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

Paul W X Foley, Berthold Stegemann, Kelvin Ng, Sud Ramachandran, Anthony Proudler, Michael P Frenneaux, Leong L Ng, Francisco Leyva, Paul W X Foley, Berthold Stegemann, Kelvin Ng, Sud Ramachandran, Anthony Proudler, Michael P Frenneaux, Leong L Ng, Francisco Leyva

Abstract

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-beta-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.

Figures

Figure 1
Figure 1
Kaplan–Meier survival curves for elevations in growth differentiation factor-15 and N-terminal pro-B-type natriuretic peptide in relation to outcome.
Figure 2
Figure 2
Kaplan–Meier survival curves for elevations in growth differentiation factor-15 and N-terminal pro-B-type natriuretic peptide in relation to outcome, using dichotomous variables.
Figure 3
Figure 3
Box-and-whisker plot for pre-implant growth differentiation factor-15 and N-terminal pro-B-type natriuretic peptide in relation to response or non-response to cardiac resynchronization therapy. The five horizontal lines represent the 10th, 25th, 50th, 75th, and 90th percentiles, from bottom to top. For calculation of the combined biomarker index, see text.
Figure 4
Figure 4
Box-and-whisker plot for changes from baseline in growth differentiation factor-15 and N-terminal pro-B-type natriuretic peptide in relation to response or non-response to cardiac resynchronization therapy. The five horizontal lines represent the 10th, 25th, 50th, 75th, and 90th percentiles, from bottom to top. For calculation of the combined biomarker index, see text.

References

    1. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass D, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM for the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac resynchronization therapy with or without an implantable defibrillator in advanced heart failure. N Engl J Med. 2004;350:2140–2150.
    1. Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L for the Cardiac Resynchronization-Heart Failure (CARE-HF) study investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549.
    1. Bax JJ, Abraham T, Barold SS, Breithardt OA, Fung JWH, Garrigue S, Gorcsan J, III, Hayes DL, Kass DA, Knuuti J, Leclercq C, Linde C, Mark DB, Monaghan MJ, Nihoyannopoulos P, Schalij MJ, Stellbrink C, Yu C-M. Cardiac resynchronization therapy: part 1—issues before device implantation. J Am Coll Cardiol. 2005;46:2153–2167.
    1. Chung E, Leon A, Tavazzi L, Sun J, Nihoyannopoulos P, Merlino J, Abraham W, Guio S, Leclerq C, Bax J, Yu C-M, Gorcsan J, III, Sutton M, De Sutter J, Murillo J. Results of the Predictors of Response to CRT (PROSPECT) Trial. Circulation. 2008;117:2608–2616.
    1. Maisel A. Biomarkers in heart failure. Does prognostic utility translate to clinical futility? J Am Coll Cardiol. 2007;50:1061–1063.
    1. Bootcov M, Basuskin A, Valenzuela S, Moore A, Bansal M, He X, Zhang H, Donnellan M, Mahler S, Pryor K, Walsh B, Nicholson R, Fairlie W, Por S, Robbins J, Breit S. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci USA. 1997;94:11514–11519.
    1. Bottner M, Laaff M, Schechinger B, Rappold G, Unsicker K, Suter-Crazzolara C. Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1) Gene. 1999;237:105–111.
    1. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res. 2006;98:351–360.
    1. Blobe G, Schiemann W, Lodish H. Role of transforming growth factor beta in human disease. N Engl J Med. 2000;342:1350–1358.
    1. Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, Peter T, Siegbahn A, Venge P, Drexler H, Wallentin L. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation. 2007;116:1540–1548.
    1. Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M, Doehner W, Ponikowski P, Filippatos G, Rozentryt P, Drexler H, Anker S, Wollert K. Prognostic utility of growth-differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol. 2007;50:1054–1060.
    1. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36:959–969.
    1. Assomull RG, Prasad SK, Lyne J, Smith G, Burman ED, Khan M, Sheppard MN, Poole-Wilson PA, Pennell DJ. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48:1977–1985.
    1. Rector TS, Kubo SH, Cohn JN. Patient's self-assessment of their congestive heart failure. Content, reliability and validity of a new measure—The Minnesota living with heart failure questionnaire. Heart Failure. 1987;3:198–207.
    1. Guyatt GH, Sullivan MJ, Thompson PJ. The 6 min walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132:919–923.
    1. Ritter P, Padeletti L, Gillio-Meina L, Gaggini G. Determination of the optimal atrioventricular delay in DDD pacing: comparison between echo and peak endocardial acceleration measurements. Europace. 1999;1:126–130.
    1. Wollert KC, Kempf T, Peter T, Olofsson S, James S, Johnston N, Lindahl B, Horn-Wichmann R, Brabant G, Simoons ML, Armstrong PW, Califf RM, Drexler H, Wallentin L. Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation. 2007;115:962–971.
    1. Ng L, O'Brien R, Demme B, Jennings S. Non-competitive immunochemiluminometric assay for cardiotrophin-1 detects elevated plasma levels in human heart failure. 2002;102:411–416.
    1. Harrell FJ. The Design Package. 2007.
    1. Harrell FJ, Lee K, Califf R, Pryor D, Rosati R. Regression modelling strategies for improved prognostic prediction. Stat Med. 1984;3:143–152.
    1. Harrell FJ, Lee K, Mark D. Multivariate prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15:361–387.
    1. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, Anand I, Maggioni A, Burton P, Sullivan MD, Pitt B, Poole-Wilson PA, Mann DL, Packer M. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113:1424–1433.
    1. Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika. 1982;69:239–241.
    1. Efron B. Bootstrap method: another look at the jacknife. Ann Stat. 1979;7:1–26.
    1. Heagerty P, Zheng Y. Survival model predictive accuracy and ROC curves. UW Biostatistics Working Paper Series. 2003 Working Paper 219.
    1. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667.
    1. Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, Hewett TE, Breit SN, Molkentin JD. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res. 2006;98:342–350.
    1. Azhar M, Schultz Jel J, Grupp I, Dorn GW, 2nd, Meneton P, Molin DG, Gittenberger-de Groot AC, Doetschman T. Transforming growth factor beta in cardiovascular development and function. Cytokine Growth Factor Rev. 2003;14:391–407.
    1. Bruins S, Fokkema MR, Romer JW, Dejongste MJ, van der Dijs FP, van den Ouweland JM, Muskiet FA. High intraindividual variation of B-type natriuretic peptide (BNP) and amino-terminal proBNP in patients with stable chronic heart failure. Clinical chemistry. 2004;50:2052–2058.
    1. Wu AH, Smith A, Wieczorek S, Mather JF, Duncan B, White CM, McGill C, Katten D, Heller G. Biological variation for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure. Am J Cardiol. 2003;92:628–631.

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