Overexpression of endothelin-1 and endothelin receptors in the pulmonary arteries of failed Fontan patients

BackgroundEndothelin-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 (ETAR) and type B (ETBR) in the pulmonary arteries of failed Fontan patients were not elucidated.MethodsImmunohistochemistry 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).ResultsThe 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, ETAR, and ETBR 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, ETAR, and ETBR were significantly increased in the failed Fontan patients (P < 0.05 vs. normal controls).ConclusionThe 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.