Does lipoprotein(a) inhibit elastolysis in abdominal aortic aneurysms?

PURPOSE: to test the hypothesis that there is a negative association between serum levels of lipoprotein(a) (Lp(a)) and elastin-derived peptides (EDP) as well as matrix metalloproteinase (MMP)-9 activation in the aneurysm wall in patients with asymptomatic abdominal aortic aneurysms (AAA). MATERIAL AND METHODS: from 30 patients operated for asymptomatic AAAs, preoperative serum samples and AAA biopsies were collected. Lp(a) (mg/L) and EDP (ng/ml) in serum were measured by enzyme linked immunosorbent assays. MMP-9 activity (arbitrary units) in the AAA wall was measured by gelatin zymography and the ratio: active MMP-9/total MMP-9 were calculated. RESULTS: there was a significant negative correlation (Spearman's rho) between serum levels of Lp(a) and EDP (r= -0.707, p<0.001), as well as the share of activated MMP-9 (r= -0.461, p=0.01) in the AAA wall.CONCLUSION: this preliminary study indicate that Lp(a) inhibit elastolysis in asymptomatic AAA.     

Functional matrix metalloproteinase-9 polymorphism (C-1562T) associated with abdominal aortic aneurysm

PURPOSE: Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase with activity against both collagens and elastin. Expression of MMP-9 is elevated in vascular disease, and in particular within aneurysm tissues. This study tested the hypothesis that the functionally more active T allele of the MMP9 C-1562T polymorphism may be overrepresented in patients with abdominal aortic aneurysm (AAA) compared with control subjects and patients with atherosclerotic peripheral vascular disease (PVD). METHODS: Seven hundred eighty-nine unrelated persons (AAA, n = 414; control subjects, n = 203; PVD, n = 172) were genotyped for the common C-1562T functional promoter polymorphism of the MMP9 gene. RESULTS: Genotypes containing the T allele of this polymorphism were significantly more common in patients with AAA compared with both control subjects and patients with PVD (adjusted odds ratio, 2.41 and 2.94, respectively). The greatest shift between groups was observed in male patients, with a difference of 20.6% in CT/TT genotypes. and 12.1% in T allele frequency between patients with AAA compared with patients with PVD. CONCLUSIONS: This study provides further evidence to support the role of MMP-9 in the pathogenesis of AAA, and indicates that the MMP9 C-1562T functional polymorphism may represent a genetic component contributing to susceptibility to this vascular disease.     

Systemic dilation diathesis in patients with abdominal aortic aneurysms: a role for matrix metalloproteinase-9?

INTRODUCTION: Accumulating evidence suggests that patients with abdominal aortic aneurysm (AAA) suffer from a systemic dilating condition affecting all arteries. Matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), appear to be involved in aneurysm formation, as evidenced by increased aortic tissue MMP activity and plasma MMP levels in patients with AAA. Hypothesizing that an imbalance in plasma MMP/TIMP level might be associated with a systemic dilation diathesis, we studied mechanical vessel wall properties of non-affected arteries of patients with either AAA or aorto-iliac obstructive lesions in association with plasma MMP-9 and TIMP-1 levels. METHODS: Twenty-two patients with AAA and 12 with aorto-iliac occlusive disease (AOD) were included. Diastolic diameter (d) and distension (Deltad) were measured at the level of the common carotid artery (CCA) and suprarenal aorta (SA) using ultrasonography. Distensibility (DC) and compliance (CC) were calculated from d, Deltad and brachial pulse pressure. Plasma MMP-9 and TIMP-1 were determined with specific immunoassays. RESULTS: The average (+/-SD) age was 72.3+/-5.6 and 65.0+/-8.2 years for the AAA and AOD patients, respectively, (P=0.005). CCA diameter was 9.1+/-1.3mm in AAA patients and AOD 7.8+/-1.4mm in AOD patients, P=0.009. This difference persisted after correction for age. Plasma MMP-9 and TIMP-1 did not differ significantly between AAA and AOD patients. In the total 34 patients, the MMP-9/TIMP-1 ratio was correlated inversely with distensibility (r=-0.74, P=0.002) and to compliance (r=-0.58, P=0.024) of the suprarenal aorta. CONCLUSIONS: The CCA diameter was larger in AAA patients compared to AOD patients. MMP-9/TIMP-1 ratio was associated with decreased distensibility and compliance of the suprarenal aorta. These data support the idea that AAA patients exhibit a systemic dilation diathesis, which might be attributable to MMP/TIMP imbalances.     

