The University of Chicago Medicine - Comer Children's Hospital

Department of Pediatrics 2017 Annual Report

Genomics & Organ Physiology Cardiology

Daniel Gruenstein, MD, with patient Aziyah Hall

We’re making heart devices a reality for our youngest patients

Daniel Gruenstein, MD, and Rachel Simon, RN, BSN, CPN, in the Pediatric Cath Lab 

Pediatric interventional cardiologists have long been frustrated at the dearth of FDA-approved cardiac devices designed specifically for children. “To find innovative ways to repair cardiac defects in children noninvasively in the cath lab, we’ve often had to resort to using adult devices intended for other cardiac problems,” says Daniel Gruenstein, MD, director of the pediatric cardiac catheterization lab. It was only in 2004 that the first device—the Amplatzer duct occluder I (ADO I)—was approved to treat patent ductus arteriosus (PDA) specifically in children. But the device, which closes a blood vessel that connects the aorta and the pulmonary artery, is still fairly large and has to be deployed with stiff delivery sheaths, making it unsuitable for most children younger than six months of age or six kilograms.

Gruenstein conducted the preclinical research to develop and test a device that was smaller and could be deployed with a significantly smaller and more flexible catheter. In addition, the symmetrical design of the device allows it to be implanted without placing the catheter through the heart, making insertion potentially less traumatic for the smaller blood vessels of younger children. Gruenstein then led the 25-center phase I trial of the ADO II device in 192 patients. The recently published two-year follow-up study showed that the device was successfully implanted in 93 percent of patients, with complete closure in 98 percent of successful implantations, matching the success rates of the first-generation larger device. “Another advantage is that there is significantly less radiation exposure to children with this new device, which is faster and easier to deploy than the earlier version,” says Gruenstein.

Another advantage is that there is significantly less radiation exposure to children with this new device.

~ Daniel Gruenstein, MD

The data from Gruenstein’s study have pushed forward an even smaller version of the device, the ADO II AS, which is being used in Europe to treat PDA in premature infants and is being evaluated in a clinical trial in the United States. “Premature babies are most at risk of PDA and still require an open-chest surgical procedure to repair the defect,” says Gruenstein. PDA is found in roughly 0.02 to 0.006 percent of babies born at term and 20 to 60 percent of babies born prematurely.

Reducing radiation exposure in kids—especially those with complex heart disease who may require multiple cardiac catheterizations, X-rays, and CT scans—is paramount at Comer Children’s, says Gruenstein. The state-of the art hybrid pediatric cardiac catherization lab was designed specifically to minimize radiation exposure, including real-time dose tracking of radiation exposure to patients. “The University of Chicago has unique capabilities to reduce radiation exposure in children, and our cath lab is visited by pediatric and adult cardiologists and radiologists from around the country,” says Gruenstein.

We now understand how genetic mutations cause congenital heart disease

Ivan Moskowitz, MD, PhD

Congenital heart disease (CHD) is the most significant class of human birth defect. Over the last several decades, researchers have identified many genes that contribute to CHD. But they have only just begun to understand the link between a gene’s role in heart development and how its mutation causes CHD—information required to develop diagnostic and therapeutic approaches beyond postnatal surgery, the current mainstay of CHD treatment.

Cardiac progenitor cells in the embryo will ultimately differentiate into heart muscle cells, or cardiomyocytes, to form the heart. But how this differentiation process is regulated is not well understood. Ivan Moskowitz, MD, PhD, and Megan Rowton, PhD, a postdoctoral scholar on his research team, have, for the first time, shown how the timing of the differentiation process is determined. They have shown that the Hedgehog signaling pathway, a network that plays a role in several organ systems during embryonic development, determines the timing of cardiac progenitor differentiation, unlocking a novel molecular mechanism controlling heart development and providing greater understanding for some types of CHD.

The progenitor cells never have the opportunity to close holes in the heart because they turn into muscle too early, outside of the heart itself.

~ Ivan Moskowitz, MD, PhD

Hedgehog signaling initiates a program in cardiac progenitor cells that causes them to differentiate at the proper time during embryonic development. When Hedgehog signaling is functioning normally, it blocks differentiation, maintaining cardiac progenitor cells as progenitors and allowing them to proliferate and migrate into the heart to build necessary heart structures. As the progenitor cells move away from active Hedgehog signaling and into the heart, the removal from Hedgehog signaling allows them to differentiate. A defective Hedgehog pathway, however, causes the progenitors to differentiate precociously before getting into the heart. “The progenitor cells never have the opportunity to close holes in the heart because they turn into muscle too early, outside of the heart itself,” says Moskowitz.

Moskowitz, Rowton and collaborators are now using genome sequencing to confirm these discoveries in humans. “The defective genes are the same in mice and in humans, so we have every reason to believe that problems in this pathway will also cause congenital heart disease in humans,” Moskowitz says.

It’s also possible that the Hedgehog pathway may play a role in the timing of cellular differentiation throughout the body. “This mechanism may be important in the development of organs other than the heart and may even have implications in other contexts in which progenitor status is inappropriately maintained, such as cancer,” says Moskowitz.

“Our future work will include analysis of how differentiation timing is determined in these other contexts,” adds Moskowitz. We hope that a greater understanding of how the differentiation process is regulated in health and disease may allow novel approaches to disease diagnosis or therapeutic intervention.”

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