Reproducible porcine model of thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for the 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 present 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 periadventitial application of crystalline CaCl2 (0.5 g). Three weeks after TAA induction, aortas were harvested and tissue was collected for biochemical and histological measurements. A subset of animals underwent MRI preoperatively and at terminal surgery. Results were compared with sham-operated controls (n=6). Three weeks after TAA induction, aortic luminal area increased by 38 ± 13% (P=0.018 versus control). Aortic structural changes included elastic lamellar degradation and decreased collagen content. The protein abundance of matrix metalloproteinases 3, 8, 9, and 12 increased in TAA tissue homogenates, whereas tissue inhibitors of metalloproteinases 1 and 4 decreased. CONCLUSIONS: These data demonstrate aortic dilatation, aortic medial degeneration, and alterations in matrix metalloproteinase/tissue inhibitors of metalloproteinase 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 provides a reproducible test bed for examining diagnostic, prognostic, and therapeutic strategies.

Plasma profiles of matrix metalloproteinases and tissue inhibitors of the metalloproteinases predict recurrence of atrial fibrillation following cardioversion.

Atrial fibrosis is considered to contribute to atrial fibrillation (AF) recurrence following cardioversion. This study tested the hypothesis that circulating levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) can predict AF recurrence postcardioversion. Precardioversion plasma samples (n = 82) were assayed for MMPs (eight types), TIMPs (all four types), N-terminus pro B-type natriuretic peptide, and high-sensitivity C-reactive protein levels. Patients were followed for AF recurrence postcardioversion. Despite 100 % restoration of sinus rhythm, 36 (44 %) reverted to AF within 3 months. Left atrial volume was increased in patients in whom AF recurred. Precardioversion MMP-9 was higher and TIMP-4 lower with AF recurrence. MMP-9, MMP-3, and TIMP-4 independently predicted AF recurrence. In multivariate analysis, combination of MMP-9, MMP-3, and TIMP-4 increased prediction of AF recurrence. Circulating levels of MMPs and TIMPs predict AF recurrence postcardioversion and may be used in a novel biomarker panel to guide AF stratification and therapy.