Exploring novel treatments to prevent aortic aneurysm growth in Marfan syndrome

Widening of the aorta (aneurysm) may occur during ageing or in patients with genetic predisposition, such as in Marfan Syndrome (MFS). Aneurysm growth eventually leads to aortic rupture and death. Currently no pharmacological treatment is present to combat aneurysm growth. In this thesis, treatment strategies are explored in murine aneurysm models. In the angiotensin-II aneurysm model, the immunosuppressive drug azathioprine prevented aneurysm formation, however, it reduced aneurysm progression mildly. In the murine MFS model, the anti-inflammatory drugs methylprednisolone and abatacept reduced aortic influx of inflammatory cells, however, they did not inhibit aneurysm growth. Complement activation is part of our immune response, and was observed in aortic tissue of MFS patients. However, inhibition of complement activation by cetor did not decrease aneurysm growth in MFS mice. Collectively, anti-inflammatory medication should probably not be considered as effective treatment strategy. In contrast, the polyphenol resveratrol was able to inhibit aneurysm growth in MFS mice, by protecting the elastic laminae and smooth muscle cells in the aorta through downregulation of microRNA-29b.
Furthermore, two phenomena were observed in MFS mice, which provide insight in development of aortic disease. First, aortic microcalcification was observed in MFS patients and MFS mice, and correlated to enhanced elastin degradation. Therefore, visualization of microcalcification may be a marker for local aortic disease, prior to aneurysm growth. Secondly, cystic kidney disease was observed in a MFS mouse with accelerated aneurysm growth. Cystic kidneys are common, thus monitoring cystic kidneys in MFS patients can provide insight in the relevance for aneurysm growth.