Grant: Operating Grant

The human heart consists of four chambers that contract in a repeated, rhythmic and synchronized manner to pump blood in the body. The heart also has four valves ensuring that blood flow goes only in one direction. One of these valves is called the aortic valve. The aortic valve lies between the main heart chamber (left ventricle) and the aorta, which is the largest artery that distributes blood to all parts of the body. The aortic valve is normally tricuspid, i.e. formed by three valve leaflets. The failure of the leaflets to separate during heart development can produce a valve with two leaflets referred to as bicuspid aortic valve (BAV). BAV is the most frequent congenital heart defect and is frequently associated with aortic valve stenosis (AVS). AVS is a life threatening disease with no medical treatment available other than open heart surgery to replace the diseased valve. More than one third of valve replacements are performed in patients with BAV. BAV is thus a serious medical condition and an important economic medical burden. Unfortunately our understanding of the disease is limited. The goal of this project is to identify the genetic determinants of BAV and understand the disease at the most fundamental levels. We will take advantage of the best approaches in genomic research as well as the large volume of clinical and biological materials that we have collected during the last few years to study patients with BAV. DNAs and aortic valves removed at surgery from patients with or without BAV will be compared using the most modern genomic approaches. The results of human studies will be further refined with a unique cellular model developed in our laboratories. The innovative and integrative approaches used in this project are unprecedented in the field. We foresee high-impact outcomes including the identification of mutations causing BAV, justifying new screening programs for families at risk, and the identification of novel drug targets.