Rapamycin suppresses experimental aortic aneurysm growth

OBJECTIVE: Inflammatory modulators are important in the pathogenesis of aneurysmal disease. Gene expression profiling of experimental abdominal aortic aneurysm (AAA) tissue demonstrated upregulation of the FK506BP12 (rapamycin binding protein) gene product. Rapamycin is a potent immunosuppressor that prevents recurrent stenosis. However, its effect on aneurysm formation has not been studied. We therefore examined the effect of rapamycin in an experimental rat AAA model. METHODS: Adult male Wistar rats underwent elastase infusion into isolated infrarenal aortas to create experimental aneurysms. Rats were randomized to receive either rapamycin or placebo via gastric lavage daily starting on the day of surgery. On postoperative day 7 the aneurysm was measured, the infrarenal aorta was harvested, and the rats were euthanized. NF kappa B was measured with Western blotting as a marker of inflammation. Matrix metalloproteinase (MMP)-9 protein levels were measured. Hematoxylin-eosin and elastin staining were used to examine tissue inflammation and elastin preservation. RESULTS: Aneurysms were significantly smaller in diameter in the rapamycin-treated group (3.3 +/- 0.7 mm vs 4.5 +/- 0.5 mm; P <.0001). NF kappa B levels were significantly reduced by 64% +/- 14% in rapamycin-treated aortas (P =.023). MMP-9 was reduced in rapamycin-treated aortas by 54% +/- 22% (P =.043). Hematoxylin-eosin and elastin staining showed no changes in inflammatory infiltrate or degradation of elastin fibers in elastase-infused aortic segments in rapamycin-treated rats. CONCLUSION: Rapamycin significantly reduces the rate of aneurysm expansion in the experimental AAA rat model by 40%. Biochemical evidence suggests that this is related to suppression of inflammatory signaling and decreased MMP-9 levels. Rapamycin could provide a new treatment for small aneurysms. CLINICAL RELEVANCE: Human aortic aneurysms are characterized histologically by an inflammatory infiltrate with severe proteolytic destruction. Rapamycin is an immunosuppressive agent commonly used to control transplant rejection and intimal hyperplasia by modulating the inflammatory cascade. In this experimental model rapamycin suppressed aneurysm expansion, decreased NF kappa B activation (a marker of inflammation), and decreased matrix metalloproteinase-9 levels. It is hoped that rapamycin or other similar anti-inflammatory drugs will one day be able to control aneurysm expansion in patients     

Anti-CD 18 monoclonal antibody slows experimental aortic aneurysm expansion

Purpose: Inflammation has been implicated as a contributing factor in the expansion of abdominal aortic aneurysms (AAA). To test this hypothesis, we examined the effects of a monoclonal antibody (MAB) to the leukocyte CD18 adhesion molecule on the expansion of experimental AAA.Methods: Aneurysms were induced by perfusion of an isolated segment of the infrarenal aorta with elastase in 22 normotensive (WKY) and 17 genetically hypertensive (WKHT) rats. Animals of both strains were randomly allocated to control or MAB-treated groups (MAB, 5 μg/100 gm body weight intraperitoneally, daily, beginning on the operative day for a total of four doses). The activity of the MAB against rat leukocytes had first been determined by in vitro immunofluorescence flow cytometry. Aortic size was directly measured initially and on day 14. At that time, a segment of aorta was stained with hematoxylin and eosin and mononuclear leukocytes and neutrophils were counted in each of 10 microscopic fields (400×).Results: The initial aortic size in all animals was 1.11 ± 0.15 mm. All groups developed aneurysms significantly larger than the initial aortic size ( p < 0.01). However, the MAB-treated animals had significantly smaller aneurysms than the untreated controls (mm): WKY: 3.63 ± 1.26, WKY-MAB: 2.08 ± 0.30, WKHT: 4.54 ± 1.86, WKHT-MAB: 2.37 ± 0.40, p < 0.0001. There also were significantly fewer monocytes in the MAB-treated normotensive rats: WKY: 35.5 ± 29.9, WKHT: 40.6 ± 28.8, WKY-MAB: 8.9 ± 8.5, WKHT-MAB: 32.3 ± 25.7, p = 0.03. Neutrophil counts did not differ significantly between the groups.Conclusions: Treatment with anti-CD18 monoclonal antibody slows the expansion of AAA in this experimental model. The associated inflammatory process at day 14, as indicated by monocyte infiltration, is reduced, but this effect may be opposed by the presence of hypertension. Further evaluation of the role of leukocytes and adhesion molecules in the expansion of AAA is warranted. (J VASC SURG 1996;23:301-7.)     

