hyponatremia in heart failure

8/14/2019 Hyponatremia in Heart Failure

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Hyponatremia in Heart Failure

Introduction

Hyponatremia (plasma sodium < 135 mEq/L) is a common finding in heart failure. It is associatedwith 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 patients discomfort. Combinationof hypertonic saline (eg NaCl 3%) and loop diuretics is often added to fluid restriction, but thisover aggressive approach has been associated with abrupt increase in plasma sodiumconcentration leading to CNS demyelinisation. Moreover, Furosemide administration is, in fact,associated with potentially lethal electrolyte abnormalities, neurohormonal activation, worseningrenal function, and lastly, resistance to its administration (2). In current practice, there is atendency to view hyponatremia as dilutional effect from fluid accumulation, but no integratedapproach is taken to manage it. However, only recently a novel therapeutic modality has beendeveloped to cope with hyponatremia while simultaneously improve hemodynamic status andprognosis of patients with heart failure (3).

Why does hyponatremia occur in heart failure?

Hypervolemic Hyponatremia in heart failure originates from reduced cardiac output and bloodpressure, which stimulates vasopressin, cathecholamine, and the renin-angiotensin-aldosteroneaxis. Increased vasopressin levels have been reported in patients with impaired left ventricularfunction 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, andrenal afferent arterioles leads to increased sympathetic discharge, activation of the renin-angiotensin-aldosterone system, and nonosmotic release of vasopressin among otherneurohormones.(1) Despite increased total fluid volume,increased sympathetic drive contributesto avid sodium and water retention, and the enhanced vasopressin release results in anincreased number of aquaporin water channels in the collecting duct of the kidney that promoteabnormal 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 itsmajor 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:

Receptorsubtypes

Site of action AVP activation effects

V1a Vascular smooth muscle cellsPlateletsLymphocytes and monocytesAdrenal cortex

VasoconstrictionPlatelet aggregationCoagulation factor releaseGlycogenolysis

V1b Anterior pituitary ACTH and endorphin releaseV2 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 invarious physiological processes, including body fluid regulation, vascular tone regulation andcardiovascular contractility. V1a receptors are located on both vascular smooth muscle cells andcardiomyocytes, and have been shown to modulate blood vessel soconstriction and myocardial


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function. V2 receptors are located on renal collecting duct principal cells, which are coupled toaquaporine water channels and regulate volume status through stimulation of free water and ureareabsorption.

The primary function of AVP, or formerly known as antidiuretic hormone (ADH), is to regulatewater and solute excretion by the kidney. AVP plays a significant role in volume homeostasisunder normal physiological conditions through continuous response to changes in plasmatonicity. When plasma tonicity changes by as little as 1%, osmoreceptor cells located in thehypothalamus undergo changes in volume and subsequently stimulate neurons of the supraopticand paraventricular nuclei. Based upon the degree of tonicity change, activationof these neuronsmodulates the degree of AVP secretion from the axon terminals of the posterior pituitary. Afterrelease into the circulation, AVP binds to V2 receptors located on collecting duct principal cells inthe kidney.

This binding activates a guanine nucleotide binding protein (Gs) which in turn activates adenylatecyclase, subsequently increasing intracellular cyclic-3_-5_-adenosine monophosphate (cAMP)

synthesis. The generated cAMP then activates protein kinase A (PKA), which stimulates thesynthesis of aquaporin-2 (AQ2) water channel proteins and their shuttling to the apical surface ofthe collecting duct. These channels allow free water to be reabsorbed across the apicalmembrane of the collecting duct, via the renal medullary osmotic gradient, for ultimate return tothe intravascular circulation. Thus, AVP secretion alters collecting duct permeability, increasesfree water reabsorption, and ultimately decreases plasma osmolality.In healthy individuals, whenplasma becomes hypertonic (> 145 mEq/L of serum sodium), plasma AVP concentrations exceed5.0 pg/mL and urine becomes maximally concentrated (1200 mOsm/kg water) in thecollectingduct of the nephron. Conversely, when plasma becomes hypotonic (


