優秀演題11（III-OEP11）
小児心不全薬物治療ガイドラインUpdate

[III-OEP11-2] 小児心不全では、AT1アンジオテンシン受容体を抑制すべきか刺激すべきか？

^○山田 充彦 (信州大学 医学部 分子薬理学教室)

Keywords:Pediatric heart failure, AT1 angiotensin receptor blocker, Beta-arrestin

It is well established that the inhibition of AT₁ angiotensin receptors (AT1R) with AT1R inhibitors (ARB) such as candesartan significantly improves the prognosis of adult chronic heart failure patients; however, it is ill defined if it is also the case in pediatric heart failure. We recently for the first time found that angiotensin II (AngII) causes strong positive inotropic effect on the heart by activating L-type Ca²⁺ channels through AT1R of cardiac myocytes in mice only before weaning. This effect was mediated by β-arrestin 2 but not G_q/11 proteins. Actually, a β-arrestin-bias AT1R agonist (BBA), TRV027 which activates β-arrestin but inhibits G_q/11 proteins significantly increased twitch Ca²⁺ transients in isolated neonatal mouse ventricular myocytes as well as human iPS cell-derived cardiac myocytes which exhibits immature phenotype. TRV027 caused sustained positive inotropic effect on the neonatal mouse heart. Finally, TRV027 significantly improved the prognosis before weaning of knock-in mice bearing a mutation in cardiac troponin T that causes human congenital dilated cardiomyopathy without causing any adverse effects on their wild-type littermates. In contrast, the inhibition of both G_q/11 and β-arrestin with candesartan not only failed to improve the prognosis of the knock-in mice but dramatically shortened the life span of their wild-type littermates before weaning. These results suggest that heart failure of children before weaning should be treated with BBA but not ARB and that ARB could be harmful at these ages.