Growth differentiation factor 15 is a new biomarker of the risk of death in patients with CHF that provides prognostic information beyond established clinical and biochemical markers.

Background: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor ␤ (TGF-␤) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease. Methods: We developed an IRMA that uses a polyclonal, affinity chromatography-purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF). Results: The assay had a detection limit of 20 ng/L, an intraassay imprecision of <10.6%, and an interassay imprecision of <12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-␤. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly indi-

Background-An invasive treatment strategy improves outcome in patients with non-ST-elevation acute coronary syndrome at moderate to high risk. We hypothesized that the circulating level of growth differentiation factor 15 (GDF-15) may improve risk stratification. Methods and Results-The Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial randomized patients with non-ST-elevation acute coronary syndrome to an invasive or conservative strategy with a follow-up for 2 years. GDF-15 and other biomarkers were determined on admission in 2079 patients. GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (Ͼ1800 ng/L) in 493 patients (23.7%). Elevated levels of GDF-15 independently predicted the risk of the composite end point of death or recurrent myocardial infarction in the conservative group (Pϭ0.016) but not in the invasive group. A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point. The occurrence of the composite end point was reduced by the invasive strategy at GDF-15 levels Ͼ1800 ng/L (hazard ratio, 0.49; 95% confidence interval, 0.33 to 0.73; Pϭ0.001), between 1200 and 1800 ng/L (hazard ratio, 0.68; 95% confidence interval, 0.46 to 1.00; Pϭ0.048), but not Ͻ1200 ng/L (hazard ratio, 1.06; 95% confidence interval, 0.68 to 1.65; Pϭ0.81). Patients with ST-segment depression or a troponin T level Ͼ0.01 g/L with a GDF-15 level Ͻ1200 ng/L did not benefit from the invasive strategy. Conclusions-GDF-15 is a potential tool for risk stratification and therapeutic decision making in patients with non-ST-elevation acute coronary syndrome as initially diagnosed by ECG and troponin levels. A prospective randomized trial is needed to validate these findings.

GDF-15 is a new biomarker in STEMI that provides prognostic information beyond established clinical and biochemical markers.

Background-Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. Methods and Results-The circulating concentration of GDF-15 was measured at baseline (nϭ1734) and at 12 months (nϭ1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (Ͼ1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; PϽ0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; PϽ0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; Pϭ0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups (Pϭ0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. Conclusions-GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT. (Circulation. 2010;122:1387-1395.)