The arginine vasopressin system as an important link in the pathogenesis of chronic heart failure: from theory to the search for therapeutic strategies

Current data describing the features of arginine vasopressin (AVP) system activation in healthy individuals and in patients with chronic heart failure (CHF) are presented. This article presents current data on the cardiovascular effects of interactions between AVP system mediators and specific receptors. Based on an analysis of current literature, the osmotic and non-osmotic pathways of AVP system activation are described in detail, both under physiological conditions and in CHF. The authors are the first in Russian-language literature to use the term “osmotic incompetence” in a broader context, extending beyond the syndrome of inappropriate antidiuretic hormone secretion to describe the mechanism of AVP system activation despite increased plasma osmolality. It is emphasized that despite the potential attractiveness of this mediator of the AVP system as a diagnostic and prognostic marker in various acute conditions and decompensation of chronic diseases, to date, a very small number of studies have been conducted, both in our country and worldwide, devoted to its role in the pathogenesis of various diseases, including CHF. Along with a detailed description of the mechanisms of AVP system imbalance, the authors provide clinical scenarios of osmotic incompetence in patients with various diseases. Particular attention is given to the role of copeptin as a surrogate marker for assessing the activity of the arginine vasopressin system. The authors aimed to highlight the complexity of the relationships between osmosis-dependent and osmosis-independent pathways of AVP activation in CHF, emphasizing the prospects for studying the AVP system, understanding the functioning of which in CHF conditions should lead to the development of targeted therapeutic strategies that can alleviate symptoms, improve treatment results, clinical outcomes and improve the quality of life of patients with heart failure.

1. Galyavich AS, Tereshchenko SN, Uskach TM, et al. 2024 Clinical practice guidelines for Chronic heart failure. Russian Journal of Cardiology. 2024;29(11):6162. (In Russ.) DOI: 10.15829/1560-4071-2024-6162.

2. Shalmi TW, Jensen ASB, Goetze JP. Cardiac natriuretic peptides. Adv Clin Chem. 2024;122:115-39. DOI: 10.1016/bs.acc.2024.06.009.

3. Chiorescu RM, Lazar RD, Buksa SB, et al. Biomarkers of volume overload and edema in heart failure with reduced ejection fraction. Front Cardiovasc Med. 2022;9:910100; DOI: 10.3389/FCVM.2022.910100.

4. Oliver G, Schäfer EA. On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication. J Physiol. 1895;18(3):277-9. DOI: 10.1113/jphysiol.1895.sp000565.

5. Camerino C. The long way of oxytocin from the uterus to the heart in 70 years from its discovery. Int J Mol Sci. 2023;24(3):2556. DOI: 10.3390/IJMS24032556.

6. Chauvet MT, Chauvet J, Acher R. Ontogeny of the bovine neurohypophyseal hormone precursors: Foetal neurohormones and neurophysins. Int J Pept Protein Res. 1984;24(1):66-73; DOI: 10.1111/j.1399-3011.1984.tb00929.x.

7. Wasilewski MA, Myers VD, Recchia FA, et al. Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cell Signal. 2016;28(3):224-33. DOI: 10.1016/j.cellsig.2015.07.021.

8. Aliyevа AM, Almazova II, Pinchuk TV, et al. The value of copeptin in the diagnosis and prognosis of cardiovascular diseases. Clinical Medicine (Russian Journal). 2020;98(3):203-9. (In Russ.) DOI: 10.30629/0023-2149-2020-98-3-203-209.

9. Robertson GL. Physiology of ADH secretion. Kidney Int Suppl. 1987;21: S20-6.

10. Rasouli M. Basic concepts and practical equations on osmolality: Biochemical approach. Clin Biochem. 2016;49(12):936-41. DOI: 10.1016/j.clinbiochem.2016.06.001.

11. Pigarova EA, Dzeranova LK. Metabolic mechanisms of development and compensation of osmotic stress in the brain. Obesity and metabolism. 2017;14(4):73-6. (In Russ.) DOI: 10.14341/omet2017473-76.

12. Yasir M, Mechanic OJ. Syndrome of Inappropriate Antidiuretic Hormone Secretion. 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507777/

13. Ishikawa SE. Hyponatremia associated with heart failure: pathological role of vasopressin-dependent impaired water excretion. J Clin Med. 2015;4(5):933-47. DOI: 10.3390/JCM4050933.

14. Goldsmith SR. Arginine vasopressin antagonism in heart failure: Current status and possible new directions. J Cardiol. 2019;74(1):49-52. DOI: 10.1016/j.jjcc.2019.03.001.

15. Manolis AA, Manolis TA, Manolis AS. Neurohumoral activation in heart failure. Int J Mol Sci. 2023;24(20):15472. DOI: 10.3390/IJMS242015472.

16. Gurger M, Telo S. The diagnostic value of plasma copeptin level in patients with acute appendicitis. Clin Lab. 2022;68(9):1930-5. DOI: 10.7754/CLIN.LAB.2022.220133.

17. Yamane Y. Plasma ADH level in patients with chronic congestive heart failure. Jpn Circ J. 1968;32(5):745-59. DOI: 10.1253/JCJ.32.745.

18. Kitada S, Kawada Y, Nakasuka K, et al. Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure. Heart Vessels. 2024;39(12):1018-28. DOI: 10.1007/S00380-024-02429-Y.

19. Urbach J, Goldsmith SR. Vasopressin antagonism in heart failure: a review of the hemodynamic studies and major clinical trials. Ther Adv Cardiovasc Dis. 2021;15:1753944720977741; DOI: 10.1177/1753944720977741.

