Intravenous Infusion of the β(3)-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs with Systolic Heart Failure: β(3)-Adrenergic Receptor Antagonist in Heart Failure
Sabbah HN, Zhang K, Gupta RC, Xu J, Singh-Gupta V, Ma M, Stauber K, Nguyen N, and Adams J. Intravenous Infusion of the β(3)-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs with Systolic Heart Failure: β(3)-Adrenergic Receptor Antagonist in Heart Failure. J Card Fail 2020.
Journal of cardiac failure
BACKGROUND: Unlike β(1)- and β(2)-adrenergic receptors (ARs), β(3)-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β(3)-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous (i.v.) infusions of the β(3)-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF).
METHODS AND RESULTS: Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure.
CONCLUSIONS: Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF.
ePub ahead of print