Novel Glycomimetics Protect against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro via Attenuation of the RAGE/ERK/CREB Pathway.

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against ß-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI). We used an established osteogenic in vitro vascular smooth muscle cell (VSMC) model. Osteoprotegerin (OPG), sclerostin and glycation levels were all significantly increased in CLI serum compared to healthy controls, while the vascular calcification marker osteocalcin (OCN) was down-regulated in CLI patients vs. controls. Incubation with both CLI serum and g-LDL (10 µg/mL) significantly increased VSMC calcification vs. controls after 21 days, with CLI serum-induced calcification apparent after only 10 days. Glycomimetics (C2 and C3) significantly inhibited g-LDL and CLI serum-induced mineralisation, as shown by a reduction in alizarin red (AR) staining and alkaline phosphatase (ALP) activity. Furthermore, secretion of the osteogenic marker OCN was significantly reduced in VSMCs incubated with CLI serum in the presence of glycomimetics. Phosphorylation of cyclic AMP response element-binding protein (CREB) was significantly increased in g-LDL-treated cells vs. untreated controls, which was attenuated with glycomimetics. Blocking CREB activation with a pharmacological inhibitor 666-15 replicated the protective effects of glycomimetics, evidenced by elevated AR staining. In silico molecular docking simulations revealed the binding affinity of the glycomimetics C2 and C3 with the V domain of RAGE. In conclusion, these findings demonstrate that novel glycomimetics, C2 and C3 have potent anti-calcification properties in vitro, inhibiting both g-LDL and CLI serum-induced VSMC mineralisation via the inhibition of LDLR, RAGE, CREB and subsequent expression of the downstream osteogenic markers, ALP and OCN.

Loss of SIRT1 in diabetes accelerates DNA damage-induced vascular calcification.

AIMS: Vascular calcification is a recognized predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress-associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs). METHODS AND RESULTS: Immunohistochemistry revealed decreased SIRT1 and increased DNA damage marker expression in diabetic calcified arteries compared to non-diabetic and non-calcified controls, strengthened by findings that vSMCs isolated from diabetic patients show elevated DNA damage and senescence, assessed by the Comet assay and telomere length. Hyperglycaemic conditions were used and induced DNA damage and enhanced senescence in vSMCs in vitro. Using H2O2 as a model of oxidative stress-induced DNA damage, pharmacological activation of SIRT1 reduced H2O2 DNA damage-induced calcification, prevented not only DNA damage, as shown by reduced comet tail length, but also decreased yH2AX foci formation, and attenuated calcification. While Ataxia Telanglectasia Mutated (ATM) expression was reduced following DNA damage, in contrast, SIRT1 activation significantly increased ATM expression, phosphorylating both MRE11 and NBS1, thus allowing formation of the MRN complex and increasing activation of the DNA repair pathway. CONCLUSION: DNA damage-induced calcification is accelerated within a diabetic environment and can be attenuated in vitro by SIRT1 activation. This occurs through enhancement of the MRN repair complex within vSMCs and has therapeutic potential within the diabetic patient.

Elevated levels of endothelial-derived microparticles, and serum CXCL9 and SCGF-ß are associated with unstable asymptomatic carotid plaques.

Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques, and may correlate with serum markers of plaque instability and inflammation. Circulating EMPs, platelet MPs (PMPs) and inflammatory markers were measured in healthy controls and patients undergoing carotid endarterectomy. EMP/PMPs were quantified using flow cytometry. Bioplex assays profiled systemic inflammatory and bone-related proteins. Immunohistological analysis detailed the contribution of differentially-regulated systemic markers to plaque pathology. Alizarin red staining showed calcification. EMPs and PMPs were significantly higher in patients with carotid stenosis (≥ 70%) compared to controls, with no differences between asymptomatic vs symptomatic patients. Asymptomatic patients with unstable plaques exhibited higher levels of EMPs, CXCL9 and SCGF-ß compared to those with stable plaques. CXCL9, and SCGF-ß were detected within all plaques, suggesting a contribution to both localised and systemic inflammation. Osteopontin and osteoprotegerin were significantly elevated in the symptomatic vs asymptomatic group, while osteocalcin was higher in asymptomatic patients with stable plaque. All plaques exhibited calcification, which was significantly greater in asymptomatic patients. This may impact on plaque stability. These data could be important in identifying patients at most benefit from intervention.

