Skip to main content
SpringerLink
Log in

Significance of hyponatremia in heart failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Heart failure is one of the most common, costly, disabling and growing diseases (McMurray and Pfeffer in Lancet 365(9474):1877–1889, 2005). Hyponatremia, conventionally defined as a serum-sodium concentration equal or less than 135 mmol/l (American Heart Association in Heart disease and stroke statistics—2007 update. American Heart Association, Dallas, 2007; Stewart et al. in Eur J Heart Fail 4:361–371, 2002), is a common phenomenon in patients with heart failure, with an incidence of 20–25% (Krumholz et al. in Arch Intern Med 157:e99–e104, 1997; Rosamond et al. in Circulation 117(4):e25–e146, 2008; Adrogue and Madias in N Engl J Med 342:1581–1589, 2000) and seems to be of prognostic importance in patients with heart failure (Luca et al. in Am J Cardiol 96:19L–23L, 2005; Gheorghiade et al. in Eur Heart J 28:980–988, 2007; Gheorghiade et al. in Arch Intern Med 167:1998–2005, 2007). So far treatment strategies have been limited and burdened by side effects. The development of hyponatremia in the setting of heart failure is related to the arginine vasopressin (AVP) dysregulation. Thus, AVP receptor antagonists are a promising approach to treatment. However, several questions remain: whether there is a cause-and-effect mechanism, if the correction of hyponatremia improves outcomes, and defining the specific cut-off level of serum-sodium that should be used to define hyponatremia. In this review, we aim to summarize the literature on hyponatremia in patients with heart failure within several aspects: incidence in clinical trials and registries, prognostic value, underlying mechanisms, therapeutic options, and possible future perspectives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. McMurray JJ, Pfeffer MA (2005) Heart failure. Lancet 365(9474):1877–1889

    Article  PubMed  Google Scholar 

  2. American Heart Association (2007) Heart disease and stroke statistics—2007 update. American Heart Association, Dallas

    Google Scholar 

  3. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ (2002) The current cost of heart failure to the national health service in the UK. Eur J Heart Fail 4:361–371

    Article  PubMed  Google Scholar 

  4. Krumholz HM, Parent EM, Tu N, Vaccarino V, Wang Y, Radford MJ et al (1997) Readmission after hospitalization for congestive heart failure among medicare beneficiaries. Arch Intern Med 157:e99–e104

    Article  Google Scholar 

  5. Rosamond W, Flegal K, Furie K et al (2008) Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117(4):e25–e146

    Article  PubMed  Google Scholar 

  6. Adrogue HJ, Madias NE (2000) Hyponatremia. N Engl J Med 342:1581–1589

    Article  PubMed  CAS  Google Scholar 

  7. De Luca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele F, Gheorghiade M (2005) Hyponatremia in patients with heart failure. Am J Cardiol 96:19L–23L

    PubMed  Google Scholar 

  8. Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O’Connor CM, She L, Yancy CW, Young J, Fonarow GC (2007) Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J 28:980–988

    Article  PubMed  CAS  Google Scholar 

  9. Gheorghiade M, Rossi JS, Cotts W, Shin DD, Hellkamp AS, Pina IL, Fonarow GC, DeMarco T, Pauly DF, Rogers J, DiSalvo TG, Butler J, Hare JM, Francis GS, Stough WG, O’Connor CM (2007) Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE trial. Arch Intern Med 167:1998–2005

    Article  PubMed  Google Scholar 

  10. Klein L, O’Connor CM, Leimberger JD, Gattis-Stough W, Pina IL, Felker GM, Adams KF Jr, Califf RM, Gheorghiade M (2005) Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation 111:2454–2460

    Article  PubMed  CAS  Google Scholar 

  11. Sica DA (2005) Hyponatremia and heart failure—pathophysiology and implications. Congest Heart Fail 11:274–277

    Article  PubMed  Google Scholar 

  12. Kearney MT, Fox KA, Lee AJ, Prescott RJ, Shah AM, Batin PD, Baig W, Lindsay S, Callahan TS, Shell WE, Eckberg DL, Zaman AG, Williams S, Neilson JM, Nolan J (2002) Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure. J Am Coll Cardiol 40:1801–1808

