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Making the invisible visible to improve heart surgery outcomes

Scientists find a way in mice to illuminate the cardiac conduction system during surgery to prevent unintended damage to healthy tissue.

When Will Goodyer, MD, PhD, was looking for a research project, his colleagues asked him to tackle a seemingly impossible task: Find a way for heart surgeons to see an invisible network of cells so they can avoid damaging it during surgery.

It was 2015, and Goodyer was starting his fellowship training in pediatric cardiac electrophysiology, becoming a specialist of children's heart rhythm disorders. He decided he was up for the research challenge, which he hoped could help avert a common cause of heart-rhythm problems.

The rhythm of the heart is controlled by a network of specialized cells called the cardiac conduction system, which paces the heart and coordinates the actions of its four pumping chambers.

"The conduction system is invisible to the naked eye," said Goodyer, now a pediatric cardiologist and electrophysiologist at Stanford Medicine Children's Health and an assistant professor of pediatrics at the Stanford School of Medicine. "The cells are not neurons; they're actually specialized heart muscle cells. They look like the surrounding heart muscle tissue."

Because these special muscle cells look the same as their neighbors, surgeons may inadvertently damage them during heart surgery. They try to avoid harm by using anatomical landmarks to estimate where they shouldn't cut or sew, but that approach is imperfect. Some part of the cardiac conduction system is injured in 1% to 3% of all intracardiac surgeries, with complications arising more frequently during the most complex operations to fix major congenital heart defects.

"Unfortunately, the majority of people who have damage to the conduction system end up needing a pacemaker for the rest of their lives," said Goodyer.

His research in the past several years has centered on developing a way to make the conduction system visible during surgery by using antibodies that temporarily deliver a harmless dye to the surface of those cells, a method that has proven successful in mice. Now, his team is expanding their research with the goal of pursuing clinical trials.

Finding and exploiting molecular differences

Think of the conduction system as the symphony conductor for the lub-dub music of heartbeats: It sets the rhythm of muscular contractions and gives other heart muscle cells cues to join in. The system is made up of two big clumps of cells, called nodes, which are linked to long tendrils of electricity-carrying cells that fan out across the heart.

The sinoatrial node, located near the top of the heart, is nature's pacemaker. Its role is to start each heartbeat, then send electrical signals through a network of cells that cause the top two heart chambers to contract. It's also responsible for speeding up and slowing down the heartbeat in response to the body's needs.

Antibodies that bind to surface markers found on specific cells in the cardiac conduction system make otherwise hard-to-see tissue visible (gold) during heart surgery in a mouse.

The atrioventricular node, found in the middle of the heart near the junction of its upper and lower chambers, slows the electrical signal while the top heart chambers are contracting. This gives time for blood to flow into the relaxed lower chambers.

Then, when the lower chambers are full of blood, electricity passes through the atrioventricular node and shoots through the network of conducting cells in the lower part of the heart, generating the big push of muscular contraction that sends blood toward the lungs and to the aorta for its journey through the rest of the body.

As a postdoctoral fellow in the lab of Stanford Medicine cardiologist Sean Wu, MD, PhD, Goodyer began investigating what makes the cardiac conduction cells biologically different from other heart muscle cells. The researchers have characterized which genes are uniquely active in the conduction cells and have identified molecular surface markers that are found only on conduction cells.

This discovery helped Goodyer realize he might be able to solve the invisibility problem by borrowing an idea from cancer surgeons: attaching antibodies, which bind to surface markers found on specific cells, to dye molecules that in turn become fluorescent under near-infrared light.

Surgeons across the country, including Eben Rosenthal, MD, an otolaryngology/head & neck surgeon-scientist now at Vanderbilt University, who collaborated with Goodyer, are conducting clinical trials in which they give cancer patients similar antibody-dye conjugates before surgery. In the operating room, surgeons use a near-infrared camera to spot the dyed cancer cells and excise as much of the cancer as possible.

Instead of targeting malignant cells, Goodyer's approach uses a conduction-specific antibody-plus-dye combo to help surgeons avoid damaging healthy cells in the heart. His team identified two types of cell markers on the cardiac conduction system that could be targeted by antibodies, and attached these antibodies to the near-infrared dye. They gave single injections of the antibody-dye combinations to mice.

So far, the technique works. A study published in August 2022 in the Journal of Clinical Investigation demonstrated, in mice, that the antibodies bind only to the conducting cells of the heart; that they are safe and don't interfere with heartbeat; and that the dye made the cardiac conduction system clearly visible, even for networks of cells much thinner than the width of a human hair.

The team is gathering more data to apply for permission from the U.S. Food and Drug Administration for a human clinical trial, which they hope to launch in a few years.

Who will benefit?

"My vision is that every child and adult that needs heart surgery would ultimately receive a single injection of this product,  allowing their surgeons to visualize the conduction system in real time," Goodyer said.

Adults patients could benefit, he said, especially those who require repairs of the one-way valves in the heart, as they are close to the atrioventricular node, leaving it vulnerable to damage in valve surgeries.

However, Goodyer said children with congenital heart disease may benefit the most from the new technique. These children, who are born with hearts that have variation in their structure, often receive surgery early in life to correct their cardiac anatomy. Attempts by surgeons to estimate the locations of the children's cardiac conduction systems are even less reliable than usual because sometimes their hearts' anatomical landmarks aren't in the usual places.

"It'll be super fascinating to see the natural variation in how the system is wired from one child to another, even in kids with structurally normal hearts, let alone those with congenital heart disease," he said. "From my nerdy perspective, I'm very excited to see what all these conduction systems look like, because we've never seen that!"

Image from the Goodyer Lab, reprinted with permission from the Journal of Clinical Investigation.

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