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.     

基质金属蛋白酶9在胸主动脉瘤和胸主动脉夹层中的表达

目的 观察基质金属蛋白酶(MMP)-9在DebakeyI型胸主动脉夹层(TAD)和胸主动脉瘤(TAA)中的表达,探讨其在TAD和TAA中的作用.方法 苏木素-伊红(HE)染色、铁苏木素染色、TUNEL染色、免疫组织化学染色分别观察11例TAD和10例TAA的病理特征、弹力纤维断裂、管壁细胞凋亡、MMP-9在动脉管壁中的表达和定位,并分析MMP-9表达与各项临床参数的关系.结果 MMP-9在TAD和TAA中高表达(P<0.05),主要位于中外膜平滑肌细胞和炎性细胞,MMP-9表达与主动脉直径显著相关(P<0.05).结论 MMP-9在TAD和TAA中高表达,中外膜平滑肌细胞和炎性细胞是其主要表达细胞;MMP-9可能通过弹力板层的破坏来影响管壁重构过程.     

Aminoterminal propeptide of type III procollagen and matrix metalloproteinases-2 and -9 failed to serve as serum markers for abdominal aortic aneurysm.

OBJECTIVES: Matrix-metalloproteinase (MMP)-2 and -9 and aminoterminal propeptide of type III collagen (NIIINP) have been reported to be elevated in patients with abdominal aortic aneurysm (AAA). The aim of our study was to test NIIINP, MMP-2 and -9 as potential serum markers for AAA in a large population group at risk for AAA. METHODS: Fifty-five to 70 year old men were screened for AAA by abdominal ultrasound. Simultaneously, blood samples were taken and the patients were interviewed for known risk factors for AAA. Patients with a dilatation of the infrarenal aorta of > or =25mm (Group 1, n=76) were compared to randomly assigned patients with normal aortic diameters (Group 2, n=83). A third group consisted of patients scheduled for operation of AAA (n=19). RESULTS: A total of 987 men were investigated with ultrasound. Seventy-six (7.7%) had an aortic dilatation > or =25mm. Aortic dilatation was correlated with age (P=0.0001). However, serum levels of NIIINP and MMP 2 were not different between the three groups of patients. For MMP-9 there was a weak inverse correlation with lower serum levels in patients with aortic dilatation (P=0.043). CONCLUSIONS: Both MMP-2 and -9 and NIIINP failed to show relevance as serum markers for aortic dilatation. Our results are, therefore, in contradiction to previous published results. AAAs cannot be diagnosed with a simple blood test.     

Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study

BACKGROUND: The primary purpose of this study was to evaluate compliance, side effects, and safety associated with prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms (AAAs). A secondary goal was to determine how treatment with doxycycline influences circulating levels of matrix metalloproteinase-9 (MMP-9) in this patient population. METHODS: Thirty-six patients with AAAs (30 men and 6 women; mean age, 69 +/- 1 years) were enrolled into a 6-month phase II study to evaluate treatment with doxycycline (100 mg orally twice a day). Aneurysm size was measured before and after treatment, and compliance and side effects were monitored. Plasma levels of doxycycline were measured midway through the study, and plasma MMP-9 concentrations were measured at baseline, 3 months, and 6 months. RESULTS: Thirty-three of the 36 patients (92%) completed 6 months of doxycycline treatment. Significant treatment-related side effects occurred in five patients (13.9%), including three with cutaneous photosensitivity reactions (8.3%), one with tooth discoloration (2.8%), and one with yeast infection (2.8%). A high rate of compliance with treatment was seen, despite minor but frequent side effects, including nonspecific gastrointestinal symptoms (25%), easily managed episodes of photosensitivity (22.2%), and reversible tooth discoloration (5.5%). The mean plasma doxycycline level after 3 months was 4.62 +/- 0.68 ug/mL (median, 3.64 microg/mL; range, 1.31 to 14.39 microg/mL; n = 23 patients). No significant change was seen in AAA diameter (42.7 +/- 1.3 mm at 6 months versus 41.0 +/- 0.9 mm at baseline), and the overall rate of AAA expansion was 0.63% +/- 0.25% per month. The mean plasma MMP-9 level (n = 19 patients) was elevated at baseline (118.9 +/- 37.9 ng/mL; upper limit of normal, 85 ng/mL) but subsequently decreased to 83.8 +/- 32.9 ng/mL at 3 months (not significant versus baseline) and to 66.4 +/- 24.2 ng/mL at 6 months (P =.022 versus baseline). Only 21% of patients had an elevated level of plasma MMP-9 after 6 months of treatment compared with 47% at baseline (P <.05). CONCLUSION: Prolonged administration of doxycycline is safe and well tolerated by patients with small asymptomatic AAAs and is associated with a gradual reduction in plasma MMP-9 levels. Further studies are needed to evaluate the long-term effects of doxycycline on the rate and extent of aneurysm growth and the potential use of plasma MMP-9 levels as a biomarker of aneurysm disease progression.     

