Aortic dilatation with bicuspid aortic valves: cusp fusion correlates to matrix metalloproteinases and inhibitors.
BACKGROUND
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).


METHODS
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]).


RESULTS
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.


CONCLUSIONS
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.
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA. ctsxresearch@musc.edu
John S
JS
Ikonomidis
Jean Marie
JM
Ruddy
Stewart M
SM
Benton
Jazmine
J
Arroyo
Theresa A
TA
Brinsa
Robert E
RE
Stroud
Ahmed
A
Zeeshan
Joseph E
JE
Bavaria
Joseph H
JH
Gorman
Robert C
RC
Gorman
Francis G
FG
Spinale
Jeffrey A
JA
Jones
D000328:Adult; D000368:Aged; D001011:Aorta / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D017545:Aortic Aneurysm, Thoracic / Q000453:epidemiology / Q000209:etiology; D001021:Aortic Valve / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D019917:Blood Vessel Prosthesis Implantation; D004108:Dilatation, Pathologic / Q000201:enzymology; D004198:Disease Susceptibility; D004547:Elastic Tissue / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis*; D008875:Middle Aged; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis*
D016326:Extracellular Matrix Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases