Not far away: Using the force to halt heart malformation

The stain of the active Rac1 protein appears in the left atrioventricular valve (similar to the human heart’s mitral valve) in an embryonic chick. This chick has been treated with the right-atrial ligation procedure, which diverts more blood into the left side chamber, which increases mechanical loading – or force. This results in the accelerated development of the valve.
Jonathan Butcher
Russell Gould

Cornell biomedical engineers have found natural triggers that can override developmental, biological miscues – research that could reduce the chance of life-threatening, congenital heart defects among newborn infants and lead to proper embryonic heart and valve formation. The research is published Dec. 24 in Current Biology.

“The heart is the first organ to form in the embryo. It morphs dynamically and rapidly all the while pumping nutrients to the developing body,” said senior author Jonathan Butcher, associate professor at Cornell’s Nancy E. and Peter C. Meinig School of Biomedical Engineering.

More than 40,000 babies in the United States – or about 1 in 100 births – are born annually with a congenital heart defect, making it the most common defect, according to the Children’s Heart Foundation.

The early embryonic heart originates as a looped tube, without valves or pumping chambers. During the last few weeks of the first trimester, these heart chambers form, but need something to maintain one-way blood flow.

“Wispy globular masses (called cushions because of their shape in the heart wall) need to condense and elongate to form thin robust leaflets capable of fast and resilient opening and closing,” Butcher said. “It is this maturation process that’s likely disrupted in many clinical cases.”

Until this study, scientists did not know how – or if – mechanical forces drove the biological remodeling of cushions into valves. Medical science understood that the embryonic heart needed blood flow to grow, but the valve component’s role was not entirely understood, Butcher said.

“We identified a mechanism that transduced – or translated – a mechanical force into a biological response,” Butcher said. “That biological response over time creates these thin, flexible, formative leaflets. If this tissue fails to get thinner, that’s a problem. If the tissue fails to elongate, that’s a problem. And these are all problems we see in the clinic.”

The researchers found that cyclic stretches and stressing forces activate sensitive enzymes called GTPases, specifically RhoA and Rac1, which coordinate the embryonic heart’s maturation. Without the RhoA and Rac1 activating at the proper times, heart valves do not form correctly.

Early cushion formation required RhoA signaling, but later cushion remodeling into leaflets was driven by Rac1. Cyclic stretch, another force, was needed to flip the switch between RhoA and Rac1 driving the remodeling, they found. To demonstrate in vivo, the researchers conducted microsurgery in an embryonic chick to show that blood flow shunted away from the valve maintains a RhoA driven cushion, but by increasing flow to the valve region deactivates RhoA and accelerates the Rac1 elongation and maturation process.

This work lays a foundation for hemodynamically informed surgical interventions to potentially retard valve malformation – or to restore it, Butcher said.

Lead author Russell Gould, Ph.D. ‘15, formerly a member of Butcher’s laboratory, is a postdoctoral researcher at Johns Hopkins University. Other researchers on the study, “Cyclic Mechanical Loading is Essential For Rac1 Mediated Elongation and Remodeling of the Embryonic Mitral Valve,” were Huseyin Yalcin of Dogus University, Istanbul, Turkey; Joanna MacKay and Sanjay Kumar, both of the University of California, Berkeley; and Kimberly Sauls, Medical University of South Carolina.

The National Science Foundation, the National Institutes of Health and the American Heart Association supported the research.

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Daryl Lovell