Localized Administration of Doxycycline Suppresses Aortic Dilatation in an Experimental Mouse Model of Abdominal Aortic Aneurysm
Article Outline
Treatment with doxycycline suppresses the development of abdominal aortic aneurysms (AAAs) in experimental animal models, but its use in humans can be accompanied by dose-related side effects. We sought to determine if localized administration of doxycycline can achieve inhibition of AAAs equivalent to that achieved by systemic treatment. C57BL/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs. After 14 days, the mean increase in aortic diameter was reduced from 167.2 ± 7.8% in untreated mice to only 129.7 ± 13.8% in mice treated with 100 mg/kg/day oral doxycycline (p < 0.05). Using osmotic minipumps to provide continuous periaortic infusion of doxycycline, localized infusion at rates of 0.75 to 1.0 mg/kg/day suppressed AAAs to an equivalent or even greater extent than systemic treatment [mean increase in aortic diameter 131.5 ± 14.4% at 0.75 mg/kg/day, p < 0.05; 103.2 ± 13.5% at 1.0 mg/kg/day, p < 0.01). Mean plasma doxycycline levels reached 332 ± 62 ng/mL during oral administration, but the drug was undetectable in the circulation during localized infusion. The doxycycline concentration in aortic tissue extracts was 22 ± 6 ng/mL during systemic treatment compared to only 5.6 ± 2.2 ng/mL [at 0.75 mg/kg/day] and 7.8 ± 4.0 ng/mL [at 1.0 mg/kg/day] during localized infusion (p < 0.05). Localized administration of doxycycline can effectively suppress experimental AAAs with undetectable plasma drug levels, even at doses 100-fold lower than those used during oral drug administration. Localized delivery of doxycycline holds promise as a novel strategy to inhibit the progressive expansion of aortic aneurysms, perhaps as a pharmacological adjunct to endovascular (stent graft) treatment.
INTRODUCTION
Abdominal aortic aneurysms (AAAs) are a common and potentially life-threatening condition. Although surgical and endovascular repair of AAAs are both effective in preventing deaths from aneurysm rupture, current clinical evidence only supports such interventions in patients with AAAs greater than 5.5 cm in diameter.1, 2 AAAs can be readily identified by ultrasound screening, but most are too small to warrant repair at the time of initial detection, leading to the need for long-term imaging surveillance. The development of nonsurgical therapies to prevent aneurysm expansion would therefore be an attractive option for patients with small, asymptomatic AAAs.3
Human and experimental AAAs are associated with a chronic transmural inflammatory response and destructive remodeling of the aortic wall elastic media.4, 5 Because degradation of aortic elastin appears to be mediated in large part by matrix metalloproteinases (MMPs) secreted by inflammatory and mesenchymal cells, MMP inhibition has emerged as a potential pharmacotherapeutic approach to limit the development and progression of AAAs.5, 6, 7, 8 Tetracycline antibiotics are known to exhibit MMP-inhibiting effects that are chemically distinct from their antimicrobial activities and have therefore been investigated in various conditions associated with chronic inflammation and excessive connective tissue proteolysis.9 Systemic administration of doxycycline has been shown to effectively suppress AAAs in experimental rodent models6, 10, 11, 12, 13 and to reduce aortic wall and plasma levels of MMP-9 in patients with AAAs.14, 15 Treatment with doxycycline has also shown promising early results in studies of patients with small AAAs, suggesting the need for further clinical evaluation of this therapeutic strategy.15, 16
In a recent clinical study, we found that oral administration of doxycycline (100 mg bid) for 6 months was well tolerated by most patients with small AAAs but that in some patients the drug was associated with dose-dependent side effects, such as cutaneous photosensitivity, dental discoloration, and gastrointestinal tract disturbances.15 Based on the likelihood that these limitations could be prevented by tissue-specific drug treatment to minimize systemic drug levels, we undertook a series of experiments to determine if localized (periaortic) administration of doxycycline can inhibit the development of experimental AAAs as effectively as systemic treatment. We also determined blood and aortic tissue doxycycline concentrations associated with successful inhibition of AAAs and examined if continuous doxycycline treatment is required to achieve sustained inhibition of AAAs. The results of this study indicate that localized administration of doxycycline holds promise as a novel strategy to inhibit the progression of aortic aneurysms.
METHODS
Experimental Animals
C57BL/6J mice were purchased from Jackson Laboratories (Bangor, ME) and bred in our institution. All experimental procedures were performed in male animals that had reached maturity (8–10 weeks of age) according to a protocol approved by the Animal Studies Committee at Washington University School of Medicine.
Elastase-Induced Model of AAA
Mice (20–35 g) were anesthetized with 55–60 mg/kg intraperitoneal sodium pemobarbital, and a laparotomy was performed under sterile conditions. The abdominal aorta was isolated with the assistance of an operating stereomicroscope (Leica, Deerfield, IL), and temporary 7–0 silk ligatures were placed around the proximal and distal aorta as previously described (Fig. I).6 A small opening was created at the aortic bifurcation using the tip of a 30-gauge needle, and a heat-tapered segment of PE-10 polyethylene tubing was introduced through the aortotomy and secured in position with 7–0 silk. The aortic lumen was perfused for 5 min at 100 mm Hg with saline solution containing type I porcine pancreatic elastase (0.414 units/mL; Sigma, St. Louis, MO). After removing the perfusion catheter, the aortotomy was repaired without constriction of the lumen and flow was restored to the lower extremities. Animals were allowed free access to food and water for either 14 or 28 days, followed by a second laparotomy under anesthesia. The previously perfused segment of the abdominal aorta was reexposed and measured in situ prior to euthanasia and tissue procurement.
Aortic Diameter Measurements and Extent of Dilatation
Aortic diameter (AD) measurements were obtained using ×20 stereomicroscopic visualization and a calibrated ocular grid. Preperfusion AD measurements (AD Pre) were obtained at the time of initial exposure of the aorta for elastase perfusion, and postperfusion measurements (AD Post) were obtained 5 min after restoring flow to the lower extremities. Final AD measurements (AD Final) were obtained at the time of repeat laparotomy, either 14 or 28 days after elastase perfusion. For each animal, the initial extent of aortic dilatation was calculated as the percent increase between preperfusion and postperfusion AD measurements (Pre'Post), and the overall extent of aortic dilatation was calculated as the percent increase between the preperfusion and final AD measurements (Pre'Final). AAAs were defined as an overall extent of aortic dilatation >100%.17
Systemic Treatment
As a nontreatment control, one group of mice underwent elastase perfusion followed by observation for 14 days with free access to standard drinking water. A second (systemic treatment) control group underwent elastase perfusion followed by administration of doxycycline at 100 mg/kg/day provided as a supplement to the drinking water.
Localized Drug Infusion
For mice receiving localized drug infusion, an osmotic minipump (catalog 1002, Alzet Osmotic Pumps; Durect, Cupertino, CA) was implanted into the dorsal subcutaneous space at the time of the elastase perfusion procedure (Fig. 1). These mini-pumps had a nominal reservoir volume of 100 μL and provided a specified infusion rate of 0.25 μL/hr for at least 14 days. Prior to placement, the mini-pumps were primed with normal saline and loaded with an appropriate concentration of doxycycline hydrochloride (Sigma) to achieve final drug delivery rates of 0, 0.25, 0.50, 0.75, or 1.00 mg/kg/day. Each minipump was fitted with a polyurethane microcatheter (Braintree Scientific, Braintree, MA) that was tunneled from the subcutaneous space to the periaortic retroperitoneum, where the catheter tip was secured with a polypropylene suture into a 7 × 3 × 2 mm3 piece of polyvinyl alcohol sponge. The sponge was positioned directly over the anterior surface of the aorta and fixed into position with several additional polypropylene sutures placed to the retroperitoneal tissues.
Fig. 1.
Experimental model. Schematic diagram illustrating techniques used for elastase perfusion and placement of an osmotic minipump and catheter-based system for local drug infusion in mice, (a) After measuring preperfusion AD, a segment of infrarenal abdominal aorta was isolated between temporary ligatures and a catheter was placed through an arteriotomy at the aortic bifurcation. Dilute elastase solution was instilled at 100 mm Hg for 5 min. The arteriotomy was repaired and the ligatures released after perfusion. (b) A preloaded osmotic minipump was placed in the dorsal subcutaneous tissues along the back, from which a polyurethane catheter was tunneled through the retroperitoneal space to lie over the aorta. The catheter tip was secured into a 7 × 3 × 2 mm3 polyvinyl alcohol sponge, which was then attached to the retroperitoneal tissues to lie immediately over the anterior aorta, (c) Cross-sectional view of catheter and sponge placement, (d) The abdominal aorta was reexposed by laparotomy 14 days after elastase perfusion and the final AD measured. IVC, inferior vena cava.
