The role of mechanical forces in the torsional component of cardiac looping

Abstract

During early development, the initially straight heart tube (HT) bends and twists (loops) into a curved tube to lay out the basic plan of the mature heart. The physical mechanisms that drive and regulate looping are not yet completely understood. This paper reviews our recent studies of the mechanics of cardiac torsion during the first phase of looping (c-looping). Experiments and computational modeling show that torsion is primarily caused by forces exerted on the HT by the primitive atria and the splanchnopleure, a membrane that presses against the ventral surface of the heart. Experimental and numerical results are described and integrated to propose a hypothesis for cardiac torsion, and key aspects of our hypothesis are tested using experiments that perturb normal looping. For each perturbation, the models predict the correct qualitative response. These studies provide new insight into the mechanisms that drive and regulate cardiac looping.

Figure 1

Schematic for cardiac rotation hypothesis. Ventral views (a,b,c) and cross-sectional views (a′,b′,c′) are shown, with locations of cross sections indicated by dashed lines in a,b,c. (HT = heart tube, LA = primitive left atrium, RA = primitive right atrium, OT = outflow tract, CJ = cardiac jelly, MY = myocardium, EN = endocardium, SPL = splanchnopleure, DM = dorsal mesocardium, FG = foregut) (a,a′) Straight heart tube before looping. (b,b′) Both atria push against caudal end of the heart tube, and relatively greater force exerted by the left atrium displaces and rotates the heart tube slightly toward the right. (c,c′) The splanchnopleure pushes the heart tube dorsally, completing torsion. (from 24)

Figure 2

Effects of removing splanchnopleure (SPL) on c-looping in embryonic chick heart. To visualize torsion, fluorescent labels were placed along the ventral midline. (Stages 10, 11, and 12 are 36, 42, and 48 hr of incubation, respectively.) (A to C) Control heart rotates rightward, as labels move to outer curvature. (D to F) SPL removal at stage 10 results in little or no rotation at stage 11 (E), but full rotation by stage 12 (F). (+) = SPL intact, (−) = SPL removed. Scale bar = 300 μm. (from 20)

Figure 3

Three-dimensional finite element model for looping heart without splanchnopleure (ventral view). Nodes on the ventral midline are marked to visualize rotation. (a) Undeformed configuration with morphogenetic loads indicated; insert shows side view. (HT = heart tube, CT = conotruncus, DM = dorsal mesocardium) (b) Deformed configuration. Midline nodes move rightward as HT rotates, similar to experiment (see Fig. 2B). (from 24)

Figure 4

Experimental and computational effects of atria removal on looping. (a–c,d–f) Initial configuration (stage 10) with splanchnopleure (SPL) and at least one atrium removed (solid lines indicate cut locations). (a′–c′, d′–f′) Final configuration (approximately 12 hr later). Midline labels (experiment) and nodes (model) are used to visualize rotation. Top row: Left atrium is removed; heart loops leftward. Middle row: Right atrium is removed; heart loops rightward with abnormal morphology. Bottom row: Both atria are removed; rightward rotation occurs. In each case, the model predicts approximately the correct heart shape, as indicated by dotted traces. (from 24)

Figure 5

Two-dimensional model for cardiac rotation including mechanical feedback in the myocardium. The time points shown in each case correspond to the experimental time points shown in Fig. 2D–F. (a) Model geometry for stage-10 heart (MY = myocardium, DM = dorsal mesocardium, CJ = cardiac jelly, FG = foregut wall). The heart is given a small initial rightward push, and then the load is removed. (b) Little rotation occurs during the first six hours. (c) After 12 hours, the heart has rotated fully. (from 24)