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Radke P.W.,University of Lübeck | Joost A.,University of Lübeck | Hartwig S.,Biotronik SE and Co. KG | Bayer G.,Biotronik SE and Co. KG | Wittchow E.,Biotronik SE and Co. KG
EuroIntervention | Year: 2011

Aims: The vascular effects of drug- eluting balloon (DEB) deployment in the absence of coronary stents have not been characterised. This study evaluated potential vascular effects of paclitaxel-coated angioplasty balloons using different excipients in the absence of additional stents. Methods and results: A total 45 porcine arteries were treated with paclitaxel-coated DEBs using four different excipients (all 3.0 μg/mm2): A) iopromide (n=9), B) ATEC excipient (n=8), C) BTHC excipient (n=10), D) lecithine excipient (n=10). Uncoated bare angioplasty balloons served as controls (n=8). Histology, histomorphometry, and quantitative angiography analysis were performed 28 days following intervention. Tissue concentrations of paclitaxel were measured in selected animals using BTHC excipient (n=39 arteries) and reached maximum concentrations of 165 ng/mg 30 min after delivery in coronary target tissue. There were no differences in efficacy endpoints using histomorphology or quantitative angiography between groups. In contrast, however, treatment with DEBs using BTHC excipient or iopromide was associated with increased fibrin deposition and inflammation indicating delayed vascular healing. DEBs using lecithin excipient or uncoated angioplasty balloons did not induce any comparable vascular effects. Conclusions: Effective excipients are necessary to accomplish successful balloon facilitated paclitaxel delivery, which is associated with delayed vascular healing as a sign of successful drug transfer. The potential of DEBs to diminish restenosis following angioplasty may be insufficient in the absence of additional stents. © Europa Edition 2011. All rights reserved.

Wollmann C.G.,Hospital Of St Polten Lilienfeld | Wollmann C.G.,Institute of Research on Ischemic Heart Diseases and Rhythmology | Steiner E.,Institute of Diagnostic Imaging | Vock P.,Hospital Of St Polten Lilienfeld | And 4 more authors.
Journal of Cardiovascular Magnetic Resonance | Year: 2012

Background: The purpose of this study was to evaluate the feasibility of the magnetic resonance (MR) conditional pacemaker (PM) system (Evia SR-T and DR-T with Safio S leads) under MR conditions. Methods. Patients with standard PM indications and Evia PM were eligible for enrollment in this single center prospective non-randomized pilot study. Patients underwent MR of the brain and lower lumbar spine at 1.5 Tesla. Atrial (RA) und ventricular (RV) lead parameters (sensing, pacing threshold [PTH], pacing impedance) were assessed immediately before (baseline follow-up [FU]) and immediately after MRI (1 st FU), after 1 month (2nd FU) and 3 months (3 rd FU). The effect of MR on serious adverse device effect (SADE) free-rate, on atrial and ventricular sensing (AS/VS; mV) and atrial (RA) and ventricular (RV) pacing thresholds (PTH; V/0.4 ms) were investigated between baseline and 2nd FU. Continuous variables are expressed as meanSD and were compared using paired Students t-test. A p<0.05 was considered significant. Results: Thirty-one patients were enrolled. One patient had to be excluded because of an enrollment violation. Therefore, data of 30 patients (female 12 [40%], age 7312 years, dual chamber PM 15 [50%]) were included in this analysis. No MR related SADE occurred. Lead measurements were not statistically different between the baseline FU and the 2nd FU (AS/VS at baseline 3.22.1/15.06.0, at 2nd FU 3.22.1/14.96.5; p=ns. RA-PTH/RV-PTH at baseline 0.680.18/0.780.22, at 2nd FU 0.710.24/0.780.22; p=ns). The presence of the permanent pacemakers led to MR imaging artifacts on diffusion weighted sequences of the brain, but did not affect other sequences (e.g. FLAIR and T2 weighted spin-echo images). Conclusion: The use of the MR conditional Evia PM in a MR environment under predefined conditions is feasible. No MR related SADEs nor clinically relevant changes in device functions occurred. © 2012 Wollmann et al.; licensee BioMed Central Ltd.

