Medical Professional Publications

New Understandings About the Genetic Basis of Aortic Valve Disease

Columbus, OH — March 2017

Vidu Garg, MD, was the lead author of a seminal 2005 publication in Nature showing mutations in the NOTCH1 gene cause aortic valve disease in humans. The discovery provided a jumping-off point for more than a decade of investigations into NOTCH1 and other genes implicated in the disease; more recently, a variety of models have allowed research into underlying mechanisms of bicuspid aortic valve and calcific aortic valve disease.

Dr. Garg, director of the Center for Cardiovascular Research at The Research Institute at Nationwide Children’s Hospital, is now the senior author of a review of much of that work in Current Opinion in Cardiology.

“While the human genetic studies demonstrated an association between NOTCH1 mutations and aortic valve disease, the basic molecular mechanisms for the link between the gene and disease were unknown,” says Dr. Garg, who is also a member of The Heart Center at Nationwide Children’s and a professor of Pediatrics and Molecular Genetics at The Ohio State University.

“Much of the additional investigation in NOTCH1 has been to determine how these phenotypes occur when NOTCH1 is mutated. My group and others in our field are looking at deciphering the underlying molecular pathways, with an eye on possible targets for therapy,” he says.

The role of NOTCH1 in aortic valve disease has been well established over the last ten years, and mutations of the gene have since been associated with a number of others malformations affecting the human cardiac outflow tract (including tetralogy of Fallot). Another gene, GATA5, has also been linked to bicuspid aortic valve in humans, and is another robust area of investigation, says Dr. Garg.

The relationship of NOTCH1 to disease, and the molecular pathways for aortic valve calcification, are becoming more apparent through mouse and cellular models, according Dr. Garg. For example, the protein encoded by NOTCH1 appears to be expressed in both valve interstitial cells (VICs) and valve endothelial cells (VECs), and alterations in signaling pathways between VICs and VECs have been implicated in calcification.

Most recently, a 2016 Canadian study identified the long noncoding RNA H19 as a NOTCH1 repressor with a clear role in calcification of VICs. Inhibiting H19 limits mineralization, and ultimately, it could become a therapeutic target for calcific aortic valve disease.

Dr. Garg’s own group at Nationwide Children’s is exploring two avenues of research. One builds upon his 2013 study showing that endothelial nitric oxide signaling regulates expression of NOTCH1. If the mechanism by which nitric oxide signaling disrupts Notch signaling can be determined, it could open additional therapeutic avenues for calcific aortic valve disease, Dr. Garg says.

The second avenue uses genomic approaches to identify genes inappropriately expressed in a mouse model, in which Notch1 is mutated, for bicuspid aortic valve. While additional studies are needed, all are “potential disease-contributing” genes for bicuspid aortic valve disease, Dr. Garg says.


Koenig SN, Lincoln J, Garg V. Genetic basis of aortic valvular disease. Current Opinion in Cardiology. 2017 Feb 2. [Epub ahead of print]

Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005 Sep 8; 437(7056): 270-4.

Hadji F, Boulanger MC, Guay SP, Gaudreault N, Amellah S, Mkannez G, Bouchareb R, Marchand JT, Nsaibia MJ, Guauque-Olarte S, Pibarot P, Bouchard L, Bossé Y, Mathieu P. Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1.Circulation. 2016 Dec 6;134(23):1848-1862.

Bosse K, Hans CP, Zhao N, Koenig SN, Huang N, Guggilam A, LaHaye S, Tao G, Lucchesi PA, Lincoln J, Lilly B, Garg V. Endothelial nitric oxide signaling regulates NOTCH1 in aortic valve disease. Journal of Molecular and Cellular Cardiology. 2013 Jul;60: 27-35.

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