English Polski
Vol 19 (2024): Continuous Publishing
Review paper
Published online: 2023-12-22

open access

Page views 870
Article views/downloads 126
Get Citation

Connect on Social Media

Connect on Social Media

The role of biomarkers of stress in heart failure

Saira Rafaqat1, Sana Rafaqat2
DOI: 10.5603/fc.95029


According to the literature, there are numerous stress biomarkers. However, for the first time, this review article summarizes the role of major physiological stress biomarkers in heart failure collectively which include chromogranin A, catecholamines, copeptin, cortisol, liver-type fatty acid-binding protein (L-FABP), superoxide dismutase (SOD) and catalase, fibrinogen, malondialdehyde, heat shock proteins. Chromogranin A (CgA) serum levels are increased in patients with chronic heart failure and are a predictive factor for mortality. A novel mechanistic insight for elevated catecholamine levels in plasma commonly seen in chronic heart failure (HF) conditions, suggests that increased trans-synaptic activation of the chromaffin cells within the adrenal medulla may increase catecholamines in the circulation and, in turn, contribute to the enhanced neurohumoral drive. Elevated copeptin plasma concentrations seen in HF patients were linked to an increased risk of all-cause death suggesting that copeptin may function as an HF outcome predictor. Since cortisol is a general stress indicator, serum cortisol levels in congestive heart failure (CHF) may reflect worse hemodynamic parameters and systemic sympathetic nerve activity. In individuals with acute heart failure, an elevated urine L-FABP level before therapy may indicate worsening renal function. Compared to children without heart failure, children with heart failure have decreased levels of SOD. In contrast to children without heart disease, children with heart failure had greater catalase (CAT) levels. In children with left-to-right shunt congenital heart disease (CHD), oxidative stress was the primary factor contributing to the development of heart failure. The individuals with acute aggravation of chronic heart failure who have high fibrinogen levels (> 284 mg/dL) were independently predicted to die. Malondialdehyde is a sign of lipid peroxidation which was detected in the plasma of congestive heart failure patients with varied levels of clinical symptoms and in healthy individuals. HSPs can reduce heart dysfunction in HF and carry out a variety of additional functions, including regulating apoptosis and possessing anti-oxidant and anti-inflammatory properties.

