Hyponatremia In Heart Failure

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 reninangiotensin-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 [email protected] full articles of cited references are available upon request. References:

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