Publications by authors named "Peter Stachon"

55 Publications

Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial.

Lancet Respir Med 2021 07 14;9(7):755-762. Epub 2021 May 14.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Germany; Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Germany.

Background: We sought to clarify the benefit of cytokine adsorption in patients with COVID-19 supported with venovenous extracorporeal membrane oxygenation (ECMO).

Methods: We did a single-centre, open-label, randomised, controlled trial to investigate cytokine adsorption in adult patients with severe COVID-19 pneumonia requiring ECMO. Patients with COVID-19 selected for ECMO at the Freiburg University Medical Center (Freiburg, Germany) were randomly assigned (1:1) to receive cytokine adsorption using the CytoSorb device or not. Randomisation was computer-generated, allocation was concealed by opaque, sequentially numbered sealed envelopes. The CytoSorb device was incorporated into the ECMO circuit before connection to the patient circuit, replaced every 24 h, and removed after 72 h. The primary endpoint was serum interleukin-6 (IL-6) concentration 72 h after initiation of ECMO analysed by intention to treat. Secondary endpoints included 30-day survival. The trial is registered with ClinicalTrials.gov (NCT04324528) and the German Clinical Trials Register (DRKS00021300) and is closed.

Findings: From March 29, 2020, to Dec 29, 2020, of 34 patients assessed for eligibility, 17 (50%) were treated with cytokine adsorption and 17 (50%) without. Median IL-6 decreased from 357·0 pg/mL to 98·6 pg/mL in patients randomly assigned to cytokine adsorption and from 289·0 pg/mL to 112·0 pg/mL in the control group after 72 h. One patient in each group died before 72 h. Adjusted mean log IL-6 concentrations after 72 h were 0·30 higher in the cytokine adsorption group (95% CI -0·70 to 1·30, p=0·54). Survival after 30 days was three (18%) of 17 with cytokine adsorption and 13 (76%) of 17 without cytokine adsorption (p=0·0016).

Interpretation: Early initiation of cytokine adsorption in patients with severe COVID-19 and venovenous ECMO did not reduce serum IL-6 and had a negative effect on survival. Cytokine adsorption should not be used during the first days of ECMO support in COVID-19.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(21)00177-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121541PMC
July 2021

Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe mice.

Mol Metab 2021 May 12;53:101250. Epub 2021 May 12.

University Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, Germany. Electronic address:

Objective: Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro. Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis.

Methods: Female ApoeLysmIrf5 and ApoeIrf5 mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques.

Results: Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo. While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5-deficient Apoe mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfβ expression. Irf5-deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5-deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5-deficient macrophages proliferated less in the plaque.

Conclusion: Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.
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http://dx.doi.org/10.1016/j.molmet.2021.101250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178123PMC
May 2021

Deficiency of Endothelial CD40 Induces a Stable Plaque Phenotype and Limits Inflammatory Cell Recruitment to Atherosclerotic Lesions in Mice.

Thromb Haemost 2021 Feb 22. Epub 2021 Feb 22.

Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Objectives:  The co-stimulatory CD40L-CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis.

Methods And Results:  Atherosclerotic plaques of apolipoprotein E-deficient ( ) mice and humans displayed increased expression of CD40 on ECs compared with controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCre-driven) deficiency of CD40 in mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs.

Conclusion:  Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.
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http://dx.doi.org/10.1055/a-1397-1858DOI Listing
February 2021

The Use and Outcomes of Cerebral Protection Devices for Patients Undergoing Transfemoral Transcatheter Aortic Valve Replacement in Clinical Practice.

JACC Cardiovasc Interv 2021 01;14(2):161-168

University Heart Center Freiburg, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Objectives: This study hypothesized that cerebral protection prevents strokes in patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) in clinical practice.

Background: Preventing strokes is an important aim in TAVR procedures. Embolic protection devices may protect against cardiac embolism during TAVR, but their use and outcomes in clinical practice remain controversial.

Methods: Isolated transfemoral TAVR procedures performed in Germany with or without cerebral protection devices were extracted from a comprehensive nationwide billing dataset.

Results: A total of 41,654 TAVR procedures performed between 2015 and 2017 were analyzed. The overall share of procedures incorporating cerebral protection devices was 3.8%. Patients receiving cerebral protection devices were at increased operative risk (European System for Cardiac Operative Risk Evaluation score 13.8 vs. 14.7; p < 0.001) but of lower age (81.1 vs. 80.6 years; p = 0.001). To compare outcomes that may be related to the use of cerebral protection devices, a propensity score comparison was performed. The use of a cerebral protection device did not reduce the risk for stroke (adjusted risk difference [aRD]: +0.88%; 95% confidence interval [CI]: -0.07% to 1.83%; p = 0.069) or the risk for developing delirium (aRD: +1.31%; 95% CI: -0.28% to 2.89%; p = 0.106) as a sign of acute brain failure. Although brain damage could not be prevented, in-hospital mortality was lower in the group receiving a cerebral protection device (aRD: -0.76%; 95% CI: -1.46% to -0.06%; p = 0.034).

Conclusions: In this large national database, cerebral embolic protection devices were infrequently used during TAVR procedures. Device use was associated with lower mortality but not a reduction in stroke or delirium. Future studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.jcin.2020.09.047DOI Listing
January 2021

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.

Basic Res Cardiol 2020 12 9;115(6):78. Epub 2020 Dec 9.

Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany.

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.
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http://dx.doi.org/10.1007/s00395-020-00838-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725697PMC
December 2020

Cardiogenic shock: incidence, survival and mechanical circulatory support usage 2007-2017-insights from a national registry.

