Plasma Growth Differentiation Factor-15 Research Articles

Circulating GDF-15 levels predict future secondary manifestations of cardiovascular disease explicitly in women but not men with atherosclerosis

BackgroundElevated serum levels of growth differentiation factor-15 (GDF-15), is an established risk factor for a range of cardiovascular diseases.We aimed to evaluate the predictive value of plasma GDF-15 as a biomarker for secondary cardiovascular events (CVE) in patients with atherosclerosis undergoing carotid endarterectomy (CEA). Secondly, we determined whether plasma GDF-15 was associated with carotid plaque characteristics. MethodsCirculating GDF-15 levels were determined by Luminex assay in a cohort of 1056 patients from the Athero-Express biobank. Composite endpoint was defined as major CVE, death and peripheral vascular interventions. Findings were validated in 473 patients from the independent Carotid Plaque Imaging Project biobank. ResultsGDF-15 levels did not associate with secondary CVE in the total cohort. However, following a significant interaction with sex, it was found to be strongly, independently predictive of secondary CVE in women but not men (quartile 4 vs. quartile 1: HR 3.04 [95% CI 1.35–6.86], p=0.007 in women vs. HR 0.96 [95% CI 0.66–1.40], p=0.845 in men). This was also observed in the validation cohort (women: HR 2.28 [95% CI 1.04–5.05], p=0.041), albeit dependent upon renal function. In addition, GDF-15 was associated with the presence of plaque smooth muscle cells and calcification. ConclusionHigh circulating GDF-15 levels are predictive of secondary CVE in women but not in men with carotid atherosclerotic disease undergoing CEA, suggesting a potential use for GDF-15 as a biomarker for secondary prevention in women. Sex differences in the role of GDF-15 in atherosclerotic disease deserve further interest.

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.

Association between pentraxin 3 and growth differentiation factor-15 in adolescent male swimmers.

The purpose of this study was to evaluate plasma pentraxin 3 (PTX3) and growth differentiation factor-15 (GDF-15) concentrations in adolescent male swimmers and compare any possible interactions with canonical biochemical parameters. Twenty-six adolescent male swimmers and 29 gender- and age-matched sedentary controls participated in this study. Fasting blood samples were taken from the participants. Biochemical values and plasma PTX3 and GDF-15 levels were measured. Plasma PTX-3 levels were markedly higher in the adolescent male swimmers than in the sedentary controls (378.44 ± 173.93 vs 257.82 ± 103.20 pg mL-1, p = 0.002). There was no significant difference in GDF-15 levels between the two groups (186.12 ± 40.65 vs 203.60 ± 36.77 pg mL-1 in the swimmers and the sedentary, respectively, P = 0.068). Relationship between PTX3 and GDF-15 was linear. This is the first study showing that adolescent male swimmers have higher PTX3 levels than sedentary controls and that there is a linear relationship between PTX3 and GDF-15 (Tab. 3, Fig. 2, Ref. 26).

Preoperative plasma growth-differentiation factor-15 for prediction of acute kidney injury in patients undergoing cardiac surgery.

