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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 (

Die Lungenembolie (LE) ist das dritthaufigste akute kardiovaskulare Syndrom. Der steigende Trend der LE-assoziierten Mortalitat und Morbiditat in Deutschland und anderen europaischen Landern ist parallel zu der Alterung der Bevolkerung. Die 2019-ESC-Leitlinie zum Management der LE enthalt Optimierungen in den diagnostischen Algorithmen mit dem Ziel, die Spezifitat der klinischen Wahrscheinlichkeit und des D‑Dimer-Tests zu erhohen und damit den unnotigen Einsatz ionisierender Strahlung in der Abklarung eines LE-Verdachts zu vermeiden. Standardisierte diagnostische Schritte wurden inzwischen auch bei schwangeren Patientinnen mit klinisch vermuteter akuter LE validiert und werden in der neuen Leitlinie empfohlen. In der Risikostratifizierung wird auf den prognostischen Wert der echokardiographischen oder computertomographischen Einschatzung des rechten Ventrikels – zusatzlich zu klinischen Parametern – hingewiesen, insbesondere wenn eine Fruhentlassung und anschliesende ambulante Behandlung der LE in Betracht gezogen wird. Nicht-Vitamin-K-abhangige orale Antikoagulanzien (NOAK) werden als Therapie der ersten Wahl fur die meisten Patienten mit akuter LE empfohlen, wahrend eine Reperfusionsbehandlung hamodynamisch instabilen Patienten vorbehalten ist. Die 2019-Leitlinie unterstutzt die Bildung interdisziplinarer LE-Teams mit dem Ziel, die in jedem Krankenhaus vorhandenen Ressourcen und Expertise zur Akutbehandlung von Patienten mit hohem oder intermediar-hohem Risiko abzustimmen und optimal einzusetzen. Aktualisiert wurden daruber hinaus die Empfehlungen (i) zu den Indikationen einer verlangerten Antikoagulation nach LE unter Berucksichtigung des gunstigeren Sicherheitsprofils der NOAK im Vergleich zu den Vitamin-K-Antagonisten und (ii) zu der Langzeitverlaufsbeobachtung der Patienten mit dem Ziel, Spatkomplikationen der LE zu verhindern bzw. diese fruh zu erkennen und zu behandeln.

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

To compare antegrade versus retrograde recanalization, in terms of procedural time, radiation and contrast agent exposure, number and total length of implanted stents and procedural complications, in long and calcified, de novo femoropopliteal occlusions. We performed retrospective matching of prospectively acquired data by lesion length, occlusion length and lesion calcification by the peripheral arterial calcium scoring system (PACSS) score in patients who were referred for endovascular treatment due to symptomatic peripheral artery disease (PAD). Forty-two consecutive patients with antegrade and 23 patients with retrograde after failed antegrade recanalization were identified (mean lesion length = 32.1 ± 6.9 cm; mean occlusion length = 24.6 ± 7.7 cm; PACSS score = 3.25 ± 0.91). 23% of the patients had intermittent claudication, whereas 77% exhibited critical limb ischemia (CLI). Patients who underwent retrograde versus antegrade recanalization required a significantly lower number of stents (0.9 ± 1.0 versus 1.8 ± 1.4, p = 0.01) and a lower total stent length (6.8 ± 8.5 cm versus 11.7 ± 9.9 cm, p

Summary. Deep vein thromboses lead to post thrombotic syndrome in up to 50% of patients, which entails significant morbidity and socioeconomic costs. Endovascular treatment of iliofemoral deep vein thrombosis aims to reduce the development and the severity of post thrombotic syndrome. This case series of four cases demonstrates that acute and chronic thrombotic stenoses or occlusions can be safely managed by ultrasound guided endovascular treatment minimizing the number of interventions, bleeding risk and radiation exposure.

Summary: Background: Traditionally endarterectomy has been considered as the gold standard technique for the treatment of common femoral artery (CFA) lesions. The aim of this study is to investigate the procedural safety and mid-term outcomes of minimal invasive Phoenix atherectomy for the treatment of CFA lesions. Patients and methods: Phoenix atherectomy was used for treatment of 61 consecutive, moderately to heavily calcified CFA lesions in 56 patients. Lesions were classified based on the CFA occlusive disease classification (Type I, II&III lesions). Primary endpoints were technical, procedural, and clinical success rate. Safety endpoints (vessel perforation, peripheral embolization) and clinically driven target lesion revascularization (TLR) were also assessed. Results: Of 61 CFA lesions, 58 (95%) exhibited at least moderate/severe calcification (PACSS3 in 38 (62%) and PACSS4 in 20 (33%) cases). Type III lesions were present in 30 (49%), type I/II lesions in 31 (51%) cases. Technical and procedural success was achieved in 30 (49%) and all 61 (100%) lesions, respectively with low complication rates (0% perforation, 2% embolization). Adjunctive treatment after atherectomy was performed using drug-coated balloon (DCB) in 35 (57%) and bail-out stenting in 6 (10%) cases. Target lesion revascularization (TLR) occurred in 4 (7%) cases during a mean follow-up duration of 11±7months. All patients exhibited clinical improvement at follow-up, showing mean Rutherford category reduction from 3.7±1.1 to 1.5±1.1 (p

Summary: Background: Physical attributes of conventional stents used in the ilio-caval territory are often unfavorable in the presence of external compression close to the bifurcation. A hybrid oblique stent was developed for the treatment of common iliac vein compression without compromising the contralateral iliac vein inflow. Patients and methods: The ongoing international monitored TOPOS study enrolled 60 patients with post-thrombotic syndrome (PTS) treated with the sinus-Obliquus stent (optimed) and provisional distal stent extension. At 3-month follow-up, patency rates were obtained from duplex ultrasound, and clinical outcomes were assessed by the Villalta score, revised venous severity score (rVCSS), pain intensity score and chronic venous disease quality of life questionnaire (CIVIQ-20). Results: Mean age was 46.6 ± 14.9 years (68.3 % women). Mean number of implanted stents was 1.9 ± 0.6; 12 (20 %) patients received the hybrid oblique stent only. Forty-eight (80 %) patients had distal stent extension, and 42 (70 %) had stents below the inguinal ligament. Four (7 %) patients (all with stent extension) developed stent thrombosis. Primary and secondary patency rates at 3 months were 93.1 % (95 %CI 83.3–98.1 %), and 100 % (95 %CI 93.8–100 %), respectively. Improvement in Villalta, rVCSS, CIVIQ-20, and pain intensity score from baseline to 3-month follow-up was 6.9 ± 1.4 points (95 %CI 4.1–9.8; p

Abstract. Postthrombotic syndrome (PTS) is the most common complication after iliofemoral deep vein thrombosis. It reduces quality of life and increases deep vein thrombosis (DVT)-related costs. The clinical symptoms and severity of PTS may vary; the most common symptoms include edema, pain (venous claudication), hyperpigmentation, lipodermatosclerosis, and ulceration. PTS is based on the principle of outflow obstruction, which may be caused by venous hypertension and may lead to valvular damage and venous reflux or insufficiency. Recent technical developments and new stent techniques now allow recanalisation of even complex venous outflow obstructions within the iliac vein and the inferior vena cava. This manuscript gives an overview on the latest standards for venous recanalisation.

