Short-term effects on sacubitril/valsartan therapy on right ventricle work and mechanics in patients with heart failure and reduced ejection fraction

Abstract Introduction In previous studies, sacubitril/valsartan (ARNI) therapy has been shown to have a positive effect on right ventricle (RV) function and on systolic pulmonary artery pressure in addition to improvement of left ventricle (LV) function in patients with heart failure and reduced ejection fraction (HFrEF). Recently, it was shown that a short-term ARNI therapy compared to valsartan-only therapy led to reduced systemic blood pressure and LV mechanical work, contributing to reduced LV myocardial perfusion and oxygen consumption. Purpose This paper aimed to study the effect of short-term ARNI therapy on RV mechanics and work and pulmonary and LV filling pressures compared to valsartan-only therapy in patients with HFrEF. Methods The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with NYHA class II–III heart failure and LV ejection fraction (LVEF) <= 35 %. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, and cardiac and systemic hemodynamics were quantified using echocardiography and 11C-acetate PET before and after 6 weeks of therapy (on stable dose) in 55 patients. The analyses were done with ANCOVA adjusting for pre-randomization values. Results The RV myocardial resting perfusion (mean difference of 0.056 (95% CI, 0.02 to 0.109) ml/g/min, p = 0.041) and RV myocardial oxygen consumption (0.005 (0.001 to 0.010) 1/min, p = 0.015) were significantly lower in the ARNI group compared with the valsartan-only group. The left atrial end-diastolic volume indexed to body surface area (geometric mean difference of 1.071 (95% CI, 0 to 1.148) ml/m2, p = 0.048) and the ratio of early mitral inflow velocity to medial mitral annular early diastolic velocity (mean difference of 2.467 (95% CI, 0.096 to 4.838), p = 0.042) were also significantly lower in the ARNI group compared with the control group. There was no difference between the groups in peak systolic right ventricle to right atrial pressure gradient. Still, the tricuspid annular plane systolic excursion was significantly higher in the valsartan-only group compared with the ARNI group (0.221 (0.039 to 0.404) cm, p = 0.018). There was no difference in RV free wall strain, fractional area change or systolic excursion velocity between the treatment arms (p> 0.262). Conclusions In addition to our earlier findings, sacubitril when added to valsartan appears to reduce also right ventricle myocardial perfusion and oxygen consumption. There was also a reduction in left atrial end-diastolic volume and in early mitral inflow to medial mitral annular early diastolic velocity in the sacubitril/valsartan group as compared to the valsartan-only group, which suggest decreased LV filling pressure.