Interleukin-6 receptor pathways in abdominal aortic aneurysm.

METHODS: We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. RESULTS: Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. CONCLUSIONS: A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

Elective sac perfusion to reduce the risk of neurologic events following endovascular repair of thoracoabdominal aneurysms.

Spinal cord ischemia (SCI) is a catastrophic complication of thoracoabdominal aortic aneurysm (TAAA) repair. This article describes our early experience with a technique for maintaining perfusion of segmental vessels (intercostals and lumbars) in the early postoperative period after endovascular repair of a TAAA, with "sac perfusion branches" added to custom-made stent grafts. These are closed 7 to 10 days after the first procedure to complete exclusion of the aneurysm. We have used this technique in 10 patients with type II TAAAs. One developed monoparesis of the right leg during a period of hypotension secondary to a cardiac event and died within 30 days. Two patients developed lower limb weakness after closure of the perfusion branches, both with full recovery. Controlled perfusion of segmental vessels with perfusion branches is feasible and may be a useful adjunct to prevent SCI, providing protection to spinal cord perfusion during the immediate postoperative period when risk of SCI is greatest.

Techniques for removing bilateral renal artery stents prior to fenestrated endovascular aneurysm repair.

PURPOSE: To demonstrate 2 endovascular methods for successful intravascular stent extraction. TECHNIQUE: In preparation for fenestrated endovascular aneurysm repair, renal artery stents may be implanted for focal vessel stenosis at the ostium. In a recent case, bilateral renal artery stents were deployed with >50% protruding into the aortic lumen, thus rendering fenestrated endografting impossible. Two techniques were employed to extract the stents. In the left renal artery, the stent was extracted using an endovascular snare, but the right renal artery stent could not be removed with this method. Instead, an endoscopic forceps was advanced down a 16-F sheath, and the stent was grasped, extracted, and released into the aneurysm sac. The endovascular repair then proceeded in the usual fashion. CONCLUSION: The need to remove a stent prior to endovascular aneurysm repair is not a common problem encountered by most endovascular specialists; however, these methods should be in their armamentarium should the need arise.

Venous malformations: Coagulopathy control and treatment methods.

Venous malformations (VMs) are ectatic channels which arise as a result of vascular dysmorphogenesis, commonly caused by activating mutations in the endothelial tyrosine kinase receptor (TIE2)/phosphatidylinositol 3-kinase (PI3Kinase) pathway. With a prevalence of 1% in the general population, and a diverse clinical presentation depending on site, size and tissue involvement, their treatment requires a personalised and multidisciplinary approach. Larger lesions are complicated by local intravascular coagulopathy (LIC) causing haemorrhagic and/or thrombotic complications which can progress to disseminated intravascular coagulopathy (DIC). METHODS: We performed a literature review using a PubMed® search and identified 15 articles to include. References of these texts were examined to further expand the literature review.Principle findings: Several treatment options have been explored, including compression, sclerotherapy, laser therapy, cryoablation and surgery in addition to the management of LIC with low-molecular-weight-heparin (LMWH) and other anticoagulants. Targeted molecular therapies acting on the phosphatidylinositol 3-kinase (PI3Kinase)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are newly emerging. CONCLUSION: Despite a wealth of literature, larger, multi-centric, randomised and prospective trails are required to offer further clarification on the therapeutic management of coagulopathy control and to provide symptomatic benefit to patients with VMs. There should be efforts to provide long term follow up and to use standardised risk stratification tools and quality of life (QOL) questionnaires to aid comparison of agents and treatment protocols.

A gene-centric study of common carotid artery remodelling.

BACKGROUND: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. METHODS: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). RESULTS: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. CONCLUSIONS: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Genomic research to identify novel pathways in the development of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a common disease with a large heritable component. There is a need to improve our understanding of AAA pathogenesis in order to develop novel treatment paradigms. Genomewide association studies have revolutionized research into the genetic variants that underpin the development of many complex diseases including AAA. This article reviews the progress that has been made to date in this regard, including mechanisms by which loci identified by GWAS may contribute to the development of AAA. It also highlights potential post-GWAS analytical strategies to improve our understanding of the disease further.

Genome wide association studies of abdominal aortic aneurysms-biological insights and potential translation applications.

Abdominal aortic aneurysm (AAA) is a complex disease with important environmental risk factors and a heritability of approximately 70%. Genome wide association studies have revolutionised the study of complex disorders and offer the potential for innovative insight into disease pathogenesis and development of individualised therapeutic options. This paper reviews the progress of genome wide association studies in AAA, highlighting novel disease pathways and potential translational applications of genomic discoveries.

