OBJECTIVE: This study aimed to determine the importance of biomarkers of chronic heart failure (CHF) for assessing disease severity in euvolemic stable patients. PATIENTS AND METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, galectin-3, cystatin-C, soluble suppression of tumorigenicity 2 (sST2), tissue type inhibitor of matrix metalloproteinase (TIMP)-1, and ceruloplasmin levels were measured in euvolemic patients with stable CHF. Severity of CHF was defined by echocardiographic and biochemical parameters. RESULTS: In 160 patients (123 men and 37 women, mean age: 65.8±12.2 years), we found strong associations between NT-proBNP and bilirubin levels (r = 0.434) and the estimated glomerular filtration rate (r = -0.321). GDF-15 and cystatin-C levels were significantly correlated with parameters of kidney function. In multivariable regression analysis, NT-proBNP levels were associated with the left ventricular ejection fraction and left ventricular end-systolic volume (coefficient of determination R2 = 0.777). Additionally, GDF-15 levels were correlated with urea levels (R2 = 0.742), and cystatin C levels were correlated with urea and bilirubin levels (R2 = 0.732). CONCLUSION: Besides NT-proBNP, GDF-15 and cystatin C are promising biomarkers for establishing the severity of disease in euvolemic patients with stable CHF.

3rd Faculty of Medicine Charles University Prague

Department of Clinical Biochemistry Haematology and Immunology Na Homolce Hospital Prague Czech Republic

Department of Medical Biophysics and Medical Informatics 3rd Faculty of Medicine Charles University Prague

Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Na Homolce Hospital Cardiovascular Center Prague Czech Republic

See more in PubMed

Braunwald E. Biomarkers in heart failure. New Engl J Med 2008; 358: 2148–2159. PubMed

Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004; 110: 2168–2174. PubMed

McCullough PA, Nowak RM, McCord J. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002; 106: 416–422. PubMed

Jourdain P, Gueffet P, Helloco J. Benefit of BNP for optimizing therapy in patients with heart failure duet to systolic dysfunction: the Sytolic Heart Failure Treatment Supported by BNP Trial (STARS-BNP) multicenter randomized study. Eur J Heart Fail Suppl 2005; 4: 120–128.

Pfisterer M, Buser P, Riskli H, et al. BNP-guided vs symptom-guided heart failure therapy: The Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009; 301: 383–392. PubMed

Tang WWH, Francis GS, Morrow DA, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical utilization of cardiac biomarker testing in heart failure. Circulation 2007; 116: e99–e109. PubMed

Sharma UC, Pokharel S, Van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation 2004; 110: 3121–3128. PubMed

Lok DJ, Van Der Meer P, De La Porte PW, et al. Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from DEAL-HF study. Clin Res Cardiol 2010; 99: 323–328. PubMed PMC

De Boer RA, Voors AA, Muntendam P, et al. Galectin-3: a novel mediator of heart failure development and progression. Eur J Heart Fail 2009; 11: 811–817. PubMed

Weinberg EO, Shimpo M, Hurwitz S, et al. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 2003; 107: 721–726. PubMed

Januzzi JL, Jr, Peacock WF, Maisel AS, et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE study. J Am Coll Cardiol 2007; 50: 607–613. PubMed

Mueller T, Dieplinger B, Gegenhuber A, et al. Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failure. Clin Chem 2008; 54: 752–756. PubMed

Manzano-Fernandez S, Mueller T, Pascual-Figal D, et al. Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am J Cardiol 2011; 107: 259–267. PubMed PMC

Januzzi JL, Mebazaa A, Di SS. ST2 and prognosis in acutely decompensated heart failure: the International ST2 Consensus Panel. Am J Cardiol 2015; 115: 26B–31B. PubMed

Mebazaa A, Di Somma S, Maisel AS, et al. ST2 and multimarker testing in acute decompensated heart failure. Am J Cardiol 2015; 115: 38B–43B. PubMed

Zile MR, ÓMeara E, Claggett B, et al. Effects of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFrEF. J Am Col Cardiol 2019; 73: 795–806. PubMed

Kempf T, Eden M, Strelau J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006; 98: 351–360. PubMed

Lok DJ, Klip IT, Lok SI, et al. Incremental prognostic power of novel biomarkers (growth-differentiation factor-15, high-sensitivity C-reactive protein, galectin-3, and high-sensitivity troponin-T) in patients with advanced chronic heart failure. Am J Cardiol 2013; 112: 831–837. PubMed

