Prognostic Value Of Growth Differentiation Factor-15 Research Articles

Growth differentiation factor-15 and plasminogen activator inhibitor-1 are possible predictors of cardiovascular events in atrial fibrillation patients after elective PCI

Abstract Introduction Patients (pts) with AF (atrial fibrillation), undergoing elective PCI (percutaneous coronary intervention), receiving combined antithrombotic therapy (AT) have high risk of stroke/systemic embolism, coronary events and bleedings. Minimizing the duration of combined AT is the main way to improve the safety of treatment. However, due to the high risk of thrombotic events, patient stratification is necessary. Biomarkers of high risk cardiovascular events (CVE) could be the rational reason to prolong combined AT for some pts. The search for them is relevant. There is data on relationship between growth differentiation factor-15 (GDF-15) level, plasminogen activator inhibitor-1 (PAI-1) level and adverse CVE. Purpose To investigate the prognostic value of GDF-15 and PAI-1 levels in AF pts after elective PCI during 1 year follow up. Methods 150 pts (104 males), aged 70.8±8.5 years, with AF after elective PCI were enrolled in the prospective study. All pts received direct oral anticoagulants and double (89.3%) or single (10.7%) antiplatelet therapy. Median duration of follow up period was 11.5 months [IQR 8.0; 12.0]. Efficacy endpoint of the study was the sum of CVE: ACS (acute coronary syndrome), ischemic stroke (IS), VTE (venous thrombotic events), cardiovascular death and need for unplanned PCI. Plasma samples for GDF-15 and PAI-1 were taken before PCI and analyzed using ELISA. Results AF pts receiving combined AT demonstrated high thrombotic risk (CHA2DS2-VASc, Med 5 [IQR 4; 6]), high rate of comorbidity (index Charlson, Med 7 [IQR 5; 9]). Frequency of CVE during follow up period was 16% (ACS 2; fatal IS 2; VTE 2, include 1 fatal pulmonary embolism; cardiovascular death 2; pts needed an unplanned PCI 16). Median GDF-15 level was 1270 pg/ml [IQR 953; 1778]. Median PAI-1 level was 10.15 U/ml [6,3; 17,0]. By linear correlation analysis (r=0.24; p=0.0037) and by regression model (F-ratio 157.4, p<0.0001) GFD-15 and PAI-1 are exhibited a relation. According to ROC analysis GDF-15 level >1191 pg/ml (sensitivity 83.0, specifity 50.0) and PAI-1 level >13.2 U/ml (sensitivity 58.3, specifity 68.6) increases the probability of the development of CVE (AUC=0.647, p=0.0076, CI 0.565–0.723; AUC=0.652, p=0.0135, CI 0.569–0.728 respectively). Kaplan-Meier curves demonstrated significant difference in CVE free survival between the patients with GDF-15 level > and ≤1191 pg/ml (75.9% and 94.0% respectively, p=0.0032 [HR 4.36, CI 1.50–7.48]); and with PAI-1 level > and ≤13.2 U/ml (74% and 89% respectively, p=0.0112 [HR 2.73, CI 1.28–6.98]). The multivariable Cox regression model demonstrated that GDF-15 (p=0.0363) and PAI-1 (p=0.0074), were independently associated with an increased risk of CVE (op=0.0022). Conclusions GDF-15 and PAI-1 are correlated, and they are new markers of CVE in AF pts after elective PCI. Funding Acknowledgement Type of funding sources: None.

Prognostic Value of GDF-15 in Predicting Prolonged Intensive Care Stay following Cardiac Surgery: A Pilot Study.

