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Thromb Haemost 2022; 122(05): 703-714
DOI: 10.1055/a-1695-8327
Coagulation and Fibrinolysis

The Prognostic Potential of Growth Differentiation Factor-15 on Bleeding Events and Patient Outcome after Cardiac Surgery—A Prospective Cohort Study

Niema Kazem
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Andreas Hammer
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Lorenz Koller
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Felix Hofer
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Barbara Steinlechner
2   Division of Cardiac Thoracic Vascular Anaesthesia, Department of Anesthesiology, Medical University of Vienna, Vienna, Austria
,
Günther Laufer
3   Division of Cardiac Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
,
Christian Hengstenberg
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Johann Wojta
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Patrick Sulzgruber
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Alexander Niessner
1   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
› Author Affiliations Funding None.
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Abstract

Background GDF-15 (growth/differentiation factor 15) is induced by myocardial stretch, volume overload, inflammation, and oxidative stress. Its expression is tightly linked with cardiovascular events as well as the risk for major bleeding and all-cause mortality. The present study aimed to elucidate the prognostic potential of GDF-15 in patients after cardiac surgery.

Methods A total of 504 patients undergoing elective cardiac valve and/or coronary artery bypass graft surgery were prospectively enrolled. GDF-15 levels were measured prior to surgery to evaluate the impact on bleeding events, thromboembolic events, and mortality.

Results Preoperative GDF-15 was associated with the primary endpoint of intra- and postoperative red blood cell transfusion (for bleeding risk factors adjusted [adj] OR [odds ratio] per 1-SD [standard deviation] of 1.62 [95% confidence interval [CI]: 1.31–2.00]; p < 0.001). Higher concentrations of GDF-15 were observed in patients reaching the secondary endpoint of major or clinically relevant minor bleeding (for bleeding risk factors adj. OR per 1-SD of 1.70 [95% CI: 1.05–2.75]; p = 0.030) during the first postoperative year, but not for thromboembolic events. GDF-15 was a predictor for cardiovascular mortality (for comorbidities adj. HR [hazard ratio] per 1-SD of 1.67 [95% CI: 1.23–2.27]; p = 0.001) and all-cause mortality (for comorbidities adj. HR per 1-SD of 1.55 [95% CI: 1.19–2.01]; p = 0.001). A combined risk model of GDF-15 and EuroSCORE II outperformed the EuroSCORE II alone for long-term survival (C-index: 0.75 [95% CI: 0.70–0.80], p = 0.046; net reclassification improvement: 33.6%, p < 0.001).

Conclusion Preoperative GDF-15 concentration is an independent predictor for intra- and postoperative major bleeding, major bleeding during the first year, and for long-term cardiovascular or all-cause mortality after cardiac surgery.

Keywords

GDF-15 - postoperative atrial fibrillation - cardiac surgery - bleeding - survival - mortality

Author Contributions

A.N., P.S., and N.K. contributed to the conception and design of the work. F.H., L.K., and A.H. contributed to the acquisition, analysis, or interpretation of data for the work. N.K. drafted the manuscript. C.H., G.L., B.S., J.W., P.S., and A.N. critically revised the manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.


Supplementary Material



Publication History

Received: 01 June 2021

Accepted: 11 November 2021

Accepted Manuscript online:
12 November 2021

Article published online:
08 February 2022

© 2021. Thieme. All rights reserved.

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Comment to this article:

Growth Differentiation Factor 15 in Cardiovascular Diseases: Predicting Bleeding after Cardiac Surgery and Beyond That!Thromb Haemost 2022; 122(05): 657-660
DOI: 10.1055/a-1768-4206

 