Activity of matrix metalloproteinase-2 and -9 in abdominal aortic aneurysms. Relation to size and rupture.

OBJECTIVES: to investigate the activity of matrix metalloproteinase (MMP)-2 and -9 in asymptomatic abdominal aortic aneurysms (aAAAs) and ruptured abdominal aortic aneurysms (rAAAs). DESIGN: cross-sectional study. MATERIALS AND METHODS: MMP-2 and MMP-9 activity was estimated in biopsies from the anterior wall of 60 AAAs using gelatin zymography. There were 20 medium-sized (diameter 5<7 cm) aAAAs, 20 large (>57 cm) aAAAs and 20 rAAAs. MMP activity was quantified using a laser densitometer and expressed as arbitrary units (au). RESULTS: mean (SEM) MMP-9 activity was significantly lower in large aAAAs (1190 au +/-247) than in rAAAs (2647 au +/-498, p<0.05). There was no difference in MMP-2 activity. CONCLUSION: High MMP-9 activity in the AAA wall is associated with rupture.     

Presence of Chlamydia pneumoniae in abdominal aortic aneurysms is not associated with increased activity of matrix metalloproteinases.

OBJECTIVE: to test the hypothesis that the presence of Chlamydia pneumoniae (C. pneumoniae) in the wall of abdominal aortic aneurysms (AAA) is associated with increased activity of matrix metalloproteinase (MMP)-2 and/or MMP-9.DESIGN: case-control study. MATERIAL AND METHODS: in a series of 40 patients with AAA > or =5cm in maximal cross-sectional diameter, C. pneumoniae-DNA was identified in the aneurysm wall by nested PCR in 14 (35%) patients. Another 14 C. pneumoniae-DNA-negative AAA patients from the same series, matched for gender and aneurysm diameter, were used as controls. In each group there were 7 asymptomatic (aAAA) and 7 ruptured (rAAA) aneurysms. MMP-2 and -9 activity was estimated in AAA wall biopsies by gelatin zymography. RESULTS: patients with a C. pneumoniae-DNA-positive aneurysm wall specimen showed an over-all lower activity of MMP-2 and MMP-9 (pro- and active enzyme) compared to the C. pneumoniae-DNA negative patients. However, there were no statistically significant differences in MMP activity between the two groups of patients with aAAA. Among patients with rAAA both pro-MMP-9 (p=0,026) and active-MMP-9 (p=0.007) were significantly lower in C. pneumoniae-DNA-positive patients compared to C. pneumoniae-DNA-negative patients, whereas there were no significant differences in pro-MMP-2 or active-MMP-2. CONCLUSION: this preliminary study does not support the hypothesis that the presence of C. pneumoniae in the AAA wall is associated with increased activity of MMP-2 and MMP-9.     

Cigarette smoking increases aortic dilatation without affecting matrix metalloproteinase-9 and -12 expression in a modified mouse model of aneurysm formation