Discontinuous Treatment
An additional series of animals underwent elastase perfusion followed by localized (minipump) delivery of either doxycycline [1.00 mg/kg/day] or saline solution alone. On day 14, the minipumps were disconnected from the catheters within the subcutaneous space in order to prevent further drug administration. A subset of animals treated with doxycycline were killed at various intervals over the next 5 days (three or four mice at each interval) to determine the rate of decline in aortic tissue drug levels after the local drug infusion had been discontinued. The remaining animals were observed until day 28, when final AD was measured and the overall extent of dilatation determined.
Doxycycline Levels
Plasma samples were obtained at the time of death and stored at −20°C prior to analysis. Aortic tissue specimens were obtained by excising the entire segment of aorta that had been previously perfused with elastase (approximately 10 mm in length). Tissues were extracted in phosphate-buffered saline (1 mL/mg tissue) on a shaking incubator overnight at 37°C, and the supernatant was recovered after centrifugation at 2,000g for 20 min. Each extract sample was normalized to a total protein concentration of 1 mg/mL as measured by spectrophotometry. Doxycycline concentrations in plasma and aortic tissue extract samples were measured using a liquid chromatography/mass spectroscopy technique by PPD Development (Middleton, WI). The lower limit of detection in these assays was ∼1 ng/mL, based on standard curves using exogenous doxycycline.
Light Microscopy
Specimens of abdominal aorta were excised after systemic perfusion-fixation with 10% neutral buffered formalin (120 mm Hg for 10 min) and embedded in paraffin. Cross sections of the aortic wall (5 μm) were stained with Verhoeff-van Gieson (VVG) for elastin and examined by light microscopy. Digitized images of stainable elastic fibers were taken from serial sections along the entire length of the abdominal aorta, and computerized reconstruction was used to create three-dimensional images.
RESULTS
Localized Infusion of Doxycycline Suppresses Elastase-Induced AAAs
There were no differences in preperfusion or immediate postperfusion AD measurements between any of the experimental groups or controls, with mean AD increasing from 0.53 ± 0.00 mm before elastase perfusion to 0.91 ± 0.01 mm immediately after (Table I). Consistent with our previous studies, there was a significant secondary increase in AD by 14 days after elastase perfusion in the nontreatment (drinking water) control group, from 0.54 ± 0.01 mm before perfusion to 1.44 ± 0.04 mm, with final AD measurements after treatment with oral doxycycline being 13% lower than observed in untreated controls (1.25 ± 0.07 mm, p < 0.05). There were no differences in final AD between untreated controls and mice treated with localized doxycycline at delivery rates up to 0.50 mg/kg/day; however, final AD measurements were 16% lower in animals treated at 0.75 mg/kg/ day (1.21 ± 0.07 mm, p < 0.05) and 25% lower in animals treated at 1.0 mg/kg/day (1.08 ± 0.07 mm, p < 0.01).
Table I. Effects of doxycycline (DOX) administration on aortic diameter measurements
| Experimental group | n | AD Pre (mm) | AD Post (mm) | AD Final (mm) | |
|---|---|---|---|---|---|
| Systemic treatment | |||||
| Drinking water alone | 26 | 0.54 ± 0.01 | 0.91 ± 0.01 | 1.44 ± 0.04 | |
| Oral DOX [100 mg/kg/day] | 13 | 0.55 ± 0.01 | 0.90 ± 0.01 | 1.25 ± 0.07* | |
| Localized drug infusion | |||||
| Saline alone | 20 | 0.53 ±0.00 | 0.92 ± 0.01 | 1.43 ± 0.06 | |
| DOX (0.25 mg/kg/day] | 9 | 0.52 ± 0.01 | 0.92 ± 0.02 | 1.36 ± 0.06 | |
| DOX [0.50 mg/kg/day] | 7 | 0.50 ± 0.01 | 0.90 ± 0.01 | 1.31 ± 0.08 | |
| DOX [0.75 mg/kg/day] | 14 | 0.53 ± 0.01 | 0.90 ± 0.02 | 1.21 ± 0.07* | |
| DOX [1.00 mg/kg/day] | 9 | 0.53 ± 0.01 | 0.90 ± 0.02 | 1.08 ± 0.07** | |
| ANOVA | NS | NS | p < 0.001 | ||
By comparison with untreated controls, the extent of overall aortic dilatation was reduced by ∼22% in animals treated with oral doxycycline (from 167 ± 8% for drinking water to 130 ± 14% for oral doxycycline, p ≤ 0.05) and the incidence of AAAs was reduced by 44% (from 96% to 54%, p < 0.05) (Fig. 2). Significant suppression of aneurysmal dilatation (22%) was also observed in mice treated with localized doxycycline infusion at 0.75 mg/kg/day (131.5 ± 14.4%, p < 0.05, versus drinking water), along with a 33% reduction in the incidence of AAAs (64%, p < 0.05). Localized doxycycline infusion at 1.0 mg/kg/day tended to be even more effective at suppressing aneurysmal dilatation, with a 38% decrease in the extent of aortic dilatation (103.2 ± 13.5%, p < 0.01, versus drinking water) and a 42% decrease in the incidence of AAAs (56%, p < 0.05); however, there were no significant differences in the extent of aortic dilatation between the groups treated with oral doxycycline or localized doxycycline at infusion rates of either 0.75 or 1.00 mg/kg/day. Thus, localized infusion of doxycycline at 0.75 to 1.0 mg/kg/day inhibited the development of experimental AAAs to an equal or greater extent than oral doxycycline at 100 mg/kg/day.
Fig. 2.
Effects of doxycycline administration on aneurysmal dilatation. C57BL/6 mice were subjected to elastase perfusion followed by treatment with either standard drinking water alone, drinking water supplemented with 100 mg/kg/day oral doxycycline, or minipump-directed local infusion of doxycycline at dosages ranging from 0 to 1.00 mg/kg/day. The overall increase in AD for each animal was determined as the percent change from the preperfusion AD measurement to the final AD measurement on day 14, with AAAs defined as an increase >100%. Data represent mean ± standard error of the mean, with the number of mice (n) and the incidence of AAAs (%) shown for each group. Between-group comparisons were made using one-way analysis of variance with the Student-Newman-Kuels multiple comparisons test (*p < 0.05 vs. water alone, **p < 0.01 vs. water alone). The incidence of AAAs between groups was compared by Fisher's exact test (†p ≤ 0.05 vs. water alone).
Localized Treatment with Doxycycline Suppresses Aortic Wall Elastin Degradation
At 14 days after elastase perfusion, light microscopy showed a pronounced aortic wall inflammatory response in saline-treated controls along with fragmentation and degradation of the medial elastic lamellae (Fig. 3). Localized infusion of doxycycline at rates >0.75 mg/kg/day was associated with morphological preservation of aortic elastin but no detectable difference in the extent of inflammatory cell infiltration. There were no detectable differences in morphology between animals treated with oral doxycycline and those treated by local doxycycline infusion at rates of 0.75 or 1.00 mg/kg/day, but the differences in aortic geometry and overall elastin content between saline-and doxycycline-treated mice were particularly apparent following three-dimensional reconstruction of digitized images.
Fig. 3.
Preservation of aortic elastin following localized treatment with doxycycline. Representative aortic cross sections stained with VVG-elastin were obtained 14 days after elastase perfusion in mice treated with localized infusion of either saline (top panels) or 1 mg/kg/day doxycycline (bottom panels), (a, d) Under low power, the periaortic sponge used to provide localized drug delivery is visible (asterisks), (b, e) Extensive fracturing of the elastic lamellae in association with transmural inflammation was evident in saline-treated controls (arrow), whereas animals treated with doxycycline exhibited a decreased extent of elastin degradation, (c, f) Computerized reconstruction of digitized images showing stain-able elastic fibers in serial cross sections of the abdominal aorta, illustrating diminished dilatation and elastin degradation following localized doxycycline infusion.
Plasma and Aortic Wall Doxycycline Levels
To determine if localized treatment with doxycycline was accomplished without systemic drug absorption, doxycycline concentrations were measured in plasma samples obtained 14 days after elastase perfusion in each experimental group. Although plasma doxycycline levels reached 332 ± 62 ng/mL after oral drug administration at 100 mg/kg/day, circulating drug levels were below the limit of detection in almost all mice receiving local infusion (Fig. 4a).
Fig. 4.
