Growth Differentiation Factor-15 In Patients Research Articles

Predictive value of growth differentiation factor-15 in patients with myocardial infarction

Aim. To evaluate the prognostic value of growth differentiation factor-15 (GDF-15) in patients with acute myocardial infarction (MI).Material and methods. The study included 118 patients under the age of 70 with STand non-ST segment elevation myocardial infarction, who, in addition to routine examination, were tested for GDF-15 by enzyme-linked immunosorbent assay in the first 48 hours from the onset. The statistical significance of the differences in quantitative indicators was assessed by the Student’s t-test for a normal distribution and by the nonparametric U Mann-Whitney test for a non-normal distribution, while in qualitative indicators — by Pearson’s chisquared test. Pearson’s correlation coefficient and Spearman’s rank correlation coefficient were used as an indicator of strength of relationship between quantitative indicators.Results. The average GDF-15 level in patients with MI was 2,25±1,0 ng/ml. For 6 months of follow-up, 15,25% of patients were rehospitalized for unstable angina or recurrent myocardial infarction. The GDF-15 level in 82,6% of cases was in the third and fourth quartiles (≥2,07 ng/ml). All patients with recurrent MI had GDF-15 levels in the upper quartile (≥2б73 ng/ml). Patients with GDF-15 levels in the upper quartile had a significantly higher risk of rehospitalization (hazard ratio, 3,3 (95% CI, 1,65-6,76), p<0,05) compared with patients with GDF-15 levels in other quartiles. The potential for the combined use of GDF-15 and N-terminal probrain natriuretic peptide (NT-proBNP) levels to assess the risk of readmission has been evaluated. Patients who had both GDF-15 and NT-proBNP levels in the upper quartiles (GDF-15>2,73 ng/ml, NT-proBNP>1418 pg/ml) had 4,8 times higher risk of rehospitalizations for unstable angina or recurrent myocardial infarction.Conclusion. In patients with MI, the determination of the GDF-15 level has prognostic value and may serve as an additional marker of the risk of recurrent cardiovascular events.

Serum Levels of Growth Differentiation Factor-15 as an Inflammatory Marker in Patients with Unstable Angina Pectoris.

Background: Growth differentiation factor-15 (GDF-15), a member of transforming growth factors, is a stress-responsive marker whose levels may significantly increase in response to pathological stresses associated with inflammatory tissue injuries such as unstable angina pectoris (USAP). This study evaluated the diagnostic value of GDF-15 in patients with USAP. Methods: The present cross-sectional study recruited 39 patients with USAP criteria and 30 patients with stable angina pectoris (SAP), referred to Shahid Beheshti Hospital, Kashan, Iran. All the patients with USAP had at least 1 coronary artery stenosis (>50%) in angiography. The control group comprised 42 healthy individuals. The serum levels of GDF-15 were measured in all the participants by ELISA. Also analyzed were the relationship between GDF-15 levels and thrombolysis in myocardial infarction (TIMI) and the Global Registry of Acute Coronary Events (GRACE) risk scores in the patients with USAP to determine the severity of the disease. Result: The study population consisted of 111 subjects, 62 women and 49 men, divided into 3 groups of USAP (n=39, mean age=60.07±14.10 y), SAP (n=30, mean age=67.56±9.88 y), and control (n=42, mean age=61.21±7.76 y). The mean serum level of GDF-15 in the USAP group was significantly different from the other 2 groups (P<0.001), while no significant difference was observed in this regard between the SAP and control groups (P=0.797). No correlation was found between the mean GDF-15 serum level and the GRACE (P=0.816) and TIMI (P=0.359) risk scores in the USAP group. Conclusion: The mean serum level of GDF-15 exhibited a rise in our patients with USAP. GDF-15 may be a diagnostic biomarker of USAP and its severity.

Evaluation of Growth Differentiation Factor-15 in Patients with or without Coronary Artery Disease.

Background:Growth-differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta cytokine superfamily expressed in human atherosclerotic plaque macrophages. In this study, we sought to compare GDF-15 between patients with coronary artery disease and control group.Methods:In this cross-sectional study, 176 subjects were enrolled, consisted of 88 coronary artery disease patients (CAD group) and 88 non-CAD participants (control group. Clinical and demographic data, comprising of family history of CAD, history, and lifestyle factors, hypertension, diabetes, and some blood parameters (e.g. glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)), triglyceride, high-sensitivity C-reactive protein (hs-CRP)).Results:Mean age of the patients was 55.5±11.1 years (age range: 28–80 years). Of all the participants, 91 (51.7%) were male and 85 (48.3%) female. Hs-CRP, LDL-C, and GDF-15 levels were significantly higher in the CAD patients (P=0.091, P=0.008, and P<0.001, respectively). Total cholesterol, hematocrit, and hemoglobin were significantly higher in the controls (P=0.002, P=0.011, and P=0.055, respectively). The area under the receiver operating characteristic curve yielded the satisfactory result of 0.9 (95% CI, 0.8-0.9; P<0.001). The optimum cut-off value of GDF-15 was 1233 ng/L with 71% specificity and 71% sensitivity for CAD diagnosis.Conclusion:These data suggest that serum GDF-15 might be useful in prediction of CAD. (www.actabiomedica)