Koppara T.,TU Munich | Wittchow E.,Biotronik SE and Co. KG | Byrne R.A.,TU Munich | Bayer G.,Biotronik SE and Co. KG | And 2 more authors.
EuroIntervention | Year: 2016

Aims: The purpose of the present study was to examine the comparative vascular healing response to stents coated with permanent or biodegradable polymer and uncoated stents in a porcine model of coronary artery stenting. Methods and results: Juvenile pigs were randomly allocated to implantation of stents coated with permanent polymer (PP, methacrylate-based, n=10), biodegradable polymer (BP, poly-lactic acid-based, n=10) or bare metal control stents (n=10), in the absence of antiproliferative drugs. At 28 days, animals were sacrificed and specimens prepared for histopathologic assessment. Endothelialisation was complete in all treatment groups. Vascular injury at 28 days was greater in PP stents as compared with uncoated stents (p=0.05) though not as compared with BP-coated stents (p=ns). PP stents showed increased inflammatory scores compared with BP-coated (p=0.03) and uncoated stents (p=0.02). There was also greater neointimal growth with PP-coated stents compared with uncoated stents (p=0.02). Conclusions: In the absence of antiproliferative drugs, stents coated with methacrylate-based PP, but not with poly-lactic acid-based BP, provoked significant vessel wall inflammatory reactions resulting in greater vascular injury and increased neointimal growth compared with uncoated stents. Biodegradable polymer coatings may be considered preferable to facilitate drug elution with minimal vessel wall toxicity. © Europa Digital & Publishing 2016. All rights reserved.

Koenig S.,Medical University of Graz | Schernthaner M.,Medical University of Graz | Maechler H.,Medical University of Graz | Kappe C.O.,University of Graz | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

TRPC-mediated Ca2+ entry has been implicated in the control of smooth muscle proliferation and might represent a pivotal mechanism underlying in-stent restenosis. As we have observed significant expression of TRPC3 in human smooth muscle from the coronary artery as well as the aorta, we tested the efficiency of a recently discovered TRPC3 selective Ca2+ entry blocker Pyr3 to prevent vascular smooth muscle proliferation and stent implantation-induced hyperplasia of human aorta. The effect of Pyr3 on proliferation was measured by detection of BrdU incorporation and PCNA expression in human coronary smooth muscle and microvascular endothelium, which displays significantly smaller expression levels of TRPC3 as compared with smooth muscle. Pyr3 inhibited smooth muscle proliferation but lacked detectable effects on endothelial proliferation. Measurements of ATP-induced Ca 2+ signals revealed that Pyr3 suppressed agonist-induced Ca 2+ entry more effectively in vascular smooth muscle than in endothelial cells. Inhibitory effects of Pyr3 on stent implantation-induced arterial injury was tested using a novel in vitro model of in-stent hyperplasia in human arteries based on organ typical culture of human aortic constructs. Pyr3 effectively prevented increases in tissue levels of PCNA and Ki-67 at 2 weeks after stent implantation into human aortae. Similarly, proliferation markers were significantly suppressed when implanting a Pyr3-releasing stent prototype as compared with a bare metal stent (BMS) control. Our results suggest TRPC3 as a potential target for pharmacological control of smooth muscle proliferation. Selectively inhibition of TRPC Ca2+ entry channels in vascular smooth muscle is suggested as a promising strategy for instent restenosis prevention. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Koppara T.,Deutsches Herzzentrum Munich | Joner M.,Deutsches Herzzentrum Munich | Bayer G.,Biotronik Se and Co. Kg | Steigerwald K.,Deutsches Herzzentrum Munich | And 2 more authors.
Thrombosis and Haemostasis | Year: 2012