Introduction Predicting intensive care unit length of stay and outcome following cardiac surgery is currently based on clinical parameters. Novel biomarkers could be employed to improve the prediction models. Materials and Methods We performed a qualitative cytokine screening array to identify highly expressed biomarkers in preoperative blood samples of cardiac surgery patients. After identification of one highly expressed biomarker, growth differentiation factor 15 (GDF-15), a quantitative ELISA was undertaken. Preoperative levels of GDF-15 were compared in regard to duration of intensive care stay, cardiopulmonary bypass time, and indicators of organ dysfunction. Results Preoperatively, GDF-15 was highly expressed in addition to several less highly expressed other biomarkers. After qualitative analysis, we could show that preoperatively raised levels of GDF-15 were positively associated with prolonged ICU stay exceeding 48 h (median 713 versus 1041 pg/ml, p = 0.003). It was also associated with prolonged mechanical ventilation and rates of severe sepsis but not with dialysis rates or cardiopulmonary bypass time. In univariate regression, raised GDF-15 levels were predictive of a prolonged ICU stay (OR 1.01, 95% confidence interval 1–1.02, and p = 0.029). On ROC curves, GDF-15 was found to predict prolonged ICU stay (AUC = 0.86, 95% confidence interval 0.71–0.99, and p = 0.003). Conclusion GDF-15 showed potential as predictor of prolonged intensive care stay following cardiac surgery, which might be valuable for risk stratification models.

Circulating growth differentiation factor-15 as a novel biomarker in heart transplant.

AimsThis study aimed to examine (i) whether circulating growth differentiation factor‐15 (GDF‐15) is associated with acute cellular cardiac allograft rejection (ACR); (ii) a longitudinal trend of GDF‐15 after heart transplantation; and (iii) the prognostic value of GDF‐15 in predicting a composite outcome of severe primary graft dysfunction (PGD) and 30 day mortality post‐transplant.Methods and resultsSerum samples were collected before heart transplantation and at every endomyocardial biopsy (EMB) post‐heart transplantation in de novo transplant patients. A total of 60 post‐transplant serum samples were matched to the corresponding EMBs. Seven (12%) were considered International Society for Heart Lung Transplantation Grade 1R ACR, and one (2%) was identified as Grade 2R ACR. GDF‐15 levels in patients with ACR were not different from those in the non‐rejection group (6230 vs. 6125 pg/mL, P = 0.27). GDF‐15 concentration gradually decreased from 8757 pg/mL pre‐transplant to 5203 pg/mL at 4 weeks post‐transplant. The composite adverse outcome of PGD and 30 day mortality was significantly associated with increased post‐operative GDF‐15 (odds ratio: 40; 95% confidence interval: 2.01–794.27; P = 0.005) and high inotrope score post‐transplant (odds ratio: 18; 95% confidence interval: 1.22–250.35; P = 0.01).ConclusionsCirculating GDF‐15 concentration was markedly elevated in patients with end‐stage heart failure and decreased after heart transplantation. GDF‐15 was significantly associated with post‐transplant PGD and mortality. A lack of association between ACR and GDF‐15 did not support routine use of GDF‐15 as a biomarker to detect ACR. However, GDF‐15 may be potentially useful to determine heart transplant recipients at high risk for adverse post‐transplant outcomes. We suggest that GDF‐15 levels in recipient serum can provide risk stratification for severe PGD including death during post‐operative period. This novel biomarker may serve to inform and guide timely interventions against severe PGD and adverse outcomes during the first 4 weeks after transplantation. Further studies to support the utility of GDF‐15 in heart transplantation are required.

GDF-15 as a Biomarker in Cardiovascular Disease.

ResumoNos últimos anos, vários biomarcadores estão ganhando importância clínica na avaliação diagnóstica e prognóstica de pacientes com doenças cardiovasculares. O fator de crescimento e diferenciação celular-15 (GDF-15) é uma citocina induzida por estresse e inflamação, membro da família do TGF-, cuja produção no miocárdio foi demonstrada experimentalmente em resposta à injúria isquêmica ou sobrecarga cardíaca. Este novo marcador foi positivamente correlacionado com aumento do risco de eventos cardiovasculares em estudos populacionais e configurou-se preditor independente de mortalidade e prognóstico adverso em pacientes com doença arterial coronariana e insuficiência cardíaca. Este trabalho tem como objetivo revisar o valor diagnóstico e prognóstico do GDF-15 em diferentes cenários na cardiologia.

