Right now, someone in Seattle is awaiting a heart transplant, and they may help to dramatically change the way heart failure is treated.

By serving as an incubator for his or her own stem cells, this person is taking part in an experiment designed to figure out some of the mysteries of re-growing heart cells: heart muscle regeneration. It’s a process that may lead to a new era in congestive heart failure therapy.

“What started out as a wild idea a long time ago — that you could use stem cells to repair the heart — has turned into a much bigger thing,” says Charles E. (Chuck) Murry, M.D., Ph.D., Res. ’92, UW professor of pathology, director of the Center for Cardiovascular Biology, co-director of the Institute for Stem Cell and Regenerative Medicine (ISCRM), and the Arra and Eva Woods Endowed Professor.

This is where heart failure/transplant cardiologist April Stempien-Otero, M.D., Fel. ’97, FACC (and the patients) enters the picture.

Stempien-Otero directs injection of stem cells — harvested from each patient’s own bone marrow — into the hearts Feature > of patients who are critically ill with coronary artery disease. These volunteers are awaiting heart transplants, and, like former Vice President Dick Cheney, are using left ventricular assist devices (LVADs) to survive.

Because the implanted LVADs pump blood to the body, stem cells can be injected into the heart without risk to the patient’s health. After the patient receives a new heart, the damaged organ is examined to determine if the injected cells helped to regenerate heart muscle tissue.

The need for new therapies for damaged hearts is acute.

“There are about one million heart attacks in the U.S. a year,” says W. Robb MacLellan, M.D., UW professor of medicine, head of the Division of Cardiology, and the Robert A. Bruce Endowed Chair in Cardiovascular Research. “A real concern — if you make it through a heart attack — is that you develop a syndrome called heart failure.”

Heart failure, also known as congestive heart failure (CHF), means that the heart loses its ability to pump blood forward through the body. Major causes include coronary artery disease and cardiomyopathy (weakening of the heart muscle) due to high blood pressure, toxins such as alcohol and chemotherapy, viral infections or genetic factors.

“Unlike the liver,” says MacLellan, “the adult heart, once it is injured, has very little capacity to regenerate itself.” Due to the scarcity of healthy donor hearts, fewer than 2,500 heart transplants are performed each year in the U.S. Thus, many patients who need heart transplants can’t get them. At the same time, no new CHF therapies that dramatically improve mortality have been developed in the last 10 years (although the survival rate after transplant has improved).

“The major advancements have been in mechanical devices, but they’re extremely expensive. That’s why there’s so much interest in regenerative solutions,” explains MacLellan. Experimenting with stem cells to regenerate heart cells has been going on for the past decade, but so far, he says, “the results have been quite variable — we don’t know how the stem cells work.”

“What April is doing is really trying to study this in a systematic way — what’s happening to these cells? Are they grafting to the heart? Because if we knew how they worked, we would be better able to pick patients who might benefit from the therapy,” MacLellan says.

Patient Tony Arena (center), with Chuck Murry, M.D., Ph.D., and April Stempien-Otero, M.D., is taking part in an exciting study designed to advance stem cell therapies for heart failure. Photo: Clare McLean

Stem cells do help people with heart disease. Studies in Europe have shown increased blood flow in the hearts of patients with coronary artery disease-induced heart failure after the injection of bone marrow-derived stem cells. The mechanisms of improvement, however, are unknown.

Stempien-Otero’s experiment, which builds on those already undertaken, has two primary goals. The first is to determine how certain bone marrow and other stem cells can improve blood vessel formation and decrease scar tissue formation in ischemic hearts — hearts receiving insufficient blood. The second is to have her study serve as a proof-ofprinciple for the process of injecting cells into damaged heart tissue and then examining the cells after the heart is retrieved.

The study offers “a way that we can very directly test different strategies for improving heart muscle structure,” Stempien-Otero explains.

Her project is part of a suite of studies at UW Medicine — funded by a grant from the National Heart, Lung and Blood Institute (part of the National Institutes of Health) — ultimately aimed at developing cellbased therapies to regenerate the human heart.

This next century is about curing disease through
regenerative medicine.
— Robb MacLellan

Stempien-Otero, a UW associate professor of medicine and the Craig Tall Family Endowed Professor in Heart Failure Research, is conducting her study under the auspices of the Center for Cardiovascular Biology and the Institute for Stem Cell and Regenerative Medicine. “[UW Medicine] is one of the few places in the country where I could have done this,” she says.

UW Medicine is a leader in cardiac regeneration research. From bioengineering myocardium (heart tissue), to using pluripotent stem cells (pluripotent cells can differentiate into different types of cells in the body) to regenerate heart muscle, to converting fibroblast stem cells (located throughout the body and easy to obtain) into heart cells, “there’s a very multidisciplinary, multi-investigator approach at UW Medicine to solve what is a huge public health issue,” MacLellan says.

In addition to addressing this major public health issue, Stempien-Otero’s program is significant because it represents “first-in-human” work that’s being done here in Seattle.

“April’s work is not just like a standard clinical trial; it’s a scientifically driven study to understand [the effect of the cells on the surrounding tissue],” says Murry. “Once you start understanding how something works, then you can rationally try to improve it.”

“This study is actually faster than a normal clinical trial,” says Stempien- Otero. “Each patient can test several different types of cells at the same time, and you can address these questions much more quickly.”

Thus far, Stempien-Otero has studied five patients out of the 12 needed to complete this initial study. In the hearts of the first two patients, she was able to track the area where the cells were injected.

“Our ultimate goal is to be the first institution in the world to actually do pluripotent stem cell therapy,” says MacLellan.

“This next century is about curing disease through regenerative medicine,” he adds. “We’ll never be able to prevent heart attacks entirely, but for those patients who do have a heart attack, we hope to regenerate the heart back to the way it was.”

by Deirdre Schwiesow

BRIDGING THE GAP BETWEEN SCIENCE AND PATIENTS

The research of April Stempien-Otero, M.D., Fel. ’97, FACC, is deeply informed by her work as a clinician, and vice versa.

“I realized the difference that research could make when I was in college,” she says. As part of a three-month research project at the University of Connecticut School of Medicine, she looked at the outcomes of patients who were given calcium chloride after a cardiac arrest. All the patients died, she says, and “a year later, calcium chloride was taken off the protocol.”

The impact of that experience ultimately resulted in Stempien-Otero, who now holds the Craig Tall Family Endowed Professorship in Heart Failure Research, coming to UW Medicine for a fellowship in basic research in cardiology.

Meanwhile, clinically, she became interested in treating heart disease — and in becoming a mentor. “I think it’s critical to train translational researchers,” she says, “people who bridge the gap between basic science and clinical practice.”

By giving clinical fellows exposure to the work in her lab and helping Ph.D. students to understand the experience of working with patients, Stempien-Otero and her colleagues are trying to bridge the gap between the lab and the clinic.

More formally, one way UW Medicine is bridging the gap is through the Division of Cardiology’s Research First program, a specialized fellowship pathway that begins with two years of dedicated research training followed by two years of clinical training.

“Our Research First program is specifically targeted to train young physicians who want to be physician-scientists so they can pick up the baton,” says W. Robb MacLellan, M.D., UW professor of medicine, head of the Division of Cardiology, and holder of the Robert A. Bruce Endowed Chair in Cardiovascular Research.

“Regenerative medicine is going to dominate research for the next several decades at least, and we’re trying to make sure that we’re producing the cardiologists who are going to be leading in this area,” MacLellan says.