Azman, Z.; Piscopo, B. R.; Sutherland, A. E.; Thiel, A.; Zahra, V.; Pham, Y.; Nitsos, I.; Hossain, M. M.; Malhotra, A.; Miller, S. L.; Bubb, K. J.; Polglase, G. R.; Allison, B. J.

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 1 and {beta}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 (ControlVENT n=6; FGRVENT n=6), or asphyxia (ControlASPHYXIA n=12; FGRASPHYXIA 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 1 and {beta}1 adrenergic responses were assessed via phenylephrine (10-5 to 10-2 mmol/L) and dobutamine (10-7 to 10-4) administration, respectively. Results: FGRASPHYXIA lambs had lower BP during asphyxia (p<0.05 vs ControlASPHYXIA) and took longer to reach a diastolic BP of 10mmHg (14.5 {+/-} 0.8 min vs. 19.2 {+/-} 1.3 min; p=0.005). FGRASPHYXIA 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/dtmax and dP/dtmin (p<0.03 vs ControlASPHYXIA). Baseline LVDP, HR and CPP were similar between groups, however FGRASPHYXIA lambs had increased LVDP responses to phenylephrine and dobutamine (p<0.05 vs ControlASPHYXIA), 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 1 and {beta}1 adrenergic receptor function, which may increase susceptibility to cardiovascular dysfunction in the neonatal period.