BackgroundGrowth-differentiation factor-15 (GDF-15) is an emerging humoral marker for risk stratification in cardiovascular disease. Cardiac-surgery-associated acute kidney injury (CSA-AKI), an important complication in patients undergoing cardiac surgery, is associated with poor prognosis. The present secondary analysis of an observational cohort study aimed to determine the role of GDF-15 in predicting CSA-AKI compared with the Cleveland-Clinic Acute Renal Failure (CC-ARF) score and a logistic regression model including variables associated with renal dysfunction.MethodsPreoperative plasma GDF-15 was determined in 1176 consecutive patients undergoing elective cardiac surgery. Patients with chronic kidney disease stage 5 were excluded. AKI was defined according to Kidney-Disease-Improving-Global-Outcomes (KDIGO) - creatinine criteria. The following variables were screened for association with development of postoperative AKI: age, gender, additive Euroscore, serum creatinine, duration of cardiopulmonary bypass, duration of surgery, type of surgery, total circulatory arrest, preoperative hemoglobin, preoperative oxygen-supplemented cerebral oxygen saturation, diabetes mellitus, hemofiltration during ECC, plasma GDF-15, high sensitivity troponin T (hsTNT), and N-terminal prohormone of B-type natriuretic peptide (NTproBNP).ResultsThere were 258 patients (21.9 %) with AKI (AKI stage 1 (AKI-1), n = 175 (14.9 %); AKI-2, n = 6 (0.5 %); AKI-3, n = 77 (6.5 %)). The incidence of AKI-1 and AKI-3 increased significantly from the lowest to the highest tertiles of GDF-15. In logistic regression, preoperative GDF-15, additive Euroscore, age, plasma creatinine, diabetes mellitus, and duration of cardiopulmonary bypass were independently associated with AKI. Inclusion of GDF-15 in a logistic regression model comprising these variables significantly increased the area under the curve (AUC 0.738 without and 0.750 with GDF-15 included) and the net reclassification ability to predict AKI. Comparably, in receiver operating characteristic analysis the predictive capacity of the CC-ARF score (AUC 0.628) was improved by adding GDF-15 (AUC 0.684) but this score also had lower predictability than the logistic regression model. In random forest analyses the predictive capacity of GDF-15 was especially pronounced in patients with normal plasma creatinine.ConclusionThis suggests that preoperative plasma GDF-15 independently predicts postoperative AKI in patients undergoing elective cardiac surgery and is particularly helpful for risk stratification in patients with normal creatinine.Trial registration NCT01166360 on July 20, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1482-3) contains supplementary material, which is available to authorized users.

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.

Plasma growth differentiation factor 15 predicts first-ever stroke in hypertensive patients.

Growth differentiation factor 15 (GDF-15) is a relatively new biomarker that predicts adverse stroke outcomes. However, the association of GDF-15 with first-ever stroke in hypertensive patients has not yet been evaluated. The objective of this study was to evaluate the clinical implications of plasma GDF-15 on the development of first-ever stroke in patients with hypertension.In total, 254 patients with hypertension without a history of stroke were included from March 2010 to August 2010 and followed up until June 2013. The baseline circulating GDF-15 was determined by enzyme-linked immunosorbent assays.During a follow-up of 3.0 ± 0.6 years, 22 (8.7%) first-ever strokes were identified, including 12 ischemic strokes and 10 intracerebral hemorrhages (ICH). According to tertiles of GDF-15, survival free of first-ever stroke was lower in the highest tertile of GDF-15 (log-rank P = 0.001). By backward stepwise Cox-regression analysis, adjusted for age, gender, diabetes mellitus, hyperlipidemia, hypertension stage, body mass index, cigarette smoking, anti-hypertensive drugs, and uric acid, every 100 pg/mL-increase in plasma of GDF-15 predicted an 11% greater risk of first-ever stroke (hazard ratios [HR]: 1.11, 95% confidence interval [CI]: 1.03-1.20, P = 0.010) and an 18% increase in ischemic stroke risk (HR: 1.18, 95% CI: 1.07-1.30, P = 0.001). Receiver operating characteristic analysis indicated that GDF-15 had reasonable accuracy to predict first-ever stroke (area under curve = 0.73, 95% CI: 0.62-0.83, P < 0.001).This study identifies that GDF-15 is an independent predictor of first-ever stroke, especially for ischemic stroke in the patients with hypertension.

Plasma levels of growth differentiation factor-15 are associated with myocardial injury in patients undergoing off-pump coronary artery bypass grafting.