20. Dhalla NS, Mota KO, Elimban V, et al. Role of vasoactive hormone-induced signal transduction in cardiac hypertrophy and heart failure. Cells. 2024;13(10):856. DOI: 10.3390/CELLS13100856.

21. Vinod P, Krishnappa V, Chauvin AM, et al. Cardiorenal syndrome: role of arginine vasopressin and vaptans in heart failure. Cardiol Res. 2017;8(3):87-95. DOI: 10.14740/CR553W.

22. Bhattarai A, Shah S, Baidya S, et al. Association of copeptin levels with patient prognosis and survival in sepsis syndromes: a meta-analysis. Int J Surg. 2024;110(4):2355-65. DOI: 10.1097/JS9.0000000000001069.

23. Parthasarathi A, Padashetti VC, Padukudru S, et al. Association of serum albumin and copeptin with early clinical deterioration and instability in community-acquired pneumonia. Adv Respir Med. 2022;90(4):323-7. DOI: 10.3390/ARM90040042.

24. Demir O, Az A, Cakmak S, Sogut O. Prognostic role of serum copeptin levels in adults with graded traumatic brain injury. Ir J Med Sci. 2025;194(1):353-60. DOI: 10.1007/S11845-024-03818-Y.

25. Mu D, Cheng J, Qiu L, Cheng X. Copeptin as a diagnostic and prognostic biomarker in cardiovascular diseases. Front Cardiovasc Med. 2022;9:901990. DOI: 10.3389/FCVM.2022.901990.

26. Winther JA, Brynildsen J, Høiseth AD, et al. Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 study. Respir Res. 2017;18(1):184. DOI: 10.1186/S12931-017-0665-z.

27. Ciortea DA, Petrea Cliveți CL, Verga Răuță GI, et al. Beyond biomarkers: blending copeptin and clinical cues to distinguish central diabetes Insipidus from primary polydipsia in children. Biomedicines. 2025;13(10):2573. DOI: 10.3390/BIOMEDICINES13102573.

28. Karki KB, Towbin JA, Shah SH, et al. Elevated copeptin levels are associated with heart failure severity and adverse outcomes in children with cardiomyopathy. Children (Basel). 2023;10(7):1138. DOI: 10.3390/CHILDREN10071138.

29. Podzolkov VI, Dragomiretskaya NA, Medvedev ID, et al. Levels of cardiac biomarkers and three-year survival rate in hospitalized patients with heart failure and community-acquired pneumonia. Russian Journal of Cardiology. 2024;29(6):5875. (In Russ.) DOI: 10.15829/1560-4071-2024-5875.

30. Neuhold S, Huelsmann M, Strunk G, et al. Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure. Рrediction of death at different stages of the disease. J Am Coll Cardiol. 2008;52(4):266-72. DOI: 10.1016/j.jacc.2008.03.050.

31. 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):771-8. DOI: 10.1111/J.1365-2362.2006.01724.X.

32. Nadziakiewicz P, Szczurek-Wasilewicz W, Jurkiewicz M, et al. Copeptin, routine laboratory parameters, and ischemic etiology of heart failure predict outcomes in elderly patients with decompensated heart failure. Biomedicines. 2025;13(9):2048. DOI: 10.3390/BIOMEDICINES13092048.

33. Voors AA, von Haehling S, Anker SD, et al. 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):1187-94. DOI: 10.1093/EURHEARTJ/EHP098.

34. Schneider MP, Schmid M, Nadal J, et al.; GCKD study investigators. Copeptin, natriuretic peptides, and cardiovascular outcomes in patients with CKD: the German Chronic Kidney Disease (GCKD) study. Kidney Med. 2023;5(11):100725. DOI: 10.1016/j.xkme.2023.100725.

35. Nattero-Chávez L, Martínez-García MÁ, Redondo López S, et al. High serum copeptin may be a marker of an increased carotid intima-media thickness in asymptomatic patients with type 1 diabetes. J Diabetes Complications. 2022;36(1):108085. DOI: 10.1016/j.jdiacomp.2021.108085.

36. Pose A, Almenar L, Gavira JJ, et al. Benefit of tolvaptan in the management of hyponatraemia in patients with diuretic-refractory congestive heart failure: the SEMI-SEC project. ESC Heart Fail. 2017;4(2):130-7. DOI: 10.1002/EHF2.12124.

37. Goldsmith SR, Burkhoff D, Gustafsson F, et al. Dual vasopressin receptor antagonism to improve congestion in patients with acute heart failure: design of the AVANTI trial. J Card Fail. 2021;27(2):233-41. DOI: 10.1016/j.cardfail.2020.10.007.

38. Lee CR, Watkins ML, Patterson JH, et al. Vasopressin: a new target for the treatment of heart failure. Am Heart J. 2003;146(1):9-18. DOI: 10.1016/S0002-8703(02)94708-3.

39. Choy KW, Wijeratne N, Chiang C, Don-Wauchope A. Copeptin as a surrogate marker for arginine vasopressin: analytical insights, current utility, and emerging applications. Crit Rev Clin Lab Sci. 2025;62(1):24-4. DOI: 10.1080/10408363.2024.2383899.

40. Kataoka H. Arginine vasopressin as an important mediator of fluctuations in the serum creatinine concentration under decongestion treatment in heart failure patients. Circ Rep. 2021;3(6):324-32. DOI: 10.1253/CIRCREP.CR-21-0005.