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 #
5R01HL083048-06
Application #
8691979
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
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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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
Watanabe, Michiko; Rollins, Andrew M; Polo-Parada, Luis et al. (2016) Probing the Electrophysiology of the Developing Heart. J Cardiovasc Dev Dis 3:
Wang, Yves T; Rollins, Andrew M; Jenkins, Michael W (2016) Infrared inhibition of embryonic hearts. J Biomed Opt 21:60505
Ma, Pei; Chan, Dennis C; Gu, Shi et al. (2016) Volumetric optical mapping in early embryonic hearts using light-sheet microscopy. Biomed Opt Express 7:5120-5128
Ma, Pei; Gu, Shi; Karunamuni, Ganga H et al. (2016) Cardiac neural crest ablation results in early endocardial cushion and hemodynamic flow abnormalities. Am J Physiol Heart Circ Physiol 311:H1150-H1159
Blech-Hermoni, Yotam; Sullivan, Connor B; Jenkins, Michael W et al. (2016) CUG-BP, Elav-like family member 1 (CELF1) is required for normal myofibrillogenesis, morphogenesis, and contractile function in the embryonic heart. Dev Dyn 245:854-73
Fu, Xiaoyong; Patel, Dhruti; Zhu, Hui et al. (2015) Miniature forward-viewing common-path OCT probe for imaging the renal pelvis. Biomed Opt Express 6:1164-71
Gu, Shi; Wang, Yves T; Ma, Pei et al. (2015) Mapping conduction velocity of early embryonic hearts with a robust fitting algorithm. Biomed Opt Express 6:2138-57
Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu et al. (2015) Using optical coherence tomography to rapidly phenotype and quantify congenital heart defects associated with prenatal alcohol exposure. Dev Dyn 244:607-18

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