Grant: Travel Awards - Institute Community Support

Marfan syndrome is a genetic disorder, which affects the body's connective tissues that are responsible for providing strength and flexibility to the ligaments, muscles and blood vessels, among other structures. With an incidence of 1 in 5000 individuals, the most common cause of death in those affected by Marfan is aortic aneurysm (dilation of the blood vessel that supplies blood from the heart to the rest of the body) due to disruption and weakening of the blood vessel wall integrity. This can result in rupture of the blood vessel and death. Unfortunately, there is currently no cure for Marfan syndrome-associated aneurysm, and management involves blood pressure lowering medications to slow down the aneurysm growth, and delay eventual surgery to replace the dilated aorta if detected early enough. There is therefore great need for alternative treatment options. Our team has recently shown that Losartan, a blood pressure lowering medication commonly prescribed to Marfan patients, slows down the progression of aortic aneurysm by increasing the level of nitric oxide within the aortic wall, a molecule that controls blood pressure among other cellular mechanisms in the blood vessel. Here we have found other drug analogs of Losartan capable at both preventing aortic root aneurysm and increasing nitric oxide production more effectively than Losartan. We have also identified a drug analog, which has a therapeutic effect without lowering blood pressure. Therefore, this study brings into question the therapeutic value of blood pressure lowering medications in the management of Marfan syndrome, and provides insights into the role of nitric oxide and the mechanisms of action of Losartan and its analogs, opening a new direction for drug development in a disease that currently has no effective treatment options.