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

[Display omitted] •β-arrestin–biased AT1 agonist TRV027 causes a neonatal-specific, long-acting positive inotropic effect with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion.•Although TRV027 stimulates adrenaline secretion, it does not contribute to the inotropic effect.•TRV027 also increases twitch Ca2+ transients in human iPS cell–derived cardiac myocytes bearing immature phenotype and improves the contractility of the compromised heart of neonatal knock-in mice bearing a mutation causing human congenital dilated cardiomyopathy.•TRV027 and related peptides are also known to cause an antiapoptotic effect on the heart, dilate resistant arteries to reduce afterload, and increase Na+ diuresis to reduce preload.•Thus, TRV027 could be utilized as a valuable inotropic vasodilator specific for pediatric heart failure. 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.