Measurement Of Growth Differentiation Factor 15 Research Articles

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 association of growth differentiation factor 15 (GDF-15) level with extent of left atrial fibrosis in patients with nonvalvular atrial fibrillation

Aim To study the relationship between the serum level of growth differentiation factor 15 (GDF-15) and clinical and functional characteristics and severity of left atrial (LA) fibrosis in patients with nonvalvular atrial fibrillation (AF).Material and methods The study included 87 patients with nonvalvular AF (62 patients with paroxysmal AF and 25 patients with persistent AF) aged 27 to 72 years (mean age, 56.9±9.2 years, 32 women). 85 % of these patients had arterial hypertension (AH), 33 % had AH and ischemic heart disease, and 12.6 % had isolated AF and were hospitalized for primary catheter ablation. General clinical evaluation, echocardiography, laboratory tests including measurement of GDF-15 and NT-proBNP concentrations in blood were performed. As a surrogate substrate of LA fibrosis during the electroanatomical voltage mapping, the area of low-voltage (&lt;0.5 mV) zones in LA was calculated, including the total LA fibrosis area (Sf, cm2) and a percentage of fibrosis of the total LA area (Sf%).Results Median concentration of GDF-15 was 767.5 [590.0; 951.0] pg /ml. The GDF-15 level positively correlated with age, presence and severity of AH and chronic heart failure, body mass index, and degree of obesity, CHA2DS2 VASc score, level of NT-proBNP, and LA fibrosis area (Sf and Sf%) and negatively correlated with the indexes of left ventricular diastolic function, e' septal and e' lateral. The area of fibrosis increased with increasing GDF-15 concentrations divided into quartiles; Sf% exceeded 20 % at GDF-15 levels higher than median. After a comparative analysis of patients with Sf% ≤20 % and &gt;20 %, statistically significantly different variables were included into a stepwise logistic regression analysis. Two independent predictors of LA fibrosis &gt;20% were identified: a concentration of GDF-15 higher than median (odd ratio (OR), 3.318, 95 % confidence interval (CI): 1.184-9.298) and LA volume index (OR, 1.079, 95 % CI: 1.014-1.147). According to results of the ROC analysis, the area under the curve (AUC) was 0.762 (p=0.000), the model specificity was 72.3 %, sensitivity was 72.4 %, and the prediction accuracy was 72.4 %.Conclusion Blood levels of GDF-15 were associated with the presence and severity of major risk factors for AF and the area of LA fibrosis. In this study, a level of GDF-15 above the median and the LA volume index were independent predictors of LA fibrosis &gt; 20% of the LA area.

Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions.

Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins. In this study, we aimed to validate the diagnostic reliability of FGF21 and GDF15 assays in MDs and to evaluate a possible correlation between serum levels of the two biomarkers with genotype of MD patients. Serum FGF21 and GDF15 levels were measured by a quantitative ELISA. Our results showed increased serum FGF21 and GDF15 levels in MD patients; however, GDF15 measurement seems to be more sensitive and specific for screening tests for MD than FGF21. Moreover, we showed a positive correlation with both FGF21 and GDF15 levels and the number of COX-negative fibers. Finally, we also demonstrated that the increase of FGF21 and GDF15 was related to MDs caused by mitochondrial translation defects, and multiple and single mtDNA deletions, but not to MDs due to mutations in the respiratory chain subunits.

Repeated measurement of growth-differentiation factor-15 in Chinese Han patients with post-myocardial infarction chronic heart failure.