Growth differentiation factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiovascular diseases. We therefore aimed to investigate the role of GDF-15 in the occurrence of cardiac injury during off-pump coronary artery bypass grafting (OPCAB). 55 consecutive patients with coronary artery diseases were recruited in this prospective, observational study. All patients were operated for OPCAB surgery. Serial blood samples were collected preoperatively, 12 hours and 36 hours after surgery. GDF-15, together with C-reactive protein, cardiac troponin I, creatine kinase MB and N-terminal pro B-type natriuretic peptide levels in plasma were measured at each time-point. GDF-15 levels increased significantly at 12 hours after surgery, attaining nearly 2.5 times the baseline levels (p < 0.001). Postoperative GDF-15 levels correlated positively with cTnI (p = 0.003) and EuroSCORE II (p = 0.013). According to the ROC curves, postoperative plasma GDF-15 was found to be the best biomarker to predict perioperative cardiac injury, compared with cTnI, CK-MB and EuroSCORE II. Circulating GDF-15 is a promising novel biomarker for identifying perioperative myocardial injury in patients undergoing OPCAB.

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.

Interleukin 6, galectin 3, growth differentiation factor 15, and soluble ST2 for mortality prediction in critically ill patients

PurposeThe aim of this study was to compare the prognostic value of interleukin 6 (IL-6), galectin 3, growth differentiation factor 15 (GDF-15), and soluble ST2 (sST2) in an unselected cohort of critically ill patients. MethodsDuring a study period of 1 year, we recruited 530 consecutive patients admitted to a medical intensive care unit of a tertiary care hospital. We examined a combination of inflammatory, renal, and cardiac biomarkers for the prediction of 90-day all-cause mortality. ResultsDuring follow-up, 118 patients died (22%). In univariate analyses, increased IL-6, galectin 3, GDF-15, and sST2 plasma concentrations at baseline were strong prognostic markers. However, in the multivariate models, only IL-6 and sST2 remained independent biomarkers adding additional prognostic information to the routinely used Simplified Acute Physiology Score (SAPS) II. Using a simple multimarker approach, patients with increased SAPS II, IL-6, and sST2 (ie, SAPS II >35, IL-6 >32.3pg/mL, and sST2 >103ng/mL) had the poorest outcome. ConclusionsIn this heterogeneous group of critically ill patients, only SAPS II, IL-6, and sST2 remained independent and additive prognostic markers for 90-day all-cause mortality. A combination of the SAPS II with the 2 complementary biomarkers might provide a valuable tool for risk stratification of critically ill patients.

Riesgo cardiovascular a largo plazo tras un síndrome coronario agudo, todavía un reto

Growth Differentiation Factor-15 (GDF-15) predicts death and cardiovascular events in acute coronary syndromes (ACS). We aimed to assess the long-term prognostic value of GDF-15 in ACS.We included 358 patients with ACS who underwent coronary angiography. Plasma GDF-15 was measured and clinical data and long-term events were registered. Incremental value of GDF-15 for prognosing all-cause death above a clinical model including GRACE score, left ventricular ejection fraction <40%, prior myocardial infarction and age was assessed.GDF-15 concentrations >1800 ng/L were associated with an increased prevalence of cardiovascular risk factors. During 6.5 years of follow-up 56 patients died, 7 had values of GDF-15 < 1200 ng/L, 7 between 1200 and 1800 ng/L and 42 > 1800 ng/L. After adjustment for potential confounders, GDF-15 > 1800 ng/L were independently associated with all-cause death (HR 4.09; 95% CI 1.57–10.71; p = .004) and the composite of major adverse cardiovascular events (MACE) (HR 2.48; 95% CI 1.41–4.34; p = .001). For long-term all-cause death a significant increase of ROC curve was seen after addition of GDF-15 to a clinical model 0.876 (95% CI 0.823–0.928; p = .014). Same improvements were found for net reclassification improvement (0.776; 95% CI 0.494–1.037; p < .001) and integrated discrimination improvement (0.112; 95% CI 0.055–0.169; p < .001). Multivariate competing risk model showed a significant association between GDF-15 > 1800 ng/L and the incidence of heart failure but not of myocardial infarction.In the setting of ACS, GDF-15 is associated with long-term all-cause death, MACE and heart failure and provides incremental prognostic value beyond traditional risks factor.

Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction.

