Selective beta-3 adrenergic receptor blockade increases contractility of human ventricular trabeculae from HFrEF donors

Alterations of the beta-adrenergic system have been extensively described in the setting of heart failure (HF). Upregulation of beta-3 adrenergic receptor (β3-AdrR) expression in human failing hearts depresses myocardial contractility and, during an acute decompensation event, can be considered a maladaptive compensatory mechanism that exacerbates cardiac dysfunction. APD418 is a selective β3-AdrR antagonist currently in development for patients who have acute heart failure with reduced ejection fraction (HFrEF). APD418 is designed to improve myocardial contractility by selectively antagonizing the β3-AdrR and thereby avoiding the cAMP/Ca2+ signaling pathway stimulated by current inotropes.

This study evaluated the effect of a selective β3-AdrR antagonist (APD418) on contractile responses in explanted human ventricular trabeculae obtained from normal and HFrEF hearts.

Left ventricular trabeculae from normal and HFrEF donors were electrically stimulated (1 Hz) ex-vivo to analyze force generated during contractions. First, BRL37344, a selective β3-AdrR agonist, was applied at increasing concentrations (0.01–10 μM) to confirm β3-AdrR mediated negative inotropy in human myocardial tissue. To test the effect of a selective β3-AdrR antagonist on contractile force, myocardial tissue was pre-treated with APD418 or vehicle for 5 minutes, followed by treatment with non-selective β-AdrR agonists isoproterenol (10 nM) or norepinephrine (5 μM).

In heart tissue from normal donors, the β3-AdrR agonist BRL37344 did not affect contractile function at 0.01 and 0.1 μM. However, in heart tissue from HFrEF donors, BRL37344 induced a significant decrease in contractility at 0.01, 0.1 and 1 μM (85.9±1.8% with 0.1 μM BRL37344 vs 104.1±2.9% with vehicle). Selective blockade of β3-AdrR with APD418 had no effect on force of contraction induced by norepinephrine in cardiac tissue from normal donors. In contrast, APD418 potentiated the force of contraction induced by either isoproterenol (49.1±20.6% increase with 0.1 μM APD418 compared to baseline) or norepinephrine (26.5±4.9% increase with 0.01 μM APD418 compared to baseline) in cardiac tissue from HFrEF patients.

This is, to our knowledge, the first evidence showing that selective blockade of β3-AdrR increases contractility of human ventricular trabeculae from HFrEF donors and suggests that further studies evaluating the therapeutic benefit of APD418 in patients with HFrEF are warranted.

Type of funding source: Private company. Main funding source(s): Arena Pharmaceuticals