First-in-man trial of b3-adrenoreceptor agonist treatment in chronic heart failure – impact on diastolic function

Abstract Background Diastolic dysfunction (DD) in heart failure (HF) is associated with increased myocardial cytosolic calcium, and calcium-efflux via the sodium-calcium-exchanger depends on sodium gradient. Beta-3-adrenoceptor (β3-AR)-agonist lowers has been shown to reverse organ congestion. Purpose To assess whether β3-AR-agonist treatment improves DD. Methods In a first-in-man randomized controlled, double-blind trial, we assigned 70 patients HF reduced ejection fraction (HFrEF) (NYHA II–III) LVEF <40% receive mirabegron (300 mg/day) or placebo for 6 months, addition recommended HF-therapy. Patients were assessed echocardiography cardiac computed tomography (CCT) at baseline follow-up. DD was graded according current American/European guidelines. Results Baseline follow-up echocardiographic data available 57 (59±11 years, 88% male, 49% ischemic disease). 34%±8%. No significant change grade found between groups follow-up, p=0.72. Neither there any clinical differences singular diastolic parameters within by (E/e' placebo: 13.3±6.9 12.6±5.1, p=0.19 vs. mirabegron: 12.0±5.7 12.8±7.9, p=0.67, mean difference 1.12 [95% CI −1.68 4.3], p=0.37), CCT (left atrial max volume index: group 0.2 −6.2 5.6] ml/m2, p=0.91). Conclusions HFrEF, no improvement nor worsening gradings after β3-AR stimulation compared identified. The findings add previous literature questioning role of impaired Na+-Ca2+ mediated Ca2+ export as major culprit Funding Acknowledgement Type funding sources: Foundation. Main source(s): Heart Centre Research Foundation, RigshospitaletThe Novo Nordic Foundation