Three separate heart defects share a common defect at the molecular level, according to a study by members of the Center for Molecular and Human Genetics.

Aortic Valve Stenosis (AVS), Coarctation of the Aorta (COA), and Hypoplastic Left Heart Syndrome (HLHS) are three cardiac defects that involve the heart’s left ventricular outflow tract (LVOT). All three are serious defects, particularly HLHS, which still causes death in up to 40 percent of infants born with the condition, despite aggressive surgical intervention. Presumably, these defects are caused by a developmental mechanism involving the inner lining of the heart. Yet until now, a molecular similarity between the three defects had not been identified.

“Clinicians traditionally thought of these heart defects as separate entities,” said Kim McBride, MD, principal investigator in the Center for Molecular and Human Genetics and lead author of this study. “More recent views have grouped them together based on findings from cardiac developmental biology, observations of clustering in families, and our own previous work on inheritance analysis.”

In this study, researchers hypothesized that mutations in the NOTCH1 gene may be implicated in AVS, COA and HLHS. Notch is a signaling pathway involved in multiple developmental processes, and mutations of the NOTCH1 gene have been identified in a condition called bicuspid aortic valve, which is more common in families with LVOT malformations.

Ninety-one patients with LVOT malformations had their DNA screened for mutations in NOTCH1 and were compared to 216 ethnically matched samples without LVOT malformations. Results showed that NOTCH1 gene mutations are present in AVS, COA and HLHS. A detailed functional assessment using a cell based system showed two specific mutations reduce signaling through the Notch signaling pathway.

The molecular mechanisms by which these mutations affect Notch signaling are, as yet, unclear. Still, this study suggests that the levels of Notch signaling play a vital role during cardiovascular development, and relatively minor changes may promote LVOT defects. These findings also emphasize the hereditary nature of these defects and explain why they co-occur within families.
“This is the first time a common molecular event has been elucidated for AVS, COA, and HLHS. This supports our previous idea that these defects may share a common developmental pathogenesis,” said Dr. McBride. “Further, we have evidence the developing endocardium and endothelium may play a role in the causation of these defects. We can now focus our research to better understand what goes wrong during development. Identifying a specific gene also now holds hope for eventually providing better risk counseling for families.”

Source: Research Children’s Hospital, June 30, 2008