Association of Growth Differentiation Factor-15 Polymorphisms and Growth Differentiation Factor-15 Serum Levels with Susceptibility to Multiple Myeloma in a Chinese Population.

The aim of our study was to evaluate the relationship between growth differentiation factor-15 (GDF15) rs1058587, rs4808793, and rs1059369 polymorphisms, serum concentrations of GDF15, and International Staging System (ISS) staging or Durie-Salmon staging system (DS) staging in multiple myeloma patients and whether its polymorphism affects the expression of serum GDF15 in Chinese population. A total of 120 patients with multiple myeloma and 119 healthy controls were included in the study. The SNaPshot technique was used to detect the GDF15 gene polymorphisms. Serum GDF15 levels were measured using an Enzyme-Linked ImmunoSorbent Assay (ELISA) kit. There was no significant difference in genotype distribution or allele frequency of three loci between multiple myeloma patients and healthy controls. However, the genotype distribution and allele frequencies of rs1059369 in ISS stage I were significantly different from those in ISS stage II (p = 0.008), and the distribution of rs1058587 genotype was different between ISS stage II and ISS stage III (p = 0.014). The overall serum concentration of GDF15 and the same genotype at the same locus (rs1058587: GC, GG; rs4808793: CC, GC; rs1059369: AA, AT, and TT) in patients with multiple myeloma was significantly higher than in the healthy control group (all p < 0.05). Our results showed the genotype distribution and allele frequencies of rs1059369 and rs1058587 of GDF15 gene have some association with ISS and DS stage. But the polymorphism of GDF15 did not affect the expression of serum GDF15 in patients with multiple myeloma.

Level of the growth differentiation factor-15 in patients with acute myocardial infarction

Aim To reveal relationships between growth differentiation factor-15 (GDF-15) and laboratory and instrumental indexes in patients with myocardial infarction in acute phase.Material and methods The study included 118 patients younger than 70 years with ST-segment elevation or non-ST segment elevation myocardial infarction (MI). For these patients, GDF-15 was measured by enzyme immunoassay within 48 h of MI clinical onset along with a routine examination. Statistical significance of differences in qualitative variables was assessed by the Student's t-test for normal distribution and by the nonparametric Mann-Whitney U-test; significance of differences in quantitative variables was assessed by the Pearson's chi-squared test. The presence of a relationship between quantitative variables was assessed with the Pearson's correlation coefficient and the Spearman's rank correlation coefficient.Results For patients with MI, mean GDF-15 concentration was 2.25±1.0 ng/ml. Moderate correlations were found for GDF-15 and levels of natriuretic peptide (r=0.36, p&lt;0.01), white blood cells (r=0.32, p&lt;0.01), and ejection fraction (Simpson rule) (r=-0.32, p&lt;0.01); weak correlations were found with levels of troponin I (r=0.21, p=0.02) and urea (r=0.20, p=0.04), and interventricular septal thickness by echocardiography (r= -0.26, p&lt;0.01). GDF-15 was higher in patients with ST-segment elevation MI (2.36±1.02 vs 1.99±0.96, p&lt;0.05) and in the presence of hypo- or akinetic areas (2.35±1.05 vs 1.85±0.70, p&lt;0.05). No dependence of GDF-15 on the presence of traditional cardiovascular risk factors was observed.Conclusion GDF-15 correlates with major markers of myocardial injury; its level is higher in patients with ST-segment elevation MI regardless of the infarct location.

Therapeutic and Diagnostic Value of Caspase-12 and Study of Growth Differentiation Factor-15 in Patients with Acute Myocar-dial Infarction.

