In vivo assessment of murine elastase-induced abdominal aortic aneurysm with high resolution magnetic resonance imaging.

OBJECTIVES: There are, to date, no published non-invasive or longitudinal studies performed in mice to measure aortic diameter and wall thickness in an elastase-induced abdominal aortic aneurysm. This MRI study at 11.75 T aimed at evaluating the reliability of longitudinal in vivo aortic diameter and wall thickness measurements in this particular model. METHODS: Adult male C57BL/6 mice underwent transient elastase or heat-inactivated elastase perfusion (controls). Aortic dilatation was measured before, during and immediately after elastase perfusion, and again 14 days after, with a calibrated ocular grid. MRI was performed just before initial surgery and at day 14 before harvest using an 11.75 T MR microscopy imager. RESULTS: Aortic diameter was significantly greater in elastase-perfused mice compared to controls as measured by optic grid (1.150 ± 0.153 mm vs 0.939 ± 0.07 mm, P = 0.038) and according to MRI measurement of the outer diameter on spin echo images (1.203 ± 0.105 mm vs 1070 ± 0.048 mm, P = 0.0067). Aortic wall thickness was found to be significantly increased in elastase-perfused mice at day 14. CONCLUSIONS: This study demonstrates in the mouse elastase-induced aneurysm model that characterization of aneurysm development by its inner and outer vessel diameter and vessel wall thickness can be carried out longitudinally using high resolution MRI without significant mortality.

Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.

Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The purpose of this study was to determine if human macrophage elastase (HME; MMP-12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosclerotic occlusive disease (AOD) tissues (six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two products of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than normal aorta (P < 0.001), and the extracted enzyme exhibited activity in vitro. Production of HME was demonstrated in the media of AAA tissues by in situ hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was specifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to fivefold greater than other elastases found in AAA tissue. Therefore, HME is prominently expressed by aneurysm-infiltrating macrophages within the degenerating aortic media of AAA, where it is also bound to residual elastic fiber fragments. Because elastin represents a critical component of aortic wall structure and a matrix substrate for metalloelastases, HME may have a direct and singular role in the pathogenesis of aortic aneurysms.

Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages.

Abdominal aortic aneurysms (AAA) are characterized by disruption and degradation of the elastic media, yet the elastolytic proteinases involved and their cellular sources are undefined. We examined if 92-kD gelatinase, an elastolytic matrix metalloproteinase, participates in the pathobiology of AAA. Gelatin zymography of conditioned medium from normal, atheroocclusive disease (AOD), or AAA tissues in organ culture showed that all tissues produced 72-kD gelatinase. AOD and AAA cultures also secreted 92-kD gelatinase, but significantly more enzyme was released from AAA tissues. ELISA confirmed that AAA tissues released approximately 2-fold more 92-kD gelatinase than AOD tissue and approximately 10-fold more than normal aorta. Phorbol ester induced a 5.3-fold increase in 92-kD gelatinase secretion by normal aorta and AOD and an 11.5-fold increase by AAA. By immunohistochemistry, 92-kD gelatinase was not detected in normal aorta and was only occasionally seen within the neointimal lesions of AOD tissue. In all AAA specimens, however, 92-kD gelatinase was readily localized to numerous macrophages in the media and at the adventitial-medial junction. The expression of 92-kD gelatinase mRNA by aneurysm-infiltrating macrophages was confirmed by in situ hybridization. These results demonstrate that diseased aortic tissues secrete greater amounts of gelatinolytic activity than normal aorta primarily due to increased production of 92-kD gelatinase. In addition, the localization of 92-kD gelatinase to macrophages in the damaged wall of aneurysmal aortas suggests that chronic release of this elastolytic metalloproteinase contributes to extracellular matrix degradation in AAA.

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.

Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis.

The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases.

Experimental abdominal aortic aneurysms in mice lacking expression of inducible nitric oxide synthase.

