If you are a pig or a mouse, said Michael Simons, M.D. ’84, chief of cardiovascular medicine and Robert W. Berliner Professor of Medicine, physicians can control tissue damage following a heart attack, but it’s not as easy if you’re human. Since biological therapies of the vasculature began in 1992, they have been based on animal models that use growth factors to treat ischemia. The goal, Simons told the audience at the alumni research symposium, is “to induce the growth of new arteries in such a way that we can essentially create a biological bypass.” In both mice and pigs such growth factors as VGEF induce the growth of new blood vessels, preventing the spread of tissue damage after a heart attack. However, in clinical trials, the animal models did not translate to humans. The nature of these animals may have confused the issue, Simons explained, because mice are resistant to vascular disease and pigs used in labs tend to be young and healthy.
Instead, Simons and his lab have “gone back to the bench” to understand “how the biology works” in clinical patients. They noticed that a patient with a 10-year history of diabetes had clogged vessels but was unable to create new arteries, while an older patient with years of angina and clogging but no diabetes was able to create new arteries. Why? Recent studies show that about 25 percent of the general population has pre-existing collateral arteries, while others do not. Simons’ lab found that although there were no differences in any of the growth factor levels between individuals who had collateral circulation and those who didn’t, these two groups had very different genetic profiles when their white blood cells were analyzed. A subset of genes appears to control whether we have collateral arteries or not. In addition, the activation of the arteriogenesis cascade is influenced by diabetes and high cholesterol—the very conditions that often cause and accompany cardiac disease (and which were absent in animal models). The defective activation of this signaling cascade is another reason why simply administering growth factors may not be effective. The field is now exploring the activation of post-receptor signaling as a way to overcome these barriers to induction of growth of new collateral circulation.
Frank J. Giordano, M.D., associate professor of medicine, spoke at the symposium about the use of genetic techniques to address cardiac problems. Unlike Simons, who repeated the quote, “gene therapy is in our future … and always will be,” Giordano sees current methods of using zinc-finger proteins to turn on the VGEF growth factor gene as “a start” to promising new approaches to genetic and epigenetic aspects of cardiovascular disease. His lab, which studies the interaction between gene expression and oxygen levels, has found that an increased need for oxygen in cardiac walls can lead to both atherosclerosis and spontaneous heart attacks. Giordano’s future research will further explore the genetic and epigenetic links between a high-fat diet and impaired vascularization across generations of subjects.