Adventitial delivery minimizes the proinflammatory effects of adenoviral vectors

PURPOSE: Adenovirus-mediated arterial gene transfer is a promising tool in the study of vascular biology and the development of vascular gene therapy. However, intraluminal delivery of adenoviral vectors causes vascular inflammation and neointimal formation. Whether these complications could be avoided and gene transfer efficiency maintained by means of delivering adenoviral vectors via the adventitia was studied. METHODS: Replication-defective adenoviral vectors encoding a beta-galactosidase (beta-gal) gene (AdRSVnLacZ) or without a recombinant gene (AdNull) were infused into the lumen or the adventitia of rabbit carotid arteries. Two days after infusion of either AdRSVnLacZ (n = 8 adventitial, n = 8 luminal) or AdNull (n = 4 luminal), recombinant gene expression was quantitated by histochemistry (performed on tissue sections) and with a beta-gal activity assay (performed on vessel extracts). Inflammation caused by adenovirus infusion was assessed 14 days after infusion of either AdNull (n = 6) or vehicle (n = 6) into the carotid adventitia. Inflammation was assessed by means of examination of histologic sections for the presence of neointimal formation and infiltrating T cells and for the expression of markers of vascular cell activation (ICAM-1 and VCAM-1). To measure the systemic immune response to adventitial infusion of adenovirus, plasma samples (n = 3) were drawn 14 days after infusion of AdNull and assayed for neutralizing antibodies. RESULTS: Two days after luminal infusion of AdRSVnLacZ, approximately 30% of luminal endothelial cells expressed beta-gal. Similarly, 2 days after infusion of AdRSVnLacZ to the adventitia, approximately 30% of adventitial cells expressed beta-gal. beta-gal expression was present in the carotid adventitia, the internal jugular vein adventitia, and the vagus nerve perineurium. Elevated beta-gal activity (50- to 80-fold more than background; P <.05) was detected in extracts made from all AdRSVnLacZ-transduced arteries. The amount of recombinant protein expression per vessel did not differ significantly between vessels transduced via the adventitia (17.1 mU/mg total protein [range, 8.1 to 71.5]) and those transduced via a luminal approach (10.0 mU/mg total protein [range, 3.9 to 42.6]). Notably, adventitial delivery of AdNull did not cause neointimal formation. In addition, vascular inflammation in arteries transduced via the adventitia (ie, T-cell infiltrates and ICAM-1 expression) was confined to the adventitia, sparing both the intima and media. Antiadenoviral neutralizing antibodies were present in all rabbits after adventitial delivery of AdNull. CONCLUSION: Infusion of adenoviral vectors into the carotid artery adventitia achieves recombinant gene expression at a level equivalent to that achieved by means of intraluminal vector infusion. Because adventitial gene transfer can be performed by means of direct application during open surgical procedures, this technically simple procedure may be more clinically applicable than intraluminal delivery. Moreover, despite the generation of a systemic immune response, adventitial infusion had no detectable pathologic effects on the vascular intima or media. For these reasons, adventitial gene delivery may be a particularly useful experimental and clinical tool.     