To determine if nitric oxide synthase (NOS) contributes to the pathophysiology of abdominal aortic aneurysms (AAAs), C57BL/6J mice underwent transient aortic injury to induce a chronic inflammatory response. Wild-type mice developed a significant increase in aortic diameter within 14 days of elastase perfusion (115+/-16%, 40% incidence of AAAs), along with intense and widespread staining for nitrotyrosine, mononuclear inflammation, and delayed destruction of the elastic lamellae. Expression of both endothelial and neuronal forms of NOS was substantially decreased within AAAs, whereas inducible NOS (iNOS) mRNA was increased 360%, and the enzyme was localized to infiltrating inflammatory cells. By using mice with targeted deletion of iNOS to evaluate the functional importance of this enzyme, male iNOS(-/-) mice developed the same extent of aneurysmal dilatation as congenic controls (121+/-22%, 40% incidence of AAAs) and exhibited similar structural features except for diminished nitrotyrosine staining. Aneurysmal dilatation was actually enhanced in female iNOS(-/-) mice (141+/-16%, 80% incidence of AAAs; P<0.05), but this effect was reversed by previous oophorectomy. Although extensive protein nitration and increased expression of iNOS accompany the development of elastase-induced experimental AAAs, iNOS is not required in this process and its absence may be deleterious.

Reaction of tetrahydrofolic acid with cyanate from urea solutions: formation of an inactive folate derivative.

Liver extracts prepared in 6 M urea contain significantly less microbiologically assayable folates than extracts prepared in hot 1% ascorbate. The possibility that inactive folate derivatives are formed by reaction with the cyanate present in the urea solution was investigated. Doubly labeled 2-14C, 3',5',9(n)-3H tetrahydrofolic acid reacted under hydrogen with sodium cyanate gave a compound which, after acidification to remove excess cyanate, shows a single UV absorbing peak at 285 nm. The 14C/3H ratios of starting material and product were the same. Reaction of 14C urea with nonradioactive tetrahydrofolic acid yielded the 14C labeled derivative. The compound does not support Lactobacillus casei growth. It is postulated that folate inactivation in cyanate or thiocyanate treated patients and in uremic patients may have clinical significance.

Role of matrix metalloproteinases in abdominal aortic aneurysms.

Considerable progress has been made toward characterizing the enzymes and proteolytic events that occur in established human abdominal aortic aneurysms (AAA). Through studies involving a number of different laboratories and various experimental approaches, enzymes of the matrix metalloproteinase (MMP) family have consistently emerged as important molecular participants in aneurysm disease. The finding that elastolytic MMPs, particularly MMP-9 and MMP-2, are expressed and produced in increased amounts in human aneurysm tissue, has led to the possibility that these enzymes might serve as rational targets for pharmacotherapy in this disease. Recent studies using MMP-inhibiting tetracycline derivatives in the elastase-induced rodent model of AAA indicate that metalloproteinase suppression is a feasible and successful approach in the experimental setting. The definitive proof-of-principle for the therapeutic efficacy of anti-MMP or other anti-proteinase strategies to limit the growth of small AAA, however, will remain unknown until specifically tested in clinical trials.

MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial.

Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition associated with a life-threatening risk of rupture. The evolution of AAAs is thought to involve the progressive degradation of aortic wall elastin and collagen, and increased local production of several matrix metallo-proteinases (MMPs) has been implicated in this process. We have previously shown that tetracycline derivatives and other MMP inhibitors suppress aneurysm development in experimental animal models of AAA. Doxycycline also reduces the expression of MMP-2 and MMP-9 by human vascular wall cell types and by AAA tissue explants in vitro. To determine whether this strategy might have a role in the clinical management of small AAA, we examined the effect of doxycycline on aortic wall MMP expression in vivo. Patients were treated with doxycycline (100 mg p.o. bid) for 7 days prior to elective AAA repair, and aneurysm tissues were obtained at the time of surgery (n = 5). Tissues obtained from an equal number of untreated patients with AAA were used for comparison. By reverse transcription-polymerase chain reaction and Southern blot analysis, MMP-2 and MMP-9 were both found to be abundantly expressed in the aneurysm wall. Preoperative treatment with doxycycline was associated with a 3-fold reduction in aortic wall expression of MMP-2 and a 4-fold reduction in MMP-9 (p < 0.05 compared to untreated AAA). These preliminary results suggest that even short-term treatment with doxycycline can suppress MMP expression within human AAA tissues. Given its pleiotropic effects as an MMP inhibitor, doxycycline may be particularly effective in suppressing aortic wall connective tissue degradation. While it remains to be determined whether MMP inhibition will have a clinically significant impact on aneurysm expansion, it is expected that this question can be resolved by a properly designed prospective randomized clinical trial.

Bile peritonitis from a cholecystohepatic bile ductule: an unusual complication of cholecystectomy.