Clin Res Cardiol 2020 Nov 30. Epub 2020 Nov 30.

Heart Center Freiburg University, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.

Background: A central element in the management of cardiogenic shock (CS) comprises mechanical circulatory support (MCS) systems to maintain cardiac output (CO). This study aims to quantify incidence, outcome and influence of MCS in CS over the last decade.

Methods: All patients hospitalized with CS in a tertiary university hospital in Germany between 2007 and 2017 were identified utilizing the international coding system ICD-10 with code R57.0. Application of MCS was identified via German procedure classification codes (OPS).

Results: 383,983 cases of cardiogenic shock were reported from 2007 to 2017. Patients had a mean age of 71 years and 38.5% were female. The incidence of CS rose by 65.6% from 26,828 cases in 2007 (33.1 per 100,000 person-years, hospital survival 39.2%) to 44,425 cases in 2017 (53.7 per 100,000 person-years, survival 41.2%). In 2007, 16.0% of patients with CS received MCS (4.6 per 100,000 person-years, survival 46.6%), dropping to 13.9% in 2017 (6.6 per 100,000 person-years, survival 38.6%). Type of MCS changed over the years, with decreasing use of the intra-aortic balloon pump (IABP), an increase in extracorporeal membrane oxygenation (VA-ECMO) and percutaneous ventricular assist device (pVAD) usage. Significant differences regarding in-hospital survival were observed between the devices (survival: overall: 40.2%; medical treatment = 39.5%; IABP = 49.5%; pVAD = 36.2%; VA-ECMO = 30.5%; p < 0.001).

Conclusions: The incidence of CS is increasing, but hospital survival remains low. MCS was used in a minority of patients, and the percentage of MCS usage in CS has decreased. The use rates of the competing devices change over time.
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http://dx.doi.org/10.1007/s00392-020-01781-zDOI Listing
November 2020

Outcome of acute respiratory distress syndrome requiring extracorporeal membrane oxygenation in Covid-19 or influenza: A single-center registry study.

Artif Organs 2021 Jun 18;45(6):593-601. Epub 2020 Dec 18.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is used to sustain blood oxygenation and decarboxylation in severe acute respiratory distress syndrome (ARDS). It is under debate if V-V ECMO is as appropriate for coronavirus disease 2019 (Covid-19) ARDS as it is for influenza. In this retrospective study, we analyzed all patients with confirmed SARS-CoV-2 or influenza A/B infection, ARDS and V-V ECMO, treated at our medical intensive care unit (ICU) between October 2010 and June 2020. Baseline and procedural characteristics as well as survival 30 days after ECMO cannulation were analyzed. A total of 62 V-V ECMO patients were included (15 with Covid-19 and 47 with influenza). Both groups had similar baseline characteristics at cannulation. Thirty days after ECMO cannulation, 13.3% of all patients with Covid-19 were discharged alive from our ICU compared to 44.7% with influenza (P = .03). Patients with Covid-19 had fewer ECMO-free days (0 (0-9.7) days vs. 13.2 (0-22.1) days; P = .05). Cumulative incidences of 30-day-survival showed no significant differences (48.6% in Covid-19 patients, 63.7% in influenza patients; P = .23). ICU treatment duration was significantly longer in ARDS patients with V-V ECMO for Covid-19 compared to influenza. Thirty-day mortality was higher in Covid-19, but not significant.
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http://dx.doi.org/10.1111/aor.13865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753485PMC
June 2021

Impact of Preprocedural Aortic Valve Calcification on Conduction Disturbances after Transfemoral Aortic Valve Replacement.

Cardiology 2021 23;146(2):228-237. Epub 2020 Sep 23.

University Heart Center Freiburg, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Aim: The present study analyzes in depth the impact of different calcification patterns on disturbances of the conduction system in transcatheter aortic valve replacement (TAVR) patients.

Methods And Results: A total of 169 preprocedural TAVR multislice computed tomography scans from consecutive transfemoral (TF) TAVRs performed between 2014 and 2017 using either Edwards SAPIEN or Medtronic Evolut R valves were retrospectively evaluated. The volume, distribution, and orientation of annular and valvular aortic valve calcification were measured and their impact on postoperative conduction disturbances was determined using linear and logistic regression analyses. The total volume of calcification and distribution at the aortic annulus or valve did not influence the conduction system. Oval calcification of the left aortic cusp was independently associated with an elevated risk for an increase in atrioventricular block degree (+0.6, p = 0.03). Moreover, orthogonal calcifications at the level of the aortic annulus were associated with an increased risk for QRS prolongation (+26 ms, p = 0.004) and an increased risk for permanent pacemaker implantation (OR 4.3, p = 0.03) after TF TAVR. This was more pronounced in patients undergoing TF TAVR using a balloon-expandable Edwards SAPIEN 3 valve (QRS +38.195 ms, p < 0.001; OR permanent pacemaker 15.48, p = 0.013).

Conclusion: Orthogonal annular calcification confers an increased risk for conduction disturbances after TAVR. This is even more pronounced after implantation of balloon-expandable valves.
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http://dx.doi.org/10.1159/000509389DOI Listing
September 2020

Incidence and predictors of delirium on the intensive care unit after acute myocardial infarction, insight from a retrospective registry.

Catheter Cardiovasc Interv 2020 Sep 14. Epub 2020 Sep 14.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Objectives: This study aimed to identify the incidence and potential risk factors for delirium after myocardial infarction (MI).

Background: Delirium is a common complication on intensive care units. Data on incidence and especially on predictors of delirium in patients after acute MI are rare.