Background:To investigate the therapeutic and diagnostic value of caspase-12 and study of growth differentiation factor-15 (GDF-15) in patients with acute myocardial infarction (AMI).Methods:Overall, 78 patients with AMI admitted to Weifang People's Hospital Brain Hospital, Weifang, China from Apr 2016 to Apr 2019 were enrolled as AMI group. Seventy-five non-AMI people undergoing physical examination during the same period were enrolled as non-AMI group. The expression levels of caspase-12 and GDF-15 were detected and compared. The correlation between the expressions of GDF-15, caspase-12 and clinical characteristics and efficacy was detected. Single and combined detection of GDF-15 and caspase-12 were performed analyze their role in the early diagnosis, the prediction of efficacy, and the guidance of clinical therapy.Results:After treatment, the levels of GDF-15 and caspase-12 in AMI group were significantly lower than those before treatment (P<0.001). The expression levels of GDF-15 and caspase-12 were significantly correlated with blood pressure (P<0.05). The expression levels of GDF-15 and caspase-12 were significantly negatively correlated with clinical efficacy in AMI group. The diagnostic value of combined detection of GDF-15 and caspase-12 was higher than that of single diagnosis. The levels of serum caspase-12 and GDF-15 proteins were significantly up regulated in AMI patients. With the better therapeutic effect, the levels of serum caspase-12 and GDF-15 proteins decreased significantly.Conclusion:The levels of serum caspase-12 and GDF-15 proteins may be a key indicator in the clinical diagnosis of acute myocardial infarction and may be used to guide the treatment of AMI patients and predict the therapeutic efficacy.

Abstract PO-001: Increased growth differentiation factor 15 serum levels in pancreatic cancer patients

Abstract Pancreatic cancer has poor outcomes with a 5-year survival rate of 9%. Growth differentiation factor 15 (GDF15) has been shown to play a role in pancreatic cancer progression and tumor growth. It is a stress response cytokine that plays a role in inflammation and cellular metabolism. Signaling via its receptor, glial cell derived neurotropic factor family receptor alpha like (GFRAL), GDF15 influences metabolic homeostasis and immune regulation, which may contribute to favorable energy utilization and immune suppression in pancreatic cancer tumors. We hypothesized that GDF15 levels are associated with pancreatic cancer tumor stage and clinical outcomes. GDF15 levels were measured in human serum from healthy control patients and patients diagnosed with pancreatic cancer. Serum samples and associated clinical data were obtained from an IRB approved institutional repository. In healthy control patients, GDF15 had a mean level of 598 pg/mL (SD +/- 304 pg/mL, n=150). Contrastingly, in a cohort of pancreatic cancer patients across various stages of disease, GDF15 levels were significantly higher with a mean of 2294 pg/mL (SD +/- 2005 pg/mL, n=152) (p-value &amp;lt; 0.0001). GDF15 levels were associated with pancreatic cancer stage (p-value = 0.1824, n=150). GDF15 levels were compared for a subset of pancreatic cancer patients who underwent surgical resection; there was a trend for increased levels of GDF15 in patients who received neoadjuvant treatment compared to those that did not receive neoadjuvant treatment (P-value = 0.0674, n=106). When GDF15 levels measured at the time of surgical resection were compared among patients that later developed recurrence and those that did not, GDF15 levels trended to be lower in patients who did not develop recurrence (p-value = 0.3004, n=52). Additionally, the mean GDF15 serum levels for surgical resection patients whose survival status was deceased (2392 pg/mL, SD +/- 1947 pg/mL, n=36) compared to those that are still alive (1907 pg/mL, SD +/- 1416 pg/mL, n=70) on the date of last follow-up were higher (p-value = 0.1295). Overall, these results showed that GDF15 is significantly elevated in pancreatic cancer patients compared to healthy control patients. In our cohort there is an associated trend between increased GDF15 and the administration of neoadjuvant chemotherapy treatment, increasing pancreatic cancer stage, recurrence and decreased survival. We appreciated trends with GDF-15 serum levels and clinical outcomes, which need to be further validated in a larger cohort of patients. These results suggest that GDF15 or its receptor, GFRAL, may be effective novel targets for the treatment of pancreatic cancer patients. Citation Format: Veronica R. Placencio-Hickok, Arsen Osipov, Sejal Mehta, Subhash D. Katewa, Jiping Zha, Andrew E. Hendifar. Increased growth differentiation factor 15 serum levels in pancreatic cancer patients [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-001.

Association Between Growth Differentiation Factor-15 and Heart Failure Complicating Acute Myocardial Infarction

Background - Growth differentiation factor-15 (GDF15) is an emerging biomarker in cardiovascular diseases. We aimed to evaluate the association of GDF15 levels at admission with HF occurrence during hospitalization for acute myocardial infarction (AMI). Methods - Our prospective study included all patients admitted from June 2016 to February 2018 for type 1 AMI in the coronary care unit of the Dijon-Bourgogne University Hospital. In-hospital severe heart failure (HF) was defined as Killip class >2. Serum levels of GDF15 were obtained from blood samples were taken on admission. Results – Among the 284 AMI patients, median age was 67 years, and 27% were women. GDF15 levels were strongly correlated with age and positively correlated with most cardiovascular risk factors (hypertension and diabetes) and inflammation (CRP>3 mg/L). When compared with patients without HF (274/284), GDF15 in patients with in-hospital HF (10/284) was more than two times higher. Multivariate regression showed that GDF15 >5,000 ng/L was an independent marker of HF. Conclusions - These results suggest that GDF15 could be an integrative biomarker for severe in-hospital HF in patients with AMI. Further studies are needed to elucidate the underlying mechanisms linking this cytokine to the development of HF. Clinical Trial BIOCARDIS - 2016 – 9205AAO034S02117, from June 2016 to February 2018

