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.
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.
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