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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126747-02
Application #
9100909
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Evans, Frank
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ford, S M; Watanabe, M; Jenkins, M W (2018) A review of optical pacing with infrared light. J Neural Eng 15:011001
Elahi, Sahar; Gu, Shi; Thrane, Lars et al. (2018) Complex regression Doppler optical coherence tomography. J Biomed Opt 23:1-8
Menon, Vinal; Eberth, John F; Junor, Lorain et al. (2018) Removing vessel constriction on the embryonic heart results in changes in valve gene expression, morphology, and hemodynamics. Dev Dyn 247:531-541
Thrane, Lars; Gu, Shi; Blackburn, Brecken J et al. (2017) Complex decorrelation averaging in optical coherence tomography: a way to reduce the effect of multiple scattering and improve image contrast in a dynamic scattering medium. Opt Lett 42:2738-2741
McPheeters, Matthew T; Wang, Yves T; Werdich, Andreas A et al. (2017) An infrared optical pacing system for screening cardiac electrophysiology in human cardiomyocytes. PLoS One 12:e0183761
Karunamuni, Ganga; Sheehan, Megan M; Doughman, Yong Qiu et al. (2017) Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure. Alcohol Clin Exp Res 41:1917-1927
Ford, Stephanie M; McPheeters, Matthew T; Wang, Yves T et al. (2017) Increased regurgitant flow causes endocardial cushion defects in an avian embryonic model of congenital heart disease. Congenit Heart Dis 12:322-331
Peterson, Lindsy M; Gu, Shi; Karunamuni, Ganga et al. (2017) Embryonic aortic arch hemodynamics are a functional biomarker for ethanol-induced congenital heart defects [Invited]. Biomed Opt Express 8:1823-1837
Lothet, Emilie H; Shaw, Kendrick M; Lu, Hui et al. (2017) Selective inhibition of small-diameter axons using infrared light. Sci Rep 7:3275
Watanabe, Michiko; Rollins, Andrew M; Polo-Parada, Luis et al. (2016) Probing the Electrophysiology of the Developing Heart. J Cardiovasc Dev Dis 3:

Showing the most recent 10 out of 13 publications