Abstract 13448: Impact of Diabetes on Growth Differentiation Factor 15 and Mortality in Patients With Stable Coronary Artery Disease: The ANOX Study

Background: Diabetes mellitus (DM) is still significantly associated with the risk of mortality in the general population. Higher circulating growth differentiation factor 15 (GDF-15) levels are associated with the risk of mortality in the general population, in patients with DM, and in those with coronary artery disease (CAD). However, whether GDF-15 levels differ according to the diabetic status and whether DM modifies the relationship between GDF-15 and mortality in patients with stable CAD are unclear. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between diabetic status and GDF-15 and the impact of DM on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 797 DM and 663 non-DM patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with DM exhibited significantly higher levels of GDF-15 compared to those without DM (median [interquartile range], 1472 [1049-2258] vs. 1274 [868-1874] pg/mL, respectively; P <0.001). Stepwise multiple linear regression analysis revealed that the log-transformed (Ln-) GDF-15 level was independently associated with higher age, DM, current smoking, lower estimated glomerular filtration rate, anemia, no use of aspirin, Ln-N-terminal pro-natriuretic peptide, and Ln-high-sensitivity C-reactive protein ( P <0.005 for all). In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders (hazard ratio per 1-SD increase [HR], 1.51; 95% confidence interval [CI], 1.33-1.71). This association was still significant in patients with DM (HR, 1.52; 95% CI, 1.30-1.79) and in those without DM (HR, 1.57; 95% CI, 1.25-1.96). However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in the entire cohort and in patients with DM, but not in those without DM. Conclusions: Higher levels of GDF-15 were independently associated with DM in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with DM.

Abstract 13423: Impact of Anemia on Growth Differentiation Factor 15 and Mortality in Patients With Stable Coronary Artery Disease: The ANOX Study

Background: Growth differentiation factor 15 (GDF-15) is a stress responsive cytokine of the transforming growth factor superfamily. Circulating levels of GDF-15 are elevated in various conditions including anemia and stable coronary artery disease (CAD), and associated with the risk of mortality in patients with stable CAD. However, whether anemia modifies the relationship between GDF-15 and mortality in patients with stable CAD is unknown. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between anemic status and GDF-15 and the impact of anemia on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 564 anemic and 896 non-anemic patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with anemia exhibited significantly higher levels of GDF-15 compared to those without anemia (median [interquartile range], 1953 [1302-3110] vs. 1175 [838-1579] pg/mL, respectively; P <0.001). Stepwise multiple linear regression analysis revealed that the log-transformed (Ln-) GDF-15 level was independently associated with higher age, diabetes, current smoking, lower estimated glomerular filtration rate, anemia, no use of aspirin, Ln-N-terminal pro-natriuretic peptide, and Ln-high-sensitivity C-reactive protein ( P <0.005 for all). In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders (hazard ratio per 1-SD increase [HR], 1.51; 95% confidence interval [CI], 1.33-1.71). This association was still significant in patients with anemia (HR, 1.71; 95% CI, 1.44-2.05) and in those without anemia (HR, 1.44; 95% CI, 1.21-1.71). However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in the entire cohort and in patients with anemia, but not in those without anemia. Conclusions: Higher levels of GDF-15 were independently associated with anemia in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with anemia.

Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19.

Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown. Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers. Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P<0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, P<0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (P<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, P<0.001). GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.

Growth differentiation factor 15 in adverse cardiac remodelling: from biomarker to causal player.