The Growth Differentiation Factor-15 (GDF-15) levels are increased in patients with compound heterozygous sickle cell and beta-thalassemia (HbS/βthal), correlate with markers of hemolysis, iron burden, coagulation, endothelial dysfunction and pulmonary hypertension

The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. GDF-15, a multifactorial cytokine, is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury, while high levels of serum GDF-15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. In this context we aimed to evaluate GDF-15 levels in 89 patients with HbS/βthal at steady phase and in 20 apparently healthy individuals, and correlate with clinical features of the disease and markers of hemolysis, iron burden, inflammation, coagulation and endothelial dysfunction. We found that: GDF-15 levels were elevated in patients with HbS/βthal compared to controls (1980.7 ± 159.8 vs 665.4 ± 50.9 pg/mL, p < 0.0001) and correlated significantly with LDH (p < 0.001), Hepcidin-25/Ferritin molar ratio (p = 0.002), vWF:antigen (p < 0.05), HbA% (p < 0.001) and Mean Pulmonary Artery Pressure (p < 0.001). These findings demonstrate for first time an important multifactorial role of GDF-15 in patients with HbS/βthal, however, prior to its clinical usefulness, this biomarker must undergo through rigorous validation in multiple cohorts.

Effect of bariatric surgery on plasma GDF15 in humans.

Bariatric surgery results in marked body weight loss and improves type 2 diabetes in most patients with obesity. The growth differentiation factor 15 (GDF15) has recently emerged as a novel satiety factor. To begin to understand whether GDF15 is involved in mediating the effects of bariatric surgery on body weight and glycemia in humans, we measured plasma GDF15 in patients with obesity ( n = 25) and in patients with obesity and diabetes ( n = 22) before and after Roux-en-Y gastric bypass (RYGB) surgery. GDF15 was increased 1 wk after RYGB compared with before surgery (689 ± 45 vs. 487 ± 28 pg/ml, P < 0.001) and GDF15 remained elevated at 3 mo (554 ± 37 pg/ml, P < 0.05), at 1 yr (566 ± 37 pg/ml, P < 0.05), and at 2.5-4 yr (630 ± 50 pg/ml, P < 0.001) after RYGB surgery. Both age and insulin sensitivity correlated with GDF15 before the surgery ( r = 0.46, P < 0.0001 and r = 0.34, P < 0.001, respectively). These correlations disappeared at 2.5-4 yr following the surgery. Conversely, weight loss magnitude correlated with GDF15, measured 2.5-4 yr postsurgery ( r = 0.21, P < 0.0055). In summary, circulating GDF15 increases and correlates with body weight loss following RYGB surgery.

Growth differentiation factor 15 as an integrative biomarker of heart failure in patients with acute myocardial infarction

Growth differentiation factor 15 (GDF15), a stress-responsive cytokine member of the transforming growth factor-β family, is an emerging biomarker in cardiovascular (CV) diseases. GDF15 is weakly expressed in normal condition but increased in pathological situations such as inflammation, oxidative stress, and left-ventricular remodeling. Recent data suggest GDF15 as a marker in heart failure (HF). We aimed to measure the levels of GDF15 in patients admitted for an acute myocardial infarction (AMI) and HF. In our prospective study, we included all consecutive patients admitted from June 2016 to October 2017 with type 1 AMI from the ‘obseRvatoire des Infarctus de Côte d’Or’ (RICO) survey. Chronic congestive HF patients were excluded. Admission and hospital HF were diagnosed by killip class > 1. Serum levels of GDF15 were measured using a commercially available ELISA kit. Among the 219 AMI patients, median-age was at 69(58–80) y, 29% were women, 25% had diabetes and 63% were hypertensive. GDF15 levels (median = 1254 (819–2140) ng/L) were strongly correlated with age ( r = 0.558, P < 0.001), and elevated with most CV risk factors (i.e. hypertension, diabetes, hypercholesterolemia), prior CAD, chronic kidney disease ( P < 0.001 for all) and in patients with CRP > 3 mg/L ( P < 0.001). When compared with patients without HF, patients who developed HF on admission (22%) or in-hospital (6%), GDF15 was markedly higher ( Fig. 1 ). GDF15 levels were negatively correlated with LVEF ( r = -0.142, P < 0.05). Moreover, Receiving Operating Curve analysis showed that GDF15 was associated with HF (AUC = 0.69 (0.61–0.77), P < 0.001). These preliminary results suggest that GDF15 could be an integrative biomarker of HF in patient with AMI. Further studies are needed to elucidate the underlying mechanisms linking the cytokine with the development of HF and to investigate its use for patient monitoring in AMI.