Plasma (A) and aortic tissue (B) doxycycline levels following elastase perfusion. C57BL/6 mice were subjected to elastase perfusion followed by minipump-directed local infusion of doxycycline at dosages ranging 0 to 1.00 mg/kg/day, while mice receiving treatment with drinking water supplemented with 100 mg/kg/day oral doxycycline served as a control. Doxycycline levels were measured by mass spectrometry in plasma samples (a) and aortic wall tissue extracts (b, c). Data represent means ± standard error of the mean, (a) Mean plasma doxycycline levels were below the limit of detection in mice receiving local drug infusion compared to plasma levels of 332 ± 62 ng/mL in mice receiving oral doxycycline at 100 mg/kg/day. (b) Mean aortic tissue doxycycline levels increased with the rate of doxycycline infusion, reaching 7.8 ± 4 ng/mL at an infusion rate of 1.0 mg/kg/day, whereas mice receiving oral doxycycline [100 mg/kg/day] exhibited mean aortic tissue levels of 22.5 ± 6.4 ng/mL (*p < 0.05 vs. local infusion at 1.0 mg/ kg/day, analysis of variance with Dunn's multiple comparisons test). (c) Decline in mean aortic tissue doxycycline levels following local infusion at 1.0 mg/kg/day and removal of the minipumps on day 14 (n = 3–5 mice at each interval), with undetectable tissue drug levels reached within 48 hr and a calculated half-life of 26.5 hr.
To assess local tissue concentrations of doxycycline associated with effective inhibition of AAAs, doxycycline levels were also measured in soluble extracts of aortic tissue. Doxycycline was detectable in aortic tissue from all mice treated at localized infusion rates of 0.5 mg/kg/day or greater, with a concentration of 5.6 ± 2.2 ng/mL at the 0.75 mg/ kg/day infusion rate and a maximum concentration of 7.8 ± 4 ng/mL at 1.0 mg/kg/day (Fig. 4b). By comparison, aortic wall doxycycline concentrations were 188% higher in mice treated with oral doxycycline at 100 mg/kg/day [22.5 ± 6.4 ng/mL; p < 0.05 vs. local infusion at 1.0 mg/kg/day]. These results indicate that the suppression of AAAs achieved by localized doxycycline infusion occurred without detectable plasma drug levels and with considerably lower tissue drug concentrations than the suppression of AAAs achieved by oral drug administration at a 100-fold greater systemic dose.
Sustained Suppression of AAAs after Discontinuation of Doxycycline
To determine if continuous localized treatment with doxycycline is necessary to maintain suppression of AAAs, an additional series of mice underwent elastase perfusion and localized infusion of either doxycycline [1.0 mg/kg/day] or saline alone. The minipumps were disconnected and removed from the subcutaneous tissue on day 14, with a rapid decline in aortic tissue doxycycline concentrations within 48 hr (Fig. 4c). On day 28, mice treated for 14 days with doxycycline exhibited a lower final AD (1.06 ± 0.00 mm) and a lower overall extent of aortic dilatation (99.1 ± 6.4%) compared to saline-treated controls (final AD 1.26 ± 0.06 mm, overall extent of aortic dilatation 137.6 ± 12.1%; p < 0.01, Mann-Whitney) (Table II). Although there was also a trend toward a lower incidence of AAAs in the doxycycline group (64% vs. 100%), this difference did not reach statistical significance. These results indicate that effective and sustained suppression of aneurysmal dilatation can be achieved by a relatively limited period of localized doxycycline infusion, at least when administered early in lesion development, suggesting that continuous treatment with doxycycline is not necessary to achieve inhibition of AAAs.
Table II. Late aneurysmal dilatation following short-term doxycycline treatment
| Saline (n = 9) | Doxycycline (n = 11) | p | |
|---|---|---|---|
| AD Pre (mm) | 0.53 ± 0.01 | 0.54 ± 0.01 | NS |
| AD Post (mm) | 0.94 ± 0.02 | 0.91 ± 0.01 | NS |
| Immediate dilatation (Pre → Post) | 77.1 ± 3.9% | 70.2 ± 3.7% | NS |
| AD Day 28 (mm) | 1.26 ± 0.06 | 1.06 ± 0.03 | p < 0.01 |
| Overall dilatation (Pre → Day 28) | 137.6 ± 12.1% | 99.1 ± 6.4% | p < 0.01 |
| Incidence of AAAs | 100% | 64% | NS |
DISCUSSION
The present study demonstrates that localized administration of doxycycline effectively suppresses the development of experimental aortic aneurysms at doses 100-fold lower than required by systemic drug administration. Localized doxycycline administration was not associated with detectable plasma drug levels, but aortic tissue drug concentrations reached levels approximately 50% of those obtained after systemic treatment. Additional experiments showed that a limited period of localized doxycycline infusion was associated with sustained inhibition of aneurysmal dilatation and that doxycycline-mediated suppression of AAAs was correlated with preservation of aortic elastin despite the presence of a local inflammatory cell response. Taken together, these results indicate that localized treatment with doxycycline holds promise as a novel strategy to inhibit the development and progression of aortic aneurysms.