Heart failure is a growing health issue as a negative consequence of improved survival upon myocardial infarction, unhealthy lifestyle, and the ageing of our population. The large and complex pathology underlying heart failure makes diagnosis and especially treatment very difficult. There is an urgent demand for discriminative biomarkers to aid disease management of heart failure. Studying cellular pathways and pathophysiological mechanisms contributing to disease initiation and progression is crucial for understanding the disease process and will aid to identification of novel biomarkers and potential therapeutic targets. Growth differentiation factor 15 (GDF15) is a proven valuable biomarker for different pathologies, including cancer, type 2 diabetes, and cardiovascular diseases. Although the prognostic value of GDF15 in heart failure is robust, the biological function of GDF15 in adverse cardiac remodelling is not fully understood. GDF15 is a distant member of the transforming growth factor‐β family and involved in various biological processes including inflammation, cell cycle, and apoptosis. However, more research is suggesting a role in fibrosis, hypertrophy, and endothelial dysfunction. As GDF15 is a pleiotropic protein, elucidating the exact role of GDF15 in complex disease processes has proven to be a challenge. In this review, we provide an overview of the role GDF15 plays in various intracellular and extracellular processes underlying heart failure, and we touch upon crucial points that need consideration before GDF15 can be integrated as a biomarker in standard care or when considering GDF15 for therapeutic intervention.

P5507Growth differentiation factor-15 and mortality in suspected or known coronary heart disease patients with chronic kidney disease: a subanalysis of the ANOX study

Abstract Background Chronic kidney disease (CKD) is an independent risk factor for the development and progression of coronary heart disease (CHD). Growth differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-β cytokine superfamily, plays a role in the initiation of inflammation in atherosclerotic lesions. Elevated GDF-15 was found in various diseases including CKD and stable CHD, and was reported to predict mortality and cardiovascular events in general or established CHD population. However, the prognostic value of GDF-15 in suspected or known CHD patients with CKD is unknown. Methods Serum GDF-15 levels were measured in 999 suspected or known CHD patients with CKD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 154 patients died from any cause, 61 died from cardiovascular disease, and 96 developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.78; 95% confidence interval [CI], 1.57–2.00), cardiovascular death (HR, 1.88; 95% CI, 1.58–2.25), and MACE (HR, 1.54; 95% CI, 1.32–1.79). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.401; 95% CI, 0.231–0.571; P&lt;0.001; integrated discrimination improvement [IDI], 0.041; 95% CI, 0.021–0.062; P&lt;0.001) and cardiovascular death (NRI, 0.297; 95% CI, 0.039–0.555; P=0.024; IDI, 0.032; 95% CI, 0.010–0.055; P=0.005), but not that of MACE (NRI, 0.138; 95% CI, v0.070–0.347; P=0.194; IDI, 0.012; 95% CI, −0.000–0.024; P=0.053). Conclusions In suspected or known CHD patients with CKD undergoing elective coronary angiography, elevated GDF-15 levels may predict all-cause and cardiovascular mortality independent of established risk factors and cardiovascular biomarkers. Acknowledgement/Funding The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.

P3825Long-term prognostic value of growth differentiation factor-15 in acute coronary syndrome

