How German vascular surgeons and angiologists judge walking exercise for patients with PAD.

Background: To determine the physician's perspective and perception on walking exercise as well as barriers in guideline-directed best medical treatment of patients with lower extremity peripheral arterial disease (PAD). Patients and methods: All members of the German Society for Vascular Surgery and Vascular Medicine and of the German Society for Angiology - Society for Vascular Medicine with valid email address were invited to participate in an electronic survey on walking exercise for treatment of intermittent claudication that was developed by the authors. Results: Amongst 3910 invited participants, 743 (19%) provided valid responses (33% females, 84% vascular surgery, 15% angiology). Thereof, 65% were employed by non-university hospitals, 16% by university institutions, and 18% by outpatient facilities. A mean of 14 minutes were spent per patient to counsel and educate, while only 53% responded they had enough time in everyday clinical practice. While 98% were aware of the beneficial impact of structured exercise training (SET) on pain free walking distance and 90% advise their patients to adhere to SET, only 44% provided useful guidance to patients to find local SET programmes and merely 42% knew how to prescribe SET as service that can be reimbursed by medical insurances. Approximately 35% knew a local SET programme and appropriate contact person. Health-related quality of life was assessed in a structured way by only 11%. Forty-seven percent responded that medical insurances should be responsible to implement and maintain SET programmes, while only 4% held hospital physicians responsible to achieve this task. Conclusions: This nationwide survey study amongst vascular specialists illustrates the current insufficient utilisation of SET as an evidence-based therapeutic cornerstone in patients with lower extremity PAD in Germany. The study also identified several barriers and flaws from the physician's perspectives which should be addressed collectively by all health care providers aiming to increase the SET use and eventually its' impact on patients with PAD.

Analysis of endovascular therapy for peripheral arterial disease in all German hospitals.

Background: The quality of vascular care has significantly improved in part by the expansion of endovascular techniques for the treatment of symptomatic peripheral artery disease (PAD) in recent years. In Germany these are primarily provided by the three disciplines of vascular surgery, angiology, and interventional radiology (IR). However, the relative contribute of angiologists to the total number of cases performed is unknown. Patients and methods: In the present study, we analysed the respective contribution of vascular surgery, angiology, and IR to the delivery of endovascular revascularisations in symptomatic PAD in Germany based on the legally mandatory quality reports representative for the reporting year 2018. Results: Vascular surgery is the most common speciality reporting procedures in German hospitals (n=579; 25.1%), followed by IR (n=264; 11.5%), angiology (n=189; 8.2%) and cardiology (n=17; 0.7%). The combination of vascular surgery and IR was reported in 202 (8.8%), vascular surgery and angiology in 167 (7.2%) and angiology and IR in 65 (2.8%) hospitals, and 63 (2.7%) hospitals reported the combination of all three disciplines. Not every department performed catheter interventions. The analysis of procedures per centre revealed that angiology centres provided the highest numbers for both basic procedures and more complex techniques such as atherectomy, rotational thrombectomy, lithoplasty, selective thrombolysis or the use of re-entry devices. In total, angiology centres provided 24.4% of the total procedures or 23.9% of the so-called basic procedures as a surrogate for patient numbers. Conclusions: While each of the disciplines contribute significantly to the endovascular procedures, angiology centres perform more procedures per centre and more complex procedures than the other disciplines highlighting the important quantitative and qualitative contribution of angiology specialists to the care of vascular patients. The inpatient catheter interventional care of patients with PAD is still too rarely carried out in a multi-disciplinary manner in Germany.

Endovascular interventions in outpatient care.

