION: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Growth differentiation factor-15 and metabolic features in chronic heart failure: Insights from the SUPPORT Trial -GDF15 across the BMI spectrum.

BACKGROUND: GDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood. METHODS: We assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 65.9 ± 10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m2; n = 50], healthy weight [18.5-22.9; n = 27 5], overweight [23-24.9; n = 234], and obese [≥25; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death. RESULTS: Compared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21-596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2-81.0]). Persistently high GDF15 levels (≥1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [95%CI 1.1-2.9]). CONCLUSIONS: In underweight patients with CHF, GDF15 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome.

Prognostic value of growth differentiation factor-15 in heart failure among whole ejection fraction phenotypes.

AIMS: The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model. METHODS AND RESULTS: This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0 years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P = 0.002) and a higher MAGGIC risk score (P < 0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4 year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.20-1.54; P < 0.001] and HF rehospitalization (HR = 1.75, 95% CI: 1.57-1.95; P < 0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR = 1.73, 95% CI: 1.40-2.14; P < 0.001; HF rehospitalization: HR = 3.37, 95% CI: 2.73-4.15; P < 0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index = 0.021, 95% CI: 0.002-0.041; IDI = 0.011, 95% CI: 0.001-0.025; continuous NRI = 0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index = 0.034, 95% CI: 0.005-0.063; IDI = 0.021, 95% CI: 0.007-0.032; continuous NRI = 0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup. CONCLUSIONS: GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups.

GDF-15 Levels and Other Laboratory Findings as Predictors of COVID-19 Severity and Mortality: A Pilot Study.

Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine associated with acute and chronic inflammatory states. This prospective observational study aimed to investigate the prognostic roles of GDF-15 and routine clinical laboratory parameters in COVID-19 patients. Upon the admission of 95 adult hospitalized COVID-19 patients in Croatia, blood analysis was performed, and medical data were collected. The patients were categorized based on survival, ICU admission, and hospitalization duration. Logistic regression and ROC curve methods were employed for the statistical analysis. Logistic regression revealed two independent predictors of negative outcomes: CURB-65 score (OR = 2.55) and LDH (OR = 1.005); one predictor of ICU admission: LDH (OR = 1.004); and one predictor of prolonged hospitalization: the need for a high-flow nasal cannula (HFNC) upon admission (OR = 4.75). The ROC curve showed diagnostic indicators of negative outcomes: age, CURB-65 score, LDH, and GDF-15. The largest area under the curve (AUC = 0.767, specificity = 65.6, sensitivity = 83.9) was represented by GDF-15, with a cutoff value of 3528 pg/mL. For ICU admission, significant diagnostic indicators were LDH, CRP, and IL-6. Significant diagnostic indicators of prolonged hospitalization were CK, GGT, and oxygenation with an HFNC upon admission. This study reaffirms the significance of the commonly used laboratory parameters and clinical scores in evaluating COVID-19. Additionally, it introduces the potential for a new diagnostic approach and research concerning GDF-15 levels in this widespread disease.

Engineered Exosomes with Growth Differentiation Factor-15 Overexpression Enhance Cardiac Repair After Myocardial Injury.

Background: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair. Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment. Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI. Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI. RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells. AMPK signaling was activated after GDF15-EVs. Silencing TERT impaired the protective effects of GDF15-EVs on H2O2-injured H9C2 cells. Conclusion: GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway. GDF15-EVs might be exploited to design new therapies for AMI.

Biomarkers to predict improvement of left ventricular ejection fraction after atrial fibrillation ablation.

BACKGROUND: Atrial fibrillation (AF) and heart failure frequently coexist. Prediction of left ventricular ejection fraction (LVEF) recovery after catheter ablation (CA) for AF remains difficult. OBJECTIVE: The purpose of this study was to evaluate the value of biomarkers, alone and in combination with the Antwerp score, to predict LVEF recovery after CA for AF. METHODS: Patients undergoing CA for AF with depressed LVEF (<50%) were included. Plasma levels of 13 biomarkers were measured immediately before CA. Patients were categorized into "responders" and "nonresponders" in a similar fashion to the Antwerp score performance derivation and validation cohorts. The predictive power of the biomarkers alone and combined in outcome prediction was evaluated. RESULTS: A total of 208 patients with depressed LVEF were included (median age 63 years; 39-19% female; median indexed left atrial volume 42 (33-52) mL/m2; median LVEF 43 (38-46)%). At a median follow-up time of 30 (20-34) months, 161 (77%) were responders and 47 (23%) were nonresponders. Of 13 biomarkers, -4-angiopoietin 2 (ANG2), growth differentiation factor 15 (GDF15), fibroblast growth factor 23, and myosin binding protein C3-were significantly different between responders and nonresponders (P ≤ .001) and their combination could predict the end point with an area under the curve of 0.72 (95% confidence interval [CI] 0.64-0.81) overall, 0.69 (95% CI 0.59-0.78) in heart failure with mildly reduced ejection fraction, and 0.88 (95% CI 0.77-0.98) in heart failure with reduced ejection fraction. Only ANG2 and GDF15 remained significantly associated with LVEF recovery after adjustment for age, sex, and Antwerp score and significantly improved the accuracy of the Antwerp score predictions (P < .001). The area under the curve of the Antwerp score in the outcome prediction improved from 0.75 (95% CI 0.67-0.83) to 0.78 (95% CI 0.70-0.86). CONCLUSION: A biomarker panel (ANG2 and GDF15) significantly improved the accuracy of the Antwerp score.