BackgroundGrowth-differentiation factor-15 (GDF-15) is a promising prognostic biomarker in patients with chronic heart failure (CHF). Comparatively little is known about the value of repeated measurement of GDF-15 with CHF in Chinese Han population. This study sought to identify the clinical value of repeated measurement of GDF-15 in Chinese Han patients with post-myocardial infarction CHF.MethodsIn total, 232 consecutive Chinese Han patients with post-myocardial infarction CHF were enrolled prospectively from January 2014 to June 2016.The plasma concentration of GDF-15 was determined on admission and over 12 months. Patients were followed up for all-cause death and a composite outcome of major adverse cardiac events (MACE) included all-cause death, myocardial infarction and first heart failure (HF) re-hospitalization. Association with other clinical variables and adverse outcomes of repeated measurement of GDF-15 was explored.ResultsThe median baseline GDF-15 level was 2025 ng/L. Baseline GDF-15 was moderately associated with baseline N-terminal pro-B type natriuretic peptide (NT-proBNP) (coefficient 0.561, P < 0.001). During a median follow-up of 20 months, there were 53 deaths and 100MACE. GDF-15 remained an independent predictor of all-cause death (adjusted hazard ratio 1.826 per 1 Ln U, 95% CI: 1.037–8.360; P = 0.037) and MACE (adjusted hazard ratio 2.243 per 1 Ln U, 95% CI: 1.181–1.775; P < 0.001) adjusted for established risk factors. Repeated measurement of GDF-15 was performed in 173 survivals over 12months. Increase of GDF-15 over 12 months was associated with dilatation of left ventricle and acted as an independent predictor of subsequent all-cause death (adjusted HR = 3.164, 95% CI: 1.245–0.041; P = 0.015). In the joint model, GDF-15 was also shown to be a risk factor for all-cause death (HR = 2.749, 95% CI: 1.667–3.831; P < 0.001) and MACE (HR = 2.434, 95% CI: 1.425–3.443; P < 0.001).ConclusionsRepeated measurements of GDF-15 have promising prognostic value of the risk of all-cause death in Chinese Han patients with CHF post-myocardial infarction. GDF-15 may influence the post-myocardial infarction CHF through the path physiological pathway of myocardial remodeling.

Defining reference intervals for a serum growth differentiation factor-15 (GDF-15) assay in a Caucasian population and its potential utility in diabetic kidney disease (DKD)

Growth differentiation factor-15 (GDF-15), a stress responsive cytokine, is a promising biomarker of renal functional decline in diabetic kidney disease (DKD). This study aimed primarily to establish normative data and secondarily to evaluate the potential utility of GDF-15 in DKD using Roche Diagnostics electrochemiluminescence immunoassay (ECLIA) in an Irish Caucasian population. Following informed consent, 188 healthy volunteers and 128 participants with diabetes (72 with and 56 without DKD) were recruited to a cross-sectional study. Baseline demographics, anthropometric measurements and laboratory measurements were recorded. Blood for GDF-15 measurement was collected into plain specimen tubes kept at room temperature and processed (centrifugation, separation of serum, freezing at -80 °C) within 1 h of phlebotomy pending batch analyses. Reference intervals were determined using the 2.5th and 97.5th percentiles for serum GDF-15 concentration. Of 188 healthy participants, 63 failed to meet study inclusion criteria. The reference interval for serum GDF-15 was 399 ng/L (90% confidence interval [CI]: 399-399) - 1335 ng/L (90% CI: 1152-1445). Receiver operator characteristics (ROC) curve analysis for DKD determined the area under the ROC curve to be 0.931 (95% CI: 0.893-0.959; p<0.001). The optimum GDF-15 cutoff for predicting DKD was >1136 ng/L providing a diagnostic sensitivity and specificity of 94.4% and 79%, respectively, and positive likelihood ratio of 4.5:1 (95% CI: 3.4-6.0). The reference interval for serum GDF-15 in a healthy Irish Caucasian population using Roche Diagnostics ECLIA was established and a preliminary determination of the potential of GDF-15 as a screening test for DKD was made. Further prospective validation with a larger DKD cohort will be required before the cutoff presented here is recommended for clinical use.

Predictive value of long-term changes of growth differentiation factor-15 over a 27-year-period for heart failure and death due to coronary heart disease.

