Background: Sacubitril/Valsartan (S/V) reduces heart failure (HF) hospitalisations and cardiovascular death in patients with HF and reduced left ventricular ejection fraction (HFrEF). The detailed mechanistic understanding of the effects of S/V on myocardial function is incomplete. This study aimed to analyse the changes in left ventricular (LV) end-systolic elastance (Ees), effective arterial elastance (Ea), and the ventricular-arterial coupling ratio (Ea/Ees) after initiation treatment with S/V.

Material and Methods: From April 2020 to November 2021, 117 consecutive patients with symptomatic HF and left ventricular ejection fraction (LVEF) <40% in whom treatment with S/V was initiated were prospectively enrolled across two centers in Germany. Transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements were used for non-invasive pressure-volume loop analyses. The primary endpoints were changes in Ees, Ea and, Ea/Ees ratio after six months of S/V treatment. The study is registered with ClinicalTrials.gov, NCT04498780.

Results: Median [IQR] age was 65 [57;74] years and 30% were female. The etiology of HFrEF was ischemic heart disease in 54.7%, non-ischemic cardiomyopathy in 41.0% and myocarditis in 4.3% of the patients. 102 of the 117 patients completed the 6-months follow-up. 61.8% were on the target dose of S/V. At 6 months, there was a significant increase of Ees (0.66 [0.45;0.95] vs. 0.78 [0.56;1.10], p=0.001) and decrease of Ea (1.76 [1.47;2.13] vs. 1.62 [1.36;1.96], p=0.014). Hence, the Ea/Ees ratio significantly improved (2.53 [1.86;4.07] vs. 1.93 [1.49;2.64], p<0.001). From baseline to 6 months, there was a regression of the LV end-systolic (LVESV: 142 ml [115;180] vs. 96 ml [65;124]) and end-diastolic volumes (LVEDV: 216 ml [179;247] vs. 165 ml [132;200]), LV end-diastolic pressure (LVEDP: 19.6 mmHg [18.2;22.4] vs. 17.8 mmHg [16.6;19.9]) and an improvement of LVEF (33% [27;37] vs. 43% [36;49]), p<0.001 respectively. The percentage of patients with NYHA class III changed from 25.6% to 5.9%, median NT-proBNP level decreased from 1770 pg/ml [805;5374] to 724 pg/ml [298;1600] and mean (±SD) 6-minute walking distance increased from 371 m (±132) m to 423 m (±122), p<0.001 respectively.

Conclusion: Initiation of Sacubitril/Valsartan in patients with heart failure and reduced left ventricular ejection fraction was associated with an increase in LV contractility, afterload reduction and reverse cardiac remodelling. These hemodynamic changes were associated with symptomatic and biomarker improvements.