Introduction
Hyponatremia (plasma sodium < 135 mEq/L) is a common
finding in heart failure.
It is associated with a poor prognosis. Symptomatic
patients are usually managed by fluid restriction
that results in a negative water balance, increases in plasma osmolality, and increases in
plasma
sodium.(1) Unfortunately, this therapy is not very effective and may cause patient’s discomfort. Combination of hypertonic saline (eg NaCl
3%) and loop diuretics is often added to fluid restriction, but this over aggressive approach has been associated with abrupt increase in plasma sodium concentration leading to CNS demyelinisation. Moreover, Furosemide
administration is, in fact,
associated
with
potentially
lethal electrolyte abnormalities, neurohormonal activation,
worsening renal
function, and lastly, resistance to its administration.(2) In current practice, there is a tendency to view hyponatremia as dilutional effect from
fluid
accumulation, but no integrated approach is taken to manage it. However,
only recently a novel therapeutic modality has been developed
to cope with hyponatremia while simultaneously
improve hemodynamic status
and prognosis of patients with heart failure. (3)
Why does hyponatremia occur in heart failure?
Hypervolemic Hyponatremia in heart failure originates from reduced cardiac output and blood pressure, which stimulates vasopressin, cathecholamine, and the renin-
angiotensin-aldosterone axis. Increased vasopressin levels have been reported
in patients with impaired
left ventricular function before the onset of symptomatic heart failure.(4,5) In patients
with
worsening HF, decreased stimulation of mechanoreceptors in the left ventricle, carotid sinus,
aortic arch, and renal afferent
arterioles leads to increased
sympathetic discharge, activation of the renin-angiotensin-aldosterone system, and nonosmotic
release of vasopressin among other
neurohormones.(1) Despite increased
total fluid volume,increased sympathetic
drive contributes to avid
sodium and water retention, and the enhanced
vasopressin release results
in an increased number of aquaporin water channels in the collecting duct of the kidney that promote abnormal
free water retention and contribute to the development of hypervolemic hyponatremia.
Vasopressin a new target for the treatment
of heart failure
Initially, vasopressin was named for its pressor effect
but,as more information surfaced and its major role in water balance emerged, its name has been interchanged with antidiuretic hormone. Vasopressin receptors have diverse physiological
actions on liver, smooth muscle,
myocardium,
platelets, brain and kidney (6)
There are three receptor subtypes of AVP (arginine
vasopressin) (7,8) as shown below:
Receptor
subtypes
|
Site of action
|
AVP activation
effects
|
V1a
|
Vascular smooth
muscle cells Platelets Lymphocytes
and monocytes Adrenal cortex
|
Vasoconstriction
Platelet aggregation Coagulation factor release
Glycogenolysis
|
V1b
|
Anterior pituitary
|
ACTH and β–
endorphin release
|
V2
|
Renal
collecting duct
principal cells
|
Free water
reabsorption
|
Physiological actions
of AVP (7)
Through activation of its V1a and V2 receptors, AVP has demonstrated to play an integral
role in various physiological
processes, including body fluid regulation, vascular tone regulation
and cardiovascular contractility. V1a receptors
are located on both vascular
smooth muscle cells and cardiomyocytes, and have been shown to
modulate blood vessel soconstriction
and myocardial function. V2 receptors are located on renal collecting duct principal cells, which are coupled to
aquaporine water channels and regulate volume status through stimulation of free water and urea reabsorption.
The primary function of AVP, or formerly
known
as antidiuretic hormone (ADH), is to regulate
water and solute excretion
by the kidney. AVP plays a significant role in volume homeostasis under normal
physiological conditions through
continuous response to changes in plasma
tonicity. When plasma
tonicity changes by as
little as 1%, osmoreceptor
cells located in the hypothalamus
undergo changes in volume and subsequently stimulate neurons
of the supraoptic and
paraventricular nuclei. Based upon the degree of
tonicity change, activationof these neurons modulates the degree of AVP secretion from the axon terminals of the posterior pituitary. After release into the circulation, AVP binds to V2 receptors
located on collecting duct principal
cells in the kidney.