BackgroundGrowth differentiation factor-15 (GDF-15), Cystatin C and C-reactive protein (CRP) have been discussed as biomarkers for prediction of cardiac diseases. The aim of this study was to investigate the predictive value of single and repeated measurements of GDF-15 compared to Cystatin C and CRP for incidence of heart failure (HF) and death due to coronary heart disease (CHD) in the general population.Methods and resultsLevels of GDF-15, CRP and Cystatin C were determined in three repeated measurements collected 5 years apart in the DAN-MONICA (Danish-Multinational MONitoring of trends and determinants in Cardiovascular disease) cohort (participants at baseline n = 3785). Cox regression models adjusted for cardiovascular risk factors revealed significantly increased hazard ratios (HR) for GDF-15 for incident HF 1.36 (HR per interquartile range (IQR) increase, 95% confidence interval (CI): 1.16; 1.59) and for death from CHD 1.51 (HR per IQR increase, 95% CI: 1.31, 1.75) (both with p<0.001). Joint modeling of time-to-event and longitudinal GDF-15 over a median 27-year follow-up period showed that the marker evolution was positively associated with death of CHD (HR per IQR increase 3.02 95% CI: (2.26, 4.04), p < 0.001) and HF (HR per IQR increase 2.12 95% CI: (1.54, 2.92), p<0.001). However using Cox models with follow-up time starting at the time of the third examination, serial measurement of GDF-15, modeled as changes between the measurements, did not improve prediction over that of the most recent measurement.ConclusionsGDF-15 is a promising biomarker for prediction of HF and death due to CHD in the general population, which may provide prognostic information to already established clinical biomarkers. Repeated measurements of GDF-15 displayed only a slight improvement in the prediction of these endpoints compared to a single measurement.

Myocardial fibrosis detected by magnetic resonance in systemic sclerosis patients – Relationship with biochemical and echocardiography parameters

ObjectivesSystemic scleroderma (SSc) is a rare connective tissue disease presenting with fibrosis affecting skin and internal organs. Cardiovascular magnetic resonance (CMR) with quantification of extracellular volume (ECV) and T1 mapping might help to detect heart involvement. We aimed to evaluate whether myocardial involvement correlates with functional and laboratory parameters. MethodsThirty-three asymptomatic SSc patients (29 women, aged 56.6±12.2years) and 20 controls (10 women, 53.7±13.1years) were examined using CMR, echocardiography, functional pulmonary test and laboratory assessment. ResultsSSc patients had higher ECV (27.5±2.8 vs. 22.8±1.9%, P<0.0001) and native T1 values (1258.9±51.2 vs. 1192.2±32.6, P<0.0001) compared to controls. Plasma level of growth differentiation factor 15 (GDF-15) and galectin-3 correlated with ECV (r=0.35; P=0.0076 and r=0.38; P=0.0081) and native T1 (r=0.31; P=0.023 and r=0.35; P=0.012). GDF-15 was also negatively correlated with diffusing capacity of the lung for carbon monoxide (r=−0.58; P=0.0004) and positively correlated with modified Rodnan skin score (r=0.59; P=0.0003). Conventional echocardiography parameters were similar in SSc patients and controls. However, the global longitudinal peak systolic strain (GLPS) was lower in SSc patients compared to controls (18.6±1.6 vs. 21.1±1.2%; P<0.0001). GLPS also negatively correlated with native T1 (r=−0.35; P=0.0097), ECV (r=−0.33; P=0.014), GDF 15 (r=−0.31; P=0.022), and galectin-3 (r=−0.37; P=0.0076). ConclusionsAsymptomatic heart involvement is common in SSc patients and includes focal and diffuse myocardial fibrosis. GDF-15 and galectin-3 were positively correlated with myocardial fibrosis parameters. Future outcome studies must show whether measurement of GDF-15 and galectin-3 in SSC patients might be may be useful in clinical practice.

