Increased Vasoconstriction of the Pulmonary Vasculature in Response to a Hypoxic Challenge in Swine Exposed to Hypoxia in the Neonatal Period

Abstract

IntroductionAdvances in neonatal care improved the survival of very prematurely born infants. Exposure to high oxygen is often necessary to ensure adequate oxygen uptake in these infants, leading to halted development and oxidative injury of the pulmonary vasculature which is often accompanied by increased pulmonary arterial pressure (PAP). Although pressures normalize in school age childhood, various stressors as hypoxia and exercise may unmask increased pulmonary vasoreactivity. Furthermore, now that these infants reach adulthood, it is increasingly recognized that this large, preterm born adult cohort has a less favorable cardiopulmonary risk profile. Particularly male subjects were shown to respond with a higher increase in PAP upon re‐exposure to hypoxia, which might be a predisposition to pulmonary vascular disease later in life. Pathophysiological risk factors causing this predisposition are unidentified and challenging to investigate in the human population.ObjectiveTo assess if swine with perinatal oxidative injury of the pulmonary vasculature respond differently to re‐exposure to a hypoxic stimulus compared to healthy swine.Methods6 male swine were exposed to 10–12% hypoxia in the neonatal period (NH‐swine) for a maximum of 4 weeks to interfere with normal lung development, while 5 male control pigs (healthy swine) were raised in normoxic conditions. In the NH‐swine, a symptom‐guided method (echocardiographic changes and clinical symptoms) orchestrated timing of the return to normoxic conditions. At the age of 8 weeks, NH and healthy swine were chronically instrumented. In week 10, hemodynamics were evaluated at rest and during exposure to 14–15% oxygen for 20 minutes.ResultsNH‐swine were exposed to a 23±5 days of hypoxia. 2 NH‐swine passed away as a consequence of heart failure before chronic instrumentation. At the age of 10 weeks, baseline PAP (14.6±2 vs 13.8±1 mmHg) and pulmonary vascular resistance (PVR, 4.1±0.7 vs 2.8±0.4 WU) at rest was not different in NH‐swine compared to healthy swine. During the hypoxic challenge, oxygen saturation decreased similarly in both groups compared to baseline measurements. PAP increased upon exposure to hypoxia due to an increase in PVR. The increases in PAP and PVR showed a transient peak after two minutes, which were larger in in NH‐swine compared to healthy swine. PAP and ΔPVR stabilized between 10 and 20 minutes of hypoxia exposure at levels that were not different between groups.ConclusionsInterfering with normal lung development in the first weeks of life induces a transiently exaggerated increase in PAP and PVR during a hypoxic challenge at the age of ten weeks. Normalization of PAP and PVR suggests effective counter mechanisms to reduce cardiac work and increase arterial oxygen saturation. The increased response to hypoxia of the pulmonary circulation suggest long‐term structural and/or functional changes that possibly predisposes the pulmonary circulation to adult pulmonary vascular disease.Support or Funding InformationErasmusMC M‐RACEHypoxic challenge data in 10 week old swine exposed to neonatal hypoxia (NH‐swine) compared to healthy swine. A: Arterial oxygen saturation (sO2), B: Pulmonary arterial pressure (PAP), C: Difference in pulmonary vascular resistance compared to baseline values (ΔPVR). BL ‐ baseline, WU ‐ Wood units. *=p<0.05 between groups, †=p<0.05 compared to baseline valuesFigure 1