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Macitentan attenuates cardiovascular remodelling in infant rats with chronic lung disease
Philipp Baumann1,2, Francesco Greco1,2,3, Susanne Wiegert1,2,3
1Department of Intensive Care Medicine and Neonatology, University Children's Hospital Zurich, Zurich, Switzerland.
Insights
Macitentan, an endothelin-1 receptor antagonist, reduced cardiovascular remodelling in a rat model of preterm chronic lung disease. This finding suggests macitentan may decrease cardiovascular issues in preterm infants.
Area of Science:
- Neonatal physiology and pathology
- Pharmacology and therapeutics
- Cardiovascular and respiratory medicine
Background:
- Preterm infants with chronic lung disease (CLD) face increased mortality due to cardiovascular impairment.
- Endothelin-1 receptor antagonists, like macitentan, show promise in mitigating pulmonary and cardiovascular remodeling.
Purpose of the Study:
- To investigate the effects of macitentan on cardiovascular and pulmonary changes in a rat model of preterm CLD.
- To assess macitentan's potential to attenuate disease-induced cardiac and vascular remodeling.
Main Methods:
- A prospective, randomized, placebo-controlled study using Sprague-Dawley rats exposed to high oxygen (1.0 FiO2) for 19 days.
- Macitentan or placebo was administered via gavage from postnatal days 5 to 19.
- Evaluated parameters included alveolar morphology, pulmonary vessel density, vascular smooth muscle actin, cardiomyocyte size, and cardiac dimensions.
Main Results:
- High oxygen exposure induced CLD features: alveolar enlargement, vessel rarefaction, increased arteriolar smooth muscle actin, and cardiac hypertrophy.
- Macitentan treatment significantly increased pulmonary vessel count and reduced the right to left ventricular wall diameter ratio.
- While endothelin-1 plasma concentrations increased, key markers of lung and cardiac remodeling remained unchanged with macitentan.
Conclusions:
- Macitentan, an endothelin-1 receptor antagonist, attenuated cardiovascular remodeling in an infant rat model of preterm CLD.
- This study highlights macitentan's potential therapeutic role in reducing cardiovascular morbidity in preterm infants with CLD.
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 (FiO2) 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:
FiO2 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.
