Recapitulation of single ventricle haemodynamics and associated interplay with breathing mechanics using clinically validated multimodal simulators

Abstract A range of congenital heart diseases result in a single functioning ventricle. This is palliatively treated by connecting the systemic and pulmonary vasculature in series, establishing what is known as the Fontan circulation. This physiology allows post-natal survival but causes aberrant haemodynamics that causes high morbidity and mortality. Due to limited clinical data, accurate modelling of single ventricle haemodynamics is critical for improving patient care. Although sophisticated haemodynamic models have been developed, their clinical relevance is hindered by their inability to mimic the biomechanical interactions of breathing pressures with vascular reservoirs as one interdependent unit which governs flow patterns and flow reversal in this physiology. Here, we report the development of a tuneable biomimetic single ventricle simulator platform that re-creates breathing mechanics and recapitulates Fontan venous flow patterns. Benchtop characterization, computational modelling, and MRI-based clinical validation demonstrate the ability of the platform to emulate the underlying mechanisms of the coupled breathing and flow mechanics that lead to venous flow reversal. We leverage this multimodal simulator platform to identify respiratory effort and rate as independent drivers for increased caval flow reversal in the Fontan physiology and measure haemodynamic parameters that cannot be obtained comprehensively in the clinic. Enabled by the modularity of this class of simulators, we evaluate the impact of gravity on the relationship between respiration and flow. Finally, we demonstrate the suitability of the clinically validated in vitro and in silico simulators as test platforms for Fontan support strategies which can help guide development of interventions to improve patient’s quality of life.