Jason K. Lee

Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms

Abdominal aortic aneurysms represent a life-threatening condition characterized by chronic inflammation, destructive remodeling of the extracellular matrix, and increased local expression of matrix metalloproteinases (MMPs). Both 92-kD gelatinase (MMP-9) and macrophage elastase (MMP-12) have been implicated in this disease, but it is not known if either is necessary in aneurysmal degeneration. We show here that transient elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12. Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors. These results demonstrate that inflammatory cell expression of MMP-9 plays a critical role in an experimental model of aortic aneurysm disease, suggesting that therapeutic strategies targeting MMP-9 may limit the growth of small abdominal aortic aneurysms.

Elevated Plasma Levels of Matrix Metalloproteinase-9 in Patients with Abdominal Aortic Aneurysms: A Circulating Marker of Degenerative Aneurysm Disease

PURPOSE Matrix metalloproteinase-9 (MMP-9) is abundantly expressed in abdominal aortic aneurysms (AAAs), where it plays a pivotal role in connective tissue destruction. Elevated plasma concentrations of MMP-9 (MMP-9PL) also have been reported in patients with AAAs, but it is unclear if this can distinguish patients with AAAs from those with atherosclerotic occlusive disease (AOD). The purpose of this study was to further define the utility of elevated MMP-9PL levels in the diagnosis and evaluation of AAAs, and to examine if changes in MMP-9PL can be used as a functional biomarker of degenerative aneurysm disease. MATERIALS AND METHODS Peripheral venous blood was obtained from 25 patients with AAAs, 15 patients with AOD, and five normal control subjects. MMP-9PL levels were determined by an enzyme-linked immunosorbent assay. In four patients undergoing open AAA repair, MMP-9PL levels were directly compared with the amount of MMP-9 produced in aortic tissue. Six additional patients undergoing operative AAA repair were followed for 3-10 months to determine how treatment affected elevated MMP-9PL concentrations. RESULTS Mean (+/- SE) MMP-9PL was 36.1 +/- 7.7 ng/mL in normal control subjects, 54.7 +/- 10.5 ng/mL in patients with AOD, and 99.4 +/- 17.4 ng/mL in patients with AAAs (P < .05 versus normal control subjects and patients with AOD). Elevated MMP-9PL levels (> 87.8 ng/mL) were found in 12 of 25 (48%) patients with AAA but in only one of 15 (7%) patients with AOD (P < .05). MMP-9PL levels did not correlate significantly with either age, gender, or aneurysm diameter, although there was a trend toward the highest values in male patients with large AAAs. Production of MMP-9 in aneurysm tissues paralleled MMP-9PL levels, and elevated MMP-9PL levels decreased by 92.7% +/- 3.2% after surgical AAA repair. CONCLUSIONS Elevated MMP-9PL levels were observed in approximately one half of patients with AAAs and less than 10% of those with AOD (positive predictive value of 92.3%), but normal MMP-9PL levels had limited utility in excluding the presence of an aortic aneurysm (negative predictive value, 52%). MMP-9PL levels in patients with AAAs appeared to directly reflect the amount of MMP-9 produced within aneurysm tissue, and MMP-9PL levels decreased substantially after aneurysm repair. Measures of circulating MMP-9 may provide a biologically relevant marker of connective tissue metabolism in patients with AAAs.

Altered patterns of gene expression distinguishing ascending aortic aneurysms from abdominal aortic aneurysms: Complementary DNA expression profiling in the molecular characterization of aortic disease

OBJECTIVES The purpose of this study was to profile altered patterns of gene expression that characterize degenerative ascending thoracic aortic aneurysms and to compare these patterns with those observed for infrarenal abdominal aortic aneurysms. METHODS Full-thickness aortic wall tissues were obtained during surgical repair of degenerative thoracic aortic aneurysms and infrarenal abdominal aortic aneurysms (n = 4 each), with normal thoracic and abdominal aortas from organ transplant donors used as control preparations. Radiolabeled complementary DNA was prepared for each specimen and hybridized to complementary DNA microarrays, and differential levels of gene expression between aneurysmal and normal aortic tissues at each site were assessed by parametric statistics. RESULTS Of 1185 genes examined, 112 (9.5%) were differentially expressed (P <.05) between thoracic aortic aneurysms and normal thoracic aorta, with 105 increased and 7 decreased. There were 104 genes (8.8%) differentially expressed between infrarenal abdominal aortic aneurysms and normal abdominal aorta (65 increased and 39 decreased). Quantitative increases in expression for 97 genes were unique to thoracic aortic aneurysms, whereas increases for 61 genes were unique to infrarenal abdominal aortic aneurysms. Although 8 gene products were significantly altered in both thoracic and infrarenal abdominal aortic aneurysms, these changes were directionally concordant for only 4 (matrix metalloproteinase 9/gelatinase B, v-yes-1 oncogene, mitogen-activated protein kinase 9, and intercellular adhesion molecule 1/CD54). Results for 9 genes were independently confirmed by quantitative reverse transcriptase-polymerase chain reaction. CONCLUSIONS Thoracic aortic aneurysms and infrarenal abdominal aortic aneurysms exhibit distinct patterns of gene expression relative to normal aorta from the same sites, with most alterations being unique to each disease. Degenerative aneurysms arising in different locations are thus characterized by a high degree of molecular heterogeneity, reflecting different pathophysiologic mechanisms.

