The Role of Altered Hemodynamics in Cardiac Growth and Remodeling

Oregon Health & Science University, Portland OR

Investigators

Abstract

? DESCRIPTION (provided by applicant): Blood flow during early embryonic stages plays a critical role in heart development, as constant interactions between blood and tissues generate biomechanical forces that modulate cardiac growth and remodeling. Key morphogenetic events coincide with periods of major hemodynamic change, including myofibril organization and early valvulogenesis when a subset of endocardial cells transform into mesenchyme (EMT). Normal blood flow conditions are essential for proper cardiac development, while altered hemodynamic loads (pressure and shear stresses) on cardiac tissues are known to result in heart defects seen in congenital heart disease. Although it is clear that biomechanical forces are fundamental components of heart morphogenesis, the ways in which abnormal blood flow leads to congenital heart defects are unknown. The goal of the proposed study is to characterize the role of hemodynamics in cardiac development and elucidate mechanotransduction events underlying cardiac remodeling and malformation. The overall hypothesis is that the embryonic cardiac system responds to altered blood flow environments and develops congenital heart defects in a hemodynamic load-dependent manner. This hypothesis will be tested by surgically modifying blood flow in a chick embryo model. A well-established intervention called outflow tract banding will be used to constrict the diameter of the early embryonic outflow tract of the heart, in order o increase the hemodynamic load on cardiac tissues. These perturbed forces are known to ultimately lead to a wide spectrum of congenital heart defects. Our work determined that the amount of increased blood pressure, flow velocity, and wall shear rate due to outflow tract banding can be controlled by the degree of band tightness. Varied outflow tract band tightness produces a range of hemodynamic perturbation, which I will use to evaluate how the developing cardiovascular system responds to diverse hemodynamics loads. This study will elucidate initial abnormal structural tissue remodeling following altered blood flow using 3D electron microscopy and immunohistochemistry, and the functional and structural cardiac defects that occur late in development with ultrasound biomicroscopy and X-ray micro- computed tomography. Preliminary data shows that cell density in the outflow tract is increased after banding, and dependent on band tightness and therefore the specific hemodynamic conditions. My data also demonstrates that normal endocardium organization is altered after banding, and the hemodynamics created by specifically tight bands trigger detrimental development processes that result in ventricular septal defect. The specific aims of this proposal are as follows: (1) determine the effects of changes in pulsatile pressure and flow on in vivo cellular structure of the outflow tract wall, (2) determine the effects of altered hemodynamic shear stress on EMT in vitro, and (3) determine how varied pulsatile pressure and flow during development affect mature cardiac formation. New information about the origins of cardiac defects will lead to improved intervention strategies for infants with congenital heart disease.