Maternal levels of growth differentiation factor-15 in patients with preeclampsia

ABSTRACTObjective: Growth differentiation factor-15 (GDF-15) is a stress-induced cytokine and related to the prognosis of cardiovascular diseases. Our purpose is to measure the maternal levels of GDF-15 in patients with early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE).Methods: This cross-sectional study was conducted including 72 pregnant women, 23 with normal pregnancies and 49 with preeclampsia (26 with EOPE and 23 with LOPE). Maternal serum levels of GDF-15 were measured by using enzyme-linked immunosorbent assay kits.Results: The median serum GDF-15 level was found to be the highest in the EOPE group (EOPE: 441.7 pg/ml). The median serum GDF-15 levels were higher in women with preeclampsia than in the control group (309.7 pg/ml vs. 436.6 pg/ml, p: 0.009).Conclusion: Our findings suggest GDF-15 increased as a response to endothelial injury caused by cytokines triggered by preeclampsia.

The Growth Differentiation Factor-15 Levels Are Increased in Patients with Compound Heterozygous Sickle Cell and Beta-Thalassemia, Correlate with Hepcidin-25/Ferritin Molar Ratio and with Markers of Hemolysis, Endothelial Dysfunction and Angiogenesis

Background: The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. SCD is also characterized by the presence of chronic inflammation manifested by leukocytosis and monocytosis and increased circulating levels of pro-inflammatory cytokines and chemokines. Growth Differentiation Factor-15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1) or non-steroidal anti-inflammatory drug-activated gene (NAG-1) is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury. Recently, GDF-15 and Twisted Gastrulation Protein (TWSG1) have been proposed to be erythroblast-derived factors, although not erythroblast specific, that mediate Hepcidin-25 suppression under conditions of increased erythropoietic activity. High levels of GDF15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. However, the role of GDF15 in Hepcidin-25 regulation under physiologic conditions and in other disorders is unclear and has been debated.Aims: The aim of this study was to evaluate the GDF-15 levels in patients with compound heterozygous HbS and beta-thalassemia (HbS/βthal) and to explore possible associations with disease features, such as Hepcidin-25 production, hemolysis, inflammation, endothelial dysfunction and angiogenesis.Methods: Seventy-five adult Caucasian patients with HbS/βthal were included in the study, while 20 healthy individuals served as controls. Patients with HbS/βthal divided in two groups: group A included 36 patients under hydroxycarbamide (HC+) treatment and group B included 39 patients without hydroxycarbamide (HC-) treatment. Along with hematology and blood chemistry parameters determination, measurements of circulating levels of GDF-15, hepcidin-25, hs-CRP, vWF-antigen, hs-TnT and Placental Growth Factor (PlGF) were performed in both patients with HbS/βthaland controls using immunoenzymatic techniques.Results: The main results of the study included: GDF-15 levels were elevated in patients with HbS/βthal compared to controls ((1,980.7±159.8 vs 665.4±50.9 pg/mL, p<0.001). Regarding hydroxycarbamide treatment, GDF-15 levels were elevated in (HC+) patients compared to (HC-) patients (p=0.002), or 30/36 vs 21/39 patients had elevated GDF-15 levels (p=0.002). In contrast, Hepcidin-25 levels were significantly lower in patients with HbS/βthal compared to controls (57.2±12.3 vs 67.3±9.1 ng/mL, p<0.01). The reduction of Hepcidin-25 levels was more pronounced in (HC-) patients compared to (HC+) patients (p=0.005). In addition, a markedly low Hepcidin-25/Ferritin molar ratio was obsereved in patients with HbS/βthal compared to controls (p<0.001). Whilst, no direct correlation was found between GDF-15 and hepcidin-25 levels, a significant negative correlation between GDF-15 levels and Hepcidin-25/Ferritin molar ratio was detected in patients with HbS/βthal(p=0.002). GDF-15 levels also correlated significantly with markers of erythropoiesis, such as Hb, HbF, ferritin and reticulocytes (p<0.05), with markers of hemolysis, such as LDH and uric acid (p<0.01), and with markers of endothelial dysfunction and angiogenesis such as vWF-antigen and PlGF (p<0.01). Surprisingly, no correlation was found between GDF-15 and hs-CRP levels.Conclusions: These findings demonstrate a multifactorial role of GDF-15 in patients with HbS/βthal as it correlates with erythropoiesis, hemolysis, endothelial dysfunction and angiogenesis. However, we found no direct specific function, despite the negative correlation with Hepcidin-25/Ferritin molar ratio. Interestingly, the higher GDF-15 levels measured in patients treated with hydroxycarbamide may reflect possible drug induced sub-clinical cardiotoxicity, although this has not been described to-date. To this end, our knowledge is restricted only to doxorubicin-induced cardiotoxicity, where GDF-15 up-regulation seems to be more sensitive than that of hs-TnT, LDH and NT-proBNP. Further studies will reveal the role of GDF-15 in the biology of HbS/βthal. DisclosuresOstland:Intrinsic LifeScienc s: Employment, Equity Ownership. Westerman:Intrinsic LifeSciences: Employment, Equity Ownership. Terpos:Genesis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria.

