Insulin and Glucose Metabolism in Pediatric Heart Failure
Thanks to progress in treatments and surgical techniques, about 30,000 children born with heart defects now reach adulthood every year in the United States. As a result, the number of adults who live with congenital heart disease has exceeded one million. And, of these, nearly 100,000 are living with severe heart defects.
This has raised concern among pediatric cardiologists for problems like heart failure that their young patients may face down the road. Discovery Institute investigators Drs. Patrick Jay and Charles Canter share this concern. These Washington University School of Medicine pediatric cardiologists and an interdisciplinary team of specialists are collaborating on a Children’s Discovery Institute-funded project aimed at providing long-term, good-quality survival for young heart failure patients.
“Children are not little adults, but most heart failure treatments draw from the adult experience.” said Dr. Jay. “The biology of a child with heart failure and the typical adult with heart failure is different. For one thing, adults with heart failure are likely to have other problems such as diabetes, atherosclerosis, or metabolic syndrome. Most pediatric patients, on the other hand, don’t have other organ diseases. Future therapeutic strategies might then be more or less applicable to children because of intrinsic differences in their hearts or risks of side effects related to diseases that they don’t have.”
It’s that single medical issue that makes pediatric heart patients prime candidates for the treatment that the investigators are exploring.
“From studies of adults and animal models, we know that in the early stages of heart failure, the amount of glucose reaching the heart muscle is increased,” said Dr. Jay. “This is thought to boost the delivery of energy to an energy-starved heart. We wonder whether this is just part of a greater adaptive response that leads to the preservation of cardiac function.”
Over time, however, the patient (or mouse) becomes “insulin resistant,” the condition that exists when the body can make insulin but cannot use it properly to convert glucose into energy. Likewise, the failing heart may not be able to take in as much glucose as needed. In experiments with transgenic mice, Dr. Paul Hruz, a pediatric endocrinologist, and Dr. Jay showed that the degree of insulin resistance parallels the severity of heart failure—as insulin resistance worsens, so does the heart.
So, if heart failure is exacerbated by limiting the amount of glucose getting to the heart muscle, can enhanced glucose uptake be beneficial? According to their research, the answer is yes. “Administering a drug that targets insulin resistance significantly improved heart function and survival in our mouse models.”
But will these drugs help children with heart failure?
“The first thing we need to do is establish that children follow the same progression with regard to the relationship between glucose uptake and heart failure,” said Dr. Jay. An enormous amount of effort and time have gone into building the infrastructure to explore this relationship using methods never applied before in pediatric heart failure.
This past fall, Dr. Jay and Dr. Robert Gropler, professor of medicine and radiology, obtained the approvals at the institutional and federal levels needed to do the studies. Meanwhile, Dr. Canter enlisted other midwestern pediatric heart failure/transplant centers to recruit patients for these studies. Collaborations have been established with Cardinal Glennon Children’s Medical Center in St. Louis, Children’s Memorial Hospital in Chicago, and Arkansas Children’s Hospital in Little Rock.
Enrollment has already begun. Volunteers can undergo one of two types of tests for insulin sensitivity, as well as cardiac PET (positron emission tomography) imaging (a technology developed at Washington University) to assess glucose uptake by the heart. The team expects to enroll more than 100 pediatric heart patients and 100 normal subjects, ages 1-18, in the study over the next three years.
“What we learn from these studies about the progression of heart disease in children will set the stage for clinical trials that will certainly benefit future patients,” said Dr. Canter. And, if these studies confirm the investigators’ hypothesis, targeting insulin resistance may well become an important new therapeutic strategy in pediatric heart care in the future.