A Simple Heart

Its shape, in zebra fish, goes with the (blood) flow.

Zebrafish
Tom Moore

Blood is amazingly delicate and unstable. Essentially a suspension of cells and proteins in water, blood forms clots or clumps in response to any harsh mechanical treatment. That property keeps blood from pouring out uncontrollably after a break in a blood vessel, but it has also made it impossible so far to devise an artificial device that can pump blood without degrading its components and thereby increasing the risk of stroke.

The human heart is so miraculously gentle that it avoids that pitfall. Even as it contracts a hundred thousand times a day, pushing blood through a network of piping that is astonishingly complex, it keeps clotting to a minimum—in part because of its shape. What has been a mystery is how the heart achieves its shape, because its form doesn't seem to be entirely the responsibility of the genes that are active as the organ develops. Biomechanists studying the hearts of embryonic zebra fish have discovered that what shapes the heart, in part, are the forces of blood flow—the very same forces that, in other circumstances, turn blood into clotted goo.

heart valves

Cutaway ventral (“front”) views (not to scale) of three vertebrate hearts—human (left), bird (center), and amphibian—demonstrate the variety of shapes that the organ can assume. In the human and the bird hearts, the right side (the nomenclature reflects the heart owner's point of view) sends blood (blue) to the lungs to be oxygenated; on returning to the heart, the oxygenated blood (red) is then pumped to the rest of the body. Amphibian hearts have a three-chambered structure; although deoxygenated blood enters on the right of the heart and oxygenated blood enters on its left, the two flows are united (purple) in a Y-shaped structure called the conus arteriosus before they branch toward the lungs (and skin) or the rest of the body.

Tom Moore

Fish are half-hearted when it comes to blood flow, at least compared with mammals. The mammalian heart is actually two conjoined pumps: one sends blood to the lungs, to be oxygenated; the other supplies blood to the tissues of the body. A fish's heart, however, has a single pump that pushes blood into a bed of capillaries in the gills, before circulating it at low pressures throughout the rest of the body. In spite of such a major organizational difference, the early development of fish and human hearts is similar, and both kinds of heart have a similarly gentle effect on the fluid they pump.

The zebra fish, a common denizen of home aquariums, has become a favorite subject of study by developmental biologists because its embryonic stage is transparent and a good size for microscopy, two attributes that make its organ systems easy to observe as they form. If you watch closely, you can see the heart of a zebra fish embryo beating rhythmically within a day of fertilization. That heartbeat has been a long-standing puzzle: Why does it begin so early, far sooner than seems necessary? At that stage, the embryo is still so small that diffusion alone could readily supply oxygen and nutrients to its tissues. Yet, there is the tiny heart, busily working away, pushing blood through a rudimentary circulatory system.

Jay R. Hove, a physiologist now at the University of Cincinnati, and Reinhard W. Köster, now a biologist at the the Institute of Developmental Genetics in Munich, and colleagues at Caltech have presented convincing evidence that the paradoxically early appearance of the fish's heart enables fluid forces to shape the young pump into a gentle giant. Earlier investigations had already demonstrated that cardiac endothelial cells, primordial cells that control the development of the heart, change shape when subjected to shear forces—just the kind of forces a fluid exerts when it flows past a fixed object. Hove and Köster have shown experimentally that the shear forces of flowing blood in the developing heart are strong enough to reshape the heart as it matures.

Measuring fluid forces in the heart of an embryonic zebra fish a day and a half after fertilization is no mean feat. After all, the entire embryo could fit on the head of a pin, and the heart is far thinner than a human hair. No probe available is small enough to measure flow directly in something that size. The investigators had to rely instead on clever but indirect techniques.

The heart of the embryonic zebra fish first appears as a clear, straight tube, except for two regions of swelling along its length [see diagrams at right]. The two swellings contract in sequence, just as they do once they fully differentiate into the atrium, which receives blood from the body, and the ventricle, which pushes the fluid pumped into it from the atrium back out. Hove, Köster, and their colleagues estimated the amount of blood pumped with each stroke by measuring the initial and final volume of the ventricle, the larger of the two chambers of the heart. To make the measurement, they highlighted the blood of a number of zebra fish with a glowing green dye, then filmed the heart as it fully contracted and expanded.

zebrafish heart

Zebra fish heart thirty-seven hours into development (a) is essentially a tube with two bulges, the atrium and the ventricle, that pump blood through the circulatory system. After four and a half days (b) the heart bends so that the atrium lies next to the ventricle, another contractile chamber called the bulbus arteriosis forms, and valves develop between chambers to prevent reverse movement of blood. Surgically inserted glass beads, either at the entrance to the atrium (c) or the exit from the ventricle (e), prevent normal development of the heart: the heart does not bend, neither the bulbus arteriosis nor the valves form, and the ventricle fuses shut (d, f).

Tom Moore

From the volume of blood pumped and the duration of a single heartbeat, the team calculated the speed of the blood as it flowed through the heart. And once they had the fluid speed, they could determine the shear stress in the heart wall. The forces they calculated might seem small, but in a fish just thirty-seven hours old, the forces are strong enough to change which genes are turned on or off in endothelial cells, thereby reshaping the cells. Perhaps the shear forces trigger the cell membrane to release proteins that affect gene expression.

A different technique showed that even greater shear forces can develop in older embryos. By four and a half days after fertilization, a zebra fish has grown to about an eighth of an inch long, and its heart has become as wide as a human hair. The heart is bent in such a way that the atrium and the ventricle lie next to each other, and valves to prevent blood from flowing backwards are already recognizable. Again the investigators filmed dark blood cells as they swirled in bright green-dyed plasma through the heart, then tracked the filmed positions of the cells frame-by-frame with the help of a computer. On the basis of that analysis they built a computer-based model of the blood flow, which showed that a high-speed jet of blood passes from atrium to ventricle with each beat, creating vortexes in the blood. The shear forces exerted by the vortexes are strong enough to rearrange the cytoskeleton of an endothelial cell, and thus to change the cell's shape.

The biomechanists hadn't proved that blood flow, rather than blood pressure, is the most important factor in heart development. To make sure, the workers implanted a microscopic spherical bead, either at the entrance or the exit of each heart: a bead that blocks the entrance reduces both blood flow and pressure in the heart, whereas one that blocks the exit reduces just the flow, not the pressure. After only twenty hours the results were clear. With either blockage the heart failed to develop normally: the valves did not form, the atrium and ventricle did not lie next to each other, and a contractile third chamber that appears in the normal heart never developed. Shear force is the major player in shaping the developing heart.

The heart works, in fact, largely because it is flexible. The genome does not code for a pump of specific shape, but rather for a cell type that can respond to shear, the force that damages blood cells. Those cells ensure that as the heart develops, it grows in ways that minimize shear. The end result is a pump gentle enough to circulate blood without causing dangerous clots.

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