New strategies in the treatment of aortic aneurysms

Aortic aneurysms are characterized by a focal dilatation of the aorta to a size of 50% or greater than the normal diameter of the vessel. Globally the death rate of this disease increases each year. Generally, patients do not have symptoms until rupture or dissection occurs, events associated with a high mortality rate. The indication for surgical treatment depends on the balance between the natural history of the disease versus the risks of the surgical procedure. These two factors largely depend on the size of the aneurysm, its location, and patient co-morbidities. Conventional open or endovascular surgery is the only established therapeutic option. Traditionally, open surgery is associated with worse short-term results but endovascular treatments show disappointing long-term outcome. Therefore, continuous research and improvement of the therapeutic options is needed.

To accomplish this, a good large animal model with pathophysiological features of human aneurysms is needed. We showed that some histological findings of human surgical specimens like inflammation, thinning of the media, and loss of elastin could be reproduced in a sheep model. Unfortunately, none of the extrapolated small animal models effectively induced a reliable diameter increase, and long-term data showed stabilization and regression of the inflammatory response. No perfect model of the human AAA was developed in sheep. Therefore, studies in humans should always complement animal model studies.

Electro-reactive hydrogels can be adapted to have specific functionalities after electrical stimulation, like geometric changes and release of biological active agents. As this might improve outcome of endovascular treatments, several electro-responsive hydrogels were studied in this thesis (chapter 2). In vitro evaluation of the resistance to flow in a pulse duplicator, swelling characteristics, and cytotoxic effects enabled us to select an appropriate hydrogel for in vivo testing. These tests showed that long-term occlusion of an artery could be obtained with only mild effects on the vessel wall. These findings will help future development of responsive hydrogels for intra-vascular applications.

The external support of small aortic aneurysms might prevent aortic complications or the future need for extensive cardio-vascular surgery. Histological evaluations of a specific macroporous mesh in chapter 3 indicated that incorporation in the vessel wall was achieved and was associated with an increase in stiffness and tensile strength. This is in contrast with conventional low-porosity vascular grafts. Based on these results more clinical applications are being assessed.

In the last chapter, we investigated the effect of the first selective non-peptide AT2R agonist, compound 21, on TAA growth. Our study revealed that C21 was ineffective - at the doses studied - to attenuate aneurysm growth in a MFS mouse model. Simultaneously, it was confirmed that specific AT1R antagonism was more effective when it comes to aortic root dimensions then the dual AT1R / AT2R blockade, with ACE-I. In this chapter, we discussed that the role of the AT2R and RAS is probably much more complex and that further investigation of the pathophysiological processes, in MFS in particular, and AA in general, is needed. Elucidation of these pathways will help the development of new therapeutic strategies which will be based on disease- and patient-related factors. This will make future therapies more personalized and patient-specific.