Endovascular arterial revascularisations for the treatment of symptomatic peripheral arterial disease are constantly increasing in importance and number due to the changing age structure and high numbers of comorbidities in the German population. Patients with peripheral artery disease are often at increased risk for peri- and post-procedural complications including severe cardiovascular events. Due to limited financial and human resources and considerable risks of hospitalization, endovascular interventions that were previously reserved for hospitalized patients are now progressively considered to be performed as day case procedures. More than one third of these procedures are performed in Germany by internists with a specialization in angiology. In the current position paper the German Society of Angiology endorsed by the European Society of Vascular Medicine, summarizes the requirements and risk factors to be considered for the planning, safe performance and post procedural care of endovascular revascularizations in outpatients. The performance of endovascular procedures for peripheral artery disease both in hospitalised and outpatients should be accompanied by a mandatory quality assurance process that should not only capture procedural data, but also require documentation of complications and longterm outcome.

Photoablative atherectomy followed by a paclitaxel-coated balloon to inhibit restenosis in instent femoro-popliteal obstructions (PHOTOPAC).

Background: To evaluate the safety and effectiveness of preparing instent femoropopliteal lesion with photoablative laser atherectomy or plain balloon angioplasty (POBA) prior to drug-coated balloon (DCB) angioplasty. Patients and methods: The prospective, multicenter, randomized study enrolled patients with Rutherford-Becker-class (RBC) 1 to 5 and instent lesions located in superficial femoral artery and/or popliteal artery above the knee joint. Primary endpoint was target lesion percent stenosis at 1 year as determined by the angiographic core-laboratory. Secondary endpoints included procedural success, major adverse event rate, clinical improvement and improvement in ankle-brachial index (ABI), clinically-driven target lesion revascularization (CD-TLR), and primary patency rate at until 2-year follow-up. Results: The study was terminated prior to the enrollment goal due to slow enrollment. Thirty patients were included in the laser plus DCB cohort and 31 patients in the control cohort. Primary endpoint was not significantly different (p=0.331). Procedural success was 83.3% and 87.1% for the laser plus DCB and the control cohort, respectively. Serious adverse events at 30 days and 1-year were not statistically different between the two cohorts. For the ABI, significant improvements were present at discharge as well as at the follow-up visits. This was also evident for the RBC at the follow-up visits. One- and two-year freedom from CD-TLR was 86.7% vs. 87.1%, and 63.6% vs. 72%, respectively. Duplex derived primary patency was 90% at 6-months, 65.5% at one year and 56.5% at two year for the laser cohort and 90.3%, 75.9% and 53.8% for the control cohort. Conclusions: Safety of instent photoablative laser atherectomy followed by DCB angioplasty is confirmed by this study. Due to the small sample size, no benefit over POBA as vessel preparation could be shown.

Demographic and procedural characteristics in the RECording COurses of vasculaR Diseases (RECCORD) registry - the first 1000 patients.

Background: The RECcording COurses of vasculaR Diseases (RECCORD) registry established by the German Society of Angiology - Society for Vascular Medicine aimed to address the lack in contemporary real-world data regarding current practice of medical and interventional care in vascular patients. We herein report the demographic and procedural characteristics of the first 1000 patients undergoing endovascular revascularization (EVR) for symptomatic peripheral artery disease (PAD). Patients and methods: RECCORD is an observational, prospective, multicenter, all-comers registry. Only patients undergoing EVR for symptomatic PAD are included and followed up for at least 1 year. Demographic characteristics, comorbidities, previous peripheral vascular interventions, medication, clinical stage of lower extremity artery disease (Rutherford category), hemodynamic parameters, and procedural data including complications are recorded via an entirely web-based platform. Results: Of the first 1000 patients (mean age 70 ± 10 years, 35% female) with 1096 EVR at 1477 vascular segments of the lower extremities, 25.0% were at the stage of chronic limb threatening ischemia (CLTI) and 75.0% at non-CLTI. The femoropopliteal segment was the dominant target lesion site (61.0%), followed by iliac (26.4%) and below-the-knee EVR (10.3%). Only angioplasty was performed in 130 EVR (11.9%), adjunctive drug coated balloons (DCB) in 498 (45.4%), additional stenting in 633 (57.8%). Debulking devices were used in 106 (9.7%) EVR. Clinical (Rutherford categories) and hemodynamic parameters (ankle-brachial-index) as well as secondary preventive medication were significantly improved post EVR. Periprocedural complications occurred in 63 (5.7%) EVR with pseudoaneurysm as the leading complication type in 26 (2.4%) EVR. Conclusions: The baseline data of the first 1000 patients from the RECCORD registry representing the real-world setting illustrate that the majority of EVR are performed in patients with claudication. Adjunctive use of DCB and stenting are the dominant types of EVR, while periprocedural complications are at an acceptable low rate.