Methods: In this retrospective study, all patients hospitalized for MI treated with coronary angiography in an university hospital in 2018 were included and analyzed. Onset of delirium within the first 5 days after MI was attributed to the MI and was defined by a Nursing Delirium screening scale (NuDesc) ≥2. This score is taken as part of daily care in every patient on intensive care unit three times a day by especially trained nurses.

Results: A total of 624 patients with MI (age 68.5 ± 13.2 years, ST-elevation MI 41.6%, hospital mortality 3.2%) were included in the study. Delirium was detected in 10.9% of all patients. In the subgroup of patients with a stay on the intensive care unit (ICU) for more than 24 hr (n = 229), delirium was detected in 29.7%. Hospital and ICU stay were significantly longer in patients with delirium (p < .001). Delirium was an independent predictor of prolonged ICU-stay. Independent predictors of delirium were age, dementia, alcohol abuse, cardiac arrest, hypotension, and leucocytosis. Infarct size or presentation with ST-elevation were not associated with incidence of delirium.

Conclusion: Development of delirium is frequent after acute MI and prolongs hospitalization. Incidence of delirium is associated with clinical instability, preexisting comorbidity, and age rather than MI type or size.
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http://dx.doi.org/10.1002/ccd.29275DOI Listing
September 2020

Bleeding Complications Drive In-Hospital Mortality of Patients with Atrial Fibrillation after Transcatheter Aortic Valve Replacement.

Thromb Haemost 2020 Nov 22;120(11):1580-1586. Epub 2020 Aug 22.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background:  Atrial fibrillation (AF) is a risk factor for poor postoperative outcome after transfemoral transcatheter aortic valve replacement (TF-TAVR). The present study analyses the outcomes after TF-TAVR in patients with or without AF and identifies independent predictors for in-hospital mortality in clinical practice.

Methods And Results:  Among all 57,050 patients undergoing isolated TF-TAVR between 2008 and 2016 in Germany, 44.2% of patients ( = 25,309) had AF. Patients with AF were at higher risk for unfavorable in-hospital outcome after TAVR. Including all baseline characteristics for a risk-adjusted comparison, AF was an independent risk factor for in-hospital mortality after TAVR. Among patients with AF, EuroSCORE, New York Heart Association classification class, or renal disease had only moderate effects on mortality, while the occurrence of postprocedural stroke or moderate to major bleeding substantially increased in-hospital mortality (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.61-4.30,  < 0.001 and OR 3.12, 95% CI 2.68-3.62,  < 0.001). However, the strongest independent predictor for in-hospital mortality among patients with AF was severe bleeding (OR 18.00, 95% CI 15.22-21.30,  < 0.001).

Conclusion:  The present study demonstrates that the incidence of bleeding defines the in-hospital outcome of patients with AF after TF-TAVR. Thus, the periprocedural phase demands particular care in bleeding prevention.
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http://dx.doi.org/10.1055/s-0040-1715833DOI Listing
November 2020

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice.

Sci Rep 2020 08 6;10(1):13211. Epub 2020 Aug 6.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes.
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http://dx.doi.org/10.1038/s41598-020-70043-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413393PMC
August 2020

Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B-Reactive CD4 T-Regulatory Cells.

Circulation 2020 Sep 24;142(13):1279-1293. Epub 2020 Jul 24.

Division of Vaccine Discovery (B.P., A.S.), La Jolla Institute for Immunology, CA.

Background: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4 T cells with an atheroprotective, regulatory T cell (T) phenotype in healthy individuals. Yet, the function of apoB-reactive T and their relationship with pathogenic T1 cells remain unknown.

Methods: To interrogate the function of autoreactive CD4 T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B (apoB) at the single-cell level.

Results: We found that apoB T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T-like transcriptome, although only 21% of all apoB T cells expressed the T transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB T cells formed several clusters with mixed T signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T1, T helper cell type 2 (T2), and T helper cell type 17 (T17), and of follicular-helper T cells. ApoB T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T1/T17-like cells with proinflammatory properties and only a residual T transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T1/T17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB T in lineage tracing of hyperlipidemic mice. In adoptive transfer experiments, converting apoB T failed to protect from atherosclerosis.

Conclusions: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive T as a novel cellular target in atherosclerosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515473PMC
September 2020

Prone positioning in severe ARDS requiring extracorporeal membrane oxygenation.

Crit Care 2020 07 8;24(1):397. Epub 2020 Jul 8.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Prone positioning (PP) has shown to improve survival in patients with severe acute respiratory distress syndrome (ARDS). To this point, it is unclear if PP is also beneficial for ARDS patients treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) support.

Methods: We report retrospective data of a single-centre registry of patients with severe ARDS requiring VV ECMO support between October 2010 and May 2018. Patients were allocated to the PP group if PP was performed during VV ECMO treatment or the supine positioning group. VV ECMO weaning success and hospital survival were analysed before and after propensity score matching.

Results: A total of 158 patients could be analysed, and 38 patients (24.1%) received PP. There were no significant differences in VV ECMO weaning rate (47.4% vs. 46.7%, p = 0.94) and hospital survival (36.8% vs. 36.7%, p = 0.98) between the prone and supine groups, respectively. The analysis of 38 propensity score matched pairs also showed no difference in hospital survival (36.8% vs. 36.8%, p = 1.0) or VV ECMO weaning rate (47.4% vs. 44.7%, p = 0.82). Hospital survival was superior in the subgroup of patients treated with early PP (cutoff < 17 h via Youden's Index) as compared to late or no PP (81.8% vs. 33.3%, p = 0.02).