Abstract Introduction Biomarkers plays a critical role in diagnostic, prognostication, and decision-making in cardiovascular medicine. Growth differentiation factor-15 (GDF-15) has been reported as a potential biomarker in acute coronary syndrome (ACS). However, there is limited data on the long-term prognostic value after an ACS. Purpose To study the long-term prognostic value of GDF-15 in ACS. Methods We included patients with ACS who underwent coronary angiography. During angiography an arterial blood sample was collected. Plasma GDF-15 were measured and clinical data and long-term events were obtained. As previously reported, risk categories were defined as low risk (&lt;1200ng/L), intermediate (1200–1800ng/L) and high risk (&gt;1800ng/L). Incremental prognostic value of GDF-15 for all-cause death was assessed on top of a clinical model (GRACE score, LVEF&lt;40% and age). Results A total of 358 patients were included; 157 as a low risk, 85 as an intermediate and 116 as a high risk. The median (IQR) age was 65 (56–74) years and 27.4% were female. Of all patients, 61.5% were admitted with non-ST-elevation myocardial infarction, 24.0% with ST-elevation myocardial infarction and 14.5% with unstable angina. Higher values of GDF-15 were consistently associated with an increased prevalence of cardiovascular risk factors. During 6 years of follow-up 54 patients died. Of those patients, 7 (4.5%) had values of GDF-15 below 1200ng/L, 6 (7.1%) between 1200–1800ng/L and 41 (35.3%) above 1800ng/L. After adjustment for a multivariate Cox regression model, GDF-15 &gt;1800ng/L were independently associated with all-cause death (HR 4.5; 95% CI 1.8–11.6; p=0.002) and the composite of major adverse cardiovascular events (MACE) which were identified as all-cause death, nonfatal MI and heart failure (HR 2.5; 95% CI 1.4–4.4; p=0.001). For long-term all-cause death a significant increase of the c-statistic was seen after addition of GDF-15 to the clinical model 0.871 (95% CI 0.817–0.924; p=0.019) as well as net reclassification improvement (0.769; 95% CI 0.487–1.051; p&lt;0.001) and integrated discrimination improvement (0.117; 95% CI 0.062–0.172; p&lt;0.001). Of 18 events of heart failure, 17 occurred in patients with GDF&gt;1800ng/L. A multivariate competing risk model showed a significant association between GDF-15&gt;1800ng/L and incidence of heart failure (adjusted HR 30.8; 95% CI 4.1–231.5; p=0.001) but non-significant association were found for myocardial infarction. KM figures and all-cause death ROC curve Conclusions In the setting of ACS GDF-15 can predict long-term all-cause death, MACE and heart failure and provides incremental prognostic value beyond traditional risks factors in the long-term all-cause death.

5195Growth differentiation factor-15 and mortality in suspected or known coronary heart disease patients with diabetes: a subanalysis of the ANOX study

Abstract Background Diabetes is a risk factor for coronary heart disease (CHD), but further risk stratification in patients with diabetes is necessary to improve the prediction and prevention of cardiovascular events and deaths. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine, which plays an important role in the regulation of the inflammatory response, growth and cell differentiation. Elevated GDF-15 was found in various diseases including diabetes and stable CHD, and was reported to predict mortality and cardiovascular events in general or established CHD population. However, the prognostic value of GDF-15 in suspected or known CHD patients with diabetes is unknown. Methods Serum GDF-15 levels were measured in 1,087 suspected or known CHD patients with diabetes undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 147 patients died from any cause, 47 died from cardiovascular disease, and 94 developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.66; 95% confidence interval [CI], 1.48–1.86), cardiovascular death (HR, 1.63; 95% CI, 1.34–1.99), and MACE (HR, 1.41; 95% CI, 1.20–1.65). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.344; 95% CI, 0.172–0.517; P&lt;0.001; integrated discrimination improvement [IDI], 0.049; 95% CI, 0.026–0.072; P&lt;0.001), but not that of cardiovascular death (NRI, −0.013; 95% CI, −0.300–0.274; P=0.931; IDI, 0.023; 95% CI, 0.003–0.043; P=0.026) or MACE (NRI, 0.059; 95% CI, −0.151–0.268; P=0.583; IDI, 0.005; 95% CI, −0.004–0.015; P=0.244). Conclusions In suspected or known CHD patients with diabetes undergoing elective coronary angiography, elevated GDF-15 levels may predict all-cause mortality independent of established risk factors and cardiovascular biomarkers. Acknowledgement/Funding The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.

