Growth Differentiation Factor 15 Levels Research Articles

Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer

PurposeAlthough increased plasma growth differentiation factor-15 (GDF15) levels have been reported in patients with various cancers, the predictive role of PD-1/PD-L1 inhibitors in advanced cancers remains unknown. This study aimed to investigate GDF15 levels as a predictive marker in advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors and analyze their association with immune cell populations.MethodsThis study included 87 patients with advanced NSCLC receiving anti-PD-1/PD-L1 inhibitors between March 2018 and May 2020. Blood samples were obtained immediately before and months after PD-1/PD-L1 inhibitor administration.ResultsThe objective response rate (ORR) was significantly higher in the low GDF15 than in the high GDF15 group (39.2% vs. 15.3%, P = 0.013). The median progression-free survival (PFS) was significantly longer in the low GDF15 than in the high GDF15 group (13.2 [95% CI 7.6–18.9] vs. 7.2 [95% CI 4.8–9.6] months, P = 0.048). Moreover, plasma GDF15 levels negatively correlated with PD-1+/CD8+ T cells (r = − 0.399, P = 0.003) and positively with PD-1+/Treg cells (r = 0.507, P < 0.001) and PD-1+Treg/CD4+ T cells (r = 0.439, P < 0.001). The ORR was significantly higher in the group with decreased GDF15 from baseline than in the increased GDF15 group (37.2% vs. 10.0%, P = 0.026). The median PFS was significantly longer in the decreased GDF15 group (14.8 [95% CI 10.4–19.2] vs. 5.9 [95% CI 2.8–9.0] months, P = 0.002). Plasma GDF15 levels were associated with PD-1+CD8+ T cells and PD-1+ Treg cells.ConclusionPlasma GDF15 could be a potential biomarker for predicting the efficacy and survival benefit of immunotherapy in advanced NSCLC.

Growth differentiation factor-15 predicts major bleeding, major adverse cardiac events and mortality in patients with end-stage kidney disease on haemodialysis: findings from the VIVALDI study.

Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular events and bleeding. Optimizing risk assessment of ESKD patients regarding the risk of thromboembolism and bleeding complications in comorbid conditions, including atrial fibrillation and coronary heart disease, is challenging. To improve risk prediction we investigated growth differentiation factor-15 (GDF-15), a promising cardiovascular biomarker, and its relation to adverse outcomes. In this prospective, multicentre, population-based cohort study, GDF-15 was measured in 594 ESKD patients on haemodialysis (median age 66years, 38% female), who were followed up for a median of 3.5years. The association of GDF-15 with major bleeding, arterial thromboembolism, major adverse cardiac events (MACE) and death was analysed within a competing risk framework. Further, we evaluated the additive predictive value of GDF-15 to cardiovascular and death risk assessment. GDF-15 levels were in median 5475ng/l (25th-75th percentile 3964-7533) and independently associated with major bleeding {subdistribution hazard ratio [SHR] 1.31 per double increase [95% confidence interval (CI) 1.00-1.71]}, MACE [SHR 1.47 (95% CI 1.11-1.94)] and all-cause mortality [SHR 1.58 (95% CI 1.28-1.95)] but not arterial thromboembolism [SHR 0.91 (95% CI 0.61-1.36)]. The addition of GDF-15 to the HAS-BLED score significantly improved discrimination and calibration for predicting major bleeding [C-statistics increased from 0.61 (95% CI 0.52-0.70) to 0.68 (95% CI 0.61-0.78)]. Furthermore, we established an additive predictive value of GDF-15 beyond current risk models for predicting MACE and death. GDF-15 predicts the risk of major bleeding, cardiovascular events and death in ESKD patients on haemodialysis and might be a valuable marker to guide treatment decisions in this challenging patient population.

Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability.

Most physiopathological mechanisms underlying blood pressure variability (BPV) are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging" and the hallmark "mitochondrial dysfunction" due to age-related stress. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine growth/differentiation factor 15 (GDF-15) and two inflammatory biomarkers, interleukin 6 (IL-6) and tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. The study population consisted of 1096 community-dwelling participants [median age 75 (72-78) years; 699 females, 63.7%] aged ≥ 70years from the MAPT study. Plasma blood sample was collected 12months after enrolment and BP was assessed up to seven times over a 4-year period. Systolic (SBPV) and diastolic BPV (DBPV) were determined through several indicators taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for relevant covariates [adjusted 1-SD increase in GDF-15: β (SE) = 0.07 (0.04), p < 0.044, for coefficient of variation%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.

Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice.

Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels are increased in the context of obesity. Recombinant GDF15 reduces body weight and improves glycemia in obese models, which is largely attributed to the central action of GDF15 to suppress feeding and reduce body weight. Despite these advances in knowledge, the tissue-specific sites of GDF15 production during obesity are unknown, and the effects of modulating circulating GDF15 levels on insulin sensitivity have not been evaluated directly. Here, we demonstrate that hepatocyte Gdf15 expression is sufficient for changes in circulating levels of GDF15 during obesity and that restoring Gdf15 expression specifically in hepatocytes of Gdf15 knockout mice results in marked improvements in hyperinsulinemia, hepatic insulin sensitivity, and to a lesser extent peripheral insulin sensitivity. These data support that liver hepatocytes are the primary source of circulating GDF15 in obesity.

Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure.

Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-β) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental, preclinical, and clinical studies are warranted to confirm the potential role of GDF15 in T2DM patients.

A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects

Background and aimsMetformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15. MethodsCultured hepatocytes and myotubes, and wild-type and Gdf15-/- mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin. ResultsA low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15-/- mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS. ConclusionOverall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.

A Rising Star of the Multimarker Panel: Growth Differentiation Factor-15 Levels Are an Independent Predictor of Mortality in Acute Heart Failure Patients Admitted to an Emergency Clinical Hospital from Eastern Europe.

(1) Background: Acute heart failure (HF) represents one of the most common yet extremely severe presentations in emergency services worldwide, requiring prompt diagnosis, followed by an adequate therapeutic approach, and a thorough risk stratification. Natriuretic peptides (NPs) are currently the most widely implemented biomarkers in acute HF, but due to their lack of specificity, they are mainly used as ruling-out criteria. Growth differentiation factor-15 (GDF-15) is a novel molecule expressing different pathophysiological pathways in HF, such as fibrosis, remodeling, and oxidative stress. It is also considered a very promising predictor of mortality and poor outcome. In this study, we aimed to investigate the GDF-15's expression and particularities in patients with acute HF, focusing mainly on its role as a prognosis biomarker, either per se or as part of a multimarker panel. (2) Methods: This unicentric prospective study included a total of 173 subjects, divided into 2 subgroups: 120 patients presented in emergency with acute HF, while 53 were ambulatory-evaluated controls with chronic HF. At admission, all patients were evaluated according to standard clinical echocardiography and laboratory panel, including the assessment of GDF-15. (3) Results: The levels of GDF-15 were significantly higher in patients with acute HF, compared to controls [596 (305-904) vs. 216 (139-305) ng/L, p &lt; 0.01]. GDF-15 also exhibited an adequate diagnostic performance in acute HF, expressed as an area under the curve (AUC) of 0.883 [confidence interval (CI) 95%: 0.828-0.938], similar to that of NT-proBNP (AUC: 0.976, CI 95%: 0.952-1.000), or troponin (AUC: 0.839, CI 95%: 0.733-0.944). High concentrations of GDF-15 were significantly correlated with mortality risk. In a multivariate regression model, GDF-15 was the most important predictor of a poor outcome, superior to NT-proBNP or troponin. (4) Conclusions: GDF-15 proved to be a reliable tool in the multimarker assessment of patients with acute HF. Compared to the gold standard NT-proBNP, GDF-15 presented a similar diagnostic performance, doubled by a significantly superior prognostic value, making it worth being included in a standardized multimarker panel.

Multimarker Analysis of Serially Measured GDF-15, NT-proBNP, ST2, GAL-3, cTnI, Creatinine, and Prognosis in Acute Heart Failure.

Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78-2.57) unadjusted, 1.96 (1.49-2.53) after adjustment for clinical confounders and 1.44 (1.05-1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78-3.33) and 1.52 (1.15-2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. URL: https://www.trialregister.nl/trial/1783; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893.).

