Altered inflow hemodynamics affects heart development in a side specific manner in the embryonic heart

Abstract

Background: Hemodynamics, forces from the flowing blood in the heart, is a major epigenetic factor for heart development. Disturbed hemodynamics were shown to induce cardiac malformations in the embryonic heart. Clinically relevant congenital heart defects (CHDs) can be introduced surgically in the lab by disturbing the hemodynamics, like Hypoplastic left heart syndrome (HLHS), characterized by underdeveloped left ventricle is underdeveloped. Left atrial ligation (LAL) on chick embryo is an experimental technique to produce a HLHS-like phenotype. Aims: To reveal mechanobiological mechanisms associated with disturbed hemodynamics that influence the progression of left ventricular hypoplasia using chick embryo model. We also introduce a new technique which we called right atrial ligation (RAL), to examine effect of flow disturbance in right heart. Methods: We combined multiple novel techniques in this research: Heart function was assessed via Echocardiography. Computational fluid dynamics (CFD) analysis was adapted for detailed hemodynamics assessment, such as wall shear stress and blood flow patterns. Heart morphology was assessed by histology., and micro-CT. Results: Echocardiography and CFD analysis showed flow and WSS levels decreased for the flow constricted side resulting in the flow diversion to the opposite side: LAL diverted flow to right side and RAL to left side. This disturbance resulted in underdevelopment of left heart (valve and ventricle) in LAL and underdevelopment of right heart in RAL, revealed with histology and micro-CT. Left side was affected more compared to right side, demonstrating higher plasticity in left heart. Conclusion: This study indicates the critical importance of altered inflow hemodynamics in cardiac development specifically valve and ventricle development. Our comprehensive approach can be used to predict the initiation and growth of congenital heart defects