About 1% newborn babies have congenital heart disease (CHD), the leading cause of death among children. The majority of CHD cases are believed not to have a genetic cause. Other factors, such as abnormal blood flow during embryonic and fetal stages can lead to heart malformations and thus CHD through poorly understood mechanisms. This project will elucidate early cardiac adaptations (changes in the rates of extracellular-matrix protein deposition, cell proliferation and apoptosis) in response to altered blood flow conditions and the progression of these adaptations at later stages of development in an in vivo animal model. The project will use chick embryos as models of cardiac development, focusing on the heart outflow tract (OFT), which gives rise to the intraventricular septum and semilunar valves. Blood flow exerts mechanical stimuli (stresses/strains) on the walls of the heart that can be quantified using techniques developed during the previous awarded period. Normal blood flow in chick embryos will be altered at day 3 (HH18) using surgical interventions that change blood pressure and shear stresses by constricting or ligating vessels with surgical sutures.
Aims are:
Aim 1 : Determine early changes in mechanical stimuli in response to hemodynamic interventions. Initial changes (within 2 hrs of intervention) in stresses/strains to which the OFT has to adapt will be quantified using optical coherence tomography (OCT) imaging and computational models of the OFT.
Aim 2 : Determine early cardiac adaptations to abnormal mechanical stimuli induced by hemodynamic interventions. Changes (with respect to controls) in extracellular matrix deposition and cellular proliferation and apoptosis in the heart OFT 24hrs after intervention will be determined using histology and immunohistochemistry techniques, and incorporated into a cardiac adaptation atlas. The extent to which adaptation patterns are locally driven by distributions of mechanical stimuli will also be determined.
Aim 3 : Elucidate the progression of early cardiac adaptations to altered hemodynamic stimuli. After 24hrs of intervention, the surgical interventions will be reversed by removing surgical sutures. The progression of early adaptations 1, 3, and 6 days after hemodynamic 'restoration' (embryonic days 5, 7, and 10) will then be determined using histology, immunohistochemistry, and ultrasound data. The study will elucidate the conditions under which early cardiac adaptations are reversible (hearts continue to develop normally) and the thresholds of mechanical stimuli beyond which reversibility is no longer possible.
Although blood flow has long been recognized as a key factor in heart development, the mechanisms by which hemodynamic conditions 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 these relationshis could eventually be used in the prevention and treatment of cardiovascular malformations, including CHD.
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| 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 |
| Kheradvar, Arash; Zareian, Ramin; Kawauchi, Shimako et al. (2017) Animal Models for Heart Valve Research and Development. Drug Discov Today Dis Models 24:55-62 |
| 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 |
| Rugonyi, Sandra (2016) Genetic and flow anomalies in congenital heart disease. AIMS Genet 3:157-166 |
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