First-In-Man Trial of β3-Adrenoceptor Agonist Treatment in Chronic Heart Failure: Impact on Diastolic Function

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Diastolic dysfunction (DD) in heart failure is associated with increased myocardial cytosolic calcium and calcium-efflux through the sodium–calcium exchanger depends on the sodium gradient. Beta-3-adrenoceptor (β3-AR) agonists lower cytosolic sodium and have reversed organ congestion. Accordingly, β3-AR agonists might improve diastolic function, which we aimed to assess. In a first-in-man, randomized, double-blinded trial, we assigned 70 patients with HF with reduced ejection fraction, New York Heart Association II-III, and left ventricular ejection fraction <40% to receive the β3-AR agonist mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended heart failure therapy. We performed echocardiography and cardiac computed tomography and measured N-terminal probrain natriuretic peptide at baseline and follow-up. DD was graded per multiple renowned algorithms. Baseline and follow-up data were available in 57 patients (59 ± 11 years, 88% male, 49% ischemic heart disease). No clinically significant changes in diastolic measurements were found within or between the groups by echocardiography (E/e′ placebo: 13 ± 7 to 13 ± 5, P = 0.21 vs. mirabegron: 12 ± 6 to 13 ± 8, P = 0.74, between-group follow-up difference 0.2 [95% CI, −3 to 4], P = 0.89) or cardiac computed tomography (left atrial volume index: between-group follow-up difference 9 mL/m2 [95% CI, −3 to 19], P = 0.15). DD gradings did not change within or between the groups following 2 algorithms (P = 0.72, P = 0.75). N-terminal probrain natriuretic peptide remained unchanged in both the groups (P = 0.74, P = 0.64). In patients with HF with reduced ejection fraction, no changes were identified in diastolic measurements, gradings or biomarker after β3-AR stimulation compared with placebo. The findings add to the previous literature questioning the role of impaired Na+-Ca2+–mediated calcium export as a major culprit in DD.
TidsskriftJournal of Cardiovascular Pharmacology
Udgave nummer5
Sider (fra-til)466-473
Antal sider8
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
Supported by The Heart Centre Research Foundation, Rigshospitalet; The A.P. M\u00F8ller and Chastine Mc-Kinney M\u00F8ller Foundation; and The Novo Nordic Foundation. The sponsors did not influence the study's design or the collection, analysis or interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication.

Publisher Copyright:
© 2024 Lippincott Williams and Wilkins. All rights reserved.

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