Proteolytic injury: Beyond the well established observation that protease activities are the driving force of aneurysm development by degrading extracellular matrix and participating in smooth muscle cell disappearance, it is now necessary to specify the roles and distribution of metallo- and serine-proteases within the arterial wall, in order to define new targets for diagnosis and therapeutics. In the last few years several partners of the consortium have proposed a role for the intraluminal thrombus as a conveyor of proteases in AAA. The purpose of the FAD project will be to further explore this pathway. New diagnostic tools linked to thrombus activities and adventitial responses will be developed in humans including plasma surrogate markers and functional imaging of thrombus activities. Areas of mucoid degeneration, at the site of matrix degradation and smooth muscle cell disappearance in TAA, will be described and analyzed.

Gene expression profiling in smooth muscle cells of TAA will be conducted to examine how the arterial wall responds to proteolytic injury. Furthermore, immuno inflammatory components will be explored in the adventitia in human tissue to identify antigens released by the thrombus or the media responsible for the shift from innate to adaptive immunity in the adventitia.

Biomechanics: Whatever their localization, aneurysms are characterized by rheologic perturbations of the blood flow in response to morphological changes. In normal human aorta, the regular geometry (tubular shape and parallel walls) results in an organised blood flow (mainly laminar under resting conditions) and in uniform shear rates, maintaining a physiological steady-state among the blood components and between circulating blood and arterial wall. Changes in arterial geometry considerably modify rheologic parameters and therefore influence interactions between blood components.

From a structural mechanical point of view, aneurysm rupture occurs when the stresses acting within the wall exceed its strength. This has led to speculations that increasing wall stresses and/or decreasing wall strength could be the ultimate cause of TAA and AAA rupture.

The aim of this part of the FAD project is to develop biomechanical models, which integrate biochemical knowledge, and hence elucidate the role of mechanical factors in the growth and eventual rupture of aortic aneurysms. To this end, biomechanical forces/stresses generated by the circulating blood are predicted with well-established, patient-specific reconstruction and fluid-structure interaction analysis tools.

The results observed and the concept developed in pathophysiology of AAA and TAA will be translated into diagnostic and therapeutic applications.