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Collectively known as congenital heart defects (CHDs), cardiac abnormalities at birth are the most common forms of neonatal defects. Being principally responsible for the heart‘s pumping power, ventricles are particularly affected by developmental abnormalities, such as flow disturbances or genomic defects. Hypoplastic Right Heart Syndrome (HRHS) is a rare disease where the right ventricle is underdeveloped. In this study, we introduce a surgical procedure performed on chick embryo, termed right atrial ligation (RAL) for disturbing hemodynamics within the right heart aiming in order to generate an animal model of HRHS. RAL is a new surgical manipulation, similar to the well-studied left atrial ligation (LAL) surgery but it induces the hemodynamic change into the right side of the heart. After inducing RAL, We utilized techniques such as Doppler ultrasound, x-ray micro-CT, histology, and computational fluid dynamics (CFD) analysis, for a comprehensive functional and structural analysis of a developing heart. Our results displayed that RAL does not induce severe flow disturbance and ventricular abnormalities consistent with clinical findings. This study allows us to better understand the hemodynamics-driven CHD development and sensitivities of ventricles under disturbed flows.

The heart is the first organ that starts to function in a developing embryo. It continues to undergo dramatic morphological changes while pumping blood to the rest of the body. Genetic regulation of heart development is partly governed by hemodynamics. Chick embryo is a major animal model that has been used extensively in cardiogenesis research. To reveal mechanosensitive pathways, a variety of surgical interferences and chemical treatments can be applied to the chick embryo to manipulate the blood flow. Such manipulations alter expressions of mechanosensitive genes which may anticipate induction of morphological changes in the developing heart. This paper aims to present different approaches for generating clinically relevant disturbed hemodynamics conditions using this embryonic chick model and to summarize identified mechanosensitive genes using the model, providing insights into embryonic origins of congenital heart defects. Qatar National Research Fund

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.