Meta-analysis of the association between peripheral artery disease and growth of abdominal aortic aneurysms.

BACKGROUND: The role of atherosclerosis in the pathogenesis of abdominal aortic aneurysm (AAA) is controversial. Atherosclerosis-associated peripheral artery disease (PAD) has been reported to be a risk factor for AAA in population screening studies; its relationship with AAA growth is controversial. METHODS: A systematic search of MEDLINE, Scopus, CINAHL and the Cochrane Central Register of Controlled Trials was conducted in April 2016 and repeated in January 2017. Databases were screened for studies reporting AAA growth rates in patients with, and without PAD. The included studies underwent quality assessment and, where possible, were included in the meta-analysis. A subgroup analysis was performed, including only studies that adjusted for confounding factors. RESULTS: Seventeen studies, including a total of 4873 patients, met the review entry criteria. Data from 15 studies were included in the meta-analysis. There was marked heterogeneity in study design, methodology and statistical analyses used. In the main analysis, PAD was associated with reduced AAA growth (mean difference - 0·13, 95 per cent c.i. -0·27 to -0·00; P = 0·04). However, statistical significance was not maintained in sensitivity analysis. In a subanalysis that included only data adjusted for other risk factors, no significant association between PAD and AAA growth was found (mean difference -0·11, -0·23 to 0·00; P = 0·05). CONCLUSION: This systematic review suggests that currently reported studies demonstrate no robust and consistent association between PAD and reduced AAA growth.

From tissue iron retention to low systemic haemoglobin levels, new pathophysiological biomarkers of human abdominal aortic aneurysm.

Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3-5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.

Plasma profiling by a protein array approach identifies IGFBP-1 as a novel biomarker of abdominal aortic aneurysm.

OBJECTIVE: Cytokines are important mediators of immune-inflammatory responses implicated in abdominal aortic aneurysm (AAA) pathogenesis. Our objective was to investigate the cytokine expression profile in plasma of AAA patients. METHODS: Cytokine protein expression was measured in plasma of 5 large AAA patients (aortic size >50mm) and 5 controls (aortic size <30 mm) using a 20-cytokine antibody-based protein array. IGFBP-1 plasma concentrations were analyzed by ELISA. IGFBP-1 protein levels were analyzed in AAA thrombus by immunohistochemistry and Western blot. Platelet aggregation was assessed by conventional optical aggregometry. RESULTS: Several proteins including MIP-3 alpha (CCL20), Eotaxin-2 and IGFBP-1 were increased in AAA patients compared to controls. Among them, IGFBP-1 concentrations were significantly higher in large AAA patients vs control subjects. These data were validated in plasma of patients with large AAA (n = 30) compared to matched controls (n = 30) [834(469-1628) vs 497(204-893) pg/ml, p<0.01]. Furthermore, the potential association of IGFBP-1 with AAA size was analyzed in a second independent group of subjects [large AAA (n = 59), small AAA patients (aortic size = 30-50mm, n = 54) and controls (n = 30)]. Interestingly, IGFBP-1 levels correlated with AAA size (r = 0.4, p<0.001), which remained significant after adjusting for traditional risk factors. IGFBP-1 was localized in the luminal part of AAA thrombus and IGFBP-1 levels were increased in AAA thrombus conditioned media compared to media layer and healthy media. Interestingly, IGFBP-1 abrogated the potentiation of ADP-induced platelet aggregation triggered by IGF-1. CONCLUSIONS: IGFBP-1 has been identified by a protein array approach as a potential novel biomarker of AAA. The biological role of IGFBP-1 in AAA pathogenesis could be related to the modulation on the effect of IGF-1 on platelet aggregation.

Anaemia, iron and vitamin deficits in patients with peripheral arterial disease.

INTRODUCTION: Anaemia can compromise muscle and organ function. Related iron and vitamin body stores have seldom been assessed in patients with peripheral arterial disease. REPORT: We retrospectively analysed basal prevalence of anaemia, iron, B(12)-vitamin and folic acid deficits in 420 patients with claudication and 204 patients with critical limb ischaemia (CLI). The prevalence of the evaluated parameters was 9.8%, 6.7%, 6.7% and 2.9% among patients with claudication but 49.5%, 31.9%, 15.7% and 6.4% among CLI patients, respectively (p < 0.05 for all). DISCUSSION: Anaemia, iron and vitamin deficits are uncommon among patients with ischemic claudication but very prevalent among patients with CLI.

Soluble TWEAK plasma levels predict expansion of human abdominal aortic aneurysms.