Rapid expansion of another downstream aortic aneurysm with the elephant trunk

A 75-year-old man developed persistent dysphagia 2 months after successful total arch replacement with a long elephant trunk (ET) for a distal arch aneurysm. Enhanced computed tomography revealed not only complete thrombosis of the distal arch aneurysm, but also rapid expansion of another downstream aortic aneurysm with esophageal compression. Thoracic endovascular aortic repair was undertaken for this symptomatic aortic aneurysm, which was totally thrombo-excluded. ET might produce turbulent or jet-like blood flow from its tip in some situations and have a potential to accelerate the expansion of the downstream aneurysm. Additional endovascular ET completion is simple, effective, and less invasive.     

Differentiation of ruptured aortic aneurysm from acute expansion by computerised tomography

CT scans were obtained in five patients who presented with abdominal pain and were found to have an abdominal aortic aneurysm without evidence of hypovolaemia. A periaortic haematoma and evidence of a rupture was found on scanning in three of the patients and confirmed at immediate operation. A retrospective diagnosis of rapidly expanding (acute) aneurysm was made in the other two patients in whom no other pathology was found at early elective operation. CT scanning is useful in differentiating small well-controlled ruptures from rapidly expanding aneurysms.     

Acute expansion of a hospital-acquired methicillin-resistant Staphylococcus aureus-infected abdominal aortic aneurysm

Infected aortic aneurysms (IAAs) are rare but can have devastating outcomes, particularly if diagnosis and treatment are delayed. The incidence of IAA is between 0.65% and 2% of all aortic aneurysms. The disease has a poor prognosis because these aneurysms have an increased tendency to grow rapidly and to rupture, and patients often have severe comorbidities and coexisting sepsis. Typical microorganisms associated with IAA are Salmonella, Streptococci, and Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus (MRSA) continues to emerge as a cause of serious infections, but its association with IAA is extremely rare. We present a rare case of infected abdominal aortic aneurysm caused by hospital-acquired (HA) MRSA. This case adds another presentation to the clinical spectrum of HA MRSA infections, and it highlights the problems encountered in the choice of the therapy of serious HA or health care-acquired infections in an era of increasing MRSA infections. We will discuss the clinical spectrum of HA MRSA infections as well as the problems encountered in the management of IAA, and will review the relevant literature.     

Hyperhomocysteinaemia is associated with the rate of abdominal aortic aneurysm expansion.

OBJECTIVES: Previous literature has suggested an association between AAA and the presence of elevated plasma homocysteine levels (HCY). Homocysteine can stimulate elastolysis in the arterial media via activation of elastase and matrix metalloproteinases. No evidence in the literature exists correlating aneurysm expansion and HCY. The study objective is to identify whether the rate of AAA expansion is related to HCY. METHODS: 108 patients undergoing surveillance for AAA were identified at our vascular surgical unit. AAA size and growth rate were assessed by serial ultrasonographic measurements. Fasting total HCY levels were measured using fluorescence polarisation immunoassays. Demographic details and atherosclerotic risk factors were noted all AAA patients. A multivariate analysis was performed for growth rate vs. HCY, hypertension and hypercholesterolaemia. The correlation between AAA growth rate, AAA size and HCY levels were calculated. RESULTS: 60% of patients with AAA had some degree of hyperhomocysteinaemia (> 15 micromol/l). Multivariate analysis showed HCY to be the only significant factor affecting AAA growth rate. A positive correlation was demonstrated between HCY levels and AAA growth rate using a linear regression model (R=0.28, p=0.003). Median growth rate among patients with hyperHCY was double that of patients with normal HCY (0.5 mm/month vs. 0.25 mm/month, p=0.003). A growth rate of > 10 mm/year was seen in 25% of hyper HCY patients and in only 2% of patients with normal HCY. In addition patients with hyper HCY and larger AAAs (> 4 cm) had a growth rate twice as fast as patients with hyper HCY and AAAs < 4 cm. CONCLUSIONS: A correlation between HCY and growth rate exists, although this is weak due to the multifactorial aetiology of AAAs. HyperHCY patients have faster expansion rates than patients with normal HCY, with significant numbers demonstrating rapid expansion (> 10 mm/year) and therefore an increased risk of rupture.     

