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Treating hyponatremia in heart failure

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Abstract

Hyponatremia is common and associated with adverse outcomes in patients with congestive heart failure (CHF). In many patients who have CHF with hyponatremia, plasma arginine vasopressin (AVP) is elevated inappropriately. AVP causes water retention by interacting with V2 receptors in the renal collecting duct, leading to dilutional hyponatremia and increased ventricular preload. AVP also may contribute to pathophysiologic process in CHF by interacting with V1A receptors on vascular smooth muscle cells and myocytes. The potential utility of AVP antagonists —V2 antagonists and dual V1A /V2 antagonists—in correcting hyponatremia and relieving the congestion and edema associated with CHF is being actively explored. Combined antagonists may offer additional benefit by interfering with excessive V1A signaling. Unlike diuretics, which increase urine volume and electrolyte excretion, AVP antagonists of these types produce an aquaresis characterized by an increase in free water clearance concomitant with sparing of electrolytes. Studies in experimental CHF as well as preliminary clinical trials with selective and nonselective V2 antagonists have been encouraging, suggesting that these agents may hold promise for treatment of hyponatremia in CHF.

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References and Recommended Reading

  1. American Heart Association. Heart Disease and Stroke Statistics —2004 Update. Dallas: American Heart Association; 2003.

    Google Scholar 

  2. Fonarow GC, ADHERE Scientific Advisory Committee: The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med 2003, 4(Suppl 7):S21-S30.

    PubMed  Google Scholar 

  3. Cuffe MS, Califf RM, Adams KF Jr, et al.: Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002, 287:1541–1547.

    Article  PubMed  CAS  Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. Wong PS, Davidsson GK, Timeyin J, et al.: Heart failure in patients admitted to hospital: mortality is still high. Eur J Intern Med 2002, 13:304–310.

    Article  PubMed  Google Scholar 

  6. Chen M-C, Chang H-W, Cheng C-I, et al.: Risk stratification of in-hospital mortality in patients hospitalized for chronic congestive heart failure secondary to non-ischemic cardiomyopathy. Cardiology 2003, 100:136–142.

    Article  PubMed  Google Scholar 

  7. Krumholz HM, Chen Y-T, Bradford WD, Cerese J: Variations and correlates of length of stay in academic hospitals among patients with heart failure resulting from systolic dysfunction. Am J Managed Care 1999, 5:715–723.

    CAS  Google Scholar 

  8. Lee DS, Austin PC, Rouleau JL, et al.: Predicting mortality among patients hospitalized for heart failure. Derivation and validation of a clinical model. JAMA 2003, 290:2581–2587.

    Article  PubMed  CAS  Google Scholar 

  9. Klein L, O’Connor CM, Leimberger JD, et al.: 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 2005, 111:2454–2460. The definitive paper regarding prognosis of hyponatremia in acute heart failure patients treated with contemporary therapy.

    Article  PubMed  CAS  Google Scholar 

  10. Lee WH, Packer M: Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986, 73:257–267.

    PubMed  CAS  Google Scholar 

  11. Kearney MT, Fox KAA, Lee AJ, et al.: Predicting death due to progressive heart failure in patients with mild-tomoderate chronic heart failure. J Am Coll Cardiol 2002, 40:1801–1808.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Riegger GAJ, Lebau G, Kochsiek K: Antidiuretic hormone in congestive heart failure. Am J Med 1982, 72:49–52.

    Article  PubMed  CAS  Google Scholar 

  14. Francis GS, Benedict C, Johnstone DE, et al.: 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 1990, 82:1724–1729.

    PubMed  CAS  Google Scholar 

  15. Goldsmith SR, Francis GS, Cowley AW, et al.: Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol 1983, 1:1385–1390.

    Article  PubMed  CAS  Google Scholar 

  16. Goldsmith SR, Francis GS, Cowley AW Jr: Arginine vasopressin and the renal response to water loading in congestive heart failure. Am J Cardiol 1986, 58:295–299.

