The pivotal role of matrix metalloproteinases in the development of human abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition and impart the risk of a life-threatening episode of rupture. Chronic inflammation and destructive remodeling of the extracellular matrix of the aortic wall constitute trademarks of this entity. Multiple studies have implicated a group of locally produced matrix endopeptidases-the matrix metalloproteinases (MMPs)-as the main culprits of this process. For this reason, extensive research on the identification of the role of these enzymes, as well as possible alternative pharmacological treatments of AAAs, has taken place during the last few years. The exact role of the several members of the group of metalloproteinases has already been discovered, and conservative therapeutic strategies oriented towards these agents have been suggested, but a definite treatment plan is still a controversial topic. The possible role of a genetic predisposition to AAAs is another crucial topic that remains to be determined, as it would render the confrontation of this condition much more efficient.     

Infrarenal abdominal aortic aneurysms

Opinion statement Screening programs should be instituted to identify patients with small asymptomatic abdominal aortic aneurysms (AAAs) in the community. Screening for AAAs reduces the rate of aneurysm rupture and reduces death from aneurysmal disease in the population. The indications for aneurysm surgery have been defined by two recent randomized clinical trials. Patients with symptomatic or ruptured AAAs should be treated by urgent or emergency surgery. Patients with asymptomatic AAAs should not undergo surgical repair until the aneurysm exceeds 5.4 cm in maximum diameter. The most appropriate surgical option for the majority of patients with AAAs is conventional inlay grafting. This may be approached transperitoneally, although the retroperitoneal approach is favored for inflammatory or juxtarenal aneurysms. Conventional aneurysm repair may be performed with acceptable mortality and good long-term durability in specialized centers with a high volume of cases. The place of endovascular aneurysm repair remains to be defined. Endovascular repair is the best option in high-risk patients with suitable aneurysm morphology. The questions over the long-term durability of endovascular aneurysm surgery in preventing aneurysm rupture make it unsuitable for young patients. Randomized trials will define the indications for this technique. Endovascular surgery is likely to become the most appropriate treatment for ruptured aneurysms in the next decade.     

Management of abdominal aortic aneurysms

Optional statement Abdominal aortic aneurysms (AAAs) are a lethal disease. Ultrasound is the modality of choice for screening patients for AAAs. It is reasonable to screen patients over age 60, particularly men, women with cardiovascular risk factors, smokers, and patients with a family history of AAAs. Patients with small (< 5.5 cm) AAAs should be followed with serial ultrasound. Medical management should focus on treating comorbidities, particularly those that put patients at risk for other cardiovascular diseases. Smoking cessation is mandatory in these patients. Patients with large or symptomatic AAAs should be evaluated for surgery; this includes careful imaging of the abdomen, aggressive treatment of comorbidities, and perioperative β blockade. Endovascular repair has lower short-term morbidity compared with conventional open repair. Trials assessing long-term results are in progress. Basic science and translational research focusing on the underlying pathogenesis of AAAs will likely pave the way for medical therapies in the future.     

The association between the gene encoding 5-lipoxygenase activating protein and abdominal aortic aneurysms

BackgroundGenetic variation in the gene ALOX5AP, encoding arachidonate 5-lipoxygenase-activating protein, have been suggested to increase risk for myocardial infarction and stroke. Leukotrienes (LTs) that derive from the 5-lipoxygenase (5-LO) cascade have been implicated in the pathogenesis of abdominal aortic aneurysm (AAA).Methods and resultsThe association of the ALOX5AP haplotypes with AAA was assessed in a large population-based cohort of 613 men aged ≥65 years with screen-detected AAAs and 707 randomly selected age-matched controls without AAA. Taqman assays were used to assess seven previously described single nucleotide polymorphisms (SNPs) of ALOX5AP. Haplotypes A and B were defined by the four SNPs (SG13S25, SG13S114, SG13S89, SG13S32) and (SG13S377, SG13S114, SG13S41, SG13S35), respectively. After adjustment for cardiovascular risk factors, there were no significant differences in the distribution of ALOX5AP haplotypes between cases and controls.ConclusionA genetic predisposition to up-regulation of LT mediators is unlikely to play a dominant role in the pathogenesis of AAA.     