The wrapping method using biodegradable felt strips has a preventive effect on the thinning of the aortic wall: experimental study in the canine aorta

OBJECTIVES: Wrapping methods have been widely used to reinforce the anastomotic site in vascular surgery; however, postoperative changes in the aortic wall wrapped by nonbiodegradable felt have not been well characterized. The purposes of this investigation are to elucidate the sequelae of wrapping with nonbiodegradable felt on the aortic wall and to modify those changes by using biodegradable felt with or without basic fibroblast growth factor (bFGF). METHODS: The descending thoracic aortas of 15 beagles were wrapped with three different materials: nonbiodegradable polytetrafluoroethylene (PTFE) felt, biodegradable polyglycol acid (PGA) material, and PGA with 100 microg bFGF (n = 5 in each group). The descending thoracic aorta was resected after 3 months. The thickness of the aortic wall, vessel density in the media and the adventitia, and the wall strength were assessed. Untreated native aortic wall served as a normal control. RESULTS: The thickness of the media of the PTFE group was lower than that of the PGA + bFGF group (66% +/- 5% vs 85% +/- 6% of control, P < .05). The adventitia-media ratio in the PTFE group decreased compared with controls (59.1% of normal, P < 0.05), whereas those in the PGA and PGA + bFGF groups increased (172.1% and 189.6% of normal, respectively, P < .01). The collagen-smooth muscle ratio in the media was higher in the PTFE group than in the controls (0.14 +/- 0.02 vs 0.07 +/- 0.01, P < .01). The number of vessels in the adventitia was higher in the PGA + bFGF group than those in PTFE or PGA groups (29.6 +/- 2.5/mm2 vs 6.4 +/- 0.8/mm2, 19.0 +/- 1.1/mm2, P < .01). The PGA + bFGF group demonstrated larger failure force than the PTFE group (4.0 +/- 0.3 kgf vs 1.6 +/- 0.3 kgf, P < .01). The failure stress in the PGA and PGA + bFGF groups was larger than that in PTFE group (PTFE:PGA + bFGF = 5.3 +/- 0.9 x10(2) kPa:11.7 +/- 1.7 x 10(2) kPa, P < .01; PTFE:PGA = 5.3 +/- 0.9 x 10(2) kPa:11.2 +/- 1.2 x 10(2) kPa, P < .05). CONCLUSION: The aortic wall wrapped with nonbiodegradable PTFE felt showed a reduced thickness and diminished vessels in the adventitia. Biodegradable felt (PGA), with or without bFGF, modified these histologic changes. The vessel-rich thickened adventitia, after wrapping by PGA with bFGF, was associated with increased aortic wall strength. CLINICAL RELEVANCE: This investigation was conducted in an attempt to elucidate mechanisms underlying the occurrence of late postoperative false aneurysm after aortic surgery. We hypothesized that sustaining compression of the aorta by the felt strip may cause structural derangement and local ischemia on the aortic wall. We used a simple wrapping of the aorta with a felt strip rather than a felt strip at anastomotic sites to simplify the experimental model and to exclude confounding factors brought by technical inconsistency on the surgical anastomosis. We further attempted to find a clue for preventing adverse effects of wrapping with a conventional felt strip. Practically, we pursued a possible application of a biodegradable felt strip to aortic wrapping in our experimental model before we proceed in a clinical application of the new material.     

Matrix metalloproteinase 9 activity in patients before and after endovascular or surgical repair of abdominal aortic aneurysms

The objective of this prospective study was to assess matrix metalloproteinase 9 (MMP-9) activity in patients undergoing open surgery or endovascular repair of abdominal aortic aneurysms (AAAs), comparing changes in plasma levels in the two groups. We studied 12 patients after conventional open surgery and 9 patients after endovascular aneurysm repair. MMP-9 was assayed in plasma at baseline and 1 week and 1 month thereafter. Preoperative MMP-9 levels were similar in the two groups (41.7 +/- 19.1 vs 44.4 +/- 24.6 ng/mL; p = not significant). Assessment 1 week later showed that MMP levels in both repair groups had increased. In the open surgery group, they increased significantly (59.7 +/- 16.8 ng/mL; p < .05) but not in the endovascular group (49.3 +/- 32.4 ng/mL). One month later, MMP-9 levels decreased in both groups but not significantly (to 32.6 +/- 24.6 ng/mL for open surgery repair and to 34.7 +/- 23.5 ng/mL for endovascular repair). At 1 month after repair, MMP-9 levels decreased significantly only in smokers, whereas in nonsmokers, they did not (from 46.9 +/- 22.1 to 31.7 +/- 21.5 ng/mL in smokers [p < .05] vs from 34.7 +/- 17.4 to 37.1 +/- 28.9 ng/mL in nonsmokers). This study confirms that enzyme secretion changes during the postoperative course. The differing patterns of MMP-9 expression prevent us from reaching definitive conclusions about the use of MMP-9 as a marker during early postprocedural follow-up. An important matter to clarify is the role of MMP-9 in long-term follow-up, especially after endovascular AAA repairs.     

