Cardiac looping, which begins with ventral bending and rightward rotation of the primitive heart tube, is an essential morphogenetic event that occurs early in vertebrate development. The biophysical mechanism that drives this process is unknown. It has been speculated that increased stiffness along the dorsal side of the ventricle combined with an intrinsic cardiac force causes the heart to bend. There is no experimental support for this hypothesis, however, since little is known about regional mechanical properties of the heart during looping. We directly measured diastolic stiffness of the inner curvature (IC), outer curvature (OC), and dorsal-ventral sides of the stage 12 chick heart by microindentation. The IC of intact hearts was found to be significantly stiffer than either the OC or the sides. which were of similar stiffness. Isolated cardiac jelly, which is a thick, extracellular matrix compartment underlying the myocardium, was approximately an order of magnitude softer than intact hearts. The results of a computational model simulating the indentation experiments, combined with the stiffness measurements, suggests the regional variation in stiffness is due to the material properties of the myocardium. A second model shows that a relatively stiff IC may facilitate bending of the heart tube during looping.

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Early in development, the heart is a single muscle-wrapped tube without formed valves. Yet survival of the embryo depends on the ability of this tube to pump blood at steadily increasing rates and pressures. Developmental biologists historically have speculated that the heart tube pumps via a peristaltic mechanism, with a wave of contraction propagating from the inflow to the outflow end. Physiological measurements, however, have shown that the flow becomes pulsatile in character quite early in development, before the valves form. Here, we use a computational model for flow though the embryonic heart to explore the pumping mechanism. Results from the model show that endocardial cushions, which are valve primordia arising near the ends of the tube, induce a transition from peristaltic to pulsatile flow. Comparison of numerical results with published experimental data shows reasonably good agreement for various pressure and flow parameters. This study illustrates the interrelationship between form and function in the early embryonic heart.

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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