Higher Growth Differentiation Factor 15 Levels Research Articles

Growth differentiation factor-15 is a predictor of important disease outcomes in patients with COPD.

Increased levels of growth differentiation factor-15 (GDF15) are associated with cachexia, cardiovascular disease and all-cause mortality. The role of GDF15 in chronic obstructive pulmonary disease (COPD) is unknown.The study included 413 patients with COPD from the Bergen COPD Cohort Study. All patients had a forced expiratory volume in 1 s (FEV1) <80% predicted, a FEV1 to forced vital capacity (FVC) ratio <0.7 and a history of smoking. Spirometry, fat free mass index, blood gases and plasma GDF15 were measured at baseline. Patients were followed for 3 years regarding exacerbations and changes in lung function, and 9 years for mortality. Yearly exacerbation rate, survival and yearly change in FEV1/FVC were evaluated with regression models.Median plasma GDF15 was 0.86 ng·mL-1 (interquartile range 0.64-1.12 ng·mL-1). The distribution was not normal and GDF15 was analysed as a categorical variable. High levels of GDF15 were associated with a higher exacerbation rate (incidence rate ratio 1.39, 95% CI 1.1-1.74, p=0.006, adjusted values). Furthermore, high levels of GDF15 were associated with higher mortality (hazard ratio 2.07, 95% CI 1.4-3.1, p<0.001) and an increased decline in both FEV1 (4.29% versus 3.25%) and FVC (2.63% versus 1.44%) in comparison to low levels (p<0.01 for both).In patients with COPD, high levels of GDF15 were independently associated with a higher yearly rate of exacerbations, higher mortality and increased decline in both FEV1 and FVC.

Growth Differentiation Factor-15 Is a Predictor of Mortality in Critically Ill Patients with Sepsis.

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily related to inflammation and macrophage activation. Serum concentrations of GDF-15 can predict poor survival in chronic diseases, but its role in sepsis is obscure. Therefore, we investigated GDF-15 as a prognostic biomarker in critically ill patients. We measured GDF-15 levels in 219 critically ill patients (146 with sepsis, 73 without sepsis) upon admission to the intensive care unit (ICU), in comparison to 66 healthy controls. GDF-15 levels were significantly increased in ICU patients compared to controls. GDF-15 was further increased in sepsis and showed a strong association with organ dysfunction (kidney, liver and lactate) and disease severity (APACHE II and SOFA score). High GDF-15 concentrations at admission independently predicted ICU (HR 3.42; 95% CI 1.33–8.78) and overall mortality (HR 2.02, 95% CI 1.02–3.88) in all ICU critically ill patients as well as in a large subgroup of sepsis patients (ICU mortality: HR 3.16; 95% CI 1.10–9.07; overall mortality: HR 2.62; 95% CI 1.14–6.02). Collectively, serum GDF-15 levels are significantly increased in critically ill patients, associated with sepsis, organ failure, and disease severity. High GDF-15 levels at ICU admission predict short- and long-term mortality risk.

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.

Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia.

Vascular pathology plays an important role in the development of cognitive decline and dementia. In this context, growth differentiation factor-15 (GDF-15) has been suggested to be a biomarker due to its regulatory roles in inflammatory and trophic responses during tissue injury. However, limited data exist on the associations of GDF-15 with either cerebrovascular disease (CeVD) burden or the spectrum of cognitive impairment. Therefore, we aimed to study peripheral levels of GDF-15 incognitive impairment no dementia (CIND) or Alzheimer disease (AD) subjects assessed for CeVD using a case-control cohort design, with cases recruited from memory clinics and controls from memory clinics and the community. All subjects underwent detailed neuropsychological assessment, 3-Tesla magnetic resonance imaging, and venous blood draw. Subjects were classified as CIND or AD based on clinical criteria, while significant CeVD was defined as the presence of cortical infarcts and/or 2 lacunes or more, and/or confluent white matter hyperintensities (WMHs) in 2 or more brain regions. A total of 324 subjects were included in the study, of whom 80 had no cognitive impairment, 144 CIND and 100with AD. Higher GDF-15 levels were significantly associated with disease groups, especially in the presence of CeVD, namely, CIND with CeVD (odds ratios [OR]: 7.21; 95% confidence interval [CI]: 2.14-24.27) and AD with CeVD (OR: 21.87; 95% CI: 2.01-237.43). Among the different CeVD markers, only WMH was associated with higher GDF-15 levels (OR: 3.97; 95% CI: 1.79-8.83). The associations between GDF-15 and cognitive impairment as well as with WMH remained significant after excluding subjects with cardiovascular diseases. In conclusion, we showed that increased GDF-15 may be a biomarker for CIND and AD in subjects with WMH.

