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

Background— Growth-differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β 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. Methods and Results— 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. Conclusions— 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.

[1]  G. Brabant,et al.  Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. , 2007, Clinical chemistry.

[2]  H. Drexler,et al.  The Transforming Growth Factor-&bgr; Superfamily Member Growth-Differentiation Factor-15 Protects the Heart From Ischemia/Reperfusion Injury , 2006 .

[3]  A. Siegbahn,et al.  FRISC score for selection of patients for an early invasive treatment strategy in unstable coronary artery disease , 2005, Heart.

[4]  Robert M Califf,et al.  Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. , 2004, The New England journal of medicine.

[5]  L. Wallentin,et al.  Natriuretic peptides in unstable coronary artery disease. , 2004, European heart journal.

[6]  A. Larsson,et al.  Biochemical indicators of cardiac and renal function in a healthy elderly population. , 2004, Clinical biochemistry.

[7]  M. Lalu,et al.  Peroxynitrite in Myocardial Ischemia-Reperfusion Injury , 2004, Heart Failure Reviews.

[8]  R. Califf,et al.  N‐Terminal Pro‐Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)‐IV Substudy , 2003, Circulation.

[9]  E. Topol,et al.  Long-Term Results After the Glycoprotein IIb/IIIa Inhibitor Abciximab in Unstable Angina: One-Year Survival in the GUSTO IV-ACS (Global Use of Strategies To Open Occluded Coronary Arteries IV—Acute Coronary Syndrome) Trial , 2003, Circulation.

[10]  M. Sabatine,et al.  The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. , 2001, The New England journal of medicine.

[11]  C. Vassanelli,et al.  [Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban]. , 2001, Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology.

[12]  M. Simoons.  Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial , 2001, The Lancet.

[13]  A. Siegbahn,et al.  Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. , 2000, The New England journal of medicine.

[14]  Ric,et al.  CARDIAC TROPONIN T LEVELS FOR RISK STRATIFICATION IN ACUTE MYOCARDIAL ISCHEMIA , 2000 .

[15]  W. D. Fairlie,et al.  MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Thompson,et al.  Production of C-reactive protein and risk of coronary events in stable and unstable angina , 1997, The Lancet.

[17]  F. Harrell,et al.  Cardiac troponin T levels for risk stratification in acute myocardial ischemia. GUSTO IIA Investigators. , 1996, The New England journal of medicine.