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Patients with critical limb ischaemia have a high rate of amputation and mortality. We tested the hypothesis that non-viral 1 fibroblast growth factor (NV1FGF) would improve amputation-free survival. In this phase 3 trial (EFC6145/TAMARIS), 525 patients with critical limb ischaemia unsuitable for revascularisation were enrolled from 171 sites in 30 countries. All had ischaemic ulcer in legs or minor skin gangrene and met haemodynamic criteria (ankle pressure <70 mm Hg or a toe pressure <50 mm Hg, or both, or a transcutaneous oxygen pressure <30 mm Hg on the treated leg). Patients were randomly assigned to either NV1FGF at 0·2 mg/mL or matching placebo (visually identical) in a 1:1 ratio. Randomisation was done with a central interactive voice response system by block size 4 and was stratified by diabetes status and country. Investigators, patients, and study teams were masked to treatment. Patients received eight intramuscular injections of their assigned treatment in the index leg on days 1, 15, 29, and 43. The primary endpoint was time to major amputation or death at 1 year analysed by intention to treat with a log-rank test using a multivariate Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00566657. 259 patients were assigned to NV1FGF and 266 to placebo. All 525 patients were analysed. The mean age was 70 years (range 50–92), 365 (70%) were men, 280 (53%) had diabetes, and 248 (47%) had a history of coronary artery disease. The primary endpoint or components of the primary did not differ between treatment groups, with major amputation or death in 86 patients (33%) in the placebo group, and 96 (36%) in the active group (hazard ratio 1·11, 95% CI 0·83–1·49; p=0·48). No significant safety issues were recorded. TAMARIS provided no evidence that NV1FGF is effective in reduction of amputation or death in patients with critical limb ischaemia. Thus, this group of patients remains a major therapeutic challenge for the clinician. Sanofi-Aventis, Paris, France.

Current evidence suggests that endothelial progenitor cells (EPC) contribute to ischemic tissue repair by both secretion of paracrine factors and incorporation into developing vessels. We tested the hypothesis that cell-free administration of paracrine factors secreted by cultured EPC may achieve an angiogenic effect equivalent to cell therapy. EPC-derived conditioned medium (EPC-CM) was obtained from culture expanded EPC subjected to 72 hours of hypoxia. In vitro, EPC-CM significantly inhibited apoptosis of mature endothelial cells and promoted angiogenesis in a rat aortic ring assay. The therapeutic potential of EPC-CM as compared to EPC transplantation was evaluated in a rat model of chronic hindlimb ischemia. Serial intramuscular injections of EPC-CM and EPC both significantly increased hindlimb blood flow assessed by laser Doppler (81.2+/-2.9% and 83.7+/-3.0% vs. 53.5+/-2.4% of normal, P<0.01) and improved muscle performance. A significantly increased capillary density (1.62+/-0.03 and 1.68+/-0.05/muscle fiber, P<0.05), enhanced vascular maturation (8.6+/-0.3 and 8.1+/-0.4/HPF, P<0.05) and muscle viability corroborated the findings of improved hindlimb perfusion and muscle function. Furthermore, EPC-CM transplantation stimulated the mobilization of bone marrow (BM)-derived EPC compared to control (678.7+/-44.1 vs. 340.0+/-29.1 CD34(+)/CD45(-) cells/1x10(5) mononuclear cells, P<0.05) and their recruitment to the ischemic muscles (5.9+/-0.7 vs. 2.6+/-0.4 CD34(+) cells/HPF, P<0.001) 3 days after the last injection. Intramuscular injection of EPC-CM is as effective as cell transplantation for promoting tissue revascularization and functional recovery. Owing to the technical and practical limitations of cell therapy, cell free conditioned media may represent a potent alternative for therapeutic angiogenesis in ischemic cardiovascular diseases.

Arteriovenous malformations (AVMs) are characterized by pathological high flow, low resistance connections between arteries and veins. Treatment is critically dependent on correct interpretation of angioarchitectural features. However, some microfistular AVMs do not match the characteristics described in current AVM classification systems. Therefore, we propose a new subgroup of microfistular AVMs, composed of enlarged, fistulous paths on the venous half of capillaries and/or dilated draining venules (hyperdynamic, capillary-venulous malformation [CV-AVM]). CV-AVMs still ensure arterial flow to the periphery and fistulous venous drainage is less pronounced than in classical AVMs such that these lesions are often misinterpreted as venous malformations. We developed a computational model to study the effects of microvascular anomalies on local hemodynamics, as well as their impact on angiographic contrast propagation. Flow rates and pressures were computed with a lumped parameter description, while contrast propagation was determined by solving the 1D advection-diffusion equation. For the newly proposed CV-AVM angioarchitecture, the computational model predicts increased arterio-venous contrast agent transit times and highly dispersive transport characteristics, compared to microfistular, interstitial type IV AVMs and high flow type II and III AVMs. We related these findings to time-contrast intensity curves sampled from clinical angiographies and found that there is strong evidence for the existence of CV-AVM.