Growth differentiation factor-15 predicts the prognoses of patients with acute coronary syndrome: a meta-analysis.

BackgroundRecent studies have shown Growth differentiation factor–15 (GDF-15) that is a member of the transforming growth factor β (TGF-β) superfamily might be a potential predictive cytokine for the prognosis of Acute coronary syndrome (ACS). However, there are discrepancies in these studies.MethodsPublication searches of the PubMed/Medline and EMBASE databases were performed without any time or ethnicity restrictions. The inclusion and exclusion criteria, when clear, were addressed. Random effects models were used for all analyses. Publication bias was tested using funnel plots and the Egger test.ResultsWe identified eight eligible studies that provided mortality data. Five of these studies provided recurrent myocardial infarction (MI) data. The maximal duration of follow-up ranged from 6 months to 6 years. A significant association was found between the patients with the highest and lowest GDF-15 levels (overall analyses) in terms of mortality (p < 0.00001; RR = 6.08; 95 % CI = 4.79–7.71) and recurrent MI (p < 0.00001; RR = 1.76; 95 % CI = 1.49–2.07). We also found significant associations between the subgroup analyses stratified by ACS types, cutoff points and follow-up durations (p < 0.001). The combined hazard ratio was high for GDF-15 to ACS (HR = 1.656, 95 % CI = 1.467–1.871).ConclusionHigh plasma GDF-15 levels are associated with an increased risk of mortality and recurrent MI in patients with ACS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-016-0250-2) contains supplementary material, which is available to authorized users.

GDF15 promotes EMT and metastasis in colorectal cancer.

Metastasis is the major cause of cancer deaths, and the epithelial-mesenchymal transition (EMT) has been considered to be a fundamental event in cancer metastasis. However, the role of growth differentiation factor 15 (GDF15) in colorectal cancer (CRC) metastasis and EMT remains poorly understood. Here, we showed that GDF15 promoted CRC cell metastasis both in vitro and in vivo. In addition, the EMT process was enhanced by GDF15 through binding to TGF-β receptor to activate Smad2 and Smad3 pathways. Clinical data showed GDF15 level in tumor tissues, and the serum was significantly increased, in which high GDF15 level correlated with a reduced overall survival in CRC. Thus, GDF15 may promote colorectal cancer metastasis through activating EMT. Promisingly, GDF15 could be considered as a novel prognostic marker for CRC in the clinic.

Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study.

Growth differentiation factor-15 (GDF-15) predicts death and composite cardiovascular (CV) events in patients with acute coronary syndrome (ACS). We investigated the independent associations between GDF-15 levels and major bleeding, the extent of coronary lesions and individual CV events in patients with ACS. Growth differentiation factor-15 was analysed at baseline ( ITALIC! n = 16 876) in patients with ACS randomized to ticagrelor or clopidogrel in the PLATO (PLATelet inhibition and patient Outcomes) trial. Growth differentiation factor-15 levels were related to extent of coronary artery disease (CAD) and to all types of non-coronary artery bypass grafting (CABG)-related major bleeding, spontaneous myocardial infarction (MI), stroke, and death during 12-month follow-up. In Cox proportional hazards models adjusting for established risk factors for CV disease and prognostic biomarkers (N-terminal pro B-type natriuretic peptide, cystatin C, high-sensitive C-reactive protein, and high-sensitive troponin T), 1 SD increase in ln GDF-15 was associated with increased risk of major bleeding with a hazard ratio (HR) 1.37 (95% confidence interval: 1.25-1.51) and with a similar increase in risk across different bleeding locations. For the same increase in ln GDF-15, the HR for the composite of CV death, spontaneous MI, and stroke was 1.29 (1.21-1.37), CV death 1.41 (1.30-1.53), all-cause death 1.41 (1.31-1.53), spontaneous MI 1.15 (1.05-1.26), and stroke 1.19 (1.01-1.42). The ITALIC! C-statistic improved for the prediction of CV death and non-CABG-related major bleeding when adding GDF-15 to established risk factors. In patients with ACS, higher levels of GDF-15 are associated with raised risks of all types of major non-CABG-related bleeding, spontaneous MI, and stroke as well as CV and total mortality and seem to improve risk stratification for CV-mortality and major bleeding beyond established risk factors. www.clinicaltrials.gov; NCT00391872.

