Intravenous infusion of the beta-3 adrenergic receptor antagonist APD418 improves left ventricular function in dogs with systolic heart failure despite long-term therapy with beta-blockers

Document Type

Conference Proceeding

Publication Date

7-2022

Publication Title

Eur J Heart Fail

Abstract

Background: Unlike β1 and β2-adrenergic receptors (ARs), β3-AR stimulation inhibits cardiac contractility and relaxation through coupling to inhibitory G proteins and activation of nitric oxide-cGMP signaling. In the failing left ventricular (LV) myocardium, β3-ARs are upregulated, a maladaptation that can contribute to LV dysfunction. We previously showed acute intravenous (i.v.) infusions of the β3-AR antagonist APD418 improves LV systolic and diastolic function in dogs with systolic heart failure (HF) (with reduced ejection fraction) in the absence of any background therapy. The current study tested the hypothesis that improvement of LV function with i.v. APD418 is maintained in dogs with systolic HF despite long-term chronic background therapy with the β-blockers carvedilol (CARV) and metoprolol (MET). Methods: 24 HF dogs were used in the study. 8 dogs were treated for 3 months with CARV (6.25 mg twice daily), 8 were treated for 3 months with MET (25 mg twice daily) and 8 were not treated with β-blockers. At the end of 3 months, dogs were treated with i.v. APD418 (4.224 mg/kg) administered over 4 hours. Dogs not treated with β-blockers were also studied with iv. vehicle alone (control group, CON) administered over 4 hours. Heart rate (HR), systemic vascular resistance (SVR), LV EF, LV fractional area of shortening (FAS) and stroke volume (SV) as well as the diastolic function measures Ei/Ai and mitral inflow velocity deceleration time (DCT) were measured at baseline and at 4 hours after i.v. APD418 or vehicle. Treatment effect Δ was measured in each group as the difference between baseline and 4 hours. Results: β-blocker therapy improved LV EF but function remained depressed. There were no significant differences in HR or SVR among the 4 test groups. LV EF, FAS, SV, Ei/Ai and DCT improved significantly with i.v. APD418 compared to vehicle (Table). The extent of improvement of LV EF, FAS, SV, Ei/Ai and DCT was similar in groups with or without background β-blockers therapy (Table). Conclusions: Acute i.v. infusions of APD418 in systolic HF dogs elicit positive inotropic and lusitropic effects despite long-term background therapy with β-blockers. The findings further support the development of APD418 for the in-hospital treatment of patients with exacerbation of chronic HF.

Volume

24

First Page

104

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