Hyponatremia in Patients with Heart Failure beyond the Neurohormonal Activation Associated with Reduced Cardiac Output: A Holistic Approach Free

Hyponatremia, usually defined as serum sodium <135 mmol/L, is the most common electrolyte disorder in clinical practice and is associated with increased morbidity and mortality. The severity of symptoms associated with hyponatremia depends on the rapidity and degree of serum sodium concentration reduction. Patients with acute (<48 h) or severe (sodium levels <120 mmol/L) hyponatremia may present with nonspecific symptoms such as nausea, vomiting, and headache up to stupor, coma, seizures, respiratory depression, and death. Chronic moderate (sodium levels 120–129 mmol/L) and mild (sodium levels 130–134 mmol/L) hyponatremia may present with subtle manifestations, such as fatigue, cognitive impairment, gait deficits, falls, impaired bone metabolism, and fractures [1]. Heart failure (HF) is a relatively frequent cause of hyponatremia [2]. Conversely, hyponatremia may affect up to one-third of patients with HF [3-5]. The main underlying mechanism of HF-related hyponatremia is the enhanced non-osmotic release of antidiuretic hormone (ADH) due to effective circulating volume depletion. However, the pathogenesis of hyponatremia in HF is usually multifactorial, something which is frequently overlooked. Indeed, even in the most recent guidelines of the European Society of Cardiology (ESC) for the diagnosis and treatment of HF, it is stated that “hyponatremia in HF patients reflects neurohormonal activation” [6]. In this context, we aimed to draw the attention to the mechanisms of hyponatremia beyond the neurohormonal activation due to ineffective circulating volume in these patients (Table 1). The treatment of hyponatremia in HF is also discussed.

A PubMed search was performed up to March 2021 using combinations of the following keywords: hyponatremia, sodium, heart failure, drugs, electrolyte abnormalities, co-morbidities, syndrome of inappropriate antidiuretic hormone secretion (SIAD), alcohol, infections, autoimmune diseases, thyroid diseases, diabetes, depression, cachexia, arthritis, cancer, stroke, chronic kidney disease, and lung diseases. Data from case reports, randomized controlled trials, original papers, and review articles were collected. References of these articles were scrutinized for relevant articles.

Hyponatremia is attributed either to loss of effective solutes (sodium plus potassium) in excess of water or to water retention. The capacity for water excretion is sufficient in normal states; thus, water retention occurs when renal excretion of water is impaired. An exception to this rule is primary polydipsia, in which the disproportionate water intake (10–15 L) exceeds the normal renal excretory capacity (“acute water intoxication”). High serum levels of ADH are a prerequisite for the development and maintenance of hyponatremia, as the suppression of ADH secretion plays a fundamental role in the renal excretion of any water load. Consequently, most causes of hyponatremia (except for low dietary solute intake, renal failure, primary polydipsia, or beer potomania syndrome) are accompanied by increased ADH, mainly due to the SIAD or to effective circulating volume depletion (true hypovolemia and edematous states) [7].

The reduced cardiac output in HF (either due to HF with reduced, mildly reduced, or preserved ejection fraction) decreases the stretch at the carotid and renal baroreceptors, leading to sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) activation along with enhancement of ADH excretion and action [8]. The role of neurohormonal activation in the development of hyponatremia in patients with HF is well established [9]. Specifically, angiotensin II (AT II) increases efferent arteriolar tone, promoting sodium and water absorption by way of the accompanying rise in the filtration fraction [10]. Furthermore, it promotes the release of ADH [10, 11] and stimulates thirst, increasing free water intake [12]. ADH causes vasoconstriction and increases water retention in the collecting ducts through vasopressin 2 receptors [9]. AT II also stimulates the secretion of aldosterone; the latter decreases water and sodium excretion in the distal tubules and collecting ducts [13]. The activation of the SNS promotes renal vasoconstriction, consequently decreasing glomerular filtration rate. The diminished sodium and water delivery to the distal tubules also reduces renal water excretion [14]. Importantly, factors that provoke HF may be implicated in the development of hyponatremia. Furthermore, HF patients frequently have comorbidities which contribute to the development or preservation of hyponatremia. Finally, several drugs used in HF may trigger or aggravate hyponatremia.

