Circulation Journal

Official Journal of the Japanese Circulation Society

EDITORIAL
http://www. j-circ.or.jp

Arginine Vasopressin in Heart Failure

San-e Ishikawa, MD

I
mpaired water excretion is primarily involved in water re-
tention in congestive heart failure. In 1981, Schrier’s group
initially demonstrated increased release of arginine va-
sopressin (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 hy-
ponatremia. In 2010, tolvaptan, a non-peptide AVP V2 recep-
tor antagonist, enables us to treat water retention and hypo-
natremia 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 car-
diac failure and in congestive heart failure in humans, it has
been demonstrated that plasma AVP, renin activity, aldoste-
rone 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 baro-
receptors on the high pressure side of the circulation can sense
arterial underfilling, and they are found in the left atrium, ca-
rotid 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

Figure 1.  Augmented release of argi-

nine vasopressin (AVP) in congestive
heart failure.

The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society.
Received July 10, 2014; accepted July 10, 2014; released online July 29, 2014
Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
Mailing address: San-e Ishikawa, MD, Department of Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma,
Omiya-ku, Saitama 330-8503, Japan.   E-mail: saneiskw@jichi.ac.jp
ISSN-1346-9843  doi: 10.1253/circj.CJ-14-0752
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal Vol.78, September 2014

2160
Figure 2.  Pathogenesis of increased circulatory blood vol-
ume and deterioration of cardiac dysfunction. AVP, arginine
vasopressin; R-A-A, renin-angiotensin-aldosterone.
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 pro-
pose 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-angioten-
sin-aldosterone (R-A-A) system, and the non-osmotic release
of AVP.8,9 However, it is as yet undetermined how the baro-
receptors sense the decrease in effective circulatory blood vol-
ume linked to low cardiac output in congestive heart failure.
We verified an elevation of plasma AVP levels in conges-
tive 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 nega-
tive correlation with cardiac index.10 Increased AVP release
was closely linked to the afferent pathways of the barorecep-
tors, which were stimulated by reduced effective circulatory
blood volume as noted earlier (Figure 1).
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
Circulation Journal Vol.78, September 2014
ISHIKAWA S
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 ex-
cess 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 mem-
brane-bound form.12 The fraction of AQP2 excreted into the
urine is approximately 3% of the AQP2 protein present in col-
lecting 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 pro-
gressively 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, baro-
receptor-mediated activation of AVP, R-A-A and catechol-
amines increases water and sodium retention, resulting in in-
creased circulatory blood volume. Water retention is more
predominant than sodium retention, thus creating dilutional hy-
ponatremia.9 Essentially, excessive circulatory blood volume
augments cardiac preload in the failing heart, and further de-
teriorates the impairment in cardiac contraction (Figure 2).
What is a recent topic is that hyponatremia predicts worsen-
ing 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 pa-
tients 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 anal-
ysis showed a significant difference between groups in terms
of overall survival over 2 years. Cox regression analysis clar-
ified that higher plasma AVP levels were significantly associ-
ated with decreased survival. The observation is basically simi-
lar 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 fail-
ure receiving cardiac resynchronization therapy.13
Hyponatremia is derived from excessive circulatory blood
volume because of impaired water excretion, and thus is dilu-
tional 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 baro-
receptor sensitivity, which senses the effective circulatory blood
volume and cardiac output in congestive heart failure. Name-
ly, an alteration in plasma AVP level is closely linked to baro-
receptor 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.
AVP in HF
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