Evidence That Platelets from Transfusion-Dependent Thalassemia Patients Induce T Cell Activation

Introduction: A hypercoagulable state leading to increased risk for thrombotic events represents one of the most common complications observed in transfusion-dependent thalassemia (TDT) patients. TDT patients have increased frequencies of circulating activated platelets. However, there is no information so far if platelets from TDT patients can activate T cells.In the present study we examined the potential of T cell activation from platelets from TDT patients. Methods: After written informed consent was obtained, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood obtained from 50 patients with TDT (27 women and 23 men, mean age 38 years ) at the time of hospital admission just before their transfusion. We also analyzed 30 age-matched healthy subjects ( mean age 39,5 years) who served as the control group. Platelet rich plasma or plasma alone were isolated from all patients and healthy controls and used in mixed short term cultures with the isolated PBMCs. The membrane expression of CD69 was used as a marker for T-cell activation. We also analyzed the percentages of CD4+CD25+highCD127low+ cells representing the regulatory subset (Tregs) by flow cytometry. The soluble (s) P-selectin, soluble Urokinase-type Plasminogen Activator Receptor (suPAR) and the Growth Differentiation Factor-15 (GDF15) levels were also measured. The study was approved by the Ethics Committee of the "Aghia Sophia" University Hospital, Athens, Greece. Results: We first examined T cell activation following incubation with platelets obtained from TDT patients. T cells treated with platelets from TDT patients showed statistically increased surface expression of CD69 compared to the T cells treated with platelets from healthy individuals (12.75±2.27 vs 4.03± 0.92 %, p=0.004, Figure 1A). When T cells were incubated with platelets from patients previously treated with aspirin, T cell activation was not as efficient as the activation observed in patients who were not treated with aspirin (6.53±2.11 vs 11.30±4.90 %, p=0.32, Figure 1A).Of note, patients with splenectomy showed increased T cell activation compared to patients with intact spleen (16.20±3.20 vs 8.15±1.96%, p=0.07). No T cell activation was observed following incubation with plasma alone, nor with platelets from healthy subjects. We next examined the percentages of CD4+CD25+high and CD127low cells (Tregs). TDT patients showed statistically significant increased levels of Tregs compared to healthy controls (5.47±0.38 vs 0.55±0.13 %, respectively p<0,0001, Figure 1B). Patients who were on aspirin on a daily basis showed slightly lower levels of Tregs, compared to the patients who were not treated with aspirin (5.25±0.6 vs 5.62±0.5% , p=0.64). Additionally, we observed a positive statistically significant correlation between the percentages of Tregs and the platelet-induced activated T cells in patients who were not treated with aspirin (p=0.009, r2=0.70). We next analysed the expression of sP-selectin, suPAR and GDF-15 in TDT patients. These molecules were selected as they are implicated in platelet activation. TDT patients showed increased levels of sP-selectin, suPAR and GDF-15 compared to healthy volunteers levels ( 174.4±12.67 vs 66.8±3.84 pg/mL respectively, p<0.0001, 3.39±0.15 vs 1.90±0.08 pg/mL respectively, p<0.0001, and 6633±215.9 vs 678.9±50.14 pg/mL respectively, p<0.0001). A positive, statistically significant correlation was observed between T cell activation after platelet incubation and sP-selectin levels (r2=0.3 p=0.03). A positive correlation was also detected between circulating activated T cell and suPAR levels (r2=0.56, p=0.01). Conclusion: Our data concur with previous reports supporting the hypothesis that platelets play a role in the immune homeostasis. We show for the first time that platelets from TDT patients can activate T cells in vitro. This activation correlates with markers of platelet activation like sP-selectin and suPAR. TDT patients who showed increased platelet-induced T cell activation, showed also increased numbers of Tregs, perhaps in an effort to eliminate immune dysregulation, conceivably secondary to platelet activation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 14368: Growth Differentiation Factor-15 in Heart Failure Across Body Mass Index Categories: The PREHOSP-CHF Study

