Abstract
Infants born premature are at increased risk for development of bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), and ultimately right ventricular (RV) dysfunction, which together carry a high risk of neonatal mortality. However, the role alveolar simplification and abnormal pulmonary microvascular development in BPD affects RV contractile properties is unknown. We used a rat model of BPD to examine the effect of hyperoxia-induced PH on RV contractile properties. We measured in vivo RV pressure as well as passive force, maximum Ca2+ activated force, calcium sensitivity of force (pCa50) and rate of force redevelopment (ktr) in RV skinned trabeculae isolated from hearts of 21-and 35-day old rats pre-exposed to 21% oxygen (normoxia) or 85% oxygen (hyperoxia) for 14 days after birth. Systolic and diastolic RV pressure were significantly higher at day 21 in hyperoxia exposed rats compared to normoxia control rats, but normalized by 35 days of age. Passive force, maximum Ca2+ activated force, and calcium sensitivity of force were elevated and cross-bridge cycling kinetics depressed in 21-day old hyperoxic trabeculae, whereas no differences between normoxic and hyperoxic trabeculae were seen at 35 days. Myofibrillar protein analysis revealed that 21-day old hyperoxic trabeculae had increased levels of beta-myosin heavy chain (β-MHC), atrial myosin light chain 1 (aMLC1; often referred to as essential light chain), and slow skeletal troponin I (ssTnI) compared to age matched normoxic trabeculae. On the other hand, 35-day old normoxic and hyperoxic trabeculae expressed similar level of α- and β-MHC, ventricular MLC1 and predominantly cTnI. These results suggest that neonatal exposure to hyperoxia increases RV afterload and affect both the steady state and dynamic contractile properties of the RV, likely as a result of hyperoxia-induced expression of β-MHC, delayed transition of slow skeletal TnI to cardiac TnI, and expression of atrial MLC1. These hyperoxia-induced changes in contractile properties are reversible and accompany the resolution of PH with further developmental age, underscoring the importance of reducing RV afterload to allow for normalization of RV function in both animal models and humans with BPD.
Highlights
Infants born prematurely are at increased risk for a number of comorbidities, including the development of chronic lung disease of prematurity, or bronchopulmonary dysplasia (BPD)
A total of 49 rats were exposed to postnatal normoxia, and 40 rats were exposed to postnatal hyperoxia
Fitting the force-pCa relationships with the Hill equation yielded similar pCa50 values and nH values for hyperoxic and age matched normoxic trabeculae. These results suggest that the neonatal exposure to hyperoxia has profound early effects on steady-state force production and that these effects wane as the pulmonary hypertension (PH) resolves
Summary
Infants born prematurely are at increased risk for a number of comorbidities, including the development of chronic lung disease of prematurity, or bronchopulmonary dysplasia (BPD). After preterm birth, these infants generally require resuscitation, and are often supplemented with life-sustaining oxygen therapy for prolonged periods. Rodent models of BPD, characterized by postnatal hyperoxia exposure, recapitulate many of the findings of human disease, including arrested alveolar and vascular development, PH and RV dysfunction (Goss et al, 2015, 2017; Dumas de la Roque et al, 2017; Liang et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
