Arginine Vasopressin in Heart Failure

Impaired water excretion is primarily involved in water retention in congestive heart failure. In 1981, Schrier’s group initially demonstrated increased release of arginine vasopressin (AVP) despite hypo-osmolality in congestive heart failure.¹ Several recent studies have clarified that dilutional hyponatremia predicts the long-term outcome of heart failure, and that this pathological state is profoundly linked to non-osmotic release of AVP.^2,3 The timely study by Imamura et al⁴ in the present issue of the Journal showed that higher plasma AVP levels were significantly linked to reduced survival in patients with congestive heart failure, in association with hyponatremia. In 2010, tolvaptan, a non-peptide AVP V2 receptor antagonist, enables us to treat water retention and hyponatremia in patients with heart failure.^5,6 Since then, the pathological role of AVP has become an issue of interest to cardiologists.

Article p 2259

Pathogenesis of AVP Release

In several animal models of low-output and high-output cardiac failure and in congestive heart failure in humans, it has been demonstrated that plasma AVP, renin activity, aldosterone and norepinephrine are significantly increased.⁷ Renal excretion of sodium and water is predominantly regulated by the integrity of the arterial circulation, which is determined by cardiac output and peripheral vascular resistance. Several baroreceptors on the high pressure side of the circulation can sense arterial underfilling, and they are found in the left atrium, carotid sinus, aortic arch and renal afferent arterioles. Reduction in baroreceptor sensitivity occurs because of a decrease in systemic arterial pressure, stroke volume, renal perfusion or peripheral vascular resistance. In the state of cardiac failure, cardiac output is decreased in association with reduced stroke volume despite an increase in total circulatory volume. We propose the hypothetical term “effective circulatory blood volume”, which is involved in the sensitivity of baroreceptors. A decrease in effective circulatory blood volume impairs the sensitivity of baroreceptors, which leads to an increase in the activity of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone (R-A-A) system, and the non-osmotic release of AVP.^8,9 However, it is as yet undetermined how the baroreceptors sense the decrease in effective circulatory blood volume linked to low cardiac output in congestive heart failure.

We verified an elevation of plasma AVP levels in congestive heart failure. Plasma AVP levels increased gradually in association with higher New York Heart Association (NYHA) class.¹⁰ The cardiac index gradually decreased according to the severity of NYHA class, and the plasma AVP level had a negative correlation with cardiac index.¹⁰ Increased AVP release was closely linked to the afferent pathways of the baroreceptors, which were stimulated by reduced effective circulatory blood volume as noted earlier (Figure 1).

Figure 1.

Augmented release of arginine vasopressin (AVP) in congestive heart failure.

Impaired Water Excretion and Aquaporin2 (AQP2)

Two studies using animal models of congestive heart failure have shown the enhanced hydro-osmotic action of AVP. The AQP2 water channel is located in renal collecting duct cells, and AQP2 is regulated by AVP, namely, short- and long-term regulation. Short-term regulation by AVP has been shown to involve cellular trafficking of AQP2 from cytosolic vesicles to the apical membrane of collecting duct cells. AQP2 per se then permeates water from the apical space to the cells. In addition, AVP stimulates the expression of AQP2 mRNA, followed by the synthesis of AQP2 protein (long-term regulation). Non-suppressible AVP release is remarkably involved in abnormal antidiuresis in pathological states of heart failure. Chronic excess AVP may be closely linked to abundant AQP2 protein in collecting duct cells.¹¹ Thus, long-term regulation of AQP2 could be a major factor in impaired water excretion.

AQP2 is excreted into urine, in both the soluble and membrane-bound form.¹² The fraction of AQP2 excreted into the urine is approximately 3% of the AQP2 protein present in collecting duct cells. We clarified a positive correlation of urinary AQP2 excretion with plasma AVP levels in normal subjects and heart failure patients. Urinary excretion of AQP2 was progressively increased in patients with heart failure according to progression of NYHA class.¹⁰

Hyponatremia, Plasma AVP Levels and Prognosis

Gheroghiade et al demonstrated that hyponatremia less than 135 mmol/L was not infrequently found in 19.7% of 48,612 patients with congestive heart failure.² As noted earlier, baroreceptor-mediated activation of AVP, R-A-A and catecholamines increases water and sodium retention, resulting in increased circulatory blood volume. Water retention is more predominant than sodium retention, thus creating dilutional hyponatremia.⁹ Essentially, excessive circulatory blood volume augments cardiac preload in the failing heart, and further deteriorates the impairment in cardiac contraction (Figure 2).

Figure 2.

Pathogenesis of increased circulatory blood volume and deterioration of cardiac dysfunction. AVP, arginine vasopressin; R-A-A, renin-angiotensin-aldosterone.