OBJECTIVE: The development of abdominal aortic aneurysms (AAA) is presumed to result from multiple genetic and environmental factors, with exposure to tobacco smoke the single largest known factor predisposing to aneurysm growth. We have attempted to adapt the elastase-perfused animal model to determine whether tobacco exposure can lower the threshold of aortic injury necessary for AAA development. METHODS: Adult C57BL/6 mice underwent transient perfusion of the infrarenal aorta with an active solution of elastase: high-dose (HDE, 0.19 U/mL, n=9), standard-dose (SDE, 0.16 U/mL, n=21) or low-dose (LDE, 0.07 U/mL, n=24). Control animals (n=24) were treated with heat inactivated elastase (HIE). Twenty LDE perfused mice were exposed to cigarette smoke (LDE-S) beginning 2 weeks before perfusion and continuing until aortic harvest. Aortic diameter (AD) was measured preperfusion, postperfusion, and at harvest on day 14. AAA was defined as %DeltaAD>or=100% between preperfusion and harvest. Aortas from each group (except HDE) were analyzed for matrix metalloproteinase-9 (MMP-9) and MMP-12 expression by real-time polymerase chain reaction normalized to glyceraldehyde-3-phosphate dehydrogenase. RESULTS: All SDE mice developed large AAA by %DeltaAD (189.3%+/-16.9%, mean+/-standard error of the mean), but control mice had only a small dilatation (69.7%+/-3.7%, P<.01). Higher doses of elastase did not produce larger aneurysms in HDE mice. In contrast, only 63% of LDE mice showed aneurysmal dilatation, and these were significantly smaller (104.3%+/-4.2%, P<.01). When exposed to cigarette smoke, LDE animals developed significantly larger aneurysms (%DeltaAD, 134.5%+/-7.9%, P=.0021). There was no difference in normalized aortic MMP-9 and MMP-12 expression between elastase doses or between smoke-exposed and unexposed animals. Histologic analysis revealed that smoking increased the extent of aortic elastin degradation when compared with LDE-S animals. CONCLUSION: Aneurysm development in the elastase model is dependent on the quantity of active elastase infused. Exposure of animals to tobacco smoke after a relatively minor aortic elastase injury produces increases in elastin degradation and aneurysm size without affecting MMP-9 or MMP-12 expression. To our knowledge, this is the first demonstration in an animal model that smoking can act as a synergistic factor in AAA development. Further understanding of the relationship between smoking and AAA in this model may help unveil the pathophysiologic pathways involved between cigarette smoke and AAAs.     

Matrix metalloproteinase expression in the ascending aorta and aortic valve

Extracellular matrix degradation and increased proteolytic enzyme (matrix metalloproteinase (MMP)) activity characterise abdominal aortic aneurysm formation. Post-stenotic dilatation of ascending aorta is associated with aortic stenosis and regurgitation, haemodynamically normal bicuspid aortic valve (BAV) and following AV replacement. We aimed to determine an association between ascending aortic pathology and abnormal AV, with particular reference to MMPs, and ascertain differences between BAV and tricuspid (TAV) AV. Subset of the study population (n=19) with a preoperative ascending aorta of >4 cm was analysed. Samples of ascending aorta and AV were obtained from 82 patients (TAV, n=54, BAV, n=28) undergoing surgery. Gene expression of MMP-1, -2, -9 and tissue inhibitor of metalloproteinase (TIMP)-1 and -2 was quantified by real-time RT-PCR. No significant difference was seen in gene expression level of MMPs, TIMPs and ratio of MMPs/TIMPs in ascending aorta and AV between patients with BAV and TAV. MMP-2/TIMP-1 in ascending aorta was greater in BAV, in the subset of patients with preoperative aortic dilatation (P<0.05). No difference exists in gene expression of MMPs in ascending aorta and AV between patients with BAV and TAV. However, patients with larger aortic diameters have increased MMP-2/TIMP-1. Modifying MMP expression may have a role in development of aneurysms.     

四环素抑制实验性大鼠腹主动脉瘤形成的初步研究

目的；研究四环素对实验性大鼠腹主动脉瘤形成的作用。方法：建立大鼠腹主动脉瘤弹力蛋白酶灌注模型，随机分为实验组（10只）皮下注射四环素（25mg/d)，对照组（10只）皮下注射生理盐水，观察两组动脉瘤形成率和动脉瘤组织学改变，并应用免疫组织化学和分子原位杂交技术检测基质金属蛋白酶－2和9的表达。结果：灌注2周后实验组大鼠腹主动脉瘤形成率10％，对照组大鼠动脉瘤形成率为10％，两组差异有显著意义（P＜0．05），实验组大鼠动脉壁组织MMP－2，MMP－9蛋白表达为弱阳性或阴性，对照组动物瘤组织中两者表达明显增高，两位杂交检测结果表明两组mRNA表达强度无明显差异。结论：四环素能够降低基质金属蛋白酶－2和9的表达，从而减低动脉壁组织弹力纤维的降解，抑制实验性大鼠腹主动脉瘤的形成。     

Proteolysis of the abdominal aortic aneurysm wall and the association with rupture.