Background Atherosclerosis is a chronic inflammatory disease of the arterial wall. Adjacent to lamina intima lesion progression, a cellular compound develops in the lamina adventitia, defined as tertiary lymphoid organs (TLO) in mice. But in human system, it remains unknown whether these adventitial cellular accumulations represent these highly organized immunological structures. Patients and methods In this study, we investigated whether the adventitial cellular compounds represent TLOs in 72 human coronary artery samples by immunoenzyme staining. Results The study showed that the adventitial cellular compound partly represented TLOs in human coronary arteries affected by atherogenesis in patients suffering from ischemic heart disease (56%) or a fatal myocardial infarction (100%), but not dilated cardiomyopathy. In addition, we established a classification for human TLOs, stage I–III, and showed that all stages were present in diseased coronary arteries. The stage of TLOs highly correlated with lesion size as well as plaque instability and rupture, and all patients with a myocardial infarction had stage III. Additionally, there were cellular infiltration and destruction of the lamina media, which were restricted to TLOs next to ruptured plaques in patients with a fatal myocardial infarction. Conclusions TLOs are present in patients with a coronary artery disease and highly correlated with lesion size, plaque instability, and rupture. Further studies are needed to investigate whether TLOs might be a specific diagnostic and drug target to modify plaque instability/rupture.

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

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.

Galectin-3 binding protein (Gal-3BP) is a secreted protein associated with inflammation and carotid atherosclerosis. We hypothesized that high Gal-3BP levels may indicate unfavorable plaque morphology and outcome in coronary artery disease (CAD).Gal-3BP plasma levels were measured by ELISA in 233 patients (63 ± 10 years, 50.2% male) undergoing computed coronary angiography tomography (CCTA).In 149 patients, CCTA confirmed CAD (stenosis grade20%). Mean Gal-3BP plasma levels were 5.9 ± 2.7 μg/mL and did not differ between patients with or without CAD. Over a follow-up time of up to 4.4 years (median 2.5 years), there were 17 cases of revascularization, five cases of myocardial infarction, and five deaths (four non-cardiac, one fatal myocardial infarction). Kaplan-Meier analysis revealed that high Gal-3BP levels were significantly associated with long-term mortality (p 0.001). Cox proportional hazards regression analysis showed that this association was independent of cardiovascular risk factors (HR 1.238, 95%-CI 1.012-1.514, p = 0.038). After adjustment for troponin T and C-reactive protein (hs-CRP) levels, significance was lost (p = 0.123). Further analysis revealed that Gal-3BP levels were significantly related to body mass index and hs-CRP levels indicating an association with metabolic and inflammatory distress. There was no correlation between Gal-3BP and calcium score, plaque volume, or vascular remodeling.While high Gal-3BP plasma levels are associated with long-term mortality, we could not confirm it as a marker of cardiac mortality or unstable plaque morphology.

This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy.Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation.Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients.Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank).CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.

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

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Christian Erbel,1 Christian A Gleissner,1 Fabrice F Darche,1 Dierk Thomas,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, Heidelberg University Hospital, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Purpose: Early posttransplant atrial fibrillation (AF) has been associated with worse clinical outcomes after heart transplantation (HTX). The type of surgical technique may constitute a relevant risk factor for AF. Patients and methods: This retrospective single-center study included 530 adult patients. Patients were stratified by surgical technique (biatrial, bicaval, or total orthotopic HTX) and early posttransplant heart rhythm (AF or sinus rhythm). Univariate and multivariate analyses were performed to evaluate risk factors for AF. Results: A total of 161 patients received biatrial HTX (30.4%), 115 bicaval HTX (21.7%), and 254 total orthotopic HTX (47.9%). Sixty-one of 530 patients developed early posttransplant AF (11.5%). Patients with AF showed a statistically inferior 5-year survival compared to those with sinus rhythm (P

We sought to determine the ability of quantitative myocardial perfusion reserve index (MPRI) by cardiac magnetic resonance (CMR) and high-sensitive troponin T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant (HT) recipients. In 108 consecutive HT recipients (organ age 4.1 ± 4.7 years, 25 [23%] with diabetes mellitus) who underwent cardiac catheterization, CAV grade by International Society for Heart & Lung Transplantation (ISHLT) criteria, MPRI, late gadolinium enhancement (LGE) and hsTnT values were obtained. Outcome data including cardiac death and urgent revascularization (“hard cardiac events”) and revascularization procedures were prospectively collected. During a follow-up duration of 4.2 ± 1.4 years, seven patients experienced hard cardiac events and 11 patients underwent elective revascularization procedures. By multivariable analysis, hsTnT and MPRI both independently predicted cardiac events, surpassing the value of LGE and CAV by ISHLT criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and low MPRI showed the highest rates of cardiac events (annual event rate = 14.5%), while those with low hsTnT and high MPRI exhibited excellent outcomes (annual event rate = 0%). In conclusion, comprehensive “bio-imaging” using hsTnT, as a marker of myocardial microinjury, and CMR, as a marker of microvascular integrity and myocardial damage by LGE, may aid personalized risk-stratification in HT recipients.