Stellarex drug-coated balloon for treatment of femoropopliteal arterial disease-The ILLUMENATE Global Study: 12-Month results from a prospective, multicenter, single-arm study.

OBJECTIVES: The purpose of this study was to assess the safety and performance of Stellarex Drug-coated balloon (DCB). BACKGROUND: DCB coatings differ in excipients, paclitaxel dose, and coating morphologies. Due to these differences, a class effect with DCBs has not been demonstrated. Consequently, each DCB needs to be evaluated independently based on its own clinical study results. METHODS: The ILLUMENATE Global Study is a prospective, multicenter, single-arm study. Patients with intermittent claudication or ischemic rest pain due to superficial femoral artery (SFA) and/or popliteal peripheral artery disease (PAD) were treated with the Stellarex DCB. The primary efficacy endpoint was primary patency, defined as freedom from restenosis with peak systolic velocity ratio ≤2.5 or clinically-driven target lesion revascularization (CD-TLR) at 12 months. The primary safety endpoint was freedom from device and procedure-related death through 30 days postprocedure and freedom from target limb major amputation and CD-TLR through 12 months. RESULTS: In total, 417 lesions were treated in 371 patients. The mean lesion length was 7.5 ± 5.3 cm, 40.8% of lesions were severely calcified per core laboratory fluoroscopy criteria and 31.3% were total occlusions. Primary patency by independent duplex core lab evaluation was 81.4% and the freedom from CD-TLR was 94.8% day 365 per Kaplan-Meier estimate. The majority of patients experienced improvements in their Rutherford classification (90.3%) and walking impairment questionnaire score (83.6%) at 12 months compared to baseline. CONCLUSIONS: This study validated previous positive findings and confirms the strong safety profile and effectiveness outcomes.

Rationale and design of the RECording COurses of vasculaR Diseases registry (RECCORD registry).

BACKGROUND: The prevalence of peripheral artery disease (PAD) is increasing worldwide. Revascularization procedures constitute a cornerstone of the therapy in PAD, not only in critical limb ischaemia but increasingly also in patients with intermittent claudication. The German Society of Angiology - Society for Vascular Medicine is establishing a nationwide, prospective, multicentre registry to address the lack of contemporary real life data regarding current practice of medical and interventional care in vascular patients and its subsequent long-term outcome. PATIENTS AND METHODS: The RECording COurses of vasculaR Diseases registry (RECCORD registry) is an observational, prospective, multicentre, all-comers registry platform. In the initial phase, patients referred for endovascular revascularization of PAD of the lower limbs will be prospectively included and followed up for at least one year. At baseline, data on patients' demographic characteristics, comorbidities, previous peripheral interventions, medication, and clinical stage of PAD (Rutherford category), haemodynamic parameters, and procedural data including complications will be assessed. Major adverse cardiac and limb events will be recorded at planned (at six and 12 months) and at any unplanned visits. The therapeutic management will be exclusively left to the discretion of the vascular specialists. RESULTS AND CONCLUSIONS: The RECCORD registry will provide a comprehensive dataset depicting the current real life practice and outcome of vascular care. The seven predefined quality indicators will be used for benchmarking the participating centres. Moreover, identifying factors promoting a favourable outcome might pave the way for an evidence-based therapeutic strategy and a dedicated therapeutic pathway for patients with PAD including patient-oriented best interventional approaches. In the future, the RECCORD registry may provide a general platform to study the courses of various defined vascular diseases in order to get detailed insights into the real life current practice of health care provided to vascular patients.