Some causes of HF, as presented in the guidelines of the ESC [6], may be potential causes of hyponatremia.

Chronic alcohol abuse has been associated with deleterious effects on the cardiovascular system [15] either via increased SNS and RAAS activation [16, 17] or due to contractile dysfunction [15, 18-20]. Hyponatremia is commonly observed in chronic alcoholics. The most important underlying mechanisms are as follows.

• Pseudohyponatremia due to alcohol-induced severe hypertriglyceridemia [21].

• Hypovolemia due to gastrointestinal losses.

• Beer potomania syndrome, characterized by excessive hypo-osmolar drinking usually accompanied by low solute intake. Hence, kidneys cannot excrete free water sufficiently and hypo-osmotic hyponatremia occurs [22].

• Reset osmostat syndrome [23], which is characterized by a decrease in plasma osmolality threshold for ADH excretion. Thus, plasma sodium concentration is adjusted to a lower level, typically between 125 and 135 mmol/L [24].

Cocaine is a well-known cardiotoxic agent [25, 26], whereas its use has been associated with dilated [25] and Takotsubo cardiomyopathy [27]. Cocaine blocks the presynaptic reuptake of serotonin and catecholamines, increasing their bioavailability at postsynaptic receptors, subsequently stimulating ADH release [28]. Hyponatremia develops due to excessive ADH release.

Methamphetamine use has been associated both with HF and hyponatremia [29, 30]. Methamphetamine-associated cardiomyopathy is the consequence of catecholamine excess, direct cardiotoxicity, coronary arterial vasoconstriction, and ischemia [31]. Methamphetamines may cause severe and life-threatening hyponatremia in the context of increased ADH secretion combined with excessive water intake in an effort to counteract hyperthermia [32].

The use of antidepressant and antipsychotic drugs has been associated with HF [33-35]. Among antidepressants, a significant association with dilated cardiomyopathy was found with tricyclic (clomipramine, amitriptyline) and serotoninergic (fluvoxamine) antidepressants [36]. An acute reversible type of diffusely depressed myocardial contractility has been described with venlafaxine overdose [37].

The administration of antidepressant and antipsychotic drugs is a well-recognized cause of SIAD [38] and hyponatremia [39, 40]. These drugs enhance the release of ADH and the renal responsiveness on its action [41]. Moreover, the sensation of dry mouth caused by psychotropic drugs stimulates water intake, whereas psychogenic polydipsia frequently occurs in psychiatric patients further aggravating hyponatremia [32].

Numerous cases of reversible dilated cardiomyopathy have been reported after treatment with interferon-α [42, 43], while interleukin-2 (IL-2) treatment has been associated with reversible left ventricular dysfunction [44]. Furthermore, several molecular-targeted therapies, including trastuzumab, sunitinib, sorafenib, and imatinib, appear to impair cardiac mitochondrial function, leading to cardiomyocyte and endothelial cell dysfunction, subsequently deteriorating myocardial contractility [45]. The aforementioned agents may cause hyponatremia via SIAD [46].

Cyclophosphamide. Cyclophosphamide cardiotoxicity ranges from subtle electrocardiographic changes to potentially fatal cardiomyopathy, especially when given in high doses or following treatment with anthracycline and mediastinal radiation [47]. Myocarditis, and rarely HF, may occur during the first 2 weeks post therapy [36, 47]. Cyclophosphamide administration may enhance the renal effect of ADH or its central release. Vigorous hydration with hypotonic fluids to prevent hemorrhagic cystitis may also be involved [46].

Ifosfamide. Ifosfamide may promote severe left ventricular dysfunction acutely [48]. Hyponatremia has been reported after ifosfamide administration and is probably attributed to SIAD [46].

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for HF hospitalization in patients with HF [49]. NSAIDs may aggravate HF through sodium and water retention, increased systemic vascular resistance, and blunted response to diuretics [50]. These drugs occasionally cause hyponatremia by diminishing the normal inhibitory effect of prostaglandins on ADH activity [39].