GDF15 Promotes Osteoclast Differentiation and High Serum GDF15 Levels are Associated with Multiple Myeloma Bone Disease

Introduction Growth differentiation factor 15 (GDF15) is a multifunctional growth factor of the transforming growth factor beta (TGFbeta) family that plays a complex role in several types of cancers. In multiple myeloma, GDF15 was recently shown to enhance the tumor-initiating and self-renewal potential of the cancer cells (Tanno et al, Blood 2014). Moreover, blood and bone marrow plasma levels of GDF15 are elevated in myeloma patients compared with healthy persons, and high serum levels are associated with a poor prognosis (Corre et al, Cancer Research 2012). GDF15 seems important for bone remodeling during hypoxia (Hino et al, JBMR 2012), and one study proposed GDF15 to increase osteoclast activation in prostate cancer metastasizing to bone (Wakchoure et al, Prostate 2009). Whether GDF15 plays a role in the bone disease of multiple myeloma is not well characterized. Aim Our aim was to investigate whether high GDF15 serum levels are associated with multiple myeloma bone disease and to characterize the effect of GDF15 on osteoclast differentiation in vitro. Methods GDF15 was measured in serum samples obtained at diagnosis from 138 myeloma patients and 58 age and sex-matched healthy controls. The patient serum samples were collected for the Nordic Myeloma Study Group during a randomized phase 3 clinical trial which compared the effect of two different doses of pamidronate on bone. The bone disease was therefore particularly well-characterized in this study (Gimsing et al, Lancet Oncol 2010). Peripheral blood mononuclear cells (PBMC) isolated from buffy coats were cultured in osteoclast medium (a-MEM with human serum (20%), M-CSF (30ng/ml) and RANKL (50ng/ml)) for up to 14 days with or without GDF15. Purchased pre-osteoclasts (Lonza Inc.) were cultured in purchased bullet kit (OC medium with M-CSF (33ng/ml) and RANKL (66ng/ml)) for 7 days with or without GDF15. Cells positive for tartrate resistant acidic phosphatase (TRAP) staining and with more than two nuclei were counted as osteoclasts. Results GDF15 was significantly higher in serum obtained from myeloma patients (median 1.08 ng/ml, range 27.91) compared with healthy controls (median 0.46 ng/ml, range 1.66, Independent samples Kruskal-Wallis test p In vitro, addition of GDF15 (0-100 ng/ml) to osteoclast precursors or PBMC increased numbers of multi-nucleated TRAP positive cells in a dose dependent manner (n=3, O ng/ml GDF15 mean 25.7, SEM 5.9, 2 ng/ml GDF15 mean 29.7, SEM 4.3, 20 ng/ml GDF15 mean 38.7, SEM 4.9, 50 ng/ml GDF15 mean 53.3, SEM 11.6, 100 ng/ml GDF15 mean 78.7 SEM 7.8). OPG inhibited the pro-osteoclastogenic activity of GDF15 inferring that the effect is mediated by RANKL. Hence, GDF15 increases osteoclast differentiation. Conclusion Serum GDF15 is elevated in myeloma patients with advanced osteolytic bone disease compared to patients with no lesions. GDF15 increases osteoclast differentiation in vitro. Hence, GDF15 could play a role in regulating bone remodeling in myeloma patients. Disclosures No relevant conflicts of interest to declare.

