Establishing a Fetal Lamb Model for Hypoplastic Left Heart Syndrome—A Feasibility Pilot Study

Background: A major bottleneck for evaluating and developing different medical and surgical management strategies for the hypoplastic left heart syndrome (HLHS) consists in the lack of a large fetal animal model of HLHS. To this end, we present a feasibility pilot study to implement a recently developed fetal animal model for HLHS in Switzerland.[1]

Methods: Eight pregnant ewes (four with twins) with a mean (SD) body weight 69.5 ± 10.8 kg were anesthetized and intubated at two time points: (A) at mid of gestation (0.5) for percutaneous left atrial (LA) coil implantation guided by fetal ultrasound to induce a mitral valve stenosis with reduced filling of the left ventricle, and (B) at late gestation before birth (0.9) for cardiac and cerebral magnetic resonance imaging (MRI). For twin fetuses only one fetus underwent coil implantation and the other served as control. Successful development of HLHS was determined by functional cardiac MRI on a 3T scanner and 2D quantitative flow MRI at the ductus arteriosus and the proximal ascending aorta. Furthermore, high resolution ex vivo cerebral imaging was performed on a 1.5T system including T2 weighted fast spin echo anatomical imaging and microstructural imaging by means of diffusion tensor imaging.

Results: The LA size at coil implantation was 5.4 ± 1.8 mm. Two to four coils with a mean loop diameter of 6.6 ± 1.4 mm and length of 5.6 ± 2.9 mm were implanted per LA. Two ewes died due to periprocedural complications. At (B), mother’s body weight increased to 77.6 ± 13.0 kg (p = 0.01), and all nine fetal lambs survived (three with twins). Out of the nine fetal lambs three fetal lambs developed LV hypoplasia. The left ventricular end-diastolic volume in the LV hypoplasia group was decreased with 0.32 mL/kg (±0.05) versus 0.46 mL/kg (±0.05) in controls. The flow in the proximal ascending aorta was reduced with 26.7 mL/kg/min (± 0.2) versus 184.1 mL/kg/min (± 45.0) in controls. This was also associated with increased flow in the ductus arteriosus 215.6 (± 43.0) vs 164.0 (± 54.1). Cerebral findings were analyzed in post mortem T2 weighted fast spin echo anatomical imaging as well as DTI.

Conclusion: Beside a dropout rate due to periprocedural complication of 25%, this large animal model is feasible and offers in the future a sustainable research platform for better understanding of the cardiac, circulatory and cerebral physiology to support the development of new therapeutic strategies improving cardiac and neurocognitive outcome of HLHS.

Publication History

Article published online:
13 February 2024

• Reference

• 1 Reuter MS, Sokolowski DJ, Javier Diaz-MejiaJ. et al; Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling. Commun Biol 2023; 6 (1) 770