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

Toshihide Kashihara1, Hiroyuki Kawagishi1,2, Tsutomu Nakada3

  • 1Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.

JACC. Basic to Translational Science
|December 9, 2020
PubMed

Insights

TRV027, a novel drug, shows promise for treating pediatric heart failure by enhancing cardiac function in immature heart cells. This targeted approach offers a potential new therapy for a critical unmet medical need in children.

Area of Science:

  • Cardiovascular Research
  • Pediatric Cardiology
  • Pharmacology

Background:

  • Pediatric heart failure remains a significant unmet medical need.
  • Angiotensin II plays a crucial role in perinatal circulation via the angiotensin type 1 receptor (AT1R) and β-arrestin pathway.
  • TRV027, a β-arrestin-biased AT1R agonist, has shown safety but limited efficacy in adult heart failure.

Purpose of the Study:

  • To investigate the efficacy of TRV027 in treating pediatric heart failure.
  • To explore the specific mechanism of action of TRV027 on immature cardiac myocytes.
  • To evaluate the potential of TRV027 as a targeted therapy for pediatric heart conditions.

Main Methods:

  • Utilized β-arrestin-biased AT1R agonist TRV027.
  • Examined the effects on immature cardiac myocytes.
  • Assessed impact on heart rate, oxygen consumption, reactive oxygen species, and aldosterone secretion.

Main Results:

  • TRV027 demonstrated a long-acting positive inotropic effect specifically in immature cardiac myocytes.
  • The effect was mediated through the AT1R/β-arrestin/L-type Ca2+ channel pathway.
  • Minimal impact was observed on heart rate, oxygen consumption, reactive oxygen species, and aldosterone secretion.

Conclusions:

  • TRV027 exhibits a specific and beneficial effect on immature cardiac myocytes.
  • The drug's targeted mechanism suggests its potential as a valuable therapeutic agent for pediatric heart failure.
  • TRV027 represents a promising candidate for addressing a critical gap in pediatric cardiovascular medicine.

Keywords:
AT1R, angiotensin type 1 receptorAngII, angiotensin IIBBA, β-arrestin–biased angiotensin type 1 receptor agonistECG, electrocardiographyGPCR, G protein–coupled receptorLTCC, CaV1.2 L-type Ca2+ channelOCR, oxygen consumption ratePHF, pediatric heart failureROS, reactive oxygen speciesTRV027UCG, ultrasound cardiogramcongenital dilated cardiomyopathyhiPSC-CM, human induced pluripotent stem cell–derived cardiac myocytehuman induced pluripotent stem cell-derived cardiac myocytesinotropic vasodilatormNVCM, mouse neonatal ventricular cardiac myocyteneonatepediatric heart failureβ-arrestin–biased AT1 angiotensin receptor agonist

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