    Article  PubMed  Google Scholar 

  13. Senni M, De Maria R, Gregori D, Gonzini L, Gorini M, Cacciatore G, Gavazzi A, Pulignano G, Porcu M, Maggioni AP (2005) Temporal trends in survival and hospitalizations in outpatients with chronic systolic heart failure in 1995 and 1999. J Card Fail 11:270–278

    Article  PubMed  Google Scholar 

  14. Oren RM (2005) Hyponatremia in congestive heart failure. Am J Cardiol 95(Suppl):2B–7B

    Article  PubMed  CAS  Google Scholar 

  15. Adhere Registry: Insights from the Adhere Registry: data from over 100,000 patient cases. 2005

  16. Kumar S, Rubin S, Mather PJ, Whellan DJ (2007) Hyponatremia and vasopressin antagonism in congestive heart failure. Clin Cardiol 30(11):546–551

    Article  PubMed  Google Scholar 

  17. Gheorghiade M, Gattis WA, O’Connor CM et al (2004) For the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial (ACTIV). JAMA 291:1963–1971

    Article  PubMed  CAS  Google Scholar 

  18. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 297:1319–1331

    Article  PubMed  CAS  Google Scholar 

  19. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM (1997) Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 95(12):2660–2667

    PubMed  CAS  Google Scholar 

  20. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV (2003) Predicting mortality among patients hospitalized for heart failure derivation and validation of a clinical model. JAMA 290(19):2581–2587

    Article  PubMed  CAS  Google Scholar 

  21. Kearney MT, Nolan J, Lee AJ, Brooksby PW, Prescott R, Shah AM, Zaman AG, Eckberg DL, Lindsay HS, Batin PD, Andrews R, Fox KA (2003) A prognostic index to predict long-term mortality in patients with mild to moderate chronic heart failure stabilised on angiotensin converting enzyme inhibitors. Eur J Heart Fail 5(4):489–497

    Article  PubMed  CAS  Google Scholar 

  22. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, Anand I, Maggioni A, Burton P, Sullivan MD, Pitt B, Poole-Wilson PA, Mann DL, Packer M (2006) The Seattle heart failure model: prediction of survival in heart failure. Circulation 113:1424–1433

    Article  PubMed  Google Scholar 

  23. Felker GM, Leimberger JD, Califf RM, Cuffe MS, Massie BM, Adams KF Jr, Gheorghiade M, O’Connor CM (2004) Risk stratification after hospitalization for decompensated heart failure. J Card Fail 10(6):460–466

    Article  PubMed  Google Scholar 

  24. Vazquez R, Bayes-Genis A, Cygankiewicz I, Pascual-Figal D, Grigorian-Shamagian L, Pavon R, Gonzalez-Juanatey JR, Cubero JM, Pastor L, Ordonez-Llanos J, Cinca J, Bayes de Luna A on behalf of the MUSIC Investigators (2009) The MUSIC risk score: a simple method for predicting mortality in ambulatory patients with chronic heart failure. Eur Heart J 30:1088–1096

    Google Scholar 

  25. O’Connor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM, Fiuzat M, Rogers JG, Leier CV, Stevenson LW (2010) Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol 55(9):872–878

    Article  PubMed  Google Scholar 

  26. Oh MS (2002) Pathogenesis and diagnosis of hyponatremia. Nephron 92(Suppl 1):2–8

    Article  PubMed  CAS  Google Scholar 

  27. Neilsen S, Kwon TH, Christensen BM, Promeneur D, Frøkiaer J, Marples D (1999) Physiology and pathophysiology of renal aquaporins. J Am Soc Nephrol 10:647–663

    Google Scholar 

  28. Penit J, Faure M, Jard S (1983) Vasopressin and angiotensin II receptors in rat aortic smooth muscle cells in culture. Am J Physiol 244:E72–E82

