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Summary: Standard nitinol stents (SNS), with or without drug eluting technology, are an essential tool within the interventional armamentarium in the treatment of patients with peripheral arterial disease. However, they are plagued by a number of limitations: a.) stent fractures, although observed predominately in first-generation stents, do still occur in state-of-the art stent platforms, b.) lack of radial strength, resulting in inadequate stent expansion, c.) kinking up to a complete collapse of the stent, therefore compromising its use in areas of high mechanical stress such as bending zones. In contrast, the interwoven design of the SuperaTM stent, also referred to as “vascular mimetic implant”, overcomes all of the above limitations of SNS. Several registries and studies not only confirmed its mechanical superiority (lack of stent fractures etc.) but also demonstrated remarkable clinical performance (patency and freedom from target lesion revascularization), despite its use in challenging lesions (calcification etc.) and territories (popliteal arteries etc.). Increasing confidence in the mechanical properties of the SuperaTM stent platform prompted interventionalists to further “push the limits” of this unique implant. The present article summarizes the clinical data and shows examples of “extreme” applications of this dedicated stent platform.

We report on retrograde retrieval of the soft end of dislodged guidewires during complex interventions. Interventionalists may consider this as an option for the endovascular management of this complication if an antegrade retrieval is not possible or fails.

Background Paclitaxel drug-coated balloon (DCB) catheter angioplasty is the preferred treatment for revascularization of femoropopliteal lesions in peripheral artery disease, but mortality is a safety concern. Purpose To assess 2-year efficacy and safety of DCB angioplasty compared with conventional balloon angioplasty (also known as plain old balloon angioplasty or POBA). Materials and Methods This prospective, multicenter, randomized controlled trial enrolled consecutive participants with symptomatic superficial femoral and/or popliteal artery disease at 11 German centers between September 2015 and December 2016. Participants underwent DCB angioplasty or conventional balloon angioplasty. Primary outcome of 6-month late lumen loss showed superiority of DCB angioplasty over conventional balloon angioplasty. Evaluation at 2 years included secondary outcomes of primary patency and target lesion revascularization (TLR) estimated with Kaplan-Meier analysis, clinical and hemodynamic improvement, quality of life, target limb amputation, and all-cause mortality. Results A total of 171 participants (mean age, 69 years ± 8; 111 men) were evaluated. At 2 years, primary patency was achieved in 90.2% (95% confidence interval [CI]: 80.4%, 95.2%) of DCB angioplasty and 62.7% (95% CI: 50.0%, 73.0%) of conventional balloon angioplasty participants (

Aims In peripheral artery disease (PAD), endovascular treatment success of heavily calcified lesions is often compromised by a number of vascular complications, such as recoils, dissections and need for target vessel re-interventions. The increasing use of scoring balloon techniques has raised the hope for better periprocedural outcomes; however, the knowledge regarding the actual benefits of the scoring balloon technique in comparison to standard therapy is still limited. Thus, the aim of the current study was to determine the safety and effectiveness of scoring balloon angioplasty in a real-life patients’ collective with PAD. Methods and Results A total of 425 patients with moderate to severely calcified femoropopliteal lesions received interventional treatment between 2011 and 2018 at the single center; 230 received a treatment with a scoring balloon (AngioSculpt™), and 195 received a plain procedure without AngioSculpt™. Key questions of this analysis were: (1) whether AngioSculpt™ can be used as a safe and effective stand-alone treatment in heavily calcified lesions in a 24-month follow-up, as well as (2) whether target lesion preparation with scoring balloon bears additional benefits to standard treatment (PTA ± stent implantation). In terms of freedom from target lesion revascularization there were no significant differences between AngioSculpt™ and standard procedure (82.3% vs. 78.1%, P > 0.05). Vessel preparation with balloon angioplasty had no additional effects on survival and amputation rates in comparison to standard treatment without AngioSculpt™ (P > 0.05). The deployment of a scoring balloon did not reduce the subsequent need for additional stent implantations (32.6%, and 32.3%, P > 0.05). Conclusion Lesion preparation with AngioSculpt™ scoring balloon represents a safe and effective tool in the treatment of complex femoropopliteal lesions. In this retrospective analysis, AngioSculpt™ scoring balloon angioplasty did not significantly improve vessel patency- both when used as an adjunctive in preparation for stenting and as stand-alone treatment. A prospective study is needed to further investigate the scoring balloon treatment options. Graphic abstract

OBJECTIVES The goal of this study was to evaluate the 5-year follow-up data of the IN.PACT DEEP (Randomized IN.PACT Amphirion Drug-Coated Balloon [DCB] vs. Standard Percutaneous Transluminal Angioplasty [PTA] for the Treatment of Below-the-Knee Critical Limb Ischemia [CLI]) trial. BACKGROUND Initial studies from randomized controlled trials have shown comparable short-term outcomes of DCB angioplasty versus PTA in patients with CLI with infrapopliteal disease. However, the long-term safety and effectiveness of DCB angioplasty remain unknown in this patient population. METHODS IN.PACT DEEP was an independently adjudicated prospective, multicenter, randomized controlled trial that enrolled 358 subjects with CLI. Subjects were randomized 2:1 to DCB angioplasty or PTA. Assessments through 5 years included freedom from clinically driven target lesion revascularization, amputation, and all-cause death. Additional assessments were conducted to identify risk factors for death and major amputation, including paclitaxel dose tercile. RESULTS Freedom from clinically driven target lesion revascularization through 5 years was 70.9% and 76.0% (log-rank p = 0.406), and the incidence of the safety composite endpoint was 59.8% and 57.5% (log-rank p = 0.309) in the DCB angioplasty and PTA groups, respectively. The rate of major amputation was 15.4% for DCB angioplasty compared with 10.6% for PTA (log-rank p = 0.108). Given the recent concern regarding a late mortality signal in patients treated with paclitaxel-coated devices, additional analyses from this study showed no increase in all-cause mortality with DCB angioplasty (39.4%) compared with PTA (44.9%) (log-rank p = 0.727). Predictors of mortality included age, Rutherford category >4, and previous revascularization but not paclitaxel by dose tercile. CONCLUSIONS Tibial artery revascularization in patients with CLI using DCB angioplasty resulted in comparable long-term safety and effectiveness as PTA. Paclitaxel exposure was not related to increased risk for amputation or all-cause mortality at 5-year follow-up. (Study of IN.PACT Amphirion (R) Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia [INPACT-DEEP]; NCT00941733) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background: Cardiac manifestation of COVID-19 has been reported during the COVID pandemic. The role of cardiac arrhythmias in COVID-19 is insufficiently understood. This study assesses the incidence of cardiac arrhythmias and their prognostic implications in hospitalized COVID-19-patients. Methods: A total of 166 patients from eight centers who were hospitalized for COVID-19 from 03/2020&ndash, 06/2020 were included. Medical records were systematically analyzed for baseline characteristics, biomarkers, cardiac arrhythmias and clinical outcome parameters related to the index hospitalization. Predisposing risk factors for arrhythmias were identified. Furthermore, the influence of arrhythmia on the course of disease and related outcomes was assessed using univariate and multiple regression analyses. Results: Arrhythmias were detected in 20.5% of patients. Atrial fibrillation was the most common arrhythmia. Age and cardiovascular disease were predictors for new-onset arrhythmia. Arrhythmia was associated with a pronounced increase in cardiac biomarkers, prolonged hospitalization, and admission to intensive- or intermediate-care-units, mechanical ventilation and in-hospital mortality. In multiple regression analyses, incident arrhythmia was strongly associated with duration of hospitalization and mechanical ventilation. Cardiovascular disease was associated with increased mortality. Conclusions: Arrhythmia was the most common cardiac event in association with hospitalization for COVID-19. Older age and cardiovascular disease predisposed for arrhythmia during hospitalization. Whereas in-hospital mortality is affected by underlying cardiovascular conditions, arrhythmia during hospitalization for COVID-19 is independently associated with prolonged hospitalization and mechanical ventilation. Thus, incident arrhythmia may indicate a patient subgroup at risk for a severe course of disease.

