β-Arrestin-biased activation of type I angiotensin II receptors improves prognosis of murine pediatric heart failure.

The pharmacological treatment of pediatric heart failure (PHF) remains a long-standing unmet medical need. We previously reported that TRV027, a peptidyl angiotensin type 1 receptor (AT1R) agonist that selectively activates β-arrestin over G protein signaling and avoids G protein-mediated vasoconstriction, increased cardiac contractility in neonatal, but not adult, mice by activating CaV1.2 L-type Ca2 + channels via casein kinase 2 without detectable adverse effects. TRV027 also significantly increased twitch Ca2+ transients in human induced pluripotent stem cell-derived cardiomyocytes. To examine whether TRV027 ameliorates PHF, its effects were evaluated in preweaning cTnTΔK210 knock-in mice, a model of human pediatric dilated cardiomyopathy with overt heart failure, using candesartan (Cand) as a reference AT1R blocker. Saline, TRV027, or Cand was administered chronically by daily subcutaneous injection from postnatal day 1-30 to homozygous (HOMO) mice and wild-type littermates. TRV027, but not Cand, significantly improved the survival rate of HOMO mice at P35. Echocardiography showed that TRV027 significantly slowed the time-dependent decline in left ventricular ejection fraction and wall motion in HOMO mice, without arrhythmias or obvious toxicities in major organs. Conversely, Cand did not slow PHF progression in HOMO mice and further impaired postnatal metanephrogenesis in both genotypes. Our findings strongly support cardiac AT1R/β-arrestin signaling as a promising, safe, and effective therapeutic axis for PHF, addressing the long-standing unmet medical needs in pediatric cardiology.