Hemodynamic Regulation Of Cardiac Outflow Morphogenesis
Throughout development, blood flow guides cardiac morphogenesis, sculpting tissue by promoting growth in response to increased mechanical demands. Alterations in flow patterns during critical stages of development may therefore lead to adverse tissue remodeling and subsequent functional cardiac defects. Distinguishing the specific effects due to hemodynamics and genetic mutations is a current challenge, as the role of hemodynamics in outflow tract and pharyngeal arch artery morphogenesis is poorly understood. There exists a need for more clinically relevant animal models that allow for the study of disease pathogenesis both structurally and molecularly. My work begins to delineate the effects of structural changes resulting from abnormal hemodynamic patterning and elucidate their effects in the creation of congenital heart defects through a combination of experimental interventions and computational modeling. Two- photon microscopy guided femtosecond laser pulses were used to nucleate and control the growth of cavitation bubbles within developing outflow vessels without disturbing surrounding tissues. These cavitation bubbles temporarily occluded the vessel, while a more stable occlusion while a more stable occlusion was formed by ablating the circulating thrombocytes that accumulated behind the bubble. Using this approach, I examined the effects of PAA vessel occlusions on embryonic viability, hemodynamic rearrangement, and downstream outflow tract morphogenesis (Chapter 3). A zero-dimensional (0D) electric analog model that allows for global tuning of the embryo's vasculature relative to the arches was developed (Chapter 4). A 3D-0D model was used to characterize natural variation in day3, day4, and day 5 arch artery pressure, flow, and shape changes. These 0D bounds served as a basis for prediction of flow distribution to the cranial and caudal outlets when switching between normal and aberrant flow (Chapter 5). Results revealed distinct morphology dynamics for day3, day4, and day 5 geometries, as well as natural shifts in arch artery dominance at different stages and across individual days. Immediate remodeling of the arch artery vasculature took place following day 3 experimental occlusions. In some embryos, that remodeling worked to lessen the severity of increased pressure magnitude in the cranial part of the aortic sac. My findings contribute a more detailed picture of arch artery growth and adaptation across a critical window of development.
hemodynamics; cardiogenesis; mathematical modeling
Noden,Drew Morrison; Schaffer,Chris; Vignon-Clementel,Irene
Ph.D. of Biomedical Engineering
Doctor of Philosophy
dissertation or thesis