Elevated growth differentiation factor 15 levels predict outcome in patients undergoing transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) has emerged as a treatment of aortic stenosis in patients at high surgical risk. However, risk stratification in this elderly population is challenging, as patients at extreme risk might not benefit from TAVI. While several clinical criteria have been proposed for estimating the outcome, prediction of individual risk remains difficult. Therefore, our aim was to assess the prognostic value of the biomarker growth differentiation factor 15 (GDF15). Over a 2.9-year period, we prospectively enrolled 217 patients undergoing TAVI. Clinical parameters, risk scores, and biomarkers (NT-proBNP and GDF15) were measured at baseline. The primary endpoint was survival time; prognostic factors were analysed by Cox regression analysis. Mean age of study participants was 81.8 ± 6.0 years. Median Logistic EuroSCORE was 20.1 (Q1-Q3 13.6-32.6). Thirty-day mortality was 6.9%; 30.4% of the patients died during follow-up [median 349 days (Q1-Q3 106-660)]. Median pre-procedural GDF15 values were 2256 pg/mL (1585-3082). High GDF15 levels were associated with numerous factors that could contribute to poor outcome. Analyses comparing the upper quartile with the lower three quartiles for biomarker levels revealed a hazard ratio (HR) of increased GDF15 for adverse outcome of 2.4 [95% confidence interval (CI) 1.5-3.9, P < 0.001]. Of note, in multiple analyses, elevated GDF15 levels were superior to NT-proBNP for predicting negative outcome (adjusted HR of GDF15 1.97, 95% CI 1.2-3.3; P = 0.009). Elevated GDF15 levels were superior to NT-proBNP for TAVI risk stratification and provided additional prognostic information. Thus, patient selection for TAVI may benefit from measurement of GDF15.

Growth differentiation factor-15 in children and adolescents with thalassemia intermedia: Relation to subclinical atherosclerosis and pulmonary vasculopathy.

Heart disease is the leading cause of mortality and one of the main causes of morbidity in β-thalassemia. Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor-β superfamily, is a marker of ineffective erythropoiesis in several anemias. To determine GDF-15 levels in children and adolescents with TI and the relation to hemolysis, iron overload and cardiovascular complications. GDF-15 was measured in 35 TI patients without symptoms for heart disease and correlated to echocardiographic parameters and carotid intima media thickness (CIMT). GDF-15 levels were significantly higher in TI patients compared with controls (p < 0.001). Transfusion dependent patients had higher GDF-15 than non-transfusion dependent patients. TI patients with splenectomy, pulmonary hypertension risk, and heart disease had higher GDF-15 levels than those without. GDF-15 was lower among hydroxyurea-treated patients. Multiple linear regression analysis revealed that transfusion index (p=0.012), serum ferritin (p < 0.001), tricuspid regurgitant jet velocity (p < 0.001), ejection fraction (p=0.01) and CIMT (p=0.007) were independently related to GDF-15. According to ROC curve analysis, the cutoff value of GDF-15 at 1500 pg/mL could differentiate patients with and without heart disease. GDF-15 would identify TI patients at increased risk of pulmonary and cardiovascular complications as well as subclinical atherosclerosis.

Letter: GDF15 Is a Novel Biomarker for Impaired Fasting Glucose (Diabetes Metab J 2014;38:472-9).

Growth differentiation factor-15 (GDF15) is widely distributed in mammalian tissues and has been shown to play multiple roles in inflammation, cancer, and cardiovascular diseases [1,2]. It has protective roles in tissue injury or inflammation [1,3,4]; acute tissue injury induces GDF15 level increased compensatively [5,6]. In addition, the fact that overexpression of GDF15 results in improved insulin sensitivity [7,8] and resistance to both genetic and dietary-induced obesity [8], whereas genetic deletion of GDF15 increases glucose level in diabetic rat model [9] supports its favorable effect on metabolic diseases. Despite its beneficial role in experimental studies, subjects with chronic diseases such as cancer, cardiovascular diseases, and metabolic disorders showed paradoxically elevated level of GDF15 [1]. GDF15 level was also increased in subjects with diabetes or prediabetes [10,11]; however, its level in other chronic diseases (e.g., cardiovascular disease) is glucose-independent [12,13]. Cardiovascular disease has been consistently reported to be associated with elevated GDF15 level [6,12,14], and GDF15 is an independent risk factor of cardiovascular disease even after adjusting for glucose level [12,13]. Hong et al. [11] showed that GDF15 levels were elevated in impaired fasting glucose (IFG) and diabetic groups compared with normal glucose tolerance (NGT) group and suggested GDF15 as a novel diagnostic marker for IFG. Considering the increasing epidemiology of IFG or impaired glucose tolerance (IGT) and their impact on cardiovascular disease risk, clinically easier screening tools for the detection of IFG or IGT might be important. However, several things should be considered to address whether GDF15 is a useful diagnostic marker for IFG. First, the main determinant of GDF15 should be investigated. Hong et al. [11] showed the significant correlates of GDF15 levels in monovariate analysis. I wonder what the independent determinants of GDF15 level are in multivariate model including glucose, homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profile. Even in the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) trial which showed high GDF15 level is a risk factor for the progression of glucose intolerance, GDF15 concentration was higher only in individuals with IGT but not in those with IFG compared with those with NGT [10]. IGT state has been reported to show higher peripheral insulin resistance [15] and higher cardiovascular risk as compared with IFG [16]. The results of XENDOS trial [10] and the phenotype of transgenic mouse model [7,8] implied that GDF15 concentration might reflect insulin resistance rather than glucose level itself. HOMA-IR is a very useful marker for insulin resistance; however, it is not a diagnostic marker of IFG or IGT. Second, measurement of hemoglobin A1c (HbA1c) along with glucose level is a better validated tool than measuring GDF15 for the diagnosis of prediabetes. What is the strength of GDF15 in the diagnosis of IFG compared with HbA1c? The area under the receiver operating characteristic curve of GDF15 for detection of IFG was less than 0.7 in Hong's study [11], which implied GDF15 is not a useful diagnostic marker for IFG [17].