Infections usually aggravate the symptoms of HF, while they may also cause acute HF in a previously healthy myocardium [51]. In septic patients, the high output along with reduced systemic vascular resistance and low arterial blood pressure leads to activation of SNS and RAAS and increased ADH concentration. The subsequent sodium and water retention may lead to ventricular enlargement, remodeling, and HF [52].

Hyponatremia associated with infections is usually multifactorial [53]. Edematous states including HF may be provoked by an infectious agent [54-56]. Moreover, infections may deplete the effective circulating volume due to gastrointestinal losses, excessive sweating, systemic vasodilatation, or increased vascular permeability [53], subsequently stimulating ADH secretion.

Beyond the appropriate secretion of ADH in response to the decrease in the effective circulating volume, some infections, especially central nervous system and pulmonary infections, may cause hyponatremia via SIAD or cerebral salt-wasting syndrome [53, 57-59]. Furthermore, interleukin-6 (IL-6) may be implicated in the non-osmotic release of ADH [60]. Of note, IL-6 is one of the most important cytokines implicated in the hyper-inflammation syndrome in patients with COVID-19, while IL-6 levels were inversely correlated with serum sodium levels in these patients [61, 62]. Interestingly, 48 h after the administration of tocilizumab, a humanized monoclonal antibody against IL-6 receptor, sodium levels increased significantly in patients with hyponatremia [61].

Hyponatremia observed in the course of an infection may be due to infection-induced hyperglycemia (see below) or adrenal insufficiency (primary or secondary) [53, 63-65]. Several antibiotics, e.g., trimethoprim, may also be involved in the development of hyponatremia [66]. Ciprofloxacin rarely causes hyponatremia possibly via SIAD [39]. Of note, pseudohyponatremia sometimes occurs in patients with underlying infections and hypergammaglobulinemia secondary to β-lymphocyte activation [53].

Autoimmune diseases may be complicated with the development of HF [51]. Hyponatremia in these patients may be the consequence of steroid-induced hyperglycemia [67], while other commonly prescribed drugs, such as NSAIDs and methotrexate, may lead to or deteriorate hyponatremia. Specifically, methotrexate in high doses may activate natriuretic peptides or change the distribution of body fluid volumes [32, 46]. Importantly, autoimmune adrenalitis expressed as primary adrenal insufficiency should always be suspected in patients with autoimmune disorders and new-onset hyponatremia [68]. Pseudohyponatremia due to the existing hypergammaglobulinemia or intravenous immunoglobulin administration should also be considered [32, 69]. Of note, intravenous immunoglobulin has been used for the treatment of autoimmune disease-related HF [70].

In glycogen storage diseases, abnormal glycogen accumulates in the myocardium, and HF may develop [51, 71]. Hypertriglyceridemia or mixed dyslipidemia may also occur; thus, pseudohyponatremia may be observed.

HF is a major long-term complication of diabetes mellitus (DM). Diabetic subjects are prone to electrolyte disorders [72]. Hypovolemia is among the most common causes of hyponatremia in diabetic subjects. Osmotic diuresis in uncontrolled DM or DM-associated diarrhea and vomiting, either from the disease itself or antidiabetic therapy (i.e., metformin, glucagon-like peptide-1 receptor analogs), is the usual culprit of hypovolemia [67].

Hyponatremia frequently develops secondarily to chronic kidney disease (CKD), a common complication of DM [73]. Furthermore, hyporeninemic hypoaldosteronism, usually associated with mild to moderate CKD, may be the cause of mild hyponatremia in diabetic individuals [74].

Importantly, several drugs used in DM may cause or worsen hyponatremia. First generation sulphonylureas, nowadays seldom prescribed [39], and amitriptyline used for diabetic neuropathy [75], may induce hyponatremia. However, drug-associated hyponatremia in diabetic individuals usually occurs when several culprit agents are co-administered [67]. Interestingly, in the Rotterdam study, DM per se was associated with hyponatremia [1], probably via induction of aquaporin-2 by insulin [76].

