Combined Detection of Plasma Tumor Necrosis Factor-α Converting Enzyme and Notch1 is Valuable in Screening Endoleak After Endovascular Abdominal Aortic Aneurysms Repair.

OBJECTIVES: Endoleaks may be present in up to 25% of patients after endovascular abdominal aortic aneurysm repair (EVAR) and there is no clear consensus on valuable biomarkers to determine endoleak presence. The aim of this study was to examine the potential value of plasma tumor necrosis factor-α converting enzyme (TACE) and Notch1 concentrations in determining endoleak presence after EVAR. METHODS: A total of 110 patients with abdominal aortic aneurysm who underwent EVAR were enrolled in our study, and plasma TACE and Notch1 concentrations were measured prior to and 6 months after EVAR. Logistic regression was performed to assess the association of postoperative plasma TACE and Notch1 concentrations with endoleak after adjusting for potential confounders. The ability of plasma TACE and Notch1 concentrations to determine endoleak presence was assessed using receiver operating characteristic curves and area under the curve (AUC). RESULTS: Twenty-four patients developed endoleaks 6 months after EVAR. Both postoperative plasma TACE and Notch1 concentrations were higher in patients with endoleak than in those without endoleak (2376.4 ± 28.1 pg/ml vs. 2094.1 ± 27.3 pg/ml, P < 0.01; 218.6 ± 1.9 pg/ml vs. 195.0 ± 2.1 pg/ml, P < 0.01, respectively). The AUCs from receiver operating characteristic curve analysis of plasma TACE and Notch1 concentrations in determining endoleak presence were 0.844 (95% CI 0.771 to 0.918, P < 0.01) and 0.860 (95% CI 0.791 to 0.930, P < 0.01), respectively. Combining the detection of plasma Notch1 and TACE concentrations could improve the accuracy in determining endoleak presence (AUC 0.930, 95% CI 0.883 to 0.978, P < 0.01). The predicted probability cutoff of 0.22 yielded a sensitivity of 95.8% and a specificity of 82.6% for endoleak presence. CONCLUSIONS: Plasma TACE and Notch1 levels can discriminate patients with and without endoleak 6 months after EVAR, and have a potential role in screening patients requiring computed tomography angiography.

Platelets reflect the fate of type II endoleak after endovascular aneurysm repair.

OBJECTIVE: The management of type II endoleak (T2E) remains controversial because of the heterogeneous outcome. For blood-based screening to detect malignant T2E, we focused on platelets after endovascular aneurysm repair (EVAR) and compared them with the prognosis of T2Es. METHODS: From 2007 to 2015, there were 249 patients treated with EVAR for abdominal aortic aneurysm who were evaluated retrospectively. The mean follow-up period was 3.5 ± 0.2 years. T2Es that had aneurysm sac enlargement or converted to type I or type III endoleak were defined as malignant; the other T2Es were considered benign. Cases without any complications, including T2E, were defined as completed. We compared the platelet count on postoperative days (PODs) 1 to 7 with preoperative baseline values among the three groups. Sequentially, we calculated the cutoff of the platelet ratio on POD 7 to the baseline value in relation to malignant T2E using receiver operating characteristic analysis, and the cutoff ratio was 113% (sensitivity, 79%; specificity, 58%). We then reclassified T2E patients into T2E-high platelet (T2E-HP; ≥113%) or T2E-low platelet (T2E-LP; <113%) groups. The influence of platelets on T2E was evaluated with reintervention rate and cumulative aneurysm sac enlargement rate using the Kaplan-Meier method. RESULTS: T2Es were found in 70 patients (28%), and 179 patients were assigned to the completed group. Malignant and benign T2Es were found in 33 and 37 patients, respectively. No difference was found in the preoperative baseline values. On POD 7, the platelet count in the malignant T2E group was significantly lower than that in the completed and benign T2E groups (168 × 103/µL vs 207 × 103/µL and 201 × 103/µL; P = .0124). Then, 27 and 43 patients were assigned to the T2E-HP and T2E-LP groups, respectively. The reintervention-free survival rate in the T2E-LP group was lower than that in the completed group (at 3 years, 66.4% ± 8.0% vs 71.9% ± 4.0%; P = .0031). Among T2E patients, the cumulative aneurysm sac enlargement rates in the T2E-LP group were significantly higher than those in the T2E-HP group (at 3 years, 34.6% ± 8.2% vs 20.6% ± 8.2%; P = .0105). Univariate Cox proportional hazards analysis for the cumulative aneurysm sac enlargement rates among T2E patients showed that sex, dual antiplatelet therapy, and lower platelet ratio (<113%) were significant predictors; multivariate analysis showed that T2E-LP was the only significant predictor (hazard ratio, 2.60; P = .0355). CONCLUSIONS: The platelet count of patients with malignant T2Es on POD 7 was definitively lower than that of patients with completed EVAR or with benign T2Es. The lower platelet count on POD 7 could be a risk factor for aneurysm sac enlargement among patients with T2Es.