Low anti-phosphorylcholine (PC) IgM plasma levels have been associated with increased incidence of adverse events in coronary artery disease (CAD). The underlying mechanisms are unclear. We hypothesized that atheroprotection mediated by anti-PC IgM antibodies is associated with reduced vascular remodeling and therefore tested whether anti-PC IgM plasma levels independently predict vascular remodeling. In a prospective cross-sectional study, anti-PC IgM plasma levels were measured in 175 consecutive patients with suspected CAD undergoing cardiac computed tomography angiography. Plaque morphology was thoroughly analyzed. Vascular remodeling was defined by a change in the vessel diameter at the plaque site in comparison to the reference segment proximal to the lesion (reference diameter) of ≥10 %. Mean age of the patients was 64.8 ± 10.7 years, 48.6 % were female. In 98 patients CAD was diagnosed, 57 (58.2 %) of which displayed non-obstructive CAD (stenosis

Andreas O Doesch,1 Susanne Mueller,1 Christian Erbel,1 Christian A Gleissner,1 Lutz Frankenstein,1 Stefan Hardt,1 Arjang Ruhparwar,2 Philipp Ehlermann,1 Thomas Dengler,3 Hugo A Katus1 1Department of Cardiology, 2Department of Cardiovascular Surgery, University of Heidelberg, Heidelberg, 3SLK Plattenwald Hospital, Bad Friedrichshall, Germany Background: Due to graft denervation, sinus tachycardia is a common problem after heart transplantation, underlining the importance of heart rate control without peripheral effects. However, long-term data regarding the effects of ivabradine, a novel If channel antagonist, are limited in patients after heart transplantation. Methods: In this follow-up analysis, the resting heart rate, left ventricular mass indexed to body surface area (LVMI), tolerability, and safety of ivabradine therapy were evaluated at baseline and after 36 months in 30 heart transplant recipients with symptomatic sinus tachycardia versus a matched control group. Results: During the study period, ivabradine medication was stopped in three patients (10% of total). Further analysis was based on 27 patients with 36 months of drug intake. The mean patient age was 53.3±11.3 years and mean time after heart transplantation was 5.0±4.8 years. After 36 months, the mean ivabradine dose was 12.0±3.4 mg/day. Resting heart rate was reduced from 91.0±10.7 beats per minute before initiation of ivabradine therapy (ie, baseline) to 81.2±9.8 beats per minute at follow-up (P=0.0006). After 36 months of ivabradine therapy, a statistically significant reduction of LVMI was observed (104.3±22.7 g at baseline versus 93.4±18.4 g at follow-up, P=0.002). Hematologic, renal, and liver function parameters remained stable during ivabradine therapy. Except for a lower mycophenolate mofetil dose at follow-up (P=0.02), no statistically significant changes in immunosuppressive drug dosage or blood levels were detected. No phosphenes were observed during 36 months of ivabradine intake despite active inquiry. Conclusion: In line with previously published 12-month data, heart rate reduction with ivabradine remained effective and safe in chronic stable patients after heart transplantation, and also during 36-month long-term follow-up. Further, a significant reduction of LVMI was observed only during ivabradine therapy. Therefore, ivabradine may have a sustained long-term beneficial effect with regard to left ventricular remodeling in heart transplant patients. Keywords: heart transplantation, heart rate control, ivabradine, left ventricular mass

Abstract. Post-thrombotic syndrome is common after iliofemoral vein thrombosis. Conservative therapy, mainly limited to compression and anticoagulation therapy, might not be sufficient in controlling symptoms. Interventional recanalization of the chronically occluded iliac veins is an evolving method, promising rapid relief of symptoms. Here, we present two cases of complex interventions in one patient with preceding pelvic radiotherapy due to a plasmacytoma and in another patient in whom a cava wedge resection had been performed because of cystic echinococcosis in the liver.

Background and aims Galectin-3 binding protein (Gal-3BP) has been associated with inflammation and cancer, however, its role in coronary artery disease (CAD) and cardiovascular outcome remains unclear. Methods Gal-3BP plasma levels were measured by ELISA in 2922 individuals from the LURIC study (62.7 ± 10.6 years, 62.7% male). All-cause and cardiovascular mortality was assessed by Kaplan-Meier analysis and Cox proportional hazards regression. Causal involvement of Gal-3BP was tested for by Mendelian randomization. Gal-3BP effects on human monocyte-derived macrophages were assessed in vitro . Results During 8.8 ± 3.0 years, 866 individuals died, 654 of cardiovascular causes. There was a significant increase in all-cause and cardiovascular mortality with increasing Gal-3BP quintiles. After thorough adjustment, all-cause mortality remained significantly increased in the fifth Gal-3BP quintile (HR Q5 1.292 (1.030–1.620), p = 0.027); cardiovascular mortality remained increased in Gal-3BP quintiles two to five (HR Q5 1.433 (1.061–1.935, p = 0.019). Gal-3BP levels were not associated with diagnosis and extent of coronary artery disease. In addition, Mendelian randomization did not show a direct causal relationship between Gal-3BP levels and mortality. Gal-3BP levels were, however, independently associated with markers of metabolic and inflammatory distress. In vitro , Gal-3BP induced a pro-inflammatory response in human monocyte-derived macrophages. Adding Gal-3BP levels to the ESC score improved risk assessment in patients with ESC SCORE-based risk >5% ( p = 0.010). Conclusions In a large clinical cohort of CAD patients, Gal-3BP levels are independently associated with all-cause and cardiovascular mortality. The underlying mechanisms may likely involve metabolic and inflammatory distress. To further evaluate the potential clinical value of Gal-3BP, prospective studies are needed.

Summary Following heart transplantation, cardiac biomarkers remain elevated for several weeks eventually as a result of membrane leakage of the donor organ. We now test the predictive power of blood levels of troponin T (TNT) measured by the new hsTNT assay (Roche Diagnostics, Roche Diagnostics, Mannheim, Germany) early after heart transplantation. TNT was determined in 141 cardiac allograft recipients and 40 controls. Our findings demonstrate that patients who died within the first year after transplantation had significantly higher median hsTNT serum levels 6 weeks after transplantation (156 ng/l ± 203 vs. 29 ng/l ± 21, P = 0.0002). Using ROC analysis, a serum hsTNT concentration of 33.55 ng/l 6 weeks after transplantation was found to be the best cutoff to predict death at 1 year (HR 0.16, 95%CI:0.05–0.46, P = 0.001) with a sensitivity of 90.91% and a specificity of 70.97%. In addition, survival at 5 years (HR 0.15, 95% CI 0.06–0.35, P

