Congenital heart defects (CHDs) afflict 36,000 babies born in the US each year and survivors often require several surgical interventions in their shortened lifetime. Despite continuous efforts, the mechanisms leading to CHDs remain largely unclear. In part, this is because most developmental cardiology studies fail to address the influential role of altered cardiac function in cardiogenesis. Myocardial excitation, cardiomyocyte contraction and hemodynamics are all likely to modify expression pathways responsible for heart development. However, due to the lack of proper imaging tools, these biomechanical and electrophysiological signals are not fully identified or well understood especially at early loopin stages, when the trajectory to heart defects can begin. In the previous funding period, we developed and demonstrated 4-D optical coherence tomography (OCT) technology as a powerful tool to image contraction dynamics and hemodynamics in the early looping heart. In this proposed project period, we will complement OCT with optical mapping (OM) using potentiometric and calcium-sensitive fluorescent dyes to reveal patterns of cardiac conduction and calcium signaling. With an integrated imaging system that can capture contraction mechanics, hemodynamics, calcium transients, and electrical conduction throughout the developmental stages during which the heart tube is looping, we will be able to investigate these individual factors, the complex interplay between them and their role in the emergence of CHDs. The integration of OCT and OM will support and enable new technology and experimental methods. We will utilize OCT to correct motion during OM imaging, obviating the need for excitation-contraction (E-C) decoupling drugs, thus enabling E-C coupling to be studied directly and comprehensively for the first time in the developing heart. We will develop 3-D OM using second-harmonic generating potentiometric dyes will and optical coherence microscopy, enabling discrimination of the 3-D heterogeneity of the conduction system of the radially asymmetric embryonic heart tube. We will develop in vivo calcium imaging by infecting quail embryos causing them to genetically express a Ca++-sensitive protein. These new tools may be applied to numerous experimental models such as ablation (e.g. neural crest cells, NCCs), environmental perturbation (e.g. hypoxia), or chemical exposure (e.g. alcohol). We have chosen to focus on the connections between the etiology of CHDs associated with Fetal Alcohol Syndrome (FAS), NCCs, and their ability to influence cardiac function from an early stage. Based on the literature and our own preliminary findings, we propose that ethanol exposure in the embryonic model at a vulnerable stage disrupts NCC development, and leads to heart defects through the impairment of cardiac function. We also hypothesize that a combination of folate/myo-inositol (FA/MI) will alleviate these functional abnormalities, and prevent FAS- related CHDs. Our proposed studies could comprise a first step toward developing new therapeutic strategies based on FA/MI prevention of birth defects to benefit public health.

Public Health Relevance

The ways that congenital heart defects (CHDs) form are largely unclear, especially the role of abnormal biophysical forces caused by pumping action, blood flow and electrical signals. This project will develop an multi-modality instrument and methods to image the tiny embryonic heart while it is beating to study how abnormal cardiac function contributes to CHDs. Better understanding of the causes of CHDs (such as Fetal Alcohol Syndrome) can potentially lead to better prediction of outcomes, and earlier, more effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL083048-05A1
Application #
8439971
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Buxton, Denis B
Project Start
2006-08-01
Project End
2017-05-31
Budget Start
2013-06-28
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$620,585
Indirect Cost
$131,237
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Peterson, Lindsy M; Gu, Shi; Jenkins, Michael W et al. (2014) Orientation-independent rapid pulsatile flow measurement using dual-angle Doppler OCT. Biomed Opt Express 5:499-514
Karunamuni, Ganga H; Ma, Pei; Gu, Shi et al. (2014) Connecting teratogen-induced congenital heart defects to neural crest cells and their effect on cardiac function. Birth Defects Res C Embryo Today 102:227-50
Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu et al. (2014) Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects? Am J Physiol Heart Circ Physiol 306:H414-21
Karunamuni, Ganga H; Gu, Shi; Ford, Matthew R et al. (2014) Capturing structure and function in an embryonic heart with biophotonic tools. Front Physiol 5:351
Fu, Xiaoyong; Wang, Zhao; Wang, Hui et al. (2014) Fiber-optic catheter-based polarization-sensitive OCT for radio-frequency ablation monitoring. Opt Lett 39:5066-9
Wang, Yves T; Gu, Shi; Ma, Pei et al. (2014) Optical stimulation enables paced electrophysiological studies in embryonic hearts. Biomed Opt Express 5:1000-13
Ma, Pei; Wang, Yves T; Gu, Shi et al. (2014) Three-dimensional correction of conduction velocity in the embryonic heart using integrated optical mapping and optical coherence tomography. J Biomed Opt 19:76004
Gu, Shi; Jenkins, Michael W; Peterson, Lindsy M et al. (2012) Optical coherence tomography captures rapid hemodynamic responses to acute hypoxia in the cardiovascular system of early embryos. Dev Dyn 241:534-44
Kang, Wei; Wang, Hui; Wang, Zhao et al. (2011) Motion artifacts associated with in vivo endoscopic OCT images of the esophagus. Opt Express 19:20722-35
Wang, Hui; Kang, Wei; Carrigan, Thomas et al. (2011) In vivo intracardiac optical coherence tomography imaging through percutaneous access: toward image-guided radio-frequency ablation. J Biomed Opt 16:110505

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