Prognostic utility of biomarker growth differentiation factor-15 in patients with acute decompensated heart failure

Objective Growth differentiation factor-15 (GDF-15) has established promising prognostic value in various cardiovascular diseases, although there is very little information available about it in patients with acute heart failure, particularly with regard to long-term outcomes. The aim of our study was to determine the prognostic value of GDF-15 in patients with acute decompensated heart failure (ADHF).Methods and results A total of 107 consecutive patients (median age 70 [interquartile range, IQR: 60-73.5]; 36% women), hospitalized for ADHF, were examined. The primary and secondary endpoints were to determine the differences in both mortality and rehospitalization due to heart failure after one year, depending on the GDF-15 plasma level. The control group consisted of 25 healthy people of a similar age. The patients with ADHF had significantly higher level of GDF-15 on admission (median 3481 [IQR: 2113-5090]), than the subjects in the control group (887.5 (IQR: 763.75-960.25] ng/L). A high GDF-15 level on admission remained a significant predictor for adverse clinical events, shown by a multivariable regression analysis (hazard ratio [HR], 3.08; 95% confidence interval [CI], 1.06-8.35, P< 0.05), together with left ventricle ejection fraction (P <0.05). Kaplan-Meier curve analysis showed a significantly higher probability of death and HF rehospitalization in patients with higher levels of GDF-15. Patients with both GDF-15 and BNP levels above the median on admission had the highest mortality rate.Conclusion In patients with ADHF, an elevated GDF-15 value on admission was a strong predictor of an adverse clinical outcome regarding mortality and HF rehospitalization 1-year after the initial hospitalization.

Ischemia-modified albumin, brain natriuretic peptide, and growth differentiation factor-15 levels in patients with nasal polyps.

Nasal polyps (NP) are a chronic inflammatory disease of the nasal mucosa; their etiology is suspected to involve oxidative stress. Growth differentiation factor-15 (GDF-15), brain natriuretic peptide (BNP), and ischemia-modified albumin (IMA) are biomarkers used especially in the early diagnosis and follow-up of cardiovascular diseases. The aim of this study was to assess levels of serum GDF-15, BNP, and IMA in patients with NP and to compare them with those of healthy subjects. This was a prospective study enrolling 41 patients with NP and 48 healthy controls, all aged 18-65 years and referred to the Department of Otorhinolaryngology, Head and Neck Surgery, between January 2014 and February 2015. After a 12-h fast, venous blood (3mL) was drawn and centrifuged (3000rpm, 10min) to collect serum. Blood samples were drawn before endoscopic sinus surgery in the NP group. Serum GDF-15, BNP, and IMA levels were measured. GDF-15, BNP, and IMA levels of patients with NP were statistically significantly higher than in controls and GDF-15 values were higher than the normal upper limit. GDF-15, BNP, and IMA levels were significantly correlated in both groups. As GDF-15 is a marker of chronic inflammation and oxidative stress, our finding of increased serum GDF-15 in patients with NP supports the hypothesis that its pathogenesis involves chronic inflammation and oxidative stress.

Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia.

BackgroundElevated serum levels of growth differentiation factor-15 (GDF-15) are associated with type 2 diabetes. Therefore, the effects of atorvastatin on metabolic parameters and GDF-15 levels in patients with type 2 diabetes and dyslipidemia were evaluated.MethodsIn this prospective randomized trial from February 2013 to March 2014, 50 consecutive type 2 diabetic patients with a low density lipoprotein cholesterol (LDL-C) levels ≥100 mg/dL were enrolled. The patients were divided into two groups based on the amount of atorvastatin prescribed, 10 mg/day (n=23) or 40 mg/day (n=27). The effect of atorvastatin on metabolic parameters, including lipid profiles and GDF-15 levels, at baseline and after 8 weeks of treatment were compared.ResultsThe baseline metabolic parameters and GDF-15 levels were not significantly different between the two groups. After 8 weeks of treatment, the total cholesterol (TC) and LDL-C levels were significantly decreased in both groups. The mean changes in TC and LDL-C levels were more significant in the 40 mg atorvastatin group. The GDF-15 level was decreased in the 10 mg atorvastatin group, from 1,460.6±874.8 to 1,451.0±770.8 pg/mL, and was increased in the 40 mg atorvastatin group, from 1,271.6±801.0 to 1,341.4±855.2 pg/mL. However, the change in the GDF-15 level was not statistically significant in the 10 or 40 mg atorvastatin group (P=0.665 and P=0.745, respectively).ConclusionThe GDF-15 levels were not significantly changed after an 8-week treatment with atorvastatin in type 2 diabetic patients.