Growth differentiation factor-15 (GDF-15) levels are associated with cardiac and renal injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

ObjectiveGrowth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB).MethodsFive arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured.ResultsPlasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels.ConclusionsDuring cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.

Iron overload in transfusion-dependent β-thalassemia patients: defining parameters of comorbidities

Background Iron overload represents a consistent and almost inevitable complication in patients with transfusion-dependent β-thalassemia. The frequently needed erythrocyte transfusions are known to be the leading source of body iron. Increased iron deposition in tissues was strongly suggested to underlie poor growth and development in transfusion-dependent β-thalassemia. This study aimed to investigate the pattern of increase in iron-overload parameters in relation to the therapeutic measures used and explore its effect on the physical growth of patients with transfusion-dependent β-thalassemia. Patients and methods The study included 60 transfusion-dependent β-thalassemia patients (median age 12.5 years, interquartile range 8-17 years) and 20 age-matched and sex-matched controls; each group was further subcategorized into less than 12-year-old and more than 12-year-old subgroups. The studied clinical parameters comprised weight and height, which were used to calculate the body mass index (BMI). Laboratory assays included complete blood counts for the assessment of pretransfusion hemoglobin, serum iron, total iron-binding capacity, ferritin, and growth differentiation factor 15 (GDF15), and the calculation of the transferrin iron saturation percentage (TISP). Results Less than one-third (30%) of the patients had a low BMI; no patient was overweight or obese. The median pretransfusion hemoglobin was 7.1 g/dl (interquartile range 6.8-7.2 g/dl). Fifty-two (86.7%) patients were inadequately chelated, showing serum ferritin levels more than 1000 ng/ml. In patients older than 12 years of age, the BMI was significantly lower in comparison with controls of the same age subgroup as well as patients less than 12 years old. Patients with a low BMI had significantly higher median values of TISP, ferritin, and GDF15 than those with a normal BMI. GDF15 values of the more than 12-year-old patients showed significant positive correlations with TISP and ferritin levels. Setting optimal cutoffs at 63% for TISP and 1210 ng/ml for serum ferritin (area under the curve 0.965 and 0.957, respectively) had indicated low BMI with higher certainties compared with GDF15 at a level of 10 000 pg/ml (area under the curve 0.783) in the more than 12-year-old patients.Conclusion Avoiding iron overload should be warranted for transfusion-dependent β-thalassemia patients to have normal BMI. Although a high GDF15 level is helpful in pointing toward the development of a low BMI, it added no value to TISP or ferritin as indictors of patients' growth retardation.

