Abstract
BACKGROUND: Cardiovascular impairment contributes to increased mortality in preterm infants with chronic lung disease. Macitentan, an endothelin-1 receptor antagonist, has the potential to attenuate pulmonary and cardiovascular remodelling. METHODS: In a prospective randomized placebo-controlled intervention trial, Sprague-Dawley rats were exposed to 0.21 or 1.0 fraction of inspired oxygen (FiO(2)) for 19 postnatal days. Rats were treated via gavage with placebo or macitentan from days of life 5 to 19. Alveoli, pulmonary vessels, α-smooth muscle actin content in pulmonary arterioles, size of cardiomyocytes, right to left ventricular wall diameter ratio, and endothelin-1 plasma concentrations were assessed. RESULTS: FiO(2) 1.0 induced typical features of chronic lung disease with significant alveolar enlargement (p = 0.012), alveolar (p = 0.048) and pulmonary vessel rarefaction (p = 0.024), higher α-smooth muscle actin content in pulmonary arterioles (p = 0.009), higher right to left ventricular wall diameter ratio (p = 0.02), and larger cardiomyocyte cross-sectional area (p < 0.001). Macitentan treatment significantly increased pulmonary vessel count (p = 0.004) and decreased right to left ventricular wall diameter ratios (p = 0.002). Endothelin-1 plasma concentrations were higher compared to placebo (p = 0.015). Alveolar number and size, α-smooth muscle actin, and the cardiomyocyte cross-sectional area remained unchanged (all p > 0.05). CONCLUSION: The endothelin-1 receptor antagonist macitentan attenuated cardiovascular remodelling in an infant rat model for preterm chronic lung disease. This study underscores the potential of macitentan to reduce cardiovascular morbidity in preterm infants with chronic lung disease.