Complex aortic valve repair as a durable and effective alternative to valve replacement in children with aortic valve disease

OBJECTIVE: This study was undertaken to determine the utility of aortic valve repair in children. METHODS: A retrospective analysis was conducted on aortic valve surgery from 1973 to 2004 at Children's Hospital of Wisconsin. RESULTS: Procedures were classified as simple repairs (blunt valvotomy, commissurotomy with or without thinning, n = 147), repair of aortic insufficiency with ventricular septal defect (n = 22), complex repairs (any combination of additional procedures including suspension of prolapsed leaflets, leaflet extensions, repair of torn or perforated leaflets, annuloplasty, reduction of sinus of Valsalva plasty, and concomitant repair of supravalvular or subvalvular stenosis, n = 57), and replacements (n = 57, 20 mechanical, 2 porcine, and 35 human valves). Freedoms from reintervention for simple repairs and repair of aortic insufficiency with ventricular septal defect at 10 years were 86% +/- 5% and 93.3% +/- 6%, respectively. For complex valve repair, freedoms from reintervention at 1, 5, and 10 years were 94% +/- 3%, 85% +/- 6%, and 44% +/- 15%, versus 96% +/- 3%, 77% +/- 9%, and 77% +/- 9% for valve replacement ( P = .3). At intermediate follow-up, patients with complex valve repair had a residual gradient of 20 +/- 21 mm Hg, and 94% were free of severe aortic insufficiency. Residual aortic stenosis ( P < .05) but not the preoperative diagnosis of combined aortic stenosis and insufficiency predicted the need for reintervention. CONCLUSION: Freedom from reintervention after complex valve repairs was not different from that after valve replacement, with acceptable residual aortic stenosis and insufficiency. Simple repairs and repair of aortic insufficiency with ventricular septal defect yielded excellent long-term freedom from reintervention.     

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.     

A biologic basis for asymmetric growth in descending thoracic aortic aneurysms: a role for matrix metalloproteinase 9 and 2

OBJECTIVE: This study was undertaken to define matrix metalloproteinase (MMP) expression in the anterior and posterior wall of descending thoracic aortic aneurysms (TAAs) and correlate it with specific computed tomography (CT) image sites within the descending thoracic aorta. METHODS: Serial CT images of patients with TAAs were compared with age- and gender-matched normal descending thoracic aortas at levels T4-T12. The mean circumference of the TAAs was 153 mm (n = 12) and 148 mm (n = 11) at T8 and T10, respectively, compared with 75 mm (n = 12) and 75 mm (n = 10) in controls (P < .001). Aortic tissue was collected from a separate set of eight patients undergoing descending TAA resection (processed < or =12 hours of excision) and six cadavers (processed < or =24 hours of death). Tissue collected between the intercostals arteries was defined as posterior wall, and directly opposite was the anterior wall. MMP-9 and MMP-2 messenger RNA (mRNA) extracted from aortic tissue was analyzed by quantitative real time polymerase chain reaction (PCR) and normalized to beta-actin. Immunohistochemistry was performed for MMP-9 and MMP-2. CT aortic measurements and MMP expression were compared by t tests and analysis of variance, respectively. RESULTS: The ratio of arc distance between the intercostals on the posterior wall to total aortic circumference was 0.14 in healthy controls compared with 0.08 in TAAs at vertebral level T8 (P = .001). At T10, the ratio was 0.15 in healthy controls compared with 0.11 in TAAs (P = .001). MMP-9 expression in TAAs was 4.3-fold higher in the anterior wall compared with the posterior wall (P = .03). Conversely, MMP-2 expression in TAAs was 3.2-fold higher in the posterior wall compared with the anterior wall (P = .008). MMP expression was not detected in control cadaver aortas. CONCLUSION: Anterior walls of expanding TAAs grow at a greater rate than the posterior wall, as determined from the lower ratio of intercostal arc distance to total circumference in TAAs. Differential MMP expression appears to be a biologic marker for asymmetric growth in the TAA wall. CLINICAL RELEVANCE: The pathogenesis of thoracic aortic aneurysms (TAAs) is poorly understood. Multiple lines of evidence suggest that matrix metalloproteinases (MMPs), a family of enzymes, are important in aneurysm development. Earlier experiments documented a regional variation of MMP-9 in stimulated rodent aortas, with production greater in the abdominal aorta compared with the thoracic aorta. The present study extends that observation and documents asymmetric aneurysm development in the TAA wall, with increased anterior wall growth in correlation to increased MMP-9 production. An improved understanding of the mechanisms by which MMP production is regulated is critical.     