PURPOSE: to investigate proteolysis of the abdominal aortic aneurysm (AAA) wall and the association with rupture. METHODS: levels of matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) were measured in the walls of medium-sized (5-7 cm in diameter) ruptured AAA (rAAA) (n =30) and large (> or = 7 cm in diameter) asymptomatic AAA (aAAA) (n=30). RESULTS: MMP-2 levels (median, range) were significantly higher in the walls of large aAAA (165 ng/g AAA tissue, 50-840) than from medium-sized rAAA (110 ng/g AAA tissue, 47-547, p=0.007). MMP-9 levels were significantly higher in the walls of medium-sized rAAA (107 ng/g AAA tissue, 19-582) than from large aAAA (55 ng/g AAA tissue, 11-278, p=0.012). TIMP-1 and TIMP-2 levels were equivalent. There was a positive correlation between MMP-2 and the diameter of aAAA (r=0.54, p=0.002), but a negative correlation with MMP-9 (r= -0.44, p=0.017). No significant correlations were found between aAAA diameter and TIMP-1 or TIMP-2. CONCLUSION: AAA rupture is associated with higher levels of MMP-9. There is no association with TIMP-1 or TIMP-2 levels. MMP-2 levels are positively, whereas MMP-9 levels are negatively, correlated with aAAA size. MMP-9 may play a role in the progression towards rupture, whereas MMP-2 may play a role in expansion.     

Uptake of tetracycline by aortic aneurysm wall and its effect on inflammation and proteolysis.

BACKGROUND: Proteolytic degradation of the aortic wall by matrix metalloproteinases (MMPs) is considered important in the pathogenesis of abdominal aortic aneurysms (AAAs). Many of these MMPs are inhibited by tetracycline derivatives, which may have the potential to retard aneurysm growth. METHODS: Patients undergoing elective repair of an AAA (n = 5) received an intravenous bolus of tetracycline (500 mg) on induction of anaesthesia and levels of tetracycline in serum, aneurysm wall and mural thrombus were assessed by microbiological assay. In a separate series of patients (n = 7) aneurysm biopsies were placed into explant culture (with and without tetracyline) and the accumulation of protein, hydroxyproline, MMP-9, interleukin (IL) 6 and monocyte chemoattractant protein (MCP) 1 in the medium was assessed by colorimetric assay or immunoassay. RESULTS: At aortic cross-clamping the median concentration of tetracycline was 8.3 microg/ml in serum, 2.9 microg per g tissue in aortic wall and zero in mural thrombus. Tetracycline inhibited, in a concentration-dependent manner, both MMP-9 and MCP-1 secretion (P = 0.022 and P = 0.018 respectively), but did not alter hydroxyproline or IL-6 secretion. At the highest concentration of tetracycline (100 microg/ml) median MMP-9 secretion was reduced from 27 to 5 ng/ml (P = 0.007) and median MCP-1 secretion was reduced from 50 to 10 ng/ml (P = 0.008). CONCLUSION: Tetracycline rapidly penetrates the aortic wall, but the concentration achieved may be insufficient to alter collagen turnover through limitation of MMP production or activity.     

