Aortic aneurysms rank 13th as a leading cause of death in this country. Preliminary findings suggested that 1) the atherogenic theory of fusiform aneurysm development did not explain all of the known facts about the disease, and 2) that there might be a genetic predisposition to abdominal aortic aneurysms (AAA). This latter hypothesis seemed relevant considering that a mutant mouse (Blotchy) develops spontaneous fusiform aneurysms. Four observations during the 01-03 years of support are summarized, along with propoals for continuing studies during the 04-06 years. 1) An amine has been isolated from human skin (co-eluting with pyridinoline) that is decreased in Marfan's syndrome and increased in AAA as a ratio to Hy-lys. If this increase is confirmed in a larger series of 50 AAA's and 50 controls, our hypothesis that there is a deficiency of lysyl-oxidase dependent crosslinkages in AAA may have to be modified. The possibility of failure in some subsequent step in crosslink maturation should be examined. We also propose to A) Study the unknown in skin as a function of aging; B) Determine whether fibroblasts from patients with AAA synthesize this amine in-vitro; and C) Characterize this amine by mass spectroscopy. 2) One hundred families with clustering of AAA's in first-order relatives have been collected, including three sets of identical twins. In 13 families with completed pedigrees, the ratio of affected to unaffected members is 10% after excluding the proband and one additional affected member. We propose to complete ascertainment of these families and to initiate a follow-up study with unbiased assignment. 3) Clustering of carcinomas also occurs in some of these families, and a preliminary study suggests that the risk-odds ratio for cancer in patients with AAA is increased 3-fold over atherosclerotic controls. Experiments in the Blotchy mouse are proposed to study patterns of tumor growth, which may have matrix-dependent characteristics and be relevant to the possible association of AAA and cancer in man. 4) Hydrocortisone accelerates the development of aneurysms in the heterozygous Blothcy mouse. This model will be used to study prevention of aneurysms by pharmacological means. The significance of these studies is that it may eventually become possible to reduce the growth rate of small AAA's in man, or to prevent aneurysms in individuals whose susceptibility is detected by screening for phenotypic markers.
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