To facilitate precise local ablation of hepatocellular carcinoma (HCC) in a setting of combined ablation and transarterial chemoembolization (TACE), we evaluated accuracy and efficiency of a novel technique for navigated positioning of ablation probes using intrahepatic tumor referencing and electromagnetic (EM) guidance, in a porcine model. An angiographic wire with integrated EM reference sensor at its tip was inserted via a transarterial femoral access and positioned in the vicinity of artificial liver tumors. The resulting offset distance between the tumor center and the intrahepatic endovascular EM reference was calculated. Subsequently, EM tracked ablation probes were inserted percutaneously and navigated toward the tumor center, relying on continuous EM guidance via the intrahepatic reference. Targeting accuracy was assessed as the Euclidean distance between the tip of the ablation probe and the tumor center (Target Positioning Error, TPE). Procedural efficiency was assessed as time efforts for tumor referencing and tumor targeting. In 6 animals, 124 targeting measurements were performed with an offset distance < 30 mm (clinically most feasible position), resulting in a mean TPE of 2.9 ± 1.6 mm. No significant correlation between the TPE and different intrahepatic offset distances (range 21 to 61 mm, n = 365) was shown as long as the EM reference was placed within the liver. However, the mean TPE increased when placing the EM reference externally on the animal skin (p < 0.01). TPE was similar when targeting under continuous ventilation or in apnea (p = 0.50). Mean time for tumor referencing and navigated targeting was 6.5 ± 3.8 minutes and 14 ± 8 seconds, respectively. The proposed technique allows precise and efficient navigated positioning of ablation probes into liver tumors in the animal model. We introduce a simple approach suitable for combined ablation and TACE of HCC in a single treatment session.

Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction–defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

Neutrophil extracellular traps (NETs) are web-like structures of decondensed extracellular chromatin fibers and neutrophil granule proteins released by neutrophils. NETs participate in host immune defense by entrapping pathogens. They are pro-inflammatory in function, and they act as an initiator of vascular coagulopathies by providing a platform for the attachment of various coagulatory proteins. NETs are diverse in their ability to alter physiological and pathological processes including infection and inflammation. In this review, we will summarize recent findings on the role of NETs in bacterial/viral infections associated with vascular inflammation, thrombosis, atherosclerosis and autoimmune disorders. Understanding the complex role of NETs in bridging infection and chronic inflammation as well as discussing important questions related to their contribution to pathologies outlined above may pave the way for future research on therapeutic targeting of NETs applicable to specific infections and inflammatory disorders.

Background Angioplasty and stenting have emerged as endovascular treatment options for arteriogenic erectile dysfunction over the past few years. Considerable anatomical variation of the erection related pelvic arteries can be challenging during these procedures, leading to time-consuming repetitive super-selective angiograms for navigation. Technique We report a novel technique of using C-arm Cone-Beam CT and vessel navigation software to facilitate super-selective catheterization. Conclusion Cone-Beam CT-guided navigation for vascular assessment of arteriogenic ED is an optional approach compared to exclusive angiographic assessment. Compared to CT angiography, C-arm Cone-Beam CT offers benefits regarding usage of contrast media and radiation exposure. It has the advantage to combine imaging with endovascular procedures in a single session, reduces time to target navigation in complex pelvic arteries anatomy and may increase therapy safety in endovascular treatment of ED.

Mutations in the CYP2C19 gene can affect the conversion of clopidogrel to its active metabolite, leading to varying degrees of platelet inhibition. Based on prior studies evaluating CYP2C19 gene polymorphisms in patients with acute coronary syndrome, we hypothesized that patients with peripheral artery disease (PAD) carrying loss of function (LoF) alleles could experience heightened rates of major adverse cardiac events and those carrying gain of function (GoF) alleles could experience increased rates of major bleeding compared with non-carriers.1-4 EUCLID (NCT01732822) was a double-blind, multicenter, randomized active-comparator trial of 13,885 patients with symptomatic PAD randomly assigned to receive ticagrelor (90 mg twice daily) or clopidogrel (75 mg daily). Eligible patients had to be ≥50 years of age and have symptomatic PAD defined as previous lower extremity revascularization >30 days before randomization or an ankle-brachial index (ABI) of ≤0.80.5

Arteria lusoria is a rare vascular aberration; its presence is frequently associated with dysphagia or dyspnea due to esophageal or bronchial compression. We present a case of a stenotic arteria lusoria causing upper extremities blood pressure difference, claudication, and Raynaud’s syndrome of the right hand. The patient opted against endovascular recanalization and was treated conservatively. This case demonstrates a rare cause of upper extremity blood pressure difference that must be considered as differential diagnosis. Furthermore, the knowledge of arteria lusoria is pivotal for successful transbrachial coronary or peripheral endovascular interventions.

Peripheral artery disease (PAD) is a major cause of cardiovascular ischemic events and amputation. Knowledge gaps exist in defining and measuring key factors that predict these events. The objective of this study was to assess whether duration of limb ischemia would serve as a major predictor of limb and patient survival. The FReedom from Ischemic Events: New Dimensions for Survival (FRIENDS) registry enrolled consecutive patients with limb-threatening peripheral artery disease at a single tertiary care hospital. Demographic information, key clinical care time segments, functional status and use of revascularization, and pharmacotherapy data were collected at baseline, and vascular ischemic events, cardiovascular mortality, and all-cause mortality were recorded at 30 days and 1 year. A total of 200 patients with median (interquartile range) age of 76 years (65-84 years) were enrolled in the registry. Median duration of limb ischemia was 0.75 days for acute limb ischemia (ALI) and 61 days for chronic critical limb ischemia (CLI). Duration of limb ischemia of <12, 12 to 24, and >24 hours in patients with ALI was associated with much higher rates of first amputation (P = .0002) and worse amputation-free survival (P = .037). No such associations were observed in patients with CLI. For individuals with ischemic symptoms <14 days, prolonged limb ischemia is associated with higher 30-day and 1-year amputation, systemic ischemic event rates, and worse amputation-free survival. No such associations are evident for individuals with chronic CLI. These data imply that prompt diagnosis and revascularization might improve outcomes for patients with ALI.