Faculty Spotlight: Yerem Yeghiazarians, MD

Heart attacks remain the leading cause of death in the United States, claiming the lives of more than 500,000 Americans each year. More than 1.5 million Americans have a new or recurrent heart attack each year.

Over the last two decades, new therapies and technologies have significantly improved survival and long-term outcomes for heart attack patients. For some individuals, though, today's treatments are not enough. These patients progress to end-stage heart failure, in which the heart is unable to pump enough blood to meet the body's needs even while the patient is at rest and receiving optimal medications. Most critically, no current treatments can replace or regenerate the heart muscle cells, or cardiomyocytes, that are injured or destroyed during a heart attack.

Dr. Yerem Yeghiazarians, director of the UCSF Translational Cardiac Stem Cell Program, is helping to lead groundbreaking research that may offer new hope to such patients. During a heart attack, a blood clot blocks the flow of oxygen to the left ventricle of the heart, causing the destruction of cardiomyocytes and the subsequent formation of scar tissue. Over time, the scar tissue expands and replaces healthy tissue, further weakening the heart's pumping capacity and leading to heart failure.

Dr. Yeghiazarians and others in the field hope that stem cells will offer a way to repair the damage to the heart that results from heart attack. These "master cells" have the ability to renew themselves and to generate any of the specialized cell types that comprise the body, including cardiomyocytes. By potentially enabling us to minimize the scar after a heart attack, stem cells could serve as a "fountain of youth" for heart attack patients.

The Promise of Stem Cells

Since 2003, when he was recruited to UCSF to head the Translational Cardiac Stem Cell Program, Dr. Yeghiazarians and his team have explored this very promising area of inquiry. The group has focused its efforts on three stem cell types that may be particularly relevant for use in future therapies. These include bone marrow-derived cells, native cardiac stem cells, and human embryonic stem cells.

In order to begin conducting their studies, the team developed a novel ultrasound-guided stem cell delivery method for injecting stem cells directly into the hearts of mice. Dr. Yeghiazarians' lab was the first in the world to use this innovative technique to demonstrate that stem cells can decrease scar size and improve cardiac function after a heart attack. Now, he and his colleagues are working to pinpoint the exact mechanisms by which this improvement occurs.

"In the case of bone marrow-derived cells, we have found that the primary mechanism of cardiac functional improvement is that these cells produce beneficial proteins that save cardiomyocytes from death during a heart attack," said Dr. Yeghiazarians. The team has identified specific receptors for this cardioprotective protein on the heart muscle cell and is conducting studies to ascertain whether it can use drugs to activate the production of these beneficial proteins. The UCSF Office of Technology Management considers the lab's findings to date so encouraging that it has applied for a patent for this endeavor.

Native cardiac stem cells, on the other hand, appear to improve heart function not only via the signals they emit to nearby cells, but also by integrating themselves into the blood vessels of the heart and generating new vessels. "Given that a heart attack involves the blockage or loss of blood vessels, the ability to generate new vessels capable of carrying blood back to the heart after a heart attack is a tremendous step forward toward the development of improved treatments for patients," Dr. Yeghiazarians said.

Dr. Yeghiazarians and his group have also discovered and published a novel method to more efficiently differentiate human embryonic stem cells into cardiomyocytes and have found that these cells, too, improve cardiac function after a heart attack. Interestingly, even these cells appear to improve the cardiac function primarily via the cellular communication signals they emit.

Much Research Lies Ahead

While his team and other labs around the world have made great strides, Dr. Yeghiazarians noted that researchers are still at the beginning of their journey of understanding stem cells. To create a dependable and effective therapy for widespread use in humans, a lot of clinical research lies ahead.

Some of the many questions that remain to be answered include: Exactly which stem cell types will comprise the most effective therapy in humans? How many cells should be delivered to the heart after a heart attack? When should the cells be delivered? Should a therapy consist of a combination of cells? What is the best mode of delivery? Who are the ideal patients for cell-based therapies? Can we improve the retention of stem cells in the heart after cell delivery?

To investigate the optimal method of retaining stem cells in the heart, Dr. Yeghiazarians has partnered with a bioengineering lab at UC Berkeley to develop a biodegradable scaffold upon which they can embed stem cells. They seek to verify whether the use of this scaffold-stem cell combination will allow more stem cells to remain in the heart after a heart attack, which in turn may enhance overall cardiac function even more significantly.

In the future, Dr. Yeghiazarians believes that the scientific community may even have the capability to generate bioartificial tissue and organs, including human hearts, by embedding patient-specific stem cells onto biomechanical scaffolds, "growing" the organs in the lab, then transplanting them into the patient. "Will it happen in my lifetime?" asked Dr. Yeghiazarians. "I don't know, but that is the direction we're headed. If I had unlimited funding, this would be the project that I would focus on, especially given the shortage of donor organs worldwide."

Private support has been critical to the success of the UCSF Translational Cardiac Stem Cell Program. "Our stem cell studies require a multitude of experiments that take a long time and are very costly," said Dr. Yeghiazarians. "Traditional sources of funding like the National Institutes of Health won't really support these kinds of activities at the start. By enabling us to pursue our most innovative ideas, our friends in the community have helped us construct a premier center for cardiac stem cell research at UCSF, and I am very grateful."

To view Dr. Yeghiazarians' complete presentation, "Stem cells: What's New and Where Are We Headed?" please visit HealthyHeart.ucsf.edu.