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(minimum of 50 mOsm/kg water) as it is excreted. Under isotonic conditions, AVP is secreted toan intermediate plasma concentration of 2.5 pg/mL, subsequently producing a urine osmolalityapproximating 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 smoothmuscle cells. AVP release is stimulated when cardiopulmonary and sinoaortic baroreceptorsdetect reductions in pressure, such as during dehydration, profound hypotension or shock.Conversely, detectable increases in pressure by these baroreceptors leads to a reduction in theproduction and release of AVP. In response to minor decreases in arterial, venous andintracardiac pressure, stimulation of the V1a receptors by AVP results in potent arteriolevasoconstriction with significant increases in systemic vascular resistance (SVR). In healthyindividuals, however, physiological increases in AVP release do not usually produce significantincreases in blood pressure, since AVP also potentiates the sinoaortic baroreceptor reflex inresponse to elevated SVR. Augmentation of the baroreceptor reflex, which is mediated throughV2 receptor stimulation, subsequently lowers both heart rate and cardiac output to maintainconstant blood pressure. Thus, in normal individuals, AVP release increases SVR withoutincreasing 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 forhyponatremia (serum sodium concentration < 135 mEq/L) in congestive heart failure (CHF). Thestimulation of atrial and arterial baroreceptors in response to hypotension and volume depletionresults in the nonosmotic release of AVP. The predominance of nonosmotic AVP secretion overosmotic AVP release plays a key role in the development of water imbalance and hyponatremiain CHF and other edematous disorders. The AVP-receptor antagonists are a new class of agentsthat 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 allowingspecific correction of water and sodium imbalance. This review summarizes recent data fromclinical trials evaluating the efficacy and safety of these promising agents for the treatment ofhyponatremia

Acute Hemodynamic Effects of V2 receptor blocker

In 181 patients with advanced HF, Tolvaptan a vasopressin V2 receptor antagonist was studied inrandomized 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 reducedright atrial pressure (- 4.4 + 6.9 mm Hg [p < 0.05], - 4.3 + 4.0 mm Hg [p < 0.05], - 3.5 + 3.6 mmHg, and - 3.0 + 3.0 mm Hg for the 15-mg,30-mg, 60-mg, and placebo groups, respectively) andpulmonary 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). Tolvaptanincreased urine output by 3 h in a dose-dependent manner (p < 0.0001), without changes in renalfunction.Conclusions In patients with advanced HF, tolvaptan resulted in favorable but modest changes infilling pressures associated with a significant increase in urine output. These data provide


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mechanistic support for the symptomatic improvements noted with tolvaptan in patients withdecompensated HF.

Take-home message:

Hyponatremia in patients with heart failure may reflect a marker of neurohormomal activation andhence the severity of this disease. With the elaboration of AVP dysregulation in heart failure andintroduction of vasopressin antagonist(such as tolvaptan) to clinical practice, a promisingstrategy is now at the horizon for a better management of patients with heart failure.

Iyan Darmawan,MDMedical [email protected]

full articles of cited references are available upon request.

References:

1. 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.

2. 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 failureIt is a lot about fluidaccumulationAm Heart J 2008;155:1-5.

3. 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 AcuteHemodynamic Effects of Tolvaptan, a Vasopressin V2 Receptor Blocker, in Patients WithSymptomatic 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

4. Sterns RH and Stephen M. SilverSeldin and Giebisch's The Kidney (Fourth Edition), 2008,

Pages 1179-1202

5. Berl T, Schrier RW. Vasopressin Antagonists in Physiology and Disease Textbook of Nephro-

Endocrinology, 2009, Pages 249-260

6. Schlanger LE and Sands JMVasopressin in the Kidney: Historical Aspects. Textbook ofNephro-Endocrinology, 2009, Pages 203-223

7. Lee CR, Watkins ML, Patterson JH, Gattis W, OConnor CM, Gheorghiade M, Adams KF, Jr

Vasopressin: a new target for the treatment of heart failure. American Heart Journal, Volume146, Issue 1, July 2003, Pages 9-18

8. Thierry H. LeJemtel , Claudia Serrano Vasopressin dysregulation: Hyponatremia, fluid

retention and congestive heart failure. International Journal of Cardiology 120 (2007) 19
mailto:[email protected]:[email protected]

hyponatremia in heart failure

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