Introduction: Growth differentiation factor-15 (GDF-15), a stress-responsive member of the transforming growth factor ꞵ cytokine superfamily is an independent prognostic predictor in patients with heart failure (HF). GDF-15 has been also reported to be associated with cardiac cachexia and malnutrition. However the association of GDF-15 and prognosis in patients with HF according to body mass index (BMI) is unclear. Methods: The PREHOSP-CHF study is a multicenter prospective cohort study among patients with HF. A total of 1,024 patients (mean age, 75.5 years, 58.7% male) were included in the analyses. Serum levels of GDF-15, as well as N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP), were measured. We divided the patients into 3 groups based on the tertile of BMI: low (≤19.9), middle (19.9&lt;, ≤23.4), and high (&gt;23.4). Results: The low BMI group were older, and had more female, HF with preserved ejection fraction (≥50%), and NYHA 3/4. NT-proBNP levels were higher in the low group, but hs-cTnI and hs-CRP were comparable between the 3 subgroups. Median GDF-15 levels in the low, middle and high groups were 2271, 2264, and 1888 pg/ml, respectively. During 2 years follow-up, all-cause death and major adverse cardiovascular events (MACE: cardiovascular death and HF hospitalization) occurred in 111 and 130 in the low group, 66 and 132 in the middle group, and 34 and 88 in the high group. After adjustment for clinical confounders and cardiac biomarkers, higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the entire cohort. BMI subgroup analysis revealed that higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the middle and high groups, but not in the low group (Figure). Conclusions: Among HF, higher GDF-15 was significantly associated with all-cause death and MACE especially in the middle and high BMI groups.

Growth Differentiation Factor-15 as a Predictor of Functional Capacity, Frailty, and Ventricular Dysfunction in Patients With Aortic Stenosis and Preserved Left Ventricular Ejection Fraction

In aortic stenosis (AS), left ventricular (LV) remodeling often occurs before symptom onset, and early intervention may be beneficial. Risk stratification remains challenging and identification of biomarkers may be useful. We evaluated the association between growth differentiation factor-15 (GDF-15) and soluble suppression of tumorigenicity 2 (sST2) and known markers of poor prognosis in AS. Baseline plasma GDF-15 and sST2 levels were measured in 70 patients with moderate-severe AS (aortic valve area <1.5 cm2) and preserved LV ejection fraction (>45%). Patients were categorized into "low GDF-15" versus "high GDF-15" and "low sST2" versus "high sST2" groups. Groups were compared for differences in cardiovascular risk factors, 6-minute walk test, 5 m gait speed, cognitive function (Montreal Cognitive Assessment), and echocardiographic parameters. Overall, 44% of patients were deemed asymptomatic by New York Heart Association class, 61% had severe AS (aortic valve area <1 cm2) and all patients had preserved LV ejection fraction. GDF-15 levels were not predictive of AS severity. However, high GDF-15 (>1,050 pg/ml) was associated with LV dysfunction as shown by lower indexed stroke volume (p <0.01), worse LV global longitudinal strain (p=0.04), greater mean E/e' (p=0.02) and indexed left atrial volume (p <0.01). It was also associated with decreased functional capacity with shorter 6-minute walk test (p=0.01) and slower 5 m gait speed (p=0.02). Associations between sST2 levels and markers of poor prognosis were less compelling. In this study of patients with moderate to severe AS, elevated GDF-15 levels are associated with impaired functional capacity, poorer performance on fragility testing, and LV dysfunction. In conclusion, GDF-15 may integrate these markers of adverse outcomes into a single biomarker of poor prognosis.

Neonatal hemochromatosis with εγδβ-thalassemia: a case report and analysis of serum iron regulators

BackgroundNeonatal hemochromatosis causes acute liver failure during the neonatal period, mostly due to gestational alloimmune liver disease (GALD). Thalassemia causes hemolytic anemia and ineffective erythropoiesis due to mutations in the globin gene. Although neonatal hemochromatosis and thalassemia have completely different causes, the coexistence of these diseases can synergistically exacerbate iron overload. We report that a newborn with εγδβ-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation.Case presentationA 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδβ-thalassemia by genetic testing, and required frequent red blood cell transfusions. At 2 months after birth, exacerbation of jaundice, grayish-white stool, and high serum ferritin levels were observed, and liver biopsy showed iron deposition in hepatocytes and Kupffer cells. Magnetic resonance imaging scans showed findings suggestive of iron deposits in the liver, spleen, pancreas, and bone marrow. The total amount of red blood cell transfusions administered did not meet the criteria for post-transfusion iron overload. Administration of an iron-chelating agent was initiated, but iron overload rapidly progressed to liver failure without improvement in jaundice and liver damage. He underwent living-donor liver transplantation from his mother, after which iron overload disappeared, and no recurrence of iron overload was observed. Immunohistochemical staining for C5b-9 in the liver was positive. Serum hepcidin levels were low and serum growth differentiation factor-15 levels were high prior to living-donor liver transplantation.ConclusionsWe reported that an infant with εγδβ-thalassemia developed NH due to GALD, and that coexistence of ineffective erythropoiesis in addition to erythrocyte transfusions may have exacerbated iron overload. Low serum hepcidin levels, in this case, might have been caused by decreased hepcidin production arising from fetal liver damage due to neonatal hemochromatosis and increased hepcidin-inhibiting hematopoietic mediators due to the ineffective hematopoiesis observed in thalassemia.

