Perinatal Asphyxia Alters Physiological Responses and Ex Vivo Cardiovascular Function of Preterm Growth-Restricted Lambs
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Introduction
Fetal growth restriction (FGR) arises from chronic hypoxia and increases the risk of cardiovascular dysfunction following perinatal asphyxia, although the underlying mechanisms are unknown. We investigated whether FGR lambs have altered cardiovascular responses to perinatal asphyxia compared to control lambs, and whether impairments in α 1 and β 1 adrenergic receptor function underlie these responses.
Methods
Single or twin-bearing ewes underwent sterile fetal surgery at 89 days gestation (dGA; term=148d) to induce FGR (single umbilical artery ligation) or sham surgery (Control). At 126dGA, lambs were delivered via caesarean section, instrumented and randomised to immediate ventilation (Control VENT n =6; FGR VENT n =6), or asphyxia (Control ASPHYXIA n =12; FGR ASPHYXIA n =11) induced by umbilical cord occlusion while withholding resuscitation until diastolic blood pressure (BP) decreased to 10mmHg. Lambs were ventilated for 8 hours before baseline ex vivo cardiac function was assessed via Langendorff perfusion to measure left ventricular developed pressure (LVDP), heart rate (HR) and coronary perfusion pressure (CPP). Ex vivo α 1 and β 1 adrenergic responses were assessed via phenylephrine (10 −5 to 10 −2 mmol/L) and dobutamine (10 −7 to 10 −4 ) administration, respectively.
Results
FGR ASPHYXIA lambs had lower BP during asphyxia (p<0.05 vs Control ASPHYXIA ) and took longer to reach a diastolic BP of 10mmHg (14.5 ± 0.8 min vs. 19.2 ± 1.3 min; p=0.005). FGR ASPHYXIA lambs had lower BP in the first 5 minutes after return of spontaneous circulation (p<0.05) due to impaired vascular contractility, with reduced Tau, dP/dt max and dP/dt min (p<0.03 vs Control ASPHYXIA ). Baseline LVDP, HR and CPP were similar between groups, however FGR ASPHYXIA lambs had increased LVDP responses to phenylephrine and dobutamine (p<0.05 vs Control ASPHYXIA ), without significant changes to HR or CPP.
Conclusion
FGR lambs have altered physiological responses to perinatal asphyxia due to impaired vascular contractility and dysregulated cardiac α 1 and β 1 adrenergic receptor function, which may increase susceptibility to cardiovascular dysfunction in the neonatal period.
