Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through β3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure: A Randomized Invasive Clinical Trial. (27th June 2022)

• Record Type: Journal Article
• Authors: Bundgaard, Henning; Axelsson Raja, Anna; Iversen, Kasper; Valeur, Nana; Tønder, Niels; Schou, Morten; Christensen, Alex Hørby; Bruun, Niels Eske; Søholm, Helle; Ghanizada, Muzhda; Fry, Natasha A.S.; Hamilton, Elisha J.; Boesgaard, Søren; Møller, Mathias B.; Wolsk, Emil; Rossing, Kasper; Køber, Lars; Rasmussen, Helge H.; Vissing, Christoffer Rasmus
• Is Part Of: Circulation. Volume 15:Number 7(2022)
• Page Start: e009120
• Publication Date: 2022-06-27
• Subjects: adrenoreceptor, beta3 -- blood pressure -- cardiac output -- clinical trials, randomized -- heart rate -- systolic heart failure; Heart failure -- Periodicals; 616.129005
• DOI: 10.1161/CIRCHEARTFAILURE.121.009120
• Languages: English
• ISSNs: 1941-3289

Abstract

Abstract : Background: β3-AR (β3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the β3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. Methods: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III–IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week's treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure. Results: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07–0.75] L/min/BSA; P =0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (−1.6 [CI, −0.4 to −2.8] Wood units; P =0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. Conclusions: Oral treatment with the β3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: 2016-002367-34.