Prognostic significance of NT-proBNP and sST2 in patients with heart failure with preserved and mildly reduced ejection fraction

Aim. To study the prognostic significance of cardiobiomarkers - NT-proBNP and soluble suppression of tumorigenecity (sST2) in patients with CHF with preserved (CHFpEF) and mildly reduced EF (CHFmrEF).

Material and methods. Along with a clinical examination, 207 patients (111 men and 96 women), mean age - 72.6 ± 11.4 years, underwent tests for the level of NT-proBNP and sST2 in serum. All patients were divided into 3 groups: 1 - CHFpEF (n=85), 2 - CHFmrEF (n=50); 3 (comparison group)- CHFrEF (n=72). All patients signed informed consent to participate in the study. The primary endpoint was all-cause death in 12 months. Statistical processing of the results was carried out using the Statistica 12.0 and Medcalc programs.

Results. The initial values ​of NT-proBNP in patients with CHFmrEF were 691.9 [248; 1915.5] pg/ml and were significantly higher than those of CHFpEF - 445.8 [214.6; 945.7] pg/ml, but significantly lower than in CHFrEF - 1131.4 [411.5;3039.5] pg/ml, p<0.05. sST2 values ​​in group 1 (23.21 [12.17;48.7] ng/ml and group 2 (27.11 [16.98;53.76] ng/ml) did not differ, but were significantly lower than in patients with CHFrEF (44.6 [21.1; 93.5] ng/ml). After a median of 12 months 51 patients reached the primary endpoint.  All-causes mortality in patients with HFpEF was 11.8%, HFmrEF - 31.9% (p <0.05), and HFrEF – 36%. A retrospective analysis of the data showed that in patients independent of their initial ejection fraction, who survived for 12 months, the levels of NT-proBNP and sST2 were significantly lower than those of the deceased.  In survivors and deceased patients with CHFpEF the values ​​of NT-proBNP and sST2 were 443 [154;862,8] vs 1143,2 [223,9;2021,9] pg/ml (p=0.009) and 22,8 [12,3;33,8]  vs 26,8 [9,6;74,8] ng/mL (p<0.05). In survivors and deceased patients with CHFmrEF the values ​​of NT-proBNP and sST2 were 397.4 [128.9;1088.5] vs 1939.7 [441.9;2536] pg/ml (p=0.009) and 18.6 [14.9;30.27.1] vs 59.9 [53.76;84.4] ng/mL (p=0.002). There were no significant differences in NT-proBNP and sST2 values ​​in patients with cardiac and non-cardiac causes of death. sST2 parameters in deceased patients with CHFpEF (26.8 [9.6;74.8] ng/mL) and CHFmrEF (59.9 [53.76;84.4] ng/mL) also had no significant differences (p >0.05). At ROC analysis to one-year adverse events, both NT-proBNP and sST2 showed a significant predictive value in patients with EF >40% with an optimal cut-off value of 746 pg/ml (AUC 0.709; p = 0.005, sensitivity 62%, specificity 69%) and 27.1 ng/ml (AUC 0.742; p = 0.03, sensitivity 80%, specificity 75.8%) respectively.

Conclusion: NT-proBNP levels >746 pg/ml and sST2 >27.1 ng/ml should be considered as predictors of poor prognosis in CHF patients with LVEF >40%.

1. 2020 Clinical practice guidelines for Chronic heart failure. Russian Journal of Cardiology. 2020;25(11):4083 (In Russ.) DOI:10.15829/1560-4071-2020-4083.

2. Drapkina OM, Boytsov SA, Omelyanovskiy VV, et al. Socio-economic impact of heart failure in Russia. Russian Journal of Cardiology. 2021;26(6):4490 (In Russ.) DOI:10.15829/1560-4071-2021-4490.

3. Murray CJL. The Global Burden of Disease Study at 30 years. Nat Med. 2022;28(10):2019-2026. DOI:10.1038/s41591-022-01990-1.

4. Polyakov DS, Fomin IV, Belenkov YuN, et al. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiologiia. 2021;61(4):4-14 (In Russ.) DOI:10.18087/ cardio.2021.4.n1628.

5. Gavryushina SV, Ageev FT. Heart failure with preserved left ventricular ejection fraction: epidemiology, patient «portrait», clinic, and diagnostics. Kardiologiia. 2018;58(4S):55-64 (In Russ.). DOI:10.18087/ cardio.2467.

6. Bayés-Genís A, Núñez J, Lupón J. Heart failure with mid-range ejection fraction: a transition phenotype? Eur J Heart Fail. 2017;19(12):1635-1637. DOI:10.1002/ ejhf.977.

7. McDonagh T, Metra M, Adamo M, et al. ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Eur Heart J. 2021;42(36):3599-3726. DOI:10.1093/eurheartj/ehab368.

8. Larina VN, Skiba IK, Skiba AS. Summary of updates to the 2021 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure. Russian Journal of Cardiology. 2022;27(2):4820 (In Russ) DOI:10.15829/1560-4071-2022-4820.

9. Kozhevnikova MV, Belenkov YuN. Biomarkers in Heart Failure: Current and Future. Kardiologiia. 2021;61(5):4-16 (In Russ.) DOI:10.18087/cardio.2021.5.n1530.

10. Podzolkov VI, Tarzimanova AI, Loriya IZ. Сhanges in the level of natriuretic peptides in patients with atrial fibrillation treated with antiarrhythmic drugs. Rational Pharmacotherapy in Cardiology. 2015;11(4):365-370 (In Russ.) DOI:10.20996/1819-6446-2015-11-4-365- 370.