Differential impact of diabetes mellitus type II and arterial hypertension on collateral artery growth and concomitant macrophage accumulation.

BACKGROUND: Diabetes mellitus type II and arterial hypertension are major risk factors for peripheral arterial disease and have been considered to reduce collateral growth (arteriogenesis). Collateral growth proceeds through different stages. Vascular proliferation and macrophage accumulation are hallmarks of early collateral growth. MATERIAL AND METHODS: We here compare the impact of arterial hypertension and diabetes mellitus type II on collateral proliferation (Brdu incorporation) and macrophage accumulation (ED 2 staining) as well as collateral vessel function (collateral conductance) in a rat model of peripheral vascular disease (femoral artery occlusion), diabetes mellitus type II (Zucker fatty diabetic rats and Zucker lean rat controls) and arterial hypertension (induced via clip placement around the right renal arteriy). We furthermore tested the impact of monocyte chemoattractant protein-1 (MCP­1) on collateral proliferation and macrophage accumulation in these models RESULTS: Diabetic animals showed reduced vascular proliferation and macrophage accumulation, which however did not translate into a change of collateral conductance. Hypertensive animals on the contrary had reduced collateral conductances without altered macrophage accumulation and only a marginal reduction in collateral proliferation. Infusion of MCP­1 only enhanced vascular proliferation in diabetic animals. CONCLUSIONS: These findings illustrate that impaired monocyte/macrophage recruitment is responsible for reduced collateral growth under diabetic conditions but not in arterial hypertension suggesting that diabetes mellitus in particular affects early stages of collateral growth whereas hypertension has its impact on later remodeling stages. Successful pro-arteriogenic treatment strategies in a patient population that presents with diabetes mellitus and arterial hypertension need to address different stages of collateral growth and thus different molecular and cellular targets simultaneously.

The analysis of microRNA expression profiling for coronary artery disease.

OBJECTIVES: To investigate the underlying molecular mechanisms of coronary artery disease (CAD) using microarray expression profiles. METHODS: The microRNA (miRNA) expression-profiling dataset GSE28858 was obtained from the Gene Expression Omnibus database, including 24 samples from 12 patients with CAD and 12 age- and sex-matched healthy controls. Differentially expressed miRNAs were identified with false discovery rate (FDR) = 1% by the SAM (Significant Analysis of Microarray) algorithm. The target genes of selected differentials expressed miRNAs that were not only related to CAD, but were also in two databases (TargetScan, miRanda). Then, the interactive objects of selected target genes were predicted using the STRING database to construct an interaction network (confidence score = 0.4). These target genes and interactive objects were put into the KEGG (Kyoto Encyclopedia of Genes and Genomes) database, and the significant signaling pathway was obtained by hypergeometric function enrichment analysis (p < 0.05). RESULTS: MiRNA-526b was the only differentially expressed miRNA that was upregulated in patients with CAD (FDR = 1%). Toll-like receptor 4 (TLR4) was the target gene of miRNA-526b that occurred with the highest frequency. The objects that interacted with TLR4 were predicted using the STRING database and the interaction network was obtained. The vascular endothelial growth factor (VEGF) signaling pathway was the only selected significant pathway related with CAD in the interaction network (p < 0.05). CONCLUSION: The miRNA-526b is significantly upregulated in patients with CAD and the target gene of miRNA-526b participates in the VEGF signaling pathway. Whether or not the miRNA-526b can be used as a biomarker remains to be elucidated in a larger prospective study.

[Interventional therapy of pulmonary embolism - update]. / Interventionelle Therapie der Lungenembolie ­ aktueller Stand.

Several catheter-based systems have been developed for interventional recanalization of pulmonary embolism. These include local ultrasound assisted thrombolysis (EKOS), in-toto-thrombectomy via retriever and aspiration system (FlowTriever) and the Indigo mechanical aspiration system. Safety and efficacy in the removal of thrombus have been demonstrated for all systems. Interventional recanalization strategies for high- and intermediate-high risk pulmonary embolism are potentially more effective in the removal of thrombus and restoration of right heart function than systemic thrombolysis with a lower risk of major bleeding complications. Preliminary data from registries and observational studies are very promising whereas the evidence for systemic thrombolysis treatment in high and intermediate-high risk pulmonary embolism is low. Randomized controlled clinical trials are currently performed comparing catheter based interventional therapies to systemic thrombolysis for the treatment of intermediate-high risk pulmonary embolisms. Primary outcome measurements include mortality, hemodynamic collapse, and major bleedings. Results are expected in 2025. The introduction of interventional therapies for pulmonary embolism was accompanied by an increased awareness of the complexity of pulmonary embolism management. The need for specialized interdisciplinary pulmonary embolism response teams (PERT-teams) and a well-structured approach including a PDCA cycle was recognized.

Acceleration of collateral development by carcinoembryonic antigen-related cell adhesion molecule 1 expression on CD11b/⁺Gr-1⁺ myeloid cells--brief report.

OBJECTIVE: Previously, we demonstrated the relevance for endothelial carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression in collateral formation. However, a proarteriogenic role for CEACAM1(+) myeloid cells is unknown. Here, we investigated the contribution of CEACAM1(+) myeloid cells on collateral formation. METHODS AND RESULTS: Collateral growth and vascular remodeling were analyzed in CEACAM1-competent and CEACAM1 null mice after femoral artery ligation in hindlimb ischemia. Reperfusion of the adductor muscles was evaluated by Laser Doppler measurements and microcomputed tomography imaging. In CEACAM1 null mice, poor reperfusion and reduced collateral formation were observed, accompanied by reduction in arterial diameters. Using flow cytometry, we identified an increase of the muscle-resident CD11b(+)/granulocyte receptor-1+ (Gr-1+) population in CEACAM1 null mice only, pointing toward a CEACAM1-dependent functional deviation. Direct and reciprocal bone marrow transplantations between CEACAM1-competent and CEACAM1 null mice, and antibody-mediated depletion of the CD11b(+)/Gr-1(+) population, confirmed the requirement of CEACAM1 expression on the CD11b(+)/Gr-1(+) population for reestablishment of perfusion after arterial occlusion. CONCLUSIONS: CEACAM1 expression on CD11b(+)/Gr-1(+) myeloid cells is a prerequisite for adequate collateral formation.

Transgenic over-expression of interleukin-33 in osteoblasts results in decreased osteoclastogenesis.

Interleukin-33 (IL-33) is the most recently identified member of the IL-1 family of cytokines, which is primarily known for its proinflammatory functions. We have previously reported that IL-33 is expressed by bone-forming osteoblasts, and that administration of recombinant IL-33 to bone marrow cultures inhibits their differentiation into bone-resorbing osteoclasts. Likewise, while the inhibitory effect of IL-33 on osteoclast differentiation was fully abolished in cultures lacking the IL-33 receptor ST2, mice lacking ST2 displayed low bone mass caused by increased osteoclastogenesis. Although these data suggested a physiological role of IL-33 as an inhibitor of bone resorption, direct in vivo evidence supporting such a function was still missing. Here we describe the generation and bone histomorphometric analysis of a transgenic mouse model (Col1a1-Il33) over-expressing IL-33 specifically in osteoblasts. While we did not observe differences in osteoblast number and bone formation between wildtype and Col1a1-Il33 mice, the number of osteoclasts was significantly reduced compared to wildtype littermates in two independent transgenic lines. Since we did not observe quantitative differences in the populations of eosinophils, neutrophils, basophils or M2-macrophages from the bone marrow of wildtype and Col1a1-Il33 mice, our data demonstrate that an inhibition of osteoclastogenesis is one of the major physiological functions of IL-33, at least in mice.

CEACAM1+ myeloid cells control angiogenesis in inflammation.

