When “Blue Babies” Grow Up
A typical human heart has two pumping chambers called ventricles—one to pump oxygen-depleted blood to the lungs, the other to send oxygen-rich blood to the rest of the body. However, every year, about 1000 babies in the United States are born with only one ventricle.
“These patients used to be called ‘blue babies’ because they don’t have enough oxygen when they’re born,” said Colleen Crouch, an assistant professor in the Department of Biomedical Engineering (BME) who uses advanced medical imaging techniques to study cardiovascular disease.
In the 1990s, surgeons standardized a series of procedures that can save these infants. The last of these surgeries, the Fontan procedure, is typically performed before a child turns three.
Unfortunately, while the procedure has allowed many thousands of children to grow up, Fontan patients face heart failure in their late teens and early twenties. The only real cure for this “Fontan failure” is a heart transplant.
“Doctors did what they could to keep these babies alive in the short term,” said BME Assistant Professor Bryan Good, who researches the underlying mechanics of cardiovascular disease with experimental and computational modeling. “But these patients end up having longer-term complications that you couldn’t have foreseen 30 years ago.”
Fontan patients see cardiologists regularly throughout their lives, but there is still no way to predict when Fontan failure will occur. However, Good and Crouch are confident that biomolecules in and around the heart change before patients experience symptoms. Untangling the patterns in those biomarkers could help doctors and patients start preparing for heart transplants years in advance of Fontan failure.
Earlier this year, Good and Crouch were awarded a three-year, $600,000 grant from the nonprofit Additional Ventures to search for these elusive molecules in collaboration with pediatric Fontan specialists from the University of Tennessee Health Sciences Center (UTHSC) in Memphis, Tennessee, and the Nationwide Children’s Hospital in Columbus, Ohio.
“Our project is unique in that we are covering such a wide breadth of techniques—combining computational modeling using actual patient geometries with a ‘basic science’ approach of studying individual molecules in patient cells,” Crouch said.
Rhythm Helps Heart Health
When a heart has only one ventricle, it pumps a mixture of oxygenated and deoxygenated (oxygen-poor) blood to both the lungs and the rest of the body. The Fontan procedure connects returning blood vessels straight to the pulmonary (lung) artery, bypassing the heart so deoxygenated blood can flow passively into the lungs and only oxygenated blood goes to the body.
The natural rhythm of a normal beating heart creates a cycle of greater and lesser stress on blood vessels, which is a key factor in cardiovascular cells working correctly. Good and Crouch believe that the lack of this cycle in Fontan patients’ pulmonary arteries may be contributing to Fontan failure.
To test their hypothesis, the BME professors are collaborating with Jason Johnson, the division chief of pediatric cardiology at UTHSC, which includes a state-of-the-art cardiovascular imaging device; and Mingtao Zhao, who directs the research center on patient-derived induced pluripotent stem cells (iPSCs) at Nationwide Children’s Hospital.
A Multi-Factor, Long-Term Study
Using images from Johnson’s patients, Good’s lab will create computer simulations and silicone models to investigate the hemodynamics (blood flow dynamics) in the hearts of real Fontan patients.
Zhao will use lines of Fontan patient-derived stem cells to create endothelial cells—the type of cells that line the pulmonary artery. Crouch’s lab will grow those cells on the inside of Good’s silicone models so that the team can study how real Fontan patients’ cells respond to real Fontan patients’ hemodynamics.
During hemodynamics experiments, Crouch will use a technique called mass spectrometry imaging (MSI) to identify molecules in the endothelial cells. The imaging technique is so sensitive that it can identify whether cells in one part of the model are making different biomarkers—a crucial detail for the professors’ hypothesis that unusual flow patterns cause the pulmonary artery cells unusual stress.
Importantly, this grant allows the four labs to form a long-term partnership that lets them investigate how heart architecture, biomarkers, and other health factors change as Fontan patients age.
“We may not know that one of our patients will develop Fontan failure in three years,” Crouch said. “With this long-term partnership, we will be able to compare a patient’s readings from Year One to Year Three—the same patient when they are ‘healthy’ and when they are experiencing Fontan failure.”
Improving Heart Science for All
Good, Crouch, Johnson, and Zhao’s work over the next three years will reveal the biological underpinnings of Fontan failure in unprecedented detail—and, hopefully, identify biomarkers that lead to earlier diagnosis and new treatments for Fontan failure.
The study could also improve treatment of non-Fontan patients by significantly improving medical understanding of the right ventricle. Most cardiovascular research attention goes to the left ventricle, since it sends blood to the rest of the body. However, pulmonary hypertension (high blood pressure) is one of the leading causes of heart failure in non-Fontan patients.
“This project is focused on congenital heart disease, but with these protocols and platforms that we develop, we’ll be able to investigate a lot of other pulmonary diseases,” Good said. “We could eventually translate this research to a much broader population.”
Contact
Izzie Gall ([email protected])