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     

The cellular component in the parietal infiltrate of inflammatory abdominal aortic aneurysms (IAAA)

Eight cases of inflammatory abdominal aortic aneurysm (IAAA) (group I) and a control group of ten cases of atherosclerotic abdominal aortic aneurysm (AAA) with little or no parietal inflammatory infiltrate (group II) were studied; using light microscopy, transmission electron microscopy (TEM), and immunohistochemistry. These were used to define cell composition in the inflammatory process, the degree of cell activation and alteration of connective tissue. Large numbers of B lymphocytes were present in IAAA with preservation of the T4/T8 ratio. In addition, HLA-DR and the IL2-R antigen (specific for activated cells) were widely expressed in the cell population. The interstitial matrix contained deposits of IgG, IgM and C3c together with an increase in type III collagen and a reduction in elastin which appeared fragmented and swollen. This study, therefore, characterised the cellular component of the parietal inflammatory infiltrate in IAAA. The degree of activation shown by these cell elements and the activation of complement suggest that the relevant antigen may have been localised in the aneurysm wall at the time of observation.     

Doxycycline Treatment in a Model of Early Abdominal Aortic Aneurysm

Purpose. To evaluate the effects doxycycline (Dox) in animal models of early abdominal aortic aneurysm. Methods. Of 43 male Wistar rats, 33 underwent intraluminal perfusion of the abdominal aorta with thioglycolate plus plasmin to reproduce early aortic aneurysm. These rats then were treated for 7 days with subcutaneous injections of Dox or saline. The 10 remaining rats underwent intra-aortic perfusion with saline and were injected subcutaneously with saline. On day 7, the rats were killed after abdominal aortic diameters were measured. Some aortic specimens were examined microscopically after elastica van Gieson (EVG) and hematoxylin–eosin (H&E) staining. In other specimens, the matrix metalloproteinase (MMP) activity in tissue extracts was evaluated by gelatin zymography. Results. Among the thioglycolate plus plasmin-perfused rats, the degree of aortic dilation was less in Dox–treated than in saline-treated rats. EVG staining indicated that Dox maintained a nearly normal pattern of elastic lamellae and normal medial elastin thickness. The aortic inflammatory response was not suppressed by Dox in H&E staining. In gelatin zymography, Dox reduced the MMP-9 activity, but did not significantly change either MMP-2 or the percentage of activated MMP-2. Conclusions. Dox inhibited experimental aneurysmal dilation by preserving medial elastin. This effect involved the suppression of MMP-9 but not of the MMP-2 activity. Received: February 8, 2002 / Accepted: July 2, 2002 RID="*" ID="*" Reprint requests to: K. Kaito Acknowledgments. We gratefully acknowledge the helpful suggestions of Hiroshi Ohtake, M.D., Fuminari Kasashima, M. D., and Mrs. Yoko Tanaka.     

Simultaneous resection of renal carcinoma and abdominal aortic aneurysm

A 62-year-old man with a 6.5 cm abdominal aortic aneurysm and coexistent left renal cell carcinoma was treated by simultaneous radical left nephrectomy and abdominal aortic aneurysm repair. Care was taken to avoid potential infection of the bypass graft by inadvertent contamination with urine. Pathologic examination of the left kidney revealed a renal cell carcinoma, clear cell type, with no evidence of invasion into the renal vein or lymph node metastases. The patient had an uncomplicated recovery and is well and free of disease four years after operation. In cases of equivalently life threatening surgical diseases, simultaneous resection is warranted.     

Concomitant abdominal aortic aneurysm and colorectal cancer: A decision analysis approach to a therapeutic dilemma

The therapeutic approach to a patient with concomitant abdominal aortic aneurysm and colorectal carcinoma is not clear. Decision analysis helps clarify decision options and quantify therapeutic outcomes. Variables used in decision analysis include life expectancy after resection for colorectal cancer and abdominal aortic aneurysm, rupture rate of abdominal aortic aneurysm, complications of colorectal cancer, complications of abdominal aortic aneurysmorrhaphy, and colorectal resection. The results support the concept that the symptomatic lesion should be treated first. When both lesions are asymptomatic and the aneurysm is 4–5 cm in diameter, it should be resected first, if the colorectal cancer has a <5% chance of obstruction or perforation, as is found in noncircumferential lesions. When the aneurysm is >5 cm, it should be resected first if the cancer has a <22% chance of obstructing or perforating, as with circumferential lesions. Simultaneous resection should be considered for patients with aneurysms >5 cm and cancers with a >75–80% chance of obstruction or perforation, provided the dual procedures can be performed with a <10% operative mortality and <50% complication. rate.The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the United States Government.     