Biodegradable stent coatings were recently introduced as a potential solution to overcome sustained inflammatory responses observed with permanent polymer-based drug-eluting stents. In a preliminary study, selected biodegradable or permanent polymer-based sirolimus-eluting stent (SES) formulations were screened for effectiveness in comparison to bare metal stents (BMS) at 28 days. Subsequently, the most favourable SES formulation was compared to commercially available SES (Cypher™) at 28, 90 and 180 days to investigate the histopathologic response as well as tissue, blood and organ pharmacokinetics. Overlapping SES implantation was conducted to evaluate vascular healing at 28 days in this particular setting. SES with biodegradable poly (L-lac-tide) polymer (PLLA) or poly(lactide-co-glycolide) showed the most favourable outcome with regards to reductions in neointimal area in comparison to BMS at 28 days. The PLLA SES showed a similar reduction in neointimal area compared to Cypher™ at 28 days, with significant greater reductions at 90 and 180 days (1.7 ± 0.7 mm 2 vs. 3.1 ± 1.5 mm 2, p=0.03 and 1.8 ± 1.2 mm 2 vs. 3.0 ± 1.5 mm 2, p=0.01, respectively). Si-rolimus vascular tissue concentrations were detectable up to 90 days following implantation. Overlapping stented segments showed favourable histopathologic results with respect to fibrin deposition and en-dothelialisation at 28 days. In conclusion, the use of PLLA as drug-eluting matrix resulted in mild inflammatory responses in the presence of effective sirolimus tissue concentrations. The greater efficacy observed at long-term follow-up in PLLA SES compared to Cypher™ may be a multifactorial result of stent design, polymer biocompatibility and improved release kinetics. © Schattauer 2012.

Shanmugam N.,St Georges Healthcare NHS Trust | Boerdlein A.,Biotronik SE and Co. KG | Proff J.,Biotronik SE and Co. KG | Ong P.,St Georges Healthcare NHS Trust | And 5 more authors.
Europace | Year: 2012

AimsUncertainty exists over the importance of device-detected short-duration atrial arrhythmias. Continuous atrial diagnostics, through home monitoring (HM) technology (BIOTRONIK, Berlin, Germany), provides a unique opportunity to assess frequency and quantity of atrial fibrillation (AF) episodes defined as atrial high-rate events (AHRE).Methods and resultsProspective data from 560 heart failure (HF) patients (age 67 ± 10 years, median ejection fraction 27) patients with a cardiac resynchronization therapy (CRT) device capable of HM from two multi-centre studies were analysed. Atrial high-rate events burden was defined as the duration of mode switch in a 24-h period with atrial rates of >180 beats for at least 1 or total of 14 min per day. The primary endpoint was incidence of a thromboembolic (TE) event. Secondary endpoints were cardiovascular death, hospitalization because of AF, or worsening HF. Over a median 370-day follow-up AHRE occurred in 40 of patients with 11 (2) patients developing TE complications and mortality rate of 4.3 (24 deaths, 16 with cardiovascular aetiology). Compared with patients without detected AHRE, patients with detected AHRE>3.8 h over a day were nine times more likely to develop TE complications (P 0.006). The majority of patients (73) did not show a temporal association with the detected atrial episode and their adverse event, with a mean interval of 46.7 ± 71.9 days (range 0194) before the TE complication.ConclusionIn a high-risk cohort of HF patients, device-detected atrial arrhythmias are associated with an increased incidence of TE events. A cut-off point of 3.8 h over 24 h was associated with significant increase in the event rate. Routine assessment of AHRE should be considered with other data when assessing stroke risk and considering anti-coagulation initiation and should also prompt the optimization of cardioprotective HF therapy in CRT patients.© The Author 2011.

Sternberg K.,University of Rostock | Grabow N.,University of Rostock | Petersen S.,University of Rostock | Weitschies W.,University of Greifswald | And 4 more authors.
Current Pharmaceutical Biotechnology | Year: 2013

Beyond their originally sole mechanical function, current drug-eluting stents (DES) implement the concept of local drug delivery for the re-opening of stenotic arterial vessels, and for prevention of in-stent restenosis as one of the major limitations of conventional bare metal stents (BMS). Current DES consist of a permanent metallic stent platform and an active agent being released from a drug-incorporated polymer coating or a porous stent surface. Although DES have impressively demonstrated their capability of reducing in-stent restenosis, their safety remains under debate due to potential risks, such as delayed healing, late thrombosis and hypersensitivity demanding further development. Current advancements in the stent design address the stent platform, the pharmacologically active substance and/or the drug carrier. For instance, novel biocompatible absorbable stent platforms and drug carriers are developed and novel drugs with a differential effect on vascular endothelial and smooth muscle cells, providing efficient inhibition of muscle cells without altering the endothelial cell function, are identified. Moreover, biofunctionalization of the stent's surface with capture molecules for endothelial progenitor cells are under investigation in order to achieve an in situ endothelialization of the implant. In this context, this review paper discusses the current advances in coronary stent technology with a special focus on novel stent platforms, drugs and stent coatings for the prevention of restenosis and improvement of biocompatibility. © 2013 Bentham Science Publishers.