11. Podzolkov VI, Bragina AE, Tarzimanova AI, et al. Changes in NT-proBNP levels in patients with sinus tachycardia after COVID-19. Cardiovascular Therapy and Prevention. 2022;21(12):3485. (In Russ.) DOI:10.15829/1728-8800-2022-3485.

12. Kuster N, Huet F, Dupuy AM, et al. Multimarker approach including CRP, sST2 and GDF-15 for prognostic stratification in stable heart failure. ESC Heart Fail. 2020;7(5):2230-2239. DOI:10.1002/ehf2.12680.

13. Podzolkov VI, Dragomiretsksya NA, Kazadaeva AV, et al. Relationships between the activity of neurohormonal systems and intracardiac hemodynamics in patients with heart failure: focus on galectin-3. Russian Journal of Cardiology. 2022;27(4):4957 (In Russ.) DOI:10.15829/1560-4071-2022- 4957.

14. Lotierzo M, Dupuy AM, Kalmanovich E, et al. sST2 as a value-added biomarker in heart failure. Clin Chim Acta. 2020;501:120-130. DOI:10.1016/j.cca.2019.10.029.

15. Kotsiou OS, Gourgoulianis KI, Zarogiannis SG. IL-33/ST2 Axis in Organ Fibrosis. Front Immunol. 2018;9:2432. DOI:10.3389/fimmu.2018.02432.

16. Vianello E, Dozio E, Tacchini L, et al. sST2/IL-33 signaling in cardiac fibrosis. Int J Biochem Cell Biol. 2019;116:105619. DOI:10.1016/j.biocel.2019.105619.

17. Dieplinger B, Egger M, Poelz W, et al. Soluble sST2 is not independently associated with androgen and estrogen status in healthy males and females. Clin Chem Lab Med. 2011;49(9):1515-8. DOI:10.1515/CCLM.2011.239.

18. Januzzi JL Jr, Peacock WF, Maisel AS, et al. Measurement of the interleukin family member sST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) Study. J Am Coll Cardiol. 2007;50(7):607-613. DOI:10.1016 /j.jacc.2007.05.014.

19. Najjar E, Faxén UL, Hage C, et al. sST2 in heart failure with preserved and reduced ejection fraction. Scand Cardiovasc J. 2019;53(1):21-27. DOI:10.1080/14017431. 2019.1583363.

20. Chirinos JA, Orlenko A, Zhao L, et al. Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction. J Am Coll Cardiol. 2020;75(11):1281-1295. DOI:10.1016/j.jacc.2019.12.069.

21. Moliner P, Lupón J, Barallat J, et al. Bio-profiling and bio-prognostication of chronic heart failure with mid-range ejection fraction. Int J Cardiol. 2018;257:188- 192. DOI:10.1016/j.ijcard.2018.01.119.

22. Rabkin SW, Tang JKK. The utility of growth differentiation factor-15, galectin-3, and sST2 as biomarkers for the diagnosis of heart failure with preserved ejection fraction and compared to heart failure with reduced ejection fraction: a systematic review. Heart Fail Rev. 2021;26(4):799-812. DOI:10.1007/s10741- 020-09913-3.

23. Drapkina OM, Kontsevaya AV, Kravchenko AY, et al. Biomarkers sST2 and interleukin 33 for assessing the severity of cardiac inflammation and fibrosis in patients with chronic heart failure. Russian Journal of Cardiology. 2021;26(3S):4530 (In Russ.) DOI:10.15829/1560-4071-2021-4530.

24. Cunningham JW, Claggett BL, O’Meara E, et al. Effect of Sacubitril/Valsartan on biomarkers of extracellular matrix regulation in patients with HFpEF. J Am Coll Cardiol. 2020;76(5):503-514. DOI:10.1016/j.jacc.2020.05.072.

25. Song Y, Li F, Xu Y, et al. Prognostic value of sST2 in patients with heart failure with reduced, mid-range and preserved ejection fraction. Int J Cardiol. 2020;304:95- 100. DOI:10.1016/j.ijcard.2020.01.039.

26. Sugano A, Seo Y, Ishizu T, et al. Soluble sST2 and brain natriuretic peptide predict different mode of death in patients with heart failure and preserved ejection fraction. J Cardiol. 2019;73(4):326-332. DOI:10.1016/j.jjcc.2018.10.012.

27. Grakova EV, Yakovlev AV, Shilov SN, et al. Heart failure with preserved left ventricular ejection fraction in patients with obstructive sleep apnea syndrome: prognostic value of biomarkers. Kardiologiia. 2021;61(11):77-88 (In Russ.) DOI:10.15829/1560-4071-2018-1-78-82.

28. Podzolkov VI, Dragomiretskaya NA, Beliaev IG, et al. Endothelial microvascular dysfunction and its relationship with haptoglobin levels in patients with different phenotypes of chronic heart failure. Rational Pharmacotherapy in Cardiology. 2021;17(5):674-682 (In Russ.) DOI:10.20996/1819-6446-2021-10-05.

29. Podzolkov VI, Dragomiretskaya NA, Stolbova SK, Tolmacheva AV. Hepcidin and MELD-XI score as markers of multiple organ failure in patients with heart failure with preserved and reduced ejection fraction. Cardiovascular Therapy and Prevention. 2020;19(3):2529 (In Russ.) DOI:10.15829/1728-88002020-2529.