This binding activates
a guanine nucleotide
binding protein (Gs) which in turn activates
adenylate cyclase, subsequently increasing intracellular cyclic-3_-5_-
adenosine monophosphate (cAMP) synthesis. The generated
cAMP then activates protein kinase A
(PKA), which
stimulates the synthesis
of aquaporin-2 (AQ2) water channel proteins and their shuttling to the apical
surface of the collecting duct.
These channels allow free
water to be reabsorbed across the apical membrane of
the collecting duct,
via the renal medullary osmotic
gradient, for ultimate return to the intravascular
circulation. Thus, AVP secretion alters collecting duct permeability, increases free water reabsorption,
and ultimately decreases plasma osmolality.In
healthy individuals, when plasma becomes hypertonic
(> 145 mEq/L of serum sodium), plasma AVP concentrations
exceed 5.0 pg/mL and urine becomes maximally concentrated
(1200 mOsm/kg water) in thecollecting duct of the nephron.
Conversely, when plasma becomes hypotonic (<135
mEq/L of serum sodium), plasma AVP
concentrations are undetectable and the urine remains maximally dilute (minimum of 50 mOsm/kg
water) as it is
excreted. Under isotonic
conditions, AVP is secreted to an intermediate plasma concentration of
2.5 pg/mL, subsequently producing a urine
osmolality approximating
600 mOsm/kg water.
Vascular tone regulation
In
addition
to
its
renal effects
on
the
V2
receptor
inresponse to changes in plasma
osmolality, AVP also maintains and regulates
vascular tone via V1a receptors
located on vascular smooth muscle cells.
AVP release is stimulated when cardiopulmonary and sinoaortic baroreceptors detect reductions in pressure, such as during dehydration, profound hypotension or shock. Conversely, detectable increases in pressure by these
baroreceptors leads to a reduction in the production
and release of AVP. In response to minor decreases
in
arterial, venous and intracardiac
pressure, stimulation of
the V1a
receptors
by AVP results in potent arteriole vasoconstriction with
significant increases in systemic vascular resistance(SVR). In healthy individuals,
however, physiological increases in AVP release do not
usually produce significant increases in blood pressure,
since AVP also potentiates the sinoaortic baroreceptor reflex in response to elevated SVR. Augmentation of the baroreceptor reflex, which is mediated
through V2 receptor stimulation, subsequently lowers
both heart rate and
cardiac output to maintain constant blood pressure. Thus, in normal individuals, AVP release increases SVR without increasing blood pressure via stimulation of both V1a and V2 receptors.
Blood pressure changes become
detectableonly when supraphysiological AVP concentrations are attained, and V1a -activated increases in SVR outweigh the V2-activated potentiation of the baroreceptor reflex.
VP dysregulation (8)
Arginine vasopressin (AVP) plays a central
role in the regulation of water
and
electrolyte
balance.