Elastin degradation in abdominal aortic aneurysms

Histological sections through the walls of abdominal aortic aneurysms showed scarce and disrupted elastic tissue. The elastin content of the aneurysmal aortic media was only 8.1 +/- 3.2% dry defatted weight (n = 11). The elastin content of grossly normal age and anatomically matched aortic media was 35.0 +/- 3.2% dry weight (n = 4) and the elastin content of severely atherosclerotic, stenosed infrarenal aortic media was 22.0 +/- 7.2% dry weight (n = 6). There was an inverse correlation of elastin content with the elastinolytic activity of aortic media homogenates, r = -0.78. Elastase activity, measured by the hydrolysis of [3H]elastin, was highest in aneurysmal aortic homogenates, 92.1 +/- 43.7 U/mg protein (n = 18), falling to 46.9 +/- 13.3 U/mg protein (n = 13) in severely stenosed atherosclerotic aortic homogenates and 35.5 +/- 11.9 U/mg (n = 6) in grossly normal aortic homogenates. The elastinolytic activity of stenotic aorta contained leukocyte elastase as an important component. In aneurysmal homogenates leukocyte elastase was also found but the increased elastase activity resulted from a protease(s) (Mr 95,000) extracted in 2 M urea, having minimal specificity for alanyl bonds and no immunological cross-reactivity with leukocyte elastase.     

Management of infrarenal abdominal aortic aneurysms in the elderly: “The geriatric abdominal aortic aneurysm”

Infrarenal abdominal aortic aneurysm (AAA) replacement was performed in 97 patients aged 79 or greater over a 14-year period. Sixty-eight patients had intact aneurysms and 29 had ruptured aneurysms. In the intact aneurysm group, the 30-day mortality rate from 1980 to 1986 was 11.5% and decreased to 2.3% from 1987 to 1994. In the ruptured aneurysm group, the 30-day mortality rate was 73% in the earlier period from 1980 to 1986 and 43% in the later period from 1987 to 1994. In the intact aneurysm group, the median hospital stay was 11 days for the transabdominal approach and 8 days with a retroperitoneal approach. In the ruptured aneurysm group, the median hospital stay was 26 days. The occurrence of a ruptured AAA in a patient over 79 years of age is still associated with a high mortality rate, despite the many advances in aneurysm surgery during the past few decades. Hence, in appropriately selected elderly patients, infrarenal aortic aneurysm replacement should be performed electively as the perioperative mortality is low and late survival is similar to that of agematched controls. Age alone should not be a contraindication for infrarenal aortic aneurysm replacement.Presented at the 37th Annual World Congress, International College of Angiology, Helsinki, Finland, July 1995     

Mouse models of abdominal aortic aneurysms

Many mouse models of abdominal aortic aneurysms have been developed that use a diverse array of methods for producing the disease, including genetic manipulation and chemical induction. These models could provide insight into potential mechanisms in the development of this disease. Although experimental studies on abdominal aortic aneurysms (AAAs) have used a variety of mammalian and avian approaches, there is an increasing reliance on the use of mice. The models recapitulate some facets of the human disease including medial degeneration, inflammation, thrombus formation, and rupture. Most of the mouse models of AAA are evoked either by genetically defined approaches or by chemical means. The genetic approaches are spontaneous and engineered mutations. These include defects in extracellular matrix maturation, increased degradation of elastin and collagen, aberrant cholesterol homeostasis, and enhanced production of angiotensin peptides. The chemical approaches include the intraluminal infusion of elastase, periaortic incubations of calcium chloride, and subcutaneous infusion of AngII. A common feature of these models is the reduction of AAA incidence and severity by the prophylactic administration of matrix metalloproteinase (MMP) inhibitors or genetically engineered deficiencies of specific members of this proteolytic protein family. The validation of mouse models of AAAs will provide insight into the mechanisms of progression of the human disease.     

Angiotensin II and abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) have devastating effects on the morbidity and mortality of a large portion of the elderly population. Current therapeutic options for AAAs are limited to surgical approaches, because there are no proven pharmacologic treatments. Recently, there is evolving evidence that angiotensin II (Ang II) participates in the initiation and propagation of AAAs. Animal studies have consistently demonstrated the ability of Ang II to promote the formation of AAAs, although the mechanisms of this effect have not been defined. Further definition of the role of the renin-angiotensin system in AAA formation and progression will identify potential therapeutic strategies for treatment of this disease.     

