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European Heart Journal Advance Access originally published online on August 7, 2009
European Heart Journal 2009 30(22):2749-2757; doi:10.1093/eurheartj/ehp300
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Growth differentiation factor-15 predicts mortality and morbidity after cardiac resynchronization therapy

Paul W.X. Foley1, Berthold Stegemann2, Kelvin Ng3, Sud Ramachandran4, Anthony Proudler4, Michael P. Frenneaux5, Leong L. Ng3 and Francisco Leyva1,*

1 Department of Cardiology, University of Birmingham, Good Hope Hospital, Heart of England NHS Trust, Rectory Road, Sutton Coldfield, West Midlands B75 7RR, UK
2 Medtronic Inc., Maastricht, The Netherlands
3 Department of Medicine and Therapeutics, Leicester Royal Infirmary, Leicester, UK
4 Department of Biochemistry, Good Hope Hospital, Heart of England NHS Trust, Sutton Coldfield, West Midlands, UK
5 Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK

Received 19 July 2008; revised 2 May 2009; accepted 7 July 2009; online publish-ahead-of-print 7 August 2009.

* Corresponding author. Tel: +44 121 424 2000, Email: cardiologists{at}hotmail.com

Aims: The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) predicts mortality and morbidity after cardiac resynchronization therapy (CRT). Growth differentiation factor-15, a transforming growth factor-β-related cytokine which is up-regulated in cardiomyocytes via multiple stress pathways, predicts mortality in patients with heart failure treated pharmacologically.

Methods and results: Growth differentiation factor-15 was measured before and 360 days (median) after implantation in 158 patients with heart failure [age 68 ± 11 years (mean ± SD), left ventricular ejection fraction (LVEF) 23.1 ± 9.8%, New York Class Association (NYHA) class III (n = 117) or IV (n = 41), and QRS 153.9 ± 28.2 ms] undergoing CRT and followed up for a maximum of 5.4 years for events. In a stepwise Cox proportional hazards model with bootstrapping, adopting log GDF-15, log NT pro-BNP, LVEF, and NYHA class as independent variables, only log GDF-15 [hazard ratio (HR), 3.76; P = 0.0049] and log NT pro-BNP (HR, 2.12; P = 0.0171) remained in the final model. In the latter, the bias-corrected slope was 0.85, the optimism (O) was –0.06, and the c-statistic was 0.74, indicating excellent internal validity. In univariate analyses, log GDF-15 [HR, 5.31; 95% confidence interval (CI), 2.31–11.9; likelihood ratio (LR) {chi}2 = 14.6; P < 0.0001], NT pro-BNP (HR, 2.79; 95% CI, 1.55–5.26; LR {chi}2 = 10.4; P = 0.0004), and the combination of both biomarkers (HR, 7.03; 95% CI, 2.91–17.5; LR {chi}2 = 19.1; P < 0.0001) emerged as significant predictors. The biomarker combination was associated with the highest LR {chi}2 for all endpoints.

Conclusion: Pre-implant GDF-15 is a strong predictor of mortality and morbidity after CRT, independent of NT pro-BNP. The predictive value of these analytes is enhanced by combined measurement.

Key Words: Growth differentiation factor-15 • Cardiac resynchronization therapy • Heart failure • Mortality


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