In the presence of marked hyperglycemia, the high serum osmolality drives water out of cells and dilutional hyponatremia occurs. The latter should be suspected and corrected sodium for serum glucose levels calculated (Figure 1) [67, 77]. In DM, pseudohyponatremia may be secondary to hyperglycemia-induced hypertriglyceridemia [78].

Hypothyroidism may impair cardiac contractility [79]. Hypothyroidism-induced hyponatremia is rather rare and occurs only in severe hypothyroidism. The decreased capacity of free water excretion due to elevated ADH levels seems to be the underlying mechanism [80].

Among the cardiovascular manifestations of Addison’s disease (primary adrenal insufficiency) is the development of dilated cardiomyopathy and HF [81]. Hyponatremia in Addison’s disease may be due to systemic blood pressure reduction and enhanced ADH secretion, as cortisol is a tonic inhibitor of ADH secretion [82]. Furthermore, aldosterone deficiency promotes sodium wasting and hypovolemia, leading to hyponatremia [82].

Preload, afterload, and heart rate variations during gestation result in a 30–50% increase in cardiac output and a prolonged volume overload [83]. Several complications of pregnancy may cause or increase the risk of developing HF. Namely, peripartum cardiomyopathy is characterized by the presence of signs and symptoms of HF during the last month of pregnancy or within 5 months of delivery [83], with echocardiography criteria including ejection fraction less than 45%, end-diastolic diameter greater than 2.7 cm/m², and/or M-mode fractional shortening less than 30% [84]. Also, another important complication of pregnancy, preeclampsia, is associated with a 4-fold increased risk of HF after delivery [85].

Systemic arterial vasodilatation secondary to hormonal changes leads to RAAS activation and non-osmotic ADH secretion [86]. Nausea, vomiting, and pain, frequently encountered during pregnancy and labor, enhance ADH secretion [87]. The latter occurs at a lower serum-sodium concentration threshold in pregnancy, the so-called “reset osmostat syndrome,” leading to inappropriate ADH secretion [88]. Therefore, plasma osmolality and sodium are lower by 10 mOsm/L and 4–5 mmol/L, respectively [86].

Several comorbidities which frequently accompany chronic HF may also be involved in the development or preservation of hyponatremia. These will be presented herein.

Cardiac cachexia is a serious and common condition associated with chronic HF [89]. Anorexia and reduced food intake secondary to tasteless diets with low sodium content, dyspnea, depression, visceral congestion, and intestinal malabsorption contribute to weight loss [90-92]. Increased tumor necrosis factor (TNF)-α may also be involved [91, 93].

Reduced protein intake predisposes to the development of hyponatremia due to the low rate of osmole excretion and impaired free water clearance [94]. In a recent multicenter randomized study, SODIUM-HF, HF patients with tighter diet salt restriction (1,600 mg per day vs. 2,100 mg per day) showed no significant difference in all cause death, HF hospitalizations, or visits to the emergency department for HF. However, the incidence of hyponatremia in the abovementioned study is not known [95].

HF and cancer share several risk factors [96, 97] and have some mutual pathophysiologic mechanisms [96]. HF patients have a higher risk of developing cancer [98], whereas cancer survivors are at increased risk of developing CVD and HF [99]. Furthermore, certain cancer therapies may trigger or exacerbate HF [50, 100, 101].

Hyponatremia in oncologic patients is frequent [102-105]. The main underlying mechanisms are as follows.

• Ectopic ADH production by certain tumors, namely, from the lungs (especially small-cell lung cancer) [103, 105], breast, head, or neck [102, 106].

• Pain and stress, which promote ADH secretion.

• Paraneoplastic production of atrial natriuretic peptide (ANP), e.g., in patients with small-cell lung cancer [107]. ANP suppresses the aldosterone axis [107].

• Vincristine, vinblastine, cyclophosphamide, cisplatin, melphalan [32, 39, 108], brivanib, and sorafenib [109, 110] have been associated with hyponatremia, possibly through SIAD-like mechanisms [32].

