Aneurysm development is a characteristic pathological remodelling process, of the arterial wall involving breakdown of extra cellular matrix, leading to dilatation of the arteries and eventually, to rupture

Aortic aneurysms have 2 main localizations in humans:

1 - Abdominal aortic aneurysm (AAA) is a frequent vascular disease, whose incidence has increased in the last twenty years. AAA incidence in men is less than 1% before 60 years of age, but increases rapidly and reaches 6% at 80. AAA is less frequent in women; their incidence increases after 70 years of age and reaches 4.5% after 90. In particular, the incidence of rupture may be increasing in the EU population. The infrarenal aortic diameter in the general population increases progressively with aging. The usual definition of AAA is an aortic diameter above 30 mm. The mean growth rate of AAAs is 2.6 mm/year. Nevertheless this enlargement is very heterogeneous, varying from 1 to 6.1 mm in different individuals, and varying with time in each individual depending on the initial diameter at the time of detection, suggesting that AAA growth accelerates as the aneurysm enlarges. The risk of rupture mainly depends on the diameter, the five year risk of rupture is 75% for AAA diameter > 70 mm. Rupture leads to death in 80% of cases;

There is a growing body of data from clinical trials concerning the detection and management of AAA: 1- Population screening in men reduces the risk of death from AAA rupture and is cost-effective. 2- Small AAA (4-5.5 cm diameter) are safely managed by surveillance but the potential benefit of preventive endovascular grafting is being studied in ongoing trials. 3- In endovascular repair of large AAA, a 3-fold early survival benefit (30 days) in comparison to conventional open surgery is obtained. However, the durability of endovascular repair remains uncertain and requires continuous surveillance. (Endovascular repair does not always totally exclude the aneurysmal sac, giving rise to endoleaks, expansion of the aneurysmal sac and neck and migration of the endograft). Many FAD partners are international leaders in the field of AAA research engaged in the epidemiological surveillance of the disease, in the development of new diagnostic tools, of relevant experimental models, of new endovascular devices and in the analysis of human pathology leading to new pathophysiological concepts and innovative strategies for prevention, diagnosis and therapeutics.

2 - Thoracic aortic aneurysm (TAA) is less common than AAA, and its epidemiology less well-defined. The incidence of new cases is 5/100 000 person-year. Rupture of TAA has a mortality rate of 97%, and a median survival rate of 3 days. However, epidemiological data are limited because of the often acute nature of the disease, the high mortality rate, and the absence of precise diagnosis. Clinical epidemiology of diagnosed TAA describes a trimodal distribution of the disease: 1- A first Gaussian distribution corresponding to monogenic determinants in familial syndromic and non-syndromic forms; 2- A second curve associated with bicuspid valves; and 3- a third curve in which an interaction with the aging process and environmental determinants appears to be predominant. Nevertheless, despite the molecular diversity of the aetiologies, all forms of TAA present common tissue phenotypes including matrix breakdown, smooth muscle cell disappearance, and areas of mucoid degeneration, leading to dilatation and rupture. With respect to pathophysiology and diagnosis, some FAD partners are international leaders in the field of TAA through the nosological classification of the disease, discovery of new mutations involved in genetic forms of TAA, exploration of new intermediary phenotypes between genetic anomalies and clinical expression, and investigation of experimental models. There are also extra-aortic localizations of aneurysms, including cerebral arteries, which share some pathophysiological features with aneurysms of the aorta.

The general translational, cognitive, technological and medical objectives of the Fighting Aneurysmal Disease project, are to investigate new pathophysiological concepts in aortic aneurysmal remodeling, targeting cells and molecules, linking genetics with aneurysmal phenotypes, leading to the development of new tools for diagnosis, prognosis and therapeutics in aneurysmal diseases. The project consists of a consortium integrating groups working on both AAA & TAA in a large scale European collaborative research project from Bedside to Bench.

The project integrates the medical objective of combating aneurysms, with cognitive objectives of exploring links between genomics and cell and tissue functions, and technological objectives of developing new tools for diagnosis, and new therapeutic approaches to prevention and treatment of aneurysms.

FAD takes into account the general priorities of the FP 7 of improving Health of European citizens, including competitiveness and boosting innovative capacities, emphasizing the translational approach in the 3 dimensions of descriptive, objective and projective epistemology of new knowledge in the field of aneurismal pathology, including validation of new therapies, and promotion of healthy ageing.

The FAD project integrates the three epistemologic dimensions of translational research for medical progress applied to aneurysmal pathology: 1- The observation of human disease including the nosologic definition of aneurysm, risk factors, clinical epidemiology, patient databases and public health concerns. 2- The search for new diagnostic and therapeutic targets through bedside to bench objective research on human pathology, including: genetic exploration of new determinants of susceptibility to aneurysms, human tissue collections, transcriptomic and proteomic methods applied to human tissue and cell biology derived from human tissue. 3- The projection of the observed molecular diversity to application to human aneurysms including functional genomic approaches in vitro through molecular and cell biology, and in vivo through experimental models and transgenic mice.

The FAD project is collaborative and integrative of:

1- Different partners East-West/ North-South European countries, including Turkey, with different lifestyles and scientific expertise

2- Several disciplines in different medical and biological specialities in the aneurysm field:

. Surgery . Medicine . Radiology and Nuclear Medicine . Genetics . Biochemistry and Molecular Biology . Cell biology and Haematology

3- coordination through management and organization of the consortium and dissemination of knowledge through training and defining standards for diagnostic reporting and treatments for aneurysmal disorders within EU countries.

Boosting innovative capacities

FAD includes several SMEs, implicated in innovative technologies applicable to diagnostics. Significant clinical applications should emerge from this project, improving patient-oriented strategies for primary prevention, diagnosis and management of aortic aneurysms as well as for limiting the progression of aneurysmal disease. FAD includes only a limited number of animal models, with “refinement and reduction”, but ’’replacement” is not always possible and sometimes not even desirable. Clinical trials, for safety, efficacy and proof of principle will take place in the second phase of the project, coordinated at a European level. These applications will be undertaken with due respect for ethical considerations, observing ethical law and procedures specific to each country and general to the EU community. The project will be carried out within a large network of international cooperation, including an international network of excellence (USA), and the participation of Turkish and Icelandic groups.