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

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.