Conclusion: In this propensity score matched cohort of severe ARDS patients requiring VV ECMO support, prone positioning at any time was not associated with improved weaning or survival. However, early initiation of prone positioning was linked to a significant reduction of hospital mortality.
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http://dx.doi.org/10.1186/s13054-020-03110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341706PMC
July 2020

Impact of the introduction of percutaneous edge-to-edge mitral valve reconstruction on clinical practice in Germany compared to surgical valve repair.

Clin Res Cardiol 2021 May 27;110(5):620-627. Epub 2020 May 27.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany.

Background: The introduction of percutaneous mitral valve (MV) repair had an effect on clinical practice in comparison with surgical MV repair. Complete nationwide data are useful in examining how the introduction of a new technique influences clinical practice.

Methods: We analyzed procedural numbers, patient characteristics, and in-hospital outcomes for all percutaneous edge-to-edge and surgical MV reconstruction procedures performed in Germany between 2009 and 2015.

Results: 12,664 percutaneous edge-to-edge and 22,825 surgical MV reconstructions were recorded. Numbers increased steadily, albeit more rapidly in the percutaneous edge-to-edge group (108-4079 vs. 2923-3603 with surgical MV reconstruction). Patients with percutaneous edge-to-edge MV reconstruction were older (75.6 ± 8.8 vs 61.6 ± 13.4 years, P < 0.001) and at higher operative risk (estimated logistic EuroSCORE 13.2% vs. 4.7%, P < 0.001) compared to those undergoing surgery. However, in-hospital mortality did not differ (2.9% vs. 2.8%; P = 0.395). This was also true for the subset of 2103 patients at intermediate operative risk as defined by a logistic EuroSCORE ≥ 4% and ≤ 9%. Of note, complication rates (except acute kidney injury) were more favorable in patients undergoing percutaneous edge-to-edge reconstruction.

Conclusions: Percutaneous edge-to-edge MV reconstruction has markedly changed clinical practice of MR therapy in Germany. Annual overall procedural numbers more than doubled, with a massive increase in percutaneous edge-to-edge procedures. Our data demonstrate its use mainly in high-risk patients and prove the favorable safety profile of this novel technique, with low in-hospital mortality and complication rates.
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http://dx.doi.org/10.1007/s00392-020-01675-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099833PMC
May 2021

Transapical aortic valve replacement versus surgical aortic valve replacement: A subgroup analyses for at-risk populations.

J Thorac Cardiovasc Surg 2020 Feb 29. Epub 2020 Feb 29.

Faculty of Medicine, Department of Cardiology and Angiology I, Heart Center Freiburg, University of Freiburg, Freiburg, Germany.

Background: If the transfemoral access is not feasible, a transapical access or surgical aortic valve replacement (SAVR) are alternatives for patients with aortic valve stenosis.

Objectives: To identify patient groups who benefit from SAVR or transapical transcatheter aortic valve replacement (TA-TAVR), we compared in-hospital outcomes of patients in a nationwide dataset.

Methods: We identified 19,016 isolated SAVR and 6432 TA-TAVR performed in Germany from 2014 to 2016. We adjusted for risk factors using a covariate- and propensity-adjusted analysis.

Results: Patients undergoing TA-TAVR were older, had more comorbidities, and accordingly greater estimated operative risk (logistic European System for Cardiac Operative Risk Evaluation 5.3 vs 17.0, P < .001). However, adjusted risk for in-hospital complications such as stroke, acute kidney injury, relevant bleeding, and prolonged mechanical ventilation >48 hours was lower in patients undergoing TA-TAVR (all P < .001). When we compared in-hospital mortality of all patients undergoing either TA-TAVR or SAVR, neither treatment strategy had a clear advantage (covariate-adjusted odds ratio [caOR], 1.13, P = .251; propensity-adjusted OR [paOR], 1.12, P = .309). Two patient subgroups seem to benefit more from SAVR than TA-TAVR: patients <75 years (caOR, 1.29, P = .237; paOR, 2.12, P = .001) and those with European System for Cardiac Operative Risk Evaluation 4-9 (caOR, 1.32, P = .114; paOR, 1.43, P = .041). Female patients had a tendency toward lower risk for in-hospital mortality when undergoing SAVR (caOR, 1.42, P = .030). In patients with chronic renal failure, TA-TAVR was superior (caOR, 0.56, P = .039, P = .040).

Conclusions: Patients <75 years and those at low operative risk who underwent SAVR had lower in-hospital mortality than those undergoing TA-TAVR. Patients with chronic renal failure who underwent TA-TAVR had lower in hospital mortality than those that underwent SAVR.
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http://dx.doi.org/10.1016/j.jtcvs.2020.02.078DOI Listing
February 2020

Outcomes of transcatheter aortic valve implantations in high-volume or low-volume centres in Germany.

Heart 2020 10 18;106(20):1604-1608. Epub 2020 Feb 18.

Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Faculty, University of Freiburg, Freiburg, Germany

Objective: Transcatheter aortic valve implantation (TAVI) is the most common aortic valve replacement in Germany. Since 2015, to ensure high-quality procedures, hospitals in Germany and other countries that meet the minimum requirement of 50 interventions per centre are being certified to perform TAVI. This study analyses the impact of these requirements on case number and in-hospital outcomes.

Methods: All isolated TAVI procedures and in-hospital outcomes between 2008 and 2016 were identified by International Classification of Diseases (ICD) and the German Operation and Procedure Classification codes.