Growth differentiation factor 15 (GDF15) is a cytokine highly expressed in states of inflammatory stress. We aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction(HFrEF), compared with N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of haemodynamic wall stress. Plasma GDF15 and NT-proBNP were prospectively measured in 916 consecutive patients with HFrEF (EF <50%; n = 730) and HFpEF (EF ≥50%; n = 186), and measured again at 6 months in 488 patients. Patients were followed up for a composite outcome of death or first HF rehospitalization. Median GDF15baseline values were similarly elevated in HFpEF [2862 (1812 represent the 25th percentile and 4176 represent the 75th percentile) ng/L] and HFrEF [2517 (1555, 4030) ng/L] (P = 0.184), whereas NT-proBNP was significantly lower in HFpEF than HFrEF (1119 ng/L vs. 2335 ng/L, P < 0.001). Independent correlates of GDF15baseline were age, systolic blood pressure, New York Heart Association (NYHA) class, diabetes, atrial fibrillation, sodium, haemoglobin, creatinine, diuretic therapy, high sensitivity troponin T (hsTnT) and NT-proBNP (all P < 0.05). During a median follow-up of 23 months, there were 379 events (307 HFrEF, 72 HFpEF). GDF15 remained a significant independent predictor for composite outcome even after adjusting for important clinical predictors including hsTnT and NT-proBNP (adjusted hazard ratio 1.76 per 1 Ln U, 95% confidence interval 1.39-2.21; P < 0.001), regardless of HF group (Pinteraction = 0.275). GDF15baseline provided incremental prognostic value when added to clinical predictors, hsTnT and NT-proBNP (area under receiver operating characteristic curve increased from 0.720 to 0.740, P < 0.019), with a net reclassification improvement of 0.183 (P = 0.004). Patients with ≥20% GDF156months increase had higher risk for composite outcome (adjusted hazard ratio 1.68, 95% confidence interval 1.15-2.45; P = 0.007) compared with those with GDF156months within ± 20% of baseline. The similarly elevated levels and independent prognostic utility of GDF15 in HFrEF and HFpEF suggest that beyond haemodynamic stress (NT-proBNP), inflammatory injury (GDF15) may play an important role in both HF syndromes.

Value of Plasma Growth Differentiation Factor-15 in Primary Nephrotic Syndrome

Value of Plasma Growth Differentiation Factor-15 in Primary Nephrotic Syndrome

Abstract 1153: Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody

Abstract Background: One of the most lethal and debilitating effects of cancer is the development of cancer-related anorexia-cachexia syndrome (CACS). It affects the majority of advanced cancer patients and is thought to be responsible for up to ∼30% of all cancer deaths. CACS is a complex metabolic syndrome associated with malnutrition and severe involuntary weight loss due to the loss of muscle and fat tissue, as well as the clinical manifestation of anemia, inflammation and suppression of immune functions. The precise molecular mechanisms responsible for cancer cachexia are poorly understood, thus limiting the development of effective therapeutics. Current evidence suggests that a pro-inflammatory state may be responsible for many of the symptoms associated with CACS. Growth Differentiation Factor 15 (GDF15) is a pro-inflammatory cytokine whose circulating levels are significantly increased in cachectic cancer patients and several animal models of cancer cachexia. Here we demonstrate that the inhibition of GDF15 function results in the compete reversion of the phenotypic and metabolic changes associated with CASC. Methods: Mice bearing HT-1080 human fibrosarcoma xenografts have increased plasma GDF15 levels and develop cachexia were used in this study. Tumor bearing animals were treated either with AV-380, a GDF15 neutralizing antibody or IgG1 control. The effect on body weight, muscle/fat mass and organ sizes were assessed. Metabolic changes induced by the treatment were measured by a comprehensive laboratory animal monitoring system (CLAMS). Results: Treatment with AV-380 restored body weight, muscle and fat mass as well as normal organ sizes. Analyses of the CLAMS data demonstrated that mice receiving AV-380 reversed the phenotypic and metabolic changes associated with the cachexia induced by this tumor model. Moreover, AV-380 treated mice showed an increase in locomotor activity and energy expenditure, achieving levels similar to non tumor bearing control animals. Conclusions: Inhibition of GDF15 function completely reverted body weight loss, restored normal body composition and triggered a catabolic to anabolic metabolic switch in this cancer cachexia model. The data highlights the therapeutic potential of the GDF15 inhibitory antibody AV-380 for the treatment for CACS. Citation Format: Lorena Lerner, Nianjun Tao, Brian Krieger, Richard Nicoletti, Bin Feng, Nesreen Ismail, William Winston, Yanyu Zhang, Jinwei Jiang, Solly Weiler, Jeno Gyuris. Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1153. doi:10.1158/1538-7445.AM2015-1153