A chronic (auto)immune response is the critical mechanism in atherosclerosis. Interleukin-17A is a pivotal effector cytokine, which modulates immune cell trafficking and initiates inflammation in (auto)immune and infectious diseases. However, expression of IL-17A in the context of human atherosclerosis has hardly been explored. Carotid artery plaques were collected from 79 patients undergoing endarterectomy. Patients were grouped according to their symptomatic status (TIA, stroke), plaque morphology and medication. Quantitative RT-PCR was used to analyze tissue inflammation and immunohistochemistry to assess cellular source of IL-17A expression and lesion morphology. Carotid plaques from patients with ischemic symptoms were characterized by a highly activated inflammatory milieu including accumulation of T cells (p = 0.04) and expression of IL-6 and VCAM1 (p = 0.02, 0.01). Expression of IL-17A and its positive regulators IL-21 and IL-23 was present in atherosclerotic lesions, significantly upregulated in atheromas of symptomatic patients (p = 0.005, 0.004, 0.03), and expression of IL-17A and IL-21 showed a strong correlation (p = 0.002, r = 0.52). The cellular sources of lesional IL-17A expression are T cells, macrophages, B cells and plasma cells. Vulnerable/ruptured (complicated) plaques were significantly associated with IL-17A expression levels (p = 0.003). In addition, IL-17A showed a marked negative correlation with the potent anti-inflammatory/atheroprotective cytokine IL-10 (p = 0.0006, r = −0.46). Furthermore, treatment with a HMG-CoA reductase inhibitor or acetylsalicylic acid showed reduced levels of IL-21, IL-23 and VCAM1 (all p < 0.05), but did not influence IL-17A. The association of IL-17A with ischemic symptoms and vulnerable plaque characteristics suggests that the pro-inflammatory cytokine IL-17A may contribute to atherosclerosis und plaque instability.

Modified release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. Simplification of regimen has been associated with better adherence. This study evaluated patient adherence, as well as safety and efficacy among chronic stable heart transplantation (HT) patients switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to (once daily) modified release TAC.We switched 54 chronic stable patients (41 males and 13 females) from twice daily dosing with conventional TAC or CsA to once daily dosing with modified release TAC. Self-reported adherence was assessed at baseline and at 4 months after the switch using the Basel Assessment of Adherence with Immunosuppressive Medication Scale [BAASIS]), a 4-item validated questionnaire including also a Visual Analogue Scale (VAS). Nonadherence was defined as any self-reported nonadherence on any item.Modified release TAC was discontinued in 4 patients because of diarrhea (n = 1) or gastrointestinal discomfort (n = 3) leaving 50 evaluable patients. Overall nonadherence at baseline for any of the 4 items was 74% versus 38% after 4 months (P = .0001). Thereafter, adherence improved in 28 patients (56.0%), was unchanged in 18 (36.0%), and decreased in 4 subjects (8.0%). The VAS score improved from 82.3% ± 2.6% to 97.5% ± 4.8% (P.0001). No significant changes were observed after 4 months regarding hematologic, renal, or liver function parameters (all P = NS).Therapeutic regimens for transplant recipients are often complex, contributing to a high incidence of medication nonadherence. This study in chronic, stable, heart transplantation patients demonstrated a significant improvement in patient adherence after a switch to modified release TAC, which was generally well tolerated.

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

Aims To evaluate the incremental value of low endothelial shear stress (ESS) combined with high-resolution magnetic resonance imaging (MRI)- and computed tomography angiography (CTA)-based imaging for the prediction of inflamed plaque. Methods and results Twelve hereditary hyperlipidaemic rabbits underwent quantitative analysis of plaque in the thoracic aorta with 256-slice CTA and USPIO-enhanced (ultra-small superparamagnetic nanoparticles, P904) 1.5-T MRI at baseline and at 6-month follow-up. Computational fluid dynamics using CTA-based 3D reconstruction of thoracic aortas identified the ESS patterns in the convex and concave curvature subsegments of interest. Subsegments with low baseline ESS exhibited significant increase in wall thickness and plaque inflammation by MRI, in non-calcified plaque burden by CTA, and developed increased plaque size, lipid and inflammatory cell accumulation (high-risk plaque features) at follow-up by histopathology. Multiple regression analysis identified baseline ESS and inflammation by MRI to be independent predictors of plaque progression, while receiver operating curve analysis revealed baseline ESS alone or in combination with inflammation by MRI as the strongest predictor for augmented plaque burden and inflammation (low ESS at baseline: AUC = 0.84, P < 0.001; low ESS and inflammation by molecular MRI at baseline: AUC = 0.89, P < 0.001). Conclusion Low ESS predicts progression of plaque burden and inflammation as assessed by non-invasive USPIO-enhanced MRI. Combined non-invasive assessment of ESS and imaging of inflammation may serve to predict plaque with high-risk features.

Background: Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling. Methods: A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity. Mice (25 mice/group; 10 mice/group in a confirmation study) were examined by computed tomography, histology, gene expression changes, and for survival. In vitro experiments were performed to directly study the interaction of CTGF blockade and radiation. All statistical tests were two-sided. Results: Administration of FG-3019 prevented (∼50%–80%) or reversed (∼50%) lung remodeling, improved lung function, improved mouse health, and rescued mice from lethal irradiation (P < .01). Importantly, when antibody treatment was initiated at 16 weeks after thoracic irradiation, FG-3019 reversed established lung remodeling and restored lung function. CTGF blockade abrogated M2 polarized macrophage influx, normalized radiation-induced gene expression changes, and reduced myofibroblast abundance and Osteopontin expression. Conclusion: These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases.

Aldose reductase (AR; gene AKR1B1) is the rate-limiting enzyme of the polyol pathway and has been associated with diabetes and atherosclerosis. Here, we sought to identify the mechanisms underlying differential AR expression in human atherosclerotic plaque macrophages. In vitro, M1-polarized human monocyte-derived macrophages expressed significantly higher levels of AKR1B1 mRNA and AR protein compared with M2-polarized macrophages. AR activity was significantly higher in M1 macrophages. AKR1B1 mRNA expression correlated positively with the M1 marker TNF ( r = 0.430, P = 0.006) and negatively with the M2 marker MRC1 ( r = −0.443, P = 0.044). Increased AR expression in M1 macrophages depended on hyperglycemia. Concomitantly, expression of SLC2A1 (coding for the Glc transporter GLUT-1) was significantly higher in M1 than in M2 macrophages. Pharmacological inhibition of GLUT-1 using STF-32 completely abrogated Glc-induced AR up-regulation in M1 macrophages. When analyzing AR expression in post-mortem coronary artery plaque macrophages, a history of diabetes was associated with a significantly increased proportion of CD68+AR++ macrophages, supporting the in vivo relevance of our in vitro findings. We demonstrate that the phenotype of atherosclerotic plaque macrophages may be affected by cardiovascular risk factors such as hyperglycemia. Our data illustrate the complex interplay between systemic and local factors in atherogenesis.

