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

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.

Publikationsverlauf

Eingereicht: 01. Juni 2021

Angenommen: 11. November 2021

Accepted Manuscript online:
12. November 2021

Artikel online veröffentlicht:
08. Februar 2022

• 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
• 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
• 3 Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem 2017; 63 (01) 140-151
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 19 Sulzgruber P, Thaler B, Koller L. et al. CD4⁺CD28^null T lymphocytes are associated with the development of atrial fibrillation after elective cardiac surgery. Sci Rep 2018; 8 (01) 9624
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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