Grant: Project Grant

Introduction: Aortopathies represent a complex group of diseases that affect the aorta. Typically managed with blood pressure-lowering medications, patient studies report underwhelming improvements in outcomes. Our team has observed improvements in mouse aortic stability not by lowering blood pressure but rather by increasing the aortic release of nitric oxide (NO), a poorly-understood mediator of vascular health. As our clinics sometimes use the blood pressure-lowering medications losartan (low NO) and telmisartan (high NO) for aortopathy patients, we wish to document the expected superiority of telmisartan for patient management and understand the difference NO makes with or without blood pressure lowering in animal models of aortopathies. We think that medications and approaches that mimic blood flowing on the vasculature, a known NO inducer, is behind the high NO-release effect of telmisartan and expected ability to improve outcomes, and even regress severe aortic lesions. Methods: We will compare how mutant animals with a high blood flow-NO pathway are resistant to aortopathies vs animals with normal blood flow. We also propose to compare telmisartan to losartan in patients with Marfan syndrome, a genetic aortopathy, and detect in blood new predictive biomarkers of telmisartan's effect on vessel health. Marfan animals will be used to better understand this difference. Significance: Documenting how flow stimulates the anti-aortic remodeling effects of NO and how telmisartan improves Marfan outcomes will allow us to understand what is really needed to block and even reverse aortic root widening. With our biomarkers of 'vessel health' we should be able to tell patients 'yes, you are protected' or 'no, you are not protected, let's increase your dose of telmisartan', something blood pressure monitoring does not do very well.