Unstable atherosclerotic plaque typically contains an infiltrate of activated macrophages and activated T cells. This study established a functional profile of plaque-residing dendritic cells (DC) to examine whether they can function as Ag-presenting cells to facilitate in situ T-cell activation.Carotid artery plaque tissues were collected from 19 asymptomatic and 38 symptomatic patients undergoing endarterectomy. Matched samples of normal coronary artery wall, stable nonruptured plaque, and eroded unstable plaque were harvested from patients with fatal myocardial infarction. Quantitative PCR and immunohistochemistry were used to analyze the tissues for markers of DC activation (CD83, CD86, CCL19,CCL21) and correlate them with T-cell activation (IFN-gamma,TNF-alpha).Carotid artery plaques from patients with ischemic symptoms compared to asymptomatic patients were characterized by the presence of high amount of T-cells (P0.01) and tissue production of high levels of the T-cell cytokines IFN-gamma (P=0.001) and TNF-alpha (P=0.006). Plaque tissues from patients with ischemic complications contained elevated levels of CD83 (P0.001), a marker of DC activation, and the DC chemokines CCL19 (P=0.001) and CCL21 (P0.02). Unstable coronary artery plaques were similarly correlated compared to carotid plaques from symptomatic patients with the accumulation of T cells (P=0.001) and the production of T cell chemokines IFN-gamma (P=0.001) and TNF-alpha (P=0.002). Immunohistochemistry confirmed the presence of CD83(+) DC in the shoulder region of unstable plaques, where they produced the T cell-attracting chemokines CCL19 and CCL21. Mapping of activated DC demonstrated close contact between mature DC and T cells expressing the activation marker CD40 ligand (CD40L).Activated and fully mature DC are represented in the inflammatory infiltrate characteristic for unstable carotid and coronary atheroma. Such DC produce chemokines, and thus can regulate the cell traffic into the lesion. Through the expression of the costimulatory ligand CD86, plaque-residing DC can augment T-cell stimulation and provide optimal stimulation conditions for T lymphocytes, resembling the microenvironment in organized lymphoid tissues.

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Berthold Klein,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Fabrice F Darche,1 Dierk Thomas,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch11Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, GermanyObjective: The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.Methods: A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.Results: Mean recipient age at HTX was 51.2±10.5years and the mean follow-up period after HTX was 9.7±5.9years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P

Background The platelet chemokine CXCL4 induces monocyte differentiation resulting in a macrophage phenotype called "M4", which co-expresses CD68, MMP7, and S100A8. We hypothesized that M4 macrophages are associated with plaque destabilization. Methods Atherosclerotic arteries were obtained from explanted hearts of patients with severe coronary artery disease (CAD, n=32) and of patients with dilated cardiomyopathy and no or mild CAD (controls, n=19). Coronary arteries were stained with H&E, and immuno-fluorescence was performed against CD68, MMP7, and S100A8. Results Both CD68 + macrophages representing the entire macrophage population and MMP7 + S100A8 + CD68 + M4 macrophages could be reproducibly identified within all arterial layers. The average proportion of the M4 macrophage phenotype amongst all CD68 + macrophages was 31.7±16.2%. The highest number of M4 macrophages was found in the adventitia, followed by the intima. CD68 + and M4 macrophage numbers were significantly higher in patients with severe CAD. The presence of M4 macrophages within the intima and the media was significantly associated with plaque instability as determined by Stary class. Multivariate analysis showed a highly significant contribution of cardiovascular risk factors (P=0.008) to plaque instability, while only trends were observed for age (P=0.060) and intimal prevalence of M4 macrophages (P=0.098). Conclusions We demonstrate for the first time that M4 macrophages can be reproducibly found in coronary artery plaques. The prevalence of M4 macrophages is associated with indexes of plaque instability, most likely representing a surrogate marker of inflammatory activity. These findings suggest a pathogenetic role of M4 macrophages in vulnerable atherosclerotic plaques.

Atherosclerosis is the leading cause of death worldwide. Over the past two decades, it has been clearly recognized that atherosclerosis is an inflammatory disease of the arterial wall. Accumulating data from animal experiments have supported this hypothesis, however, clinical applications making use of this knowledge remain scarce. In spite of optimal interventional and medical therapy, the risk for recurrent myocardial infarction remains by about 20% over three years after acute coronary syndromes, novel therapies to prevent atherogenesis or treat atherosclerosis are urgently needed. This review summarizes selected potential molecu-lar inflammatory targets that may be of clinical relevance. We also review recent and ongoing clinical trails that target inflammatory processes aiming at preventing adverse cardiovascular events. Overall, it seems surprising that translation of basic science into clinical practice has not been a great success. In conclusion, we propose to focus on specific efforts that promote translational science in order to improve outcome and prognosis of patients suffering from atherosclerosis.

The presence of adventitial inflammation in correlation with atherosclerotic lesions has been recognized for decades. In the last years, several studies have investigated the relevance and impact of adventitial inflammation on atherogenesis. In the abdominal aorta of elderly Apoe(-/-) mice, adventitial inflammatory structures were characterized as organized ectopic lymphoid tissue, and therefore termed adventitial tertiary lymphoid organs (ATLOs). These ATLOs possess similarities in development, structure and function to secondary lymphoid organs. A crosstalk between intimal atherosclerotic lesions and ATLOs has been suggested, and several studies could demonstrate a potential role for medial vascular smooth muscle cells in this process. We here review the development, phenotypic characteristics, and function of ATLOs in atherosclerosis. Furthermore, we discuss the possible role of medial vascular smooth muscle cells and their interaction between plaque and ATLOs.

Despite advances in the pharmacologic and interventional treatment of coronary artery disease (CAD), atherosclerosis remains the leading cause of death in Western societies. X-ray coronary angiography has been the modality of choice for diagnosing the presence and extent of CAD. However, this technique is invasive and provides limited information on the composition of atherosclerotic plaque. Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) have emerged as promising non-invasive techniques for the clinical imaging of CAD. Hereby, CCTA allows for visualization of coronary calcification, lumen narrowing and atherosclerotic plaque composition. In this regard, data from the CONFIRM Registry recently demonstrated that both atherosclerotic plaque burden and lumen narrowing exhibit incremental value for the prediction of future cardiac events. However, due to technical limitations with CCTA, resulting in false positive or negative results in the presence of severe calcification or motion artifacts, this technique cannot entirely replace invasive angiography at the present time. CMR on the other hand, provides accurate assessment of the myocardial function due to its high spatial and temporal resolution and intrinsic blood-to-tissue contrast. Hereby, regional wall motion and perfusion abnormalities, during dobutamine or vasodilator stress, precede the development of ST-segment depression and anginal symptoms enabling the detection of functionally significant CAD. While CT generally offers better spatial resolution, the versatility of CMR can provide information on myocardial function, perfusion, and viability, all without ionizing radiation for the patients. Technical developments with these 2 non-invasive imaging tools and their current implementation in the clinical imaging of CAD will be presented and discussed herein.

