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CLINICAL RESEARCH: HEART FAILURE

Prognostic Utility of Growth Differentiation Factor-15 in Patients With Chronic Heart Failure

Tibor Kempf, MD^_*,1, Stephan von Haehling, MD^,, Timo Peter, MS^_*, Tim Allhoff, MS^_*, Mariantonietta Cicoira, MD, PhD, Wolfram Doehner, MD, PhD, Piotr Ponikowski, MD^||, Gerasimos S. Filippatos, MD^#, Piotr Rozentryt, MD^_**, Helmut Drexler, MD^_*,1, Stefan D. Anker, MD, PhD^, and Kai C. Wollert, MD^_*,1,_*

^_* Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
Division of Applied Cachexia Research, Department of Cardiology, Charité, Berlin, Germany
Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom
Section of Cardiology, University of Verona, Verona, Italy
^|| Department of Cardiology, Military Hospital, Wroclaw, Poland
^# Department of Cardiology, University Hospital, Athens, Greece
^_** Department of Cardiology, Silesian Center for Heart Disease, Zabrze, Poland.

Manuscript received January 9, 2007; revised manuscript received March 2, 2007, accepted April 1, 2007.

^_* Reprint requests and correspondence: Prof. Dr. Kai C. Wollert, Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany. (Email: wollert.kai{at}mh-hannover.de).

Objectives: We explored the prognostic utility of growth differentiation factor (GDF)-15 in patients with chronic heart failure (CHF).

Background: Growth differentiation factor-15 is a stress-responsive member of the transforming growth factor-ß cytokine superfamily. It has recently been observed that patients with CHF have increased circulating levels of GDF-15. The relations of GDF-15 to other biomarkers and to mortality in CHF have never been studied.

Methods: Circulating levels of GDF-15 were determined by immunoradiometric assay in 455 patients with CHF with a median left ventricular ejection fraction (LVEF) of 32% (interquartile range 25% to 39%).

Results: The median GDF-15 level was 1,949 ng/l (interquartile range 1,194 to 3,577); 74.9% of the patients presented with GDF-15 levels >1,200 ng/l, the upper limit of normal in healthy elderly individuals. The GDF-15 levels were closely related to New York Heart Association (NYHA) functional class and to amino-terminal pro–B-type natriuretic peptide (NT-proBNP). The risk of death during follow-up increased with increasing quartiles of GDF-15. Mortality rates at 48 months were 10.0%, 9.4%, 33.4%, and 56.2% in the respective quartiles (p < 0.001). After adjustment for clinical variables and established biomarkers of adverse prognosis, including NT-proBNP, renal dysfunction, anemia, and hyperuricemia, GDF-15 remained an independent predictor of mortality (adjusted hazard ratio for 1 U in the Ln scale 2.26; 95% confidence interval 1.52 to 3.37; p < 0.001). Growth differentiation factor 15 provided prognostic information in clinically relevant patient subgroups (defined according to age, body mass index, heart failure etiology, concomitant medical therapy, renal function, and the levels of hemoglobin and uric acid) and added prognostic information to NYHA functional class, LVEF, and NT-proBNP.

Conclusions: 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.

Abbreviations and Acronyms   BNP = B-type natriuretic peptide   CHF = chronic heart failure   GDF-15 = growth differentiation factor-15   LVEF = left ventricular ejection fraction   NT-proBNP = amino-terminal pro–B-type natriuretic peptide   NYHA = New York Heart Association   ROC = receiver-operating characteristic

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