GDF15 Is Not The Sole Negative Regulator Of Hepcidin In Hereditary Xerocytosis

Hereditary xerocytosis (HX) is a rare form of hemolytic anemia with autosomal dominant inheritance in which iron loading is a prominent feature. The mutated gene causing HX has been identified as FAM38A, which codes for the PIEZO1 protein, a mechanosensitive ion channel [1].The phenotype and genotype of HX has been characterized in a large Canadian family with members spanning three generations and seven decades[2]. Affected family members demonstrate fully-compensated hemolytic anemia (average reticulocyte count 9.9%, hemoglobin 135g/L) and their red cells exhibit decreased levels of osmotic fragility. Despite elevated reticulocyte counts and elevated unconjugated bilirubin levels, serum lactate dehydrogenase levels are normal, suggesting that little if any of the erythropoiesis is ‘ineffective'. Affected family members accumulate iron with age, with average ferritin levels for adults of 478 μg/L. The mechanism behind the iron loading in HX is not known. It is now recognized that in these forms of anemia, hepcidin levels are inappropriately low for the degree of iron store, implying the presence of a mediator produced by the hematopoietic progenitors that acts on the liver to suppress hepcidin production. One pathway that appears important in regulating hepcidin synthesis is the bone morphogenetic protein (BMP)-SMAD signaling cascade. The importance of BMP6 is evident from studies using gene knockout mice. Likewise, liver-targeted knockdown of SMAD4 impairs production of hepcidin and resulted in iron overload in the mice [3]. BMP6 may act in an autocrine fashion, and its secretion by hepatocytes is upregulated in the presence of elevated iron levels.Another proposed pathway for hepcidin regulation – speculated to be involved in the erythropoietic regulation of iron – involves another cytokine also from the TGF-β superfamily. Growth differentiation factor 15 (GDF15) is expressed in high levels in placenta tissue and in smaller quantities in the liver, lungs and kidneys. It is also secreted by erythroblasts, at least in culture. Plasma levels of GDF15 are greatly increased in thalassemia and correlate with markers of erythroid mass such as the soluble transferrin receptor. Serum from thalassemic patients suppresses hepcidin mRNA expression by cultured hepatocytes, an effect partially recapitulated by recombinant GDF15, suggesting that the cytokine requires a co-factor for full hepcidin inhibition [4].We evaluated the level of hepcidin, EPOand ferritin along with GDF15 in 29 affected individuals from a single kindred with HX, and a similar number of age matched unaffected family members to explore the putative erythropoietic regulator of iron absorption in a homogeneous genetic context. We find that ferritin level positively predicts hepcidin level (p<.001) and age negatively predicts hepcidin level. After adjustment for age and ferritin, GDF15 does negatively predict hepcidin level(p=.046 in the final fully-adjusted model). However, in a regression model adjusting for ferritin, age and GDF15, xerocytosis still predicts hepcidin level, with lower hepcidin among the affected family members (p<.001).These results suggest that GDF15 may be one mediator of hepcidin suppression and iron loading in hereditary xerocytosis. However, its effect is insufficient to explain the full iron-loading propensity.'1. Zarychanski, R., et al., Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. Blood, 2012. 120(9): p. 1908-15.2. Houston, B.L., et al., Refinement of the hereditary xerocytosis locus on chromosome 16q in a large Canadian kindred. Blood Cells Mol Dis, 2011. 47(4): p. 226-31.3. Corradini, E., et al., Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology, 2011. 54(1): p. 273-84.4. Tanno, T., et al., High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med, 2007. 13(9): p. 1096-101. Disclosures:No relevant conflicts of interest to declare.

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Growth differentiation factor-15 and prognosis in acute respiratory distress syndrome: a retrospective cohort study

IntroductionWe sought to determine whether higher levels of the novel biomarker growth differentiation factor-15 (GDF-15) are associated with poor outcomes and the presence of pulmonary vascular dysfunction (PVD) in patients with acute respiratory distress syndrome (ARDS).MethodsWe conducted a retrospective cohort study in patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment (FACT) Trial. Patients enrolled in the FACT Trial who received a pulmonary artery catheter (PAC), had plasma available from the same study day and sufficient hemodynamic data to determine the presence of PVD were included. Logistic regression was used to determine the association between GDF-15 level and 60-day mortality.ResultsOf the 513 patients enrolled in the FACT Trial assigned to receive a PAC, 400 were included in this analysis. Mortality at 60 days was significantly higher in patients whose GDF-15 levels were in the third (28%) or fourth (49%) quartile when compared to patients with GDF-15 levels in the first quartile (12%) (P <0.001). Adjusting for severity of illness measured by APACHE III score, the odds of death for patients with GDF-15 levels in the fourth quartile when compared to the first quartile was 4.26 (95% CI 2.18, 10.92, P <0.001). When added to APACHE III alone for prediction of 60-day mortality, GDF-15 levels increased the area under the receiver operating characteristic curve from 0.72 to 0.77. At an optimal cutoff of 8,103 pg/mL, the sensitivity and specificity of GDF-15 for predicting 60-day mortality were 62% (95% CI 53%, 71%) and 76% (95% CI 71%, 81%), respectively. Levels of GDF-15 were not useful in identifying the presence of PVD, as defined by hemodynamic measurements obtained by a PAC.ConclusionsIn patients with ARDS, higher levels of GDF-15 are significantly associated with poor outcome but not PVD.