Atherosclerosis is a chronic inflammatory disease of the vasculature. There are various methods to study the inflammatory compound in atherosclerotic lesions. Mouse models are an important tool to investigate inflammatory processes in atherogenesis, but these models suffer from the phenotypic and functional differences between the murine and human immune system. In vitro cell experiments are used to specifically evaluate cell type-dependent changes caused by a substance of interest, but culture-dependent variations and the inability to analyze the influence of specific molecules in the context of the inflammatory compound in atherosclerotic lesions limit the impact of the results. In addition, measuring levels of a molecule of interest in human blood helps to further investigate its clinical relevance, but this represents systemic and not local inflammation. Therefore, we here describe a plaque culture model to study human atherosclerotic lesion biology ex vivo. In short, fresh plaques are obtained from patients undergoing endarterectomy or coronary artery bypass grafting and stored in RPMI medium on ice until usage. The specimens are cut into small pieces followed by random distribution into a 48-well plate, containing RPMI medium in addition to a substance of interest such as cytokines or chemokines alone or in combination for defined periods of time. After incubation, the plaque pieces can be shock frozen for mRNA isolation, embedded in Paraffin or OCT for immunohistochemistry staining or smashed and lysed for western blotting. Furthermore, cells may be isolated from the plaque for flow cytometry analysis. In addition, supernatants can be collected for protein measurement by ELISA. In conclusion, the presented ex vivo model opens the possibility to further study inflammatory lesional biology, which may result in identification of novel disease mechanisms and therapeutic targets.

Ibrahim Gueler,1 Susanne Mueller,1 Matthias Helmschrott,1 Christian U Oeing,1 Christian Erbel,1 Lutz Frankenstein,1 Christian Gleißner,1 Arjang Ruhparwar,2 Philipp Ehlermann,1 Thomas J Dengler,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, University of Heidelberg, Heidelberg, 2Department of Cardiac Surgery, University of Heidelberg, Heidelberg, 3Department of Cardiology, SLK-Kliniken Heilbronn, Bad Friedrichshall, Germany Background: Type 2 Diabetes mellitus (T2DM) is a common comorbidity in patients after heart transplantation (HTx) and is associated with adverse long-term outcomes. Methods: The retrospective study reported here analyzed the effects of vildagliptin therapy in stable patients post-HTx with T2DM and compared these with control patients for matched-pairs analysis. A total of 30 stable patients post-HTx with T2DM were included in the study. Fifteen patients (mean age 58.6 ± 6.0 years, mean time post-HTx 4.9 ± 5.3 years, twelve male and three female) were included in the vildagliptin group (VG) and 15 patients were included in the control group (CG) (mean age 61.2 ± 8.3 years, mean time post-HTx 7.2 ± 6.6 years, all male). Results: Mean glycated hemoglobin (HbA1c) in the VG was 7.4% ± 0.7% before versus 6.8% ± 0.8% after 8 months of vildagliptin therapy (P = 0.002 vs baseline). In the CG, HbA1c was 7.0% ± 0.7% versus 7.3% ± 1.2% at follow-up (P = 0.21). Additionally, there was a significant reduction in mean blood glucose in the VG, from 165.0 ± 18.8 mg/dL to 147.9 ± 22.7 mg/dL (P = 0.002 vs baseline), whereas mean blood glucose increased slightly in the CG from 154.7 ± 19.7 mg/dL to 162.6 ± 35.0 mg/dL (P = 0.21). No statistically significant changes in body weight (from 83.3 ± 10.8 kg to 82.0 ± 10.9 kg, P = 0.20), total cholesterol (1.5%, P = 0.68), or triglyceride levels (8.0%, P = 0.65) were seen in the VG. No significant changes in immunosuppressive drug levels or dosages were observed in either group. Conclusion: Vildagliptin therapy significantly reduced HbA1c and mean blood glucose levels in post-HTx patients in this study with T2DM and did not have any negative effects on lipid profile or body weight. Thus, vildagliptin therapy presented an interesting therapeutic approach for this selected patient cohort. Keywords: immunosuppression, glycated hemoglobin, mean blood glucose

Atherosclerosis and its consequences (i.e. myocardial infarction and cardiac death) remain the major cause of morbidity and mortality in Western countries (Roger et al. 2011). Despite clinical advances that have substantially improved outcomes in patients suffering from coronary artery disease, including pharmacological interventions (e.g. novel anti platelet therapies, statins, etc.) as well as interventional and surgical therapies (e.g. drug-eluting stents), there is still a huge demand for improved diagnostic tools to identify patients at risk for adverse events as well as therapeutic means to prevent adverse events in these patients. Biomarkers such as high sensitivity CRP (Ridker 2007) or high sensitivity troponin T (Kurz et al. 2011) have brought some improvement in identifying patients requiring more intense treatment; however, the clinical need for better tools remains. An important concept that may help to improve clinical care for patients with coronary artery disease is the inducement of plaque stability. Atherosclerotic lesions can show features of plaque stability or plaque instability (Naghavi et al. 2003a, Naghavi et al. 2003b). Stable plaques are characterized by a thick fibrous cap and a small necrotic core. By contrast, unstable plaques display a thin fibrous cap and a large necrotic core consisting of apoptotic macrophages, foam cells, and smooth muscle cells. Unstable plaques are more likely to rupture, and plaque rupture may subsequently result in thrombosis and occlusion of the vessel leading to a myocardial infarction or stroke. A promising approach to identify potential markers of plaque instability may be the study of atherogenesis on a cellular and molecular level. During the development of atherosclerotic lesions, blood monocytes adhere to the activated endothelium, transmigrate into the subendothelial space, and differentiate towards macrophages, dendritic cells, or foam cells (Galkina & Ley 2009). Among the various leukocyte types involved in atherogenesis, monocytes and monocyte-derived macrophages represent the major fraction. The monocyte-macrophage differentiation process is affected by the extracellular matrix as well as by the combination of chemokines and cytokines representing the micromilieu of the plaque (Shashkin et al. 2005). In addition, cell-cell interactions may also affect the fate of monocytes within the atherosclerotic plaque. Monocyte-derived cells secrete chemokines, cytokines, and other mediators, leading to attraction of other immune cells and thereby promoting plaque progression and plaque instability (Shashkin et al. 2005). While it was initially thought that monocyte-derived macrophages represent a homogenous population

Background Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/everolimus). Methods Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2 ± 8.8 years, and mean time after transplantation was 2.3 ± 4.0 years (range, 0.2–13.0 years). Results At initial examination mean daily MMF dose was 2.2 ± 0.8 g. MMF dose was kept unchanged for the duration of study ( P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5 ± 2.2 mg/L vs 2.8 ± 1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2 ± 20.3 vs 65.2 ± 38.8 mg · h/L · g [MMF]; P = .02). Conclusions Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF.

