Aims Cyclophilin A (CyPA) induces leucocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leucocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147. In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA.Methods and results Confocal imaging, proximity ligation, co-immunoprecipitation, and atomic force microscopy were performed and demonstrated an interaction of CyPA with RAGE on the cell surface. Static and dynamic cell adhesion and chemotaxis assays towards extracellular CyPA using human leucocytes and leucocytes from RAGE-deficient Ager-/- mice were conducted. Inhibition of RAGE abrogated CyPA-induced effects on leucocyte adhesion and chemotaxis in vitro. Accordingly, Ager-/- mice showed reduced leucocyte recruitment and endothelial adhesion towards CyPA in vivo. In wild-type mice, we observed a downregulation of RAGE on leucocytes when endogenous extracellular CyPA was reduced. We furthermore evaluated the role of RAGE for platelet activation and thrombus formation upon CyPA stimulation. CyPA-induced activation of platelets was found to be dependent on RAGE, as inhibition of RAGE, as well as platelets from Ager-/- mice showed a diminished activation and thrombus formation upon CyPA stimulation. CyPA-induced signalling through RAGE was found to involve central signalling pathways including the adaptor protein MyD88, intracellular Ca2+ signalling, and NF-kappa B activation.Conclusion We propose RAGE as a hitherto unknown receptor for CyPA mediating leucocyte as well as platelet activation. The CyPA-RAGE interaction thus represents a novel mechanism in thrombo-inflammation. Graphical Abstract RAGE is a novel receptor for extracellular CyPA on leucocytes and platelets. RAGE was found to interact with CyPA and to play an important role in CyPA-induced leucocyte and platelet functions. Platelet activation, coaggregate formation, and intracellular Ca2+ release by CyPA were abrogated when RAGE was absent or blocked. Similarly, CyPA-induced leucocyte migration and adhesion were found to be dependent on RAGE in vivo and in vitro. CyPA abundance was furthermore identified to regulate RAGE expression in vivo.

Aim Data on associations of invasively determined hemodynamic parameters with procedural success and outcomes in patients suffering from mitral regurgitation (MR) undergoing transcatheter edge-to-edge repair of the mitral valve (M-TEER) is limited.Methods and results We enrolled 239 patients with symptomatic MR of grade 2 + , who received M-TEER. All patients underwent extensive pre-interventional invasive hemodynamic measurements via right heart catheterization (mean pulmonary arterial pressure (mPAP), systolic- (PAPsys) and diastolic pulmonary arterial pressure (PAPdia), pulmonary arterial wedge pressure (PAWP), a-wave, v-wave, pulmonary vascular resistance (PVR), transpulmonary pressure gradient (TPG), cardiac index (CI), stroke volume index (SVI)). mPAP and PAWP at baseline were neither associated with procedural success, immediate reduction of MR, nor residual MR after 6 months of follow-up. The composite outcome (All-cause mortality (ACM) and/or heart failure induced rehospitalization (HFH)) and HFH differed significantly after M-TEER when stratified according to mPAP, PAWP, PAPdia, a-wave and v-wave. ACM was not associated with the afore mentioned parameters. Neither PVR, TPG, CI nor SVI were associated with the composite outcome and HFH, respectively. In multivariable analyses, PAWP was independently associated with the composite outcome and HFH. PVR and SVI were not associated with outcomes.Conclusion PAWP at baseline was significantly and independently associated with HFH and might serve as a valuable parameter for identifying patients at high risk for HFH after M-TEER. ACM and procedural success were not affected by pulmonary arterial pressure before M-TEER. We suggest that the post-capillary component of PH serves as the driving force behind the risk of HFH.

Objectives:The aim of this retrospective analysis was to compare the patient outcome after interventional therapy of saphenous vein graft (SVG) stenoses in an all-comers population receiving either self-expanding drug-eluting stents (SExS) or balloon expanding drug-eluting stents (BExS).Background:The interventional therapy of degenerated SVGs remains challenging. Diameter variations of stenotic segments and friable plaques can lead to malapposition and distal embolization with increased major adverse cardiac event (MACE) rates.Methods:107 patients with a total of 130 SVG interventions were separated into two groups according to either SExS (n = 51) or BExS (n = 56) treatment. Primary endpoint was the MACE rate, which is defined as the composite of cardiac death, myocardial infarction (MI), target vessel (TVR), and target lesion revascularization (TLR) at 30 days and at one-year follow-up.Results:Both patient groups did not differ significantly regarding patient characteristics. The patient outcome was significantly better in the SExS patient group: the MACE rate at 30 days was 1/51 (2.0%) in group SExS vs. 7/56 (12.5%) in group BExS; p < 0.05. At one-year follow-up, the MACE rate remained significantly lower in the SExS group 8/51(15.7%) vs. 20/56 (35.7%) in the BExS group, p < 0.02. Additionally, cardiac death occurred significantly later within the SExS patient group compared to the BExS group (p < 0.05). A better overall outcome of patients with de novo SVG-stenosis compared to patients with previous CABG (coronary artery bypass graft) intervention was noted in both groups.Conclusion:Our findings demonstrate that SVG treatment with SExS is safe and provides clinical benefits by comparatively improving short and especially long-term patient outcomes.

