β-Arrestin–Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate

Abstract

The treatment of pediatric heart failure is a long-standing unmet medical need. Angiotensin II supports mammalian perinatal circulation by activating cardiac L-type Ca²⁺ channels through angiotensin type 1 receptor (AT₁R) and β-arrestin. TRV027, a β-arrestin-biased AT₁R agonist, that has been reported to be safe but not effective for adult patients with heart failure, activates the AT₁R/β-arrestin pathway. We found that TRV027 evokes a long-acting positive inotropic effect specifically on immature cardiac myocytes through the AT₁R/β-arrestin/L-type Ca²⁺ channel pathway with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. Thus, TRV027 could be utilized as a valuable drug specific for pediatric heart failure.