Focusing Expertise on Heart Disease

Associate Professor Brent French still can’t believe his good fortune. He holds joint appointments in biomedical engineering, radiology, and cardiovascular medicine, making it much easier for him to forge the fluid series of research collaborations required to devise more effective therapies for heart disease. “The work my lab does involves complex biology and sophisticated instrumentation,” he says. “Having the resources and expertise of these three departments available to us makes a tremendous difference.”

French has made considerable progress in investigating the heart’s response to the damage caused by heart attack. Heart muscle is limited in its ability to repair itself, so it remodels itself in an effort to compensate for lost capacity. In particular, the left ventricle undergoes dramatic changes after a heart attack. Because it cannot contract as powerfully as it once did, it attempts to provide the same volume of blood to the body by growing larger. This requires the surviving tissue to stretch thinly around the enlarged chamber, further diminishing its contractile power. As a result, people who survive a severe heart attack are in danger of dying from heart failure six to nine months later.

In his efforts to understand the causes of this remodeling and prevent it, French draws on the specialties of a number of researchers at U.Va. He collaborates with Dr. Zequan Yang, an assistant professor of research in the Department of Biomedical Engineering, who developed a mouse model of heart attack that exhibits virtually the same left ventricular dysfunction and subsequent remodeling found in humans.

With Dr. Christopher Kramer, professor of radiology and internal medicine; and Frederick Epstein, an associate professor of radiology and biomedical engineering, French pioneered a new, noninvasive method to measure the damage to heart tissue caused by heart attack in mice. Basically, they adapted magnetic resonance imaging (MRI) techniques that are used to study the hearts of patients. This was no easy task, as mice hearts are 100 times smaller and beat 10 times faster than human hearts, but the effort was well worth it. It gives French and his collaborators the ability not only to compare one animal with another, but also to track the progress of disease over time.

With the mouse model of heart attack and his mouse-ready MRI techniques, French targeted an enzyme called iNOS (inducible nitric oxide synthase) that has been implicated in cardiac dysfunction. He turned to Victor Laubach, an associate professor of surgical research, who had genetically engineered a mouse that did not produce iNOS—a knockout mouse. The researchers applied Yang’s model to a group of iNOS knockout mice and normal mice, and used the MRI techniques developed with Kramer and Epstein to show that mice from both groups had sustained similar damage, and tracked the left ventricular remodeling process over time. In just 28 days, the hearts of the normal mice showed significant enlargement, while the hearts of the knockout mice were half the size.

In other words, French and his colleagues proved conclusively that if researchers could develop a drug to interfere with the action of iNOS, they had a good chance of preventing death from heart failure. French is currently testing a number of approaches, using the unique mouse system. “Having access to the exceptional set of researchers gathered around cardiovascular disease at the University helps make progress all that much faster,” he says.