Differential Patterns Of Matrix Metalloproteinase And Inhibitor Expression In Ascending Aortic Aneurysms With Bicuspid Versus Tricuspid Valves.
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Objectives: Further understanding of the differential mechanisms of development of ascending aortic aneurysm formation in patients with tricuspid (TAV) versus congenitally bicuspid aortic valves (BAV) may result in novel, specific therapeutic strategies. The matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) play an important role in aortic aneurysm formation. This study tested the hypothesis that unique MMP and TIMP profiles exist within these types of aneurysms which may help define their differing pathogenesis.
Methods: Ascending aortic aneurysm specimens were obtained from 46 patients with TAV and 56 patients with BAV at the time of resection. Tissue homogenates were analyzed by immunoblotting for representatives of the MMP subclasses in addition to TIMPs 1 through 4. The results were expressed (mean±SEM) as a percentage of a reference control group (27 patients) of aortic specimens taken during donor harvest or coronary artery bypass grafting. Regression analysis of aneurysm size (range 4.0-8.0 cm TAV, 4.0-7.95 cm BAV) vs. MMP/TIMP abundance was conducted for each group.
Results: Differential MMP/TIMP profiles were observed for each aneurysm type (Table). For example, in the TAV group increased abundance of membrane-bound MMP-14 in addition to a decrease in TIMP-2 was observed. For the BAV group, an increase in the gelatinase (MMP-2) and elastase (MMP-12) classes was demonstrated. A significant negative correlation between TIMP-2 and increasing aneurysm size was seen with TAV (p=0.009) but not BAV (p=0.77). In contrast, a significant positive correlation was observed between MMP-2 and increasing aneurysm size with BAV (p=0.02) but not TAV (p=0.17).
Conclusions: This unique study demonstrates significant differences in MMP and TIMP profiles within BAV vs. TAV ascending aortic aneurysms and models these changes to aneurysm size. The molecular pathways contributing to the formation of these two aneurysm types are likely different, implying potentially different etiologic, diagnostic and therapeutic paradigms.
Representative MMP/TIMP Subclasses in Bicuspid (BAV) vs. Tricuspid (TAV) Ascending Aortic Aneurysms| MMP/TIMP | BAV (n=56) | TAV (n=46) | p value |
| MMP-2 | 142+/-8 | 94+/-6 | <0.0001 |
| MMP-12 | 113+/-12 | 80+/-8 | 0.03 |
| MMP-14 | 64+/-11 | 179+/-41 | 0.009 |
| TIMP-2 | 92+/-8 | 59+/-4 | 0.0005 |
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