Aortic Dilatation With Bicuspid Aortic Valves: Cusp Fusion Correlates to Matrix Metalloproteinases and Inhibitors

Abstract

Congenital bicuspid aortic valves (BAVs) result from fusion of 2 valve cusps, resulting in left-noncoronary (L-N), right-left (R-L), and right-noncoronary (R-N) morphologic presentations. BAVs predispose to ascending thoracic aortic aneurysms (ATAAs). This study hypothesized that ATAAs with each BAV morphologic group possess unique signatures of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinases (TIMPs). Ascending thoracic aortic aneurysm tissue from 46 patients with BAVs was examined for MMP/TIMP abundance, and global MMP activity was compared with normal aortic specimens (n=15). Proteolytic balance was calculated as the ratio of MMP abundance to a composite TIMP score. Results were stratified by valve morphologic group (L-N [n=6], R-L [n=31], and R-N [n=9]). The BAV specimens (p<0.05 versus normal aorta, 100%) displayed elevated global MMP activity (273%±63%), MMP-9 (263%±47%), and decreased MMP-7 (56%±10%), MMP-8 (58%±11%), TIMP-1 (63%±7%), and TIMP-4 (38%±3%). The R-L group showed increased global MMP activity (286%±89%) and MMP-9 (267%±55%) with reduced MMP-7 (45%±7%), MMP-8 (68%±15%), TIMP-1 (58%±7%), and TIMP-4 (35%±3%). The L-N group showed elevated global MMP activity (284%±71%) and decreased MMP-8 (37%±17%) and TIMP-4 (48%±14) activity. In the R-N group, MMP-7 (46%±13%) and MMP-8 (36%±17%) and TIMP-1 (59%±10%) and TIMP-4 (42%±5%) were decreased. The R-L group demonstrated an increased proteolytic balance for MMP-1, MMP-9, and MMP-12 relative to L-N and R-N. Each BAV morphologic group possesses a unique signature of MMPs and TIMPs. MMP/TIMP score ratios suggest that the R-L group may be more aggressive, justifying earlier surgical intervention.