IMMUNOHISTOCHEMISTRY OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS IN THORACIC AORTIC-ANEURYSMS AND AORTIC VALVES OF PATIENTS WITH MARFANS-SYNDROME

Background-Thoracic aortic aneurysms (TAAs) and valvular insufficiency , the main cardiovascular lesions in Marfan's syndrome, are associated with destruction of connective tissue; however, their pathogenesis re mains unclear. Methods and Results-To test the hypothesis that changes in the activity of the matrix metalloproteinases (MMPs) and their tis sue inhibitors (TIMPs) are responsible for the damage to connective ti ssue in these lesions, histochemical studies of the immunoreactivity ( IR) for MMPs and their tissue TIMPs (MMP-1, MMP-2, MMP-3, MMP-9, TIMP- 1, and TIMP-2) were made in TAAs (n=7) and aortic valves (n=5) from 7 patients with Marfan's syndrome. All TAAs showed cystic medial necrosi s (CMN), with loss of elastic fibers and smooth muscle cells. Extensiv e areas of myxoid change were found in all aortic valves. 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 myxoid change showed si milar but less pronounced alterations. Conclusions-We hypothesize that the defect in fibrillin-1 in Marfan's 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, a nd (4) development of TAAs and valvular lesions.