Results: 73 467 isolated transfemoral and transapical TAVI procedures were performed in Germany between 2008 and 2016. During this period, the number of TAVI procedures per year rose steeply, whereas the overall rates of hospital mortality and complications declined. In 2008, the majority of procedures were performed in hospitals with fewer than 50 cases per year (54.63%). Until 2014, the share of patients treated in low-volume centres constantly decreased to 5.35%. After the revision of recommendations, it further declined to 1.99%. In the 2 years after the introduction of the minimum requirements on case numbers, patients were at decreased risk for in-hospital mortality when treated in a high-volume centre (risk-adjusted OR 0.62, p=0.012). The risk for other in-hospital outcomes (stroke, permanent pacemaker implantation and bleeding events) did not differ after risk adjustment (p=0.346, p=0.142 and p=0.633).

Conclusion: A minimum volume of 50 procedures per centre and year appears suitable to allow for sufficient routine and thus better in-hospital outcomes, while ensuring nationwide coverage of TAVI procedures.
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http://dx.doi.org/10.1136/heartjnl-2019-316058DOI Listing
October 2020

A logistic regression analysis comparing minimalistic approach and intubation anaesthesia in patients undergoing transfemoral transcatheter aortic valve replacement.

PLoS One 2020 5;15(2):e0227345. Epub 2020 Feb 5.

Department of Cardiology and Angiology I, Faculty of Medicine, Heart Centre Freiburg University, University of Freiburg, Freiburg, Germany.

Aims: Patients with postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR) are ventilated and hospitalized longer and suffer increased in-hospital mortality. This study hypothesized that a minimalistic approach with conscious sedation during transfemoral aortic valve replacement (TF-AVR) protects against delirium, time of mechanical ventilation, and increased length of stay in intensive care unit (ICU) compared to intubation anaesthesia.

Methods And Results: 308 patients which underwent TF-AVR in our centre between 01/2013 and 08/2017 were retrospectively evaluated regarding postoperative delirium, time of mechanical ventilation, and days in ICU. TF-AVR was performed with intubation anaesthesia in 245 patients and with conscious sedation in 63. The operative risk estimated by the logEUROScore was similar in both groups (intubation: 13.28 +/-9.06%, conscious sedation: 12.24 +/-6.77%, p = 0.395). In the conscious sedation group procedure duration was shorter (0.61 +/-0.91h vs. 1.75 +/-0.96h, p<0.001). The risk for intraprocedural complications was not influenced by the anaesthesia method (OR conscious sedation instead of intubation 1.66, p = 0.117), but days on ICU (-2.21 days, p<0.0001) and minutes of mechanical ventilation (-531.2 min, p < 0.0001) were reduced. Furthermore, the risk of POD was decreased when TF-AVR was performed under conscious sedation (6.35% vs. 18.18%, OR 0.29, p = 0.021).

Conclusions: Time of mechanical ventilation, risk of POD, and days on ICU were substantially reduced in patients who underwent TF-AVR under conscious sedation. Our data suggest that TF-AVR with conscious sedation is safe with a beneficial postoperative course in clinical practice, and should be considered the favoured approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001937PMC
April 2020

Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1.

Front Endocrinol (Lausanne) 2019 13;10:872. Epub 2019 Dec 13.

Division of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany.

Decreased serum adiponectin levels in type 2 diabetes has been linked to the onset of mitochondrial dysfunction in diabetic complications by impairing AMPK-SIRT1-PGC-1α signaling via impaired adiponectin receptor 1 (AdipoR1) signaling. Here, we aimed to characterize the previously undefined role of disrupted AdipoR1 signaling on the mitochondrial protein composition of cardiac, renal, and hepatic tissues as three organs principally associated with diabetic complications. Comparative proteomics were performed in mitochondria isolated from the heart, kidneys and liver of mice. A total of 790, 1,573, and 1,833 proteins were identified in cardiac, renal and hepatic mitochondria, respectively. While 121, 98, and 78 proteins were differentially regulated in cardiac, renal, and hepatic tissue of 1 mice, respectively; only 15 proteins were regulated in the same direction across all investigated tissues. Enrichment analysis of differentially expressed proteins revealed disproportionate representation of proteins involved in oxidative phosphorylation conserved across tissue types. Curated pathway analysis identified HNF4, NRF1, LONP, RICTOR, SURF1, insulin receptor, and PGC-1α as candidate upstream regulators. In high fat-fed non-transgenic mice with obesity and insulin resistance, AdipoR1 gene expression was markedly reduced in heart (-70%), kidney (-80%), and liver (-90%) (all < 0.05) as compared to low fat-fed mice. NRF1 was the only upstream regulator downregulated both in 1 mice and in high fat-fed mice, suggesting common mechanisms of regulation. Thus, AdipoR1 signaling regulates mitochondrial protein composition across all investigated tissues in a functionally conserved, yet molecularly distinct, manner. The biological significance and potential implications of impaired AdipoR1 signaling are discussed.
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http://dx.doi.org/10.3389/fendo.2019.00872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923683PMC
December 2019

Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice.

Sci Rep 2019 11 29;9(1):17937. Epub 2019 Nov 29.

University Heart Center Freiburg-Bad Krozingen, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany.