OBJECTIVES: Diminished soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) concentrations are associated with cardiovascular diseases. We have analyzed sTWEAK levels and its relation with expansion rate in subjects with abdominal aortic aneurysm (AAA). METHODS: sTWEAK levels were measured by ELISA. RESULTS: sTWEAK concentrations were diminished in small AAA (≤ 5 cm; 353 ± 12 pg/mL; n = 25, p = 0.03) and large AAA (>5 cm; 315 ± 21 pg/mL; n = 18, p = 0.004) compared with healthy subjects (411 ± 22 pg/mL; n=27). Moreover, sTWEAK concentrations were negatively associated with AAA size (r = -0.4; p = 0.008). sTWEAK was also negatively associated with AAA expansion rate with 5 years of follow-up (n = 79, r = -0.263; p = 0.031). Multivariate regression analysis revealed that sTWEAK levels were independently associated with AAA growth rate (ß = -0.208; p = 0.046). CONCLUSIONS: sTWEAK plasma levels were decreased in subjects with AAA and were independently related with AAA expansion rate indicating that this protein could be a novel diagnostic and prognostic biomarker of AAA.

Increased levels of thioredoxin in patients with abdominal aortic aneurysms (AAAs). A potential link of oxidative stress with AAA evolution.

OBJECTIVE: Oxidative stress is a main mechanism involved in vascular pathologies. Increased thioredoxin (TRX) levels have been observed in several oxidative stress-associated cardiovascular diseases. We aim to test the potential role of TRX as a biomarker of oxidative stress in abdominal aortic aneurysm (AAA). METHODS: TRX levels were analysed in both AAA intraluminal thrombus (ILT) tissue and in tissue-conditioned media by immunohistochemistry, Western blot and ELISA. Moreover, serum TRX levels were assessed in AAA Caucasian patients by ELISA. RESULTS: TRX was mainly localized in the luminal part of ILT in AAA. Compared with the abluminal layer, TRX release was increased in the luminal layer of the ILT of AAA (31+/-9 ng/ml vs. 9+/-3 ng/ml, p<0.05). The interest of this approach is that we can identify proteins potentially released into the blood compartment, which could serve as biomarkers of the pathology. In a training population, serum TRX levels were significantly increased in patients with AAA relative to healthy subjects (50+/-6 ng/ml vs. 26+/-3 ng/ml, p<0.05). These results were validated in a second independent group of patients. Moreover, a positive correlation between TRX and AAA size (rho=0.5, p<0.001) was observed. Finally, in AAA samples with follow-up, TRX was positively associated to aneurismal growth rate (rho=0.25, p=0.027). CONCLUSIONS: TRX release is increased in the luminal part of AAA and TRX serum levels are increased in AAA patients compared with healthy subjects. TRX levels correlates with AAA size and expansion, suggesting its potential role as a biomarker of AAA evolution.

Long-term cardiovascular outcome after elective abdominal aortic aneurysm open repair.

BACKGROUND: We analyzed the incidence of late cardiovascular events and mortality after elective infra-/juxtarenal abdominal aortic aneurysm open repair (AAA-OR). METHODS: We included patients who survived AAA-OR in our center in 1988-2006. We registered late cardiac, cerebrovascular, and peripheral vascular events, as well as all-cause and cardiovascular mortality. We calculated patient survival and freedom from cardiovascular events (Kaplan-Meier) and evaluated risk factors (multivariate analysis). RESULTS: We studied 297 patients: 292 (98.3%) men, aged 67 +/- 7 (44-83) years, 143 (48.1%) bifurcated grafts. In a mean follow-up of 78.7 +/- 52.9 months, we registered 203 cardiovascular events in 123 (41.4%) patients, at a rate of 0.16 cardiovascular events/patient-year. Eleven (3.7%) patients suffered graft-related complications. Freedom from cardiovascular events was 94.2%, 67.2%, 45.7%, and 27.6% at 1, 5, 10, and 15 years, respectively. Survival was 96.6%, 74.7%, 50.7%, and 31.5%, respectively. The main cause of death was cardiovascular disease (n = 54, 18.2%), followed by cancer (n = 43, 14.5%). Only four (1.3%) deaths were graft-related. Coronary artery disease and chronic renal failure were predictive of cardiovascular mortality (p = 0.033 and 0.006). CONCLUSION: Although long-term survival is similar to that in the general population, successful AAA-OR patients remain at increased risk of cardiovascular events throughout their lifetime. Graft-related complications are rare, confirming the durability of the procedure.

Search for serum biomarkers associated with abdominal aortic aneurysm growth--a pilot study.

INTRODUCTION: Serological biomarkers could reflect asymptomatic infrarenal aortic aneurysm (AAA) activity and guide patient management. REPORT: Serum concentrations of C-reactive protein (CRP), alpha 1-antitrypsin and lipoprotein(a) were measured in blood samples from 35 AAA patients and 35 controls and correlated with the aortic diameter and AAA growth in the previous 12 months. We found a positive correlation between CRP and AAA diameter (r=0.46; p=0.007) and alpha 1-antitrypsin and AAA growth (r=0.55; p=0.004). CONCLUSIONS: Alpha 1-antitrypsin may be a promising biomarker of AAA growth.