Skip to main content
Clinical Cardiology logoLink to Clinical Cardiology
. 2007 Sep 10;30(11):546–551. doi: 10.1002/clc.18

Hyponatremia and Vasopressin Antagonism in Congestive Heart Failure

Siva Kumar 1,, Sharon Rubin 1, Paul J Mather 1, David J Whellan 1
PMCID: PMC6653254  PMID: 17847041

Abstract

In a national heart failure registry, hyponatremia (serum sodium < 130 mEq/L) was initially reported in 5% of patients and considered a risk factor for increased morbidity and mortality. In a chronic heart failure study, serum sodium level on admission predicted an increased length of stay for cardiovascular causes and increased mortality within 60 days of discharge. Hyponatremia in patients with congestive heart failure (CHF) is associated with a higher mortality rate. Also, by monitoring and increasing serum sodium levels during hospitalization for CHF, patient outcomes may improve. This review describes the pathophysiology of hyponatremia in relation to CHF, including the mechanism of action of vasopressin receptors in the kidney, and assesses the preclinical and clinical trials of vasopressin receptor antagonists—agents recently developed to treat hyponatremia. In hospitalized patients with CHF, hyponatremia plays a major role in poor outcomes. Vasopressin receptor antagonists have been shown to be safe and effective in clinical trials in patients with hyponatremia. Copyright © 2007 Wiley Periodicals, Inc.

Keywords: congestive heart failure, euvolemia, hypervolemia, V1a and V2 receptor antagonists

Full Text

The Full Text of this article is available as a PDF (746.2 KB).