Aortic pseudoaneurysm secondary to celiac plexus block

Traumatic pseudoaneurysm of the abdominal aorta has been infrequently reported in the literature. We report a case of an infected pseudoaneurysm of the supraceliac aorta which we believe to be secondary to celiac plexus block performed for pain from chronic pancreatitis. The aneurysm was successfully repaired using a Dacron graft through a thoracoabdominal approach. The possible mechanism of aortic injury from celiac plexus block is discussed.     

Acute pancreatitis following aortic aneurysm repair: Report of three cases

This paper reports three cases of acute pancreatitis that occurred after repair of an abdominal aortic aneurysm. The aneurysms were ruptured in two patients and asymptomatic in one. No patient had biliary disease or history of pancreatitis or alcohol abuse. Two of the patients required operation for drainage and debridement; one died. The etiology and diagnosis are discussed.     

Chylous ascites following abdominal aortic surgery

Three patients, two women, one man (mean age 74 years), who had abdominal aortic aneurysms (2) or aortobifemoral surgery (1), developed chylous ascites postoperatively. They were studied to determine their clinical course and develop a plan for management of this complication. In each patient, the ascites was not manifest until abdominal swelling developed two weeks after operation, and the problem was confirmed by the finding of milky fluid on paracentesis. A low serum albumin (mean 2.6 gm) was also characteristic. The ascites was not altered by parenteral nutrition or reduction of dietary fat and ingestion of medium chain triglycerides. In one patient (man, age 93) the ascites resolved spontaneously two months after abdominal aortic aneurysm surgery. Another (woman, age 70) was cured following operative ligation of a lymphatic fistula identified at operation five weeks after abdominal aortic aneurysm repair. In the third (woman, age 60), the ascites resolved immediately following placement of a peritoneal venous shunt six weeks after an aortobifemoral bypass. Chylous ascites is rare after aortic surgery and manifests itself about two weeks after operation, at times after discharge from hospital. It has an indolent course, but may resolve spontaneously up to two months after operation. Its course appears not to be foreshortened by diet, including omission of fat, but can be successfully treated surgically with a shunt or fistula ligation. If done early a protracted hospital course may be avoided. Presented at the Ninth Annual Meeting of the Southern California Vascular Surgical Society, Newport Beach, California, September 22, 1990.     

Watanabe hyperlipidemic rabbit as a model of aortic degeneration of the medial lamellar elastin unit.

At age 3 years, WHHL rabbits are near the end of their lifespan, frequently dying from the progression of their hyperlipidemic disease from events such as myocardial infarction. Out of a colony of 20 three-year-old WHHL rabbits raised as part of a NIH breeding project, 2 rabbits actually died of a ruptured thoracic aortic aneurysm. The need for a model to study abdominal aortic aneurysm formation led us to explore further the abdominal aortic pathology in aged WHHL rabbits. Six rabbit abdominal aortas from 3-year-old WHHL rabbits were preserved in formalin, sectioned, and stained for elastin. These were compared to the same sections of six normolipidemic age matched New Zealand white (NZW) rabbits. There was significant (P less than or equal to .001) destruction of the medial lamellar elastin unit in the aorta of the WHHL rabbits compared with the control NZW rabbits. Severe cholesterol deposits appeared to destroy the medial lamellae from the inside out. No definite aneurysm formation was seen in the abdominal aorta despite the significant changes in the medial lamellar elastin units. Thus, this model could be used to study the elastin degeneration of the media, but not necessarily abdominal aortic aneurysm formation.     

Femorofemoral crossover bypass for noninfective complications of aortoiliac surgery

Between 1973 and 1989, 39 femorofemoral crossover bypasses were performed to treat unilateral noninfective complications of aortoiliac surgery. The initial revascularization procedure, performed an average of 79.5 months previously, was an aortobifemoral bypass in 29 cases, an aorto- or iliofemoral bypass in six cases, an inlay graft for abdominal aortic aneurysm and aortoiliac endarterectomy in two cases each. The indications for femorofemoral crossover bypass included prosthetic occlusion in 35 cases, thrombosed false aneurysm in two, and further degradation after endarterectomy (iliac stenosis and occlusion in one case each). There was no operative mortality. One patient with acute ischemia upon admission and another with distal gangrene required below-knee and forefoot amputations, respectively. No amputations were required during the rest of the follow-up period. Three repeat aortobifemoral bypasses were performed because of occurrence of aortic or inflow vessel lesions. Primary and secondary actuarial five year patency rates for femorofemoral crossover bypasses were 59.7% and 78.4%, respectively. Femorofemoral crossover bypass can extend the benefits derived from direct aortoiliac surgery with low mortality and morbidity in the absence of associated aortic pathology (false aneurysm at the aortic implantation site or severe obstructive lesions). kg]Key wordsPresented at the Annual Meeting of the Société de Chirurgie Vasculaire de Langue Française, May 18–19, 1990, Nancy, France.     

The peripheral vascular consequences of smoking

Cigarette smoking is associated with an increased risk and extent of advanced atherosclerotic vascular disease in peripheral as well as coronary arteries. The likelihood of claudication, amputation, stroke, abdominal aortic aneurysm, and failure of vascular reconstruction is higher in smokers than nonsmokers. Smoking exerts its deleterious effects through many interactive mechanisms. Nicotine and carbon monoxide produce acute cardiovascular consequences, including altered myocardial performance, tachycardia, hypertension, and vasoconstriction. Smoking injures blood vessel walls by damaging endothelial cells, thus increasing permeability to lipids and other blood components. Among metabolic and biochemical changes induced by smoking are elevated plasma, free fatty acids, elevated vasopressin, and a thrombogenic balance of prostacyclin and thromboxane A ₂.Chronic smoking is associated with a tendency for increased serum cholesterol, reduced high density lipoprotein, and other lipid effects that contribute to atherosclerosis. In addition to rheologic and hematologic changes from increased erythrocytes, leukocytes, and fibrinogen, smokers have alterations in platelet aggregation and survival that produce thrombosis. Considering the ubiquitous repercussions of this menace, vascular surgeons should play an active role in motivating their patients to quit smoking.     

Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor

BACKGROUND: Chronic inflammation is a characteristic feature of abdominal aortic aneurysms (AAAs), but the molecular signals responsible for recruiting monocytes into the outer aortic wall are unresolved. The purpose of this study was to examine whether AAA tissues elaborate chemotactic activity for mononuclear phagocytes and to determine whether this activity is attributable to interactions between elastin degradation peptides (EDPs) and their cell surface receptor, the 67-kD elastin binding protein (EBP). MATERIAL AND METHODS: Soluble proteins were extracted from human AAA tissues, and chemotactic activity for differentiated U937 mononuclear phagocytes was measured by use of a modified Boyden chamber. Chemotactic activity induced by N -formyl-Met-Leu-Phe was used as a positive control and checkerboard analysis was used to distinguish chemotaxis from chemokinesis. Inhibition of chemotaxis was tested by peptide competition, blocking antibodies and galactosugar-mediated dissociation of the 67-kD EBP. RESULTS: AAA extracts stimulated a concentration-dependent increase in monocyte migration that reached up to 24% of the maximal effect induced by N -formyl-Met-Leu-Phe. Checkerboard analysis demonstrated that AAA extracts stimulated chemotaxis without a chemokinetic effect. AAA-derived chemotactic activity was eliminated by competition with Val-Gly-Val-Arg-Pro-Gly (VGVAPG), a repetitive peptide found in human elastin that binds to cellular elastin receptors, and decreased nearly 40% in the presence of BA-4, an antielastin monoclonal antibody that can block EDP-mediated chemotactic activity. Monocyte chemotaxis in response to both VGVAPG and AAA extracts was abolished in the presence of lactose, a galactosugar that specifically dissociates the 67-kD EBP, but it was unaffected by either glucose, fructose, or mannose. CONCLUSIONS: These findings indicate that soluble EDPs released within human AAA tissue can subsequently attract mononuclear phagocytes through ligand-receptor interactions with the 67-kD EBP, thereby providing a plausible molecular mechanism to explain the inflammatory response that accompanies aneurysmal degeneration. Better understanding of factors regulating inflammatory cell recruitment may lead to novel forms of therapy for early stages of aneurysmal degeneration.     

Late results of small untreated abdominal aortic aneurysms

We report our experience with 73 patients who were initially selected for nonoperative management of an abdominal aortic aneurysm less than 5 cm in diameter. Size of the aneurysm was determined by ultrasound (34); arteriography (16); computerized tomography (17); plain x-ray (4); and magnetic resonance imaging (2). End points of the study were subsequent elective resection, rupture, death from cause other than rupture, or an intact aneurysm followed for a minimum of three years. Overall, 28 (38%) aneurysms were subsequently resected on an elective basis; four (5%) ruptured; 15 (21%) were intact at the time of the patient's death; and 26 (36%) remained intact during follow-up of 3 to 6.5 years. Indications for elective resection were aneurysm enlargement (21); symptoms suggesting impending rupture (3); and improvement in medical condition (4). In the 43 aneurysms initially less than 4 cm diameter, 16 (37%) had elective resection and one (2%) ruptured, and in the 30 that were 4–4.9 cm, 12 (40%) were resected and three (10%) ruptured. The four aneurysms that ruptured had enlarged to greater than 5 cm prior to rupture. We conclude that aneurysms less than 4 cm can be safely followed. Aneurysms 4–4.9 cm should be considered for operation, depending upon the size of the aneurysm, patient's life expectancy, and risk factors for surgery. Any aneurysm that enlarges should be resected, especially if the aneurysm becomes larger than 5 cm in diameter.Presented at the Annual Meeting of the Southern California Vascular Surgical Society, September 21–23, 1990.     

Mycotic aneurysm of the suprarenal aorta secondary toStreptococcus pneumoniae: An unusual pathogen

Mycotic aneurysms of the suprarenal aorta are rare lesions, accounting for less than 1% of aortic reconstructions for aneurysmal disease. The bacteriology of these lesions differs from the infrarenal aneurysms and primarily consists of Gramnegative organisms. We report an unusual case of an 87-year-old man successfully treated for a ruptured mycotic suprarenal aortic aneurysm caused byStreptococcus pneumoniae. We have not seen a previously reported case where this pathogen has been associated with a suprarenal mycotic aneurysm. The unique bacteriology of these aneurysms is reviewed along with theories of etiology and their classification. The current management of these aneurysms is summarized.     

Medial fibrodysplasia and aneurysm of the popliteal artery

Fibromuscular dysplasia of the popliteal artery is rare. We report a case in a 20-year-old man complicated by aneurysm revealed by recurrent synovial effusion of the right knee. Diagnosis was based on pathology reports which showed severe destruction in the media. Two other cases with histopathological documentation were found in the literature.     

Does division of the left renal vein during aortic surgery adversely affect renal function?

Between July 1980 and July 1988, 478 consecutive patients underwent aortic aneurysm operations at Royal Prince Alfred Hospital. Renal function was assessed by measurement of serum creatinine levels. The left renal vein was divided in 28 (8%) of the 355 patients undergoing elective aneurysm resection. The mean immediate postoperative creatinine values were significantly higher after left renal vein division, 193±174 mol/L, compared to 133±93 mol/l for those whose left renal vein remained intact (p < 0.05 by Mann-Whitney U test). After one month, serum creatinine levels had decreased but were still significantly higher in those patients in whom the left renal vein had been divided, 170±166 mol/l, compared to those in whom it was left intact 109±49 mol/l (p<0.05 by Mann-Whitney U test). The suprarenal aorta was cross-clamped in seven (25%) of the 28 patients in whom the left renal vein was divided, compared to 21 (6%) of the 327 with the left renal vein intact. A rise in creatinine level was observed after suprarenal aortic cross-clamping. The left renal vein was divided in 17 (14%) of the 123 patients having emergency surgery for ruptured aortic aneurysm, 61 (49%) of whom survived more than 30 days. The mean immediate postoperative creatinine values were significantly higher after left renal vein division, 426±277 mol/l, compared to those in whom the vein was left intact, 178±136 mol/l (p < 0.05 by Mann-Whitney U test). After one month, serum creatinine levels were still significantly higher in those patients in whom the left renal vein had been divided. Although division of the left renal vein is a useful way to improve exposure of the juxtarenal aorta, the maneuver is associated with an adverse effect on renal function.Presented at the Annual Meeting of the Peripheral Vascular Surgical Society, New York, New York, June, 1989.     