Treatment of aortoiliac aneurysms with the iliac bifurcated device for preservation of internal iliac artery flow.

INTRODUCTION: The iliac bifurcated device (IBD) is an innovative endovascular device for aortoiliac aneurysm repair. The objective of this study is to provide further evidence on the efficacy and safety of the device. STUDY DESIGN: Case series study with retrospective analysis of prospectively collected nonrandomized data. METHODS: Between 2007 and 2010, all consecutive IBD placements were analyzed. The main outcomes included (1) technical failure; (2) morbidity and mortality; and (3) late outcomes. Prospective follow-up was performed by interval computed tomography scanning. RESULTS: In all, 27 consecutive patients had elective placement of 28 IBDs. Mean operating time was 251.1 ± 65.4 minutes, mean fluoroscopy time was 63.9 ± 27.2 minutes, and mean contrast volume used was 186.2 ± 106.7 mL. Periprocedural type I endoleak occurred in 2 patients. No aneurysm-related adverse events were recorded. CONCLUSION: We demonstrate that IBDs can be used in patients with aortoiliac aneurysms and are associated with satisfactory medium-term results as expressed by high patency and low reintervention rates.

Endovascular repair of aortic arch false aneurysm with branched endograft.

This case report describes the use of a customized branched device for the treatment of a distal anastomotic false aneurysm in an ascending to descending interposition graft in a 34-year-old Jehovah's Witness with congenital aortic arch interruption. A single branched customized stent graft device was used to successfully exclude the false aneurysm. The procedure was challenging due to the abnormal congenital anatomy. The planning, operative technique, and successful execution are described in this case report.

The chimney technique in endovascular aortic aneurysm repair: late ruptures after successful single renal chimney stent grafts.

BACKGROUND: The chimney graft technique has been proposed as an alternative endovascular treatment of juxtarenal aortic aneurysms, extending the landing zone and enabling successful exclusion of the aneurysm with standard endograft devices. METHODS: A prospective observational study assigning patients with juxtarenal aortic aneurysm treated with single renal chimney grafts in a tertiary vascular center in the United Kingdom was conducted. Primary outcome endpoints were defined as technical success, perioperative morbidity and mortality, and freedom from any type of endoleak, reintervention, and aneurysm-related death. RESULTS: Nine patients were enrolled. Successful aortic and chimney graft implantation was achieved in all patients. A proximal type I endoleak noticed on completion angiogram was treated with an aortic extension cuff. None of the patients died within 30 days of treatment. Two patients developed a type IA endoleak during follow-up, resulting in aneurysm rupture and death. Both patients had had uneventful chimney procedures, and no endoleak was evident on previous surveillance computed tomographic scans. All chimney grafts remained patent, and none of the patients developed renal impairment during the follow-up period. CONCLUSIONS: Proximal type I endoleak constitutes a weak point of chimney graft interventions. Increased vigilance in surveillance of such patients to prevent late aneurysm-related complications is required. Additional research to identify potential poor prognostic morphologic indicators is expected.

Meta-analysis of outcomes of endovascular treatment of infrapopliteal occlusive disease with drug-eluting stents.

PURPOSE: To review emerging evidence regarding the use of bare metal (BMS) vs. drug-eluting stents (DES) in the treatment of infrapopliteal occlusive disease. METHODS: A systematic review of the literature was undertaken to identify all studies comparing stent treatments of infragenicular vessels in patients with chronic lower limb ischemia. Validated methods to assess the methodological quality of the included studies were applied. Outcome data were pooled, and combined overall effect sizes were calculated using fixed or random effects models. The search identified 4 randomized clinical trials and 2 observational studies reporting on 544 patients (287 treated with DES and 257 treated with BMS). Data are presented as the odds ratio (OR) with 95% confidence interval (CI) and the number-needed-to-treat (NNT). RESULTS: Primary patency, freedom from target lesion revascularization, and clinical improvement at 1 year were significantly higher in the DES recipients compared to patients treated with BMS (OR 4.511, 95% CI 2.897 to 7.024, p<0.001, NNT 3.5; OR 3.238, 95% CI 2.019 to 5.192, p<0.001, NNT 6.0; and OR 1.792, 95% CI 1.039 to 3.090, p=0.036, NNT 7.3, respectively). No significant differences in limb salvage and overall survival at 1 year were identified between the groups (OR 2.008, 95% CI 0.722 to 5.585, p=0.181; OR 1.262, 95% CI 0.605 to 2.634, p=0.535, respectively). Sensitivity analyses investigating the potential effects of study design and type of DES on the combined outcome estimates validated the results. CONCLUSION: Our analysis has demonstrated superior short-term results with DES compared with BMS, expressed by increased patency and freedom from target lesion revascularization. The influence of this finding on clinical surrogate endpoints, such as limb salvage, remains unknown.

