Study suggests mechanical forces drive early heart development
The poet in us might see the heart as "a lonely hunter"; the adolescent as a toy thatís easily broken. But the biomedical engineer sees the heart as a pump, plain and simple, a machine shaped by genetics and complex biomechanical forces.
Larry A. Taber, Ph.D., professor of biomedical engineering at Washington University in St. Louis, has been probing the forces, stresses and deformations of the heart since the mid-1980s. A major focus of his work is to show that biomechanical forces may be as important as genetics in shaping the heart. Recently, he has developed a theory on tissue growth and morphogenesis (shape change) and applied it to understanding the developing heart in chicken embryos, which is remarkably similar to its counterpart in humans.
Taber is studying a phenomenon known as looping, one of the most critical stages of embryo heart development, where the heart at just two days of age in chickens (three weeks in humans) bends outward and rotates to the right. This is an almost ballet-like move that must happen perfectly to avoid misconnections of arteries in the heart walls and holes in the heart, among other serious developmental problems.
Taberís theory factors cellular contraction into looping, and he has found that the split-second looping process of bending and rotation is actually driven by at least two different mechanical forces. His research could help scientists better understand the roles physics and mechanics play in the developing heart and in heart defects.
Because geneticists currently do most of the research in this field, Taber and other biomedical engineers studying heart development provide clues into the cause-and- effect of the geneís masterplan, as well as a different perspective.
"You can knock out a gene and the heart might do something, but you donít really know the underlying mechanism," Taber says. "You only know you take this gene out and you see this effect. My collaborators and I are between the gene and the effect that people see. Weíre tyring to understand exactly whatís driving the heart to respond the way it does.
"Genetics researchers will say ĎThe heart either loops or it doesnít, and if it loops it either goes left or right,í and those often are the only distinctions made. "They donít say, ĎItís possible that it bends and doesnít rotate.í In our experiments, however,we see that that might happen. The point weíre trying to get across now is that to understand heart development, we have to look at bending and rotation as distinct components."
Taber discussed his theory, experiments and future direction of cardiac biomechanics in "Biomechancis of Cardiovascular Development," in the 2001 edition of Annual Revue of Biomedical Engineering. His work is supported by the National Institutes of Health (NIH). The chicken embryo heart is very close to the human heart in its development processes. It takes 21 days to hatch a chicken; at day 1, tubes form on two sides of the embryo and come together to form one tube. At this juncture (two-and-a-half weeks in the human embryo) the heart is just starting to beat. During the second day, blood flow starts and by the third day the tube is beginning to look like a heart, with septums later forming in two different regions to create left and right ventricles on one side, and right and left atria on the other.
Taber and his colleagues are stumped so far on the bending component of looping, though his graduate student, Evan Zamir, has developed techniques that will help them measure the stiffness in different regions of the heart tube. It appears that regional stiffness plays a role in bending. Another student, Mathieu Remond, is looking into whether cells in one region might contract more than cells on other sides, forcing the bending.
As for rotation, another Taber collaborator, Dimitri Voronov, Ph.D., a visiting scientist at Washington University , has discovered that a membrane that covers the tube may play a major role in causing the rotation to go to the right. "We believe that when the heart is formed itís slightly biased to the right normally , and that the membrane pushes it the rest of the way," Taber explained. Taber says engineers are just now looking at growth in the mature heart. His theory will be valuable in looking at these situations. Growth occurring in the mature heart is extremely important and plays a role in adaptation to high blood pressure (thicker heart walls) and heart attack.
"On the horizon, people are going to be looking at how the mechanical properties of the heart change as it develops," Taber says. "The active properties of heart tissue cause shape changes, as well as cause the heart to beat and pump blood. Until we have a handle on these properties, we cannot trust the predictions of our theoretical models."