OBJECTIVE/BACKGROUND Retrograde recanalizations gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well-described adjunct for antegrade recanalizations. We present our experience with retrograde, infrainguinal recanalizations using the Outback re-entry catheter in challenging chronic total occlusions. METHODS We report data from a retrospective multicenter registry in complex retrograde recanalizations. Eligibility criteria included retrograde infrainguinal use of the Outback re-entry catheter where both conventional antegrade and retrograde recanalizations had been unsuccessful. Procedural outcomes included technical success (defined as successful wire passage and delivery of adjunctive therapy with

Abstract. Background: Treatment of calcified femoropopliteal lesions remains challenging, even in the era of drug-eluting balloon angioplasty. Lesion recoil and dissections after standard balloon angioplasty in calcific lesions often require subsequent stent implantation. Additionally, poor patency rates in calcified lesions despite the use of drug-eluting balloons may be due to the limited penetration depth of the antiproliferative drug in the presence of vascular calcium deposits. Therefore, preparation of calcified lesions with the AngioSculpt™ scoring balloon might be a valuable option either as a stand-alone treatment, followed by drug-eluting balloon angioplasty or prior to subsequent stent deployment. Patients and methods: In this retrospective, single centre registry, 124 calcified femoropopliteal lesions were treated in 101 subsequent patients. All patients were treated with scoring balloon angioplasty, either alone, in combination with drug-eluting balloons, or prior to stent deployment. The primary outcome was safety and technical success during the index procedure as well as patency at six and 12 months, as evaluated by duplex sonography. Results: Successful scoring was safely performed in all 124 lesions with the AngioSculpt™ balloon. Overall primary patency after 12 months was 81.2 %. Patency rates did not differ significantly between the three treatment strategies. Degree of calcification did not predict patency. Improved clinical outcomes (Rutherford-Becker class and ankle-brachial index) were also observed in the study cohort. Conclusions: Preparation with the AngioSculpt™ scoring balloon offers a safe and valuable treatment option for calcified femoropopliteal lesions.

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)

Background The indications for conservative “best medical treatment” (BMT) versus additional renal artery stenting are a matter of ongoing debate. The RADAR study aimed to evaluate the impact of percutaneous renal artery stenting on the impaired renal function in patients with hemodynamically significant atherosclerotic renal artery stenosis (RAS). Methods RADAR is an international, prospective, randomized (1:1) controlled study comparing BMT alone versus BMT plus renal artery stenting in patients with duplex sonographic hemodynamically relevant RAS. Follow-up assessments were at 2, 6, and 12 months and at 3 years. The primary endpoint was change in estimated glomerular filtration rate (eGFR) at 12 months. Results Due to slow enrollment, RADAR was terminated early after inclusion of 86 of the scheduled 300 patients (28.7%). Change in eGFR between baseline and 12 months was 4.3 ± 15.4 ml/min/1.73 m2 (stent group) and 3.0 ± 14.9 ml/min/1.73 m2 (BMT group), p > 0.999. Clinical event rates were low with a 12-month composite of cardiac death, stroke, myocardial infarction, and hospitalization for congestive heart failure of 2.9% in the stent and 5.3% in the BMT group, p = 0.526, and a 3-year composite of 14.8% and 12.0%, p = 0.982. At 3 years, target vessel (re-)vascularization occurred in one patient (3.0%) in the stent group and in 8 patients (29.4%) in the BMT group. Conclusion In RADAR, outcomes of renal artery stenting were similar to BMT. These results have to be interpreted with the caveat that the study did not reach its statistically based sample size. Trial registration Clinicaltrials.gov, NCT00640406. Registered on 17 March 2008. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2126-x) contains supplementary material, which is available to authorized users.

Aims Drug-coated balloons (DCBs) for femoropopliteal interventions have not been tested against each other. We aimed to directly compare efficacy and safety of a high-dose (In.Pact™) vs. low-dose (Ranger™) DCB with nominal paclitaxel densities of 3.5 vs. 2.0 μg/mm2. Methods and results Within a prospective, multicentre, non-inferiority, clinical trial 414 patients with symptomatic femoropopliteal lesions (Rutherford classification 2–4) were randomly assigned in a 1:1 ratio to endovascular treatment with either high- or low-dose DCB after stratification for lesion length. Primary efficacy and safety endpoints comprised primary patency and freedom from major adverse events (i.e. device and procedure-related deaths through 1 month, major amputations, and clinically driven target lesion revascularization through 12 months). We set a non-inferiority margin of −10% at 12 months. Total occlusions were observed frequently (>40%) and provisional stenting was performed in every fourth intervention. Non-inferiority was determined for both primary efficacy and safety endpoints at 12 months. Primary patency was 81.5% in the high-dose and 83.0% in low-dose DCB group {difference: 1.5% [lower bound of the 90% two-sided confidence interval (CI) −5.2%]; P non-inferiority < 0.01}. Freedom from major adverse events was determined in 92.6% in high-dose and in 91.0% in low-dose DCB group [difference −1.6% (lower bound of the 90% two-sided CI −6.5%); P non-inferiority < 0.01]. Overall death rate was low (2.0%) and no major amputation occurred. Conclusion Two DCBs with different coating characteristics exhibited comparable results with excellent effectiveness and safety through 12 months for femoropopliteal interventions including a wide range of lesion lengths. Clinical trial registration The trial is registered with ClinicalTrials.gov (NCT02701543).

AIMS Although paclitaxel drug-coated balloon (DCB) angioplasty is an established endovascular treatment for peripheral artery disease, restenosis remains a major concern. Thus, we compared a novel paclitaxel-coated DCB with nano-coating technology with uncoated plain old balloon angioplasty (POBA). METHODS AND RESULTS This multicentre trial randomly assigned 171 patients with stenotic and occlusive lesions of the femoropopliteal artery to angioplasty with a novel DCB or uncoated POBA. The primary endpoint, late lumen loss at six months, was 0.92 mm lower in the DCB group (95% CI: -1.36 to -0.49 mm, p

The Tack Endovascular System (Intact Vascular, Wayne, Pa) combines low-metallic content with focal delivery to seal areas of dissection associated with balloon angioplasty. The device system is designed to treat vascular dissections in the superficial femoral and proximal popliteal arteries. Tack implants exert low radial force and are associated with minimal metal burden, which reduces the mechanical stress on the arterial wall in treating dissections after balloon angioplasty. This study investigated the safety and effectiveness of the Tack Endovascular System in patients with dissections after drug-coated balloon (DCB) angioplasty.The Tack Optimized Balloon Angioplasty III (TOBA III) study is a prospective, multicenter, single-arm study in which patients who underwent percutaneous transluminal angioplasty with the Medtronic IN.PACT Admiral DCB (Medtronic, Dublin, Ireland) and experienced dissection after angioplasty were treated with Tack implants. The primary end points were freedom from major adverse events at 30 days and primary patency at 12 months.A total of 201 patients were enrolled in the trial, 169 with standard-length lesions (≥20 mm and ≤150 mm) and 32 with long-length lesions (150 mm and ≤250 mm). Safety and effectiveness results were favorable compared with historical benchmarks at 12 months in the standard-lesion cohort. Notably, patients in the standard-lesion cohort experienced 95.0% primary patency, 97.5% freedom from clinically driven target lesion revascularization, 100% freedom from amputation, and 100% survival at 12 months (P .0001). Primary patency in long-lesion patients was 89.3%, freedom from clinically driven target lesion revascularization was 96.8%, and freedom from amputation was 100% at 12 months. Device success was achieved in 95.8% (182/190) and 97.7% (43/44) of devices deployed into standard-lesion and long-lesion patients, respectively. Procedural success was 99.4% (168/169) and 100% (44/44) in the standard-lesion and long-lesion cohorts, respectively, with only one bailout stent placed in the entire population.The Tack Endovascular System is a safe and effective treatment option for patients with dissections after angioplasty in the superficial femoral and proximal popliteal arteries, with high patency, low rates of secondary intervention, and low incidence of bailout stenting when it is used in combination with DCB.

Background Critical limb ischemia (CLI) is the clinical end stage of peripheral artery disease and is associated with high amputation, mortality rates and poor quality of life. For CLI patients with no revascularization options, venous arterialization could be an alternative technique for limb salvage. A systematic review and meta-analysis published in 2017 concluded that venous arterialization may be considered a viable alternative. A recent development, is the Percutaneous Deep Vein Arterialization (pDVA), that is CE-marked and currently under investigation of the FDA. This procedure, called LimFlow, is a novel, minimally invasive, endovascular approach to perform a venous arterialization procedure. The limited evidence for its use necessitates a scientific judgement of the pDVA. Therefore, we initiated a prospective clinical post market trial to investigate the outcome of the pDVA in no-option critical limb ischemia. Methods/design The objective of this prospective study is to collect “real-life” clinical data among a population of patients treated with the pDVA in order to evaluate the clinical effectiveness and safety of the LimFlow System in patients with no-option critical limb ischemia. This study is a single-arm, open-label, prospective, post-market follow-up study to be conducted on up to fifty (50) eligible patients with a twelve-month follow-up period. The Primary endpoint is measured by amputation free survival. Secondary endpoints are complete wound healing, primary and secondary patency, limb salvage, renal function and technical and procedural success. Patients will be assessed at regular intervals during one year after the initial percutaneous deep vein arterialization procedure through clinical evaluation and self-completed questionnaires. Discussion The last decade several studies have been published with promising results and the number of treated patients has considerably grown. Venous arterialization could be a valuable treatment option in patients with often no other options than amputation of the affected limb. The first results in men are promising although more research and long term follow up is needed to establish the efficacy of this new treatment modality. With this prospective study, we evaluate the clinical effectiveness and safety in patients with no-option CLI treated with the pDVA (LimFlow System). Trial registration NCT03321552.

Summary. Background: To assess the impact of short- vs. long-term anticoagulation in addition to standard dual antiplatelet therapy (DAPT) upon endovascular treatment of (sub)acute thrombembolic occlusions of the lower extremity. Patient and methods: Retrospective analysis was conducted on 202 patients with a thrombembolic occlusion of lower extremities, followed by crirical limb ischemia that received endovascular treatment including thrombolysis, mechanical thrombectomy, or a combination of both between 2006 and 2015 at a single center. Following antithrombotic regimes were compared: 1) dual antiplatelet therapy, DAPT for 4 weeks (aspirin 100 mg/d and clopidogrel 75 mg/d) upon intervention, followed by a lifelong single antiplatelet therapy; 2) DAPT plus short term anticoagulation for 4 weeks, followed by a lifelong single antiplatelet therapy; 3) DAPT plus long term anticoagulation for > 4 weeks, followed by a lifelong anticoagulation. Results: Endovascular treatment was associated with high immediate revascularization (> 98 %), as well as overall and amputation-free survival rates (> 85 %), independent from the chosen anticoagulation regime in a two-year follow up, p > 0.05. Anticoagulation in addition to standard antiplatelet therapy had no significant effect on patency or freedom from target lesion revascularization (TLR) 24 months upon index procedure for both thrombotic and embolic occlusions. Severe bleeding complications occurred more often in the long-term anticoagulation group (9.3 % vs. 5.6 % (short-term group) and 6.5 % (DAPT group), p > 0.05). Conclusions: Our observational study demonstrates that the choice of an antithrombotic regime had no impact on the long-term follow-up after endovascular treatment of acute thrombembolic limb ischemia whereas prolonged anticoagulation was associated with a nominal increase in severe bleeding complications.

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

Despite recent advances in endovascular therapy of lower extremity atherosclerotic disease, mainly driven through drug eluting balloon angioplasty, treatment of complex lesions remains challenging. Drug-eluting balloons work less well in heavily calcified lesions and in particular long lesions often require bail-out stenting. Lesion preparation, as a stand-alone treatment or before delivering antiproliferative therapy or scaffolding, has gained increased recognition in recent years. Focal force or other specialty balloons are designed to prepare complex lesions to improve acute technical success and, ideally, long term patency of the vessel. There are numerous dedicated balloons on the market that use different modes of action to prepare the lesions. The current review focuses on mechanistic insights and the evidence behind those specialty balloons.