Diabetes worsens atherosclerosis progression and leads to a defect in repair of arteries after cholesterol reduction, a process termed regression. Empagliflozin reduces blood glucose levels via inhibition of the sodium glucose cotransporter 2 (SGLT-2) in the kidney and has been shown to lead to a marked reduction in cardiovascular events in humans. To determine whether glucose lowering by empagliflozin accelerates atherosclerosis regression in a mouse model, male C57BL/6J mice were treated intraperitoneally with LDLR- and SRB1- antisense oligonucleotides and fed a high cholesterol diet for 16 weeks to induce severe hypercholesterolemia and atherosclerosis progression. At week 14 all mice were rendered diabetic by streptozotocin (STZ) injections. At week 16 a baseline group was sacrificed and displayed substantial atherosclerosis of the aortic root. In the remaining mice, plasma cholesterol was lowered by switching to chow diet and treatment with LDLR sense oligonucleotides to induce atherosclerosis regression. These mice then received either empagliflozin or vehicle for three weeks. Atherosclerotic plaques in the empagliflozin treated mice were significantly smaller, showed decreased lipid and CD68 macrophage content, as well as greater collagen content. Proliferation of plaque resident macrophages and leukocyte adhesion to the vascular wall were significantly decreased in empagliflozin-treated mice. In summary, plasma glucose lowering by empagliflozin improves plaque regression in diabetic mice.
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http://dx.doi.org/10.1038/s41598-019-54224-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884628PMC
November 2019

Extracellular HtrA2 Induces Apoptosis in Human Umbilical Vein Endothelial Cells.

Int J Mol Sci 2019 Oct 31;20(21). Epub 2019 Oct 31.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

The serine protease high-temperature-required protein A2 (HtrA2) has been identified as a key intracellular molecule promoting apoptosis in cells during ischemia reperfusion (IR) injury. IR injury in ST-segment elevation myocardial infarction (STEMI) contributes to overall myocardial damage. HtrA2 has further been shown to be significantly increased in the serum of patients with STEMI. In the present pilot study, we use human umbilical vein endothelial cells (HUVECs) to investigate whether extracellular HtrA2 induces apoptosis using Annexin V staining. Furthermore, we examine whether HtrA2 is released extracellularly after staurosporine-induced apoptosis using ELISA. We find that HtrA2 is released upon induction of apoptosis by staurosporine into the cell culture medium. Furthermore, treatment of HUVECs with extracellular HtrA2-induces apoptosis, while the addition of anti-HtrA2 antibodies reduces both HtrA2- and staurosporine-induced endothelial cell apoptosis. In conclusion, we show here that extracellular HtrA2 induces apoptosis in human endothelial cells, although the exact molecular mechanisms have to be investigated in future.
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http://dx.doi.org/10.3390/ijms20215446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862081PMC
October 2019

Predictors of survival in patients with acute coronary syndrome undergoing percutaneous coronary intervention of unprotected left main coronary artery stenosis.

Catheter Cardiovasc Interv 2020 07 11;96(1):E27-E33. Epub 2019 Sep 11.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Objective: Aim of this study was to investigate predictors of survival in unstable patients with high SYNTAX-1-score.

Background: In significant unprotected left main coronary artery (ULMCA) stenosis, treatment options include percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). While CABG is recommended for stable patients with ULMCA stenosis and a SYNTAX-1-score > 32, PCI may be preferable in unstable or high operative risk patients.

Methods: Retrospective single-center all-comers registry study.

Results: A total of 142 patients underwent ULMCA-PCI (~72.9 years, 23.2% females, 54.2% survival in 2-year follow-up), 84 of whom had a SYNTAX-1 > 32 (37.4 ± 12.8). Patients in the high-SYNTAX-1-group (score > 32) were more often in an acute condition compared to low-SYNTAX-2-group (score ≤ 32) including acute myocardial infarction (76.2% vs. 57.4%, p = .024), cardiogenic shock (48.2% vs. 14.8%, p = .001), or need for mechanical support (36.1% vs. 11.1%, p = .001). Survival was predicted by the acute condition including cardiogenic shock (OR 0.06 and 0.05) and myocardial infarction (OR 0.03 and 0.34) in both groups. Performance of the SYNTAX-1-score was limited in our patient collective in both groups (c-index 0.65 vs. 0.63) while SYNTAX-2-PCI-score performed better (c-index 0.67 vs. 0.67). EuroScore II had the best discriminative ability (c-index 0.87 vs. 0.78).

Conclusions: The majority of patients undergoing ULMCA-PCI presented in acute conditions with high SYNTAX-1-score, and is therefore underrepresented in clinical trials. Prognosis was best predicted by the acute condition and the EuroScore II. These data suggest that therapy in unstable patients should be guided by clinical condition over the anatomical SYNTAX-1-score.
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http://dx.doi.org/10.1002/ccd.28495DOI Listing
July 2020

Tumor Necrosis Factor Receptor-Associated Factor 5 Promotes Arterial Neointima Formation through Smooth Muscle Cell Proliferation.

J Vasc Res 2019 22;56(6):308-319. Epub 2019 Aug 22.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins of the TNF/interleukin (IL)-1/Toll-like receptor superfamily. Ligands of this family such as TNFα, CD40L, and IL-1β promote chronic inflammatory processes such as atherosclerosis and restenosis, the latter being a common adverse reaction after vascular interventions. We previously reported overexpression of TRAF5 in murine and human atheromata and TRAF5-dependent proinflammatory functions in vitro. However, the role of TRAF5 in restenosis remains unsettled. To evaluate whether TRAF5 affects neointima formation, TRAF5-/-LDLR-/- and TRAF5+/+LDLR-/- mice consuming a high cholesterol diet (HCD) received wire-induced injury of the carotid artery. After 28 days, TRAF5-deficient mice showed a 45% decrease in neointimal area formation compared with TRAF5-compentent mice. Furthermore, neointimal vascular smooth muscle cells (vSMC) and macrophages decreased whereas collagen increased in TRAF5-deficient mice. Mechanistically, the latter expressed lower transcript levels of the matrix metalloproteinases 2 and 9, both instrumental in extracellular matrix degradation and vSMC mobilization. Additionally, TRAF5-specific siRNA interference rendered murine vSMC less proliferative upon CD40L stimulation. In accordance with these findings, fewer vSMC isolated from TRAF5-deficient aortas were in a proliferative state as assessed by Ki67 and cyclin B1 expression. In conclusion, TRAF5 deficiency mitigates neointima formation in mice, likely through a TRAF5-dependent decrease in vSMC proliferation.
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http://dx.doi.org/10.1159/000501615DOI Listing
January 2020

Residual inflammatory risk in coronary heart disease: incidence of elevated high-sensitive CRP in a real-world cohort.

