About 1% of newborn babies in the US have congenital heart disease (CHD), the leading cause of death among infants. Hemodynamic forces, which are wall shear stresses and pressures generated by the flow of blood, are key factors that regulate heart development and, if abnormal, can lead to CHD. Even when CHD has a genetic cause, altered blood-flow conditions produced by heart defects may lead to additional abnormalities. However, the extent to which alterations in hemodynamics affect cardiac cells and ultimately heart formation is not yet clear. A detailed study of the effects of hemodynamics on heart development requires quantification of hemodynamic forces and of changes in heart growth, morphology and gene expression in an intact, in vivo animal model. The objective of this project is to elucidate the relationship among hemodynamic forces, cardiac growth, heart morphology and expression of selected genes during early developmental stages;with the ultimate goal of understanding the biological mechanisms by which hemodynamics affect heart development. This project will use chick embryos at 2 early stages of development (3 and 3.5 days of a 21-day incubation period - HH18 and HH21), and will focus on the heart outflow tract (OFT), which acts like a primitive valve. Normal blood-flow dynamics will be altered by outflow tract banding, a procedure in which a suture is placed around the OFT, constraining the motion of the OFT wall;and by vitelline-vein ligation, in which a vitelline vein is clipped to obstruct blood flow. The hypothesis is that alterations of hemodynamic forces due to outflow tract banding and vitelline-vein ligation at HH18 lead to measurable, correlated changes in OFT wall morphology, growth and gene expression at HH21.
The aims of the project are:
Aim 1 : Determine in vivo changes in the motion, morphology, and growth of the OFT wall in response to altered hemodynamics. To measure wall motion and geometrical changes in the OFT of chick embryos, the OFT will be imaged using optical coherence tomography.
Aim 2 : Determine dynamic variations of hemodynamic forces in the OFT and associated expression of selected genes under normal and altered hemodynamic conditions over the cardiac cycle. Blood pressure will be measured using a servo null system. Wall shear stress will be quantified from simulations of finite element models of the OFT. Gene expression levels of integrins and collagen VI (up-regulated after OTB) will be quantified by real time polymerase chain reaction, and localization determined from in situ hybridization and immunohistochemistry.

Public Health Relevance

Although hemodynamic forces have long been recognized as key factors in heart development, the mechanisms by which these forces affect heart development and lead to congenital heart disease (CHD) are not well understood. This project seeks to better understand the relationship between alterations in hemodynamic conditions and changes in heart development - changes that could lead to CHD or even predispose the heart for failure later in life. A better understanding of the relationship between blood flow and heart formation could eventually be used in the prevention and treatment of CHD and other heart-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094570-04
Application #
8235869
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Evans, Frank
Project Start
2009-04-01
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$376,578
Indirect Cost
$129,078
Name
Oregon Health and Science University
Department
Engineering (All Types)
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Midgett, Madeline; López, Claudia S; David, Larry et al. (2017) Increased Hemodynamic Load in Early Embryonic Stages Alters Endocardial to Mesenchymal Transition. Front Physiol 8:56
Midgett, Madeline; Thornburg, Kent; Rugonyi, Sandra (2017) Blood flow patterns underlie developmental heart defects. Am J Physiol Heart Circ Physiol 312:H632-H642
Midgett, Madeline; López, Claudia S; David, Larry et al. (2017) Increased Hemodynamic Load in Early Embryonic Stages Alters Myofibril and Mitochondrial Organization in the Myocardium. Front Physiol 8:631
Rugonyi, Sandra (2016) Genetic and flow anomalies in congenital heart disease. AIMS Genet 3:157-166
Carson, James P; Rennie, Monique Y; Danilchik, Michael et al. (2016) A chicken embryo cardiac outflow tract atlas for registering changes due to abnormal blood flow. Conf Proc IEEE Eng Med Biol Soc 2016:1236-1239
Chivukula, Venkat Keshav; Goenezen, Sevan; Liu, Aiping et al. (2016) Effect of Outflow Tract Banding on Embryonic Cardiac Hemodynamics. J Cardiovasc Dev Dis 3:
Stovall, Stephanie; Midgett, Madeline; Thornburg, Kent et al. (2016) Changes in dynamic embryonic heart wall motion in response to outflow tract banding measured using video densitometry. J Biomed Opt 21:116003
Phan, Ly; Courchaine, Katherine; Azarbal, Amir et al. (2016) A Geodesics-Based Surface Parameterization to Assess Aneurysm Progression. J Biomech Eng 138:054503
Goenezen, Sevan; Chivukula, Venkat Keshav; Midgett, Madeline et al. (2016) 4D subject-specific inverse modeling of the chick embryonic heart outflow tract hemodynamics. Biomech Model Mechanobiol 15:723-43
Phan, Ly; Grimm, Cindy; Rugonyi, Sandra (2015) Visualization Techniques for the Developing Chicken Heart. Adv Vis Comput (2015) 9474:35-44

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