Dysregulation of AVP secretion, along with stimulation of AVP V2 receptors, is responsible
for hyponatremia (serum sodium concentration < 135 mEq/L) in congestive heart failure
(CHF). The stimulation of atrial and arterial baroreceptors in response to hypotension
and volume depletion
results in the nonosmotic release of AVP. The predominance of nonosmotic AVP secretion
over osmotic AVP release plays a key role in the
development of water imbalance
and hyponatremia in CHF and other edematous disorders. The AVP-receptor
antagonists are a new class of agents that block the
effects of AVP directly at V2 receptors in the renal collecting ducts. AVP-receptor
antagonism produces aquaresis, the electrolyte-sparing
excretion of water, thereby allowing specific correction
of water and sodium imbalance. This review summarizes recent data from clinical trials evaluating the efficacy and safety of these
promising agents for the treatment
of hyponatremia
Acute Hemodynamic Effects of V2 receptor blocker
In 181 patients with advanced HF, Tolvaptan a vasopressin V2 receptor antagonist was studied in
randomized double-blind treatment. Patients were
randomized to tolvaptan single oral dose (15,30 or 60 mg)
or placebo (3)
Tolvaptan at all doses significantly reduced pulmonary capillary wedge pressure (- 6.4 + 4.1 mm Hg, - 5.7 + 4.6
mm Hg, - 5.7 + 4.3 mm Hg, and - 4.2 + 4.6 mm Hg for
the 15-mg, 30-mg, 60-mg, and placebo groups, respectively; p < 0.05 for all tolvaptan
vs. placebo). Tolvaptan also reduced right atrial pressure
(- 4.4 + 6.9
mm Hg [p < 0.05], - 4.3 + 4.0 mm Hg [p < 0.05], - 3.5 + 3.6 mm Hg, and - 3.0 + 3.0 mm
Hg for the 15-mg,30-mg,
60-mg, and placebo groups, respectively) and pulmonary artery pressure ( -5.6 + 4.2 mm Hg, - 5.5 + 4.1 mm Hg, - 5.2 + 6.1 mm Hg, and - 3.0 + 4.7 mm Hg
for the 15-mg, 30-mg, 60-mg, and placebo
groups, respectively; p < 0.05). Tolvaptan
increased urine output
by 3
h
in
a
dose-dependent manner (p < 0.0001), without changes in renal function.
Conclusions
In patients with advanced HF, tolvaptan
resulted in favorable but modest changes in filling pressures associated
with a significant increase in urine
output. These data provide mechanistic support for the
symptomatic improvements noted with tolvaptan
in patients with decompensated HF.
Take-home message:
Hyponatremia in patients with heart failure may reflect a marker of neurohormomal activation and hence the severity of this disease. With the elaboration of AVP dysregulation in heart failure and introduction of vasopressin antagonist(such
as tolvaptan) to clinical
practice, a promising strategy is now at the
horizon for a better management of patients with heart failure.
References:
- De Luca L, Klein L, Udelson JE, Orlandi C, SardellaG, Fedele F, Gheorghiade M .Hyponatremia in Patients with Heart Failure The American Journal of Cardiology, Volume 96, Issue 12, Supplement 1, 19 December 2005, Pages 19-23.
- Marco Metra, MD,a Livio Dei Cas, MD,a and Michael R Bristow, MR, MD, PhDb Brescia, Italy; and Denver, CO The pathophysiology of acute heart failure—It is a lot about fluid accumulation Am Heart J 2008;155:1-5.
- Udelson JE, Orlandi C, Ouyang J, Krasa H, Zimmer CA, Frivold G, W. Haught WH, Meymandi S, Macarie C, Raef D, Wedge P, Konstam MA, Gheorghiade M Acute Hemodynamic Effects of Tolvaptan, a Vasopressin V2 Receptor Blocker, in Patients With Symptomatic Heart Failure and Systolic Dysfunction: An International, Multicenter, Randomized, Placebo-Controlled Trial.Journal of the American College of Cardiology, Volume 52, Issue 19, 4 November 2008, Pages 1540-1545
- Sterns RH and Stephen M. Silver Seldin and Giebisch's The Kidney (Fourth Edition), 2008, Pages 1179-1202 Berl T, Schrier RW. Vasopressin Antagonists in Physiology and Disease Textbook of Nephro- Endocrinology, 2009, Pages 249-260
- Schlanger LE and Sands JM Vasopressin in the Kidney: Historical Aspects. Textbook of Nephro-Endocrinology, 2009, Pages 203-223
- Lee CR, Watkins ML, Patterson JH, Gattis W, O’Connor CM, Gheorghiade M, Adams KF, Jr Vasopressin: a new target for the treatment of heart failure. American Heart Journal, Volume 146, Issue 1, July 2003, Pages 9-18
- Thierry H. LeJemtel, Claudia Serrano Vasopressin dysregulation: Hyponatremia, fluid retention and congestive heart failure. International Journal of Cardiology 120 (2007) 1–9