Correlation of Baseline Plasma and Inguinal Connective Tissue Metalloproteinases and Their Inhibitors With Late High-Pressure Endoleak After Endovascular Aneurysm Repair: Long-term Results.

Purpose: To investigate whether plasma and connective tissue matrix metalloproteinases (MMP) and their inhibitors (TIMP) may predict late high-pressure endoleak after endovascular aneurysm repair (EVAR). Materials and Methods: Samples of inguinal fascia and blood were collected in 72 consecutive patients (mean age 73.1 years; 68 men) undergoing primary EVAR with the Endurant stent-graft. Baseline plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 and baseline MMP-2 and MMP-9 activity estimated using gelatin zymography (GZ) were compared between patients who developed late endoleak in follow-up and those who did not. Subgroup analyses were performed between patients with (n=18) and without inguinal hernias and between patients with moderate-diameter (50-59 mm; n=45) or large-diameter (≥60 mm; n=27) abdominal aortic aneurysms (AAA) at primary EVAR. Results: The mean follow-up period was 63.1 months (range 7.5-91.5), during which time 13 (18.1%) patients developed type I (6 Ia and 5 Ib) or 2 type III endoleaks. Only GZ-analyzed proMMP-9 concentrations were higher in the endoleak group than in patients without endoleak (mean difference 8.44, 95% CI -19.653 to -1.087, p=0.03). The patients with primary inguinal hernia at presentation had significantly higher tissue TIMP-2 values (0.8±0.7 vs 0.5±0.4, p=0.018) but lower plasma total (pro- + active) MMP-9 values (11.9±7.8 vs 16.2±7.4, p=0.042) than patients without hernias at the time of EVAR. Patients with AAAs ≥60 mm had significantly higher mean tissue homogenate levels of total (pro- + active) MMP-9 (p=0.025) and total (pro- + active) MMP-2 (p=0.049) as well as higher proMMP-9 (p=0.018) and total (pro- + active) MMP-9 (p=0.021) levels based on GZ compared to patients with moderate-diameter AAAs. Regression analysis revealed a significant association between total (pro- + active) MMP-9 plasma samples and the presence of hernia (OR 0.899, 95% CI 0.817 to 0.989, p=0.029) and between GZ-analyzed proMMP-9 and late endoleak (OR 1.055, 95% CI 1.007 to 1.106, p=0.025). GZ-analyzed proMMP-9 and active MMP-9 were strong predictors of late endoleak in patients with hernia (p=0.012 and p=0.044, respectively) and in patients with AAAs ≥60 mm (p=0.018 and p=0.041 respectively). Conclusion: Inguinal fascial tissue proMMP-9 significantly predicted late endoleak. ProMMP-9 and active MMP-9 biomarkers are significantly associated with late endoleak in hernia patients and in patients with AAAs ≥60 mm. Considering the clinical association between hernia and AAA and the fact that the AAA wall connective tissue environment remains exposed to systemic circulation after EVAR, inguinal fascia extracellular matrix dysregulation and altered MMP activity may reflect similar changes in AAA biology, leading to complications such as endoleak.