    Article  PubMed  CAS  Google Scholar 

  17. Pruszczynski W, Vahanian A, Ardaillou R, Acar J: Role of antidiuretic hormone in impaired water excretion of patients with congestive heart failure. J Clin Endocrinol Metab 1984, 58:599–605.

    Article  PubMed  CAS  Google Scholar 

  18. Bichet DG, Kortas C, Mettauer B, et al.: Modulation of plasma and platelet vasopressin by cardiac function in patients with heart failure. Kidney Int 1986, 29:1188–1196.

    PubMed  CAS  Google Scholar 

  19. Gheorghiade M, Gattis WA, O’Connor CM, et al.: Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 2004, 291:1963–1971.

    Article  PubMed  CAS  Google Scholar 

  20. Licata G, Di Pasquale P, Parrinello G, et al.: Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J 2003, 145:459–466.

    Article  PubMed  CAS  Google Scholar 

  21. Goldsmith SIR: Baroreflex control of vasopressin secretion in normal humans. In Vasopressin: Cellular and Integrative Functions. Edited by Cowley AW, Liard J-F, Ausiello DA. New York: Raven Press; 1988:389–397.

    Google Scholar 

  22. Dillingham MA, Anderson RJ: Inhibition of vasopressin action by atrial natriuretic factor. Science 1986, 231:1572–1573.

    Article  PubMed  CAS  Google Scholar 

  23. Goldsmith SIR, Gheorghiade M: Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005, 46:1785–1791. A state of the art review of the status of the possible role of vasopressin in the pathophysiology of heart failure, as well as the current status of development of the various vasopressin antagonists.

    Article  PubMed  CAS  Google Scholar 

  24. Verbalis JG: Vasopressin V 2 receptor antagonists. J Mol Endocrinol 2002, 29:1–9. Comprehensive review of the V2 antagonists under development for hyponatremic states including heart failure.

    Article  PubMed  CAS  Google Scholar 

  25. Nielsen S, Kwon TH, Christensen BM, et al.: Physiology and pathophysiology of renal aquaporins. J Am Soc Nephrol 1999, 10:647–663.

    PubMed  CAS  Google Scholar 

  26. Hirsch AT, Dzau VJ, Majzoub JA, Creager MA: Vasopressin-mediated forearm vasodilation in normal humans. Evidence for a vascular vasopressin V2 receptor. J Clin Invest 1989, 84:418–426.

    PubMed  CAS  Google Scholar 

  27. Kaufmann JE, Oksche A, Wollheim CB, et al.: Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000, 106:107–116.

    Article  PubMed  CAS  Google Scholar 

  28. Goldsmith SR, Francis GS, Cowley AW Jr, et al.: Hemodynamic effects of infused arginine vasopressin in congestive heart failure. J Am Coll Cardiol 1986, 8:779–783.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Tanoue A, Ito S, Honda K, et al.: The vasopressin 1b receptor critically regulates hypothalamic-pituitaryadrenal axis activity under both stress and resting conditions. J Clin Invest 2004, 113:302–309.

    Article  PubMed  CAS  Google Scholar 

  32. Creager MA, Faxon DP, Cutler SS, et al.: Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system. J Am Coll Cardiol 1986, 7:758–765.

    Article  PubMed  CAS  Google Scholar 

  33. Yamamura Y, Nakamura S, Itoh S, et al.: OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 1998, 287:860–867.

    PubMed  CAS  Google Scholar 

  34. Gheorghiade M, Niazi I, Ouyang J, et al.: Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure. Results from a double-blind, randomized trial. Circulation 2003, 107:2690–2696.

    Article  PubMed  CAS  Google Scholar 

  35. Gheorghiade M, Orlandi C, Burnett JC 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.

    Article  PubMed  CAS  Google Scholar 

  36. Chan PS, Coupet J, Pack HC, et al.: VPA-985, a nonpeptide orally active and selective vasopressin V2 receptor antagonist. Adv Exp Med Biol 1998, 449:439–443.

