Perinatal Asphyxia Alters Physiological Responses andEx VivoCardiovascular Function of Preterm Growth-Restricted Lambs

  1. Zahrah Azman
  2. Beth R. Piscopo
  3. Amy E. Sutherland
  4. Alison Thiel
  5. Valerie A. Zahra
  6. Yen Pham
  7. Ilias Nitsos
  8. Mumu Mahjabin Hossain
  9. Atul Malhotra
  10. Suzanne L. Miller
  11. Kristen J. Bubb
  12. Graeme R. Polglase
  13. Beth J. Allison
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Abstract

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 α1and β1adrenergic 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 (ControlVENTn=6; FGRVENTn=6), or asphyxia (ControlASPHYXIAn=12; FGRASPHYXIAn=11) induced by umbilical cord occlusion while withholding resuscitation until diastolic blood pressure (BP) decreased to 10mmHg. Lambs were ventilated for 8 hours before baselineex vivocardiac function was assessed via Langendorff perfusion to measure left ventricular developed pressure (LVDP), heart rate (HR) and coronary perfusion pressure (CPP).Ex vivoα1and β1adrenergic responses were assessed via phenylephrine (10−5to 10−2mmol/L) and dobutamine (10−7to 10−4) administration, respectively.

Results

FGRASPHYXIAlambs 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). FGRASPHYXIAlambs 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/dtmaxand dP/dtmin(p<0.03 vs ControlASPHYXIA). Baseline LVDP, HR and CPP were similar between groups, however FGRASPHYXIAlambs 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 α1and β1adrenergic receptor function, which may increase susceptibility to cardiovascular dysfunction in the neonatal period.

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