A murine model of thoracic aortic aneurysms

BACKGROUND: The mechanisms of thoracic aortic aneurysm (TAA) formation are poorly understood, mainly due to the lack of a useful and reproducible model. Accordingly, the goal of this study was to test the hypothesis that abluminal calcium chloride (CaCl(2)) application could create TAAs in the mouse. MATERIALS AND METHODS: Adult 129/SvE mice (n = 8) were anesthetized and their thoracic aortas exposed via left thoracotomy. CaCl(2) (0.5M) was applied to the distal descending thoracic aorta for 15 min followed by chest closure. At 4 weeks, the perfusion-fixed aorta was harvested from the root to the renal arteries. Diameter measurements were made using confocal microscopy, and wall thickness was measured from hematoxylin and eosin-stained sections. RESULTS: The control (n = 15) distal descending thoracic aortic diameter was 0.60 +/- 0.04 mm and increased by 25% (0.76 +/- 0.06 mm, P < 0.05) following CaCl(2) treatment. Control aortic wall thickness was 48 +/- 9 mum and decreased by 47% in corresponding CaCl(2)-exposed segments (25 +/- 8 mum, P < 0.05). The diameter and wall thickness of the ascending aorta (used as an internal control) were not significantly different between groups. Picrosirius red staining of the TAA showed adventitial collagen breakdown and disruption of lamellar organization. CONCLUSIONS: We conclude that abluminal application of CaCl(2) to the thoracic aorta reliably produces dilation, wall-thinning, and disruption of mural architecture, the hallmark signs of aneurysm formation. To our knowledge, these findings describe for the first time the generation of a reproducible model of isolated TAA formation in a murine system.     

Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908)

BACKGROUND: Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs. METHODS: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy. RESULTS: AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; P <.05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation. CONCLUSIONS: Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs.     