Results of endoluminal grafting in an experimental aortic aneurysm model

We studied the impact of an endoluminally placed stented aortic graft on the geometry of a surgically created abdominal aortic dilation (AAD) in nonatherosclerotic mongrel dogs. Patulous iliac vein patch infrarenal aortoplasty produced a fusiform AAD, doubling the aorta diameter. Lumbar and mesenteric aortic tributaries were preserved and no mural thrombus formed. AADs created in 23 dogs were endoluminally excluded through transfemoral placement of a thin-wall Dacron graft 4 ± 2 months later. Balloon-expandable stents were used to anchor each end of the graft to the aorta. The graft was crimped radially in its body and longitudinally at its ends to provide longitudinal and radial expandability in these respective zones. Serial color duplex, angiography, and direct caliper measurements were made. Before graft placement, a 19% ± 11% diameter growth was observed. At graft placement, flow arrest immediately occurred in the space between the graft and the AAD intima in all cases. Although microscopic recanalization of the thrombus in this space was seen at sacrifice 6 and 12 months later, no macroscopic duplex flow was imaged. A 10% ± 11% reduction in AAD diameter was measured at 6 months (p < 0.001), with no further reduction at 12 months. Graft dimensions remained stable. No anastomotic leaks developed. AAD growth stopped during the first year after effective endoluminal exclusion in normotensive dogs despite patent side branches (<1.5 mm internal diameter) and no mural thrombus at the time of graft placement. Whether microscopic recanalization of the thrombus that forms outside the graft has an impact after 1 year remains to be seen. (J Vasc Surg 1996;23:819-31.)     

Randomized double-blind controlled trial of roxithromycin for prevention of abdominal aortic aneurysm expansion

BACKGROUND: Macrolide treatment has been reported to lower the risk of recurrent ischaemic heart disease. The influence of macrolides on the expansion rate of abdominal aortic aneurysms (AAAs) remains unknown. The aim was to investigate the effect of roxithromycin on the expansion rate of small AAAs. METHODS: A total of 92 subjects with a small AAA were recruited from two populations. One population consisted of 6339 men aged 65-73 years who were offered a hospital-based mass screening programme for AAA. From this population 66 subjects were recruited. The remaining 26 men were recruited from among 49 subjects diagnosed at interval screening for an initial aortic diameter between 25 and 29 mm. Subjects were randomized to receive either oral roxithromycin 300 mg once daily for 28 days or matching placebo, and followed for a mean of 1.5 years. RESULTS: During the first year the mean annual expansion rate of AAAs was reduced by 44 [corrected] per cent in the intervention group (1.56 mm per year), compared with 2.80 mm per year following placebo (P = 0.02). During the second year the difference was only 5 per cent [corrected]. Multiple linear regression analysis showed that roxithromycin treatment and initial AAA size were significantly related to AAA expansion when adjusted for smoking, diastolic blood pressure and immunoglobulin A level of 20 or more [corrected]. Logistic regression analysis confirmed a significant difference in expansion rates above 2 mm annually between the intervention and placebo groups: odds ratio = 0.09 (95 per cent confidence interval 0.01-0.83) [corrected]. CONCLUSION: In comparison to placebo, roxithromycin 300 mg daily for 4 weeks reduced the expansion rate of AAAs.     

Ruptured abdominal aortic aneurysm after endovascular aortic aneurysm repair

In treating uncomplicated abdominal aortic aenurysm, endovascular aortic aneurysm repair (EVAR) has been employed as a good alternative to open repair with low perioperative morbidity and mortality. However, the aneurysm can enlarge or rupture even after EVAR as a result of device failure, endoleak, or graft migration. We experienced two cases of aneurismal rupture after EVAR, which were successfully treated by surgical extra-anatomic bypass.