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The clinical effect of a drug-eluting stent in the femoropopliteal segment has not been investigated in a randomised trial with a contemporary comparator. The IMPERIAL study sought to compare the safety and efficacy of the polymer-coated, paclitaxel-eluting Eluvia stent with the polymer-free, paclitaxel-coated Zilver PTX stent for treatment of femoropopliteal artery segment lesions. In this randomised, single-blind, non-inferiority study, patients with symptomatic lower-limb ischaemia manifesting as claudication (Rutherford category 2, 3, or 4) with atherosclerotic lesions in the native superficial femoral artery or proximal popliteal artery were enrolled at 65 centres in Austria, Belgium, Canada, Germany, Japan, New Zealand, and the USA. Patients were randomly assigned (2:1) with a site-specific, web-based randomisation schedule to receive treatment with Eluvia or Zilver PTX. All patients, site personnel, and investigators were masked to treatment assignment until all patients had completed 12 months of follow-up. The primary efficacy endpoint was primary patency (defined as a peak systolic velocity ratio ≤2·4, without clinically driven target lesion revascularisation or bypass of the target lesion) and the primary safety endpoint was major adverse events (ie, all causes of death through 1 month, major amputation of target limb through 12 months, and target lesion revascularisation through 12 months). We set a non-inferiority margin of −10% at 12 months. Primary non-inferiority analyses were done when the minimum sample size required for adequate statistical power had completed 12 months of follow-up. The primary safety non-inferiority analysis included all patients who had completed 12 months of follow-up or had a major adverse event through 12 months. This trial is registered with ClinicalTrials.gov, number NCT02574481. Between Dec 2, 2015, and Feb 15, 2017, 465 patients were randomly assigned to Eluvia (n=309) or to Zilver PTX (n=156). Non-inferiority was shown for both efficacy and safety endpoints at 12 months: primary patency was 86·8% (231/266) in the Eluvia group and 81·5% (106/130) in the Zilver PTX group (difference 5·3% [one-sided lower bound of 95% CI −0·66]; p<0·0001). 259 (94·9%) of 273 patients in the Eluvia group and 121 (91·0%) of 133 patients in the Zilver PTX group had not had a major adverse event at 12 months (difference 3·9% [one-sided lower bound of 95% CI −0·46]; p<0.0001). No deaths were reported in either group. One patient in the Eluvia group had a major amputation and 13 patients in each group required target lesion revascularisation. The Eluvia stent was non-inferior to the Zilver PTX stent in terms of primary patency and major adverse events at 12 months after treatment of patients for femoropopliteal peripheral artery disease. Boston Scientific.

The aims of this study were, firstly, to assess the effect of concurrent peripheral artery disease (PAD) on the health-related quality of life (QOL) of people diagnosed with a small abdominal aortic aneurysm (AAA); and secondly, to test whether the peroxisome proliferator-activated receptor α agonist fenofibrate improved QOL of people diagnosed with a small AAA, including those diagnosed with concurrent PAD. The study included both a cross-sectional observational study and a randomized placebo-controlled clinical trial. 140 people diagnosed with a 35–49 mm diameter AAA, 56 (40%) of whom had concurrent PAD, and 25 healthy controls were prospectively recruited. QOL was assessed with the short form (SF) 36. Findings in participants that were diagnosed with both AAA and PAD were compared separately with those of participants that had a diagnosis of AAA alone or who had neither AAA nor PAD diagnosed (healthy controls). All participants diagnosed with an AAA were then randomly allocated to 145 mg of fenofibrate per day or identical placebo. Outcomes were assessed by changes in the domains of the SF-36 and ankle brachial pressure Index (ABPI) from randomization to 24 weeks. Data were analyzed using Mann–Whitney U tests. Participants diagnosed with both AAA and PAD had significantly worse QOL than participants diagnosed with AAA alone or healthy controls. Fenofibrate did not significantly alter SF-36 scores or ABPI over 24 weeks. Fenofibrate does not improve QOL of people diagnosed with small AAA, irrespective of whether they have concurrent PAD. Trial registration : ACTN12613001039774 Australian New Zealand Clinical Trials Registry.

Objective. Diagnostic digital subtraction angiography (DSA) and DSA with percutaneous transluminal angioplasty (DSA-PTA) are common procedures for diagnosing and treating symptomatic lower extremity arterial disease (LEAD). However, organ damage following DSA and DSA-PTA is often underrecognised and hence undiagnosed. To reduce the risk induced by invasive procedures in symptomatic LEAD patients, the method of remote ischemic preconditioning (RIPC) has been suggested. The aim of the current study was to assess the effect of RIPC intervention on the organ damage markers profile, oxidative stress, and inflammation biomarkers in LEAD patients undergoing DSA and DSA-PTA procedure. Methods. The RIPC intervention was performed by inflating a standard blood pressure cuff on the patient’s upper arm to 200 mmHg for 5 minutes four times with 5-minute perfusion between each cycle. The sham intervention was performed similarly, but the cuff was inflated to 20 mmHg. Changes in the cardiac and renal damage biomarkers’ profile, oxidative stress, and inflammation biomarkers were recorded before and 24 hours after DSA or DSA-PTA. Results. A total of 111 (RIPC 54, sham 57) patients with symptomatic LEAD scheduled for endovascular procedure were randomised, and 102 patients (RIPC 47, sham 55) completed the study protocol. RIPC significantly limited the increase of adiponectine levels after DSA and DSA-PTA, compared to sham intervention (p=0.020), but CK-MB levels were markedly lower in the sham group (p=0.047) after procedure. There was no significant difference between the RIPC and the sham group in mean changes in hs-troponin-T (p=0.25), NT-proBNP (p=0.24), creatinine (p=0.76), eGFR (p=0.61), urea (p=0.95), beta-2-microglobuline (p=0.34), or cystatine C (p=0.24) levels. Conclusion. In this controlled clinical study, RIPC failed to improve the profile of renal and cardiac biomarkers in patients with LEAD periprocedurally. RIPC significantly limits the rise in adiponectin levels and may influence the decrease of CK-MB levels 24 hours after endovascular procedure.

Patients with critical limb ischemia (CLI) have a high risk to develop cardiovascular events (CVE). We hypothesized that in CLI patients platelets would display increased baseline activation and reactivity. We investigated baseline platelet activation and platelet reactivity in patients with CLI. In this study baseline platelet activation and platelet reactivity in response to stimulation of all major platelet activation pathways were determined in 20 CLI patients (11 using aspirin and 9 using vitamin K-antagonists) included in the Juventas-trial (clinicaltrials.gov NCT00371371) and in 17 healthy controls. Platelet activation was quantified with flow cytometric measurement of platelet P-selectin expression and fibrinogen binding. CLI patients not using aspirin showed higher baseline platelet activation compared to healthy controls. Maximal reactivity to stimulation of the collagen and thrombin activation pathway was decreased in CLI patients compared to healthy controls. In line, attenuated platelet reactivity to stimulation of multiple activation pathways was associated with several traditional risk factors for cardiovascular disease. Baseline platelet activation was increased in CLI patients, whereas the reactivity of circulating platelets to several stimulatory agents is decreased. Reactivity of platelets was inversely correlated with cardiovascular risk factors.

Heme oxygenase-1 (HO-1) is an intracellular enzyme that catalyzes the oxidation of heme to generate ferrous iron, carbon monoxide (CO), and biliverdin, which is subsequently converted to bilirubin. These products have anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-thrombotic properties. Although HO-1 is expressed at low levels in most tissues under basal conditions, it is highly inducible in response to various pathophysiological stresses/stimuli. HO-1 induction is thus thought to be an adaptive defense system that functions to protect cells and tissues against injury in many disease settings. In atherosclerosis, HO-1 may play a protective role against the progression of atherosclerosis, mainly due to the degradation of pro-oxidant heme, the generation of anti-oxidants biliverdin and bilirubin and the production of vasodilator CO. In animal models, a lack of HO-1 was shown to accelerate atherosclerosis, whereas HO-1 induction reduced atherosclerosis. It was also reported that HO-1 induction improved the cardiac function and postinfarction survival in animal models of heart failure or myocardial infarction. Recently, we and others examined blood HO-1 levels in patients with atherosclerotic diseases, e.g., coronary artery disease (CAD) and peripheral artery disease (PAD). Taken together, these findings to date support the notion that HO-1 plays a protective role against the progression of atherosclerotic diseases. This review summarizes the roles of HO-1 in atherosclerosis and focuses on the clinical studies that examined the relationships between HO-1 levels and atherosclerotic diseases.