PURPOSE: To report results of renal denervation (RDN) with the first catheter-based, non-balloon occlusion ultrasonic system in patients with resistant hypertension. MATERIALS AND METHODS: In a multicenter, single-arm trial, 39 patients with resistant hypertension (defined as uncontrolled hypertension while taking ≥ 3 antihypertensive medications) were treated. The cohort consisted of 4 groups: severe resistant hypertension (office systolic blood pressure [OSBP] ≥ 160 mm Hg) treated with a unidirectional catheter (group 1; n = 14); severe resistant hypertension treated with a multidirectional catheter (group 2; n = 18); moderate resistant hypertension (OSBP 140-159 mm Hg) treated with a multidirectional catheter (group 3; n = 5); and recurrent severe resistant hypertension, after an initial response to RF RDN (group 4; n = 2). Blood pressure monitoring was performed for 6 months. RESULTS: Severe adverse events were not noted immediately after the procedure or during follow-up. Treatment time was longer withunidirectional than with multidirectional catheters (36.7 min ± 9.6 vs 11.9 min ± 5.8; P < .001). Mean reductions in office blood pressure (systolic/diastolic) at 1, 3, and 6 months were -26.1/-9.6 mm Hg, -28.0/-9.9 mm Hg, and -30.6/-14.1 mm Hg (P < .01 for all). Per-group analysis showed significant OSBP reduction for groups 1 and 2. Patients with isolated systolic hypertension had a significantly smaller reduction in OSBP after 6 months compared with patients with combined systolic/diastolic hypertension (-16.2 mm Hg ± 18.5 vs -9.9 mm Hg ± 33.4; P < .005). CONCLUSIONS: Use of the RDN system was feasible and safe in this phase I study. Significant blood pressure reductions were observed over 6 months, although less in patients with isolated systolic hypertension.

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.

Die periphere arterielle Verschlusskrankheit (PAVK) stellt aufgrund der demographischen Entwicklung eine der haufigsten Erkrankungen v. a. in westlichen Industrienationen dar. In den letzten Jahren hat sich der Trend zur uberwiegend endovaskularen Revaskularisation weiter fortgesetzt. Aufgrund der hohen Erfolgsrate und geringen Komplikationsquote ist die interventionelle Therapie in den weit uberwiegenden Fallen die Methode der Wahl. Die Behandlungsstrategie sollte interdisziplinar abgestimmt werden und idealerweise innerhalb von Gefaszentren erfolgen. Das wesentliche Problem bei Interventionen ist das Auftreten von Restenosen, insbesondere bei infrapoplitealen Lasionen. Einen deutlichen Fortschritt stellen medikamentenbeschichtete Ballonkatheter dar, die in der femoropoplitealen Strombahn die Notwendigkeit fur Reinterventionen drastisch reduzieren konnten. Eine sinnvolle Behandlungsalternative konnte der Einsatz von Kombinationstherapien, wie eine Plaqueentfernung mit anschliesender Verwendung von medikamentenbeschichteten Ballons, sein. Hierbei sind allerdings auch okonomische Gesichtspunkte zu beachten.

Purpose: To investigate the 2-year technical and clinical results of primary nitinol stent placement in comparison with percutaneous transluminal angioplasty (PTA) in the treatment of de novo lesions of the popliteal artery. Methods: The ETAP study (Endovascular Treatment of Atherosclerotic Popliteal Artery Lesions: balloon angioplasty vs. primary stenting; www.ClinicalTrials.gov identifier NCT00712309) is a prospective, randomized trial that enrolled 246 patients (158 men; mean age 72 years) who were randomly assigned to receive a nitinol stent (n=119) or PTA (n=127) for lesions averaging 42.3 mm in length. The results of the primary study endpoint were published. Secondary outcome measures and endpoints included primary patency (freedom from duplex-detected target lesion restenosis), target lesion revascularization (TLR), secondary patency, changes in ankle-brachial index and Rutherford class, and event-free survival (freedom from target limb amputation, TLR, myocardial infarction, and death). Results: In total, 183 patients (89 stent and 94 PTA) were available for the 2-year analysis. The primary patency rate was significantly higher in the stent group (64.2%) than in the PTA group (31.3%, p=0.0001). TLR rates were 22.4% and 59.5%, respectively (p=0.0001). When provisional stent placement in the PTA arm was not considered as TLR and loss in patency, the differences prevailed between the study groups but were not significant (64.2% vs. 56.1% for primary patency, respectively; p=0.44). A significant improvement in ABI and Rutherford category was observed at 2 years in both groups. Conclusion: In treatment of obstructive popliteal artery lesions, provisional stenting reveals equivalent patency in comparison to primary stenting. However, the 2-year results of this trial suggest the possibility of a shift toward higher patency rates in favor of primary stenting.

Mariya Kronlage,1 Maximilian Wassmann,1 Britta Vogel,1 Oliver J Müller,1 Erwin Blessing,2 Hugo Katus,1,3 Christian Erbel1 1Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, 2SRH Klinikum Karlsbad Langensteinbach, Karlsbad, 3DZHK German Center for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Mannheim, Germany Introduction: Peripheral artery disease (PAD) is a highly prevalent disorder with a substantial economical burden. Dual antiplatelet treatment (DAPT) upon endovascular stenting to prevent acute thrombotic reocclusions is an universally accepted practice for postinterventional management of PAD patients. However, the optimal period of time for DAPT upon endovascular stenting is not known.Methods: In the current nonrandomized, retrospective monocentric study, we evaluated the duration of DAPT upon endovascular stenting. A total of 261 endovascular SFA and iliac stenting procedures were performed on 214 patients and these patients were subdivided into a short (4–6 weeks) or a prolonged (8–12 weeks) DAPT regime group. More than 65% of the patients included were male, approximately 35% were diabetic, and 61% had a history of smoking. Of all the patients, 90% exhibited a Rutherford stage 2–3, and approximately half of the patients had a moderate-to-severe calcified target lesion with a length of >13 cm. Major safety end points were defined as any bleeding, compartment syndrome, and ischemic events. In addition to this, patency, all-cause mortality, as well as amputation were followed up over a period of 12 months upon intervention.Results: Twelve months after endovascular stenting, primary patency in our cohort was comparable between the groups (83.94% short vs 79.8% long DAPT, P>0.05). Major bleeding occurred in 18 cases without any difference between the groups (P>0.05). In addition, during the 12-month follow-up, 6 (3.4%) patients in the short and 3 (3.5%) in the prolonged DAPT regime suffered a stroke/transient ischemic attack (P>0.05). In addition, there was no difference regarding mortality and amputation rate comparing short vs prolonged DAPT regime in a 12-month follow-up.Conclusion: In the current cohort, prolonged DAPT after endovascular stenting had no beneficial effect on the outcome in a 12-month follow-up. Keywords: peripheral artery disease, stent implantation, dual antiplatelet therapy, primary patency, endovascular therapy

Background Vascular injury and access site complications in the contemporary setting of transcatheter aortic valve implantation (TAVI) are known to be associated with increased mortality and morbidity. The aim of our study was to analyse the feasibility and safety of percutaneous treatment of such vascular complications using a stent graft. Methods Between January 2010 and April 2013, 36 TAVI patients developed severe access site complications and underwent subsequent interventional treatment with a covered stent. Acute treatment success was confirmed by angiography immediately after the implantation of the stent graft, with clinical long-term patency follow-up being assessed by duplex ultrasound. Results Of the 36 patients evaluated, percutaneous treatment of the acute access site bleeding was successful in 35 patients (97%), with one patient requiring surgical intervention due to insufficient haemostasis after stent graft implantation. A subset of 5 patients underwent successful ipsilateral stent graft implantation, either because crossover sheath placement was not feasible (n = 1), or intentionally with an even sheathless approach in an effort to reduce vessel injury (n = 4). After a mean follow-up of 22 ± 8 months, stent graft patency was confirmed by duplex ultrasound in 13 patients with an additional 5 patients reporting to be free from symptoms and claudication. Thirteen patients died within the first 24 months after the procedure, however, none was due to access vessel complications. Five patients were lost for follow-up. Conclusions Our data confirm that endovascular treatment of access site complications related to TAVI is feasible, safe and efficacious, resulting in long-term vascular patency.