Genotype-phenotype relationships in an investigation of the role of proteases in abdominal aortic aneurysm expansion

BACKGROUND: The aim of the study was to investigate the effect of functional polymorphisms in promoters of matrix metalloproteinase (MMP) 2, MMP-3, MMP-9, MMP-12 and plasminogen activator inhibitor (PAI) 1 genes on the growth rate of small abdominal aortic aneurysms (AAA). METHODS: Some 455 individuals with a small AAA (4.0-5.5 cm) were monitored for aneurysm growth by ultrasonography (mean follow-up 2.6 years). They also provided a DNA sample for analysis of the -1306 C > T, -1171 5A > 6A, -1562 C > T, -82 A > G and -675 4G > 5G alleles of MMP-2, MMP-3, MMP-9, MMP-12 and PAI-1, respectively. Mean linear AAA growth rates were calculated by flexible modelling; the sample size was sufficient to detect variants that influenced the growth rate by 25 per cent. RESULTS: For MMP-2, MMP-9 and MMP-12 genotypes, growth rates were similar to the mean linear growth rate of 3.08 mm per year. For MMP-3, growth rates were 3.05 (for 5A5A), 3.19 (for 5A6A) and 2.90 (for 6A6A) mm per year. For PAI-1, patients with 4G4G, 4G5G and 5G5G genotypes had growth rates of 3.18, 2.92 and 3.47 mm per year, respectively, for aneurysms with a baseline diameter of 45.1, 44.6 and 46.2 mm. The increased growth rate for patients with PAI-1 5G5G genotype was not statistically significant (P = 0.061), although these patients had the lowest plasma PAI-1 concentrations (P = 0.018). CONCLUSION: There was no evidence that any specific MMP polymorphism had a clinically significant effect on AAA expansion. The plasminogen system may have a small but clinically significant role in AAA development. Much larger studies would be needed to evaluate genes of smaller effect.     

Matrix metalloproteinase expressions in arteriosclerotic aneurysmal disease

Medial degeneration of extracellular matrix (ECM) proteins in the wall of abdominal aortas results in smooth muscle cell destruction, a loss of architectural integrity, and abdominal aortic aneurysm (AAA) formation. It has been theorized that an imbalance between proteinases and their naturally occurring inhibitors is the cause of these observed histologic abnormalities. Therefore, the purpose of this investigation was to determine if differences in the matrix metalloproteinase (MMP) -2 and -9, tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) protein and activity levels existed between infrarenal AAA and normal abdominal aortic tissue specimens. Between November 1995 and January 1997, 10 patients undergoing elective infrarenal AAA repair had a portion of their aneurysm walls snap frozen in liquid nitrogen and processed for subsequent western blot or zymographic analysis. Tissue specimens from 6 normal abdominal aortas obtained from fresh cadaver specimens were similarly processed and served as controls. Protein levels for MMP-2, MMP-9, TIMP-1, uPA, and tPA were analyzed by western blotting. The degree of MMP-2 and MMP-9 gelatinolytic activity was analyzed by zymography. Detection and immunolocalization for MMP-2, MMP-9 and CD68 was performed on tissue sections of AAA and normal infrarenal abdominal aortas fixed in 10% formalin. MMP-9 and tPA protein levels were increased in AAAs compared to controls by western blotting. However, uPA levels were slightly increased in controls. No differences in TIMP-1 protein levels were identified. Similarly, zymography demonstrated increased MMP-2 and MMP-9 gelatinolytic activity in AAAs compared to controls (p < or = 0.05). CD68-positive cells (macrophages) in the adventitia and media demonstrated immunoreactivity to MMP-9. This investigation demonstrated increased MMP-9 proteinase activity and tPA protein levels in the walls of AAAs, as well as inflammatory leukocyte invasion of the adventitia and media compared to controls. These data suggest that leukocyte-derived MMP-9 is associated with aortic wall degeneration and aneurysm formation. Furthermore, activation of MMP-9 may be caused by increased tPA levels in the walls of AAAs.     

HMG-CoA reductase inhibitors (statins) decrease MMP-3 and MMP-9 concentrations in abdominal aortic aneurysms.

BACKGROUND: An imbalance in matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are implicated in AAA formation. 3-Hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are known to reduce MMP levels. The aim of this study was to investigate the in vivo effect of statins on MMP levels in AAA. METHODS: Infra-renal aortic biopsies were obtained from the anterior sac of 63 patients undergoing asymptomatic repair. Seventeen patients were taking a statin pre-operatively, while 46 were not. The concentrations of MMP-1, -2, -3, -8, -9, -13, TIMP-1 and TIMP-2 were quantified using ELISA. RESULTS: There was no difference in the concentration of MMP-1, -2, -8, -13, TIMP-1 or -2 in patients taking versus not taking a statin pre-operatively. In contrast levels of MMP-9 and MMP-3 were significantly lower in patients taking a statin. CONCLUSIONS: These data demonstrate that statins decrease MMP-9 and MMP-3 levels and represent a potential pharmacotherapy in established AAA.     

