Congenital heart defects (CHDs) are one of the most common and devastating birth defects, afflicting 32,000 babies born in the United States each year, and over 1 million Americans alive today. Altered hemodynamics during development has been shown to be a contributing factor to CHDs, regardless of whether the initial trigger is environmental or genetic. However, there is currently a lack of appropriate tools for studying the effects of clinically relevant hemodynamic perturbations on the development of later defects. The objective of this project is to design, construct, and apply the tools necessary to measure and precisely perturb hemodynamics in early embryonic development and then detect and quantify the resultant CHDs that develop. We propose to use optical techniques for both measurement and perturbation. We have previously demonstrated that optical coherence tomography (OCT) can measure many hemodynamic parameters, including heart rate, cardiac output, stroke volume, shear stress, and regurgitation. For this project, we will construct an ultrahigh-speed OCT system using new hardware and software algorithms to acquire hemodynamic parameters in real-time. We will build the system to be able to conduct longitudinal imaging studies of multiple embryos in parallel. New optical control (OC) technology has been developed for stimulating and inhibiting nerves and neurons, using pulsed infrared light to induce thermal effects. We have recently adapted this technology to stimulate embryonic hearts both in vivo and ex vivo and have a proof-of-concept demonstration for inhibiting cardiac activity. OC enables precise control of heart rate and development of advanced OC protocols will enable complex alteration of the heart's beat patterns (e.g. altered atrioventricular delay). We will perform further optimization of OC parameters and integrate OC into our ultrahigh-speed OCT system. This will enable the development of a closed-loop control system utilizing real-time OCT parameters as feedback to maintain hemodynamic parameters at desired values for long periods of time, even as the embryo grows and develops. We will also construct a double-sided Bessel-beam OCT system to obtain, in conjunction with optical clearing techniques, sufficient depth penetration to acquire structural images of later stage 4-chambered embryonic hearts. Finally, after validating these systems, we will apply this technology to test the hypothesis that altered regurgitation and shear stress on the developing cardiac cushions (valve precursors) will lead to valve defects. We will also explore whether compromised cardiac cushions also lead to misalignment of the great vessels (e.g. double outlet right ventricle). Upon completion, we will have developed tools and gathered significantly more information on when, how, and to what degree the developing cardiovascular system is most vulnerable to abnormal hemodynamics. With this knowledge, we will be better equipped to determine which molecular pathways are most influenced by altered hemodynamics, to develop earlier detection strategies, and potentially to treat CHDs more effectively.
Abnormal blood flow has been shown to play a role in the formation of congenital heart defects (CHDs). However, few tools exist to study how blood flow early in heart development results in later CHDs. This project will develop and implement optical tools for use in embryos to both make measurements of blood flow and heart structure and to change blood flow by altering the beating of the heart. We will further apply these tools to study how changes in blood flow can lead to valve defects, which will lead to better understanding of the origins and progression of CHDs.
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