• Hypovolemic hyponatremia due to chemotherapy-induced diarrhea and vomiting [106, 111].

• Stimulation of ADH release by palliative and pain-relief drugs (e.g., morphine and carbamazepine) [111]. Opiate-induced nausea or hypotension may also be implicated [32].

• Hyperglycemia from steroids used for the treatment of nausea, compression syndromes, and lymphomas [106].

• Adrenocortical insufficiency secondary to adrenal metastases or primary adrenal lymphoma [112, 113].

• Pseudohyponatremia, sometimes encountered in hematologic malignancies due to paraproteinemia [106].

• Iatrogenic hyponatremia as a result of the administration of hypotonic intravenous fluids [114]

Stroke and HF commonly coexist because of shared risk factors. HF is associated with an increased risk of both first [115] and recurrent ischemic stroke [116]

Hyponatremia on stroke admission is mainly ascribed to the presence of comorbidities or medications, including diuretics and antidepressants, whereas hyponatremia during hospitalization may be the consequence of hypotonic solution administration, poor solute intake, or infections (e.g., aspiration pneumonia) and the use of certain drugs in the acute setting [117]. Specifically, mannitol administered in case of cerebral edema causes dilutional hyponatremia [32]. Stroke per se may cause hyponatremia due to pituitary ischemia or hemorrhage, secondary adrenal insufficiency, SIAD, and cerebral salt-wasting syndrome [117, 118].

Depression is up to 5 times more prevalent in HF patients than in the general population [119] and is an independent risk factor for hospitalization and mortality [119, 120]. As previously mentioned, antidepressant drugs are a common cause of hyponatremia.

The close link between DM and HF as well as the possible causes of hyponatremia in diabetic individuals have already been described.

Hyperuricemia and gout are common in HF patients and may be caused or aggravated by diuretics [121]. Furthermore, rheumatoid arthritis is associated with an increased risk of HF [122], independent of the presence of ischemic heart disease [123]. Pain and stress, frequently observed in patients with arthritis, are non-osmotic stimuli for ADH secretion. Moreover, these patients frequently take NSAIDs [122], which occasionally provoke hyponatremia by enhancing the effect of ADH [32].

HF and CKD have several common risk factors and often coexist [124]. Kidneys are the key organs that maintain water homeostasis. Thus, in CKD, the urinary dilution ability is impaired, and if the volume of ingested fluids exceeds this ability, water retention and hyponatremia develop [125].

Severe long-standing chronic obstructive pulmonary disease (COPD) may be complicated by pulmonary hypertension and right-sided HF. Conversely, up to 50% of patients with chronic HF have COPD [126]. Furthermore, respiratory infections are among the most common causes of hospitalization in HF patients [127].

Several lung diseases, including lung infections, asthma, COPD, lung tumors, cystic fibrosis, and acute respiratory failure, have been associated with SIAD and, subsequently, hyponatremia [128]. Furthermore, hypercapnia reduces renal blood flow either by means of direct renal vasoconstriction or indirectly through noradrenaline secretion [129]. Accordingly, water retention and hyponatremia occur [130]. The use of diuretics, concomitant renal insufficiency, hypokalemia attributed to bronchodilators or steroids, malnutrition, and poor solute intake during acute COPD exacerbations may also trigger hyponatremia [131].

Liver diseases and especially cirrhosis are often accompanied by hyponatremia. Importantly, HF and hepatopathies do not infrequently coexist (e.g., hemochromatosis, alcohol overconsumption). Moreover, HF may cause hepatic fibrosis (“cardiac cirrhosis”), whereas liver cirrhosis may induce pulmonary arterial hypertension and deterioration of heart function [132].

Sleep disturbance and sleep-disordered breathing are among the most frequent comorbidities in patients with chronic HF [126]. Sleep disorders are associated with hyponatremia, namely, sleep deprivation reduces cortisol levels during the next day. Taking into consideration that cortisol is a tonic inhibitor of ADH, hypocortisolemia predisposes to hyponatremia [1].