  • References

  • 1 Heringlake M, Charitos EI, Gatz N. et al. Growth differentiation factor 15: a novel risk marker adjunct to the EuroSCORE for risk stratification in cardiac surgery patients. J Am Coll Cardiol 2013; 61 (06) 672-681
    CrossrefPubMedSearch in Google Scholar
  • 2 Wallentin L, Hijazi Z, Andersson U. et al; ARISTOTLE Investigators. 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 (21) 1847-1858
    CrossrefPubMedSearch in Google Scholar
  • 3 Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem 2017; 63 (01) 140-151
    CrossrefPubMedSearch in Google Scholar
  • 4 Chang K-W, Hsu JC, Toomu A, Fox S, Maisel AS. Clinical applications of biomarkers in atrial fibrillation. Am J Med 2017; 130 (12) 1351-1357
    CrossrefPubMedSearch in Google Scholar
  • 5 Esteve-Pastor MA, Roldán V, Rivera-Caravaca JM, Ramírez-Macías I, Lip GYH, Marín F. The use of biomarkers in clinical management guidelines: a critical appraisal. Thromb Haemost 2019; 119 (12) 1901-1919
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Chugh SS, Havmoeller R, Narayanan K. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129 (08) 837-847
    CrossrefPubMedSearch in Google Scholar
  • 7 Dobrev D, Aguilar M, Heijman J, Guichard J-B, Nattel S. Postoperative atrial fibrillation: mechanisms, manifestations and management. Nat Rev Cardiol 2019; 16 (07) 417-436
    CrossrefPubMedSearch in Google Scholar
  • 8 Hindricks G, Potpara T, Dagres N. et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2020; 42 (05) 373-498
    CrossrefPubMedSearch in Google Scholar
  • 9 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedSearch in Google Scholar
  • 10 Sharma A, Stevens SR, Lucas J. et al. Utility of growth differentiation factor-15, a marker of oxidative stress and inflammation, in chronic heart failure: insights from the HF-ACTION study. JACC Heart Fail 2017; 5 (10) 724-734
    CrossrefPubMedSearch in Google Scholar
  • 11 Hijazi Z, Oldgren J, Lindbäck J. et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
    Search in Google Scholar
  • 12 Hijazi Z, Oldgren J, Andersson U. 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
    CrossrefPubMedSearch in Google Scholar
  • 13 Hagström E, James SK, Bertilsson M. et al; PLATO Investigators. 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 (16) 1325-1333
    CrossrefPubMedSearch in Google Scholar
  • 14 Maesen B, Nijs J, Maessen J, Allessie M, Schotten U. Post-operative atrial fibrillation: a maze of mechanisms. Europace 2012; 14 (02) 159-174
    CrossrefPubMedSearch in Google Scholar
  • 15 Li T, Sun Z-L, Xie Q-Y. Meta-analysis identifies serum C-reactive protein as an indicator of atrial fibrillation risk after coronary artery bypass graft. Am J Ther 2016; 23 (06) e1586-e1596
    CrossrefPubMedSearch in Google Scholar
  • 16 Wu Z-K, Laurikka J, Vikman S, Nieminen R, Moilanen E, Tarkka MR. High postoperative interleukin-8 levels related to atrial fibrillation in patients undergoing coronary artery bypass surgery. World J Surg 2008; 32 (12) 2643-2649
    CrossrefPubMedSearch in Google Scholar
  • 17 Tousoulis D, Zisimos K, Antoniades C. et al. Oxidative stress and inflammatory process in patients with atrial fibrillation: the role of left atrium distension. Int J Cardiol 2009; 136 (03) 258-262
    CrossrefPubMedSearch in Google Scholar
  • 18 Kazem N, Sulzgruber P, Thaler B. et al. CD8+CD28null T lymphocytes are associated with the development of atrial fibrillation after elective cardiac surgery. Thromb Haemost 2020; 120 (08) 1182-1187
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Sulzgruber P, Thaler B, Koller L. et al. CD4+CD28null T lymphocytes are associated with the development of atrial fibrillation after elective cardiac surgery. Sci Rep 2018; 8 (01) 9624
    CrossrefPubMedSearch in Google Scholar
  • 20 Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol Cancer Ther 2003; 2 (10) 1023-1029
    PubMedSearch in Google Scholar
  • 21 Bansal N, Zelnick L, Shlipak MG. et al; CRIC Study Investigators. Cardiac and stress biomarkers and chronic kidney disease progression: the CRIC Study. Clin Chem 2019; 65 (11) 1448-1457
    CrossrefPubMedSearch in Google Scholar
  • 22 Schnaubelt S, Pilz A, Koller L, Kazem N, Hofer F, Fleck T. et al. The impact of volume substitution on post-operative atrial fibrillation. Eur J Clin Invest 2021; 51 (05) e13456
    CrossrefPubMedSearch in Google Scholar
  • 23 Yin J, Zhu Z, Guo D. et al. Increased growth differentiation factor 15 is associated with unfavorable clinical outcomes of acute ischemic stroke. Clin Chem 2019; 65 (04) 569-578
    CrossrefPubMedSearch in Google Scholar
  • 24 Otto CM, Nishimura RA, Bonow RO. et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143 (05) e35-e71
    PubMedSearch in Google Scholar
  • 25 Falk V, Baumgartner H, Bax JJ. et al; ESC Scientific Document Group. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur J Cardiothorac Surg 2017; 52 (04) 616-664
    CrossrefPubMedSearch in Google Scholar
  • 26 Levine GN, Bates ER, Bittl JA. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68 (10) 1082-1115
    CrossrefPubMedSearch in Google Scholar
  • 27 Sousa-Uva M, Neumann F-J, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur J Cardiothorac Surg 2019; 55 (01) 4-90
    CrossrefPubMedSearch in Google Scholar
  • 28 Ban N, Siegfried CJ, Lin JB. et al. GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients. JCI Insight 2017; 2 (09) e91455
    CrossrefPubMedSearch in Google Scholar
  • 29 Myhre PL, Prebensen C, Strand H. et al. Growth differentiation factor 15 provides prognostic information superior to established cardiovascular and inflammatory biomarkers in unselected patients hospitalized with COVID-19. Circulation 2020; 142 (22) 2128-2137
    CrossrefPubMedSearch in Google Scholar
  • 30 Hijazi Z, Lindbäck J, Alexander JH. et al; ARISTOTLE and STABILITY Investigators. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J 2016; 37 (20) 1582-1590
    CrossrefPubMedSearch in Google Scholar
  • 31 Camelo-Castillo A, Rivera-Caravaca JM, Marín F, Vicente V, Lip GYH, Roldán V. Predicting adverse events beyond stroke and bleeding with the ABC-stroke and ABC-bleeding scores in patients with atrial fibrillation: the Murcia AF Project. Thromb Haemost 2020; 120 (08) 1200-1207
    Thieme ConnectPubMedSearch in Google Scholar