Clin Res Cardiol 2020 Mar 19;109(3):315-323. Epub 2019 Jul 19.

Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Faculty, University of Freiburg, Freiburg, Germany.

Background: Inflammation drives atherosclerosis and its complications. Anti-inflammatory therapy with interleukin 1 beta (IL-1β) antibody reduces cardiovascular events in patients with elevated high-sensitive C-reactive protein (hsCRP). This study aims to identify the share of patients with coronary heart disease (CHD) and residual inflammation who may benefit from anti-inflammatory therapy.

Methods: hsCRP and low-density lipoprotein (LDL) levels were determined in 2741 all-comers admitted to the cardiological ward of our tertiary referral hospital between June 2016 and June 2018. Patients without CHD, with acute coronary syndrome, chronic or recurrent systemic infection, use of immunosuppressant or anti-inflammatory agents, chronic inflammatory diseases, chemotherapy, terminal organ failure, traumatic injury and pregnancy were excluded.

Results: 856 patients with stable CHD were included. 42.7% of those had elevated hsCRP ≥ 2 mg/l. Within the group of patients with LDL-cholesterol < 70 mg/dl, 30.9% shared increased hsCRP indicating residual inflammation. After multivariate adjusted backward selection elevated Lipoprotein (a) (OR 1.61, p = 0.048), elevated proBNP (OR 2.57, p < 0.0001), smoking (OR 1.70, p = 0.022), and obesity (OR 2.28, p = 0.007) were associated with elevated hsCRP. In contrast, the use of ezetimibe was associated with normal hsCRP (OR 0.51, p = 0.014). In the subgroup of patients with on-target LDL-cholesterol < 70 mg/dl, backward selection identified elevated proBNP (OR 3.49, p = 0.007) as independent predictor of elevated hsCRP in patients with LDL-cholesterol < 70 mg/dl.

Conclusion: One-third of all-comers patients with CHD showed increased levels of hsCRP despite a LDL-cholesterol < 70 mg/dl potentially qualifying for an anti-inflammatory therapy. Elevated proBNP is an independent risk factor for hsCRP elevation.
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http://dx.doi.org/10.1007/s00392-019-01511-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042185PMC
March 2020

Real-time magnetic resonance imaging - guided coronary intervention in a porcine model.

Sci Rep 2019 06 17;9(1):8663. Epub 2019 Jun 17.

Cardiology and Angiology I, Heart Center Freiburg University and Faculty of Medicine, Freiburg, Germany.

X-ray fluoroscopy is the gold standard for coronary diagnostics and intervention. Magnetic resonance imaging is a radiation-free alternative to x-ray with excellent soft tissue contrast in arbitrary slice orientation. Here, we assessed real-time MRI-guided coronary interventions from femoral access using newly designed MRI technologies. Six Goettingen minipigs were used to investigate coronary intervention using real-time MRI. Catheters were custom-designed and equipped with an active receive tip-coil to improve visibility and navigation capabilities. Using modified standard clinical 5 F catheters, intubation of the left coronary ostium was successful in all animals. For the purpose of MR-guided coronary interventions, a custom-designed 8 F catheter was used. In spite of the large catheter size, and therefore limited steerability, intubation of the left coronary ostium was successful in 3 of 6 animals within seconds. Thereafter, real-time guided implantation of a non-metallic vascular scaffold into coronary arteries was possible. This study demonstrates that real-time MRI-guided coronary catheterization and intervention via femoral access is possible without the use of any contrast agents or radiation, including placement of non-metallic vascular scaffolds into coronary arteries. Further development, especially in catheter and guidewire technology, will be required to drive forward routine MR-guided coronary interventions as an alternative to x-ray fluoroscopy.
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http://dx.doi.org/10.1038/s41598-019-45154-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572773PMC
June 2019

Nationwide outcomes of aortic valve replacement for pure aortic regurgitation in Germany 2008-2015.

Catheter Cardiovasc Interv 2020 03 4;95(4):810-816. Epub 2019 Jun 4.

Department of Cardiology and Angiology I, Medical Faculty, University of Freiburg, University Heart Center Freiburg, Freiburg, Germany.

Background: Transcatheter aortic valve replacement (TAVR) is routinely used in patients with severe aortic stenosis at increased operative risk. Due to potential technical difficulties, TAVR is not recommended for pure aortic regurgitation (AR). Smaller studies reported its use in AR, but data from big registries are lacking. The present study analyzes the nationwide use of surgical aortic valve replacement (SAVR) and TAVR in patients with AR from 2008 until 2015.

Methods: We identified 138,237 cases of aortic valve replacement in Germany based on ICD and OPS codes.