MF-tricyclic inhibits growth of experimental abdominal aortic aneurysms

BACKGROUND: Experimental abdominal aortic aneurysm (AAA) development can be pharmacologically suppressed by inhibiting matrix metalloproteinase-9 (MMP-9). Cyclooxygenase-2 (COX-2) inhibitors are potent anti-inflammatory agents that have been demonstrated to inhibit experimental aneurysm development. We hypothesized that treatment with MF-tricyclic, a selective COX-2 inhibitor, incorporated into rodent chow would inhibit aneurysm development in a rat AAA model. METHODS: Twelve male Sprague Dawley rats underwent induction of experimental AAA using intra-aortic porcine elastase infusion. Six rats received control feed, and six received MF-tricyclic rodent chow for a period of 14 days. Aortic diameters were measured pre- and postinfusion as well as at harvest. Aortic tissue samples were evaluated by real-time polymerase chain reaction (RT-PCR) for MMP-9, by immunohistochemistry for elastin. RESULTS: Elastase infusion produced AAA in all untreated rats. At 14 days MF-tricyclic-treated rats had significantly reduced aortic diameter (1.9 +/- 0.1 mm versus 2.4 +/- 0.0 mm, P = 0.00001). Percent increase in aortic diameter was also significantly less in animals receiving MF-tricyclic (65.7 +/- 8.5% versus 132.3 +/- 7.3%, P = 0.0001). RT-PCR demonstrated a decrease in the mean expression of MMP-9 in the treated animals (0.414 ng of RNA versus 1.114 ng of RNA) (P = 0.07). Sections stained for elastin demonstrated preserved elastin integrity in MF-tricyclic treated aortas. CONCLUSIONS: COX-2 inhibition helps to retard the growth of experimental AAAs possibly through inhibition of MMP-9. Experimentally treated animals demonstrated smaller aortic diameters and lower levels of tissue MMP-9 when compared to untreated animals. Selective COX-2 inhibition may offer an additional method to pharmacologically inhibit AAAs.     

Aneurysm-related death: primary endpoint analysis for comparison of open and endovascular repair

PURPOSE: The purpose of this study was to utilize an objective endpoint analysis of aneurysm treatment, which is based on the primary objective of aneurysm repair, and to apply it to a consecutive series of patients undergoing open and endovascular repair. METHOD: Aneurysm-related death was defined as any death that occurred within 30 days of primary aneurysm treatment (open or endovascular), within 30 days of a secondary aneurysm or graft-related treatment, or any death related to the aneurysm or graft at any time following treatment. We reviewed 417 consecutive patients undergoing elective infrarenal aortic aneurysm repair: 243 patients with open repair and 174 patients with endovascular repair. RESULTS: There was no difference between the groups (open vs endovascular) with regard to mean age +/- standard deviation (73 +/- 8 years vs 74 +/- 8 years) or aneurysm size (64 +/- 2 mm vs 58 +/- 10 mm) (P = not significant [NS]). The 30-day mortality for the primary procedure after open repair was 3.7% (9/243) and after endovascular repair was 0.6% (1/174, P <.05). The 30-day mortality for secondary procedures after open repair was 14% (6/41) compared to 0% after endovascular repair (P <.05). The aneurysm-related death rate was 4.1% (10/243) after open surgery and 0.6% (1/174) after endovascular repair (P <.05). Mean follow-up was 5 months longer following open repair (P <.05). Secondary procedures were performed in 41 patients following open surgery and 27 patients following endovascular repair (P = NS). Secondary procedures following open repair were performed for anastomotic aneurysms (n = 18), graft infection (n = 6), aortoenteric fistula (n = 5), anastomotic hemorrhage (n = 4), lower extremity amputation (n = 4), graft thrombosis (n = 3), and distal revascularization (n = 1). Secondary procedures following endovascular repair consisted of proximal extender cuffs (n = 11), distal extender cuffs (n = 11), limb thrombosis (n = 3), and surgical conversion (n = 2). The magnitude of secondary procedures following open repair was greater with longer operative time 292 +/- 89 minutes vs 129 +/- 33 minutes (P <.0001), longer length of stay 13 +/- 10 days vs 2 +/- 2 days (P <.0001) and greater blood loss 3382 +/- 4278 mL vs 851 +/- 114 mL (P <.0001). CONCLUSIONS: The aneurysm-related death rate combines early and late deaths and should be used as the primary outcome measure to objectively compare the results of open and endovascular repair in the treatment of infrarenal abdominal aortic aneurysms. In our experience, endovascular aneurysm repair reduced the overall aneurysm-related death rate when compared to open repair. Secondary procedures are required after both open and endovascular repair. However, the magnitude, morbidity, and mortality of secondary procedures are reduced significantly with endovascular repair.     

Valve-sparing aortic root replacement in bicuspid aortic valves: a reasonable option?