Spinale FG. Matrix metalloproteinases. Regulation and dysregulation in the failing heart. Circ Res 2002; 90: 520–530. PubMed

George J, Patal S, Wexler D, et al. Circulating matrix metalloproteinase-2 but not matrix metalloproteinase-3, matrix metalloproteinase-9, or tissue inhibitor of metalloproteinase-1 predicts outcome in patients with congestive heart failure. Am Heart J 2005; 150: 484–487. PubMed

Laterza OF, Price CP, Scott MG. Cystatin c: an improved estimator of glomerular filtration rate? Clin Chem 2002; 48: 699–707. PubMed

Arimoto T, Takeishi Y, Niizeki T, et al. Cystatin c, a novel measure of renal function, is an independent predictor of cardiac events in patients with heart failure. J Card Fail 2005; 11: 595–601. PubMed

Damman K, Van Der Harst P, Smilde TD, et al. Use of cystatin c levels in estimating renal function and prognosis in patients with chronic systolic heart failure. Heart 2012; 98: 319–324. PubMed

Cabassi A, Binno SM, Tedeschi S, et al. Low serum ferroxidase I activity is associated with mortality in heart failure and related to both peroxynitrite-induced cysteine oxidation and tyrosin nitration of ceruloplasmin. Circ Res 2014; 114: 1723–1732. PubMed

Hammadah M, Fan Y, Wu Y, et al. Prognostic value of elevated serum ceruloplasmin levels in patients with heart failure. J Card Fail 2014; 20: 946–952. PubMed PMC

Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016; 29: 277–314. PubMed

Parasuraman S, Walker S, Loudon BL, et al. Assessment of pulmonary artery pressure by echocardiography—A comprehensive review. Int J Cardiol Heart Vasc 2016; 12: 45–51. PubMed PMC

Chan YH. Biostatistics 104: correlational analysis. Singap Med J 2003; 44: 614–619. PubMed

Dong SJ, De Las Fuentes L, Brown AL, et al. N-terminal pro B-type natriuretic peptide levels: correlation with echocardiographically determined left ventricular diastolic function in an ambulatory cohort. J Am Soc Echocardiogr 2006; 19: 1017–1025. PubMed

Song BG, Jeon ES, Kim YH, et al. Correlation between levels of N-terminal pro-B-type natriuretic peptide and degrees of heart failure. Korean J Intern Med 2005; 20: 26–32. PubMed PMC

Faida O, Said A, Samir P. NT-proBNP levels, as predictor of left ventricular systolic and diastolic dysfunction in patients with chronic heart failure. Int J Collab Res Intern Med Public Health 2012; 4: 910–923.

Atabakhshian R, Kazerouni F, Raygan F. Assessment of the relationship between galectin-3 and ejection fraction and functional capacity in the patients with compensated systolic heart failure. Int Cardiovasc Res J 2014; 8: 143–147. PubMed PMC

Bayes-Genis A, De Antonio M, Vila J, et al. Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectin-3. J Am Coll Cardiol 2014; 63: 158–166. PubMed

Nadar SK, Shaikh MM. Biomarkers in routine heart failure clinical care. Card Fail Rev 2019; 5: 50–56. PubMed PMC

Wojtczak-Soska K, Pietrucha T, Sakowicz A, et al. Soluble ST2 protein in chronic heart failure is independent of traditional factors. Arch Med Sci 2013; 9: 21–26. PubMed PMC

Allen LA, Felker GM, Pocock S, et al. Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Eur J Heart Failure 2009; 11: 170–177. PubMed PMC

Shinagawa H, Inomata T, Koitabashi T, et al. Prognostic significance of increased serum bilirubin levels coincident with cardiac decompensation in chronic heart failure. Circ J 2008; 72: 364–369. PubMed

Frantz S, Stork S, Michels K, et al. Tissue inhibitor of metalloproteinases levels in patients with chronic heart failure: an independent predictor of mortality. Eur J Heart Fail 2008; 10: 388–395. PubMed

Jordán A, Roldán V, García M, et al. Matrix metalloproteinase1 and its inhibitor, TIMP-1, in systolic heart failure: relation to functional data and prognosis. J Intern Med 2007; 262: 385–392. PubMed

Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017; 136: e137–e161. PubMed

Ahmad T, Fiuzat M, Neely B, et al. Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart failure. JACC Heart Fail 2014; 2: 260–268. PubMed PMC

Diabetes mellitus in stable chronic heart failure and the combination with humoral activation, their association, and prediction of 2-year adverse outcomes. Data from the FAR NHL registry