Grant: Project Grant

About 2% of the population is born with a biscupid aortic valve, which has only two cusps rather than the normal three. The aortas of these patients commonly balloon due to breakdown of the blood vessel wall. This can cause the aorta to split, which is usually fatal. Why patients with biscupid valves are particularly prone to aortic ballooning is unknown. It may be due to their underlying genetics or it may be due to disrupted blood flow patterns through their bicuspid valve, which cause the blood to drag on the wall of the aorta in ways it shouldn't. Most likely, both factors are at play, but it is important to dissect the contributions of each so that medical and surgical plans can take them into account. We discovered in a mouse model that a protein called C-type natriuretic peptide or CNP protects against aortic ballooning. Some mice without the protective effects of CNP had bicuspid aortic valves and worse aortic ballooning than mice with tricuspid valves, just as in humans. The advantage of our mice is that they all have the same genetics and therefore the differences in ballooning are due only to the "bad" blood flow that occurs with a bicuspid valve. Using this mouse and a new imaging method we developed, we will determine which proteins and molecular pathways are disrupted by abnormal blood flow to lead to ballooning. Based on our mouse model, we will also specifically test the role of CNP in protecting against aortic ballooning. First we will test in the lab whether patterns of blood flow that are associated with aortic ballooning reduce the amount of CNP in the aorta, leading to ballooning. Second, we will examine normal and ballooned aortas removed from patients at surgery to determine whether there is less CNP in ballooned aortas and in women, which is something we have seen in heart valves. Together, these studies may lead to new targets for the treatment and diagnosis of aortic ballooning in patients with bicuspid valves.