Computational Model for Early Cardiac Looping

Ramasubramanian, Ashok; Latacha, Kimberley S.; Benjamin, Jessica M.; Voronov, Dmitry A.; Ravi, Arvind; Taber, Larry A.

doi:10.1007/s10439-006-9152-2

Cited by 54 publications

(54 citation statements)

References 28 publications

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“…This model extends and integrates our previous models for looping, which simulated bending and torsion separately (Taber et al, 1995; Taber and Perucchio, 2000; Voronov et al, 2004; Ramasubramanian et al, 2006, 2008; Shi et al, 2014). The model is built on a foundation of experimental data and is based on the fundamental principles of soft tissue mechanics, including large deformation, growth, and active cytoskeletal contraction.…”

Section: Introductionsupporting

confidence: 60%

Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry

Shi

Jiang²,

Young

et al. 2014

Front. Physiol.

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The morphogenetic process of cardiac looping transforms the straight heart tube into a curved tube that resembles the shape of the future four-chambered heart. Although great progress has been made in identifying the molecular and genetic factors involved in looping, the physical mechanisms that drive this process have remained poorly understood. Recent work, however, has shed new light on this complicated problem. After briefly reviewing the current state of knowledge, we propose a relatively comprehensive hypothesis for the mechanics of the first phase of looping, termed c-looping, as the straight heart tube deforms into a c-shaped tube. According to this hypothesis, differential hypertrophic growth in the myocardium supplies the main forces that cause the heart tube to bend ventrally, while regional growth and cytoskeletal contraction in the omphalomesenteric veins (primitive atria) and compressive loads exerted by the splanchnopleuric membrane drive rightward torsion. A computational model based on realistic embryonic heart geometry is used to test the physical plausibility of this hypothesis. The behavior of the model is in reasonable agreement with available experimental data from control and perturbed embryos, offering support for our hypothesis. The results also suggest, however, that several other mechanisms contribute secondarily to normal looping, and we speculate that these mechanisms play backup roles when looping is perturbed. Finally, some outstanding questions are discussed for future study.

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Section: Introductionsupporting

confidence: 60%

Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry

Shi

Jiang²,

Young

et al. 2014

Front. Physiol.

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“…The endodermal shortening rate we measured between HH10 and HH11 (figure 7(c)) agrees relatively well with the strain data of [23]. Our microindentation tests revealed a 2–3 fold decrease in tissue stiffness after exposure to Bleb (figure 5(b),(c)), which is consistent with those previously reported in the heart and brain of chick embryos at later stages [15, 52, 53].…”

Section: Discussionsupporting

confidence: 90%

“…Thus, we chose to inject labels at various stages and quantify endodermal contraction during the following 6 hr. Since computing the cumulative stretch ratio by multiplying incremental stretch ratios [23] could accumulate measurement errors, this method is not suitable for our analysis. Instead, we calculated the shortening rate ( Λ̇ = − λ̇ ) and assumed (to a first approximation)…”

Section: Experimental Methodsmentioning

confidence: 99%

Why is cytoskeletal contraction required for cardiac fusion before but not after looping begins?

2015

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Cytoskeletal contraction is crucial to numerous morphogenetic processes, but its role in early heart development is poorly understood. Studies in chick embryos have shown that inhibiting myosin-II-based contraction prior to Hamburger-Hamilton (HH) stage 10 (33 hr incubation) impedes fusion of the mesodermal heart fields that create the primitive heart tube (HT), as well as the ensuing process of cardiac looping. If contraction is inhibited at or after looping begins at HH10, however, fusion and looping proceed relatively normally. To explore the mechanisms behind this seemingly fundamental change in behavior, we measured spatiotemporal distributions of tissue stiffness, stress, and strain around the anterior intestinal portal (AIP), the opening to the foregut where contraction and cardiac fusion occur. The results indicate that stiffness and tangential tension decreased bilaterally along the AIP with distance from the embryonic midline. The gradients in stiffness and tension, as well as strain rate, increased to peaks at HH9 (30 hr) and decreased afterward. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that they are mainly generated by active cytoskeletal contraction, and finite-element modeling indicates that the measured mechanical gradients are consistent with a relatively uniform contraction of the endodermal layer in conjunction with constraints imposed by the attached mesoderm. Taken together, our results suggest that, before HH10, endodermal contraction pulls the bilateral heart fields toward the midline where they fuse to create the HT. By HH10, however, the fusion process is far enough along to enable apposing cardiac progenitor cells to keep “zipping” together during looping without the need for continued high contractile forces. These findings should shed new light on a perplexing question in early heart development.

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“…For more than 30 yr, computational models have been used to simulate various morphogenetic processes [38], including some used to test other hypotheses for c-looping [26,30,35,39]. Several of these models, as well as the present model, are based on the theory for finite volumetric growth of Rodriguez et al [40].…”

Section: Methodsmentioning

confidence: 99%

Bending of the Looping Heart: Differential Growth Revisited

Shi

Jiang

et al. 2014

Journal of Biomechanical Engineering

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In the early embryo, the primitive heart tube (HT) undergoes the morphogenetic process of c-looping as it bends and twists into a c-shaped tube. Despite intensive study for nearly a century, the physical forces that drive looping remain poorly understood. This is especially true for the bending component, which is the focus of this paper. For decades, experimental measurements of mitotic rates had seemingly eliminated differential growth as the cause of HT bending, as it has commonly been thought that the heart grows almost exclusively via hyperplasia before birth and hypertrophy after birth. Recently published data, however, suggests that hypertrophic growth may play a role in looping. To test this idea, we developed finite-element models that include regionally measured changes in myocardial volume over the HT. First, models based on idealized cylindrical geometry were used to simulate the bending process in isolated hearts, which bend without the complicating effects of external loads. With the number of free parameters in the model reduced to the extent possible, stress and strain distributions were compared to those measured in embryonic chick hearts that were isolated and cultured for 24 h. The results show that differential growth alone yields results that agree reasonably well with the trends in our data, but adding active changes in myocardial cell shape provides closer quantitative agreement with stress measurements. Next, the estimated parameters were extrapolated to a model based on realistic 3D geometry reconstructed from images of an actual chick heart. This model yields similar results and captures quite well the basic morphology of the looped heart. Overall, our study suggests that differential hypertrophic growth in the myocardium (MY) is the primary cause of the bending component of c-looping, with other mechanisms possibly playing lesser roles.

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Computational Model for Early Cardiac Looping

Cited by 54 publications

References 28 publications

Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry

Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry

Why is cytoskeletal contraction required for cardiac fusion before but not after looping begins?

Bending of the Looping Heart: Differential Growth Revisited

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