Effects of Repletion of Sodium Chloride on Natriuresis, Blood Pressure, and Neurohormonal Activity in Patients With Chronic Heart Failure With Reduced Ejection Fraction

Heart failure (HF) is a complex clinical syndrome characterized by symptoms and signs resulting from structural and/or functional cardiac abnormalities that lead to elevated intracardiac pressure and/or reduced cardiac output at rest or during exertion. The pathophysiology of HF is strongly associated with neurohormonal activation, including increased activity of the renin-angiotensin-aldosterone system, vasopressin, endothelin, and natriuretic peptides. Pharmacological therapies targeting these pathways, collectively referred to as guideline-directed medical therapy (GDMT) in HF with reduced ejection fraction (HFrEF), significantly reduce mortality and unplanned hospitalizations when administered at recommended doses.

Despite advances in treatment, HF remains a progressive disease characterized by recurrent episodes of decompensation and poor long-term outcomes. Epidemiological data indicate that HF affects approximately 1-2% of the general population and is associated with high annual mortality and frequent hospital admissions. Neurohormonal disturbances contribute to sodium and water retention, leading to fluid accumulation and the need for diuretic therapy to restore euvolemia. Although diuretics effectively relieve congestion-related symptoms, they do not improve long-term outcomes and may contribute to electrolyte disturbances, particularly hyponatremia, which is itself associated with worse outcomes in advanced HF.

For many years, strict dietary sodium restriction was considered a cornerstone of HF management because excessive sodium intake was believed to promote fluid retention due to impaired renal autoregulation. However, recent evidence has challenged this paradigm. Studies conducted in the era of modern neurohormonal blockade have demonstrated that sodium restriction does not improve clinical outcomes in HF patients. The SODIUM-HF trial showed no clinical benefit from dietary sodium restriction, while other studies, including those by Dauw et al., demonstrated that oral sodium chloride supplementation of 3 g/day is safe in HF patients, does not increase fluid overload, and may improve natriuresis while reducing plasma renin activity.

At the same time, a major limitation of contemporary HF treatment remains the inability to achieve optimal GDMT dosing in many patients. Hypotension frequently prevents dose escalation or initiation of additional prognostically beneficial therapies, resulting in only approximately 40% of patients receiving all recommended medications at target doses. Therefore, strategies aimed at improving blood pressure stability and sodium balance may facilitate better optimization of HF therapy.

Based on these observations, the present study was designed to evaluate whether oral sodium chloride supplementation in patients with chronic HFrEF and low serum sodium levels may safely improve sodium handling, neurohormonal balance, blood pressure, and tolerance of GDMT. Additionally, the study aims to assess whether sodium supplementation may facilitate optimization of GDMT dosing in patients prone to hypotension.

This investigation is a single-center, prospective, randomized, placebo-controlled, double-blind trial conducted at the Institute of Heart Diseases and the Department of Cardiology of Wroclaw Medical University Hospital. Thirty patients with HFrEF, low serum sodium concentration, and suboptimal GDMT dosing will be enrolled. Participants will be randomly assigned 1:1 to one of two groups: an intervention group receiving oral sodium chloride supplementation (1 g NaCl capsules administered three times daily, totaling 3 g/day) or a placebo group receiving matching lactose capsules.

Eligibility will be confirmed through a detailed preselection process, including recent serum sodium measurements and baseline laboratory evaluation. After enrollment and informed consent, all participants will continue their current HF medications and habitual diet, without medication dose modifications during the first 14 days of supplementation. Throughout the study, patients will perform daily home measurements of blood pressure, heart rate, and body weight.

Scheduled follow-up visits will include clinical assessment of HF symptoms, anthropometric measurements, and laboratory analyses of serum and urinary electrolytes, renal function parameters, NT-proBNP, renin, and aldosterone concentrations. Safety monitoring will focus on body weight changes, exercise tolerance, blood pressure, and adherence to supplementation. Supplementation will be temporarily discontinued in cases of ≥2 kg body weight increase or worsening dyspnea/exercise tolerance. Compliance will be assessed using pill counts and patient diaries, and participants missing more than 10% of planned doses will be excluded from further analysis.

An additional objective of the study is to evaluate the feasibility of GDMT dose escalation during follow-up. Eligibility for treatment optimization will be determined using predefined blood pressure criteria, including systolic blood pressure >110 mmHg and/or diastolic blood pressure >60 mmHg, while maintaining patient safety and clinical stability.

The primary goals of the study are to assess the effects of oral sodium chloride supplementation on sodium retention, natriuresis, neurohormonal activity, blood pressure, and treatment safety in patients with HFrEF and low serum sodium levels. Secondary objectives include evaluation of the potential for GDMT optimization and comparison of outcomes between intervention and placebo groups, including subgroup analyses according to gender.

Inclusion criteria

• Chronic heart failure NYHA I-III.
• LVEF ≤40% documented in the echocardiography.
• Stable Heart Failure symptoms:

• Stable symptoms (subjectively declared by the patient) over the past three months.
• No increase in peripheral edema or body weight (declared by the patient).
• Loop diuretic dose equivalent to 80 mg of furosemide or 20 mg of torasemide daily, with no changes in the past three months.
• Age over 18 and under 85 years.
• Male or female.
• Use of guideline-directed medical therapy (GDMT), with each drug group at maximum tolerated doses but no more than half of the maximum dose.
• Systolic blood pressure <100 mmHg and/or diastolic blood pressure <60 mmHg.
• Resting heart rate up to 80 bpm.
• Serum sodium concentration <140 mmol/L, regardless of the cause.

Exclusion criteria

• Hospitalization due to heart failure decompensation within the last three months.
• Primary hypertrophic or restrictive cardiomyopathy, constrictive pericarditis.
• Systemic disease known to be associated with cardiac muscle infiltration.
• Significant valvular disease (moderate or severe stenosis of any valve, moderate or severe aortic or pulmonary regurgitation, severe tricuspid or mitral regurgitation).
• Severe renal impairment (eGFR <30 mL/min/1.73 m² based on the MDRD formula).
• Stroke or transient ischemic attack (TIA) within the last three months.
• Cardiac resynchronization therapy (CRT), ICD, ablation, or pacemaker implantation (or planned implantation) within the last three months.
• Severe lung disease or "cor pulmonale" or other causes of isolated right ventricular failure not associated with left ventricular dysfunction.
• Severe lung disease with respiratory failure requiring home oxygen therapy.
• Body weight <40 kg or ≥150 kg.
• Life expectancy <12 months according to the investigator's assessment
• Pregnancy or breastfeeding.
• Ongoing drug or alcohol abuse.
• Lactose intolerance.