OHSU

Cardiac Growth Project

Cardiac Growth and Early Developmental Stages

The objective of this project is to better understand the origins of congenital heart disease (CHD), which affects about 1% of newborn babies in the U.S. and is the leading non-infectious cause of death among infants. The Rugonyi Lab is interested in the role of hemodynamic forces (forces exerted on tissues by the flow of blood) on cardiac development. In animal models, alterations of normal blood flow through the heart during embryonic development lead to cardiac defects that resemble those found in humans. While genetic defects are known to underlie some cardiac malformations, abnormal hemodynamic conditions are just as likely to be responsible for many heart defects observed in humans.

overview of cardiac growth pipeline (flowchart)Although changes in hemodynamic forces are known to lead to CHD, the mechanisms by which this happens are not fully understood. This is in part due to the complexity of the interactions between cardiac tissue, blood flow and cellular responses to mechanical stimuli; and in part due to the many technological challenges associates with measuring forces and deformations on small hearts that are beating fast.

Our goal is to use a combination of engineering and biology tools to unravel the mechanisms by which hemodynamic forces affect heart formation. To this end, we alter blood flow conditions during early embryonic cardiac development. We use chicken embryos because they are easy to access and manipulate, while genetic processes are highly conserved among vertebrate species. We use state-of-the-art imaging techniques to visualize the response of tissues to altered blood flow conditions. 

Our experiments are complemented by computational investigations of blood flow and wall stresses in the developing heart, both under normal and abnormal hemodynamic conditions. The combination of both experimental and computational approaches enables us to shed more light towards understanding development of the heart and CHD.

We have obtained valuable data on blood flow velocities, pressures and histological composition of the developing heart. Together, our data suggests that blood flow is a strong determinant of cardiac tissue growth and remodeling.

 

Sample RESULTS

4D Reconstruction of Cardiac Outflow Tract

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Beating heart outflow tract of a day 3 chick embryo (HH18). Segmented from 4D optical coherence tomography (OCT) images.

Blood Flow Through Normal and Banded Embryo (Video)

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The above video shows blood flowing through the outflow tract (OFT) of a normal embryo at day 3 (HH18). The OFT is roughly 800 microns in length.

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The above video shows blood flowing through an embryo after undergoing outflow tract banding (OTB) at day 3 (HH18). The band can be seen across the middle of the outflow tract in black. Banding increases resistance to the normal flow of blood, thereby altering normal cardiac development. This provides valuable insights into some of the possible causes for CHD.

Comparing the Endocardium of Normal and Outflow Tract Banded Embryos (Video)

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Normal HH24 chick embryo endocardium, displaying each cell as a different color. Focused ion beam scanning electron microscopy images were acquired through the endocardium layer of the outflow tract, and cellular tissue was segmented to reconstruct 3D cellular structures. 
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HH24 chick embryo endocardium after surgical manipulation, displaying each cell as a different color. Outflow tract banding was used to alter hemodynamics for 24 hours before tissue collection. Focused ion beam scanning electron microscopy images were acquired through the endocardium layer of the outflow tract, and cellular tissue was segmented to reconstruct 3D cellular structures. 

Blood Flow Dynamics within the Cardiac Outflow Tract (OFT)

Blood flow dynamics within the OFT of the representative HH18 chick embryo

Blood flow dynamics within the cardiac outflow tract (OFT) of the representative 3-day (HH18) chick embryo. (A) and (B) Comparison of centerline velocities measured with Doppler optical coherence tomography (OCT) and calculated with our Computational Fluid Dynamics (CFD) model (C) CFD model of the heart OFT at maximal wall expansion, showing velocity profiles at three cross-sectional planes: I, M and O.

Published as: Figure 9 in Liu A, Yin X, Shi L, Li P, Thornburg KL, et al. (2012) Biomechanics of the Chick Embryonic Heart Outflow Tract at HH18 Using 4D Optical Coherence Tomography Imaging and Computational Modeling. PLoS ONE 7(7): e40869. doi:10.1371/journal.pone.0040869