Response of plasma matrix metalloproteinase-9 to conventional abdominal aortic aneurysm repair or endovascular exclusion: implications for endoleak

PURPOSE: Matrix metalloproteinases are enzymes capable of breaking down all of the components of the extracellular matrix and have been implicated in the development of aneurysm formation. Because matrix metalloproteinase-9 (MMP-9) levels are elevated in aortic aneurysmal tissue and in that patient plasma, we hypothesized that plasma MMP-9 levels should decrease significantly after conventional and endovascular infrarenal abdominal aortic aneurysm (AAA) repair but that plasma MMP-9 levels would remain elevated in patients with endoleaks. METHODS: A sandwich enzyme-linked immunosorbent assay was used to measure plasma levels of MMP-9 in patients with AAA who underwent conventional (n = 26; mean age, 71.5 years) and endovascular (n = 25; mean age, 76.4 years) AAA repair. Levels were drawn before surgery and at 1 month and 3 months after surgery. Eight patients for endovascular repair had endoleaks identified on postoperative computed axial tomographic scans. RESULTS: No correlation existed between preoperative plasma MMP-9 levels when compared with age, gender, or aneurysm diameter. No significant difference in preoperative plasma MMP-9 levels or AAA diameter was identified between patients with conventional repair compared with endovascular repair. Of the 51 patients, 33 had follow-up samples available for analysis. A significant increase in mean plasma MMP-9 levels was noted 1 month (149.5 +/- 40.1 ng/mL) after conventional AAA repair compared with preoperative levels (83.9 +/- 26.1 ng/mL; P <.05) and remained elevated 3 months after surgery (129.8 +/- 56.6 ng/mL). In those patients who underwent endovascular aneurysm exclusion without endoleak, a significant decrease in mean plasma MMP-9 levels was noted at 3 months (27.4 +/- 5.2 ng/mL) when compared with preoperative values (60.8 +/- 8.8 ng/mL; P <.01). In contrast, patients with endoleak after endovascular exclusion did not have a significant decrease in plasma MMP-9 levels at 3 months. CONCLUSION: Plasma MMP-9 levels remain elevated for as much as 3 months after conventional AAA repair, whereas successful endovascular exclusion of an AAA results in decreased plasma MMP-9 levels by 3 months. MMP-9 may have clinical value as an enzymatic marker for endoleak after endovascular AAA exclusion.     

Enhanced invasive properties exhibited by smooth muscle cells are associated with elevated production of MMP-2 in patients with aortic aneurysms.

BACKGROUND: abdominal aortic aneurysms (AAA) are associated with excessive vascular matrix remodelling. Recent findings suggest a systemic overproduction of matrix metalloproteinases-2 (MMP-2) by vascular smooth muscle cells (SMC) may be pivotal aetiologically. SMC migration is facilitated by MMP mediated proteolysis of the basement membrane and extracellular matrix. Our aim was to see if enhanced MMP-2 production by these SMC exhibit increased invasion, in an in vitro model of migration. METHOD: SMC were derived from inferior mesenteric vein (IMV) harvested from patients undergoing aneurysm repair (n=6) or colectomy for diverticulosis (n=6, control). Using a modified Boyden chamber chemotaxis was measured towards platelet derived growth factor (PDGF) and foetal calf serum (FCS) and invasion through a Matrigel layer. MMP-2 production was quantified by ELISA and gelatin zymography. RESULTS: chemoattractant studies demonstrated no difference in the effect of PDGF or FCS between the two populations of SMC. However, invasive studies demonstrated a significant increase in the number of migrating SMC isolated from IMV of AAA patients. Analysis of culture media extracts revealed that this difference was associated with a significant increase in production of MMP-2. CONCLUSION: SMC derived from patients with AAA demonstrate increased invasive properties when compared to a control group. Increased migration appears to be due to overproduction of MMP-2. The enhanced migratory potential of these SMC may lead to extracellular matrix remodelling and subsequent medial disruption demonstrated in the aneurysmal aorta. These data further support evidence of the proteolytic role of MMP-2 in cell migration.     