Chimney technique in the endovascular management of complex aortic disease.

The objective of this study was to systematically review the literature reporting on the chimney technique and perform an analysis of the outcomes. A search of electronic databases was undertaken to identify all studies reporting on the outcome of the chimney technique. The selected articles were divided into those reporting on the treatment of aortic pathology involving the visceral and those involving the supra-aortic branches. Twenty-one articles reporting on the treatment of juxta/supra-renal aorta and aortic arch disease in 102 and 37 patients, respectively, were identified. In the visceral group, an overall technical success rate of 91% was achieved, the perioperative major morbidity and mortality rates were 17 and 5%, respectively, and an early type I endoleak developed in 13 patients (13%). During follow-up, one patient died of intestinal ischemia. In the supra-aortic group, the technical success rate was recorded in 95%, and three patients (8%) developed an early type I endoleak. Three patients (13%) required conversion to open surgery during follow-up. In conclusion, this technique may be viewed as a complementary technique in high-surgical-risk patients.

Multilayer stent in the treatment of popliteal artery aneurysms.

Endovascular repair of popliteal artery aneurysms is an emerging treatment in high risk surgical patients. The location in a functionally demanding anatomical area creates limitations in terms of endograft patency. Technological advancements have been conscripted in an effort to circumvent such constraints. The multilayer stent technology effects through haemodynamic modulation. We used the multilayer stent to treat 6 asymptomatic popliteal artery aneurysms in 3 patients. All procedures were successfully accomplished without any complications. Over a mean follow up period of 9 months, thrombosis occurred in two limbs, and blood flow was restored with thrombolysis, achieving a primary and secondary patency rate at 6 months of 67 % and 100 %, respectively. Partial or complete thrombosis of the aneurysm sac was achieved in all aneurysms. Even though the use of the multilayer stent in popliteal artery aneurysms was safe in the short term, our experience showed that close surveillance is required.

Percutaneous transluminal angioplasty and stenting in patients with proximal vertebral artery stenosis.

BACKGROUND: Atherosclerotic occlusive disease of the proximal vertebral artery is an important cause of cerebrovascular ischemic events with a significant associated morbidity and mortality. Endovascular treatment has emerged as a promising tool of the therapeutic armamentarium, along with medical therapy and surgical reconstruction. Our objective was to systemically review the pertinent evidence on the endovascular management of proximal vertebral artery disease and perform an analysis of the published outcomes. METHODS: A systematic review of the literature identified all studies reporting percutaneous transluminal angioplasty or stenting, or both, for proximal vertebral artery stenosis. Web-based search engines were searched using the Medical Subject Headings terms "vertebral artery," "angioplasty," and "stents" in all possible combinations. Studies comprising a series of at least five patients were considered for analysis. Periprocedural transient ischemic attack and stroke and death from any cause ≤30 days of treatment were defined as the primary outcome end points. RESULTS: One randomized controlled trial comparing angioplasty and stenting of the proximal vertebral artery and medical therapy was identified. No comparative studies of endovascular treatment and open surgical repair were found. Forty-two selected studies reported endovascular treatment (angioplasty or stenting, or both) of 1117 vertebral arteries in 1099 patients. The weighted mean technical success rate was 97% (range, 36%-100%). Periprocedural transient ischemic attack occurred in 17 patients (1.5%). The combined stroke and death rate was 1.1%. Recurrent symptoms of vertebrobasilar insufficiency developed in 65 of 967 patients (8%) within a reported follow-up of 6 to 54 months. Restenosis developed in 183 of 789 patients (23%) who underwent follow-up imaging (range, 0%-58%). Reintervention for recurrent disease during follow-up occurred in 86 patients (9%; range, 0%-35%). CONCLUSIONS: There is limited comparative evidence on the efficacy of medical, surgical, and endovascular treatment of proximal vertebral artery disease. Percutaneous transluminal angioplasty and stenting has low periprocedural neurologic adverse events and mortality.