TY - JOUR
T1 - Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through β3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure
T2 - A Randomized Invasive Clinical Trial
AU - Bundgaard, Henning
AU - Axelsson Raja, Anna
AU - Iversen, Kasper
AU - Valeur, Nana
AU - Tønder, Niels
AU - Schou, Morten
AU - Christensen, Alex Hørby
AU - Bruun, Niels Eske
AU - Søholm, Helle
AU - Ghanizada, Muzhda
AU - Fry, Natasha A S
AU - Hamilton, Elisha J
AU - Boesgaard, Søren
AU - Møller, Mathias B
AU - Wolsk, Emil
AU - Rossing, Kasper
AU - Køber, Lars
AU - Rasmussen, Helge H
AU - Vissing, Christoffer Rasmus
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - adrenoreceptor, beta3
KW - blood pressure
KW - cardiac output
KW - clinical trials, randomized
KW - heart rate
KW - systolic heart failure
UR - http://www.scopus.com/inward/record.url?scp=85134500946&partnerID=8YFLogxK
U2 - 10.1161/CIRCHEARTFAILURE.121.009120
DO - 10.1161/CIRCHEARTFAILURE.121.009120
M3 - Journal article
C2 - 35758031
VL - 15
SP - e009120
JO - Circulation. Heart failure
JF - Circulation. Heart failure
SN - 1941-3289
IS - 7
ER -