A family with abdominal aortic aneurysms

This investigation focused on 7 siblings to 2 brothers with abdominal aortic aneurysm (AAA), with respect to AAA, Chlamydia pneumoniae (CP) serology, serum cholesterol, and smoking habits. Five male and 4 female siblings were included. All siblings underwent ultrasonography, and surgical specimens from the aorta were prepared for immunohistochemical (IHC) analysis. Blood was obtained from all living siblings and serum cholesterol level was analyzed. Serologic analysis was done by microimmunofluorescence (MIF). Smoking habits were recorded. In addition to the 2 known siblings with AAA, 2 other brothers with AAA were found. Four of 8 siblings had IgG 1/512 or greater and 7 of 8 had IgA 1/64 or greater. Two of 3 were positive for CP in IHC obtained from aortic specimens. Two of 8 had hypercholesterolemia; 7 of 9 were smokers. C. pneumoniae as well as smoking seems to be important in the pathogenesis of AAA in this small cohort; however, larger patient cohorts are needed.     

Ultrasound screening in the management of abdominal aortic aneurysms

Planned surgery for abdominal aortic aneurysms carries a low mortality (0-2%). Ultrasound examination of the abdomen can identify the aorta in 92% of patients. We have undertaken a study of the asymptomatic population based on a general practice (Family Doctor) register. The long term aims of this survey will be to identify a high risk group in which surgery is indicated, a low risk group were surgery can be avoided and a group of aneurysms in whom emergency surgery is contra-indicated. Arguments are put forward against improved treatment of aneurysms as emergencies as a way of improving overall survival and against the treatment of all cases detected by ultrasound as planned procedures. The current methods of selecting high risk cases are criticised and a possible method of selecting cases for planned surgery, based on screening and ultrasound follow-up is put forward. The advantages and disadvantages of an ultrasound screening programme are discussed.     

Peptic ulcers and abdominal aortic aneurysms

Upper gastrointestinal endoscopy was performed in 106 of 204 Chinese patients with intact abdominal aortic aneurysms, ninety-seven for screening and nine for gastrointestinal bleeding or pain. Peptic disease was discovered in 38 patients: 12 duodenal ulcers, 12 gastric ulcers, four duodenal and gastric ulcers, three duodenitis, three gastritis and four previously operated for ulcers. The eight patients who bled before aneurysmectomy all had gastric ulcers; four required emergency operation and two died. Only two patients bled from duodenal ulcers, both after aneurysmectomy and one died. Excluding gastritis and duodenitis, peptic ulcer was found in 26.4% of patients with abdominal aortic aneurysms. Half of these ulcers were gastric ulcers and 50% of them bled before aneurysmectomy. Duodenal ulcers tend to remain asymptomatic before operation and two of 12 (16.7%) bled postoperatively. The risk of bleeding for ulcers associated with aneurysms was 10 of 28 (35.7%) ulcers. The result of this uncontrolled study suggests that routine endoscopic screening should be used in all patients with aortic aneurysms and early surgery should be offered for gastric ulcers.     

Ultrasonographic screening for abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) occur in 1 of 20 older men, remain asymptomatic for many years, and, if left untreated, cause death from rupture in about one third of patients. Ultrasonography is a suitable screening test for AAA, and elective repair can prevent rupture. Although these features suggest a promising target for a screening program, evidence of benefit from AAA screening has only recently become available. Four randomized trials of ultrasonographic screening involving more than 125 000 men have been reported, and each trial observed a reduction in AAA-related mortality (which was statistically significant in 2 trials), ranging from 21% to 68%. One trial in women found no benefit. Other studies indicate that screening can begin in men older than 65 years of age and does not need to be repeated if results are negative. An AAA larger than 5.5 cm in diameter should be considered for elective open or endovascular repair. Most aneurysms detected at screening are smaller and should be kept under surveillance with periodic imaging measurement. Widespread elective repair of small AAAs could reduce the benefits and increase the costs of screening. No medical treatments have been proven to reduce the enlargement rate. If elective repair is reserved for larger AAAs, one-time ultrasonographic screening for AAA can be recommended for men 65 to 79 years of age who have ever smoked [correction].