A case is presented of postoperative bile peritonitis from an accessory cholecystohepatic bile ductule after cholecystectomy for acute cholecystitis. Accessory bile ductules (ducts of Luschka) are occasionally encountered in the gallbladder fossa but do not drain directly into the gallbladder fundus. Nevertheless, they may be injured during surgery and may go unrecognized. When recognized intraoperatively, ligation is acceptable; however, when they are actively leaking bile and are greater than 2 mm in diameter, repair of injured cholecystohepatic ducts may be indicated. This case serves to reemphasize one argument for the routine placement of drains after cholecystectomy for acute cholecystitis.

Dextrocholedocholithiasis: calculous obstruction complicating double ductus choledochus in an adult.

Double ductus choledochus is a rare anomaly of the extrahepatic biliary tree in which the common bile duct is represented by two independent hepatic ducts. Patients with this abnormality may have unimpeded biliary drainage and remain symptom free, yet various forms of double ductus choledochus are occasionally encountered in patients undergoing operation for symptomatic cholelithiasis. We describe a patient in whom doubled biliary ducts were identified on exploration for cholecystectomy along with calculous obstruction of the right-sided duct (ductus choledochus dextri). This case illustrates the potential for significant injury to the biliary tree when double ductus choledochus is present. In addition to a means by which to manage this problem at the time of operation, a review of the literature, as well as a description of this rare embryologic abnormality, is presented.

Functional importance of connective tissue repair during the development of experimental abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysms (AAAs) involve an unfavorable balance between the destruction and the repair of connective tissue proteins. The purpose of this study was to assess the functional importance of connective tissue repair during experimental aneurysmal degeneration. METHODS: Male Wistar rats (n = 70) underwent transient intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase. In Study I, the aortic diameter was measured before elastase perfusion and at days 0, 2, 7, and 14 (n = 6 rats at each interval). Aortic wall concentrations of desmosine (Des) and hydroxyproline (OHP) were measured at each interval, and the expression of tropoelastin (TE), alpha1(I) procollagen (PC), and lysyl oxidase genes was evaluated by reverse transcription-polymerase chain reaction. In Study II, 22 rats were treated with beta-aminopropionitrile (BAPN) to block connective tissue repair. In Study III (n = 30), rats were treated with doxycycline, a matrix metalloproteinase inhibitor, beginning 7 days after elastase perfusion. RESULTS: AAAs consistently developed between 7 and 14 days after elastase perfusion. Aortic wall Des concentration decreased markedly during aneurysm development, reaching 3% of normal by day 14 (377 +/- 22 pmol of Des/sample on day 0 vs 9 +/- 1 pmol of Des/sample on day 14; P <.05). Aortic wall OHP decreased to only 68% of normal at the same interval (121 +/- 10 nmol of OHP/sample on day 0 vs 82 +/- 14 nmol of OHP/sample on day 14; P <.05). TE and PC expression was undetectable in healthy aorta, but they both increased by day 7 (P <.05); while TE expression decreased again by day 14, PC continued to rise. Lysyl oxidase expression progressively decreased at all intervals after elastase perfusion. Treatment with beta-aminoproprionitrile resulted in acute aortic dissection in 81% of the rats (50% mortality). These early deaths occurred between days 3 and 6, coinciding with aortic infiltration by proteinase-secreting inflammatory cells. Delayed treatment with doxycycline suppressed the progression of aneurysmal dilatation between days 7 and 21 (P <.05 vs untreated controls). CONCLUSIONS: The development of elastase-induced AAAs is accompanied by an active process of connective tissue repair. While this reparative process is necessary to stabilize the developing aneurysm wall, it is insufficient to prevent aneurysm progression. In contrast, reducing the proteolytic destruction of connective tissue proteins promotes stabilization of the aneurysmal aorta.

Long-term effectiveness of extraanatomic renal artery revascularization.

