We can celebrate the fact that children born with heart defects are living longer than ever before, thanks to advances in medicine and surgery. In fact, in the United States eight out of 10 babies born with congenital heart disease now reach their 16th birthday.
But sadly, medical treatments or surgical repair of heart defects can't always make the heart perfect, and can leave a child with persistent irregularities in how the heart works. Over time, even those babies with the best care can grow into children or young adults whose hearts fail because of long-term mechanical stresses.
When that happens, parents naturally look to their children's physicians to offer effective solutions. Patrick Jay, M.D., Ph.D., assistant professor of pediatrics at Washington University School of Medicine, is the leader of a project sponsored by the Children's Discovery Institute that asks if treatment for insulin resistance could be a new way to extend the lives of children with heart failure.
"Drugs now used to manage heart failure were developed through trials on adults and extrapolated to children," says Jay, a pediatric cardiologist at St. Louis Children's Hospital. "We know these medications slow down progression of heart failure, but they don't cure it. So we're looking for other approaches to slow or even stop heart failure in children."
As a first step, Jay and his colleagues will test children with heart failure to see if their heart muscle uses blood sugar (glucose) like normal heart muscle does. No one has performed this kind of test before on such children.
Because of past research in laboratory animals, Jay suspects he will find in children with heart failure that the heart muscle is insulin resistant. If that's the case, drugs ordinarily given to type 2 diabetics to improve glucose metabolism could help these children with failing hearts.
Jay is taking this unusual approach because of an interesting discovery by colleague Paul Hruz, M.D., Ph.D., assistant professor of pediatrics at the School of Medicine. Hruz, a pediatric endocrinologist at St. Louis Children's Hospital, noticed that certain drugs for treating HIV/AIDS block glucose from getting into tissues. He also saw that patients have a hard time exercising after taking the drug — that's because glucose is essential for muscle movement.
Jay and Hruz looked at what happened to mice with heart failure when they were given the same HIV/AIDS drug. They found that the drug, and the resulting inhibition of glucose uptake, quickly exacerbated their heart failure.
"We also knew that failing hearts in mice can become insulin resistant — meaning that the heart muscle can't take up glucose in response to insulin as normal heart muscle would," Jay says. "That's a similar situation to that of the mice getting the HIV/AIDS drug — their hearts can't absorb glucose. So we made the intellectual leap that treating insulin resistance would help these mice with heart failure live longer. We gave the mice medication used to treat type 2 diabetes, and their life spans increased dramatically."
The research Jay is conducting with funding from the Children's Discovery Institute will investigate whether children with heart failure have the same abnormalities of glucose uptake and insulin resistance as the mice. If they establish that the same underlying problem exists, they can initiate trials to see the effect on pediatric heart failure patients of insulin-sensitizing agents commonly used to treat type 2 diabetes.
"This is truly a direct translation to human medicine of some exciting results that we saw in the laboratory," Jay says. "We want to lay the groundwork for future clinical trials of insulin-sensitizing agents for treating heart disease. Because of the prevalence of type 2 diabetes now, many companies are making such drugs and investigating new ones, so these drugs will be readily available."
In addition to Jay and Hruz, other Washington University faculty working on the project include Charles Canter, M.D., professor of pediatrics; Robert Gropler, M.D., professor of radiology, of medicine and of biomedical engineering; and Farrokh Dehdashti, M.D., professor of radiology.
Canter, a pediatric cardiologist, directs the Heart Transplant Program at St. Louis Children's Hospital. Gropler is a leading expert in the glucose and fat metabolism of the heart, and heads the Cardiovascular Imaging Laboratory at the School of Medicine's Mallinckrodt Institute of Radiology. Dehdashti, an authority on the use of PET scans in cancer patients, will guide the use of that technology to examine glucose uptake in the hearts of the study participants.