    PubMed  CAS  Google Scholar 

  37. Wong F: 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.

    Article  PubMed  CAS  Google Scholar 

  38. Gerbes AL, Gülberg V, Ginès P, et al.: Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology 2003, 124:933–939.

    Article  PubMed  CAS  Google Scholar 

  39. Udelson JE, Smith WB, Hendrix GH, et al.: Acute hemodynamic effects of conivaptan, a dual V1A and V2 vasopressin receptor antagonist, bdin patients with advanced heart failure. Circulation 2001, 104:2417–2423.

    PubMed  CAS  Google Scholar 

  40. Verbalis JG, Smith N: Novel vasopressin V1A/V2 antagonist (conivaptan) increased serum sodium concentration and effective water clearance in patients with hyponatremia [abstract 3346]. Circulation 2004, 110(Suppl III):III-723.

    Google Scholar 

  41. Ghali JK, Smith N: Efficacy of the V1A/V2 antagonist conivaptan in patients with euvolemic or hypervolemic hyponatremia [abstract 3347]. Circulation 2004, 110(Suppl III):III-723.

    Google Scholar 

  42. Gross P, Smith N: Conivaptan, a novel V1A and V2 antagonist, increases serum sodium and effective water clearance in patients with hyponatremia [abstract 3345]. Circulation 2004, 110(Suppl III):III-723.

    Google Scholar 

  43. Verbalis JG, Ghali JK, Gross P, et al.: Vasopressin V1a and V2 antagonist conivaptan increased serum sodium concentration in patients with hyponatremia secondary to congestive heart failure. Abstract 166. Presented at the 9th Annual Scientific Meeting of the Heart Failure Society of America. Boca Raton, FL; September 18–21, 2005.

  44. Krämer BK, Schweda F, Riegger GAJ: Diuretic treatment and diuretic resistance in heart failure. Am J Med 1999, 106:90–96.

    Article  PubMed  Google Scholar 

  45. Greenberg A: Diuretic complications. Am J Med Sci 2000, 319:10–24.

    Article  PubMed  CAS  Google Scholar 

  46. Weber KT: Furosemide in the long-term management of heart failure: the good, the bad, and the uncertain. J Am Coll Cardiol 2004, 44:1308–1310.

    PubMed  CAS  Google Scholar 

  47. Francis GS, Siegel RM, Goldsmith SR, et al.: Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Ann Intern Med 1985, 103:1–6.

    PubMed  CAS  Google Scholar 

  48. Goldsmith SR, Francis G, Cohn JN: Attenuation of the pressor response to intravenous furosemide by angiotensin converting enzyme inhibition in congestive heart failure. Am J Cardiol 1989, 64:1382–1385.

    Article  PubMed  CAS  Google Scholar 

  49. Bayliss J, Norell M, Canepa-Anson R, et al.: Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987, 57:17–22.

    PubMed  CAS  Google Scholar 

  50. Domanski M, Norman J, Pitt B, et al.: Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 2003, 42:705–708.

    Article  PubMed  CAS  Google Scholar 

  51. McCurley JM, Hanlon SU, Wei SK, et al.: Furosemide and the progression of left ventricular dysfunction in experimental heart failure. J Am Coll Cardiol 2004, 44:1301–1307.

    Article  PubMed  CAS  Google Scholar 

  52. Hirano T, Yamamura Y, Nakamura S, et al.: Effects of the V2-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats. J Pharmacol Exp Ther 2000, 292:288–294.

    PubMed  CAS  Google Scholar 

  53. Burnett JC Jr, Costello-Boerrigter LC, Smith WB, Ouyang J, et al.: Tolvaptan (OPC-41061), a V2 vasopressin receptor antagonist, protects against the decline in renal function observed with loop diuretic therapy [abstract 184]. Circulation 2003, 108(Suppl IV):IV-398.

    Google Scholar 

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Correspondence to Steven R. Goldsmith MD.

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Goldsmith, S.R. Treating hyponatremia in heart failure. Curr Cardiol Rep 8, 204–210 (2006). https://doi.org/10.1007/s11886-006-0035-9

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