Hypertension is among the most significant risk factors for the development of HF [133-136]. Antihypertensive agents and especially diuretics are commonly associated with the development of hyponatremia (the underlying mechanisms are described in the next section) [137].

The relationship between thiazide and thiazide-like diuretics and hyponatremia is well documented [1, 138]. These drugs block Na⁺-Cl⁻ cotransporter in the distal convoluted tubule, leading to Na⁺ and Cl⁻ excretion without concomitant water diuresis since the distal convoluted tubule is impermeable to water [139]. Therefore, if treated patients ingest large quantities of water, dilutional hyponatremia may develop [139]. Moreover, the reduction of the extracellular fluid volume due to diuresis stimulates ADH release, increasing water reabsorption [139]. Importantly, thiazides increase water intake [140] and impair water excretion independent of ADH action [139, 140]. Loop and potassium-sparing diuretics (e.g., furosemide and spironolactone, respectively) have also been associated with the development of hyponatremia [141, 142]. Spironolactone inhibits sodium reabsorption at the renal collecting duct, causing salt wasting and hyponatremia [1]. Loop diuretics enhance hypotonic renal losses and thus may cause or worsen hyponatremia [32, 143].

Hyponatremia has been rarely reported in patients taking ACE inhibitors or angiotensin receptor blockers [39]. Hyponatremia may probably be attributed to SIAD caused by these agents [39, 144].

Sacubitril/valsartan is the first commercially available angiotensin receptor and neprilysin inhibitor approved for use in HF patients with reduced ejection fraction. Only 1 case of hyponatremia has been described after the initiation of sacubitril/valsartan [145]. Hyponatremia may be ascribed to neprilysin inhibition, which increases the levels of several endogenous vasoactive and natriuretic peptides [146].

Hyponatremia attributed to amiodarone is a rare but potentially lethal complication. It occurs during the loading period or the first weeks of treatment initiation. The underlying mechanism of amiodarone-induced hyponatremia is SIAD and has also been described in association with other antiarrhythmic drugs, such as lorcainide and propafenone [32].

Anticoagulant-related hemorrhage and concomitant reduction in effective circulating volume may be a potential cause of hyponatremia through activation of SNS, RAAS, and ADH secretion. Furthermore, in one study in hospitalized HF patients, the administration of heparins was significantly associated with hospital-acquired hyponatremia [147]. Both unfractionated and low molecular weight heparins decrease aldosterone levels by reducing the number and affinity of adrenal AT II receptors, thus attenuating aldosterone release from the adrenal cortex [148]. Moreover, anticoagulants may occasionally cause hyponatremia through intra-adrenal hemorrhage and adrenal failure [149].

HF is a clinical syndrome with progressively increasing public health importance associated with considerable morbidity, mortality, and immense healthcare costs [150]. Although mortality from HF has improved over the past few decades, 5-year mortality remains high, exceeding that of many cancers [150]. In patients with HF, hyponatremia is frequently encountered and represents an unfavorable prognostic factor [147, 151]. Of note, the poor prognosis in patients admitted with acute HF and hyponatremia is independent of left ventricular ejection fraction [152]. Furthermore, in a recent meta-analysis, the improvement of hyponatremia during hospitalization was associated with a lower, particularly short-term, mortality risk at follow-up [153].

Strategies aiming at the reduction of the incidence of hospital-acquired hyponatremia are of paramount importance. The administration of hypotonic fluids is common in clinical practice in hospitalized HF patients, especially in the elderly, for the avoidance of volume overload. In the hospital setting, however, patients frequently have multiple stimuli for ADH secretion (e.g., stress, pain, nausea) and thus are at an increased risk for the development of hyponatremia. Isotonic fluids (5% dextrose in a solution of 0.9% saline at a rate of 40–60 mL/h in adults and 40–60% of this amount calculated with the use of the Holliday-Segar formula in children) are considered the most suitable maintenance fluids in patients with compensated HF [154]. Moreover, the appropriate management of the associated clinical entities (Table 1) is crucial in order to prevent both the development and the deterioration of hyponatremia.