Mariya Kronlage,1,2 Ilka Printz,1 Britta Vogel,1 Erwin Blessing,3 Oliver J Müller,1,2 Hugo A Katus,1,2 Christian Erbel1 1Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 2DZHK German Center for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Heidelberg, 3SRH Klinikum Karlsbad Langensteinbach, Karlsbad, Germany Objective: The aim of this study was to compare different interventional methods for treatment of (sub)acute limb ischemia upon thrombotic occlusions of the lower extremity in terms of their safety and efficacy in a tertiary hospital setting.Design: This is a retrospective, single-center study of non-randomized data.Methods: A total of 202 patients, including 26 critically ill patients, underwent rotational thrombectomy (Rotarex®), local thrombolysis (recombinant tissue plasminogen activator), or combination of both at the University Hospital Heidelberg (2006–2015). The different interventional procedures were compared in terms of overall and amputation-free survival, as well as patency in a 1-year follow-up (Kaplan–Meier analysis).Results: The study demonstrated a primary revascularization success of >98% in all groups. One year after revascularization, primary and secondary patency after mechanical thrombectomy alone were significantly better in comparison to local thrombolysis or a combination of Rotarex® and lysis (63% and 85%, P

Background— Studies assessing drug-coated balloons (DCB) for the treatment of femoropopliteal artery disease are encouraging. However, challenging lesions, such as severely calcified, remain difficult to treat with DCB alone. Vessel preparation with directional atherectomy (DA) potentially improves outcomes of DCB. Methods and Results— DEFINITIVE AR study (Directional Atherectomy Followed by a Paclitaxel-Coated Balloon to Inhibit Restenosis and Maintain Vessel Patency—A Pilot Study of Anti-Restenosis Treatment) was a multicenter randomized trial designed to estimate the effect of DA before DCB to facilitate the development of future end point-driven randomized studies. One hundred two patients with claudication or rest pain were randomly assigned 1:1 to DA+DCB (n=48) or DCB alone (n=54), and 19 additional patients with severely calcified lesions were treated with DA+DCB. Mean lesion length was 11.2±4.0 cm for DA+DCB and 9.7±4.1 cm for DCB ( P =0.05). Predilation rate was 16.7% for DA+DCB versus 74.1% for DCB; postdilation rate was 6.3% for DA+DCB versus 33.3% for DCB. Technical success was superior for DA+DCB (89.6% versus 64.2%; P =0.004). Overall bail-out stenting rate was 3.7%, and rate of flow-limiting dissections was 19% for DCB and 2% for DA+DCB ( P =0.01). One-year primary outcome of angiographic percent diameter stenosis was 33.6±17.7% for DA+DCB versus 36.4±17.6% for DCB ( P =0.48), and clinically driven target lesion revascularization was 7.3% for DA+DCB and 8.0% for DCB ( P =0.90). Duplex ultrasound patency was 84.6% for DA+DCB, 81.3% for DCB ( P =0.78), and 68.8% for calcified lesions. Freedom from major adverse events at 1 year was 89.3% for DA+DCB and 90.0% for DCB ( P =0.86). Conclusions— DA+DCB treatment was effective and safe, but the study was not powered to show significant differences between the 2 methods of revascularization in 1-year follow-up. An adequately powered randomized trial is warranted. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique Identifier: NCT01366482.

Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E–deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A–induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E–deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.

Peripheral artery disease (PAD) is a marker disease for generalized atherosclerosis and represents one of the world's major causes of morbidity and mortality. Many studies have tried to gain insight into the molecular mechanisms involved in PAD onset, progression and prognosis. In the last decade, small non-coding RNAs, termed miRNAs, have emerged as a major research focus due to their regulating function of multiple gene sets. In the cardiovascular system, miRNAs not only impact on physiological pathways like cardiac development and angiogenesis, but also play an important role in disease mechanisms and progression of myocardial hypertrophy, acute myocardial infarction, heart failure or arrhythmias. New insights lend considerable support to the concept of miRNAs serving as highly sensitive biomarkers and therapeutic targets. To date, a comprehensive understanding of miRNA regulation of angiogenesis and maintenance of vascular integrity in PAD remains less explored. In this review, we discuss current studies and highlight the potential of miRNAs not only to act as a diagnostic tool, but also to facilitate innovative strategies for gene therapy.Die periphere arterielle Verschlusserkrankung (pAVK) stellt heutzutage mit einer weltweit steigenden Prävalenz eine führende Ursache für Morbidität und Mortalität dar und gilt als Markererkrankung für generalisierte Arteriosklerose. Viele Studien haben sich mit den molekularen Mechanismen der Entstehung, Progression und Prognose der pAVK auseinandergesetzt. In den letzten Jahren rückten kleine, nichtkodierende Ribonukleinsäuren, miRNAs genannt, zunehmend in den Fokus des wissenschaftlichen Interesses, da sie entscheidend an Prozessen wie der Herzentwicklung, Gefäßneubildung sowie Reparatur von Geweben beteiligt sind. Insbesondere auf dem Gebiet der kardiovaskulären Erkrankungen konnten für miRNAs interessante neue Funktionen identifiziert und ihre Anwendung als therapeutische oder diagnostische Zielstrukturen im Hinblick auf die Pathophysiologie charakterisiert werden. Im Gegensatz hierzu wissen wir bislang nur wenig über die Rolle von miRNAs in der Genese und Progression der pAVK. In diesem Review werden wir nicht nur aktuelle Daten zur Rolle von miRNAs in der pAVK vorstellen, sondern ihr Potential sowohl als diagnostische Biomarker, als auch als vielversprechenden Ansatz für die Gentherapie hervorheben.

Background— In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Methods and Results— Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours ( P P =0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 ( P P =0.61), and no recurrent venous thromboembolism. Conclusions— In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01166997.

Background— Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. Methods and Results— A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all P P P P Conclusions— RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00664638 and NCT00888433.