Elastase-induced matrix degradation in arterial organ cultures: An in vitro model of aneurysmal disease

Purpose: Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, induction of endogenous metalloproteinases (MMPs), and development of a chronic inflammatory infiltrate. Despite intensive analysis of end-stage tissue, aneurysm pathogenesis remains obscure. The aim of this study was to develop an in vitro model of aneurysmal disease.Methods: Porcine aortic organ cultures were preincubated with pancreatic elastase before culture in standard conditions for up to 14 days. The extent of matrix degradation at various time points was determined by quantitative histologic estimation of collagen and elastin concentration. Endogenous metalloproteinase production within the tissue was quantified by gel enzymography and immunoblotting. A separate series of experiments was performed to investigate the effect of incorporating autologous leukocytes into the culture system.Results: Although exogenous elastase was removed after 24 hours, substantial degradation of the aortic extracellular matrix occurred in the subsequent 13 days in tissue culture. Analysis of samples preincubated with elastase (100 U/ml) for 24 hours before tissue culture demonstrated that elastin degradation occurred in a time-dependent manner (p < 0.001) and was not confined to the initial phase of exogenous elastase activity. Gelatin gel enzymography revealed a time-related production of metalloproteinases (55 to 250 kDa) within the aortic tissue. The presence of MMPs-1, 2, 3, and 9 was determined by immunoblotting. Immunohistochemistry identified the vascular smooth-muscle cell as the source of MMPs-1, 2, and 3. Addition of autogenous leukocytes to elastase-pretreated tissue initiated an inflammatory infiltrate within the aortic wall, which further enhanced both matrix degradation and MMP production (p < 0.001).Conclusions: These data demonstrate that aortic samples pretreated with elastase before tissue culture undergo matrix degradation with MMP production and the development of an inflammatory infiltrate. These changes mirror the pathophysiological events within established aneurysms. It is suggested that this model may be useful in understanding early pathogenic events within aneurysmal tissue. (J Vasc Surg 1996;24:667-79.)     

Characterization of an elastase from aneurysmal aorta which degrades intact aortic elastin

Accumulating evidence suggests that abdominal aortic aneurysms (AAA) are due to a pathologic process which results in the destruction of aortic elastin and other matrix components. In this study, protein extractions were performed on both aneurysmal and normal aorta. Extracts were applied to frozen section of normal aorta elther alone or in combination with 10 mM ethylenediaminetetraacetic acid, recombinant tissue inhibitor of metalloproteases, 10 mM zinc, and 5 mM phenylmethylsulfonyl fluoride, under conditions where calcium was removed from the buffer. After incubation, the sections were stained for elastin and evaluated by computerized morphometry. Aneurysm extracts, only in the presence of calcium, showed significant elastolytic activity characterized by destruction of intact elastic lamellae that was inhibited by ethylenediaminetetraacetic acid, the recombinant metalloprotease inhibitor, and zinc. Phenylmethylsulfonyl fluoride showed no inhibitory activity. Healthy aortic extract showed no elastolytic activity. This inhibitory profile is consistent with a metalloenzyme. We conclude that aneurysmal aorta contains elastolytic activity that is secondary to a metalloenzyme which is not present in normal aorta. This activity may play a role in the destruction of the elastin matrix that is seen in AAA's.     

Alteration of Elastin, Collagen and their Cross-links in Abdominal Aortic Aneurysms

OBJECTIVES: although the mechanism of arterial dilation and aneurysm development has not been clarified, the degradation of elastin and collagen plays undoubtedly a critical role. We evaluated the elastin and collagen content through the detection of their cross-links in aneurysmal and non-aneurysmal abdominal aortic walls. MATERIALS AND METHODS: in 26 human abdominal aortic aneurysm specimens obtained during surgery and in 24 autopsy control samples of non-aneurysmal abdominal aorta the tissue content of elastin and collagen cross-links were measured by HPLC. Collagen was also detected by evaluating two characteristic amino acids, 4-hydroxyproline (4-hypro) with a colorimetric method and 5-hydroxylysine (5-hylys) by gas chromatography. RESULTS: significantly fewer elastin cross-links were found in aneurysm samples compared to controls (desmosines and isodesmosines: 90% reduction; p<0.01). The opposite was true for pyridinoline collagen cross-links (350% increase) and deoxypyridinolines (100% increase, p=0.01). Tissue content of 5-hylys, 4-hypro and total amino acids were reduced significantly by 50% in aneurysmal samples. CONCLUSIONS: beside confirming decreased elastin content in aneurysmal walls, these results show a concurrent increase of collagen cross-links. Since total collagen markers were decreased (decreased 4-hypro and 5-hylys) it is reasonable to suggest that in aneurysmal aortic walls old collagen accumulates cross-links while new collagen biosynthesis is somehow defective.