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

Objective To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc).Methods Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2–7.2 years).Results Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up.Conclusion Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.

Abstract 313: Growth-Differentiation Factor-15 and Heart Failure in Patients with Stable Ischemic Heart Disease (The Heart and Soul Study)

Background: Ischemic heart disease is the strongest risk factor for development of heart failure (HF). Growth-differentiation factor-15 (GDF-15) has been associated with future cardiovascular events in patients with heart failure but its association with incident heart failure in patients with stable ischemic heart disease is unknown. Methods: We measured serum GDF-15 and cardiac disease severity in 981 patients with stable ischemic heart disease who were recruited for the Heart and Soul Study between September 2000 and December 2002. Subsequent heart failure hospitalization was determined by chart review. Results: There were 164 HF hospitalizations over an average of 7.1 years of follow-up. HF hospitalization occurred in 31.4% (102/325) of participants with GDF-15 levels in the highest tertile vs. 3.7% (12/324) in those in the lowest tertile. Participants with GDF-15 levels in the highest tertile had a 3.4-fold higher rate of HF (HR, 3.41; 95% CI, 1.31-8.88; p=0.012) after adjustment for covariates. Each doubling in GDF-15 was associated with an increased risk of HF hospitalization (HR, 2.32; 95% CI, 1.82-3.00; p&lt;0.001). This association persisted after extensive adjustment for covariates including comorbidities, cardiac disease severity, and left ventricular function, inflammatory markers, and adipokines (HR, 1.58; 95% CI, 1.02-2.45; p=0.04). Conclusions: Higher levels of GDF-15 predict HF hospitalizations in patients with stable ischemic heart disease. GDF-15 is an emerging biomarker which identifies patients at highest risk of developing heart failure.

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2-7.2 years). Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up. Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.

Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy

BackgroundThe growth differentiation factor 15 (GDF-15) has been shown up-regulated in stress conditions and to have regulatory actions in myocyte hypertrophy. We hypothesized that GDF-15 could be related to disease severity and functional status in patients with hypertrophic cardiomyopathy (HCM). Methods and resultsWe performed a study which includes 102 consecutive outpatient HCM subjects, 73% males, aged 47.1±14.6years. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, symptom-limited treadmill exercise, 24-hour ECG-Holter monitoring, and magnetic resonance with Gadolinium. Several biomarkers, associated with myocardial remodeling and damage, were compared to GDF-15 levels. The assays were performed with commercial ELISAs or standardized methods when available. There was a significant association between GDF-15 levels and comorbidities, being higher in hypertension (p=0.001), diabetes (p=0.030), atrial fibrillation (p=0.012), dyspnea (p=0.020) and NYHA≥II functional class (p=0.037). GDF-15 levels were positively correlated with clinical variables (age, worse exercise capacity and mild renal dysfunction) and biomarkers of interstitial remodeling, such as metalloproteinase-2 (r: 0.40; p=0.009), N-terminal pro-B-type natriuretic peptide (r: 0.28; p=0.049), high-sensitivity troponin T (r: 0.30; p=0.003) and von Willebrand factor (r: 0.33; p=0.001). Multivariate analysis was assessed to estimate the involvement of these different factors in the GDF-15 levels, confirming the independent implication of severe dyspnea and functional status. ConclusionsThe present results show that higher levels of GDF-15 are associated to conditions of severe disease in HCM. Hence, GDF-15 is suggested as a novel marker related to the severity and could represent a further useful tool in monitoring functional capacity of HCM patients.