Abstract 12644: Growth Differentiation Factor-15 (GDF-15) for Risk Stratification in Patients After an Acute Coronary Syndrome: Insights From the SOLID-TIMI 52 trial

Background: Growth differentiation factor (GDF)-15, a stress responsive cytokine, is associated with the risk of CV events after an acute coronary syndrome (ACS). Unlike other established cardiac biomarkers, the level of GDF-15 remains elevated in sub-acute phase after ACS and gradually decreases over time. We evaluated the prognostic utility of GDF-15 in patients after ACS accounting for established markers and risk predictors. Methods: GDF-15 (R&amp;D Systems) and other established cardiac biomarkers (BNP, hsCRP and hsTnI) were measured at baseline in a randomly selected cohort of 4,968 patients enrolled within 30 days of hospitalization with ACS (median=14d) in SOLID-TIMI 52. Previously defined cutpoints were applied for GDF-15 concentration: &lt;1200 (n=3451), 1200-1800 (n=919), and &gt; 1800 ng/L (n=598). Analyses were adjusted for established risk predictors, days from the ACS event and other markers. MACE was defined as CV death, MI or stroke. Median follow-up was 2.5 years. Results: Patients with higher GDF-15 tended to be older, more likely to have diabetes, hypertension, history of revascularization, and CKD at baseline. Higher baseline levels of GDF-15 identified patients with higher rates of MACE as well as each individual element (p-trend &lt;0.001 for all endpoints, Fig). The rate of MI was ∼2-fold higher in those with GDF-15 concentration &gt;1800ng/L compared to patients with GDF-15 concentration &lt;1200 ng/L. After adjustment for clinical predictors and other markers, GDF-15 was independently associated with the risk of MACE (HR 1.4, 95% CI 1.1-1.7; HR 1.8, 95% CI 1.4-2.3 for GDF-15 1200-1800, &gt;1800, respectively). Individuals with GDF-15 &gt;1800 ng/L had an increased risk of MI (adj HR 1.4, 95% CI 1.1-2.0) and stroke (adj HR 2.3, 95% CI 1.3-3.9). Conclusion: In patients after ACS, GDF-15 concentration is associated with the risk of MACE including MI and stroke independent of traditional risk factors and risk markers.

Growth Differentiation Factor-15 in Patients with Light Chain (AL) Amyloidosis Has Independent Prognostic Significance and Adds Prognostic Information Related to Risk of Early Death and Renal Outcomes

