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Correcting the Heart’s Rhythm

National Institutes of Health Director’s New Innovator awardee Dr. Vasanth Vedantham works to lay a scientific foundation for new regenerative therapies for patients suffering from heart rhythm disorders. 


Failure of the heart’s natural pacemaker is a common clinical problem that cannot be delayed or reversed using any current treatment or technology. However, there is promising medical research on the treatment of heart rhythm disorders.

Dr. Vasanth Vedantham, an Indian American associate professor of medicine and cardiologist at University of California, San Francisco (UCSF), is pursuing research on regenerative therapies for patients suffering from heart rhythm disorders. Through a grant received under the National Institutes of Health Director’s New Innovator Awards 2019, Dr. Vedantham’s lab at UCSF is focusing on the basic mechanisms that allow the heart to generate and maintain its own rhythm, in order to create the scientific foundation for reconstituting this essential function of the human heart. 

A physician-scientist career path 

Dr. Vedantham was interested in science from an early age. He received a bachelor’s degree in physics and a master’s degree in biochemistry from Yale University, Connecticut, and initially planned a career as a research scientist. But he was also drawn to the human interaction in medicine and the immediacy with which physicians ease suffering and provide comfort. So, rather than choose between these two passions, Dr. Vedantham committed to a career as a physician-scientist, which allows him to both take care of patients and work as a disease-focused medical researcher. He received support for this career path from the National Institutes of Health’s Medical Scientist Training Program, simultaneously earning his medical degree as well as doctoral degree in neurobiology from Harvard University, Massachusetts.

Throughout his research career, Dr. Vedantham has been fascinated by the mechanisms that allow different cells in the body, especially brain cells and heart cells, to generate, conduct and transmit electrical signals. “With respect to heart rhythm, the human heart has evolved a sophisticated ‘wiring system’ that controls how a heartbeat originates and spreads throughout the entire organ,” he says. “Failure of the heart’s natural pacemaker is essentially an electrical problem in which the heart rhythm generator fails to transmit electrical signals to the rest of the heart at appropriate intervals, resulting in slow heartbeat.” 

According to the American College of Cardiology, approximately 200,000 pacemakers are implanted every year in the United States for patients with slow heartbeat. However, despite significant progress in developing new technologies for pacemaker and defibrillator devices, Dr. Vedantham notes, “We still require a battery-powered electronic device to detect heartbeat and stimulate it with an electrode.” While electronic pacemakers are often a life-saving treatment they can introduce their own set of problems and complications, and they leave patients with hardware inside their bodies for life. “Patients often ask me whether there are treatments that can restore the function of the heart’s natural pacemaker without the requirement for an artificial implant,” he continues. “Unfortunately, I have to explain that we don’t understand the biology well enough to design such a treatment.”

Inspired by this unmet need, Dr. Vedantham’s goal for the New Innovator Award research is to take a more targeted, biological approach with an ultimate aim of using regenerative therapies for restoring heart rhythm in patients suffering from slow heartbeat, irregular heartbeat and cardiac arrest. 

A new therapeutic approach 

Dr. Vedantham explains that slow heartbeat occurs when the specialized heart muscle cells, called pacemaker cells, which reside within the heart’s natural pacemaking region, the sinoatrial node, fail to generate enough current to activate the rest of the heart. “Our hope is that we will be able to reactivate the biological pathways that control the embryonic development of this natural pacemaker,” he says, “in order to restore function to diseased sinoatrial node tissue, thereby doing away with pacemakers all together.” 

Until recently, relatively little was known about the embryological origin of pacemaker cells and the molecular pathways controlling their formation. This is because each heart contains relatively few of these cells--several thousand out of billions of heart cells--making them hard to find and characterize. Thus, a major hurdle in this field was developing methods to isolate pacemaker cells from the rest of the heart in order to dissect their molecular machinery. “Even if you excise the entire sinoatrial node from the heart for further study, only a tiny portion of the material you end up with, about one to two percent, will consist of pacemaker cells,” says Dr. Vedantham.

However, a number of recent technological advances have allowed Dr. Vedantham’s lab to overcome this obstacle, rendering pacemaker cells easier to identify and isolate. “Our lab has developed new approaches and tools using model systems that allow us to gather information about the signals and pathways that are active in guiding the formation, growth and function of pacemaker tissue throughout heart development,” he says. “Specifically, we are able to label these cells with molecular ‘tags’ that allow us to visualize them and genetically modify them.” 

This means his research team is poised to test whether delivery of genes and compounds required for pacemaker cell development in a diseased adult heart can reactivate the developmental pathways that create pacemaker cells in the embryo. “In theory,” says Dr. Vedantham, “this could allow for permanent regeneration of the heart’s pacemaking capacity without the need for artificial pacemakers or other treatments.”

 

Hillary Hoppock is a freelance writer, former newspaper publisher and reporter based in Orinda, California.