Abstract 13290: GDF-15 at One Month After an Acute Coronary Syndrome is Associated With Increased Risk of Major Bleeding - A PLATO Biomarker Substudy

Introduction: Levels of Growth Differentiation Factor-15 (GDF-15) are associated with major bleeding events in acute coronary syndromes (ACS), when measured at the time of initial presentation. We hypothesized that an additional measurement of GDF-15 at 1 month after ACS provides additional information regarding risk of major bleeding. Methods: In the PLATO trial, levels of GDF-15 were determined in 4049 ACS patients at both baseline and at 1 month, using an immunoassay (Roche). The primary endpoint was non-CABG related major bleeding. A 1-month landmark analysis was performed, in relation to GDF-15 elevation status at baseline and 1 month, using a cutoff of 1800 ng/L. The relation between GDF-15 at 1 month and the primary endpoint from 1 month onward was evaluated using a Cox proportional hazards model; adjusting for baseline GDF-15, age, anemia (hemoglobin &lt;130 g/L in men, &lt;120 g/L in women), impaired renal function (eGFR &lt;50 mL/min/1.73m2), and history of gastrointestinal bleeding. Results: In the unadjusted analysis, patients with GDF-15 &gt;1800 ng/L at 1 month had increased bleeding rates during follow-up, irrespective of the baseline value. Patients with GDF-15 ≤1800 ng/L at 1 month had lower bleeding risk regardless of initial level (see figure). In the adjusted analysis, GDF-15 &gt;1800 ng/L at 1 month was independently associated with the outcome, hazard ratio 3.39 (95% CI 1.89-6.09). Conclusions: The level of GDF-15 at 1 month after ACS is related to the risk of bleeding during dual antiplatelet treatment. Assessment of GDF-15 level at 1 month provides additional information on the subsequent bleeding risk, regardless of the patient’s index GDF-15 level in the acute phase, and may therefore be helpful for decision-making on continued dual antiplatelet treatment.

Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders

ObjectiveThe diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often present with solitary, or a combination of, symptoms caused by each organ insufficiency, which may be the result of respiratory chain enzyme deficiency. Growth differentiation factor 15 (GDF‐15) has been reported to be elevated in serum of patients with MDs. In this study, we investigated whether GDF‐15 is a more useful biomarker for MDs than several conventional biomarkers.MethodsWe measured the serum levels of GDF‐15 and fibroblast growth factor 21 (FGF‐21), as well as other biomarkers, in 48 MD patients and in 146 healthy controls in Japan. GDF‐15 and FGF‐21 concentrations were measured by enzyme‐linked immunosorbant assay and compared with lactate, pyruvate, creatine kinase, and the lactate‐to‐pyruvate ratio. We calculated sensitivity and specificity and also evaluated the correlation based on two rating scales, including the Newcastle Mitochondrial Disease Rating Scale (NMDAS).ResultsMean GDF‐15 concentration was 6‐fold higher in MD patients compared to healthy controls (2,711 ± 2,459 pg/ml vs 462.5 ± 141.0 pg/mL; p < 0.001). Using a receiver operating characteristic curve, the area under the curve was significantly higher for GDF‐15 than FGF‐21 and other conventional biomarkers. Our date suggest that GDF‐15 is the most useful biomarker for MDs of the biomarkers examined, and it is associated with MD severity.InterpretationOur results suggest that measurement of GDF‐15 is the most useful first‐line test to indicate the patients who have the mitochondrial respiratory chain deficiency. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

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.

Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide. Currently, alpha-fetoprotein (AFP) is used as a standard serum marker for the detection of HCC, but its sensitivity and specificity are unsatisfactory, and optimal diagnostic markers for cirrhosis are lacking. We previously reported that growth differentiation factor 15 (GDF15) was significantly induced in HCV-infected hepatocytes. This study aimed to investigate GDF15 expression and its correlation with hepatitis virus-related liver diseases. A total of 412 patients with various liver diseases were studied. Healthy and Mycobacterium tuberculosis-infected subjects were included as controls. Serum and tissue GDF15 levels were measured. Serum GDF15 levels were significantly increased in patients with HCC (6.66±0.67 ng/mL, p<0.0001) and cirrhosis (6.51±1.47 ng/mL, p<0.0001) compared with healthy controls (0.31±0.01 ng/mL), though the GDF15 levels in HBV and HCV carriers were moderately elevated (1.34±0.19 ng/mL and 2.13±0.53 ng/mL, respectively). Compared with HBV or HCV carriers, GDF15 had a sensitivity of 63.1% and a specificity of 86.6% at the optimal cut-off point of 2.463 ng/mL in patients with liver cirrhosis or HCC. In HCC patients, the area under the receiver operating curve was 0.84 for GDF15 and 0.76 for AFP, but 0.91 for the combined GDF15 and AFP. Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups. GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Using a combination of GDF15 and AFP will improve the sensitivity and specificity of HCC diagnosis. Further research and the clinical implementation of serum GDF15 measurement as a biomarker for HCC and cirrhosis are recommended.

