Genes and gene-function in bicuspid aortic valves

The prevalence of a bicuspid aortic valve in the general population is
0.5-0.8%. Among family members there is a high heritability. Thus far two
studies have found mutations in the NOTCH gene in either related or unrelated
patients with a bicuspid aortic valve, important for epithelial mesenchymal
transformation (EMT), which is important for valve formation. Several other
genes have been suggested important for EMT. To date human research has not
focused on the potential importance of mutation in these genes in developing
bicuspid aortic valves.
Bicuspid aortic valves progress more rapidly into stenotic pathology than the
normal tricuspid aortic valves. Moreover these patients with a bicuspid aortic
valve are also more prone for life threatening events such as aortic dissection
and sudden cardiac death. Early identification of patients with a bicuspid
aortic valve is needed.

The primary objective of this study is to identify mutations associated with
the development of a bicuspid aortic valve. To this end the study will focus on
genes important for aortic valve formation. As an extension of the primary
objective, a second objective is to characterize the nature and effect of any
mutations identified, thus generating a more causal link to the development of
bicuspid aortic valves.

This study would be a multicenter observational cross-sectional study.
Patients whom have a planned aortic valve replacement because of severe aortic
stenosis are approached for this study. Informed consent is obtained and 20 ml
of blood will be drawn for genomic DNA extraction.
On the day of admission all patients undergo a computed tomography of the heart
in addition to the standard preoperative diagnostic imaging.
During valve surgery the aortic valves are photographed, excised and these
valves are anatomically inspected by the thoracic surgeon. The aortic wall is
inspected for dilatation and other aortic pathology. The aortic valve leaflets
are immediately taken to the department of pathology. Then the aortic valve
leaflets will be inspected and photographed by the pathologist. The aortic
valve leaflets will be subsequently bisected. One half of the material will be
snap frozen in liquid nitrogen and the remaining half will be placed in
formalin for fixation. Both frozen and fixed tissue can be placed in long-term
storage at -80 *C and room temperature, respectively, until analysis (in a
tissue bank).DNA is sequences as described. Polymerase chain reaction (PCR)
will be used to amplify candidate genes of interest, followed by sequencing
reactions to screen for mutation within the coding region of such genes.Then
the nature and effect of any mutations identified will be characterized by
functional analyses.

The risks for the patients are increased with the addition of computed
tomography of the heart for each patient. However, the risks be equal to the
social importance of early identification of these young patients.
Subsequently, 20 ml of blood will be drawn on top of regular vena punction and
the aortic valve, when excised, are obtained and stored in a tissue bank.