Growth differentiation factor 15 and the risk of cardiovascular events in patients with atrial fibrillation after elective percutaneous coronary intervention

Aim. To study the predictive value of growth differentiation factor 15 (GDF-15) in patients with atrial fibrillation (AF) after elective percutaneous coronary intervention (PCI).

Material and methods. The study included 150 patients (men, 69,3%) with AF receiving direct oral anticoagulants in combination with two (89,3%) or one antiplatelet agent (10,7%) after elective PCI. Median age was 71,0 [interquartile range, 66,0; 77,0] years. The median follow-up was 11,5 months [interquartile range, 8,0; 12,0]. The efficacy endpoint was the sum of cardiovascular events (CVEs), including cardiovascular death, ischemic stroke, venous thromboembolism, peripheral arterial thrombosis, acute coronary syndrome, and the need for emergency PCI. The safety endpoint was considered to be BARC type 2-5 bleeding. Prior to PCI, blood plasma samples were taken from patients to determine GDF-15 and D-dimer by enzyme immunoassay.

Results. The incidence of CVEs was 16%. The incidence of BARC type 2-5 bleeding was 24,7%. The median GDF-15 level was 1270,0 pg/ml [953,0; 1778,0]. According to multiple regression, the GDF-15 level is associated with D-dimer (t=3,20; p=0,0018), diabetes (t=3,97; p=0,0001) and SYNTAX score II (t=4,77; p<0,0001). In patients with single-vessel coronary artery disease, the GDF-15 level was significantly lower than in patients with three-vessel disease (p=0,0119). According to the ROC analysis, a GDF-15 >1191 pg/ml (p=0,0076) increases the likelihood of CVE (area under the curve, 0,647; confidence interval (CI), 0,5650,723). According to Kaplan-Meier survival curves, significant differences were found in terms of absence of CVEs during the follow-up period between the groups of patients with a GDF-15 >1191 and those with GDF-15 <1191 pg/ml (76% vs 94%, p=0,0032; relative risk, 4,36; CI 1,50-7,48). The relationship of GDF-15 level with BARC type 2-5 bleeding was not revealed.

Conclusion. GDF-15 is a novel marker of CVE in AF patients after elective PCI.

1. van Rein N, Heide-J0rgensen U, Lijfering W, et al. Major Bleeding Rates in Atrial Fibrillation Patients on Single, Dual, or Triple Antithrombotic Therapy. Circulation. 2019;139(6):775-86. doi:10.1161/circulationaha.118.036248.

2. 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). European Heart Journal. 2021;42(5):373-498. doi:10.1093/eurheartj/ehaa612.

3. Collet J, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal. 2021;42(14):1289-367. doi:10.1093/eurheartj/ehaa575.

4. Mennuni M, Halperin J, Bansilal S, et al. Balancing the Risk of Bleeding and Stroke in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention (from the AVIATOR Registry). Am J Cardiol. 2015;116(1):37-42. doi:10.1016/j.amjcard.2015.03.033.

5. Xanthakis V, Enserro D, Murabito J, et al. Ideal Cardiovascular Health. Circulation. 2014;130(19):1676-83. doi:10.1161/circulationaha.114.009273.

6. Adela R, Banerjee S. GDF-15 as a Target and Biomarker for Diabetes and Cardiovascular Diseases: A Translational Prospective. J Diabetes Res. 2015;2015:1-14. doi:10.1155/2015/490842.

7. Wollert K, Kempf T, Wallentin L. Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease. Clin Chem. 2017;63(1):140-51. doi:10.1373/clinchem.2016.255174.

8. Schlittenhardt D, Schober A, Strelau J, et al. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res. 2004;318(2):325-33. doi:10.1007/s00441-004-0986-3.

9. Bonaterra G, Zugel S, Thogersen J, et al. Growth Differentiation Factor-15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin-6-Dependent Inflammatory Response to Vascular Injury. J Am Heart Assoc. 2012;1(6). doi:10.1161/jaha.112.002550.

10. de Jager S, Bermudez B, Bot I, et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med. 2011;208(2):217-25. doi:10.1084/jem.20100370.

11. Ackermann K, Bonaterra G, Kinscherf R, Schwarz A. Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages. Atherosclerosis. 2019;281:128-36. doi:10.1016/j.atherosclerosis.2018.12.009.

12. Johnen H, Kuffner T, Brown D, et al. Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE-/- mice from the development of atherosclerosis. Cardiovascular Pathology. 2012;21(6):499-505. doi:10.1016/j.carpath.2012.02.003.

13. Preusch M, Baeuerle M, Albrecht C, et al. GDF-15 protects from macrophage accumulation in a mouse model of advanced atherosclerosis. Eur J Med Res. 2013;18(1):19. doi:10.1186/2047-783x-18-19.

14. Komarov AL, Novikova ES, Dobrovolsky AB, et al. Prognostic significance of DAPT scale and D-Dimer level in patients treated with elective PCI. Kardiologicheskij vestnik. 2018;13(2):39-47. (In Russ.) doi:10.17116/Cardiobulletin201813239.

15. Novikova ES, Komarov AL, Gus'kova EV, et al. Is the SYNTAX score sufficient to assess the risk for patients undergoing elective percutaneous coronary interventions? Aterotromboz. 2017;(1):80-93. (In Russ.) doi:10.21518/2307-1109-2017-1-80-93.

16. Desmedt S, Desmedt V, De Vos L, et al. Growth differentiation factor 15: A novel biomarker with high clinical potential. Critical Reviews In Clinical Laboratory Sciences. 2019;56(5):333-50. doi:10.1080/10408363.2019.1615034.

17. Wallentin L, Hijazi Z, Andersson U, et al. Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation. Circulation. 2014;130(21):1847-58. doi:10.1161/circulationaha.114.011204.

18. Hijazi Z, Oldgren J, Lindback J, et al. A biomarker-based risk score to predict death in patients with atrial fibrillation: the ABC (age, biomarkers, clinical history) death risk score. Eur Heart J. 2017;39(6):477-85. doi:10.1093/eurheartj/ehx584.

19. Krivosheeva EN, Panchenko EP, Kropacheva ES, et al. Prediction-Determining Outcomes and Their Predictors in Atrial Fibrillation Patients Receiving Multicomponent Antithrombotic Therapy in Real Clinical Practice. Kardiologiia. 2020;60(8):33-45. (In Russ.) doi:10.18087/cardio.2020.8.n1123.

20. Hijazi Z, Oldgren J, Lindback J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. The Lancet. 2016;387(10035):2302-11. doi:10.1016/s0140-6736(16)00741-8.

21. Berg D, Ruff C, Jarolim P, et al. Performance of the ABC Scores for Assessing the Risk of Stroke or Systemic Embolism and Bleeding in Patients With Atrial Fibrillation in ENGAGE AF-TIMI Circulation. 2019;139(6):760-71. doi:10.1161/circulationaha.118.038312.