Sho et al.18 recently reported similar results using localized administration of doxycycline in an elastase-induced rat model of AAAs. In their study, a single rate of local doxycycline infusion [1.5 mg/kg/day] was compared to systemic treatment by twice-daily subcutaneous injections of doxycycline at 60 mg/kg/day, with no difference between groups in the extent of suppression of aneurysmal dilatation at 14 days. Plasma levels of doxycycline in the local infusion group ranged from 16.4 ± 4.6 ng/mL to 21.1 ± 8.5 ng/mL over the course of the 14-day experiment, whereas plasma levels after subcutaneous administration ranged from 725.6 ± 242 (day 2) to 1,359.7 ± 137.1 (day 7). The present study confirms and extends these findings, illustrating that effective suppression of AAAs can be achieved at even lower drug infusion rates and in the absence of detectable plasma drug levels.
This study helps lay a foundation for future efforts to develop localized drug delivery systems in which doxycycline might be administered to patients with small, asymptomatic AAAs (i.e., through implantation of drug-eluting stems or stent grafts). Although such an approach will require further device development and in vivo testing, our results demonstrate that localized drug delivery rates as low as 0.75 to 1.0 mg/kg/day can inhibit AAAs in the mouse in the absence of circulating plasma drug concentrations. Moreover, we found that doxycycline concentrations as low as 5.6 to 7.7 ng/mL in aortic tissue extracts can be associated with suppression of AAAs. It is not yet known if equivalent aortic tissue drug concentrations would also suppress AAAs in larger animal models or in humans, if similar tissue concentrations could be achieved by endoluminal delivery as opposed to periadventitial application, or to what extent binding of tetracyclines to aortic wall elastin might influence tissue concentrations.19 Nonetheless, these data provide an initial guide for efforts in which aortic tissue doxycycline concentrations might be used to monitor device development and localized drug-delivery performance.
Although the duration of treatment with doxycycline that might be necessary to influence the growth of human AAAs is unknown, in the present study we demonstrated that sustained treatment with doxycycline is not necessarily required to achieve durable effects on aortic aneurysms in the mouse model. This suggests that limited periods of localized doxycycline delivery, achievable using drug-eluting stents or stent graft systems, might still be suitably effective in the potential long-term treatment of small AAAs. Furthermore, this notion is consistent with current knowledge regarding the pathophysiology of aneurysm disease, where brief interruption of metalloproteinase-mediated connective tissue destruction might be sufficient to permit tissue recovery through endogenous mechanisms of connective tissue repair. Thus, even a temporally limited approach to localized drug treatment might effectively “set back the clock” on the natural history of gradual aneurysm expansion in patients with small AAAs.
An additional implication of this study is the possibility that localized treatment with doxycycline might act to suppress ongoing aneurysmal degeneration in the remaining aortic wall following endovascular treatment of large AAAs. One of the current limitations of endovascular treatment for AAAs is the potential for stent graft migration or displacement, particularly at the proximal attachment site, which can result in type I endoleaks and an increased risk of aneurysm rupture. Because these complications occur in part due to proximal aortic dilatation and angulation, localized treatment with doxycycline has the potential to stabilize aortic wall diameter in this critical location. Another complication of endovascular treatment is the development of type II endoleaks, which arise from patent lumbar and inferior mesenteric arteries with access to the aneurysm sac. Suppression of inflammation and connective tissue destruction within the aneurysm wall might also help promote fibrotic healing and thrombosis of such branch vessels, thereby reducing the potential for type II endoleaks and the need for secondary procedures. Although these potential effects of localized treatment with doxycycline remain speculative, the results of this investigation support the feasibility of pursuing these applications.
Supported by National Institutes of Health grants HL64332 and HL64333 (to R. W. T.) and a research project grant from Medtronic. We are grateful to Judi Dilks for providing measurements of doxycycline in plasma and aortic tissue extracts (Early Pre-Clinical Department, PPD Development).
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Portions of this work were initially presented at the Lifeline Foundation Research Forum of the Society for Vacular Surgery, June 3–6, 2004, Anaheim, CA.
PII: S0890-5096(06)60036-8
doi:10.1007/s10016-006-9017-z
© 2006 Annals of Vascular Surgery, Inc. Published by Elsevier Inc All rights reserved.