The importance of an (auto)immune response in atherogenesis is becoming increasingly well understood. IL-17A-expressing T cells modulate immune cell trafficking, initiating inflammation and cytokine production in (auto)immune diseases. In human carotid artery plaques, we previously showed the presence of IL-17A-producing T cells and IL-23; however, IL-17A effects on atherogenesis have not been studied. Aortic root sections from 8-wk-old apolipoprotein E-deficient mice fed a standard chow diet were examined after 12 wk for lesion area, plaque composition, cellular infiltration, cytokine expression, and apoptosis. The treatment group (n = 15) received anti-IL-17A Ab and the controls (n = 10) received irrelevant Abs. Inhibition of IL-17A markedly reduced atherosclerotic lesion area (p < 0.001), maximal stenosis (p < 0.001), and vulnerability of the lesion. IL-17A mAb-treated mice showed reduced cellular infiltration, down-regulation of activation markers on endothelium and immune cells (e.g., VCAM-1), and reduced cytokine/chemokine secretion (e.g., IL6, TNFα, CCL5). To investigate possible mechanisms, different atherogenic cell types (e.g., macrophages, dendritic cells, HUVECs, vascular smooth muscle cells) were stimulated with IL-17A in addition to TNF-α, IFN-γ, or LPS to induce cellular activation or apoptosis in vitro. Stimulation with IL-17A induced proinflammatory changes in several atherogenic cell types and apoptotic cell death in murine cells. Functional blockade of IL-17A reduces atherosclerotic lesion development and decreases plaque vulnerability, cellular infiltration, and tissue activation in apolipoprotein E-deficient mice. The present data support a pathogenic role of IL-17A in the development of atherosclerosis by way of its widespread proinflammatory and proapoptotic effects on atherogenic cells.

Background. This study evaluates the objective rate of return to work after heart transplantation (HTX) in comparison with the patients' subjective rating of their work ability and identifies predictors for return to work in a German heart transplant center. Methods. A questionnaire covering demographics, clinical data, and professional aspects was sent to 200 heart transplant recipients at least 12 months after HTX. Participation was strictly anonymous enabling reliable results concerning subjective work ability. Results. Response rate was 150 of 200 (75%). During the time after HTX, 45 of 150 (30.0%) patients had ever been in a job. Thirty-five of 95 (36.8%) patients of formal working age (

Objective LIGHT (TNFSF 14) belongs to the tumor necrosis factor superfamily and is expressed by activated T cells as well as various types of antigen presenting cells. LIGHT binds to its cellular receptors TR2 and LTßR and has a co-stimulatory role in T cell activation. Here, we compared the relative expression of LIGHT in different immune cells and the biological activity of immune cell-derived LIGHT on endothelial cells. Methods and Results Surface expression of LIGHT and mRNA production by PBMC and isolated T cells (CD4+ or CD8+) significantly increased after stimulation with PMA (Phorbolester-12-Myristat-13-Acetat) + ionomycin. No LIGHT expression on PMA stimulated monocytes or monocytic-like THP-1 cells could be detected; differentiation of monocytes and THP-1 cells into macrophages, however, resulted in up-regulation of LIGHT. Supernatants of stimulated T cells contained higher concentrations of soluble LIGHT than macrophage supernatants normalized to cell numbers; release of soluble LIGHT was found to be dependent on metalloproteinase activity. Size determination of released soluble LIGHT by size exclusion chromatography revealed a molecular mass of ~60 kDa, suggesting a trimeric form. Released soluble LIGHT induced expression of proinflammatory antigens ICAM-1, tissue factor and IL-8 in human endothelial cells and caused apoptosis of IFN-γ pretreated endothelial cells. Soluble LIGHT was detected at low levels in sera of healthy controls and was significantly enhanced in sera of patients with chronic hepatitis C and rheumatoid arthritis (24.93 ± 9.41 vs.129.53 ± 49.14 and 172.13 ± 77.64; p < 0.0005). Conclusion These findings suggest that among immune cells activated T lymphocytes are the main source of soluble LIGHT with released amounts of soluble LIGHT markedly higher compared to platelets. Immune cell-derived membrane-bound and soluble trimeric LIGHT is biologically active, inducing proinflammatory changes in endothelial cells. Enhanced plasma levels of soluble LIGHT in patients with chronic infections suggest a role of LIGHT in systemic inflammatory activation.

Cardiac troponins provide excellent risk stratification in unstable angina (UA), but no reliable markers are available in troponin-negative patients. Beta2-integrin mediated T cell recruitment plays a pivotal role in coronary atherosclerotic plaque rupture. The present study investigates beta2-integrin activation on T cell subsets as a risk marker in UA. Functional activation (affinity/avidity) of beta2-integrins on T cells was measured using a flow cytometry-based whole blood assay in 87 patients with UA. Beta2-integrin activation was significantly higher in patients with severe coronary artery disease (sC) and myocardial infarction (MI) compared to patients with no/minimal coronary atherosclerosis (no/mC), irrespective of troponin status. Adjusted for cardiovascular risk factors, medication, left ventricular function, MI at enrollment and high sensitivity C-reactive protein (hsCRP), beta2-integrin activation was independently associated with incidence of revascularization, hospitalization and all major cardiovascular events during 9 months of follow-up after index investigation. The highest prognostic value of beta2-integrin activation was seen in troponin-and hsCRP-negative patients. Quantitative assessment of T cell beta2-integrin activation allows to identify high risk patients with UA and sC without established MI; furthermore, it is associated with incidence of future cardiovascular events independent of conventional risk factors (troponin, hsCRP).

