Heart failure (HF) is a clinical syndrome that occurs as a result of various structural and functional disorders that lead to the impairment of cardiac capability of delivering oxygenated blood and satisfying the metabolic needs of the tissue despite normal filling pressure or only at significantly elevated filling pressure. Given the significant progress that has been made over the past decade in the treatment of acute cardiac conditions, primarily acute myocardial infarction, and partly because of the general extension of life expectancy, the prevalence of HF is increasing in developed countries, and as a complex and progressive neuroendocrine clinical syndrome it represents ever greater social and financial burden by affecting the quality of life and the high demands of the treatment. Today 1% to 2% of the adult population has a HF, and its prevalence ≥10% in people older than 70 years (1). The Croatian multicentric study Polic et al. which included 226 patients with HF reports a median age in these patients of 67 years, presence of males with 59%, ischemic etiology in 30% and a chronic course of the disease in 68% of all hospitalizations for HF (2). The same group of authors published a five-year analysis of the Croatian Registry of Heart Failure in 2011, which on a sample of 1868 patients hospitalized for HF reported a frequency of men of 54.7% and a median age of 71±11.9, while the women were 77±9.9 years old, whereas mortality during the analyzed hospitalization was 13.6%. The above study pointed to the comparability of the Croatian with the European data (1, 3).

The scientific fields that deal with specific aspects of HF and their related areas are very dynamic. Routine clinical practice, despite continuous progress highlights some of the very important areas which are paid sufficient attention and within which we expect only large, randomized, double-blind prospective studies4. One of them is hyponatremia in patients with HF being a daily dilemma of clinicians.

Hyponatremia is defined as the serum sodium concentration lower than 136 mmol/L. It is the most common electrolyte disorder in non-hospitalized and hospitalized patients with HF and according to current insights it is an extremely important clinical problem with a clear impact on the clinical course and prognosis of the diseases. The prevalence of hyponatremia itself in HF is around 35%, although the data in the literature significantly varies and primarily depends on the values that specific trials have determined in the screening5. Notwithstanding the need for further definitions of the foregoing, there is no doubt about a high prevalence of low sodium values and a strong negative prognostic value in these patients (4). People with manifest HF and hyponatremia have a significantly elevated risk of early adverse outcome. Although hyponatremia and associated decreased plasma osmolality are associated with the propensity of causing brain edema and neurologic disorders, this does not seem to be the leading risk in patients with HF. Depending on the weight and speed of occurrence, hyponatremia is in this population associated with mortality within one month from 5% to 50%. It is worth emphasizing that the neurological manifestations may be further aggravated iatrogenically i.e. by overly rapid sodium correction, and this is especially pronounced in elderly women and in persons with concomitant hypokalemia (5).

A recently published meta-analysis Rusinaru et al. included 22 studies and on a total sample of around 15,000 patients it pointed out a negative linear correlation between the sodium values lower than 140 mmol/L and mortality within 3 years (6). Hyponatremia is also clearly associated with a longer length of hospitalization, increased risk of rehospitalization and other significant complications and higher total costs of the treatment (7, 8).

Low stroke volume, which is often present in HF, is associated with reduced arterial baroreceptor stimulation, which directly stimulates the sympathetic stimulation and activation of the renin-angiotensin-aldosterone (RAAS) and arginine- vasopressin (AVP) system. In the cascade it leads to a reduction in renal flow, accompanied increased sodium and water reabsorption, and the development of a sense of thirst with increased drinking, while the described mechanism lead to a decrease in serum sodium concentration and the development of clinically significant hyponatremia by cumulative effects. Accordingly, the patients with HF and hyponatremia have higher plasma concentrations of renin, angiotensin II, aldosterone, norepinephrine, epinephrine and dopamine than patients with HF and appropriate sodium levels (9). These mechanisms should also be added by the stimulation that can be given by medications in reducing sodium levels, primarily by thiazide diuretics that exert effect on the distal tubules. Although in most cases they stimulate a slight additional reduction of sodium levels, in some cases it can be significant. If amiloride is combined with thiazide diuretics, the risk of hyponatremia additionally increases due to its impact on the collecting tubules — retinening of K and increased excretion of Na (10).

