Growth differentiation factor 15 (GDF-15) in ST-elevation myocardial infarction (STEMI) is prognostic in first-generation radioimmunoassays. We examined GDF-15 temporal dynamics in STEMI and its predictive value using a first fully automated GDF-15 electrochemiluminescence assay.
In this prospective study, circulating GDF-15 concentration was measured at admission (0 h), 12 h and 24 h in 1026 consecutive STEMI patients treated between February 2011 and May 2016 with primary percutaneous coronary intervention. GDF-15 dynamics (0 h, 12 h, 24 h) and predictive value (30 days and 3 years) were examined.
Median GDF-15 concentration was 1443 pg/mL at 0 h, 1731 pg/mL at 12 h and 1510 pg/mL at 24 h (p<0.001). During follow-up, 94 patients died (9.2%) and 154 (15.0%) were hospitalized. GDF-15 was a strong predictor of 30-day mortality (hazard ratio [HR] 1.76, 95% confidence interval [CI], 1.33–2.34 at 0 h; HR 2.99 [95% CI, 2.18–4.09] at 12 h, and HR 1.97 [95% CI, 1.47–2.63] at 24 h) in multivariable Cox proportional hazards models. GDF-15 improved discrimination and reclassification of a clinical risk model. GDF-15 was also associated with 3-year mortality (HR 1.31 [95% CI, 1.04–1.65] at 0 h, HR 1.42 [95% CI, 1.10–1.84] at 12 h, and HR 1.51 [95% CI, 1.16–1.96] at 24 h) and 3-year composite of mortality and cardiovascular hospitalization (HR 1.17 [95% CI, 1.01–1.37] at 0 h, HR 1.20 [95% CI, 1.02–1.42] at 12 h, and HR 1.27 [95% CI, 1.08–1.50] at 24 h).
GDF-15 peaked at 12 h and remained elevated at 24 h in STEMI. GDF-15 measurement during the first 24 h in STEMI is valuable for predicting especially short- but also long-term outcomes, and may be a useful addition to risk stratification.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Roche Diagnostics supported this research by running the GDF-15, hs-TnT and NT-proBNP assays free of charge. However, the authors are solely responsible for the design and conduct of the study, all analyses and the drafting and editing of the manuscript.
Employment or leadership: None declared.
Honorarium: AB-G and JL received honoraria for lectures and advisory boards from Roche Diagnostics.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–140.10.1161/CIR.0b013e3182742c84Search in Google Scholar
2. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77.10.1093/eurheartj/ehx393Search in Google Scholar
4. Zhang S, Dai D, Wang X, Zhu H, Jin H, Zhao R, et al. Growth differentiation factor-15 predicts the prognoses of patients with acute coronary syndrome: a meta-analysis. BMC Cardiovasc Disord 2016;16:82.10.1186/s12872-016-0250-2Search in Google Scholar
5. Thygesen K, Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551–67.10.1093/eurheartj/ehs184Search in Google Scholar
6. Kempf T, Horn-Wichmann R, Brabant G, Peter T, Allhoff T, Klein G, 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. Clin Chem 2007;53:284–91.10.1373/clinchem.2006.076828Search in Google Scholar
7. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem 2010;56:254–61.10.1373/clinchem.2009.132654Search in Google Scholar
8. Johnston N, Jernberg T, Lindahl B, Lindbäck J, Stridsberg M, Larsson A, et al. Biochemical indicators of cardiac and renal function in a healthy elderly population. Clin Biochem 2004;37:210–6.10.1016/j.clinbiochem.2003.11.002Search in Google Scholar
9. Kempf T, Björklund E, Olofsson S, Lindahl B, Allhoff T, Peter T, et al. Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J 2007;28:2858–65.10.1093/eurheartj/ehm465Search in Google Scholar
10. Eitel I, Blase P, Adams V, Hildebrand L, Desch S, Schuler G, et al. Growth-differentiation factor 15 as predictor of mortality in acute reperfused ST-elevation myocardial infarction: insights from cardiovascular magnetic resonance. Heart 2011;97:632–40.10.1136/hrt.2010.219543Search in Google Scholar
11. Wollert KC, Kempf T, Peter T, Olofsson S, James S, Johnston N, et al. Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007;115:962–71.10.1161/CIRCULATIONAHA.106.650846Search in Google Scholar
12. Eggers KM, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Jantzen F, et al. Growth-differentiation factor-15 for long-term risk prediction in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome. Circ Cardiovasc Genet 2010;3:88–96.10.1161/CIRCGENETICS.109.877456Search in Google Scholar
13. Lindholm D, Hagström E, James SK, Becker RC, Cannon CP, Himmelmann A, et al. Growth differentiation factor 15 at 1 month after an acute coronary syndrome is associated with increased risk of major bleeding. J Am Heart Assoc 2017;6:e005580.10.1161/JAHA.117.005580Search in Google Scholar
14. Velders MA, Wallentin L, Becker RC, van Boven AJ, Himmelmann A, Husted S, et al. Biomarkers for risk stratification of patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: Insights from the platelet inhibition and patient outcomes trial. Am Heart J 2015;169:879–89.10.1016/j.ahj.2015.02.019Search in Google Scholar
15. Khan SQ, Ng K, Dhillon O, Kelly D, Quinn P, Squire IB, et al. Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 2009;30:1057–65.10.1093/eurheartj/ehn600Search in Google Scholar
16. Fuernau G, Poenisch C, Eitel I, de Waha S, Desch S, Schuler G, et al. Growth-differentiation factor 15 and osteoprotegerin in acute myocardial infarction complicated by cardiogenic shock: a biomarker substudy of the IABP-SHOCK II-trial. Eur J Heart Fail 2014;16:880–7.10.1002/ejhf.117Search in Google Scholar
17. Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P. Relation of growth-differentiation factor 15 to left ventricular remodeling in ST-segment elevation myocardial infarction. Am J Cardiol 2011;108:955–8.10.1016/j.amjcard.2011.05.028Search in Google Scholar
18. Widera C, Pencina MJ, Meisner A, Kempf T, Bethmann K, Marquardt I, et al. Adjustment of the GRACE score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-ST-elevation acute coronary syndrome. Eur Heart J 2012;33:1095–104.10.1093/eurheartj/ehr444Search in Google Scholar
19. Brown DA, Breit SN, Buring J, Fairlie WD, Bauskin AR, Liu T, et al. Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study. Lancet 2002;359:2159–63.10.1016/S0140-6736(02)09093-1Search in Google Scholar
20. Wiklund FE, Bennet AM, Magnusson PK, Eriksson UK, Lindmark F, Wu L, et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell 2010;9:1057–64.10.1111/j.1474-9726.2010.00629.xSearch in Google Scholar
21. Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation 2011;123:2101–10.10.1161/CIRCULATIONAHA.110.979740Search in Google Scholar
22. Rohatgi A, Patel P, Das SR, Ayers CR, Khera A, Martinez-Rumayor A, et al. Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. Clin Chem 2012;58:172–82.10.1373/clinchem.2011.171926Search in Google Scholar
23. Wang TJ, Wollert KC, Larson MG, Coglianese E, McCabe EL, Cheng S, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation 2012;126:1596–604.10.1161/CIRCULATIONAHA.112.129437Search in Google Scholar
24. Wallentin L, Zethelius B, Berglund L, Eggers KM, Lind L, Lindahl B, et al. GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men. PLoS One 2013;8:e78797.10.1371/journal.pone.0078797Search in Google Scholar
25. Kempf T, Sinning JM, Quint A, Bickel C, Sinning C, Wild PS, et al. Growth-differentiation factor-15 for risk stratification in patients with stable and unstable coronary heart disease: results from the AtheroGene study. Circ Cardiovasc Genet 2009;2:286–92.10.1161/CIRCGENETICS.108.824870Search in Google Scholar
26. Dallmeier D, Brenner H, Mons U, Rottbauer W, Koenig W, Rothenbacher D. Growth differentiation factor 15, its 12-month relative change, and risk of cardiovascular events and total mortality in patients with stable coronary heart disease: 10-year follow-up of the KAROLA study. Clin Chem 2016;62:982–92.10.1373/clinchem.2016.254755Search in Google Scholar
27. Schopfer DW, Ku IA, Regan M, Whooley MA. Growth differentiation factor 15 and cardiovascular events in patients with stable ischemic heart disease (The Heart and Soul Study). Am Heart J 2014;167:186–92.10.1016/j.ahj.2013.09.013Search in Google Scholar
28. Hagström E, Held C, Stewart RA, Aylward PE, Budaj A, Cannon CP, et al. Growth differentiation factor 15 predicts all-cause morbidity and mortality in stable coronary heart disease. Clin Chem 2017;63:325–33.10.1373/clinchem.2016.260570Search in Google Scholar
29. Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M, Doehner W, et al. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1054–60.10.1016/j.jacc.2007.04.091Search in Google Scholar
30. Anand IS, Kempf T, Rector TS, Tapken H, Allhoff T, Jantzen F, et al. Serial measurement of growth-differentiation factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan Heart Failure Trial. Circulation 2010;122:1387–95.10.1161/CIRCULATIONAHA.109.928846Search in Google Scholar
31. Chan MM, Santhanakrishnan R, Chong JP, Chen Z, Tai BC, Liew OW, et al. Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail 2016;18:81–8.10.1002/ejhf.431Search in Google Scholar
32. Cotter G, Voors AA, Prescott MF, Felker GM, Filippatos G, Greenberg BH, et al. Growth differentiation factor 15 (GDF-15) in patients admitted for acute heart failure: results from the RELAX-AHF study. Eur J Heart Fail 2015;17:1133–43.10.1002/ejhf.331Search in Google Scholar
33. Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, et al. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation 2007;116:1540–8.10.1161/CIRCULATIONAHA.107.697714Search in Google Scholar
34. Wallentin L, Lindholm D, Siegbahn A, Wernroth L, Becker RC, Cannon CP, et al. Biomarkers in relation to the effects of ticagrelor in comparison with clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2014;129:293–303.10.1161/CIRCULATIONAHA.113.004420Search in Google Scholar
35. Tentzeris I, Farhan S, Freynhofer MK, Rohla M, Jarai R, Vogel B, et al. Usefulness of elevated levels of growth differentiation factor-15 to classify patients with acute coronary syndrome having percutaneous coronary intervention who would benefit from high-dose statin therapy. Am J Cardiol 2017;120:747–52.10.1016/j.amjcard.2017.05.045Search in Google Scholar
36. Hagström E, James SK, Bertilsson M, Becker RC, Himmelmann A, Husted S, et al. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016;37:1325–33.10.1093/eurheartj/ehv491Search in Google Scholar
37. Wallentin L, Hijazi Z, Andersson U, Alexander JH, De Caterina R, Hanna M, et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014;130:1847–58.10.1161/CIRCULATIONAHA.114.011204Search in Google Scholar
38. Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, Ezekowitz MD, et al. Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Am Heart J 2017;190:94–103.10.1016/j.ahj.2017.06.001Search in Google Scholar
39. Bonaca MP, Morrow DA, Braunwald E, Cannon CP, Jiang S, Breher S, et al. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: observations from PROVE IT-TIMI 22. Arterioscler Thromb Vasc Biol 2011;31:203–10.10.1161/ATVBAHA.110.213512Search in Google Scholar
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2018-1189).
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