Atherosclerotic plaque typically contains infiltrates of activated macrophages and T cells. In human carotid artery plaques, we previously showed the presence of IL-17 producing T cells (Th17) and IL-23. Effects of inhibition of the pro-inflammatory Th1 cytokine IL-17 on atherosclerosis development was studied in a rodent model. 25 female ApoE −/ − mice fed a normal diet were treated with a specific blocking antibody against IL-17 for 12 weeks (100 μg intraperitoneally once per week). For analysis, aortic root was embedded in OCT and serially cryosectioned in 5μm intervals; distal aorta was snap frozen for mRNA analysis. Sections every 75μm were stained with Oil RedO, the lesion area was quantified using PC-based image analysis. In IL-17 treated mice no changes in LDL cholesterol and anti-ox LDL antibodies were seen. Subsets of immune cells, surface marker expression and fraction of regulatory T cells in peripheral blood / spleen were unchanged. Inhibition of IL-17 markedly reduced atherosclerotic plaque volume by 65% (p=0.004) and fractional stenosis by 68% (p=0.01). Immunohistochemistry revealed significant reduction of cellular infiltration by T cells and macrophages in atherosclerotic lesions. By quantitative RT-PCR, significantly reduced expression was shown (among others) for CD3ϵ, egr-1, Akt and RANKL (all p< 0.01). Functional blockade of Th1 cytokine IL-17 reduces atherosclerotic lesion development in an established animal model without major derangement of peripheral cellular immunity. Our findings suggest a relevant role for IL17-producing T cells in atherosclerosis warranting further study of pathogenic mechanisms and therapeutic potential.

Background CXCL4 is a platelet chemokine released at micromolar concentrations upon platelet activation. CXCL4 has been shown to promote atherogenesis by various mechanisms. However, data on CXCL4 plasma levels in patients with coronary artery disease are largely inconclusive. Computed coronary artery angiography (CCTA) represents an excellent tool to quantify and characterize coronary atherosclerotic plaques. We hypothesized that increased CXCL4 plasma levels may be associated with features of plaque instability resulting in adverse cardiovascular events. Specifically, we sought to determine whether CXCL4 levels are correlated with specific features of coronary artery disease including (1) plaque volume, (2) calcium score, (3) degree of stenosis, or (4) vascular remodeling. Methods and Results CXCL4 plasma levels were measured by ELISA in 217 patients undergoing CCTA for suspected CAD (mean age 64.2 ± 9.4 years, 107 (49.3%) male). Mean CXCL4 plasma levels were 12.5 ± 4.6 ng/mL. There was no significant correlation between CXCL4 levels and any clinical or demographic parameters including cardiovascular risk factors. CXCL4 plasma levels did not differ between patient with or without coronary artery disease (CAD: 12.5 ± 4.5 ng/ml, no CAD: 12.5 ± 4.8 ng/ml). Neither univariate nor multivariate analysis showed an association between CXCL4 levels and plaque volume, total calcium score, degree of stenosis, or vascular remodeling. Subgroup analysis of patients with CAD as confirmed by CCTA did not show any association of CXCL4 levels with the extent of CAD. Conclusions While CXCL4 may be present and active within the arterial wall, local increase of CXCL4 may not translate into systemically elevated CXCL4 levels. Further studies will have to test whether CXCL4 may still represent a suitable therapeutic target in human atherosclerosis.

Mohammadreza Akhavanpoor,1,2,* Christian A Gleissner,1,2,* Stephanie Gorbatsch,1,2 Andreas O Doesch,1,2 Hamidreza Akhavanpoor,1,2 Susanne Wangler,1,2 Frederik Jahn,1,2 Felix Lasitschka,3 Hugo A Katus,1,2 Christian Erbel1,2 1Department of Cardiology, University of Heidelberg, 2DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, 3Institute of Pathology, University ofHeidelberg, Germany *These authors contributed equally tothis work Abstract: Despite advances in the pharmacologic and interventional treatment of coronary artery disease, atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease, and elevated expression of CCL19 and CCL21 has been observed in ruptured lesions of coronary arteries of patients with myocardial infarction and carotid plaques of patients with ischemic symptoms, as well as in plasma of coronary artery disease patients. However, the exact role of CCL19 and CCL21 in atherosclerosis remains unknown. In order to identify CCL19 and CCL21 as a novel therapeutic target, we performed bone marrow transplantation as an immunomodulatory treatment concept. Bone marrow of plt/plt mice (lacking CCL19 and CCL21-Ser) was transplanted into atherogenic Ldlr-/- mice. The study demonstrated a significantly increased inflammatory cellular infiltration into the lesions of plt/plt/Ldlr-/- mice versus controls. Although the level of chemoattraction was increased, messenger ribonucleic acid and protein levels in thoracic aorta and serum of several proinflammatory cytokines (TNFα, IFNγ, IL-6, IL-12, and IL-17) were significantly reduced in plt/plt/Ldlr-/- versus control mice. Increased influx, accompanied by reduced activation of leukocytes in atherosclerotic lesion, was accompanied by increased plaque stability but unchanged lesion development. In conclusion, modulation of the chemokines CCL19 and CCL21 represents a potent immunoregulatory treatment approach, and thus represents a novel therapeutic target to stabilize atherosclerotic lesions. Keywords: atherosclerosis, chemokines, immunomodulatory therapy, bone marrow trans­plantation

Transient left ventricular (LV) ballooning syndrome, or Takotsubo syndrome, is characterized by a reversible LV dysfunction. The pathophysiology has not been fully elucidated, but an excess of catecholamines seems to have an essential role. The case of a 27-year-old man who developed transient LV dysfunction resembling Takotsubo syndrome after self-injection of adrenaline is described. The present case may provide additional evidence to the hypothesis of excess sympathetic activation in LV ballooning syndrome.

Maximilian Kraeuter,1 Matthias Helmschrott,1 Christian Erbel,1 Christian A Gleissner,1 Lutz Frankenstein,1 Bastian Schmack,2 Arjang Ruhparwar,2 Philipp Ehlermann,1 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, 2Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany Background: Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated. Methods: Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral®) according to the patients’ preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared. Results: The mean DNL (adapted to the daily CSA dose in mg) was 0.71±0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL)/mg, (P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed. Conclusion: This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well-tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient population. However, multiple switches between different generic immunosuppressants must especially be avoided in the interest of patient safety, and close follow-up examinations must be warranted. Keywords: heart transplantation, immunosuppression, generic cyclosporine A