Investigating vulnerable atheroma using combined (18)F-FDG PET/CT angiography of carotid plaque with immunohistochemical validation.

UNLABELLED: Inflammation and angiogenesis are hypothesized to be important factors contributing to plaque vulnerability, whereas calcification is suggested to confer stability. To investigate this in vivo, we combined CT angiography and PET and compared the findings with immunohistochemistry for patients undergoing carotid endarterectomy. METHODS: Twenty-one consecutive patients (18 men, 3 women; mean age ± SD, 68.3 ± 7.3) undergoing carotid endarterectomy were recruited for combined carotid (18)F-FDG PET/CT angiography. Plaque (18)F-FDG uptake was quantified with maximum standardized uptake value, and CT angiography quantified percentage plaque composition (calcium and lipid). Surgical specimens underwent ex vivo CT aiding image registration, followed by immunohistochemical staining for CD68 (macrophage density) and vascular endothelial growth factor (angiogenesis). Relationships between imaging and immunohistochemistry were assessed with Spearman rank correlation and multivariable regression. RESULTS: The mean (±SD) surgically excised carotid plaque (18)F-FDG metabolism was 2.4 (±0.5) versus 2.2 (±0.3) contralaterally (P = 0.027). There were positive correlations between plaque (18)F-FDG metabolism and immunohistochemistry with CD68 (ρ = 0.55; P = 0.011) and vascular endothelial growth factor (ρ = 0.47; P = 0.031). There was an inverse relationship between plaque (18)F-FDG metabolism and plaque percentage calcium composition on CT (ρ = -0.51; P = 0.018) and between calcium composition and immunohistochemistry with CD68 (ρ = -0.57; P = 0.007). Regression showed that maximum standardized uptake value and calcium composition were independently significant predictors of angiogenesis, and calcium composition was a predictor of macrophage density. CONCLUSION: We provide in vivo evidence that increased plaque metabolism is associated with increased biomarkers of angiogenesis and inflammation, whereas plaque calcification is inversely related to PET and histologic biomarkers of inflammation.

Effect of graduated compression stockings on limb oxygenation and venous function during exercise in patients with venous insufficiency.

Despite the established role of compression as the basis for nonoperative treatment of chronic venous insufficiency (CVI), its mechanism of action remains unclear. Near-infrared spectroscopy (NIRS) provides continuous noninvasive monitoring of changes in tissue oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb). We applied NIRS to evaluate the effect of graded stockings on venous function and calf muscle oxygenation during exercise in patients with CVI. Ten patients (age 56 +/- 5 years) with CVI were rested in supine posture for 20 minutes. NIRS optodes were attached to the calf. Venous function was assessed in each patient with and without graded compression stockings (classes I to III) at rest in the supine position, standing, with 10 tiptoe exercises, and on standard walking at 1.6 km/h for 5 minutes. Venous function was assessed by measuring changes in Hb and total hemoglobin (HbT) during the test, and muscle oxygenation was assessed by the oxygenation index (HbD), which is the difference between HbO2 and Hb. Standing without stockings caused a significant increase in Hb concentration by 10.75 +/- 2.24 micromol/L compared with the supine position (p < .001). This value was reduced when stockings were applied to 6.38 +/- 2.75 micromol/L with class III stockings (p = .005). During tiptoe exercise, the residual Hb concentration value without stockings was 7.62 +/- 2.12 micromol/L compared with 5.88 +/- 2.87, 3.77 +/- 3.37, and 3.46 +/- 2.73 micromol/L for class I, II, and III stockings, respectively. The reduction in Hb concentration reached significance with class II and III stockings compared to without stockings (p = .04). The HbT concentration was also reduced during tiptoe exercise, with increasing compression from 15.46 +/- 5.31 micromol/L without compression to 11.52 +/- 4.26 pmol/L with class III stockings (p = .048). During walking, the Hb concentration was 11.40 +/- 3.10 pmol/L without stockings, decreasing significantly (p < .001) and progressively to 8.49 +/- 3.24, 7.71 +/- 3.51, and 6.89 +/- 3.16 micromol/L with class I, II, and III stockings, respectively. Limb oxygenation (as measured by HbO2 concentration) during walking exercise, however, increased with higher-compression stockings and reached significance with class III stockings only (p = .03). In patients with venous insufficiency, graduated compression stockings may achieve their beneficial effects by reducing venous pooling and improving deeper tissue oxygenation.