OBJECTIVES: Aortic dilatation occurs in many patients with bicuspid aortic valves. We have added root replacement using the remodeling technique originally designed for tricuspid aortic valves to bicuspid aortic valve repair for treatment of the dilated root. We compared the results of remodeling in bicuspid aortic valves with those in tricuspid aortic valves. METHODS: From October 1995 through January 2004, 60 patients underwent root remodeling for bicuspid aortic valves (group A), and 130 patients underwent root remodeling for tricuspid aortic valves (group B). Correction of cusp prolapse was more often performed in group A (group A, 50/60; group B, 47/130; P < .0001). Transthoracic echocardiography was performed at 1 week, 6 and 12 months, and every year thereafter. Cumulative follow-up was 527 patient-years (mean, 2.9 +/- 2 years). RESULTS: No patient died in group A. Hospital mortality in group B was 5% (5/100; 95% confidence interval,1.6%-11.3%) after elective operations and 10% (3/30; 95% confidence interval, 2.1%-26.5%) after emergency operations. Mean systolic gradients were identical at 1 year (group A, 4.8 +/- 2.1 mm Hg; group B, 4.0 +/- 2 mm Hg) and 5 years (group A, 4.5 +/- 2.3 mm Hg; group B, 3.9 +/- 2.2 mm Hg). Freedom from aortic regurgitation of grade 2 or higher at 5 years was 96% in group A and 83% in group B ( P = .07), and freedom from reoperation at 5 years was 98% in group A and 98% in group B ( P = .73). CONCLUSIONS: Valve-sparing aortic replacement with root remodeling can be applied to aortic dilatation and a regurgitant bicuspid aortic valve. Hemodynamic function and valve stability of a repaired bicuspid aortic valve are comparable with those seen in cases of tricuspid anatomy.     

Late aortic and graft-related events after thoracoabdominal aneurysm repair

PURPOSE: Unlike abdominal aortic aneurysm repair, little information exists regarding aortic-related morbidity (synchronous/metachronous aneurysm or graft-related complications) after thoracoabdominal aneurysm (TAA) repair. This study was performed to define such events and identify factors related to their development. METHODS: Over a 15-year interval, 333 patients underwent TAA repair (type I, n = 90; 27%; type II, n = 59; 18%; type III, n = 118; 35%; and type IV, n = 66; 20%). Late aortic events were defined as aortic disease causing death or necessitating further intervention or graft-related complications (infection, pseudoaneurysm, branch occlusion) after hospital discharge. Variables were assessed for their association with aortic events with Cox proportional hazards regression. RESULTS: In-hospital mortality occurred in 28 patients (8.4%), which left 305 available for follow-up (mean length of follow-up, 26 months; interquartile range, 2.7 to 38.4 months). After TAA repair, aneurysm remained in 60 patients (19.7%; ascending/arch, n = 41; 68.3%; discontinuous infrarenal, n = 12; 20%; contiguous descending, n = 7; 11.7%; contiguous abdominal, n = 4; 6.7%). Events occurred in 33 individuals (10.8%) at 30 +/- 27 months after surgery. Twenty-four patients (73% of events; 7.9% of cohort) had aortic-related events, including another elective aneurysm repair (n = 16), urgent/emergent aneurysm operation (n = 5), acute dissection (n = 2), and atherothrombotic embolization (n = 1). Nine patients (27% of events; 2.9% of cohort) had graft-related incidents, including renovisceral occlusion (n = 5), visceral patch pseudoaneurysm (n = 2), graft infection (n = 2), and graft-esophageal fistula (n = 1). Variables independently predictive of events were female gender (odds ratio [OR], 2.3; P =.03), initial aneurysm rupture (OR, 4.8; P =.04), partial disease resection (OR, 4.2; P =.0008), and expansion of remaining aortic segments on imaging surveillance (OR, 2.5; P =.03). The event-free survival rates were 96% (95% CI, 93% to 98%) and 71% (95% CI, 60% to 83%) at 1 and 5 years. CONCLUSION: Late aortic events occur in at least 10% of patients after TAA repair and are usually the result of native aortic disease in remote (or noncontiguous) aortic segments. Graft-related complications, in particular, degeneration of inclusion anastamoses, are rare. Female gender, original presentation with rupture, and unresected disease identify those at highest risk. These findings verify the anatomic durability of TAA repair and suggest indefinite aortic surveillance is indicated for those at risk of events.