Background: Sacubitril/valsartan, a novel therapy in the treatment of heart failure with reduced ejection fraction (HFrEF), has recently proved efficacy in improving exercise tolerance and cardiac performance. Cardiopulmonary exercise test (CPET) provides functional prognostic parameters for patient with HFrEF (i.e. peakVO2 and ventilation/CO2 production [VE/VCO2] slope) and it is a well-recognized, valuable, accurate tool for risk stratification.

Aim of the study and methods: The aim of the study is to prospectively enroll a cohort of 100 HFrEF outpatients eligible for sacubitril/valsartan and perform serial CPET, laboratory and echocardiographic assessments before and during the gradual titration of the treatment, in order to evaluate its effects on cardiopulmonary function and left ventricular remodeling. The procedures will be repeated along the follow-up at 1, 2 and 3 months after the enrollment (titration period) and at 6 months after the reach of the maximum tolerated dose.

Given the recent introduction of the drug into the clinical routine, the evaluation of the experience "on the field" is important to refine the clinical management of patients treated with sacubitril / valsartan. Furthermore, at the moment sacubitril / valsartan has proven effective in some small preliminary studies in improving the ejection fraction and some echocardiographic parameters of ventricular remodeling on top of the concomitant optimal medical therapy, although further data are needed in this regard.

In particular, the potential benefits on exercise capacity, respiratory function parameters and left ventricular remodeling in heart failure patients treated with sacubitril / valsartan has not been studied extensively at the moment. In this regard, the cardiopulmonary exercise test (CPET) allows to obtain prognostic functional parameters in patients with chronic heart failure such as peak V02 (peak V02) and the ventilation / production of C02 slope (VE / VC02 slope). CPET is a valid, recognized and accurate tool for risk stratification in heart failure patients.

Furthermore, few data are available on lung diffusion (DLCO) and on specific markers of the alveolar-capillary membrane, such as type B surfactant proteins (SPB) in patients treated with sacubtril / valsartan. Our team has already shown how these biomarkers and DLCO are influenced by drug treatments such as Levosimendan and Ace inhibitors.

The aim of the study is to evaluate the exercise capacity, spirometry, echocardiographic parameters of left ventricular sistolic and diastolic function, Nt-proBNP dosage and quality of life and the related dose-effect correlation in a multicenter cohort of 100 patients with stable heart failure (class functional NYHA II e lII) and reduced left ventricular ejection fraction in patients eligible for sacubitril / valsartan treatment.

A subgroup of patients will be also analyzed for data relating to the effect of sacubitril / valsartan on DLCO and blood levels of Surfactant Bindig protein (SPB).

Sacubitril / Valsartan will be prescribed according to guidelines, initially at the lowest dosage of 24/26 mg b.i.d. to verify its tolerability with the prospect of gradually increasing the dosage during subsequent follow-up visits. The re-evaluation of the treatment and the titration of the sacubitril / valsartan dose will take place every 4 weeks until the maximum tolerated dose is reached. The dose under study will be the maximum tolerated by the patient (however not higher than 97 mg / 103mg bd).

Cardiological examination with ECG, spirometry, CPET, the Kansas City Cardiomyopathy Questionnaire, blood count, creatinine, nitrogen, sodium, potassium, chlorine and NTproBNP will be performed at each visit (from Baseline to 6 months). The colordoppler echocardiogram will instead be performed only at the baseline and after 6 months.

A subset of patients will also be subjected to analysis of the blood levels of SPB and DLCO at baseline and 6 months after reaching the maximum tolerated dose.

Inclusion Criteria:

• New York Heart Association Class (NYHA) II-III
• stable clinical conditions
• reduced ejection fraction (< 35%)
• capability to perform a cardiopulmonary exercise test (CPET)

Exclusion Criteria:

• moderate-severe chronic obstructive pulmonary disease
• chronic oxygen therapy
• contraindication to CPET
• planned procedures (i.e. cardiac surgery, revascularization procedures, CRT implantation) that could per se impact on CPET, echocardiography and laboratory values

HFrEF outpatients eligible for sacubitril/valsartan according to guidelines and perform serial CPET, laboratory and echocardiographic assessments before and during the gradual titration of the treatment