NATRIUM-HF is a multicenter, non-randomized, pre-post intervention study designed to assess renal response to intravascular fluid expansion and diuretics after sacubitril/valsartan (Entresto®) in euvolemic heart failure patients with reduced ejection fraction.~Ambulatory patients with HFrEF who remain symptomatic despite optimal treatment for more than 3 months with an ACEi or ARB, a beta-blocker and a mineralocorticoid receptor antagonist (MRA) for whom sacubitril/valsartan is indicated and is about to be initiated will be enrolled. Approximately 230 patients will attend three outpatient visits: before, and 2 months and 3 months after initiation of, or switch from treatment with angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) to, oral treatment with the angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril/valsartan (Entresto®). Patient's responses to fluid expansion and diuretic administration will be assessed at each study visit.~The same procedures will be followed at each visit. First, baseline vital signs, clinical assessments (dyspnea score, jugular vein distension, peripheral edema score, pulmonary rales), and blood samples will be obtained. Urine will be collected over a period of 3 hours and urine samples will be obtained from the collected urine at the end of the 3-hour collection period, and vital signs and clinical assessments will be obtained.~This will be followed by an infusion of 0.5 liter Ringer's (8.6 g/L sodium chloride, 0.33 g/L calcium chloride, 0.3 g/L potassium chloride) solution infused in 10 min followed by an infusion of 0.5 liter over 1 hour 50 minutes. Of note 1liter Ringer's contains 8.6 g or 374 mmol of sodium. 1 hour after the end of the infusion, clinical assessments (dyspnea score, jugular vein distension, peripheral edema score, pulmonary rales) and blood samples will be obtained. Urine will be collected over a period of 3 hours and urine samples will be obtained from the collected urine at the end of the 3-hour collection period.~After the second set of blood and urine samples are obtained, 40 mg of furosemide will be given IV and blood samples will be obtained thereafter hourly for 3 hours. Urine will be collected over a period of 3 hours and urine samples will be obtained from the collected urine at the end of the 3-hour collection period, and vital signs and clinical assessments will be obtained.~Biomarkers measured in blood and urine samples will include natriuretic peptides (NP) B-type NP (BNP) and N-terminal proBNP (NT-proBNP), NP fragments, neprilysin activity and concentration, and other biomarkers related to heart failure.~The aim of NATRIUM-HF is to assess the change in natriuretic response to intravascular fluid expansion and diuretics in euvolemic patients with heart failure and reduced ejection fraction (HFrEF) after initiation of, or switch from ACEi/ARB to, sacubitril/valsartan (Entresto®) therapy.
NATRIUM-HF is a multicenter, non-randomized, pre-post intervention study designed to assess renal response to intravascular fluid expansion and diuretics after sacubitril/valsartan (Entresto®) in euvolemic heart failure patients with reduced ejection fraction. Approximately 230 eligible patients will attend one visit prior to and visits 2 and 3 months after starting Entresto®. At each visit, the patient's responses to extravascular fluid expansion with Ringer's solution and to a loop diuretic bolus will be measured. Biomarkers measured in blood and urine samples will include natriuretic peptides (NP) B-type NP (BNP) and N-terminal proBNP (NT-proBNP), NP fragments, neprilysin activity and concentration, and other biomarkers related to heart failure.