▪Growth differentiation factor-15 (GDF-15) is a member of the TGF-beta family, which is involved in several pathological conditions, including inflammation, cancer, cardiovascular, pulmonary and renal diseases. GDF-15 has prognostic value in patients with cardiovascular disorders and adds prognostic information to conventional prognostic factors, such as NT-proBNP and high-sensitivity troponin (hs-TnT). Cardiac involvement is the most important determinant of prognosis in patients with AL amyloidosis and cardiac biomarkers have major prognostic importance in AL. The aim of the study was to explore the value of GDF-15 in patients with AL amyloidosis.We measured the circulating levels of GDF-15, NT-proBNP and hs-TnT in 77 patients with newly diagnosed AL amyloidosis, before and 3 months post frontline treatment. GDF-15 was measured by a novel pre-commercial immunoassay (Roche Diagnostics).Patients’ median age was 68 years; most patients had cardiac (61%) or renal involvement (74%); 61% had NT-proBNP >1284 pg/ml and 46% had hsTnT>54 ng/ml. Median eGFR was 57 ml/min/1.73m2, 52% had eGFR <60 ml/min/1.73m2, while 12% required dialysis at the time of treatment initiation. All patients received primary therapy with bortezomib- (49%) or lenalidomide-based regimens (51%). Median levels of GDF-15 were 3594 pg/ml (range 626-71,475pg/ml); 95% of patients with AL had GDF-15 levels >1200 pg/ml (the upper limit of normal for individuals without cardiovascular disease). GDF-15 correlated with NT-proBNP (r=0.538, p<0.001), hs-TnT (r=0.447, p=0.02) and eGFR (r=-0.570, p<0.001). Patients with GDF-15 levels within the upper quartile (>7575 pg/ml) had a very poor outcome (median overall survival (OS) 3 months) compared to patients with GDF-15 levels below the upper quartile (p=0.01; see the Figure). Among other cardiac markers, hs-TnT >54 ng/ml (12 vs >48 months, p=0.001) and NT-proBNP >1284 pg/ml (11 vs >48 months, p<0.001) were also associated with shorter OS. Higher cut-off levels for NT-proBNP and hs-TnT did not discriminate patients at high risk for early death more accurately. In a multiple logistic regression model which included GDF-15, NT-proBNP and hs-TnT, only GDF-15 in the upper quartile (HR: 8.427, 95% CI 1.73-41.1, p=0.008) was independently predictive of early death at 3 months. Similar results were obtained when these biomarkers were treated as continuous variables. Regarding OS, GDF-15 had independent prognostic significance in a multivariate model that included both NT-proBNP and hs-TnT.We also evaluated changes in the levels of GDF-15, NT-proBNP and hs-TnT in patients who received lenalidomide after 3 months of treatment. In these patients NT-proBNP often increases without obvious deterioration of cardiac function, thus complicating the assessment of cardiac response early, during the course of therapy. GDF-15 levels did not change significantly either in patients with hematological response (p=0.998) or those without hematological response (p=0.774). However, NT-proBNP levels increased substantially both in those with hematological response (p=0.05) and in those without hematological responses (p=0.013). Similarly, hs-TnT levels increased in non-responders (p=0.006) and did not change in patients with hematological response (p=0.251).As GDF-15 reflects heart and renal defects, we further evaluated whether GDF-15 could be associated with the risk of progression to ESRD and need for dialysis. Using ROC analysis, GDF-15 >median was identified to better discriminate patients which had a shorter time to dialysis (29 months vs not reached, p=0.001, see the Figure; with 38% vs. 8% progressing to ESRD, respectively). eGFR< 60 ml/min/m2 was also a strong predictor of ESRD (p=0.004). However, in multivariate analysis which included GDF-15 >median, eGFR <60 ml/min/m2 and proteinuria >5 g/day, only GDF-15 was independently associated with a higher risk of ESRD requiring dialysis (HR: 4.25, 95% CI 1.01-18, p=0.045).In conclusion, GDF-15 is a novel biomarker with prognostic implications for different outcomes in patients with AL; it is associated with a high risk of early death, with OS and also with renal outcome. More importantly GDF-15 adds prognostic information independent of the traditional cardiac biomarkers and thus, its measurement in larger series of patients is recommended. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic value of serum growth differentiation factor-15 in patients with chronic obstructive pulmonary disease exacerbation.

BackgroundInformation regarding prognostic value of growth differentiation factor 15 (GDF-15) and heart-type fatty acid-binding protein (H-FABP) in patients with chronic obstructive pulmonary disease (COPD) exacerbation is limited. The aim of this study was to investigate whether serum levels of GDF-15 and H-FABP predict an adverse outcome for COPD exacerbation.MethodsClinical variables, including serum GDF-15 and H-FABP levels were compared in prospectively enrolled patients with COPD exacerbation that did or did not experience an adverse outcome. An adverse outcome included 30-day mortality and need for endotracheal intubation or inotropic support.ResultsNinety-seven patients were included and allocated into an adverse outcome (n=10) or a control (n=87) group. Frequencies of mental change and PaCO2>37 mm Hg were significantly higher in the adverse outcome group (mental change: 30% vs. 6%, p=0.034 and PaCO2>37 mm Hg: 80% vs. 22%, p<0.001, respectively). Serum GDF-15 elevation (>1,600 pg/mL) was more common in the adverse outcome group (80% vs. 43%, p=0.041). However, serum H-FABP level and frequency of serum H-FABP elevation (>755 pg/mL) did not differ between the two groups. Multivariate analysis showed that an elevated serum GDF-15 and PaCO2>37 mm Hg were significant predictors of an adverse outcome (odds ratio [OR], 25.8; 95% confidence interval [CI], 2.7-243.8; p=0.005 and OR, 11.8; 95% CI, 1.2-115.3; p=0.034, respectively).ConclusionElevated serum GDF-15 level and PaCO2>37 mm Hg were found to predict an adverse outcome independently in patients with COPD exacerbation, suggesting the possibility that serum GDF-15 could be used as a prognostic biomarker of COPD exacerbation.

GDF‐15 in heart failure: providing insight into end‐organ dysfunction and its recovery?

GDF‐15 in heart failure: providing insight into end‐organ dysfunction and its recovery?