Growth Differentiation Factor 15: A Novel Growth Biomarker for Children With Congenital Heart Disease.

Failure to thrive (FTT), defined as weight or height less than the lowest 2.5 percentile for age, is prevalent in up to 66% of children with congenital heart disease (CHD). Risk stratification methods to identify those who would benefit from early intervention are currently lacking. We aimed to identify a novel growth biomarker to aid clinical decision-making in children with CHD. This is a cross-sectional study of patients 2 months to 10 years of age with any CHD undergoing cardiac surgery. Preoperative weight-for-age Z scores (WAZ) and height-for-age Z scores (HAZ) were calculated and assessed for association with preoperative plasma biomarkers: growth differentiation factor 15 (GDF-15), fibroblast growth factor 21, leptin, prealbumin, and C-reactive protein (CRP). Of the 238 patients included, approximately 70% of patients had WAZ/HAZ < 0 and 34% had FTT. There was a moderate correlation between GDF-15 and WAZ/HAZ. When stratified by age, the correlation of GDF-15 to WAZ and HAZ was strongest in children under 2 years of age and persisted in the setting of inflammation (CRP > 0.5 mg/dL). Diagnoses commonly associated with congestive heart failure had high proportions of FTT and median GDF-15 levels. Prealbumin was not correlated with WAZ or HAZ. GDF-15 represents an important growth biomarker in children with CHD, especially those under 2 years of age who have diagnoses commonly associated with CHF. Our data do not support prealbumin as a long-term growth biomarker.

Serum growth differentiation factor-15 levels are associated with the severity of diabetic foot ulcer.

To assess serum growth differentiation factor-15 (GDF-15) levels in patients with diabetic foot ulcer and to reveal whether any association exists between GDF-15 and the severity of diabetic foot ulcer. A cross-sectional study including three age- and sex-matched cohorts comprising 17 patients (7 F, mean age: 52 ± 7years) with diabetic foot ulcer (DMf), 17 patients with type 2 diabetes (6 F, mean age: 51 ± 6years) with no foot complication (DM), and 20 healthy controls (8 F, mean age: 50 ± 8years) (C) was conducted. DMf had higher GDF-15 levels, followed by DM and C (GDF-15, median ± IQR (pg/mL), DMf: 1039 (884-1566), DM: 649 (375-1148), and C: 296 (212-534), p < 0.001). The severity of diabetic foot disease was positively associated with serum GDF-15 (GDF-15, median ± IQR (pg/mL), Wagner grade 1: 893 (698-1039), Wagner grade 3: 1705 (1348-2197), and Wagner grade 4: 3075 (1974-4176), p for trend = 0.006). In multivariate regression model, only Wagner grade (β = 0.55, 95% CI (87-753), p = 0.02) was found to be an independent factor affecting serum GDF-15 concentration. Serum GDF-15 levels are high in patients with diabetic foot ulcer. The level is higher in more advanced lesions. GDF-15 measurement can have clinical utility in the management of diabetic foot ulcers.