Results: Of 13.2% SAVR-cases and 1.3% of TAVR cases were performed in AR. AR patients undergoing SAVR were younger with lower logistic EuroSCORE (stenosis: 6.1 ± 5.6; AR: 4.5 ± 4.9). Nevertheless, stroke rates, bleedings, prolonged mechanical ventilation, and in-hospital mortality were higher (mortality: stenosis 2.6%, AR: 4.7%). In the TAVR group, patients with AR were at higher operative risk (logistic EuroSCORE: transfemoral (TF)-TAVR: stenosis: 14.3 ± 10.4; AR: 17.3 ± 13.3. Transapical (TA)-TAVR: stenosis: 16.1 ± 11.4; AR: 15.7 ± 12.2). Stroke rates were lower, but bleedings and prolonged ventilation occurred more frequently after TF-TAVR in AR compared to stenosis. The mortality varied markedly (TF-TAVR: 15.2% in 2011; 2.8% in 2015; TA-TAVR: 17.7% in 2012 and 0% in 2014).

Conclusion: TAVR is off-label used in AR in clinical practice. TAVR seems to be a safe option for AR with regard to in-hospital outcomes. However, further research evaluating long-term outcomes is required to establish the feasibility of TAVR in pure AR.
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http://dx.doi.org/10.1002/ccd.28361DOI Listing
March 2020

Risk-Adjusted Comparison of In-Hospital Outcomes of Transcatheter and Surgical Aortic Valve Replacement.

J Am Heart Assoc 2019 04;8(7):e011504

1 University Heart Center Freiburg Department of Cardiology and Angiology I Faculty of Medicine University of Freiburg Freiburg Germany.

Background Transfemoral transcatheter aortic valve replacement (TF-TAVR) is recommended for patients suffering from aortic valve stenosis at increased operative risk. Beyond that, patients with different comorbidities could benefit from TF-TAVR. The present study compares real-world in-hospital outcomes of surgical aortic valve replacement and TF-TAVR. Methods and Results For all 33 789 isolated TF-TAVR and surgical aortic valve replacement procedures performed in Germany in 2014 and 2015, comorbidities and in-hospital outcomes were identified by International Classification of Diseases (ICD)- and OPS (Operation and procedure key)-codes. Patients undergoing TF-TAVR were older and at increased estimated risk. Outcomes were risk-adjusted to allow comparison. TF-TAVR was associated with a lower risk for acute kidney injuries (odds ratio [OR] 0.62, P<0.001), for bleeding (OR 0.17, P<0.001), and for prolonged mechanical ventilation (>48 hours, OR 0.21, P<0.001). Risk for stroke was similar (OR 1.07, P=0.558). As expected, the risk for pacemaker implantations was higher after TF-TAVR (OR 4.61, P<0.001). In all patients, none of the treatment strategies had a clear advantage on the risk for in-hospital mortality (OR 0.83, P=0.068). However, in patients aged >80 years and at high operative risk undergoing TF-TAVR in-hospital mortality was lower (TF-TAVR versus surgical aortic valve replacement 80-84, OR 0.55; P=0.002; ≥85 years, OR 0.42, P=0.006; EuroSCORE (European System for Cardiac Operative Risk Evaluation) >9: OR 0.62, P=0.001). TF-TAVR was superior in patients with renal failure and in NYHA (New York Heart Association)-Class III/IV. Other risk groups were not found to be factors favoring a treatment strategy. Conclusions The present study indicates a superiority of TF-TAVR in clinical practice for patients at increased operative risk, aged >80 years, in NYHA-Class III/IV, and with renal failure.
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http://dx.doi.org/10.1161/JAHA.118.011504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509703PMC
April 2019

Estimating the additional costs per life saved due to transcatheter aortic valve replacement: a secondary data analysis of electronic health records in Germany.

Eur J Health Econ 2019 Jun 2;20(4):625-632. Epub 2019 Jan 2.

Department of Cardiology and Angiology I, Heart Center Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79104, Freiburg, Germany.

Aortic stenosis (AS) is the most common valvular heart disease, with a dismal prognosis when untreated. Recommended therapy is surgical (SAVR) or transcatheter (TAVR) aortic valve replacement. Based on a retrospective cohort of isolated SAVR and TAVR procedures performed in Germany in 2015 (N = 17,826), we examine the impact of treatment selection on in-hospital mortality and total in-hospital costs for a variety of at-risk populations. Since patients were not randomized to the two treatment options, the two endpoints in-hospital mortality and reimbursement are analyzed using logistic and linear regression models with 20 predefined patient characteristics as potential confounders. Incremental cost-effectiveness ratios were calculated as a ratio of the risk-adjusted reimbursement and mortality differences with 95% confidence intervals obtained by Fieller's theorem. Our study shows that TF-TAVR is more costly that SAVR and that cost differences between the procedures vary little between patient groups. Results regarding in-hospital mortality are mixed. SAVR is the predominant procedure among younger patients. For patients older than 85 years or at intermediate and higher pre-operative risk TF-TAVR seems to be the treatment of choice. Incremental cost-effectiveness ratios (ICER) are most favorable for patients older than 85 years (ICER €154,839, 95% CI €89,163-€302,862), followed by patients at higher pre-operative risk (ICER €413,745, 95% CI €258,027-€952,273). A hypothetical shift from SAVR towards TF-TAVR among patients at intermediate pre-operative risk is associated with a less favorable ICER (€1,486,118, 95% CI €764,732-€23,692,323), as the risk-adjusted mortality benefit is relatively small (- 0.97% point), while the additional reimbursement is still eminent (+€14,464). From a German healthcare system payer's perspective, the additional costs per life saved due to TAVR are most favorable for patients older than 85 and/or at higher pre-operative risk.
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http://dx.doi.org/10.1007/s10198-018-1023-xDOI Listing
June 2019
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