Identification of optimal device combinations for the chimney endovascular aneurysm repair technique within the PERICLES registry

Objective: The ideal stent combination for chimney endovascular aneurysm repair remains undetermined. Therefore, we sought to identify optimal aortic and chimney stent combinations that are associated with the best outcomes by analyzing the worldwide collected experience in the PERformance of chImney technique for the treatment of Complex aortic pathoLogiES (PERICLES) registry. Methods: The PERICLES registry was reviewed for patients with pararenal aortic disease electively treated from 2008 to 2014. Eleven different aortic devices were identified with three distinct subgroups: group A (n = 224), nitinol/polyester; group B (n = 105), stainless steel/polyester; and group C (n = 69), nitinol/expanded polytetrafluoroethylene. The various chimney stent subtypes included the balloon‐expandable covered stent (BECS), self‐expanding covered stent, and bare‐metal stent. Deidentified aortic and chimney device combinations were compared for risk of chimney occlusion, type IA endoleak, and survival. Effects of high‐volume centers (>100 cases), use of an internal lining chimney stent, number of chimney stents, and number of chimney stent subtypes deployed were also considered. We considered demographics, comorbidities, and aortic anatomic features as potential confounders in all models. Results: The 1‐ and 3‐year freedom from BECS chimney occlusion was not different between groups (group A, 96% ± 2% and 87% ± 5%; groups B and C, 93% ± 3% and 76% ± 10%; Cox model, P = .33). Similarly, when non‐BECS chimney stents were used, no difference in occlusion risk was noted for the three aortic device groupings; however, group C patients receiving BECS did have a trend toward higher occlusion risk relative to group C patients not receiving a BECS chimney stent (hazard ratio [HR], 4.0; 95% confidence interval [CI], 0.85‐18.84; P = .08). Patients receiving multiple chimney stents, irrespective of stent subtype, had a 1.8‐fold increased risk of occlusion for each additional stent (HR, 1.8; 95% CI, 1.2‐2.9; P = .01). Use of a bare‐metal endolining stent doubled the occlusion hazard (HR, 2.1; 95% CI, 1.0‐4.5; P = .05). Risk of type IA endoleak (intraoperatively and postoperatively) did not significantly differ for the aortic devices with BECS use; however, group C patients had higher risk relative to groups A/B without BECS (C vs B: odds ratio [OR], 3.2 [95% CI, 1‐11; P = .05]; C vs A/B: OR, 2.4 [95% CI, 0.9‐6.4; P = .08]). Patients treated at high‐volume centers had significantly lower odds for development of type IA endoleak (OR, 0.2; 95% CI, 0.1‐0.7; P = .01) irrespective of aortic or chimney device combination. Mortality risk was significantly higher in group C + BECS vs group A + BECS (HR, 5.3; 95% CI, 1.6‐17.5; P = .006). The 1‐ and 3‐year survival for groups A, B, and C (+BECS) was as follows: group A, 97% ± 1% and 92% ± 3%; group B, 93% ± 3% and 83% ± 7%; and group C, 84% ± 7% and 63% ± 14%. Use of more than one chimney subtype was associated with increased mortality (HR, 3.2; 95% CI, 1.4‐7.5; P = .006). Conclusions: Within the PERICLES registry, use of nitinol/polyester stent graft devices with BECS during chimney endovascular aneurysm repair is associated with improved survival compared with other aortic endografts. However, this advantage was not observed for non‐BECS repairs. Repairs incorporating multiple chimney subtypes were also associated with increased mortality risk. Importantly, increasing chimney stent number and bare‐metal endolining stents increase chimney occlusion risk, whereas patients treated at low‐volume centers have higher risk of type IA endoleak.