0057 : Preoperative Growth Differentiation Factor 15 (GDF15) as a novel biomarker of acute kidney injury after cardiac bypass surgery

Previously, we demonstrated that preoperative plasma GDF15 levels significantly improved the prognostic value of the EuroSCORE for mortality after cardiac surgery. Despite the strong correlation between GDF15 and renal function, no data are available regarding the potential interest of preoperative GDF15 levels to improve the prediction of acute kidney injury (AKI) after coronary artery bypass grafting (CABG). 134 patients operated on for CABG of whom 50 underwent offpump surgery at our university hospital were included in this prospective, observational study. Exclusion criteria were age <18 years or >80 years, previous atrial fibrillation/flutter, previous severe renal failure (estimated glomerular filtration rate (eGFR) <30ml/min), previous cardiac surgery, and emergency surgery. AKI was defined according to KDIGO criteria. GDF15 levels in plasma were measured before induction and 12 hours after surgery. 42 patients developed postoperative AKI which had significantly higher preoperative plasma GDF15 levels (OR=2.851; 95%CI=1.32-6.13, p=0.008), higher preoperative serum creatinine levels (OR=1.025; 95%CI=1.003-1.05; p=0.026), and most often underwent cardiopulmonary bypass (CPB) surgery (OR=2.67; 95%CI: 1.17-6.14, p=0.020). On ROC curves, GDF15 was found to be the best preoperative biomarker to predict AKI (AUC 0.83; CI 0.75-0.89), compared with eGFR (AUC 0.67; 95%CI 0.59-0.75 p=0.003) and NT-proBNP (AUC 0.62; CI 0.51-0.72 p<0.001). GDF15 level was also significantly better than the EuroSCORE in predicting AKI (AUC 0.62, 95%CI 0.54-0.70 p<0.001). The predictive model including high blood pressure, diabetes, preoperative eGFR and CPB surgery was significantly improved when preoperative GDF15 was added. Preoperative GDF15 plasma levels are associated with postoperative AKI in CABG patients. Preoperative GDF15 may improve preoperative risk stratification and discrimination among candidates for surgery.

0058 : Low circulating levels of Growth Differentiation Factor 15 (GDF-15) before coronary artery bypass surgery may predict post-operative atrial fibrillation

Post-operative atrial fibrillation (POAF) following cardiac surgery has a high prevalence and is associated with considerable morbidity. To assess the role of GDF-15, a member of the TGFβsuperfamily, as a potential new predictor of POAF after off-pump (OFP) and on-pump (ONP) coronary artery bypass graft (CABG) surgery. This observational study recruited the first 50 patients planned for OFP surgery and the first 50 patients planned for ONP surgery. Patients referred for CABG with the following exclusion criteria: age <18 or >80 years, previous atrial fibrillation/flutter, previous treatment with Amiodarone, previous cardiac surgery, emergency surgery. Included patients were equipped with long-duration (7 days) Holter ECG monitoring. POAF was defined as an AF episode lasting >30 seconds. All patients underwent pre-operative echocardiography to assess LVEF and left atrial diameter. GDF-15 levels were assessed at induction of anaesthesia and 12 hours after the end of surgery. Among the 100 patients, 34 developed POAF. In Cox multivariate regression analysis, the EuroSCORE, left atrial diameter>45mm and low GDF- 15 levels at induction (<1200 ng/l) were independently associated with the onset of POAF. When comparing the incremental prognostic value of GDF-15 according to the time of blood sampling, we found that a low circulating level of GDF-15 at induction was a better predictor of POAF than that 12h later. In contrast, pre-operative NT-proBNP levels did not predict POAF. The use of ONP surgery was not associated with a higher incidence of POAF, even though baseline and follow-up characteristics in ONP and OFP patients were identical. In patients with no history of AF, a low plasma level of GDF- 15 before CABG surgery was a strong and independent predictor of POAF. Moreover, preoperative plasma GDF-15 levels added an incremental predictive value to classical risk factors of POAF.