What is a recent topic is that hyponatremia predicts worsening short-term and long-term prognosis in patients with heart failure. Short-term outcome included length of stay in hospital and in-hospital mortality, and long-term outcome includes post-discharge mortality and rehospitalization.^2,3 In this issue of the Journal, Imamura et al⁴ demonstrate the poor prognosis in patients with stage D heart failure. They focused on plasma AVP levels, and divided the patients into 2 groups according to a cut-off level of plasma AVP of 5.3 pg/ml. Kaplan-Meier analysis showed a significant difference between groups in terms of overall survival over 2 years. Cox regression analysis clarified that higher plasma AVP levels were significantly associated with decreased survival. The observation is basically similar to that of poor prognosis in hyponatremic patients with heart failure. In our recent study, a low serum Na concentration was only associated with the occurrence of heart failure events, among the varying humoral and cardiac parameters, during the follow-up period (mean 601 days) in patients with heart failure receiving cardiac resynchronization therapy.¹³

Hyponatremia is derived from excessive circulatory blood volume because of impaired water excretion, and thus is dilutional hyponatremia. We believe that the related circulatory blood volume expansion per se could deteriorate the already reduced cardiac contraction in the failing heart. In contrast, non-osmotic release of AVP is mediated through reduced baroreceptor sensitivity, which senses the effective circulatory blood volume and cardiac output in congestive heart failure. Namely, an alteration in plasma AVP level is closely linked to baroreceptor sensitivity. Thereafter, an elevation in the plasma AVP level could relate to water retention, increased circulatory blood volume and further dilutional hyponatremia. However, AVP hypersecretion may be indirectly associated with worsening cardiac function and survival in the pathological state of heart failure.

References

• 1.    Szatalowicz  VL,  Arnold  PE,  Chaimovitz  C,  Bichet  DG,  Berl  T,  Schrier  RW. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med 1981; 305: 263–266.
• 2.    Gheorghiade  M,  Abraham  WT,  Albert  NM,  Gatti-Stough  W,  Greenberg  BH,  O’Connor  CM, et al; OPTIMIZE-HF Investigators and Coordinators. 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 2007; 28: 980–988.
• 3.    Gheorghiade  M,  Rossi  JS,  Cotts  W,  Shin  DD,  Hellkamp  AS,  Pina  IL, et al. Characterization and prognostic value of persistent hyponatremia with severe heart failure in the ESCAPE Trial. Arch Intern Med 2007; 167: 1998–2005.
• 4.    Imamura  T,  Kinugawa  K,  Hatano  M,  Fujino  T,  Inaba  T,  Maki  H, et al. Low cardiac output stimulates vasopressin release in patients with stage D heart failure: Its relevance to poor prognosis and reversal by surgical treatment. Circ J 2014 78: 2259–2267.
• 5.    Yamamura  Y,  Nakamura  S,  Itoh  S,  Hirano  T,  Onogawa  T,  Yamashita  T, 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 Pharamacol Exp Ther 1998; 287: 860–867.
• 6.    Konstam  MA,  Gheorghiade  M,  Burnett  JC,  Grinfeld  L,  Maggioni  AP,  Swedberg  K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007; 297: 1319–1331.
• 7.    Schrier  RW. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis and pregnancy. N Engl J Med 1988; 319: 1065–1072.
• 8.    Schrier  RW,  Abraham  W. Hormones and hemodynamics in heart failure. N Engl J Med 1999; 341: 577–585.
• 9.    Ishikawa  S,  Schrier  RW. Pathophysiological roles of arginine vasopressin and aquaporin-2 in impaired water excretion. Clin Endocrinol (Oxf) 2003; 58: 1–17.
• 10.    Funayama  H,  Nakamura  T,  Saito  T,  Yoshimura  A,  Saito  M,  Kawakami  M, et al. Urinary excretion of quaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure. Kidney Int 2004; 66: 1387–1392.
• 11.    Nielsen  S,  Terris  J,  Anderson  D,  Ecelbarger  C,  Froklaer  J,  Jonassen  T, et al. Congestive heart failure in rats is associated with increased expression and trafficking of aquaporin-2 water channel in collecting duct. Proc Natl Acad Sci USA 1997; 94: 5450–5455.
• 12.    Kanno  K,  Sasaki  S,  Hirata  Y,  Ishikawa  S,  Fushimi  K,  Nakanishi  S, et al. Urinary excretion of aquaporin-2 in patients with diabetes insipidus. N Engl J Med 1995; 332: 1540–1545.
• 13.    Arao  K,  Fujisawa  T,  Sakakura  K,  Wada  H,  Sugawara  Y,  Suga  C, et al. Hyponatremia as a predictor for worsening heart failure in patients receiving cardiac resynchronization therapy. Circ J 2013; 77: 116–122.