As hyponatremia is frequently multifactorial in patients with HF, it often poses a diagnostic and therapeutic challenge. A step-by-step diagnostic evaluation of hyponatremia in HF is shown in Figure 1. It should be emphasized that the first entity a clinician should exclude in case of hyponatremia is pseudo-hyponatremia. In such cases, sodium should be measured by using direct ion-selective electrodes, as measurement only by indirect ion-selective electrode may lead to spurious hyponatremia. A measured serum osmolality within normal limits (280–295 mOsm/kg) is also suggestive of pseudohyponatremia [7, 69].

The treatment of hyponatremia should be selected on the basis of its duration, symptoms, and extracellular volume status [143, 155]. Special attention should be made to correct serum sodium levels at the appropriate rate, especially in chronic hyponatremia, in order to avoid the osmotic demyelination syndrome (ODS) [155-157]. In chronic hyponatremia, even if it is symptomatic, the correction rate of serum sodium concentration should be restricted at <10 mmol/L/24 h [155, 156]. Some individuals, including the elderly, the alcoholics, the malnourished patients, and the patients with coexisting hypokalemia, have a higher risk of developing ODS. A tighter safety limit of correction of 8 mmol/L in 24 h and 14 mmol/L in 48 h should be considered for these patients [155, 157].

In cases of severe neurological symptoms attributed to hyponatremia, an elevation in serum sodium concentration by 4–6 mmol/L within the first 4–6 h is recommended [156]. The administration of 100–150 mL of hypertonic saline (3% NaCl) over 10–20 min up to 3 times, combined with furosemide to avoid circulatory overload, is plausible until the symptoms subside. However, care should be taken not to exceed the aforementioned targets [67, 156].

Treatment of the underlying conditions associated with hyponatremia (e.g., infections, hyperglycemia, adrenal insufficiency) is crucial in the case of hypovolemic hyponatremia, where normal saline is usually used to restore the intravascular volume. Potassium deficits should be corrected by adding potassium chloride in hypotonic fluids as its addition to normal saline results in a hypertonic solution; the latter increases the risk of overcorrection of sodium levels as well as of volume overload [158].

Fluid restriction remains the first-line therapy in non-hypovolemic hyponatremia. ACE inhibitors or angiotensin receptor blockers and loop diuretics may raise serum sodium concentration. Discontinuation of suspected drugs and treatment of other superimposed factors are warranted [155, 156]. If this therapeutic approach fails, a vasopressin antagonist (vaptan) may be used to promote water diuresis; these drugs are second-line therapy for hyponatremia related to hyper- or euvolemic HF [157]. Importantly, vaptans should not be used in hypovolemic HF or in combination with hypertonic saline solution owing to case reports of associated ODS [157]. Of note, in Japan, tolvaptan is approved for HF patients with inadequate response to conventional diuretics but without coexistent hyponatremia [159].

Hyponatremia in patients with HF may be the result of neurohormonal activation due to reduced cardiac output or is associated with several comorbidities or drugs. The rapidity of hyponatremia development, serum sodium concentration per se, the likelihood of pseudohyponatremia, the presence of symptoms, and the extracellular volume status of patients should be assessed carefully. These factors along with the treatment of coexisting conditions will guide therapeutic management accordingly.

This review was written independently; no company or institution supported it financially. George Liamis has given talks and attended conferences sponsored by various pharmaceutical companies, including Bayer, Sanofi, Amgen, Novartis, Vianex, Angelini, and MSD. Drs. Katerina K. Naka, Matilda Florentin, Eliza C. Christopoulou, Panagiotis Touloupis, and Ilias Gkartzonikas have no financial interest or financial ties to disclose.

The authors received no financial support for the research, authorship, and/or publication of this article.

The design and conception of the manuscript was made by Dr. George Liamis. The first draft of the manuscript was written by Dr. Eliza Christopoulou under the supervision of Dr. Matilda Florentin. Subsequently, Dr. Katerina Naka, Dr. Panagiotis Touloupis, and Dr. Ilias Gkartzonikas edited the manuscript and approved its final version.

The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.