Abstract-Endocardial cushions are critical to maintain unidirectional blood flow under constantly increasing hemodynamic forces, but the interrelationship between endocardial cushion structure and the mechanics of atrioventricular junction function is poorly understood. Atrioventricular (AV) canal motions and blood velocities of embryonic chicks at Hamburger and Hamilton (HH) stages 17, 21, and 25 were quantified using ultrasonography. Similar to the embryonic zebrafish heart, the HH17 AV segment functions like a suction pump, with the cushions expanding in a wave during peak myocardial contraction and becoming undetectable during the relaxation phase. By HH25, the AV canal contributes almost nothing to the piston-like propulsion of blood, but the cushions function as stoppers apposing blood flow with near constant thickness. Using a custom built mesomechanical testing system, we quantified the nonlinear pseudoelastic biomechanics of developing AV cushions, and found that both AV cushions increased in effective modulus between HH17 and HH25. Enzymatic digestion of major structural constituent collagens or glycosaminoglycans resulted in distinctly different stress-strain curves suggestive of their individual contributions. Mixture theory using histologically determined volume fractions of cells, collagen, and glycosaminoglycans showed good prediction of cushion material properties regardless of stage and cushion position. Key Words: chick Ⅲ development Ⅲ modeling Ⅲ ultrasound Ⅲ flow Ⅲ aspiration T he development of the atrioventricular (AV) and semilunar valves of the heart from the endocardial cushions occurs concomitantly with a constant barrage of hemodynamic and mechanical forces. Several studies have demonstrated that both blood pressure and velocities increase during morphological development in the heart, implying that the stresses on the endocardial cushions are also increasing. [1][2][3] Early investigations highlighted the motions of cushions in concert with the contracting myocardium, suggesting that they serve a valve-like function before valves form. 4 However, a recent study showed that the atrioventricular canal in the tubular early zebrafish heart functions like a suction pump, in contrast to the peristaltic mechanism previously described. 5 These observations raise no controversy with respect to current understanding of transitions that occur structurally and molecularly in the myocardium during early tube heart development, but raise major questions with respect to the mechanism through which endocardial cushions function in promoting unidirectional blood flow during the transition from tubular heart to a septated structure. In this study we examined the mechanical properties and myocardial/endocardial cushion mechanical interaction in 3 stages of cardiac development in the chick embryo to better understand how the mechanical properties of the cushions contribute to their functional roles.Various mutant models demonstrate that genetic defects compromising valve structural maturation result in s...
In this study, we develop an innovative approach to rigorously quantify the evolving hemodynamic environment of the atrioventricular (AV) canal of avian embryos. Ultrasound generated velocity profiles were imported into Micro-Computed Tomography generated anatomically precise cardiac geometries between Hamburger-Hamilton (HH) stages 17 and 30. Computational fluid dynamic simulations were then conducted and iterated until results mimicked in vivo observations. Blood flow in tubular hearts (HH17) was laminar with parallel streamlines, but strong vortices developed simultaneous with expansion of the cushions and septal walls. For all investigated stages, highest wall shear stresses (WSS) are localized to AV canal valve forming regions. Peak WSS increased from 19.34 dynes/cm2 at HH17 to 287.18 dynes/cm2 at HH30, but spatiotemporally averaged WSS became 3.62 dynes/cm2 for HH17 to 9.11 dynes/cm2 for HH30. Hemodynamic changes often preceded and correlated with morphological changes. These results establish a quantitative baseline supporting future hemodynamic analyses and interpretations.
Here we report that mouse embryos homozygous for a gene trap insertion in the fibulin-1 (Fbln1) gene are deficient in Fbln1 and exhibit cardiac ventricular wall thinning and ventricular septal defects with double outlet right ventricle or overriding aorta. Fbln1 nulls also display anomalies of aortic arch arteries, hypoplasia of the thymus and thyroid, underdeveloped skull bones, malformations of cranial nerves and hemorrhagic blood vessels in the head and neck. The spectrum of malformations is consistent with Fbln1 influencing neural crest cell (NCC)-dependent development of these tissues. This is supported by evidence that Fbln1 expression is associated with streams of cranial NCCs migrating adjacent to rhombomeres 2-7 and that Fbln1-deficient embryos display patterning anomalies of NCCs forming cranial nerves IX and X, which derive from rhombomeres 6 and 7. Additionally, Fbln1-deficient embryos show increased apoptosis in areas populated by NCCs derived from rhombomeres 4, 6 and 7. Based on these findings, it is concluded that Fbln1 is required for the directed migration and survival of cranial NCCs contributing to the development of pharyngeal glands, craniofacial skeleton, cranial nerves, aortic arch arteries, cardiac outflow tract and cephalic blood vessels.
Abstract-Hemodynamics influence cardiac development, and alterations in blood flow may lead to impaired cardiac growth and malformations. The developing myocardium adapts to augmented workload by increasing cell number (hyperplasia). The aim of this study was to determine the influence of alterations in ventricular preload on fetal myocyte proliferation by manipulation of intracardiac shunting at the atrial level. We hypothesized that partial clipping of the right atrial appendage would increase the blood flow to the left ventricle and, in turn, lead to an increase in chamber volume and myocardial mass based on myocyte proliferation. Using an ex ovo culture setup, we performed partial right atrial clipping on embryonic day 8 chick embryos. Ultrasound imaging was performed before and after the surgery to assess the changes in left ventricular volume. Sampling after 24 hours was preceded by 2 hour of pulse-labeling with 5-bromodeoxyuridine. Ultrasound imaging showed that partial right atrial clipping led to a significant increase in left ventricular end-diastolic volume, demonstrating increased blood flow and preload. Anti-5-bromodeoxyuridine immunolabeling revealed a significant increase in myocyte proliferation in the left ventricle and atrium. No significant changes were found in the right heart structures. Increased left ventricular myocyte proliferation and myocardial mass after right atrial clipping was also observed in embryos with experimental left ventricular hypoplasia. These results demonstrate the ability of fetal myocardium to respond to increased preload by myocyte hyperplasia and support the rationale for prenatal surgical interventions in certain cases of congenital heart disease such as hypoplastic left heart syndrome. (Circ Res. 2007;100:1363-1370.)Key Words: chick embryo Ⅲ hemodynamics Ⅲ fetal surgery Ⅲ hypoplastic left heart syndrome H ypoplastic left heart syndrome (HLHS) refers to a group of congenital cardiac anomalies characterized by underdevelopment of the left side of the heart. The anatomic abnormalities include underdevelopment of the left atrium and ventricle and hypoplastic or atretic mitral and aortic valves, and the right ventricle, rather than the left, forms the apex of the heart. 1,2 HLHS affects more than 2000 infants a year in the United States alone and accounts for approximately 25% of cardiac deaths within the first year of life. 3
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