BACKGROUND: Endothelin-1 (ET-1), a potent vasoconstrictor, is considered to be implicated in failing Fontan circulation, however the expressions of ET-1 and endothelin receptor type A (ET(A)R) and type B (ET(B)R) in the pulmonary arteries of failed Fontan patients were not elucidated. METHODS: Immunohistochemistry and quantitative real-time PCR were used to analyse the expression levels of ET-1 and its receptors in the pulmonary arteries of the autopsy lung tissues of the patients who died after the Fontan procedure (n=10). We divided these patients into 3 groups, failed Fontan (n=4), heart failure (n=3) and non-failed Fontan (n=3), and then compared those to the age-matched normal controls (n=4). RESULTS: The intra-acinar pulmonary arteries of failed Fontan patients showed significant medial hypertrophy. Computational optical density analyses of the immunostaining revealed that the expressions of ET-1, ET(A)R, and ET(B)R in the intra-acinar pulmonary arteries were significantly increased in the failed Fontan patients (P<0.05 vs. normal controls), however no significant difference was observed between the non-failed Fontan patients and the normal controls. Quantitative real-time PCR analyses confirmed that the mRNA expressions of ET-1, ET(A)R, and ET(B)R were significantly increased in the failed Fontan patients (P<0.05 vs. normal controls). CONCLUSION: The overexpression of ET-1 and its receptors in the pulmonary arteries can cause pulmonary vasoconstriction and vascular remodelling, leading to failed Fontan circulation. This study suggests a histopathological rationale for the potential benefits of endothelin receptor antagonists in patients with failing Fontan circulation.
BACKGROUND:Endothelin-1 (ET-1), a potent vasoconstrictor, is considered to be implicated in failing Fontan circulation, however the expressions of ET-1 and endothelin receptor type A (ET(A)R) and type B (ET(B)R) in the pulmonary arteries of failed Fontan patients were not elucidated. METHODS: Immunohistochemistry and quantitative real-time PCR were used to analyse the expression levels of ET-1 and its receptors in the pulmonary arteries of the autopsy lung tissues of the patients who died after the Fontan procedure (n=10). We divided these patients into 3 groups, failed Fontan (n=4), heart failure (n=3) and non-failed Fontan (n=3), and then compared those to the age-matched normal controls (n=4). RESULTS: The intra-acinar pulmonary arteries of failed Fontan patients showed significant medial hypertrophy. Computational optical density analyses of the immunostaining revealed that the expressions of ET-1, ET(A)R, and ET(B)R in the intra-acinar pulmonary arteries were significantly increased in the failed Fontan patients (P<0.05 vs. normal controls), however no significant difference was observed between the non-failed Fontan patients and the normal controls. Quantitative real-time PCR analyses confirmed that the mRNA expressions of ET-1, ET(A)R, and ET(B)R were significantly increased in the failed Fontan patients (P<0.05 vs. normal controls). CONCLUSION: The overexpression of ET-1 and its receptors in the pulmonary arteries can cause pulmonary vasoconstriction and vascular remodelling, leading to failed Fontan circulation. This study suggests a histopathological rationale for the potential benefits of endothelin receptor antagonists in patients with failing Fontan circulation.
Authors: Makoto Mori; Alfredo J Aguirre; Robert W Elder; Ali Kashkouli; Alton Brad Farris; Ryan M Ford; Wendy M Book Journal: Pediatr Cardiol Date: 2014-02-15 Impact factor: 1.655
Authors: Benjamin S Frank; Ludmila Khailova; Lori Silveira; Max B Mitchell; Gareth J Morgan; Michael V DiMaria; Jesse A Davidson Journal: J Am Heart Assoc Date: 2022-03-04 Impact factor: 6.106
Authors: Sjoerd S M Bossers; Merih Cibis; Livia Kapusta; Wouter V Potters; Miranda M Snoeren; Jolanda J Wentzel; Adriaan Moelker; Willem A Helbing Journal: Pediatr Cardiol Date: 2016-01-12 Impact factor: 1.655