BACKGROUND/PURPOSE: Catheter-based renal sympathetic denervation (RDN) can reduce blood pressure (BP) and sympathetic activity in certain patients with uncontrolled hypertension. Less is known about the impact of renal anatomy and procedural parameters on subsequent BP response. METHODS/MATERIALS: A total of 564 patients with resistant hypertension underwent bilateral RDN in 9 centers in Europe and Australia using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). Anatomical criteria such as prevalence of accessory renal arteries (ARA), presence of renal artery disease (RAD), length, and diameter were analyzed blinded to patient's characteristics. RESULTS: ARA was present in 171 patients (30%), and RAD was documented in 71 patients (13%). On average 11±2.7 complete 120-s ablations were performed, equally distributed on both sides. After 6months, BP was reduced by 19/8mmHg (p4mm (-29 vs. -26 vs. -17mmHg; p

Inflammation contributes to atherosclerotic plaque initiation and progression. Recent studies suggest that nicotinic acid has anti-inflammatory effects independent of its lipid-modifying capabilities. We assessed the hypothesis that administration of nicotinic acid to older apolipoprotein E (apoE)-deficient mice with established lesions will reduce lesion size and plaque inflammation independent of its lipid-modifying effects. Therefore nicotinic acid was administered to 27-week-old apo E-deficient mice exhibiting advanced atherosclerotic lesions within the innominate artery. After 27 weeks of treatment both animal groups had no significant changes in plasma lipid levels. Mice treated with nicotinic acid (n = 22) demonstrated a 30% reduction in total lesion area compared with controls (n = 20). Furthermore, they revealed a more stable plaque composition with an increase in fibrous cap thickness and a reduction in the size of the necrotic core. Immunohistochemistry demonstrated a reduced accumulation of macrophages and a reduced expression of vascular cell adhesion molecule-1 and tissue factor. Additionally, administration of nicotinic acid significantly reduced tumor necrosis factor alpha expression in the thoracic aorta as demonstrated by real-time PCR. In conclusion, these data suggest that long-term administration of nicotinic acid has anti-atherogenic and anti-inflammatory properties on advanced atherosclerotic lesions, which are independent of its lipid-modifying actions.

Eur J Clin Invest 2011; 41 (11): 1164–1171 Abstract Background The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the inflammatory response in atherosclerosis. We sought to determine the role of bone marrow-derived RAGE in different stages of atherosclerotic development in apolipoprotein E-deficient mice (apoE−/−). Methods Seven- and 23-week-old apoE−/− mice (n = 40) were lethally irradiated and given bone marrow from RAGE null (RAGE−/−/apoE−/−) or RAGE-bearing (RAGE+/+/apoE−/−) mice to apoE−/− mice to generate double knockout bone marrow chimera (RAGE−/−/apoE−/−bmc and RAGE+/+/apoE−/−bmc-, respectively). After 16 weeks on a standard chow diet, mice were sacrificed and atherosclerotic lesion formation was evaluated. Results Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217 470 ± 17 480 μm2 for the RAGE−/−/apoE−/−bmc mice compared to 244 764 ± 45 840 μm2), whereas lesions in the brachiocephalic arteries of the older RAGE−/−/apoE−/−bmc mice had significantly smaller lesions (94 049 ± 13 0844 μm2 vs. 145 570 ± 11 488 μm2, P

Aim. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in induction of inflammatory processes. Activated factor X (FXa) is traditionally known as an important player in the coagulation cascade responsible for thrombin generation. We assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions in anin vivomodel.Methods and Results. Rivaroxaban (1 or 5 mg/kg body weight/day) or standard chow diet was administered for 26 weeks to apolipoprotein E-deficient mice (n=20per group) with already established atherosclerotic lesions. There was a nonsignificant reduction of lesion progression in the high-concentration group, compared to control mice. FXa inhibition with 5 mg Rivaroxaban/kg/day resulted in increased thickness of the protective fibrous caps (12.3±3.8 μm versus10.1±2.7 μm;P<.05), as well as in fewer medial erosions and fewer lateral xanthomas, indicating plaque stabilizing properties. Real time-PCR from thoracic aortas revealed that rivaroxaban (5 mg/kg/day) treatment reduced mRNA expression of inflammatory mediators, such of IL-6, TNF-α, MCP-1, and Egr-1 (P<.05).Conclusions. Chronic administration of rivaroxaban does not affect lesion progression but downregulates expression of inflammatory mediators and promotes lesion stability in apolipoprotein E-deficient mice.

The acute phase response to Chlamydia pneumoniae infection was analyzed over a 72 h period post-infection in C57BL/6J mice. A single intra-nasal inoculation stimulated statistically significant increases in the plasma levels of IL-2, IL-5, IL-6, IL-10, IL-12, GM-CSF, IFN-gamma, and serum amyloid A but not TNF-alpha, IL-1beta, IL-4 and serum amyloid P. There was also a decrease in the activity of the HDL protective enzyme paraoxonase as well as a reduced ability of HDL to prevent oxidation of palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine by hydroperoxyoctadecadienoic acid at 48 and 72 h post-infection. To determine whether the C. pneumoniae induced acute phase response had any effect on atherosclerotic plaque stability, we measured the frequency of intra-plaque hemorrhage as a marker of plaque disruption in the innominate arteries of apolipoprotein E deficient mice at 29-30 weeks and 1.5-2.0 years of age. There was an increased frequency of intra-plaque hemorrhage only in the older mice infected with the live organism (8/14) as compared to mice treated with killed C. pneumoniae (2/11) or sham inoculated with PBS (2/12). These results suggest that acute phase reactant proteins produced in response to pulmonary infection with C. pneumoniae may contribute to the progression and destabilization of atherosclerotic lesions.

Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD.In a single centre, single-blinded, prospective study, 36 patients with PAD at stage Fontaine II or higher and mild to moderate arterial hypertension were treated with telmisartan 40/80 mg once daily or placebo for 12 months. Primary endpoint was the improvement of the absolute treadmill WD. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), ankle-brachial index (ABI) and disease-related quality of life (DRQL) were examined as well.After 12 months, maximum WD increased by 26% in the telmisartan group (P0.001). However, in the placebo group it was comparable to baseline. FMD rose by 40% in the telmisartan group while it deteriorated in the placebo group (P0.001). IMT and ABI were comparable in both groups at baseline and did not change considerably after 12 months. In non-diabetic patients (72.2%), the ABI did not change in the placebo group, whereas it increased by 11% in the telmisartan group (P0.001). While the DRQL remained stable in the telmisartan group, placebo treatment was associated with a marked deterioration (P0.01).Telmisartan improves WD and endothelial function, the ABI in non-diabetic patients and it may prevent further loss of quality of life in patients with advanced PAD.

Sirs: The Leriche’s syndrome represents an arterial occlusion of the aortic bifurcation with ischemic symptoms of both legs. An acute occlusion of the distal aorta and iliac arteries is associated with considerable morbidity and mortality. Often, there is a latency stage between the initial pathophysiologic event and the onset of symptoms. Therefore, rapid diagnosis and therapy is crucial for the survival of the patient. Here, we report a case of acute Leriche’s syndrome with thrombotic occlusion of infrarenal aorta and upper mesenteric artery, initially presenting with neurological symptoms.