BACKGROUND: The efficacy of direct aortorenal bypass and renal artery endarterectomy are well established. The purpose of this study is to define better the results of extraanatomic renal revascularization procedures. METHODS: From April 1987 to March 1993, 124 patients underwent renal artery revascularization. Forty-eight (39%) of them (33 women, 15 men; average age, 65.9 years) underwent 49 extraanatomic renal artery bypasses. Preoperative risk factors included smoking in 30 patients (61%), history of myocardial infarction in 14 (29%), diabetes mellitus in 11 (22%), congestive heart failure in nine (18%), chronic obstructive pulmonary disease in 11 (22%), and stroke in six (12%). The average creatinine level was 2.3 mg/dl. The average number of antihypertensive medications was 2.4. Thirty iliorenal, 10 gastroduodenal-renal, seven hepatorenal, and two splenorenal bypasses were performed together with 10 contralateral nephrectomies. RESULTS: Six major postoperative complications occurred. There were no deaths. Forty-one (85%) of patients had improvement or cure of their hypertension. Seven (15%) of patients failed to respond to treatment, and three required subsequent nephrectomy. After operation the average creatinine level was 1.7 mg/dl and the average number of medications was 1.7. Mean follow-up period has been 23.2 months (range, 1 to 79 months). CONCLUSIONS: Extraanatomic bypass proved to be efficacious in treating hypertension and preserving renal function and has an acceptable rate of morbidity and mortality. We conclude that these procedures are an acceptable alternative to direct aortorenal artery revascularization.

Revascularization of the solitary kidney: a challenging problem in a high risk population.

BACKGROUND: Patients with significant atherosclerotic stenosis involving the artery to a solitary functioning kidney present a clinical challenge. METHODS: From August 1987 through August 1995, 35 of these patients (average age, 68.4 +/- 6.9 years) were treated. Comorbid conditions included previous myocardial infarction in 23% of the patients, congestive heart failure (CHF) in 34%, chronic obstructive pulmonary disease in 20%, and diabetes in 20%. The average creatinine level of the patients was 2.5 +/- 1.5 mg/dl. Indications for revascularization were hypertension in 86%, hypertensive crisis with CHF in 17%, and renal insufficiency in 69%. Procedures performed included 19 extra-anatomic bypasses, 8 concomitant with infrarenal aortic reconstruction and 2 concomitant with thoracoabdominal aortic aneurysm repair; 1 visceral segment endarterectomy; 1 renal artery endarterectomy with reimplantation; I superior mesenteric to renal artery bypass; 1 aortorenal bypass; and 2 percutaneous angioplasties with staged nephrectomies. RESULTS: At discharge, 91% of patients had stable or improved renal function with an average creatinine level of 1.7 +/- 0.8 mg/dl. Hypertension was cured or improved in 85%. Perioperative mortality was 6%, and major morbidity was 43%, including the need for permanent (9%) and temporary (9%) dialysis, respiratory insufficiency (18%), two early reoperations, six cardiac complications, one case of gastrointestinal bleeding, and one stroke. In the follow-up period (mean duration, 39.2 months), survival has been 73%, and no additional patients have required dialysis. CONCLUSIONS: Although significant perioperative morbidity exists in this high risk population, the long-term preservation of renal function and improvement in hypertension make solitary renal revascularization worthwhile.

RhoA expression during recovery from skeletal muscle disuse.

Functional overload and anabolic steroid administration induce signaling pathways that regulate skeletal muscle RhoA expression. The purpose of this study was to determine RhoA and associated protein expression at the onset of disuse and after a brief period of reloading. Male Sprague-Dawley rats were randomly assigned to cage control (Con), 3 days of hindlimb suspension (Sus), or 3 days of hindlimb suspension with 12 h of reloading (12-h Reload). The reloading stimuli consisted of 12 h of resumed normal locomotion after 3 days of hindlimb suspension. Plantaris muscle-to-body weight (mg/g) ratio decreased 17% from Con with Sus but returned to Con with 12-h Reload, increasing 13% from Sus. Sus decreased RhoA protein concentration 46%, whereas 12-h Reload induced a 24% increase compared with Sus. The ratio of cytosolic- to membrane-associated RhoA protein was not changed with either Sus or 12-h Reload. RhoA mRNA concentration was decreased 48% by Sus, and 12-h Reload induced a 170% increase from Sus. beta(1)-Integrin protein, a transmembrane protein associated with RhoA activation, was not altered by Sus but increased 155% with 12-h Reload. Although beta(1)-integrin mRNA was not altered by Sus, it increased 70% from Con with 12-h Reload. Rho family member Cdc42 protein associated with the muscle membrane was decreased 60% with Sus, and 12-h Reload induced a 172% increase compared with Sus. In conclusion, decreased RhoA protein expression and mRNA abundance are early adaptations to disuse but recover rapidly after normal locomotion is resumed.

Branched nonreversed saphenous vein graft for complex renal artery stenosis.

Use of recently developed instrumentation for venous valvotomy allows rapid construction of a branched, nonreversed saphenous vein graft. This technique was applied in a patient with renovascular hypertension and branch renal artery occlusive disease.

A low-cost, multi-channel, EMG signal processing amplifier.

There is a growing need in studies of movement control to expand the number of muscles from which EMG activity is recorded during performance of motor tasks. Optimal viewing and analysis of this EMG activity requires signal processing which provides adjustable gain and baseline offset as wells as selectable AC coupling, rectification and filtering. This paper presents a low-cost circuit that combines two channels of EMG signal processing capability in one module.

Simultaneous surgical management of aortic and renovascular disease.

The results of simultaneous elective infrarenal aortic reconstruction and renovascular surgery were retrospectively reviewed in 102 patients who consecutively underwent operation. The perioperative mortality rate (0 to 54 days) was 5% (5 of 102). Renal function had returned to baseline or was improved at discharge in 89 of 97 (92%) surviving patients. The intraoperative use of renal hypothermia was an independent predictor of improved postoperative renal function, by multivariate analysis. Twenty-five of 29 (86%) patients with severe hypertension had improvement in their blood pressure on the same or fewer medications postoperatively (p = 0.0005). A retroperitoneal incision was associated with less intraoperative crystalloid fluid administration (p = 0.03), more rapid postoperative resumption of an oral diet (p = 0.04), and better long-term survival (p = 0.02) when compared with a transperitoneal incision. We conclude that the simultaneous repair of infrarenal aortic pathology and renovascular lesions is associated with an acceptable perioperative morbidity and preserves or improves renal function in the majority of patients. The frequent use of renal hypothermia and careful consideration of the route of operative exposure will lead to optimal results.

Limb salvage and patency after aortic reconstruction in younger patients.

PURPOSE: The purpose of this report was to compare patient characteristics, treatment, and outcome in younger and older patients with aortoiliac occlusive disease. METHODS: The medical records of 56 patients < or = 50 years of age (Group < or = 50) were retrospectively reviewed and compared to the records of 128 patients > or = 60 years of age (Group > or = 60). All patients were examined and treated between April 1987 and April 1994. Postoperatively, they were enrolled in a vascular laboratory surveillance program to serially monitor the status of the vascular reconstruction. Follow-up averaged more than 3 years in both groups and was available on greater than 90% of patients. RESULTS: Patients in Group < or = 50 had a higher incidence of smoking (68% versus 51%) and a lower incidence of hypertension (29% versus 50%) than patients in group > or = 60 (smoking P = 0.03, hypertension P = 0.007). No other significant differences were noted among cardiovascular risk factors. Preoperative indications for surgery were similar among patients in both groups. An aortoiliac endarterectomy was more commonly used to revascularize the lower extremities in younger patients than in their older counterparts (23% versus 7%, P = 0.002). Graft revisions were more frequently necessary after aortic reconstruction in Group < or = 50 than in Group > or = 60 (29% versus 8%, P = 0.0003); however patency rates computed by life table analysis were not significantly different. The primary patencies for Group < or = 50 and Group > or = 60 at 5 years were 64% and 67%, respectively; their secondary patency rates at 5 years were 84% and 89%, respectively. No significant difference was found in major limb amputation (8% in Group < or = 50 versus 5% in Group > or = 60, P = 0.46). We conclude that aortoiliac reconstruction for occlusive disease can be performed with similar secondary patency and amputation rates in young and old patients. However, close postoperative surveillance and frequent surgical revision are necessary to maintain patency and minimize amputation.

Vascular smooth muscle cell apoptosis in abdominal aortic aneurysms.

Apoptosis is a naturally occurring mechanism of cell death that plays an important role in both normal and pathological remodeling of the vessel wall. Abdominal aortic aneurysms (AAA) represent a unique and dramatic example of vessel wall remodeling characterized by degeneration of the elastic media. Although much attention has been focused on the proteolytic mechanisms that underlie elastin and collagen degradation in AAA, recent studies suggest that depletion of medial smooth muscle cells (SMC) makes an important contribution to this disease by eliminating a cell population capable of directing connective tissue repair. As described in this review, these investigations have revealed that SMC depletion in human aneurysm tissues is accompanied by biochemical, morphological and molecular changes consistent with SMC apoptosis. The exact mechanisms responsible for SMC apoptosis in AAA remain to be elucidated, but current evidence indicates that elevated cellular production of p53 and p21 participates in the process. These findings provide an important new starting point for further investigations on the cellular and molecular mechanisms underlying SMC depletion in AAA and how this process might trigger the accelerated progression of aneurysm disease.