P6437Growth differentiation factor-15 and stromal cell-derived factor-1 as long-term prognosis biomarkers in acute coronary syndrome

Abstract Introduction After an acute coronary syn bdrome (ACS) patients are at high risk of cardiovascular morbidity and mortality. In this scenario, Growth differentiation factor-15 (GDF-15) and Stromal cell derived factor-1 (SDF-1) has been reported as potential biomarkers in ACS. However, there is limited data about their combined use in long-term prognosis. Purpose To study the long-term prognostic value of GDF-15 and SDF-1 in ACS. Methods We included patients with ACS who underwent coronary angiography. During angiography an arterial blood sample was collected. Plasma SDF-1 and GDF-15 were measured and clinical data and long-term events were obtained. The cut-off point of SDF-1 and GDF-15 was identified individually by receiver operating characteristic curves. Patients were classified into 3 groups: 1) both biomarkers below cut-off points; 2) only one biomarker above cut-off points; 3) both biomarkers above cut-off points. Results A total of 238 patients were included. The median (IQR) age was 64 (55–74) year and 27.3% were female. Of all patients, 60.9% were admitted with non-ST-elevation myocardial infarction, 22.7% with ST-elevation myocardial infarction and 16.4% with unstable angina. The cut-off point of SDF-1 was 3283.5pg/mL and GDF-15 was 1849ng/L. A total of 127 patients were in group 1, 64 in group 2 and 47 in group 3. Group 3 patients were associated with older age, hypertension, dyslipidemia, diabetes mellitus and history of myocardial infarction (MI), stroke, chronic kidney disease and peripheral artery disease. Besides, they were more likely to have left ventricular dysfunction (ejection fraction &lt;40%) and significant three vessels stenosis. During 6.5 years of follow-up 8 patients died (6.3%) in group 1, 7 patients died (10.9%) in group 2 and 25 patients died (53.2%) in group 3 (Figure 1). Multivariate Cox analysis showed that high levels of SDF-1 and GDF-15 (group 3) were an independent predictor of all-cause death (HR 5.8; 95% CI 2.4 - 14.1; p&lt;0.001) and the composite of major adverse cardiovascular events (MACE) which were identified as all-cause death, nonfatal MI and heart failure (HR 3.9; 95% CI 2.1 - 7.3; p&lt;0.001). During follow-up 1 patient had heart failure in group 1 (0.8%), 3 patients (4.7%) in group 2 and 9 patients (19.1%) in group 3. Despite the low number of events of heart failure, the multivariate competing risks regression showed association between group 3 and heart failure during follow-up (HR 28.0; 95% CI 3.5 - 225.2; p=0.002). Higher levels of SDF-1 and GDF-15 (group 3) were not associated with new MI in multivariate competing risks regression. Regarding group 2, all multivariate analyses were non-significant. Cumulative survival and incidence curves Conclusions Higher values of combined GDF-15 and SDF-1 are an excellent predictor of all-cause death, MACE and heart failure in long-term follow-up of patients with ACS. The combined use of SDF-1 and GDF-15 may be useful in long-term ACS prognosis.

