Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC)

22. 06. 2022

Meijers et al have published review „Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC)“ 1 and describe potential usage of biomarkers in the heart failure. There present routinely used biomarkers for the diagnosis, prognosis and management of patients with heart failure (HF)  such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), B-type natriuretic peptide (BNP), and high-sensitivity cardiac troponin (hs-cTn), and focus on new biomarkers improving decision-making management or outcomes: procalcitonin, NGAL, KIM-1, IGFBP-7, soluble suppression of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor-15 (GDF-15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic-based risk scores. Among these markers, they suggest galectin-3.

„Acute HF is associated with a high incidence (∼25%) of acute kidney injury (AKI), often superimposed on pre-existing chronic kidney disease. From multiple studies we know that nearly 50% of patients with chronic HF have an eGFR <60 mL/min/1.73 m2  To date targeting AKI in acute HF with experimental pharmacotherapies has unfortunately failed.2 It is critical to detect the development of kidney injury early in order to apply renoprotective measures (avoidance of nephrotoxic drugs, contrast media and hypotension plus protection of renal perfusion pressure), which are known to improve outcome in acute HF.3 The diagnosis of AKI is currently limited to the measurement of serum creatinine and urine output, which mostly reflects glomerular filtration. Differentiation between AKI and acute tubular necrosis is important and both entities are clearly explained in other reviews.4, 5 Additional markers which reflect tubular injury might complement to diagnose AKI at an earlier stage. Indeed, there is a clear trend to evaluate both glomerular and tubular injury to detect AKI.6 “  Kidney cellular damage markers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and IL-18 are discussed to facilitate earlier detection of AKI following ischaemic and nephrotoxic kidney injury. Specificaly, KIM-1 is produced in proximal tubular cells in kidneys, and is suggested  as a marker of tubular injury.“

„Galectin-3 is not cardiac specific therefore not specific for a distinct medical condition but is a general marker of disease risk/severity and mortality. Galectin-3 can be viewed as a regulatory protein acting at several stages along the continuum from acute to chronic inflammation and in tissue fibrinogenesis. The prognostic utility of galectin-3 measurements in HF has been demonstrated in several cohorts.7, 8 In the Framingham Offspring Cohort and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, galectin-3 was associated with an increased risk for new-onset HF and all-cause mortality after adjustment for natriuretic peptides and several other clinical variables.9, 10 This was further strengthened by a meta-analysis in over 30 000 subjects demonstrating that galectin-3 added prognostic value for new-onset HF.11 A study with 180 ambulatory patients with HF examined serial galectin-3 measurements and concluded that, in multivariable models adjusted for natriuretic peptides, cardiac troponin, and clinical variables, serial galectin-3 did not reclassify patients into higher risk groups.12 However, another much larger study [CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure)] demonstrated that in both acute and chronic HF, galectin-3 increases >15% over time were prognostic.13 Furthermore, a pooled analysis of three trials in acute HF demonstrated robust prognostic value for near-term rehospitalization if galectin-3 was >17.8 ng/mL, with a large number of patients correctly reclassified.8 Galectin-3 appears valuable in prognosticating patients with HFpEF; indeed, galectin-3 was found to be the most accurate risk predictor of adverse events within 5 years in patients with HFpEF.14 In addition, galectin-3 is able to identify HF patients at low risk for adverse events.15 No interactions between HF therapies and galectin-3 have yet been identified.16, 17 Finally, the authors suggest to investigate the modality of anti-galectin-3 therapy in cardiovascular patients, as it is conducted in other fibrotic diseases.“


1. Meijers WC et al. Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC). Eur J Heart Fail. 2021 Oct;23(10):1610-1632.

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3. Omar HR, Guglin M. Discharge BNP is a stronger predictor of 6-month mortality in acute heart failure compared with baseline BNP and admission-to-discharge percentage BNP reduction. Int J Cardiol 2016; 221: 1116– 1122.

4. Stack JR, Madigan A, Helbert L, Dunne E, Gardiner EE, Andrews RK, Finan R, Smyth E, Kenny D, McCarthy GM. Soluble glycoprotein VI, a specific marker of platelet activation is increased in the plasma of subjects with seropositive rheumatoid arthritis.PLoS One. 2017; 12:e0188027.

5. Montague SJ, Delierneux C, Lecut C, Layios N, Dinsdale RJ, Lee CS, Poulter NS, Andrews RK, Hampson P, Wearn CM, et al.. Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI.Blood Adv. 2018; 2:240–251.

6. Yamashita Y, Naitoh K, Wada H, Ikejiri M, Mastumoto T, Ohishi K, Hosaka Y, Nishikawa M, Katayama N. Elevated plasma levels of soluble platelet glycoprotein VI (GPVI) in patients with thrombotic microangiopathy.Thromb Res. 2014; 133:440–444.

7. Granata A, Serrano F, Bernard WG, McNamara M, Low L, Sastry P, Sinha S. An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death.Nat Genet. 2017; 49:97–109.

8. Schwill S, Seppelt P, Grünhagen J, Ott CE, Jugold M, Ruhparwar A, Robinson PN, Karck M, Kallenbach K. The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta.J Vasc Surg. 2013; 57:1628–36, 1636.e1.

9. Zhou Z, Feng Z, Hu D, Yang P, Gur M, Bahar I, Cristofanilli M, Gradishar WJ, Xie XQ, Wan Y. A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy.EBioMedicine. 2019; 44:98–111.

10. Sur S, Swier VJ, Radwan MM, Agrawal DK. Increased expression of phosphorylated Polo-Like Kinase 1 and histone in bypass vein graft and coronary arteries following angioplasty.PLoS One. 2016; 11:e0147937.

11. Mai J, Zhong ZY, Guo GF, Chen XX, Xiang YQ, Li X, Zhang HL, Chen YH, Xu XL, Wu RY, et al.. Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma.Theranostics. 2019; 9:3541–3554.

12. Hanna J, Hossain GS, Kocerha J. The potential for microRNA therapeutics and clinical research.Front Genet. 2019; 10:478.

13. Xie C, Huang H, Sun X, Guo Y, Hamblin M, Ritchie RP, Garcia-Barrio MT, Zhang J, Chen YE. MicroRNA-1 regulates smooth muscle cell differentiation by repressing Kruppel-like factor 4.Stem Cells Dev. 2011; 20:205–210.

14. French B, Wang L, Ky B, Brandimarto J, Basuray A, Fang JC, Sweitzer NK, Cappola TP. Prognostic value of galectin-3 for adverse outcomes in chronic heart failure. J Card Fail 2016; 22: 256– 262.

15. Meijers WC, de Boer RA, van Veldhuisen DJ, Jaarsma T, Hillege HL, Maisel AS, Di Somma S, Voors AA, Peacock WF. Biomarkers and low risk in heart failure. Data from COACH and TRIUMPH. Eur J Heart Fail 2015; 17: 1271– 1282.

16. Gandhi PU, Motiwala SR, Belcher AM, Gaggin HK, Weiner RB, Baggish AL, Fiuzat M, Brunner-La Rocca HP, Januzzi JL. Galectin-3 and mineralocorticoid receptor antagonist use in patients with chronic heart failure due to left ventricular systolic dysfunction. Am Heart J 2015; 169: 404– 411.e3.

17. Fiuzat M, Schulte PJ, Felker M, Ahmad T, Neely M, Adams KF, Donahue MP, Kraus WE, Piña IL, Whellan DJ, O’Connor CM. Relationship between galectin-3 levels and mineralocorticoid receptor antagonist use in heart failure: analysis from HF-ACTION. J Card Fail 2014; 20: 38– 44.




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