The impact of myocardial fibrosis biomarkers in a heart failure population with atrial fibrillation—The HARVEST-Malmö study

Several studies suggest that circulating biomarkers of myocardial fibrosis are associated with worse prognosis in subjects with atrial fibrillation (AF). Here, we aimed to explore associations between fibrosis biomarkers, prevalent AF, and left atrial volume (LAV) enlargement in subjects with heart failure (HF). Additionally, we evaluated the prognostic impact of fibrotic biomarkers in HF with co-existing AF. Patients hospitalized for HF (n = 316, mean age 75 years; 30% women) were screened for AF. Seven proteins previously associated with myocardial fibrosis [metalloproteinase inhibitor 4 (TIMP-4), suppression of tumorigenicity 2 (ST-2), galectin-3 (GAL-3), growth/differentiation factor-15 (GDF-15), and matrix metalloproteinase 2, 3, and 9 (MMP-3, MMP-3, and MMP-9, respectively)] were analyzed using a proximity extension assay. Proteins with significant Bonferroni-corrected associations with mortality and re-hospitalization risk were taken forward to multivariable Cox regression analyses. Further, Bonferroni-corrected multivariable logistic regression models were used to study associations between protein plasma levels, prevalent AF, and severely enlarged left atrial volume index (LAVI ≥ 48 ml/m2). Prevalent AF was observed in 194 patients at the hospitalization of whom 178 (92%) were re-hospitalized and 111 (57%) died during the follow-up period. In multivariable logistic regression models, increased plasma levels of TIMP-4, GDF-15, and ST-2 were associated with the prevalence of AF, whereas none of the seven proteins showed any significant association with severely enlarged LAVI. Increased plasma levels of five proteins yielded significant associations with all-cause mortality in patients with co-existing AF; TIMP-4 (HR 1.33; CI95% 1.07-1.66; p = 0.010), GDF-15 (HR 1.30; CI95% 1.05-1.62; p = 0.017), GAL-3 (HR 1.29; CI95% 1.03-1.61; p = 0.029), ST-2 (HR 1.48; CI95% 1.18-1.85; p < 0.001), and MMP-3 (HR 1.33; CI95% 1.09-1.63; p = 0.006). None of the proteins showed any significant association with re-hospitalization risk. In this study, we were able to demonstrate that elevated levels of three plasma proteins previously linked to myocardial fibrosis are associated with prevalent AF in a HF population. Additionally, higher levels of five plasma proteins yielded an increased risk of mortality in the HF population with or without co-existing AF.

Growth differentiation factor-15 as a modulator of bone and muscle metabolism.

This study aims to clarify the potential role of growth differentiation factor-15 (GDF-15) as a myokine in bone metabolism and muscle function in females with osteoporosis. In total, 45 female participants (71.0 ± 8.5 years) with distal radius fractures were recruited. Participants were classified as healthy/osteopenic (n=28) (CON) or osteoporotic (n=17) (OP) according to their T-score from the areal bone mineral density (aBMD) of the femoral neck. Body mass index, upper arm and calf circumferences, and handgrip strength were assessed. Total hip, femoral neck, and lumbar spine aBMD was measured via dual-energy x-ray absorptiometry. The focal bone quality of the distal radius was evaluated via 3D reconstructed computed tomographic images. Serum levels of GDF-15, insulin-like growth factor-1, and inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-1β (IL-1β), as well as the corresponding mRNA levels in the pronator quadratus muscle were determined. Participants in the OP group had higher serum GDF-15 levels than those in the CON group. The mRNA levels of GDF-15, IL-1β, and TNF-α in the pronator quadratus muscle were significantly higher in the OP group than in the CON one. Levels of both serum GDF-15 and GDF-15 mRNA in muscle were positively correlated with age and negatively associated with the aBMD of the total hip and focal bone quality of the distal radius. Handgrip power was not correlated with circulating GDF-15 levels but was correlated with circumferences of the upper arm and calf, and levels of GDF-15 mRNA in muscle specimens. The mRNA levels of GDF-15 were correlated with those of inflammatory cytokines such as TNF-α and IL-1β. The mRNA levels of TNF-α were associated with circumferences of the upper arm and calf and with the aBMD of the total hip. The mRNA levels of GDF-15 in muscle were correlated with serum levels of GDF-15 and TNF-α. GDF-15 may have associations with bone metabolism in humans via paracrinological and endocrinological mechanisms. Maintenance of muscle mass and function would be influenced more by GDF-15 in muscle than by circulating GDF-15. The role of GDF-15 in bone metabolism and muscle homeostasis could be related to inflammatory responses.

