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.

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.

Inclusion criteria:

1. Male or female patients ≥ 18 and < 80 years of age.
2. Ambulatory patients with a diagnosis of stable NYHA class II heart failure with left ventricular ejection fraction <40 %, for whom sacubitril/valsartan (Entresto®) is indicated as recommended by ESC guidelines and are about to be switched to Entresto® therapy.
3. Stable oral doses of ACEi or ARB, beta-blocker, mineralocorticoid antagonist (MRA), and loop diuretic (up to 120 mg daily furosemide or equivalent*) for > 3 months prior to Screening, except where intolerance or contraindication documented.
4. Stable HF without any recent exacerbation of symptoms and/or signs of HF, admission for HF, unplanned clinic visit or emergency service visit for HF or need for significant up titration or new administration of oral or IV diuretics, renin-angiotensin system (RAAS) blockers (including ACEi, ARB, and/or MRA) and/or beta blockers for > 3 months.
5. Euvolemia as defined by no signs of congestion (pulmonary rales or >1+ peripheral edema) by physical examination.
6. Written informed consent to participate in the study.
7. Ability to comply with all study requirements, without major morbidities compromising the patient's ability to participate and understand the study for 90 days.

Exclusion criteria:

1. Significant pulmonary disease contributing substantially to the patients' dyspnea such as FEV1< 1 liter or need for chronic steroid therapy.

2. Myocardial infarction, unstable angina, ICD or CRT implantation, or cardiac surgery, including percutaneous transluminal coronary intervention, within past 3 months.

3. History of heart transplant or on a transplant list, or using or planned to be implanted with a ventricular assist device.

4. Sustained ventricular arrhythmia with syncopal episodes within past 3 months that is untreated.

5. Presence of any hemodynamically significant valvular stenosis or regurgitation, except mitral or tricuspid regurgitation secondary to left ventricular dilatation. Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract.

6. Stroke or TIA within the past 3 months

7. Primary liver disease considered to be life threatening.

8. Any episode of symptomatic hypotension within 3 months prior to screening.

9. Known history of angioedema with ACEi or ARB use, or history of hereditary or idiopathic angioedema.

10. Coagulation or bleeding disorder.

11. Systolic blood pressure < 100 mmHg.

12. Serum sodium > 146 mEq/L (146 mmol/L).

13. Serum potassium > 5.2 mEq/L (5.2 mmol/L) or < 3.5 mEq/L (3.5 mmol/L).

14. Renal disease or eGFR < 30 ml/min/1.73m2 (as measured by the simplified MDRD formula).

15. Ultrafiltration or dialysis within 3 months prior to Screening.

16. Hypersensitivity to sacubitril, valsartan, or any of the excipients in Entresto®; or hypersensitivity to furosemide.

17. History or presence of any other diseases (i.e. including malignancies) with a life expectancy of < 3 months.

18. Participation in any CHF trial or any investigational drug or device study within the 30 days prior to Screening.

19. History of noncompliance to medical regimens and patients who are considered potentially unreliable.

20. Pregnant or nursing (lactating) women.

21. Active infection based on abnormal temperature and elevated WBC count.

22. Receipt of blood transfusion within 3 months prior to Screening.

23. Current use of any drug containing a direct renin inhibitor (aliskiren) or neprilysin inhibitor (sacubitril).

    • Equivalent oral loop diuretic doses will be considered as 1 mg bumetanide=20 mg torsemide=80 mg furosemide