Thoracic aortic aneurysms (TAAs) and valvular insufficiency, the main cardiovascular lesions in the Marfan syndrome, are associated with destruction of connective tissue; however, their pathogenesis remains unclear. To test the hypothesis that changes in the activity of the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are responsible for the damage to connective tissue in these lesions, histochemical studies of the immunoreactivity (IR) for MMPs and their tissue inhibitors (TIMPs) [MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2] were made in TAAs (n=7) and aortic valves (AVs; n=5) from seven patients with the Marfan syndrome. All TAAs showed cystic medial necrosis (CMN), with loss of elastic fibers and smooth muscle cells. Extensive areas of myxoid change (MC) were found in all AVs. Areas of CMN showed no IR for any MMPs or TIMPs. The IR of smooth muscle cells at the borders of areas of CMN was stronger for all MMPs, especially MMP-2 and MMP-9, than in other regions. The surfaces of disrupted elastic fibers showed IR for MMP-2 and MMP-9. Areas of MC showed similar but less pronounced alterations. We hypothesize that the defect in fibrillin-1 in the Marfan syndrome leads to: 1) formation of elastin that is abnormally aggregated and more easily degraded by MMPs than is normal elastin; 2) upregulation of the synthesis of MMPs; 3) progressive destruction of connective tissue by these enzymes, and 4) development of TAAs and valvular lesions.
