Driving new AFib treatments by identifying its source

Vadim Fedorov, PhD, was only six years old when his grandfather was hospitalized with a heart attack in their hometown of Voronezh, Russia, but can recall the incident in vivid detail.

“Sitting at my grandfather’s bedside in the hospital, I promised him that someday, I would find a way to make his heart beat forever,” Fedorov says.

Fedorov’s grandfather eventually recovered, but he lost his father and grandmother to sudden cardiac arrest in the years that followed. He enrolled in a Physics of Living Systems program at the Moscow Institute of Physics and Technology, resolved to develop technology that could help prevent cardiac death for families like his. And that’s exactly what he did.

Since he joined the Ohio State College of Medicine Department of Physiology and Cell Biology in 2011, Vadim Fedorov, PhD, the Corrine Frick Research Chair in Heart Failure and Arrythmia, has conducted pioneering research in cardiac arrhythmia, a condition that occurs when the electrical impulses that coordinate heart rhythms misfire, causing the heart to beat too quickly or too slowly. If not treated, cardiac arrhythmia can be fatal.

Not long after he joined the faculty, he met a kindred spirit in John Hummel, MD, an electrophysiologist at The Ohio State University Wexner Medical Center and professor in the College of Medicine. A specialist in the treatment of cardiac arrhythmia, particularly an arrhythmia called atrial fibrillation (commonly known as AFib), Dr. Hummel is always looking for new strategies to improve patient outcomes and quality of life.

His initial meeting with Fedorov would prove to be fortuitous. For much of the past decade, the two have worked together to uncover the hidden sources of atrial fibrillation and pave the way to more effective treatment for millions.

Ending the debate

AFib is a rapid, irregular heartbeat that originates from the two upper chambers of the heart called the atria. Instead of coordinating with the ventricles — the two lower chambers — to maintain a steady heartbeat, the atria essentially go rogue. Untreated, AFib can lead to blood clots, stroke and heart failure.

Ablation uses heat to interrupt the abnormal electrical activity that sustains atrial fibrillation. It’s a common procedure considered the standard of care in the treatment of AFib. Dr. Hummel and his colleagues observed that while they could successfully treat some patients by using the well-defined technique of eliminating triggers from the pulmonary veins, this approach was inadequate for others.

“For more than a decade, there was substantial controversy over whether or not there were sites outside the pulmonary veins that sustained AFib,” Dr. Hummel says. “The topic was of little interest to the world at large, but it was a burning issue within my field. Based upon existing studies in animals by other investigators, we suspected that if these sites did exist, we could target them and make them electrically silent, effectively eliminating AFib in many patients.”

The debate over whether or not these sites exist in humans ended in a laboratory on Ohio State’s campus, where Fedorov and his team developed a novel human heart model that provides a rare glimpse into the inner workings of the heart. 

Visitors who don’t know that the heart can beat outside of the human body are in for a shock when they visit the Fedorov Lab. On any given day, they may find a glass chamber containing a recently donated human heart perfused with (bathed in) a warm oxygenated solution.

This solution stimulates blood flow, allowing the heart to beat for at least 12 hours with the same rhythm as when it was inside the donor’s body.

Many of these hearts come to the Fedorov Lab from patients undergoing a heart transplant at the Richard M. Ross Heart Hospital at The Ohio State University Wexner Medical Center who’ve elected to donate their diseased heart to science, while some hearts are donated through Lifeline of Ohio.

Once the donated heart is resuscitated, Fedorov and his team place atrial tissue in a perfusion bath surrounded by four ultra-sensitive infrared cameras. They then inject fluorescent dye that can sense electrical activity straight through the atrial wall.

The combination of the dye and the infrared light reveals an unprecedented level of information about the structure and electrical function of the heart. While current clinical imaging displays 200 recordings across the heart, Fedorov’s imaging system displays 40,000.

“Essentially, this imaging allows us to see how electricity spreads across the structure of the human heart in 3D,” Fedorov says.

“It confirmed the presence of something we were already seeing in animal models: re-entrant drivers in the atria. These are small sites outside the pulmonary veins where we can observe the abnormally fast electrical activity that sustains AFib.”

Published in European Heart Journal in 2015, Fedorov’s findings definitively established the existence of re-entrant drivers and ushered in a new era for translational patient care.

Translating research into results

Dr. Hummel remembers meeting Fedorov in 2013 at a talk Fedorov delivered on disease of the sinus node, the natural pacemaker of the heart. Hummel immediately recognized the translational potential of the imaging technology Fedorov was describing, calling it a “feather in the cap of Dr. Fedorov and Ohio State.” From that day on, a fruitful collaboration emerged.

With the exception of one overseas medical facility, Ohio State is the only health center in the world employing this technology in human hearts. By inducing AFib in a donated heart, Fedorov can gather information that illuminates a better treatment strategy for patients.

One of these patients, Richard “Steve” Hines, ended up in the ICU after a routine physical revealed he was experiencing atrial fibrillation. “There would be two or three regular beats then it would be a real low one or a real quick one, just all over the charts,” remembers Hines. According to Dr. Hummel, Hines was a “poster child” for the type of recurrent, 24/7 atrial fibrillation that many of his patients experienced.

 

“By giving us greater clarity into where the drivers of AFib might be, Dr. Fedorov is helping us figure out how to deliver better therapy to the types of patients we treat every day,” Dr. Hummel says.

Two weeks after Hines’ first ablation, he learned that the procedure failed to restore his heart to a normal rhythm. His second ablation also failed to correct the problem. For his third ablation, Dr. Hummel used the 3D imaging technology developed by Fedorov to guide him.

“He explained to me that with their new procedure, they could pinpoint the problem areas and the chances of getting it was a lot better,” Hines says. “It was pretty exciting because you know that whether it does or doesn’t work, they’re going to learn something from it. I’m fortunate to be with people who think outside of the box.” 

The third time was the charm for Hines.

“If you look at our data on the patients we’re treating using the information gleaned from this new technology, the success rates at a year and a half post-ablation run around 75-78%, which is significantly better than the national average of 40-60%,” Dr. Hummel says. “Our data is still preliminary, but it’s showing signs of great promise.”

Dr. Hummel answers frequently asked questions about atrial fibrillation

To date, Fedorov and Dr. Hummel have co-authored close to 30 research articles, several of which are focused on what re-entrant driver sites look like anatomically with MRI imaging. In one publication, they reported finding that re-entrant drivers aren’t always a closed loop, as previously understood, but are instead more like hubs of electrical activity that resemble tornados.

In another joint study, they established that the right atrium is three times more sensitive than the left to adenosine, a biochemical produced during times of metabolic stress – like after a heart attack or bypass surgery. During clinical tests, the research team found that injecting adenosine affects cardiac electrical activity, making the tornados that signal atrial fibrillation even more apparent. By injecting adenosine intravenously before ablation, they were able to improve the identification of ablation targets by 80% for patients enrolled in a clinical trial.

“Everyone likes to talk about translational research, but it’s rare to find such a straight line of connection between two labs,” Dr. Hummel says. “It’s been an exciting partnership that relies on the strength of a much larger team than the two of us.”