Objectives: Predicting rupture of abdominal aortic aneurysm (AAA) requires knowledge of both the rate of extracellular matrix (ECM) degradation and the pulsatile stress on the aortic tissue. The activity of matrix metallopeptidase 9 (MMP9) and its inhibitor, TIMP1, are associated with alterations in aortic ECM but it is unknown if these changes effect the dynamic viscoelastic properties. We hypothesize that increased levels of MMP9 within AAA tissue will be associated with a greater dynamic modulus (E*), as a surrogate of increased aortic wall stress. Methods: Human aneurysmal aortic tissue was obtained at the time of open AAA repair (n=11) and age-matched non-aneurysmal cadavers (n=10). Uniaxial viscoelastic material properties were measured in the circumferential orientation under physiologic preload (110 mmHg) and cyclic strain (± 5%@1Hz). Quantitative histologic and immunohistochemistry were preformed using Fiji imaging software. Aortic MMP9 and TIMP1 content and activity were quantified using western blot and zymography. Results: E* was greater (1862±464 vs 1362±405 kPa, p=0.02) in the AAA tissue as compared to non-aneurysmal tissue. AAA tissue contained less elastin (6.7±6.7 vs 23.4±8.7%, p=0.01) and a greater collagen/elastin ratio (19.9±20.6 vs 2.3±2.5%, p=0.05). Immunohistochemistry revealed 200% greater MMP9 content in the AAA tissue (Figure A & B, 0.61 vs 0.03%, p=0.03). Increased MMP9 content was confirmed using a western blot (0.43 vs 0.06 AU, p<0.01). No difference in relative MMP9 activity (4307 vs 2324 AU, p=0.25) or level of TIMP1 (0.03 vs 0.02, p=0.6) were observed. There was a positive linear correlation (Figure C, r 2 =0.47) between E* and MMP9 as determined by quantitative immunohistochemistry. Conclusions: Our data suggests a positive relationship between E* and MMP9 content. Increased tissue stiffness may trigger MMP9 production resulting in a positive-feedback loop, progressively increasing aortic wall stress and rupture risk.
Read full abstract