Rjasanow S.,Saarland University | Weggler L.,BIOTRONIK SE and Co. KG
Mathematical Methods in the Applied Sciences | Year: 2016

A new variant of the Adaptive Cross Approximation (ACA) for approximation of dense block matrices is presented. This algorithm can be applied to matrices arising from the Boundary Element Methods (BEM) for elliptic or Maxwell systems of partial differential equations. The usual interpolation property of the ACA is generalised for the matrix valued case. Some numerical examples demonstrate the efficiency of the new method. The main example will be the electromagnetic scattering problem, that is, the exterior boundary value problem for the Maxwell system. Here, we will show that the matrix valued ACA method works well for high order BEM, and the corresponding high rate of convergence is preserved. Another example shows the efficiency of the new method in comparison with the standard technique, whilst approximating the smoothed version of the matrix valued fundamental solution of the time harmonic Maxwell system. © 2016 John Wiley & Sons, Ltd.

Herschel M.,University of Tübingen | Naumann F.,Hasso Plattner Institute For Softwaresystemtechnik | Szott S.,Konrad Zuse Zentrum fur Informationstechnik Berlin | Taubert M.,Biotronik SE and Co. KG
IEEE Transactions on Knowledge and Data Engineering | Year: 2012

Duplicate detection determines different representations of real-world objects in a database. Recent research has considered the use of relationships among object representations to improve duplicate detection. In the general case where relationships form a graph, research has mainly focused on duplicate detection quality/effectiveness. Scalability has been neglected so far, even though it is crucial for large real-world duplicate detection tasks. We scale-up duplicate detection in graph data (ddg) to large amounts of data and pairwise comparisons, using the support of a relational database management system. To this end, we first present a framework that generalizes the ddg process. We then present algorithms to scale ddg in space (amount of data processed with bounded main memory) and in time. Finally, we extend our framework to allow batched and parallel ddg, thus further improving efficiency. Experiments on data of up to two orders of magnitude larger than data considered so far in ddg show that our methods achieve the goal of scaling ddg to large volumes of data. © 2012 IEEE.

Wittchow E.,Biotronik SE and Co. KG | Adden N.,Biotronik SE and Co. KG | Riedmuller J.,Biotronik SE and Co. KG | Savard C.,AccelLAB Inc. | And 2 more authors.
EuroIntervention | Year: 2013

Aims: Among three versions of bioresorbable magnesium scaffolds featuring different paclitaxel-elution kinetics, we determined the best-performing scaffold and compared it with established, paclitaxel-eluting, permanent stents TAXUS Liberté and eucaTAX. Methods and results: Drug-elution kinetics in magnesium scaffolds were modulated by varying the composition of their bioresorbable poly(lactide-co-glycolide) coating loaded with paclitaxel. A 50:50 ratio of lactide to glycolide, or an 85:15 ratio and either high- or low-molecular-weight polymer was applied in the "50/50", "85/15H", and "85/15L" scaffolds, respectively. Seventy-three magnesium scaffolds (25 50/50, 24 85/15H, 24 85/15L) and 36 control stents (18 TAXUS Liberté, 18 eucaTAX) were implanted in coronary arteries of 50 Yucatan mini-pigs. Angiography, histomorphometry, and histopathology data were acquired at 28, 90 and 180 days. The best-performing magnesium scaffold, 85/15H, was equivalent to TAXUS Liberté and superior to eucaTAX regarding late luminal loss, intimal area, fibrin score, and endothelialisation. Intimal inflammation score was higher in 85/15H than in the control stents at 28 days, but this effect disappeared at later time points. Conclusions: By selecting suitable paclitaxel-elution kinetics, it was feasible to develop a bioresorbable magnesium scaffold whose efficacy and healing characteristics in a porcine coronary model are comparable with those of established paclitaxel-eluting permanent metallic stents.

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