PB2046 GROWTH/DIFFERENTIATION FACTOR-15, HEPCIDIN AND IRON METABOLISM BIOMARKERS IN LYMPHOPROLIFERATIVE DISEASES

Background: Lymphoma patients, even those without anemia, sometimes have levels of iron metabolism biomarkers outside the normal range. Hepcidin and ferritin, usually elevated in inflammatory and malignant states, are affected by erythropoetic activity. GDF-15 might be included in the process. Its level is elevated in some malignant and non malignant diseases and is associated with worse prognostic outcome. Aims: Our objectives were to investigate the level of the growth/differentiation factor 15 (GDF-15), hepcidin and iron metabolism biomarkers in patients with lymphoproliferative diseases and to compare these parameters between patients who needed and received lymphoma treatment and those on “watch and wait” regimen. Methods: This is an ongoing research at the Clinic for hematology, Clinical center of Vojvodina. Patients with comorbidities associated with elevated GDF-15 or hepcidin levels were excluded. The results of 29 lymphoma patients have been analyzed. CBC, ESR, LDH, CRP, β2microglobulin, Fe, transferin, ferritin, soluble transferin receptors, hepcidin, GDF-15 were evaluated in 12 lymphoma patients on “watch and wait”, while in 17 patients who needed treatment the markers were measured before therapy and will be analyzed again after treatment completion. ELISA technique from stored sera was used for GDF-15 and hepcidin evaluation. Informed written consents were collected after Approval of Ethical committee of Clinical center Vojvodina and Faculty of Medicine University of Novi Sad. Mann-Whitney U test and Spearman Rank Order Correlation were performed and p < 0.05 was significant with confidence interval of 95%. Results: The first group consisted of 12 patients, median age 64 (interquartile range (IQ) 55 to 67), the second of 17 patients who needed therapy, median age 58 years (IQ 51 to 65). Significant higher values were in the second group for: GDF-15 592pg/ml (IQ 560 to 680) vs. 840pg/ml (IQ 600 to 980) p < 0.05, hepcidin 6540pg/ml (IQ 6512 to 6552) vs. 6720pg/ml (IQ 6560 to 6920) p < 0.05, and β2microglobulin 2.08 (IQ 2.03 to 2.41) vs. 4.04 (IQ 3.12 to 4.43), p < 0.05. The second group had a significantly lower value of transferin 2.7 g/l (IQ 2.46 to 3.13) vs. 2.24 g/L (IQ 2.06 to 2.59), p < 0.05, Fe 18.2 μmol/l (IQ 15.8 to 23.3) vs. 10 μmol/l (IQ 6.3 to 13.6), p < 0.05, Hg 139 g/l (IQ 135 to149) vs. 126 g/l (IQ 115 to 135) p < 0.05, hematocrit 0.42 (IQ 0.40 to 0.43) vs. 0.39 (IQ 0.35 to 0.41), p < 0.05. There were marked positive correlation between GDF-15 and ESR (r = 0.58, p < 0.05), β2mikroglobulin (r = 0.47, p < 0.05), ferritin (r = 0.44, p < 0.05), and fibrinogen (r = 0.5, p < 0.05), and negative with transferin (r = -0.55, p < 0.05), Fe (r = -0.39, p < 0.05), hemoglobin (r = -0.43, p < 0.05), and hematocrit (r = -0.42, p < 0.05). Hepcidin positively correlated with β2microglobulin (r = 0.6, p < 0.05), and ferritin (r = 0.38, p < 0.05). Summary/Conclusion: Higher values of GDF-15 and hepcidin in the group of patients who needed therapy might be connected to a larger tumor burden and more aggressive course of lymphoproliferative disease. These data will be evaluated in larger groups of patients, alongside data collected from the second group after treatment completion. The prognostic value of GDF-15, hepcidin, and iron metabolism biomarkers in lymphoproliferative diseases is yet to be determined.

Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial

To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial. GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment. GDF-15 concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores. In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.

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 for long-term prognostication in patients with non-ST-elevation acute coronary syndrome: An Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) substudy

BackgroundNo five-year long-term follow-up data is available regarding the prognostic value of GDF-15. Our aim is to evaluate the long-term prognostic value of admission growth-differentiation factor 15 (GDF-15) regarding death or myocardial infarction (MI) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). MethodsThis is a subanalysis from the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial, including troponin positive NSTE-ACS patients. The main outcome for the current analysis was 5-year death or spontaneous MI. GDF-15 samples were available in 1151 patients. The prognostic value of GDF-15, categorized into <1200ng/L, 1200–1800ng/L and >1800ng/L, was assessed in unadjusted and adjusted Cox regression models. Adjustments were made for identified univariable risk factors. The additional discriminative and reclassification value of GDF-15 beyond the independent risk factors was assessed by the category-free net reclassification improvement (1/2 NRI(>0)) and the integrated discrimination improvement (IDI) ResultsCompared to GDF-15<1200ng/L, a GDF-15>1800ng/L was associated with an increased hazard ratio for death or spontaneous MI, mainly driven by mortality. GDF-15 levels were predictive after adjustments for other identified predictors. Additional discriminative value was shown with the IDI, not with the NRI. ConclusionIn patients presenting with NSTE-ACS and elevated troponin T, GDF-15 provides prognostic information in addition to identified predictors for mortality and spontaneous MI and can be used to identify patients at high risk during long-term follow-up.