Article available in PDF format

View PDF Download PDF file


  1. Savarese G, Becher PM, Lund LH, et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023; 118(17): 3272–3287.
  2. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). European Heart Journal. 2008; 29(19): 2388–2442.
  3. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002; 122(5): 1784–1796.
  4. Fonseca C, Bettencourt P, Brito D, et al. Representação dos Investigadores do EPICA-RAM, EPICA Investigators, EPICA Investigators. The diagnosis of heart failure in primary care: value of symptoms and signs. Eur J Heart Fail. 2004; 6(6): 795–800, 821.
  5. Dhama K, Latheef SK, Dadar M, et al. Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values. Front Mol Biosci. 2019; 6: 91.
  6. Montezano AC, Dulak-Lis M, Tsiropoulou S, et al. Oxidative stress and human hypertension: vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol. 2015; 31(5): 631–641.
  7. Noushad S, Ahmed S, Ansari B, et al. Physiological biomarkers of chronic stress: A systematic review. Int J Health Sci (Qassim). 2021; 15(5): 46–59.
  8. Cryer PE, Wortsman J, Shah SD, et al. Plasma chromogranin A as a marker of sympathochromaffin activity in humans. Am J Physiol. 1991; 260(2 Pt 1): E243–E246.
  9. Eriksson B, Arnberg H, Oberg K, et al. Chromogranins--new sensitive markers for neuroendocrine tumors. Acta Oncol. 1989; 28(3): 325–329.
  10. Goetze JP, Hilsted LM, Rehfeld JF, et al. Plasma chromogranin A is a marker of death in elderly patients presenting with symptoms of heart failure. Endocr Connect. 2014; 3(1): 47–56.
  11. Ceconi C, Ferrari R, Bachetti T, et al. Chromogranin A in heart failure; a novel neurohumoral factor and a predictor for mortality. Eur Heart J. 2002; 23(12): 967–974.
  12. Ottesen AH, Carlson CR, Louch WE, et al. Glycosylated Chromogranin A in Heart Failure: Implications for Processing and Cardiomyocyte Calcium Homeostasis. Circ Heart Fail. 2017; 10(2).
  13. Kim HN, Yang DH, Park BoE, et al. Prognostic impact of chromogranin A in patients with acute heart failure. Yeungnam Univ J Med. 2021; 38(4): 337–343.
  14. Røsjø H, Masson S, Latini R, et al. GISSI-HF Investigators. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail. 2010; 12(6): 549–556.
  15. Kobayashi K. Role of catecholamine signaling in brain and nervous system functions: new insights from mouse molecular genetic study. J Investig Dermatol Symp Proc. 2001; 6(1): 115–121.
  16. Mahata SK, Zheng H, Mahata S, et al. Effect of heart failure on catecholamine granule morphology and storage in chromaffin cells. J Endocrinol. 2016; 230(3): 309–323.
  17. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol. 1994; 19(2): 59–113.
  18. Ingwall JS. Is cardiac failure a consequence of decreased energy reserve? Monograph-American Heart Association. 1993; 87(6): VII–58.
  19. Katz AM. Is the failing heart energy depleted? Cardiol Clin. 1998; 16(4): 633–44, viii.
  20. Dandel M, Hetzer R. Deleterious effects of catecholamine administration in acute heart failure caused by unrecognized Takotsubo cardiomyopathy. BMC Cardiovasc Disord. 2018; 18(1): 144.
  21. Gaheen R, El Amrousy D, Hodeib H, et al. Plasma copeptin levels in children with pulmonary arterial hypertension associated with congenital heart disease. Eur J Pediatr. 2021; 180(9): 2889–2895.
  22. Morgenthaler NG, Struck J, Jochberger S, et al. Copeptin: clinical use of a new biomarker. Trends Endocrinol Metab. 2008; 19(2): 43–49.
  23. El Amrousy D, Abdelhai D, Nassar M. Predictive Value of Plasma Copeptin Level in Children with Acute Heart Failure. Pediatr Cardiol. 2022; 43(8): 1737–1742.
  24. Hage C, Lund LH, Donal E, et al. Copeptin in patients with heart failure and preserved ejection fraction: a report from the prospective KaRen-study. Open Heart. 2015; 2(1): e000260.
  25. Zimodro JM, Gasecka A, Jaguszewski M, et al. Role of copeptin in diagnosis and outcome prediction in patients with heart failure: a systematic review and meta-analysis. Biomarkers. 2022; 27(8): 720–726.
  26. Voors AA, von Haehling S, Anker SD, et al. OPTIMAAL Investigators. C-terminal provasopressin (copeptin) is a strong prognostic marker in patients with heart failure after an acute myocardial infarction: results from the OPTIMAAL study. Eur Heart J. 2009; 30(10): 1187–1194.
  27. Xu L, Liu X, Wu S, et al. The clinical application value of the plasma copeptin level in the assessment of heart failure with reduced left ventricular ejection fraction: A cross-sectional study. Medicine (Baltimore). 2018; 97(39): e12610.
  28. Maisel A, Xue Y, Shah K, et al. Increased 90-day mortality in patients with acute heart failure with elevated copeptin: secondary results from the Biomarkers in Acute Heart Failure (BACH) study. Circ Heart Fail. 2011; 4(5): 613–620.