Positron Emission Tomography/Computed Tomography Predicts and Detects Complications After Endovascular Repair of Abdominal Aortic Aneurysms.

Purpose: To assess if aortic 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) could play a role in predicting complications after endovascular aneurysm repair (EVAR). Materials and Methods: This study involved 2 cohorts of men with abdominal aortic aneurysm treated by EVAR: those who underwent a PET/CT scan before EVAR (n=17) and those who had a PET/CT during follow-up (n=34). Uptake of FDG was measured as the standardized uptake value (SUV). D-dimer, a marker of fibrinolysis, was measured in blood drawn concomitantly with the PET/CT. Results: A significant uptake of FDG in the aneurysm wall was detected by PET/CT before EVAR in 6 of 17 patients. During the first year after EVAR, type II endoleaks developed in 5 of these FDG+ patients vs 3 of 11 FDG- patients (p=0.04). Two of the FDG+ patients had continued sac growth and required conversion to open repair. A significant association between sac growth rate, SUV, and the presence of endoleak was found in the 34 patients who underwent PET/CT after EVAR. Finally, D-dimer was significantly increased in patients with both endoleak and positive PET/CT in the post-EVAR group. Conclusion: This study suggests that the presence of FDG uptake in the aortic wall might be a useful tool to predict patients at high risk of developing post-EVAR complications.

Circulating biomarkers are not associated with endoleaks after endovascular repair of abdominal aortic aneurysms.

OBJECTIVE: Endoleak is a common complication of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) but can be detected only through prolonged follow-up with repeated aortic imaging. This study examined the potential for circulating matrix metalloproteinase 9 (MMP9), osteoprotegerin (OPG), D-dimer, homocysteine (HCY), and C-reactive protein (CRP) to act as diagnostic markers for endoleak in AAA patients undergoing elective EVAR. METHODS: Linear mixed-effects models were constructed to assess differences in AAA diameter after EVAR between groups of patients who did and did not develop endoleak during follow-up, adjusting for potential confounders. Circulating MMP9, OPG, D-dimer, HCY, and CRP concentrations were measured in preoperative and postoperative plasma samples. The association of these markers with endoleak diagnosis was assessed using linear mixed effects adjusted as before. The potential for each marker to diagnose endoleak was assessed using receiver operating characteristic curves. RESULTS: Seventy-five patients were included in the study, 24 of whom developed an endoleak during follow-up. Patients with an endoleak had significantly larger AAA sac diameters than those who did not have an endoleak. None of the assessed markers showed a significant association with endoleak. This was confirmed through receiver operating characteristic curve analyses indicating poor diagnostic ability for all markers. CONCLUSIONS: Circulating concentrations of MMP9, OPG, D-dimer, HCY, and CRP were not associated with endoleak in patients undergoing EVAR in this study.

EVAR and OPEN treatment of abdominal aortic aneurysm: What is the role of MMP-9 in the follow-up?

INTRODUCTION: The aim of our study is to verify the role of metalloproteinases in endovascular repair (EVAR) and OPEN surgery treatment for abdominal aortic aneurysm (AAA). Postoperatively, these enzymes could represent an important biomarker to adapt diagnostic tests and further investigations during follow-up. MATERIAL AND METHOD: From 2004 to 2008, 55 patients were considered with AAA. Of these, 33 patients (mean age: 70.1 years), (mean AAA diameter: 5.4cm) were treated with OPEN surgery (group A) and 22 (mean age: 74.1 years) (mean AAA diameter: 5.1cm) were treated with EVAR. In 17 of them, there were no signs of endoleak (group B1), while in 5 patients, a presence of endoleak (group B2) was detected. Plasma samples were collected in order to determine MMP-9 activity. Enzyme immunoassay was performed preoperatively at 1, 3, 6 and 12 months. Patients treated conventionally were clinically examined after 1 and 12 months by ultrasound. Patients undergoing EVAR treatment were clinically examined by CT scan after 1, 3, 6 and 12 months. The analysis was done by assessing the interaction over time of the MMP-9 value in B1 and B2 groups. RESULTS: The average values observed for MMP-9 were preoperatively and at 1, 3, 6 and 12 months, respectively: in group A 150.8ng/mL (SD=30.5), 252.5ng/mL (SD=25.2), 315.4ng/mL (SD=22.7), 295.3ng/mL (SD=26.8), 210.7ng/mL (SD=30.2); in group B1 105ng/mL (SD=10.8), 125.6ng/mL (SD=18), 85.8ng/mL (SD=19.9), 95ng/mL (SD=20.2), 80.4ng/mL (SD=15.6); in group B2 149ng/mL (29.2), 375.4ng/mL (SD=40.2), 215ng/mL (SD=35.9), 180ng/mL (SD=20.2), 175ng/mL (SD=33.4). The MMP-9 level was higher in group B2 compared to group B1 (P=0.01), suggesting a correlation with the presence of the endoleak. CONCLUSIONS: This preliminary study shows that MMP-9 may be a biomarker of the presence of endoleak. Other further investigations and larger series are needed to show that metalloproteases could play a role in the follow-up of EVAR treated patients.

