Grant: Operating Grant

Calcific aortic valve disease or aortic stenosis (AS) is the most common valvular heart disease. Although we can make a diagnosis of AS quite early in the process we cannot treat this disorder with a medication. A 'wait and see approach' is used and when patients have a symptomatic severe process they are referred for an open heart surgery. It is worth to point out that surgery is invasive and is associated with potential complications. Hence, the development of a medical therapy that would stop the disease process when diagnosed would obviate the need of a surgery. However, before we can develop novel medical therapies for AS further research is necessary in order to understand the basic key molecular underpinnings of the disease process. My laboratory has discovered in the last several years that a gene, H19, is highly expressed within the aortic valve of patients with AS. H19 is imprinted, which means that only one copy from one parent (in the case of H19 the mother) is expressed and the other copy is silent. Hence, having only one functional copy of a gene, without any backup from the other copy, means that imprinted genes are more vulnerable to mutations and/or changes to the epigenome. Epigenome is the layer of heritable gene regulation which is not linked to the DNA sequences. Hence, modification at the DNA sequence and/or the epigenetic level may account for the level of H19 in AS. In addition, it is worth to highlight that H19 does not encode for a protein but may interfere with the expression of other genes. Our work indicates that H19 is a strong promoter of aortic valve mineralization, the culprit of AS. Therefore, in the next following years our group will investigate the genetic mechanisms controlling H19 expression and its key molecular roles in the development of AS. This work may open novel therapeutic avenues.