    PubMed  CAS  Google Scholar 

  29. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73:615–621

    Article  PubMed  CAS  Google Scholar 

  30. DiBona GF, Herman PJ, Sawin LL (1988) Neural control of renal function in edema-forming states. Am J Physiol 254:R1017–R1024

    PubMed  CAS  Google Scholar 

  31. Schrier RW, Abraham WT (1999) Hormones and hemodynamics in heart failure. N Engl J Med 341:577–585

    Article  PubMed  CAS  Google Scholar 

  32. Schuster VL, Kokko JP, Jacobson HR (1984) Angiotensin II directly stimulates sodium transport in rabbit proximal convoluted tubules. J Clin Invest 73:507–515

    Article  PubMed  CAS  Google Scholar 

  33. Goldsmith SR (2005) Current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure. Am J Cardiol 95(9 Suppl 1):B14–B23

    Article  Google Scholar 

  34. Anderson RJ, Chung HM, Kluge R, Schrier RW (1985) Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 102:164–168

    PubMed  CAS  Google Scholar 

  35. Lee CR, Watkins ML, Patterson JH et al (2003) Vasopressin: a new target for the treatment of heart failure. Am Heart J 146:9–18

    Article  PubMed  CAS  Google Scholar 

  36. Kalra PR, Anker SD, Coats AJ (2001) Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin. Cardiovasc Res 51:495–509

    Article  PubMed  CAS  Google Scholar 

  37. Xu YJ, Gopalakrishnan V (1991) Vasopressin increases cytosolic free [Ca2+] in the neonatal rat cardiomyocyte. Evidence for V1 subtype receptors. Circ Res 69:239–245

    PubMed  CAS  Google Scholar 

  38. Nakamura Y, Haneda T, Osaki J, Miyata S, Kikuchi K (2000) Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin V(1A) receptor. Eur J Pharmacol 391:39–48

    Article  PubMed  CAS  Google Scholar 

  39. Goldsmith SR (2006) The role of vasopressin in congestive heart failure. Cleve Clin J Med 73(Suppl 3):S19–S23.

    Article  PubMed  Google Scholar 

  40. Xu DL, Martin PY, Ohara M et al (1997) Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J Clin Invest 99:1500–1505

    Article  PubMed  CAS  Google Scholar 

  41. Nakamura K, Aoyagi T, Hiroyama M, Kusakawa S, Mizutani R, Sanbe A, Yamauchi J, Kamohara M, Momose K, Tanoue A (2009) Both (V1A) and (V1B) vasopressin receptors deficiency result in impaired glucose tolerance. Eur J Pharmacol 613(1–3):182–188

    Article  PubMed  CAS  Google Scholar 

  42. Goldsmith SR (2002) Congestive heart failure: potential role of arginine vasopressin antagonists in the therapy of heart failure. Congest Heart Fail 8:251–256

    Article  PubMed  CAS  Google Scholar 

  43. Francis GS, Benedict C, Johnstone DE et al (1990) Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82:1724–1729

    Article  PubMed  CAS  Google Scholar 

  44. Rouleau JL, Packer M, Moye L et al (1994) Prognostic value of neurohormonal activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol 24:583–591

    Article  PubMed  CAS  Google Scholar 

  45. Szatalowicz VL, Arnold PE, Chaimovitz C et al (1981) Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med 305:263–266

    Article  PubMed  CAS  Google Scholar 

  46. Yamane Y (1968) Plasma ADH level in patients with chronic congestive heart failure. Jpn Circ J 32:745–759

    Article  PubMed  CAS  Google Scholar 

  47. Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn JN (1983) Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol 1:1385–1390

    Article  PubMed  CAS  Google Scholar 

  48. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH (2007) Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 120(11 Suppl 1):S1–21

    Article  PubMed  CAS  Google Scholar 

  49. Palm C, Gross P (1999) 2-vasopressin receptor antagonists-mechanism of effect and clinical implications in hyponatraemia. Nephrol Dial Transplant 14:2559–2562