The association between plasma matrix metalloproteinase-9 concentration and endoleak after endovascular aortic aneurysm repair: a meta-analysis.

BACKGROUND: The most common complication after endovascular aneurysm repair (EVAR) is continued perfusion of the aneurysmal sac, known as endoleak. Assessment of markers released from the aneurysm wall into the circulation has been suggested as a possible alternative for detecting endoleaks. The aim of this meta-analysis was to examine if circulating concentrations of matrix metalloproteinase (MMP)-9 were higher in patients with endoleak after EVAR. METHODS: A systematic search of the MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library Databases was conducted. Studies reporting circulating MMP-9 concentrations in patients who did and did not have endoleaks after EVAR that met inclusion and exclusion criteria were included. A meta-analysis using a random effects model was performed to assess the association between circulating concentrations of MMP-9 and endoleak. Sensitivity analyses were performed using the one-study remove approach. Study quality was assessed using a quality assessment tool. RESULTS: Prior to EVAR, plasma concentrations of MMP-9 were similar in patients that did and did not subsequently develop an endoleak (Standardised mean difference: -0.13; 95% confidence interval, -0.63 to 0.37, p=0.60). 1 month after EVAR, plasma concentrations of MMP-9 were non-significantly higher in patients that had an endoleak (Standardized mean difference: 0.56; 95% CI -0.02 to 1.15, p=0.06). 3 months after EVAR, plasma concentrations of MMP-9 were higher in patients that had an endoleak (Standardised mean difference: 1.42; 95% confidence interval, 0.48-2.36, p<0.003). CONCLUSIONS: This meta-analysis suggests that plasma MMP-9 concentrations measured 3 months after EVAR are higher in patients that have an endoleak. It remains to be established whether plasma MMP-9 testing is sufficiently accurate for use as a surveillance test for endoleak after EVAR.

Magnetic Resonance Imaging with a Weak Albumin Binding Contrast Agent can Reveal Additional Endoleaks in Patients with an Enlarging Aneurysm after EVAR.

OBJECTIVES/BACKGROUND: To examine the additional diagnostic value of magnetic resonance imaging (MRI) after administration of a weak albumin binding contrast agent in post-endovascular aneurysm repair (EVAR) patients with aneurysm growth with no or uncertain endoleak after computed tomography angiography (CTA). METHODS: This was a prospective diagnostic cross sectional study carried out between April 2011 and August 2013. MRI was performed in all patients with aneurysm growth≥5 mm after EVAR implantation and no or uncertain endoleak on CTA, or the inability, on CTA, to identify the source of a visible endoleak. All MRI scans were performed on a 1.5 T clinical MRI scanner after administration of a weak albumin binding contrast agent. The presence of endoleaks was assessed by visually comparing pre- and post-contrast T1-weighted images with fat suppression. Post-contrast images were acquired 5 and 15 minutes after contrast administration. RESULTS: Twenty-nine patients (26 men; 90%) with a median age of 74 years (interquartile range [IQR] 67-76) were included. The median interval between EVAR and MRI was 39 months (IQR 20-50). The median increase in maximum aneurysm diameter during total follow up after EVAR was 11 mm (IQR 6-17). At CTA, 16 patients (55%) had no detectable endoleak, five patients (17%) had suspected but uncertain endoleak, and eight patients had a definite endoleak (28%). On the post-contrast MRI images, endoleak was observed in 24 patients (83%). In all patients with uncertain endoleak on CTA, endoleak was detected with MRI. For type II endoleaks, feeding vessels were detected in 22/23 patients (96%) and these were all, except one, lumbar arteries. CONCLUSION: In patients with enlarging aneurysms of unknown origin after EVAR, MRI with a weak albumin binding contrast agent has additional value for both the detection and determination of the origin of the endoleak.