Growth differentiation factor 15 (GDF-15) plasma levels increase during bleomycin- and cisplatin-based treatment of testicular cancer patients and relate to endothelial damage.

IntroductionChemotherapy-related endothelial damage contributes to the early development of cardiovascular morbidity in testicular cancer patients. We aimed to identify relevant mechanisms of and search for candidate biomarkers for this endothelial damage.MethodsHuman micro-vascular endothelial cells (HMEC-1) were exposed to bleomycin or cisplatin with untreated samples as control. 18k cDNA microarrays were used. Gene expression differences were analysed at single gene level and in gene sets clustered in biological pathways and validated by qRT-PCR. Protein levels of a candidate biomarker were measured in testicular cancer patient plasma before, during and after bleomycin-etoposide-cisplatin chemotherapy, and related to endothelial damage biomarkers (von Willebrand Factor (vWF), high-sensitivity C-Reactive Protein (hsCRP)).ResultsMicroarray data identified several genes with highly differential expression; e.g. Growth Differentiation Factor 15 (GDF-15), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG). Pathway analysis revealed strong associations with ‘p53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we measured GDF-15 protein levels in 41 testicular patients during clinical follow-up. Pre-chemotherapy GDF-15 levels equalled controls. Throughout chemotherapy GDF-15, vWF and hsCRP levels increased, and were correlated at different time-points.ConclusionAn unbiased approach in a preclinical model revealed genes related to chemotherapy-induced endothelial damage, like GDF-15. The increases in plasma GDF-15 levels in testicular cancer patients during chemotherapy and its association with vWF and hsCRP suggest that GDF-15 is a potentially useful biomarker related to endothelial damage.

Low Circulating Levels of Growth Differentiation Factor-15 Before Coronary Artery Bypass Surgery May Predict Postoperative Atrial Fibrillation.

To assess the role of growth differentiation factor-15 (GDF-15) as a potential new predictor of postoperative atrial fibrillation (POAF) after off-pump (OFP) and on-pump (ONP) coronary artery bypass graft (CABG) surgery. Prospective, single-center, observational study. University teaching hospital. The first 50 patients planned for OFP surgery and the first 50 patients planned for ONP surgery among patients referred for CABG with the following exclusion criteria: age<18 or>80 years, previous atrial fibrillation/flutter, previous treatment with amiodarone, previous cardiac surgery, and emergency surgery. Included patients were equipped with long-duration (7 days) Holter-ECG monitoring. POAF was defined as an AF episode lasting>30 seconds. All patients underwent preoperative echocardiography to assess left ventricular ejection fraction and left atrial diameter. GDF-15 levels were assessed after induction of anesthesia and 12 hours after arrival at the intensive care unit. Among the 100 patients, 34 (34%) developed POAF. In Cox multivariate regression analysis, the EuroSCORE, left atrial diameter>45 mm, and low GDF-15 levels at induction were associated independently with the onset of POAF. In contrast, preoperative NT-proBNP levels did not predict POAF. The use of ONP surgery was not associated with a higher incidence of POAF, even though baseline and follow-up characteristics in ONP and OFP patients were identical. In patients with no history of AF, a low plasma level of GDF-15 before CABG surgery was a strong independent predictor of POAF. Moreover, preoperative plasma GDF-15 levels added an incremental predictive value to classic risk factors of POAF.

Association between growth differentiation factor-15 and chronic heart failure in coronary atherosclerosis patients.

