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 Improved Therapeutic Remedies to the Electronic Pacemaker

Going ‘Beyond Mice and Molecules’ to Human Heart Disease

The National Institutes of Health recently awarded a more than $1.5 million grant to a team from The Ohio State University Dorothy M. Davis Heart and Lung Research Institute. Three Ohio State faculty members — Cynthia A. Carnes, PharmD, PhD, Vadim V. Fedorov, PhD, and Peter Mohler, PhD, — serve as the team of co-principal investigators. Equipped with ground-breaking technological capabilities developed by Dr. Fedorov, pre-clinical techniques enabled by Dr. Carnes, and molecular approaches facilitated with Dr. Mohler, the work will address human sinus node disease, a problem found in the pacemaker of the heart known as the sinoatrial node (SAN). Sinus node disease causes arrhythmias and is a precursor for atrial fibrillation (AF), a condition that currently afflicts over 2.2 million Americans. AF is an area of clinical strength for The Ohio State University Heart and Vascular Center. Ohio State is a national leader in terms of procedural volume in cardiac electrophysiology.

The study’s goal is to find improved therapeutic remedies to the electronic pacemaker, a device that has long been implanted in the heart to mitigate sinus node disease and is the current accepted standard of care.

The Team

Cynthia A. Carnes, PharmD, PhD, Vadim V. Fedorov, PhD, and Peter Mohler, PhD

The team of Drs. Carnes, Fedorov and Mohler represents a collaboration between Ohio State’s College of Medicine and College of Pharmacy. Dr. Carnes is associate dean for Graduate Studies and Research in the College of Pharmacy. Dr. Mohler is a cardiovascular scientist who serves as director of Ohio State’s Dorothy M. Davis Heart and Lung Research Institute. Dr. Fedorov, who was educated in Moscow, Russia, in physiology, is an assistant professor in Ohio State’s Department of Physiology and Cell Biology. Finally, a critical component of the team is the contribution of dedicated physician-scientists in the Department of Surgery at The Ohio State University Wexner Medical Center, led by Robert Higgins, MD.

Dr. Carnes originally came to Ohio State in the early 1990s to learn more about treating arrhythmias with a fellowship in Cardiovascular Pharmacotherapy. She met Dr. Fedorov at a conference in Washington and the two researchers discovered a mutual interest in sinus node disease. It was a stroke of good fortune a few years ago when Dr. Fedorov migrated to Ohio State. Dr. Carnes says, “Vadim has world-class capabilities when it comes to studying the sinoatrial node, and this dovetails perfectly with my interest in arrhythmias and heart failure.”

Dr. Mohler is director of Ohio State’s Davis Heart and Lung Research Institute where he oversees a group of more than 600 faculty, staff and trainees in eight different colleges. His team is working to understand the mechanisms and treatments for diseases ranging from heart failure, arrhythmia and sudden cardiac death, to pulmonary and cystic fibrosis, diabetes and kidney disease.

The Misson

In the simplest terms, Drs. Carnes, Fedorov and Mohler aspire to fix damaged human hearts. The mission is two-fold. First, they want to better understand how human sinoatrial node pacemakers dysfunction and how that dysfunction leads to atrial fibrillation (AF). Second, they hope to repair SAN dysfunction in patients with either congenital or acquired sinus node disease.

“The lack of understanding of the human pacemaker system, the sinoatrial node, and its complexity remains a critical barrier to the treatment of heart rhythm disorders. Implanting an electronic pacemaker is the default remedy, but really it is a crutch,” says Dr. Fedorov. “Electronic pacemakers beat steadily at one rate. In contrast, the SAN is the internal pacemaker of the heart, so it knows when to beat faster — for example, during exercise — and when to beat slower – during sleep or rest. With this grant, we seek to restore and heal the SAN rather than rely on pacemakers as the only remedy.”

The trio begins with a hypothesis that SAN dysfunction may result from an increased sensitivity to adenosine, a metabolite of the heart that lowers heart rate and thus conductivity. The first priority of the team’s work focuses on blocking the adenosine receptor to test the hypothesis that heart failure results from adenosine-dependent signaling in the SAN.

With Dr. Fedorov’s 3D, high-resolution, near-infrared optical mapping capabilities, he can examine the SAN internally and from all angles. “Seeing the human heart through the eyes of 3D optical fluorescence mapping allows for a broad range of exciting and novel research opportunities,” says Dr. Fedorov.

The Breakthrough

“The work we are doing is truly translational medicine. We are now able to study damaged human hearts, which is something that was just a dream five years ago. Few researchers have ever done this to study sinus node disease – we are going beyond simply mice and molecules to human disease,” says Dr. Mohler.

The team’s ability to use state-of-the-art imaging technology to study a failed heart is what makes this a rare and valuable study. All three investigators cite this development as amazing progress, and they hope and believe it is just the beginning.

The Present and Future

The consensus among the team is that at least another two years of research is needed before they can begin to work on healing the SAN. They first must determine why it is not functioning correctly. At that point, Dr. Carnes believes that drug treatments may be effective. Dr. Fedorov agrees and adds that localized stem cell repairs may also be a viable treatment. Dr. Fedorov sees the work accomplished over the next three and a half years as a cornerstone of innovation.

“The work in this proposal should provide a blueprint for SAN dysfunction. It should also provide a foundation for developing highly targeted and rational treatments for human arrhythmias originating in the SAN pacemaker complex. Future work might then focus on other signaling pathways or pharmacologic treatments or stem cell delivery to modulate SAN function,” says Dr. Federov.

Dr. Carnes believes the future is bright because of the collaborative nature of this project, which is reflective of the collegial spirit endemic to the entire Ohio State community. Having spent nearly three decades at Ohio State, she attests, “We have built a first-class operation with bench-to-bedside research in arrhythmias. Teamwork is integral to everything we do. Working with Drs. Mohler and Fedorov on this project is a great example of that.”