Prognostic Value of Growth-Differentiation Factor-15 in Patients With Non–ST-Elevation Acute Coronary Syndrome

Growth-differentiation factor-15 (GDF-15) is a member of the transforming growth factor-beta cytokine superfamily that is induced in the heart after ischemia-and-reperfusion injury. Circulating levels of GDF-15 may provide prognostic information in patients with non-ST-elevation acute coronary syndrome. Blood samples were obtained on admission from 2081 patients with acute chest pain and either ST-segment depression or troponin elevation who were included in the Global Utilization of Strategies to Open Occluded Arteries (GUSTO)-IV Non-ST-Elevation Acute Coronary Syndrome trial and from a matching cohort of 429 apparently healthy individuals. GDF-15 levels were determined by immunoradiometric assay. Approximately two thirds of patients presented with GDF-15 levels above the upper limit of normal in healthy controls (1200 ng/L); one third presented with levels >1800 ng/L. Increasing tertiles of GDF-15 were associated with an enhanced risk of death at 1 year (1.5%, 5.0%, and 14.1%; P<0.001). By multiple Cox regression analysis, only the levels of GDF-15 and N-terminal pro-B-type natriuretic peptide, together with age and a history of previous myocardial infarction, contributed independently to 1-year mortality risk. Receiver operating characteristic curve analyses further illustrated that GDF-15 is a strong marker of 1-year mortality risk (area under the curve, 0.757; best cutoff, 1808 ng/L). At this cutoff value, GDF-15 added significant prognostic information in patient subgroups defined by age; gender; time from symptom onset to admission; cardiovascular risk factors; previous cardiovascular disease; and the risk markers ST-segment depression, troponin T, N-terminal pro-B-type natriuretic peptide, C-reactive protein, and creatinine clearance. GDF-15 is a new biomarker of the risk for death in patients with non-ST-elevation acute coronary syndrome that provides prognostic information beyond that provided by established clinical and biochemical markers.

Benchmarks for the Assessment of Novel Cardiovascular Biomarkers

The investigation of novel circulating serum and plasma biomarkers in patients with cardiovascular disease has been accelerating at a remarkable pace. For example, a Medline search that uses the terms “biomarkers” and “acute coronary syndromes” (ACS) reveals an approximate tripling in the number of published reports during the 2-year interval from 2003 to 2004 compared with the period from 2001 to 2002, and this number more than doubled from 2005 to 2006. Although this expanding body of research has established firm evidence for the value of biomarkers, such as for diagnosis and risk assessment among patients with suspected ACS,1 it has also deluged the clinical and research communities with candidate biomarkers, very few of which are likely to survive the test of time as useful clinical tools.2,3 It is thus increasingly important for researchers, manufacturers, regulators, and clinicians to critically appraise the value of new biomarkers as they emerge as candidates for further investigation and possible clinical application. The superb report by Wollert and colleagues4 in the present issue of Circulation on growth differentiation factor-15 (GDF-15) as a biomarker for prognostic assessment in ACS provides an opportunity to outline a basic set of benchmarks against which new markers can be evaluated. Article p 962 Assessment of the clinical potential of a novel biomarker5 may be structured around 3 fundamental questions (Figure): (1) Can the clinician measure it? (2) Does it add new information? (3) Does it help the clinician to manage patients? A, Criteria for assessment of novel cardiovascular biomarkers for clinical use. Statements in bold font are given the highest priority. B, Clinical applications of cardiovascular biomarkers. To be clinically useful, analytical methods must be available that allow reliable measurement, optimally with capability for high throughput tests, prompt turnaround time, and reasonable cost. Evaluation of …