Restriction of daily fluid intake to 800-1100 ml is one of the simplest and cheapest methods of the treatment; however which is specified by a low level of compliance. Although the reduction in drinking is associated with a significant reduction of the current and reduced incidence of new symptoms, its impact on the long-term outcome has been very poorly investigated (4).

Significant acute hyponatremia is regularly associated with neurological symptoms (changes in motor skills, quantitative and qualitative disturbance of consciousness) and it requires an immediate parenteral correction. In these cases, a precise dosing of hypertonic saline is very important to increase serum sodium levels to the 1-2 mEq/L per hour until the symptomatic improvement is achieved, noting that the total daily change in serum sodium level should not exceed 8m Eq/L⁴.

In patients with chronic hyponatremia without significant neurological deficits, this daily limit is the only certain determinant for appropriate and maximally effective correction of the electrolyte status. When implementing these therapeutic measures, we should also bear in mind that the iatrogenic effects need not occur promptly, but their occurrence is described in the time interval of up to 72 hours from the therapeutic intervention. Central pontine myelinolysis is the name of the syndrome which with polymorphic neurological symptomatology represents a pathological response to therapeutic sodium serum correction (11).

Since they have maximal efficiency in the clean water clearance, loop diuretics represent a realistic therapeutic option in patients with whom hyperhydration is a part of HF as the developed neuroendocrine disorder. The application of hypertonic saline with concomitant administration of high doses of loop diuretics produces a significant increase in serum sodium levels and potential improvement in the longterm outcome, while the combination of the angiotensin converting enzyme (ACE) inhibitors and furosemide proved to be very efficient for the above mentioned. In the long-term correction of hyponatremia as a part of the HF, it is interesting that the addition of ACE in patients with HF in the previous furosemide therapy in long-term follow-up showed a reduction of symptoms, improvement of outcomes, but also significantly lower prevalence of hyponatremia (12, 13).

Considering the importance of the activation of AVP (arginine- vasopressin, vasopressin, argipressin or antidiuretic hormone) in HF, special group of drugs, AVP receptor antagonists has been developed today, among which tolvaptan, lixivaptan and conivaptan are to be emphasized. Although differing in affinity for certain subtypes of AVP receptors (V1A, V1B, V2), the thing that all of them have in common is a positive impact on hyponatremia, whereas their effect on the amount of excreted urine and body weight change during the treatment of decompensated heart failure is significant. The results of the impact on the pathophysiological bases of HF as a complex disorder, their ability to have effect on myocardial remodeling and the long-term impact on the clinical course and outcome can now be observed in series of small clinical studies. Additional trials are required to finally define these issues and to take an attitude towards the position of this group of drugs in the overall treatment of HF (14-16).

Particular attention is to be paid to the patients with hypovolemic hyponatremia in the correction of hyponatremia as a part of the HF syndrome (4, 17). AVP receptor antagonists should not be used in these patients, whereas the restriction of fluid intake should not be done when using these drugs and such drugs should not be used in acute and chronic renal failure (3).

Hyponatremia is the electrolyte disorder with a high prevalence in patients suffering from HF which is recognized as a marker of a higher risk for the development of comorbidities and is a convincing predictor of the adverse outcome. Although the long-term effects of an appropriate correction of reduced serum sodium levels have not been convincingly documented, the current insights, nevertheless, impose precise therapeutic requirements in sodium serum disorders in patients with heart failure. Hyponatremia in the routine work should not be overlooked in the first place, but the patients in whom it occurs should be identified as individuals at increased risk, followed by a careful correction by using available therapeutic measures that are to be individually tailored to each individual patient accompanied by doing regular controls of laboratory findings and ongoing clinical monitoring even after the serum sodium level is corrected.