Background—Clinical studies failed to provide clear evidence for a proatherogenic role of hypercoagulability. This is in contrast to the well-established detrimental role of hypercoagulability and thrombin during acute atherosclerotic complications. These seemingly opposing data suggest that hypercoagulability might exert both proatherogenic and antiatherogenic effects. We therefore investigated whether hypercoagulability mediates a beneficial effect during de novo atherogenesis.Methods and Results—De novo atherogenesis was evaluated in 2 mouse models with hyperlipidemia and genetically imposed hypercoagulability (TMPro/ProApoE−/−and FVLQ/QApoE−/−mice). In both mouse models, hypercoagulability resulted in larger plaques, but vascular stenosis was not enhanced secondary to positive vascular remodeling. Importantly, plaque stability was increased in hypercoagulable mice with less necrotic cores, more extracellular matrix, more smooth muscle cells, and fewer macrophages. Long-term anticoagulation reversed these changes. The reduced frequency of intraplaque macrophages in hypercoagulable mice is explained by an inhibitory role of thrombin and protease-activated receptor-1 on monocyte transendothelial migration in vitro. This is dependent on phospholipase-Cβ, phosphoinositide 3-kinase, and nitric oxide signaling in monocytes but not in endothelial cells.Conclusions—Here, we show a new function of the coagulation system, averting stenosis and plaque destabilization during de novo atherogenesis. The in vivo and in vitro data establish that thrombin-induced signaling via protease-activated receptor-1, phospholipase-Cβ, phosphoinositide 3-kinase, and nitric oxide in monocytes impairs monocyte transendothelial migration. This likely accounts for the reduced macrophage accumulation in plaques of hypercoagulable mice. Thus, in contrast to their role in unstable plaques or after vascular injury, hypercoagulability and thrombin convey a protective effect during de novo atherogenesis.

In der Behandlung von Patienten mit koronarer Herzerkankung kommen in der Sekundärprävention Thrombozytenaggegationshemmer, β-Blocker, ACE-Hemmer bzw. Angiotensinrezeptorantagonisten sowie Statine zum Einsatz. Eine einschleichende Therapie ist bei den erwähnten Substanzen nicht zwingend erforderlich. Bei nicht vorbehandelten Patienten mit akutem Koronarsyndrom oder im Falle einer Stentimplantation sollte zum schnelleren Wirkungseintritt eine Aufsättigung mit Acetylsalicylsäure bzw. Clopidogrel erfolgen. Zur besseren Verträglichkeit sollte die Therapie mit einem Nikotinsäurepräparat eingeschlichen werden und die Dosierung stufenweise erhöht werden. Bei Patienten mit KHK sollte eine β-Blockertherapie wenn möglich nicht abrupt beendet werden. Bei Beendigung der Therapie sollte eine engmaschige Blutdruckkontrolle und gegebenenfalls Anpassung der antihypertensiven Begleitmedikation erfolgen. Ein abruptes Absetzen einer vorbestehenden Statintherapie sollte in der Akutphase nach kardiovaskulären Ereignissen vermieden werden.

BACKGROUND Hyperlipidemia is an important complication after organ transplantation and may contribute to the development of posttransplant-accelerated coronary artery disease. Immunosuppressive therapy, especially mammalian target of rapamycin inhibitors, induces a considerable increase in cholesterol and triglyceride plasma levels. Omega-3 fatty acids (FAs) exert cardioprotective effects supporting a therapeutic role in cardiovascular conditions. METHODS An observational study of omega-3 FAs 4 g/day was performed in 15 heart transplant recipients with hypertriglyceridemia. Six patients received rapamycin, and nine received everolimus. Apart from one patient the immunosuppressive therapy was combined with mycophenolate mofetil, only one patient received steroids; two patients presented with diabetes. RESULTS Mean triglyceride levels before heart transplantation (HTx) were 137+/-54 mg/dL. After HTx, before sirolimus or everolimus treatment triglyceride level had increased to 188+/-67 mg/dL (P

We investigated tolerability and efficacy of ezetimibe treatment (10 mg/d) in 25 heart allograft recipients already on stable statin therapy. Total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglycerides (TG), immunosuppressant drug levels, laboratory and clinical parameters were assessed before, four months and one yr after initiation of ezetimibe treatment. Mean equivalent statin dose was 53.5 +/- 12.3 mg of pravastatin, remaining unchanged throughout the study period. Ezetimibe was generally well tolerated, only two patients (8%) discontinued ezetimibe due to stomach pain or headache. Mean TC decreased from 231.8 +/- 6.4 mg/dL before therapy to 202.2 +/- 8.8 mg/dL after four months and 192.9 +/- 7.0 mg/dL after one yr (p < 0.001). Mean LDL-C decreased from 143.1 +/- 5.4 mg/dL to 121.4 +/- 7.9 mg/dL (month 4; p < 0.05) and 107.1 +/- 5.6 mg/dL (one yr; p < 0.001). TG decreased from 182 +/- 14.3 mg/dL to 173.3 +/- 17.5 mg/dL after one yr (p < 0.05), whereas HDL-C was unchanged. Initial LDL-C and cardiac diagnosis before transplantation were identified as predictors of absolute LDL-C reduction. Immunosuppressant drug doses and blood concentrations were unchanged as well as other laboratory and clinical parameters. Ezetimibe appears safe and effective for further reduction of TC and LDL-C in heart allograft recipients already on stable statin therapy. Extent of pre-treatment LDL-C and cardiac disorder prior to transplantation appear to correlate with the efficacy of ezetimibe therapy.

Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.

Inflammatory mechanisms are involved in initiation and progression of atherosclerotic lesions. Previous studies demonstrated antiinflammatory and consecutive antiatherosclerotic effects of the adenosine analogue 3-Deazaadenosine (c(3) Ado) on early lesion development. The present study evaluated the effect of long-term administration of c(3) Ado in a mouse model of advanced atherosclerosis. Apolipoprotein E-deficient mice (age, 35 weeks; n = 31) with already established advanced atherosclerotic lesions were fed either a diet supplemented with c Ado or a regular chow diet for 21 weeks. Treatment resulted in a significant reduction of serum homocysteine levels. Lesion size and lesion morphology, such as frequency of intraplaque hemorrhage, size of necrotic cores, thickness of fibrous caps, and macrophage content within the plaque, were not different between the groups. Lesion calcification, expression of alpha-actin, and intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, were inhibited by treatment with c(3) Ado. We could not detect any effect on serum concentrations of interleukin-10 (IL-10) and interleukin-1beta (IL-1beta) or on soluble adhesion molecules intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Electromobility shift assays of protein extracts isolated from aortas did not demonstrate different binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) after treatment with c Ado. Long-term treatment with the adenosine analogue 3-Deazaadenosine did not show significant effects on progression and stability of advanced atherosclerotic lesions in older apolipoprotein E-deficient mice. A potential antiatherosclerotic effect of c(3)Ado (eg, mediated through inhibition of adhesion molecules) might therefore be limited to prevention of early lesion formation and does not seem to play a relevant role in modifying advanced atherosclerotic disease.

