Background
Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix (ECM) remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for detection of TAA disease. This is largely driven by the lack of a large animal model, which would permit longitudinal/mechanistic studies. Accordingly, the objective of the current study was to establish a reproducible porcine model of aortic dilatation, which recapitulates the structural and biochemical changes observed during human TAA development.
Methods and Results
Descending TAAs were induced in Yorkshire pigs (20–25 kg; n=7) through intra-adventitial injections of collagenase (5 ml, 0.35 mg/ml) and peri-adventitial application of crystalline CaCl2 (0.5 g). Three weeks post-TAA induction, aortas were harvested and tissue was collected for biochemical and histological measurements. A subset of animals underwent magnetic resonance imaging pre-operatively and at terminal surgery. Results were compared to sham-operated controls (n=6). Three weeks post-TAA induction, aortic luminal area had increased 38±13% (p=0.018 vs. control). Aortic structural changes included elastic lamellar degradation and decreased collagen content. The protein abundance of MMPs -3, -8, -9, and -12 increased in TAA tissue homogenates, while TIMPs -1, and -4 decreased.
Conclusions
These data demonstrate aortic dilatation, aortic medial degeneration, and alterations in MMP/TIMP abundance, consistent with TAA formation. This study establishes for the first time, a large animal model of TAA that recapitulates the hallmarks of human disease, and will provide a reproducible test-bed for examining diagnostic, prognostic, and therapeutic strategies.