  29. Karki KB, Towbin JA, Philip RR, et al. Copeptin: A Novel Biomarker in Pediatric Heart Failure Due to Cardiomyopathies KB Karki, JA Towbin, RR Philip, C Harrell, S Tadphale, S Shah, A Saini Circulation 140 (Suppl_1), A11217-A11217. AHA Journals. 2019; 1.
  30. Balling L, Kistorp C, Schou M, et al. Plasma copeptin levels and prediction of outcome in heart failure outpatients: relation to hyponatremia and loop diuretic doses. J Card Fail. 2012; 18(5): 351–358.
  31. Kelly D, Squire IB, Khan SQ, et al. C-terminal provasopressin (copeptin) is associated with left ventricular dysfunction, remodeling, and clinical heart failure in survivors of myocardial infarction. J Card Fail. 2008; 14(9): 739–745.
  32. Schill F, Timpka S, Nilsson PM, et al. Copeptin as a predictive marker of incident heart failure. ESC Heart Fail. 2021; 8(4): 3180–3188.
  33. Balling L, Gustafsson F. Copeptin as a biomarker in heart failure. Biomark Med. 2014; 8(6): 841–854.
  34. Stoiser B, Mörtl D, Hülsmann M, et al. Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure. Eur J Clin Invest. 2006; 36(11): 771–778.
  35. Gegenhuber A, Struck J, Dieplinger B, et al. Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure. J Card Fail. 2007; 13(1): 42–49.
  36. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998; 338(3): 171–179.
  37. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000; 21(1): 55–89.
  38. Yamaji M, Tsutamoto T, Kawahara C, et al. Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: the impact of oxidative stress. Circ Heart Fail. 2009; 2(6): 608–615.
  39. Yamak M. Cortisol as a Predictor of Early Mortality in Heart Failure. Southern Clinics of Istanbul Eurasia. 2019.
  40. Güder G, Bauersachs J, Frantz S, et al. Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure. Circulation. 2007; 115(13): 1754–1761.
  41. Yamamoto T, Noiri E, Ono Y, et al. Renal L-type fatty acid--binding protein in acute ischemic injury. J Am Soc Nephrol. 2007; 18(11): 2894–2902.
  42. Sunayama T, Yatsu S, Matsue Y, et al. Urinary liver-type fatty acid-binding protein as a prognostic marker in patients with acute heart failure. ESC Heart Fail. 2022; 9(1): 442–449.
  43. Okubo Y, Sairaku A, Morishima N, et al. Increased Urinary Liver-Type Fatty Acid-Binding Protein Level Predicts Worsening Renal Function in Patients With Acute Heart Failure. J Card Fail. 2018; 24(8): 520–524.
  44. Hishikari K, Hikita H, Nakamura S, et al. Urinary Liver-Type Fatty Acid-Binding Protein Level as a Predictive Biomarker of Acute Kidney Injury in Patients with Acute Decompensated Heart Failure. Cardiorenal Med. 2017; 7(4): 267–275.
  45. Sawyer DB, Siwik DA, Xiao L, et al. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 2002; 34(4): 379–388.
  46. Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart. 2007; 93(8): 903–907.
  47. The level of superoxide dismutase and catalase in acyanotic congenital heart disease children with heart failur. GSC Biological and Pharmaceutical Sciences. 2021; 16(1): 150–156.
  48. Qin F, Lennon-Edwards S, Lancel S, et al. Cardiac-specific overexpression of catalase identifies hydrogen peroxide-dependent and -independent phases of myocardial remodeling and prevents the progression to overt heart failure in G(alpha)q-overexpressing transgenic mice. Circ Heart Fail. 2010; 3(2): 306–313.
  49. Meng Z, Zhao Y, He Y. Fibrinogen Level Predicts Outcomes in Critically Ill Patients with Acute Exacerbation of Chronic Heart Failure. Dis Markers. 2021; 2021: 6639393.
  50. Chin BSP, Blann AD, Gibbs CR, et al. Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure. Eur J Clin Invest. 2003; 33(11): 941–948.
  51. Díaz-Vélez CR, García-Castiñeiras S, Mendoza-Ramos E, et al. Increased malondialdehyde in peripheral blood of patients with congestive heart failure. Am Heart J. 1996; 131(1): 146–152.
  52. Romuk E, Wojciechowska C, Jacheć W, et al. Malondialdehyde and Uric Acid as Predictors of Adverse Outcome in Patients with Chronic Heart Failure. Oxid Med Cell Longev. 2019; 2019: 9246138.
  53. Sharp FR, Massa SM, Swanson RA. Heat-shock protein protection. Trends Neurosci. 1999; 22(3): 97–99.
  54. Liu P, Bao HY, Jin CC, et al. Targeting Extracellular Heat Shock Protein 70 Ameliorates Doxorubicin-Induced Heart Failure Through Resolution of Toll-Like Receptor 2-Mediated Myocardial Inflammation. J Am Heart Assoc. 2019; 8(20): e012338.
  55. Ranek MJ, Stachowski MJ, Kirk JA, et al. The role of heat shock proteins and co-chaperones in heart failure. Philos Trans R Soc Lond B Biol Sci. 2018; 373(1738).
  56. Wang Y, Wu J, Wang D, et al. Traditional Chinese Medicine Targeting Heat Shock Proteins as Therapeutic Strategy for Heart Failure. Front Pharmacol. 2021; 12: 814243.
  57. Li Z, Song Y, Xing R, et al. Heat shock protein 70 acts as a potential biomarker for early diagnosis of heart failure. PLoS One. 2013; 8(7): e67964.
  58. Tanonaka K, Yoshida H, Toga W, et al. Myocardial heat shock proteins during the development of heart failure. Biochem Biophys Res Commun. 2001; 283(2): 520–525.