Local inflammation during cutaneous leishmaniasis is accompanied by accumulation of CD11b(+) cells at the site of the infection. A functional role for these monocytic cells in local angiogenesis in leishmaniasis has not been described so far. Here, we show that CD11b(+) cells express high levels of the myeloid differentiation antigen carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). In experimental cutaneous leishmaniasis in C57BL/6 wild-type (B6.WT) and B6.Ceacam1(-/-) mice, we found that only B6.Ceacam1(-/-) mice develop edemas and exhibit impairment of both hemangiogenesis and lymphangiogenesis. Because CEACAM1 expression correlates with functional angiogenesis, we further analyzed the role of the CD11b(+) population. In B6.Ceacam1(-/-) mice, we found systemic reduction of Ly-6C(high)/CD11b(high) monocyte precursors. To investigate whether CEACAM1(+) myeloid cells are causally related to efficient angiogenesis, we used reverse bone marrow transplants (BMTs) to restore CEACAM1(+) or CEACAM1(-) bone marrow in B6.Ceacam1(-/-) or B6.WT recipients, respectively. We found that angiogenesis was restored by CEACAM1(+) BMT only. In addition, we observed reduced morphogenic potential of inflammatory cells in Matrigel implants in CEACAM1(-) backgrounds or after systemic depletion of CD11b(high) macrophages. Taken together, we show for the first time that CEACAM1(+) myeloid cells are crucial for angiogenesis in inflammation.

Vimentin expression influences flow dependent VASP phosphorylation and regulates cell migration and proliferation.

The cytoskeleton plays a central role for the integration of biochemical and biomechanical signals across the cell required for complex cellular functions. Recent studies indicate that the intermediate filament vimentin is necessary for endothelial cell morphogenesis e.g. in the context of leukocyte transmigration. Here, we present evidence, that the scaffold provided by vimentin is essential for VASP localization and PKG mediated VASP phosphorylation and thus controls endothelial cell migration and proliferation. Vimentin suppression using siRNA technique significantly decreased migration velocity by 50% (videomicroscopy), diminished transmigration activity by 42.5% (Boyden chamber) and reduced proliferation by 43% (BrdU-incorporation). In confocal microscopy Vimentin colocalized with VASP and PKG in endothelial cells. Vimentin suppression was accompanied with a translocation of VASP from focal contacts to the perinuclear region. VASP/Vimentin and PKG/Vimentin colocalization appeared to be essential for proper PKG mediated VASP phosphorylation because we detected a diminished expression of PKG and p(Ser239)-VASP in vimentin-suppressed cells, Furthermore, the induction of VASP phosphorylation in perfused arteries was markedly decreased in vimentin knockout mice compared to wildtypes. A link is proposed between vimentin, VASP phosphorylation and actin dynamics that delivers an explanation for the important role of vimentin in controlling endothelial cell morphogenesis.

Carcinoembryonic antigen-related cell adhesion molecule 1 modulates vascular remodeling in vitro and in vivo.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cellular adhesion molecule of the Ig superfamily, is associated with early stages of angiogenesis. In vitro, CEACAM1 regulates proliferation, migration, and differentiation of murine endothelial cells. To prove that CEACAM1 is functionally involved in the regulation of vascular remodeling in vivo, we analyzed 2 different genetic models: in Ceacam1-/- mice, the Ceacam1 gene was deleted systemically, and in CEACAM1(endo+) mice, CEACAM1 was overexpressed under the control of the endothelial cell-specific promoter of the Tie2 receptor tyrosine kinase. In Matrigel plug assays, Ceacam1-/- mice failed to establish new capillaries whereas in CEACAM1(endo+) mice the implants were vascularized extensively. After induction of hind limb ischemia by femoral artery ligation, Ceacam1-/- mice showed significantly reduced growth of arterioles and collateral blood flow compared with their WT littermates. In agreement with a causal role of CEACAM1 in vascular remodeling, CEACAM1(endo+) mice exhibited an increase in revascularization and collateral blood flow after arterial occlusion. Our findings indicate that CEACAM1 expression is important for the establishment of newly formed vessels in vivo. Hence CEACAM1 could be a future target for therapeutic manipulation of angiogenesis in disease.

Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase.

BACKGROUND: Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase (MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide (NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function. METHODS AND RESULTS: Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease (CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD (P=0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation (P<0.01) and by acetylcholine-induced changes in forearm blood flow (P<0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function (r=0.69, P<0.01). Moreover, and consistent with this tenet, ex vivo heparin treatment of extracellular matrix proteins, cultured endothelial cells, and saphenous vein graft specimens from CAD patients decreased MPO burden. CONCLUSIONS: Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.

Self-Expanding Versus Balloon-Expandable Stents for Iliac Artery Occlusive Disease: The Randomized ICE Trial.

OBJECTIVES: Atherosclerosis of iliac arteries is widespread. As inflow vessels, they are of great clinical significance and increasingly being treated by endovascular means. Most commonly, stents are implanted. BACKGROUND: So far, due to a lack of comparative data, no guideline recommendations on the preferable stent type, balloon-expandable stent (BE) or self-expanding stent (SE), have been issued. METHODS: In this randomized, multicenter study, patients with moderate to severe claudication from common or external iliac artery occlusive disease were assigned 1:1 to either BE or SE. The primary endpoint was binary restenosis at 12 months as determined by duplex ultrasound. Key secondary endpoints were walking impairment, freedom from target lesion revascularization (TLR), hemodynamic success, target limb amputation, and all-cause death. RESULTS: Six hundred sixty patients with 660 lesions were enrolled at 18 German and Swiss sites over a period of 34 months; 24.8% of the patients had diabetes and 57.4% were current smokers. The common iliac artery was affected in 58.9%. One hundred nine (16.5%) lesions were totally occluded and 25.6% heavily calcified. Twelve-month incidence of restenosis was 6.1% after SE implantation and 14.9% after BE implantation (p = 0.006). Kaplan-Meier estimate of freedom from TLR was 97.2% and 93.6%, respectively (p = 0.042). There was no between-group difference in walking impairment, hemodynamic success, amputation rate, all-cause death, or periprocedural complications. CONCLUSIONS: The treatment of iliac artery occlusive disease with SE as compared with BE resulted in a lower 12-month restenosis rate and a significantly reduced TLR rate. No safety concerns arose in both groups. (Iliac, Common and External [ICE] Artery Stent Trial; NCT01305174).

Tissue resident cells play a dominant role in arteriogenesis and concomitant macrophage accumulation.

Collateral growth is characterized by macrophage accumulation, suggesting an important role of circulating cells. To study origin and function of macrophages during arteriogenesis, we related the extent of macrophage accumulation to vascular proliferation and investigated the fate of fluorescently (CMFDA) labeled blood cells that were injected at the time of femoral artery occlusion. The effect of bone marrow depletion via cyclophosphamide before femoral artery occlusion on collateral proliferation and macrophage accumulation was studied, and we looked for the presence of bone marrow-derived stem cells in the vicinity of growing collateral vessels. Finally, we investigated the arteriogenic effect of macrophage activation via MCP-1 in bone marrow-depleted animals. Maximal macrophage accumulation occurred during the first 3 days after femoral artery occlusion and paralleled the extent of vascular proliferation. Fluorescently labeled leukocytes homed to spleen and wound but they were absent in proliferating collateral arteries during maximal macrophage accumulation. Depletion of circulating cells did neither affect macrophage accumulation nor collateral growth. Staining of monocyte-depleted animals for BrdUrd and ED2, alphaSMA, or VE-Cadherin demonstrated local proliferation of macrophages and vascular cells, whereas C-Kit, SSEA1, or Thy1-positive bone marrow-derived stem cells were not detectable. Enhancement of macrophage accumulation via MCP-1 was independent of circulating monocytes and promoted arteriogenesis in the absence of direct effects on vascular cells. We propose that the initial phase of vascular growth is characterized by local proliferation of tissue resident precursors rather than by migration of blood born cells. The full text of this article is available online at http://circres.ahajournals.org.