Hyponatremia in Heart Failure

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 Site of action AVP activation effects
subtypes
V1a Vascular smooth muscle cells Vasoconstriction
Platelets Platelet aggregation
Lymphocytes and monocytes Coagulation factor release
Adrenal cortex 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 detectable only 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.

Iyan Darmawan,MD
Medical Director
iyan@ho.otsuka.co.id

full articles of cited references are available upon request.

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