Changes in novel cardiac extracellular matrix biomarkers in STEMI: associations with adverse outcomes

Abstract Background Ischemia-reperfusion (IR)-injury contributes to adverse outcomes following myocardial infarction undergoing reperfusion. Exaggerated remodelling of the extracellular matrix (ECM) is likely to be involved in IR-injury, potentially releasing ECM components to the systemic circulation. To improve prognostication and future therapeutic options in patients with myocardial infarction, more knowledge is warranted about ECM components associated with IR-injury. Purpose To investigate whether ECM components quantified in serum samples associate with myocardial injury and function, and clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Methods We selected biomarkers previously suggested to be involved in ECM changes in the heart, i.e. growth differentiation factor 15 (GDF-15), periostin, osteopontin, syndecan-1, syndecan-4, and bone morphogenetic protein 7. The concentrations of the biomarkers were measured in serum samples from patients with STEMI (n=239) enrolled in the POSTEMI trial, at day 1 and month 4 after hospital admission. Infarct size, microvascular obstruction (MVO), left ventricular remodelling, and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging. Major adverse cardiovascular events (MACE) and all-cause mortality were recorded after 12 months and with a median of 70 months, respectively. Results Serum levels of GDF-15, osteopontin, syndecan-1 and syndecan-4 declined, whereas periostin increased, from day 1 to month 4. Higher levels of syndecan-1 were associated with the presence of MVO (n=116) (day 1 OR 1.39 (1.06–1.82); month 4 OR 1.53 (1.08–2.17)), while higher GDF-15 and syndecan-1 were associated with the development of large infarct size (&amp;gt;75th percentile, n=57) and reduced cardiac function defined as LVEF &amp;lt;50% (n=64) at month 4. Higher levels of GDF-15 at month 4 and periostin at both time points were associated with increased risk of both MACE (n=16) (GDF-15: HR 1.42 (1.04–1.94); periostin day 1: HR 1.88 (1.09–3.25); periostin month 4: HR 1.64 (1.03–2.62)) and all-cause mortality (n=20) (GDF-15: HR 1.59 (1.28–1.97); periostin day 1: HR 1.85 (1.16–2.95); periostin month 4: HR 2.02 (1.35–3.02)) (Figure 1). On the contrary, elevated levels of syndecan-4 at month 4 were associated with lower risk of adverse outcomes, including all-cause mortality (HR 0.48 (0.28–0.84)) (Figure 1) and less IR-injury as assessed by a higher myocardial salvage index. Conclusion Elevated serum levels of GDF-15, periostin, and syndecan-1 were associated with a higher risk of adverse outcomes or detrimental remodelling in patients with STEMI. Increased levels of syndecan-4 measured 4 months after STEMI were associated with a reduced risk of all-cause mortality. Our results suggest the potential use of these biomarkers as prognostic tools and may suggest a role for these ECM components in IR injury. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health AuthorityNorwegian Health Association

Analysis of novel cardiac biomarkers in diagnosis of decompensated heart failure

Abstract Aims Heart failure (HF) remains a major therapeutic and diagnostic challenge. In this study we aimed to analyze the predictive potential of four novel cardiovascular biomarkers – soluble urokinase-type plasminogen activator receptor (suPAR), vascular cell adhesion molecule (CAM-1), heart-type fatty acid binding Protein (H-FABP) and growth/differentiation factor 15 (GDF-15) in detecting cardiac decompensation in patients with HF. Methods In total, 136 patients (40 decompensated HF, 96 compesated HF) were retrospectively enrolled and the serum biomarker concentrations of GDF-15, suPAR, H-FABP and CAM-1 were analyzed by Enzyme Linked Immunosorbent Assay (ELISA). Biomarker concentrations were correlated with clinical and biochemical parameters of enrolled patients, the predictive value for detecting cardiac decompensation was assessed by ROC-plots, as well as univariate and multivariate logistic regression analysis. Cut-offs for cardiac decompensation were calculated by means of the Youden index. Results A significant increase in the levels of suPAR (1.6-fold change, p&amp;lt;0.0001), CAM-1 (1.6-fold change, p&amp;lt;0.0001), HFABP (2.2-fold change, p=0.0458) and GDF-15 (1.7-fold change, p=0.0009) was detected in all patients with decompensated HF compared to patients with compensated HF. In univariate logistic regression analysis, plasma concentrations of GDF-15, H-FABP, suPAR and CAM-1 were significantly associated with the risk for cardiac decompensation. For GDF-15, suPAR and CAM-1, this association remained significant even after correction for confounders in a multivariate logistic regression analysis. Additionally, AUCs (GDF-15: 0.759, 95% (0.683–0.866), suPAR: 0.838, 95% (0.750–0.926), CAM-1: 0.838, 95% (0.750–0.926)) and optimal cut-offs (GDF-15: 1404.8835 pg/ml, suPAR: 4774.027 pg/ml, CAM-1: 4.74027 ng/ml) of the biomarkers were calculated. Correlation analyses found clinical and biochemical parameters such as creatinine as well as inflammatory marker CRP to be significantly correlated with novel biomarkers (r&amp;gt;0.3, p&amp;lt;0.001. In conjunction with the results for the AUC of NTproBNP (AUC=0.785), suPAR (AUC=0.838) and CAM-1 (AUC=0.838 more accurately prediced cardiac decompensation in heart failure than NTproBNP (Figure 1). Conclusion In conclusion, the investigated novel cardiovascular biomarkers could be a valuable tool to facilitate therapeutic decisions in patients with HF and suspicion of cardiac decompensation. Parameters such as renal function should be taken into account. Funding Acknowledgement Type of funding sources: None.

