Effect of Long-term Administration of Prostaglandin E₁ on Morphologic Changes in Ductus Arteriosus.

Abstract

To improve survival of patients with hypoplastic left heart syndrome, combination therapy with bilateral pulmonary artery banding and prostaglandin E₁ (PGE₁)-mediated ductal patency was developed as an alternative for high-risk neonates in Japan. However, the effect of long-term PGE₁ administration on ductus arteriosus remains unclear. Synchrotron radiation-based X-ray phase-contrast tomography (XPCT) enables clear visualization of soft tissues at an approximate spatial resolution of 12.5 μm. We aimed to investigate morphologic changes in ductus arteriosus after long-term PGE₁ infusion using XPCT. Seventeen ductus arteriosus tissue samples from patients with hypoplastic left heart syndrome were obtained during the Norwood procedure. The median duration of lipo-prostaglandin E₁ (lipo-PGE₁) administration was 48 days (range, 3 to 123). Structural analysis of ductus arteriosus was performed and compared with conventional histologic analysis. The XPCT was successfully applied to quantitative measurements of ductal media. Significant correlation was found between the duration of lipo-PGE₁ infusion and mass density of ductal media (R = 0.723, P = .001). The duration of lipo-PGE₁ administration was positively correlated with elastic fiber staining (R = 0.799, P < .001) and negatively correlated with smooth muscle formation (R = -0.83, P < .001). No significant increase in intimal cushion formation was found after long-term lipo-PGE₁ administration. Expression of ductus arteriosus dominant PGE₂-receptor EP4 almost disappeared in specimens when lipo-PGE₁ was administered over 3 days. Disorganized elastogenesis and little intimal cushion formation after long-term lipo-PGE₁ administration suggest that ductus arteriosus remodeled to the elastic artery phenotype. Because EP4 was downregulated and ductus arteriosus exhibited elastic characteristics, the dosage of lipo-PGE₁ might be decreased after a definite administration period.