Abstract 2116: Endothelin-1 and Its Receptors Are Overexpressed in the Pulmonary Arteries of Patients With Failed Fontan Circulation
Background: The Fontan procedure has been a landmark contribution to the treatment of congenital heart disease with single ventricle physiology. However, not a few patients have failure of the Fontan circulation due to high pulmonary vascular resistance. Endothelin-1 (ET-1) is a potent vasoconstrictive substance, which was shown to be associated with pulmonary arterial hypertension. The aim of this study is to clarify the expression of ET-1 and its receptors, endothelin receptor type A (ETAR) and type B (ETBR), in pulmonary arteries of patients with failed Fontan circulation.
Subjects and Methods: We analyzed autopsy lung tissues from the patients died of failed Fontan circulation (Group F, n=10), and compared those to age-matched lung tissues from the patients without cardiovascular disease (Group N, n=4). We evaluated histomorphometric alterations and expression of ET-1, ETAR and ETBR in pulmonary arteries using immunohistochemical analysis and quantitative real-time PCR.
Results: The percent wall thickness of intra-acinar pulmonary arteries in Group F was significantly increased as compared to Group N (mean ± standard error, 25.2 ± 4.0 % vs. 15.9 ± 2.6 %; P < 0.05). The computational optical density analysis of immunostaining revealed that the expression levels of ET-1, ETAR and ETBR proteins were significantly increased in Group F (ET-1, 0.514 ± 0.031 vs. 0.370 ± 0.021; ETAR, 0.489 ± 0.029 vs. 0.364 ± 0.008; ETBR, 0.457 ± 0.020 vs. 0.374 ± 0.014; P < 0.05), and the quantitative real-time PCR analysis demonstrated that the mRNA expression of ET-1, ETAR and ETBR in Group F were also significantly increased (ET-1, 0.977 ± 0.085 vs. 0.434 ± 0.069; ETAR, 1.106 ± 0.270 vs. 0.523 ± 0.071; ETBR, 1.076 ± 0.137 vs. 0.628 ± 0.043; P < 0.05).
Conclusion: The intra-acinar pulmonary arteries of patients with failed Fontan circulation exhibited significant medial hypertrophy, and the expressions of ET-1, ETAR and ETBR were significantly increased. Overexpression of ET-1 and its receptors in pulmonary arteries can deteriorate Fontan circulation due to vasoconstriction and vascular remodeling. This study suggests a pathohistological evidence for the benefits of endothelin receptor antagonists for the patients with failed Fontan circulation.