We investigated if corilagin can ameliorate or reverse atherosclerotic development via the toll-like receptor 4 (TLR4) signaling pathway and . Ana-1 cells or mouse peritoneal macrophages (MPMs) were stimulated with oxidized low-density lipoprotein followed by corilagin treatment. TLR4 expression in Ana-1 cells was upregulated by lentiviral transduction and downregulated by small interfering RNA. Peripheral blood mononuclear cells (PBMCs), plasma samples, and femoral arteries were collected from rats exhibiting peripheral artery disease (PAD). mRNA and protein expression of TLR4 and downstream molecules were decreased significantly by corilagin treatment in Ana-1 cells, MPMs, and rat PBMCs, and the reduction remained irrespective of downregulation or upregulation of TLR4 expression in Ana-1 cells. Corilagin also exerted a prominent effect on changes in plasma levels of cytokines and the pathologic manifestation of atherosclerosis in femoral arteries. Corilagin could ameliorate the development of atherosclerotic plaques by inhibiting the TLR4 signaling pathway in monocyte/macrophages and reduce the release of proinflammatory cytokines. This study provides a new therapeutic target and new targeting drug to oppose atherosclerosis and reveals the enormous potential of corilagin for control of PAD in humans.

Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch’s membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral artery disease (PAD), remains a leading cause of morbidity and limb loss. Effective vascular regeneration strategies will require increased understanding of molecular mechanisms underlying angiogenesis. Recent evidence revealed a new role for the vascular smooth muscle cell-enriched (VSMC-enriched) long noncoding RNA (lncRNA) CARMN in endothelial angiogenesis and postischemic vascular repair. CARMN was downregulated in both human CLTI muscle tissue and murine ischemia models. In VSMCs, CARMN deficiency suppressed a specific miRNA-mediated paracrine signaling axis that regulates Hedgehog signaling. In mice, deleting CARMN caused impariment in capillary growth and blood flow recovery after limb ischemia, an effect that was reversed by restoring miR-143-3p or silencing the Hedgehog inhibitor HHIP. The identification of lncRNA-mediated crosstalk between VSMCs and endothelial cells in PAD pathophysiology reveals possible therapeutic targets for CLTI and underscores the translational potential of RNA-based strategies in ischemic vascular disease.

Platelet-to-Lymphocyte Ratio (PLR) is an easily applicable blood test. An elevated PLR has been associated with poor prognosis in patients with different oncologic disorder. As platelets play a key role in atherosclerosis and atherothrombosis, we investigated PLR and its association with critical limb ischemia (CLI) and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. PLR was calculated and the cohort was categorized into tertiles according to the PLR. An optimal cut-off value for the continuous PLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in PLR. As an optimal cut-off value, a PLR of 150 was identified. Two groups were categorized, one containing 1228 patients (PLR≤150) and a second group with 893 patients (PLR>150). CLI was more frequent in PLR>150 patients (410(45.9%)) compared to PLR≤150 patients (270(22.0%)) (p<0.001), as was prior myocardial infarction (51(5.7%) vs. 42(3.5%), p = 0.02). Regarding inflammatory parameters, C-reactive protein (median 7.0 mg/l (3.0-24.25) vs. median 5.0 mg/l (2.0-10.0)) and fibrinogen (median 457 mg/dl (359.0-583.0) vs. 372 mg/dl (317.25-455.75)) also significantly differed in the two patient groups (both p<0.001). Finally, a PLR>150 was associated with an OR of 1.9 (95%CI 1.7-2.1) for CLI even after adjustment for other well-established vascular risk factors. An increased PLR is significantly associated with patients at high risk for CLI and other cardiovascular endpoints. The PLR is a broadly available and cheap marker, which could be used to highlight patients at high risk for vascular endpoints.

The association of coronary arterial calcification with cardiovascular morbidity and mortality is well-recognized. Lower limb arterial calcification (LLAC) is common in PAD but its impact on subsequent health is poorly described. We aimed to determine the association between a LLAC score and subsequent cardiovascular events in patients with symptomatic peripheral arterial disease (PAD). LLAC scoring, and the established Bollinger score, were derived from a database of unenhanced CT scans, from patients presenting with symptomatic PAD. We determined the association between these scores outcomes. The primary outcome was combined cardiac mortality and morbidity (CM/M) with a secondary outcome of all-cause mortality. 220 patients (66% male; median age 69 years) were included with follow-up for a median 46 [IQR 31-64] months. Median total LLAC scores were higher in those patients suffering a primary outcome (6831 vs. 1652; p = 0.012). Diabetes mellitus (p = 0.039), ischaemic heart disease (p = 0.028), chronic kidney disease (p = 0.026) and all-cause mortality (p = 0.012) were more common in patients in the highest quartile of LLAC scores. The area under the curve of the receiver operator curve for the LLAC score was greater (0.929: 95% CI [0.884-0.974]) than for the Bollinger score (0.824: 95% CI [0.758-0.890]) for the primary outcome. A LLAC score ≥ 4400 had the best diagnostic accuracy to determine the outcome measure. This is the largest study to investigate links between lower limb arterial calcification and cardiovascular events in symptomatic PAD. We describe a straightforward, reproducible, CT-derived measure of calcification-the LLAC score.