Changes in inflammatory, coagulopathic, and fibrinolytic responses after endovascular repair of an abdominal aortic aneurysm: relationship between fibrinogen degradation product levels and endoleaks.

PURPOSE: To compare the inflammatory, coagulopathic, and fibrinolytic responses after endovascular aneurysm repair (EVAR) of an abdominal aortic aneurysm between two stent grafts. Fibrinogen degradation product (FDP) levels were compared between patients with or without an endoleak. MATERIALS AND METHODS: EVAR was performed in 88 patients using an Excluder (37 patients) or a Zenith (51 patients). White blood cell count (WBC), C-reactive protein (CRP) levels, platelet count, and FDP levels were measured before and after EVAR. RESULTS: WBC and CRP increased and the platelet count decreased significantly on days 1 and 3 after EVAR in the Zenith group compared with the Excluder group. The change in FDP from baseline to 7 days after EVAR was -1.99 ± 7.46 vs. 8.59 ± 9.38 µg/mL in patients with (n = 24) vs. without (n = 64) an endoleak (p < 0.001). A change in FDP of 3.1 µg/mL was the optimal cutoff point for predicting the presence of an endoleak (accuracy 0.762; sensitivity 0.875; specificity 0.717). CONCLUSION: Inflammatory, coagulopathic, and fibrinolytic responses were greater in the Zenith group than in the Excluder group. A change in FDP of ≤3.1 µg/mL was predictive of an endoleak after EVAR.

Plasma matrix metalloproteinase 9 levels may predict endoleaks after endovascular aortic aneurysm repair.

A simple, noninvasive and cost-effective diagnostic test for the detection of endoleaks after endovascular aneurysm repair (EVAR) would complement (or even replace) current surveillance modalities. We reviewed the literature for studies correlating circulating levels of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs with the presence of endoleaks after EVAR. An electronic search of databases was performed to identify studies reporting circulating concentrations of MMPs in patients with and without an endoleak after EVAR. Four studies were identified. Patients with an endoleak had higher plasma MMP-9 levels compared with those without an endoleak. Two studies that also evaluated plasma MMP-3 levels after EVAR suggest that these levels may also be higher in patients with an endoleak. Preliminary evidence suggests that MMP-9 levels are increased in patients developing an endoleak after EVAR. Larger studies are required to confirm or refute our findings.

Plasma levels of matrix metalloproteinase-9: a possible diagnostic marker of successful endovascular aneurysm repair.

OBJECTIVE: The aim of the study was evaluating the diagnostic value of plasma matrix metalloproteinase- (MMP)-2 and -9 and tissue inhibitor of MMP-1 (TIMP-1) for endoleak detection after endovascular aneurysm repair (EVAR). REPORT: Consecutive EVAR patients (n = 17) with endoleak and matched controls without endoleak (n = 20) were prospectively enrolled. Increased levels of MMP-9 were observed in patients with endoleak (P < 0.001). Regression analysis showed no significant influence of age, sex or abdominal aortic aneurysm (AAA) size. The receiver operating characteristic (ROC) curve of plasma MMP-9 levels showed that a cut-off value of 55.18 ng ml(-1) resulted in 100% sensitivity and 96% specificity with an AUC value of 0.988 (P < 0.001) to detect endoleak. CONCLUSIONS: Plasma MMP-9 levels appear to discriminate between patients with and without an endoleak with high sensitivity and specificity.