Adjustment of the GRACE score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-ST-elevation acute coronary syndrome

The aim of the study was to evaluate whether knowledge of the circulating concentration of growth differentiation factor 15 (GDF-15) adds predictive information to the Global Registry of Acute Coronary Events (GRACE) score, a validated scoring system for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). We also evaluated whether GDF-15 adds predictive information to a model containing the GRACE score and N-terminal pro-B-type natriuretic peptide (NT-proBNP), a prognostic biomarker already in clinical use. The GRACE score, GDF-15, and NT-proBNP levels were determined on admission in 1122 contemporary patients with NSTE-ACS. Six-month all-cause mortality or non-fatal myocardial infarction (MI) was the primary endpoint of the study. To obtain GDF-15- and NT-proBNP-adjusted 6-month estimated probabilities of death or non-fatal MI, statistical algorithms were developed in a derivation cohort (n = 754; n = 66 reached the primary endpoint) and applied to a validation cohort (n = 368; n = 33). Adjustment of the GRACE risk estimate by GDF-15 increased the area under the receiver-operating characteristic curve (AUC) from 0.79 to 0.85 (P < 0.001) in the validation cohort. Discrimination improvement was confirmed by an integrated discrimination improvement (IDI) of 0.055 (P = 0.005). A net 31% of the patients without events were reclassified into lower risk, and a net 27% of the patients with events were reclassified into higher risk, resulting in a total continuous net reclassification improvement [NRI(>0)] of 0.58 (P = 0.002). Addition of NT-proBNP to the GRACE score led to a similar improvement in discrimination and reclassification. Addition of GDF-15 to a model containing GRACE and NT-proBNP led to a further improvement in model performance [increase in AUC from 0.84 for GRACE plus NT-proBNP to 0.86 for GRACE plus NT-proBNP plus GDF-15, P = 0.010; IDI = 0.024, P = 0.063; NRI(>0) = 0.42, P = 0.022]. We show that a single measurement of GDF-15 on admission markedly enhances the predictive value of the GRACE score and provides moderate incremental information to a model including the GRACE score and NT-proBNP. Our study is the first to provide simple algorithms that can be used by the practicing clinician to more precisely estimate risk in individual patients based on the GRACE score and a single biomarker measurement on admission. The rigorous statistical approach taken in the present study may serve as a blueprint for future studies exploring the added value of biomarkers beyond clinical risk scores.

Levels of growth differentiation factor-15 are high and correlate with clinical severity in transfusion-independent patients with β thalassemia intermedia

Transfusion-independent patients with β thalassemia intermedia (TI) experience a variety of clinical complications attributed to the underlying ineffective erythropoiesis and subsequent anemia, hemolysis, and iron overload. Growth differentiation factor-15 (GDF-15) was recently investigated as a marker of ineffective erythropoiesis in several anemias. In this work, we evaluated GDF-15 levels in 55 patients with TI. The mean GDF-15 level was 25,197.8 ± 16,208.9 pg/ml which is lower than values reported for patients with thalassemia major, yet considerably higher than those reported in patients with other congenital and acquired anemias. GDF-15 levels were significantly higher in splenectomized compared to non-splenectomized patients and correlated with anemia, markers of iron overload, and a pre-defined clinical severity score. Further studies are needed to determine the practical utility of GDF-15 measurement and its potential to reflect the severity of the clinical course in TI patients.

Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring‐sideroblasts

The disturbed erythropoiesis in patients with refractory anaemia with ring-sideroblasts (RARS) is characterized by intramedullary apoptosis of erythroid precursors and increased iron accumulation in mitochondria. To gain insight into these pathophysiological mechanisms we compared the gene expression profile (GEP) of erythroid precursors from RARS patients to the GEP of normal erythroid precursors. Three hundred sixty four probe sets were up-, and 253 probe sets downregulated in RARS cells. Interestingly, Growth Differentiation factor 15 (GDF15), a cytokine from the TGFbeta family, was dramatically upregulated in all RARS patients. Measurement of GDF15 in the sera from twenty RARS patients confirmed this finding by showing significantly, 7.2-fold, increased protein levels (3254 +/- 1400 ng/ml vs. 451 +/- 87 ng/ml in normals). In vitro studies demonstrated erythroid-specific production of GDF15 and dependence on erythropoietin. Induction of apoptosis by arsenic trioxide, a drug which acts via reduction of the mitochondrial membrane potential, also stimulated GDF15 production. Downregulation of endogenous GDF15 production in erythoblasts by specific siRNA led to diminished erythroid differentiation. Taken together, our findings demonstrate a new role for GDF15 in normal erythropoiesis as well as in the ineffective erythropoiesis of RARS patients.

Abstract 5016: Growth-Differentiation Factor-15 is an Independent Predictor of Cardiovascular Events and Mortality in Patients with Stable Coronary Artery Disease

Circulating levels of the TGF β-related cytokine, growth-differentiation factor-15 (GDF-15), provide independent prognostic information in patients with unstable coronary artery disease (CAD). To explore the prognostic utility of GDF-15 in patients with stable CAD, we analyzed the relation of GDF-15 to mortality and cardiovascular (CV) events in the AtheroGene registry which enrolled consecutive patients with stable angina and at least one stenosis &gt;30% in a larger coronary artery. Patients were followed for a median of 3.6 years. Serum samples for measurement of GDF-15 along with other biomarkers were available from 1352 patients. Two pre-specified cutoff points (1200 and 1800 ng/L) were used to identify different risk groups. 55.9%, 26.4%, and 17.7% of the patients presented with GDF-15 values &lt;1200 ng/L, between 1200 and 1800 ng/L, and &gt;1800 ng/L, respectively. Increasing levels of GDF-15 were related to age (P&lt;0.001), hypertension (P=0.01), diabetes mellitus (P&lt;0.001), low HDL cholesterol (P&lt;0.001), and the extent of CAD (P=0.001). Moreover, significant relations to hsCRP, troponin T, NT-proBNP, and reduced renal function (GFR) were observed (all P&lt;0.001). Increasing levels of GDF-15 were associated with an increased risk of all-cause mortality (P&lt;0.001, log-rank test), CV mortality (P&lt;0.001), and CV events (P&lt;0.001). Receiver operating curve analyses confirmed GDF-15 as a strong marker of 2-year adverse outcomes (area under the curve for all-cause mortality, 0.79; CV mortality, 0.81; CV events, 0.70). By multiple Cox regression analysis, GDF-15 emerged as an independent predictor of all-cause mortality (HR 2.1 per one standard deviation of lnGDF-15 [95% CI 1.6 –2.8], P&lt;0.001), CV mortality (HR 2.2 [95% CI 1.5–3.3], P&lt;0.001), and CV events (HR 1.7 [95% CI 1.3–2.4], P=0.001) after adjustment for baseline characteristics, clinical variables, LDL/HDL ratio, hsCRP, troponin T, NT-proBNP, and GFR. Patients with a GDF-15 level above 1800 ng/L had a highly elevated risk of CV mortality even in the fully adjusted model (HR 5.2 [95% CI 1.6 –16.1], P=0.005). These data identify GDF-15 as a powerful and independent biomarker of mortality and CV events in patients with stable CAD.