Serum growth differentiation factor 15 levels as a marker for liver cirrhosis and hepatocellular carcinoma on top of liver cirrhosis

Background Cirrhosis is the 14th leading cause of mortality globally. Additionally, it is subclassified by clinical stage. Hepatocellular carcinoma (HCC) was reported to account for ~4.7% of patients with chronic liver disease in Egypt. Early detection and treatment are highly beneficial. Growth differentiation factor 15 (GDF-15) proteins are implicated in the infection, fibrosis, and apoptotic processes of the liver. GDF-15 mRNA is mostly found in the heart, kidney, and lungs, as well as in the liver. The adult liver expresses the greatest amounts of GDF-15 following surgical and pharmacological therapies that produce acute liver damage. Aim This study’s objective was to assess serum GDF-15 levels in individuals with cirrhosis of the liver and HCC on top of cirrhosis of the liver. Patients and methods We have recruited 90 people in three groups: group 1 comprised 35 patients with HCC, group 2 comprised 35 individuals having cirrhosis of the liver, and group 3 comprised 20 nonhepatic individuals who acted as controls. Results In the HCC group, alpha-fetoprotein (AFP) was significantly higher than in the cirrhosis group, and the cirrhosis group has significantly higher AFP than in the control group. In comparison with the cirrhosis group, and in comparison with the control group, the HCC group had a significant increase in GDF-15 level. Conclusions GDF-15 levels were substantially greater in individuals with HCC compared with patients with cirrhosis and healthy controls. It is more sensitive, specific, and accurate than AFP. Thus, we may regard GDF-15 as a new marker for the diagnosis of HCC.

Evaluation of the associations between GDF-15, OPG, and IL-15 levels in CRC: preliminary results

Introduction: Osteoprotegerin (OPG), Interleukin-15 (IL-15), and Growth/Differentiation Factor-15 (GDF-15) are all proven to take part in the processes associated with colorectal carcinoma (CRC) including tissue remodeling, inflammation modulation, and metastasis. Aim of the study: To investigate the concentrations of GDF-15, OPG and IL-15 in tumor and margin tissues of CRC in relation to clinicopathological features of patients. Material and methods: The study used 50 specimens of tumor and tumor-free margin tissues obtained from CRC patients. To determine the GDF-15, OPG and IL-15 concentrations commercially available enzyme-linked immunosorbent assay (ELISA) kits were used. Results: Concentrations of GDF-15, OPG and IL-15 were significantly higher in the tumor in comparison with the margin. The tumor levels of GDF-15 were positively associated with those of OPG and IL-15, while tumor levels of OPG correlated positively with those of IL-15. There was no association between levels of investigated molecules and clinical features of patients. Conclusions: The levels of GDF-15, OPG and IL-15 are elevated in patients suffering from CRC. More studies are needed to establish a specific role of these cytokines in the development, tumor growth, progression, and prognosis of CRC and to examine their role as possible CRC treatment candidates.