References

  • 1. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult 2005; 112: e154–e235. [DOI] [PubMed]
  • 2. Adhere® Registry: Insights from the Adhere Registry: data from over 100,000 patient cases. 2005. www.adhereregistry.com.
  • 3. Oren RM: Hyponatremia in congestive heart failure. Am J Cardiol 2005; 95(9 suppl 1): 2B–7B. [DOI] [PubMed] [Google Scholar]
  • 4. Goh KP: Management of hyponatremia. Am Fam Physician 2004; 69: 2387–2394. [PubMed] [Google Scholar]
  • 5. Dargie HJ, Cleland JGF, Leckie BJ, Inglis CG, East BW, et al.: Relation of arrhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987; 75(suppl 4): 498–4107. [PubMed] [Google Scholar]
  • 6. Chin MH, Goldman L: Correlates of major complications or death in patients admitted to the hospital with congestive heart failure. Arch Intern Med 1996; 156: 1814–1820. [PubMed] [Google Scholar]
  • 7. Klein L, O'Connor CM, Leimberger JD, Gattis‐Stough W, Piña IL, et al.: for the OPTIME‐CHF Investigators : Lower serum sodium is associated with increased short‐term mortality in hospitalized patients with worsening heart failure. Circulation 2005; 111: 2454–2460. [DOI] [PubMed] [Google Scholar]
  • 8. Weber KT: Aldosterone in congestive heart failure. New Engl J Med 2001; 345: 1689–1697. [DOI] [PubMed] [Google Scholar]
  • 9. Schrier RW, Abraham WT: Hormones and hemodynamics in heart failure. New Engl J Med 1999; 341: 577–585. [DOI] [PubMed] [Google Scholar]
  • 10. Goldsmith SR, Francis GS, Cowley AW, Levine B, Cohn JN: Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol 1983; 1: 1385–1390. [DOI] [PubMed] [Google Scholar]
  • 11. Knoers N: Hyperactive vasopressin receptors and disturbed water homeostasis. New Engl J Med 2005; 352: 1847–1850. [DOI] [PubMed] [Google Scholar]
  • 12. Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet E, Berl T, et al.: Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. New Engl J Med 1981; 305: 263–266. [DOI] [PubMed] [Google Scholar]
  • 13. Schrier RW, Ecder T: Unifying hypothesis of body fluid volume regulation: implications for cardiac failure and cirrhosis. Mt Sinai J Med 2001; 68: 350–361. [PubMed] [Google Scholar]
  • 14. Lee CR, Watkins ML, Patterson JH, Gattis W, O'Connor CM Jr, et al.: Vasopressin: a new target for the treatment of heart failure. Am Heart J 2003; 146: 9–18. [DOI] [PubMed] [Google Scholar]
  • 15. Funayama H, Nakamura T, Saito T, Yoshimura A, Saito M, et al.:Urinary excretion of aquaporin‐2 water channel exaggerated dependent upon vasopressin in congestive heart failure. Kidney Int 2004; 66: 1387–1392. [DOI] [PubMed] [Google Scholar]
  • 16. Sonnenblick M, Friedlander Y, Rosin AJ: Diuretic‐induced severe hyponatremia. Review and analysis of 129 reported patients. Chest 1993; 103: 601–606. [DOI] [PubMed] [Google Scholar]
  • 17. Goldsmith SR: Current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure. Am J Cardiol 2005; 95(9 suppl 1): 14B–23B. [DOI] [PubMed] [Google Scholar]
  • 18. Yamamura Y, Ogawa H, Yamashita H, Chihara T, Miyamoto H, et al.:Characterization of a novel aquaretic agent, OPC‐31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Brit J Pharmacol 1992; 105: 787–791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Palm C, Reimann D, Gross P: The role of V2 vasopressin antagonists in hyponatremia. Cardiovasc Res 2001; 51: 403–408. [DOI] [PubMed] [Google Scholar]
  • 20. Udelson JE, Orlandi C, O'Brien T, Sequeira RF, Ouyang J, et al.:Vasopressin receptor blockade in patients with congestive heart failure: results from a placebo controlled, randomized study comparing the effects of tolvaptan, furosemide, and their combination [abstract].J Am Coll Cardiol 2002; 156A. [Google Scholar]
  • 21. Gheorghiade M, Gattis WA, O'Connor CM, Adams KF Jr, Elkayam U, et al.: for the ACTIV in CHF Investigators : Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 2004; 291: 1963–1971. [DOI] [PubMed] [Google Scholar]
  • 22. Abraham WT, Oren RM, Crisman TS, Robertson AD, Shakar S, et al.: Effects of an oral, nonpeptide, selective V2 receptor vasopressin antagonist in patients with chronic heart failure. J Am Coll Cardiol 1997; 29(2 suppl A): 169A. [Google Scholar]
  • 23. Abraham W, Koren M, Bichet DG, Verbalis JG, Klapholz M, et al.: Treatment of hyponatremia in patients with SIADH or CHF with intravenous conivaptan (YM 087), a new combined vasopressin V1/V2 receptor antagonist. Eur Heart J 2000; 21: 345. [Google Scholar]
  • 24. Abraham W, Suresh DP, Wagoner LE, Haas GJ, Nelson C, et al.: Pharmacotherapy for hyponatremia in heart failure: effects of a new combined V1A/V2 vasopressin receptor antagonist, conivaptan (YM087) administered orally. Eur Heart J 2000; 21: 345. [Google Scholar]
  • 25. Gheorghiade M, Orlandi C, Burnett JC, Demets D, Grinfeld L Jr, et al.: Rationale and design of the multicenter, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy of vasopressin antagonism in heart failure: outcome study with tolvaptan (EVEREST). J Card Fail 2005; 11: 260–269. [DOI] [PubMed] [Google Scholar]
  • 26. EVEREST North American Update. Otsuka Maryland Research Institute. November 29, 2005.
  • 27. Chan PS, Coupet J, Park HC, Lai F, Hartupee D, et al.:VPA‐985, a nonpeptide orally active and selective vasopressin V2 receptor antagonist. Adv Exp Med Biol 1998; 449: 439–443. [DOI] [PubMed] [Google Scholar]
  • 28. Wong F, Blei AT, Blendis LM, Thuluvath PJ: A vasopressin receptor antagonist (VPA‐985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo‐controlled trial. Hepatology 2003; 37: 182–191. [DOI] [PubMed] [Google Scholar]
  • 29. Goldsmith SR, Gheorghiade M: Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005; 46: 1785–1791. [DOI] [PubMed] [Google Scholar]
  • 30. Vaprisol® (conivaptan hydrochloride injection) [package insert]. Deerfield, Ill: Astellas Pharma US, Inc; 2006.
  • 31. Verbalis JG, Bisaha JG, Smith N: Novel Vasopressin V1a and V2 Antagonist Conivaptan Increases Serum Sodium Concentration and Effective Water Clearance in Hyponatremia Presented at: American Society of Nephrology Renal Week 2004. October 27, 2004‐November 1, 2004; St. Louis, Mo.
  • 32. Verbalis JG, Bisaha JG, Smith N: Novel vasopressin V1a and V2 antagonist (conivaptan) increases serum sodium concentration and effective water clearance in patients with hyponatremia [abstract]. J Card Fail 2004; 10(suppl 1): S27. [Google Scholar]
  • 33. Verbalis J, Ghali J, Gross P, Long W, Smith N: Novel vasopressin V1a and V2 antagonist (conivaptan) increased serum sodium concentration in patients with hyponatremia secondary to congestive heart failure [abstract]. J Card Fail 2005; 11(suppl 6): S120. [Google Scholar]
  • 34. Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, et al.:Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001; 104: 2417–2423. [DOI] [PubMed] [Google Scholar]

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES