Clinical and functional effects of beta-blocker therapy discontinuation in patients with biventricular heart failure
Authors: Slavich Massimo , Ricchetti Gianluca , Demarchi Barbara , Cavalli Giulio , Spoladore Roberto , Federico Anna , Federico Francesco , Bezzi Carolina , Margonato Alberto , Fragasso Gabriele 
Published: December 2023

Background
Nearly two-thirds of patients with heart failure with reduced ejection fraction (HFrEF) have right ventricular dysfunction, previously identified as an independent predictor of reduced functional capacity and poor prognosis. Beta-blocker therapy (β-BT) reduces mortality and hospitalizations in patients with HFrEF and is approved as first-line therapy regardless of concomitant right ventricular function. However, the exact role of sympathetic nervous system activation in right ventricular dysfunction and the potential usefulness (or harmfulness) of β-BT in these patients are still unclear.

Objectives
The aim of the study is to evaluate the medium-term effect of β-BT discontinuation on functional capacity and right ventricular remodelling based on cardiopulmonary exercise testing (CPET), echocardiography and serum biomarkers in patients with clinically stable biventricular dysfunction.

Methods
In this single-centre, open-label, prospective trial, 16 patients were enrolled using the following criteria: patients were clinically stable without signs of peripheral congestion; NYHA II-III while on optimal medical therapy (including β-BT); LVEF 40% or less; echocardiographic criteria of right ventricular dysfunction. Patients were randomized 1 : 1 either to withdraw (group 0) or continue (group 1) β-BT. In group 0, optimal heart rate was obtained with alternative rate-control drugs. Echo and serum biomarkers were performed at baseline, after 3 and 6 months; CPET was performed at baseline and 6 months. Mann--Whitney U test was adopted to determine the relationships between β-BT discontinuation and effects on right ventricular dysfunction.

Results
At 6 months’ follow up, S’ DTI improved (ΔS’: 1.01 vs. −0.92 cm/s; P = 0.03), while estimated PAPs (ΔPAPs: 0.8 vs. −7.5 mmHg; P = 0.04) and echo left ventricular-remodelling (ΔEDVi: 19.55 vs. −0.96 ml/mq; P = 0.03) worsened in group 0. In absolute terms, the only variables significantly affected by β-BT withdrawal were left ventricular EDV and ESV, appearing worse in group 0 (mean EDVi 115 vs. 84 ml/mq; mean ESVi 79 vs. 53.9 ml/mq, P = 0.03). No significant changes in terms of functional capacity were observed after β-BT withdrawal.

Conclusion
In HFrEF patients with concomitant right ventricular dysfunction, β-BT discontinuation did not produce any beneficial effects. In addition, despite maintenance of optimal heart rate control, β-BT discontinuation induced worsening of left ventricular remodelling. Our study corroborates the hypothesis that improvement in left ventricular function may likewise be a major determinant for improvement in right ventricular function, reducing pulmonary wedge pressure and right ventricular afterload, with only a marginal action of its negative inotropic effect. In conclusion, β-BT appears beneficial also in heart failure patients with biventricular dysfunction.