We explored the association between plasma growth differentiation factor 15 (GDF-15) levels and chronic heart failure (CHF) in coronary heart disease patients. We measured plasma GDF-15 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in 269 untreated coronary heart disease patients (98 with CHF, 84 without CHF, and 87 control patients) using an enzyme-linked immunosorbent assay. All subjects were examined by echocardiography and left ventricular ejection fraction. We found that plasma GDF-15 levels in coronary atherosclerosis patients with CHF [median 1622.48 (25-75th percentile: 887.53-1994.93) ng/L] were higher than those in coronary atherosclerosis patients without CHF [944.99 (856.12-999.78) ng/L] and control patients (P < 0.05). NT-proBNP showed the same trend as GDF-15. We also used the New York Heart Association functional classification to subgroup CHF patients and found that the GDF-15 level was higher in all subgroup patients with CHF. After adjusting for covariates, plasma GDF-15 levels were found to be positively related to NT-proBNP (r = 0.861, P < 0.001) and negatively related to left ventricular ejection fraction (r = -0.936, P < 0.001). Furthermore, receiver operating characteristic curves of GDF-15 and NT-proBNP were constructed and the area under the curve for the untransformed GDF-15 and NT-proBNP was 0.804 and 0.795, respectively. Plasma GDF-15 levels and NT-proBNP are associated with CHF in coronary atherosclerosis patients and can be used as biomarkers.

Knockdown of platinum-induced growth differentiation factor 15 abrogates p27-mediated tumor growth delay in the chemoresistant ovarian cancer model A2780cis.

Molecular mechanisms underlying the development of resistance to platinum-based treatment in patients with ovarian cancer remain poorly understood. This is mainly due to the lack of appropriate in vivo models allowing the identification of resistance-related factors. In this study, we used human whole-genome microarrays and linear model analysis to identify potential resistance-related genes by comparing the expression profiles of the parental human ovarian cancer model A2780 and its platinum-resistant variant A2780cis before and after carboplatin treatment in vivo. Growth differentiation factor 15 (GDF15) was identified as one of five potential resistance-related genes in the A2780cis tumor model. Although A2780-bearing mice showed a strong carboplatin-induced increase of GDF15 plasma levels, the basal higher GDF15 plasma levels of A2780cis-bearing mice showed no further increase after short-term or long-term carboplatin treatment. This correlated with a decreased DNA damage response, enhanced AKT survival signaling and abrogated cell cycle arrest in the carboplatin-treated A2780cis tumors. Furthermore, knockdown of GDF15 in A2780cis cells did not alter cell proliferation but enhanced cell migration and colony size in vitro. Interestingly, in vivo knockdown of GDF15 in the A2780cis model led to a basal-enhanced tumor growth, but increased sensitivity to carboplatin treatment as compared to the control-transduced A2780cis tumors. This was associated with larger necrotic areas, a lobular tumor structure and increased p53 and p16 expression of the carboplatin-treated shGDF15-A2780cis tumors. Furthermore, shRNA-mediated GDF15 knockdown abrogated p27 expression as compared to control-transduced A2780cis tumors. In conclusion, these data show that GDF15 may contribute to carboplatin resistance by suppressing tumor growth through p27. These data show that GDF15 might serve as a novel treatment target in women with platinum-resistant ovarian cancer.

Biomarkers of cardiovascular stress and subclinical atherosclerosis in the community.

Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described. We measured plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995-1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT >1.5 mm), and mean common carotid artery IMT. We carried out multivariable regressions for carotid measurements vs biomarkers using linear and logistic models; P < 0.0056 was deemed statistically significant. Maximal ICA IMT was significantly associated with plasma GDF-15 [β-estimate 0.04 per 1-U increase in log(GDF-15), SE 0.01, P < 0.0001]. Similarly, the odds of having carotid plaque increased 33% [odds ratio 1.33 per 1-U increase in log(GDF-15), 95% CI 1.20-1.48, P < 0.0001]. In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the 3 biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together. Increased GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.