The expression and localization of membrane type-1 matrix metalloproteinase in human abdominal aortic aneurysms

BACKGROUND AND OBJECTIVE: Matrix metalloproteinase-2 (MMP-2) degrades both fibrillar collagens and elastin. MMP-2 is secreted as a latent 72-kd proenzyme that must be proteolytically processed to the 62-kd active form. In our laboratory we demonstrated a significant increase of active, matrix-bound MMP-2 in abdominal aortic aneurysmal (AAA) tissue compared with nonaneurysmal aorta with arteriosclerotic occlusive disease and normal aortic tissue. This increase in active MMP-2 is considered to be important in aneurysm pathogenesis, but the mechanism of its activation in aortic tissue is unknown. Membrane type-1 MMP (MT-1 MMP) is known to be an activator of MMP-2. The purpose of this study was to determine MT-1 MMP expression and its involvement in pro-MMP-2 activation in human aneurysmal tissue. METHODS: Infrarenal aortic tissue was obtained during the surgical repair of AAAs or the bypass of aortoiliac occlusive disease, or from nondiseased aorta, and the expression of MT-1 MMP messenger RNA was determined with Northern blot analysis. MT-1 MMP protein was determined with immunoblot and immunohistochemistry. The ability of aortic tissue to activate pro-MMP-2 was analyzed by incubating aortic tissue with exogenous radiolabeled pro-MMP-2. RESULTS: MT-1 MMP messenger RNA and protein are increased in AAA (P <.05) compared with arteriosclerotic occlusive disease and normal aortic tissue. Immunohistochemical analysis localized MT-1 MMP to aortic smooth muscle cells and macrophages in aneurysmal tissue. AAA tissue demonstrated a greater capacity to activate exogenous pro-MMP-2 compared with atherosclerotic and normal aortic tissue (P <.05). CONCLUSION: These studies demonstrate that MT-1 MMP is increased in AAA tissue and suggest that it may be important in AAA pathogenesis through its ability to activate pro-MMP-2     

Growth rate and associated factors in small abdominal aortic aneurysms.

OBJECTIVE: To study the growth rate and factors influencing progression of small infrarenal abdominal aortic aneurysms (AAA). DESIGN: Observational, longitudinal, prospective study. PATIENTS AND METHODS: We followed patients with AAA <5 cm in diameter in two groups. Group I (AAA 3-3.9 cm, n = 246) underwent annual ultrasound scans. Group II (AAA 4-4.9 cm, n = 106) underwent 6-monthly CT scans. RESULTS: We included 352 patients (333 men and 19 women) followed for a mean of 55.2+/-37.4 months (6.3-199.8). The mean growth rate was significantly greater in group II (4.72+/-5.93 vs. 2.07+/-3.23 mm/year; p<0.0001). Group II had a greater percentage of patients with rapid aneurysm expansion (>4 mm/year) (36.8 vs. 13.8%; p<0.0001). The classical cardiovascular risk factors did not influence the AAA growth rate in group I. Chronic limb ischemia was associated with slower expansion (< or = 4 mm/year) (OR 0.47; CI 95% 0.22-0.99; p = 0.045). Diabetic patients in group II had a significantly smaller mean AAA growth rate than non-diabetics (1.69+/-3.51 vs. 5.22+/-6.11 mm/year; p = 0.032). CONCLUSIONS: The expansion rate of small AAA increases with the AAA size. AAA with a diameter of 3-3.9 cm expand slowly, and they are very unlikely to require surgical repair in 5 years. Many 4-4.9 cm AAA can be expected to reach a surgical size in the first 2 years of follow-up. Chronic limb ischemia and diabetes are associated with reduced aneurysm growth rates.