    Article  PubMed  CAS  Google Scholar 

  50. Palm C, Reimann D, Gross P (2001) The role of V2 vasopressin antagonists in hyponatremia. Cardiovasc Res 51:403–408

    Article  PubMed  CAS  Google Scholar 

  51. Gheorghiade M, Gattis WA, Barbagelata A et al (2003) Rationale and study design for a multicenter, randomized, double-blind, placebo controlled study of the effects of tolvaptan on the acute and chronic outcomes of patients hospitalized with worsening congestive heart failure. Am Heart J 145(Suppl 2):S51–S54

    Article  PubMed  CAS  Google Scholar 

  52. Burrell LM, Risvanis J, Johnston CI et al (2000) Vasopressin receptor antagonism-a therapeutic option in heart failure and hypertension. Exp Physiol 85:259S–265S

    Article  PubMed  CAS  Google Scholar 

  53. Thibonnier M, Coles P, Thibonnier A, Shoham M (2001) The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu Rev Pharmacol Toxicol 41:175–202

    Article  PubMed  CAS  Google Scholar 

  54. Goldsmith SR (1999) Vasopressin: a therapeutic target in congestive heart failure? J Card Fail 5:347–356

    Article  PubMed  CAS  Google Scholar 

  55. Quittnat F, Gross P (2006) Vaptans and the treatment of water retaining disorders. Semin Nephrol 26:234–243

    Article  PubMed  CAS  Google Scholar 

  56. Package insert (2008) Vaprisol (conivaptan). Astellas Pharma US, Deerfield

    Google Scholar 

  57. Package insert (2009) Samsca (tolvaptan). Otsuka America Pharmaceutical, Inc., Rockville

    Google Scholar 

  58. CardioKine Inc. THE BALANCE study: treatment of hyponatremia based on Lixivaptan in NYHA class III/IV cardiac patient evaluation. http://www.clinicaltrials.gov

  59. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N, Conivaptan Study Group (2007) Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 27:447–457

    Article  PubMed  CAS  Google Scholar 

  60. Annane D, Decaux G, Smith N, for the Conivaptan Study Group (2009) Efficacy and safety of Oral Conivaptan, a Vasopressin-Receptor Antagonist, evaluated in a randomized, controlled trial in patients with Euvolemic or Hypervolemic Hyponatremia. Am J Med Sci 337(1):28–36

    Google Scholar 

  61. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA et al (2006) Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab 91:2145–2152

    Article  PubMed  CAS  Google Scholar 

  62. Gheorghiade M, Niazi I, Ouyang J et al (2003) Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure. Circulation 107:2690–2696

    Article  PubMed  CAS  Google Scholar 

  63. Gheorghiade M, Konstam MA, Burnett JC Jr et al (2007) Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA 297:1332–1343

    Article  PubMed  CAS  Google Scholar 

  64. Abraham WT, Shamshirsaz AA, McFann K, Oren RM, Schrier RW (2006) Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor vasopressin antagonist, in New York Heart Association Functional Class II and III chronic heart failure patient. J Am Coll Cardiol 47(8):1615–1621

    Article  PubMed  CAS  Google Scholar 

  65. Goldsmith SR, Gheorghiade M (2005) Vasopressin antagonism in heart failure. J Am Coll Cardiol 46:1785–1791

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of the Studies of Brescia, Piazzale Spedali Civili 1, Brescia, Italy

    Luca Bettari

  2. Duke University Medical Center, Duke Clinical Research Institute, 2400 Pratt street, Durham, NC, USA

    Mona Fiuzat, Gary M. Felker & Christopher M. O’Connor

Authors
  1. Luca Bettari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mona Fiuzat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary M. Felker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher M. O’Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luca Bettari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bettari, L., Fiuzat, M., Felker, G.M. et al. Significance of hyponatremia in heart failure. Heart Fail Rev 17, 17–26 (2012). https://doi.org/10.1007/s10741-010-9193-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-010-9193-3

Keywords

Search

Navigation