Philipp Sievers,1 Lorenz Uhlmann,2 Sevil Korkmaz-Icöz,3 Christian Fastner,1 Florian Bea,1 Erwin Blessing,1 Hugo A Katus,1 Michael R Preusch11Department of Internal Medicine III, 2Institute of Medical Biometry andInformatics, 3Department ofCardiac Surgery, University of Heidelberg, Heidelberg, GermanyIntroduction: Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease. Most of the studies investigating the effects of atherosclerosis focused on early atherosclerotic lesions, whereas lesions in human disease, at the time when medical treatment is started, are already well established. Therefore, we set up a model of advanced atherosclerosis and investigated the effects of olmesartan medoxomil, amlodipine besylate, and the combination of both on atherosclerotic lesion size and lesion composition.Materials and methods: Olmesartan medoxomil (1 mg/kg/day), amlodipine besylate (1.5 mg/kg/day), and the combination of both was added to chow and was fed to apolipoprotein E-deficient (ApoE-/-) mice at 25 weeks of age. Mice were sacrificed after 25 weeks of drug administration and perfused with formalin. Innominate arteries were dissected out and paraffin embedded. Serial sections were generated, and lesion sizes and their composition – such as minimal thickness of the fibrous cap, size of the necrotic core, and presence of calcification – were analyzed. Electrophoretic mobility shift assays were used to detect DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB) in aortic tissue.Results: Treatment with the combination of olmesartan medoxomil and amlodipine besylate led to a significant reduction in atherosclerotic lesion size in ApoE-/- mice (olmesartan medoxomil/amlodipine besylate: 122,277±6,795 µm2, number [n]=14; versus control: 177,502±10,814 µm2, n=9; P

Background— Drug-coated balloon angioplasty (DCBA) was shown to be superior to standard balloon angioplasty (POBA) in terms of restenosis prevention for de novo superficial femoral artery disease. For in-stent restenosis, the benefit of DCBA over POBA remains uncertain. Methods and Results— One hundred nineteen patients with superficial femoral artery in-stent restenosis and chronic limb ischemia were recruited over 34 months at 5 German clinical sites and prospectively randomized to either DCBA (n=62) or POBA (n=57). Mean lesion length was 82.2±68.4 mm. Thirty-four (28.6%) lesions were totally occluded; 30 (25.2%) were moderately or heavily calcified. Clinical and duplex ultrasound follow-up was conducted at 6 and 12 months. The primary end point of recurrent in-stent restenosis assessed by ultrasound at 6 months was 15.4% (8 of 52) in the DCBA and 44.7% (21 of 47) in the POBA group ( P =0.002). Freedom from target lesion revascularization was 96.4% versus 81.0% ( P =0.0117) at 6 months and 90.8% versus 52.6% ( P P =0.015). No major amputation was needed. Two patients in the DCBA and 3 patients in the POBA group died. No death was procedure related. Conclusions— DCBA for superficial femoral artery in-stent restenosis is associated with less recurrent restenosis and a better clinical outcome than POBA without an apparent difference in safety. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01305070.

Objective— Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions. Methods and Results— Melagatran (500 μmol/kg/d) or control diet was administered to apolipoprotein E–deficient mice (n=54) with advanced atherosclerotic lesions. Treatment reduced lesion progression in brachiocephalic arteries ( P P P 2 versus 126 819±51730 μm 2 ; P P P P Conclusions— The direct thrombin inhibitor melagatran reduces lesion size and may promote plaque stability in apolipoprotein E–deficient mice, possibly through reduced activation of proinflammatory transcription factors and reduced synthesis of MMP-9.

Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play an essential role in thrombus formation after atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties. Therefore, the effects of IL-10 on TF expression in response to inflammation were investigated. Mouse macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a 50% decrease in TF mRNA expression and TF promoter activity. Binding of early growth response gene-1 (Egr-1) to the consensus DNA sequence, a key transcriptional activator of TF expression in response to inflammation, and the expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was independent of the induction of suppressor of cytokine signaling protein-3 by IL-10. Macrophages that had been transfected with luciferase reporter constructs containing the murine Egr-1 5′-flanking sequence exhibited reduced reporter gene activity in response to LPS stimulation with IL-10 pretreatment. Studies with deletion constructs of the Egr-1 promoter identified the proximal serum response element SRE3 as a potential regulatory site for the IL-10 mediated suppression of Egr-1 expression. Furthermore, activation of the upstream signal-transduction elements, such as mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by IL-10 pretreatment. Taken together, these results demonstrate a pathway for the IL-10 mediated inhibition of TF expression during inflammation and may explain the antiatherosclerotic effects of IL-10.

OBJECTIVES To evaluate whether antimicrobial chemotherapy prevents acceleration of atherosclerotic lesion development induced by infection with Chlamydia pneumoniae. METHODS ApoE-deficient mice which develop hyperlipidaemia and atherosclerosis spontaneously were inoculated intranasally with C. pneumoniae. Animals were treated with azithromycin for 6 weeks after the third inoculation and the atherosclerotic lesion areas in the aortic sinus were measured by computer-assisted morphometry. RESULTS At 12 weeks post-infection, infected untreated animals developed significantly larger lesion areas compared with sham-inoculated controls (8.7 x 10(4)+/-2.3 x 10(4) microm(2) versus 5.6 x 10(4)+/-2.4 x 10(4) microm(2)). However, there were no differences in lesion size of infected mice treated with azithromycin in comparison with untreated infected controls (11.0 x 10(4)+/-3.0 x 10(4) microm(2) versus 8.7 x 10(4)+/-2.3 x 10(4) microm(2)). CONCLUSIONS Antibiotic treatment against C. pneumoniae has no beneficial effects on hyperlipidaemia-induced atherosclerosis accelerated by C. pneumoniae in a mouse model.

Background: Inflammatory processes are an integral component of the initiation, progression, and destabilization of atherosclerotic lesions. Tumor necrosis factor-α (TNF-α) is considered a primary mediator of inflammatory processes. Methods and results: The role of TNF-α in plaque progression and plaque destabilization was investigated in the innominate arteries of older TNF-α receptor p55 deficient mice that were generated on a hyperlipidemic apolipoprotein E deficient background (p55−/− apoE−/−). There were no significant differences in levels of circulating cytokines, plaque progression, plaque composition or features of plaque destabilization in p55−/− apoE−/− compared to wild type (p55+/+ apoE−/−) mice. Conclusions: Progression and destabilization of advanced atherosclerotic lesions does not seem to be mediated via the TNF-α receptor p55.