Congenital heart defects are the most common birth defect, affecting 8 out of every 1,000 newborns according to the National Heart, Lung and Blood Institute. In the U.S., more than 35,000 babies are born annually with some sort of heart defect.
For nearly 20 years, Cathy Hatcher, PhD, assistant professor at Philadelphia College of Osteopathic Medicine, has been studying the causes of these defects. In a study currently published online and appearing later this month in the journal Circulation Research, Hatcher and colleagues looked at the role the Tbx5 protein plays in heart development. Specifically, they demonstrated a novel role for Tbx5 in the epicardium—the outermost cell layer of the heart, which is also the predecessor to the coronary vessels that supply blood and nutrients to the heart.
"The job of Tbx5 is to target certain genes and regulate their function within a cell at a specific point in time," Dr. Hatcher explains. In this study, "we have identified new targets of Tbx5 in the developing heart: adhesion and matrix molecules, which act as the heart's 'glue,' binding different types of cells together."
The Tbx5 protein is expressed in various cells of the heart, and existing research has shown it plays a role in the development of those cells. The protein's effects have been studied in the heart's innermost layer—the endocardium—as well its thick, middle layer—the myocardium, which is responsible for causing the heart to contract during a heartbeat. But prior to this study, Hatcher says little was known about Tbx5's role in the epicardium (outermost layer) and pericardium, which makes up the heart's protective sac, and also the coronary vessels.
In this study, Dr. Hatcher and her colleagues used animal models to study the effect of Tbx5 loss on development of the proepicardium, a group of cells in the embryo that give rise to the epicardium, pericardium and coronary vessels. They found that a loss of Tbx5 delayed the "gluing together" of that outer layer to the heart muscle, which can lead to deficiencies in the way the heart is formed.
"In development, it's important for proepicardium cells to migrate and make contact with the myocardium to properly form the epicardium," Dr. Hatcher explains. "We show that the Tbx5 protein is not only essential in regulating the development of cells in the proepicardium and epicardium, but it is also important in formation of the coronary blood vessels that are derived from these cells. This is why we believe that genetic mutations in human TBX5 can cause these coronary vessel anomalies."
Dr. Hatcher notes that there are several risk factors associated with abnormally formed coronary vessels, from mild heart arrhythmias to sudden cardiac death. While surgery can be an option for children with born with congenital heart defects, there is often what Dr. Hatcher calls a "second wave" of problems that can occur when those individuals become teenagers or adults.
"Studying how Tbx5 contributes to formation of the epicardium/pericardium and coronary vessels will provide us with a new perspective on how to treat individuals with congenital heart defects," she continues. "It can help in the development of drugs to enhance the adhesion of these cardiac cells, or even improve vascular supply."
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