Background SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin H receptor blockers (ARBs) mitigates the course o\f recentonset COVID-19. Methods ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUC(SOFA)), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. Findings Between April 20,2020, and Jan 20,2021,204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0.42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0.00 (0.00-2.00) vs 1.00 (0.00-3.00); p=0.12). Discontinuation was associated with a significantly lower AUC(SOFA) A (0.00 [0.00-9.25] vs 3.50 [0.00-23.50]; p=0.040), mean SOFA score (0.00 [0.00-0.31] vs 0.12 [0.00-0.78]; p=0.040), and 30-day SOFA score (0.00 110-90th percentile, 0.00-1.20] vs 0.00 [0.00-24.00]; p=0.023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score >= 1) or were dead (p=0.017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0.87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0.96) between the discontinuation and continuation group. Interpretation Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Surface receptor-mediated adhesion is a fundamental step in the recruitment of leukocytes and platelets, as well as platelet–leukocyte interactions. The surface receptor CD147 is crucially involved in host defense against self-derived and invading targets, as well as in thrombosis. In the current study, we describe the previously unknown interaction of CD147 with integrin αMβ2 (Mac-1) in this context. Using binding assays, we were able to show a stable interaction of CD147 with Mac-1 in vitro. Leukocytes from Mac-1−/− and CD147+/− mice showed a markedly reduced static adhesion to CD147- and Mac-1-coated surfaces, respectively, compared to wild-type mice. Similarly, we observed reduced rolling and adhesion of monocytes under flow conditions when cells were pre-treated with antibodies against Mac-1 or CD147. Additionally, as assessed by antibody inhibition experiments, CD147 mediated the dynamic adhesion of platelets to Mac-1-coated surfaces. The interaction of CD147 with Mac-1 is a previously undescribed mechanism facilitating the adhesion of leukocytes and platelets.

Aims The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y(12)-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel. Methods and results Acute coronary syndrome patients with PFT done 14days after hospital discharge were included with prior randomization to uniform prasugrel for 12months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2-5 bleeding, from PFT until 12months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n=1073), similar outcomes were observed in guided patients kept on clopidogrel [n=755, hazard ratio (HR): 1.06 (0.57-1.95), P=0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n=511, HR: 0.96 (0.47-1.96), P=0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n=188, HR: 2.16 (1.01-4.65), P=0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18-2.56), P=0.005], without interaction (P-int=0.76) between study groups. Conclusion Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.

In the placebo-controlled, double-blind BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) 2 trial, intracoronary autologous bone marrow cell (BMC) transfer did not improve recovery of left ventricular ejection fraction (LVEF) at 6 months in patients with ST-elevation myocardial infarction (STEMI) and moderately reduced LVEF. Regional myocardial perfusion as determined by adenosine stress perfusion cardiac magnetic resonance imaging (S-CMR) may be more sensitive than global LVEF in detecting BMC treatment effects. Here, we sought to evaluate (i) the changes of myocardial perfusion in the infarct area over time (ii) the effects of BMC therapy on infarct perfusion, and (iii) the relation of infarct perfusion to LVEF recovery at 6 months. In 51 patients from BOOST-2 (placebo, n = 10; BMC, n = 41), S-CMR was performed 5.1 ± 2.9 days after PCI (before placebo/BMC treatment) and after 6 months. Infarct perfusion improved from baseline to 6 months in the overall patient cohort as reflected by the semi-quantitative parameters, perfusion defect–infarct size ratio (change from 0.54 ± 0.20 to 0.43 ± 0.22; P = 0.006) and perfusion defect–upslope ratio (0.54 ± 0.23 to 0.68 ± 0.22; P < 0.001), irrespective of randomised treatment. Perfusion defect–upslope ratio at baseline correlated with LVEF recovery (r = 0.62; P < 0.001) after 6 months, with a threshold of 0.54 providing the best sensitivity (79%) and specificity (74%) (area under the curve, 0.79; 95% confidence interval, 0.67–0.92). Infarct perfusion improves from baseline to 6 months and predicts LVEF recovery in STEMI patients undergoing early PCI. Intracoronary BMC therapy did not enhance infarct perfusion in the BOOST-2 trial.

Background: MitraClip therapy is increasingly used in patients deemed inoperable to treat severe mitral regurgitation (MR), but long-tern data is scarce. Aims: The multicentre, industry-independent German Transcatheter Mitral Valve Interventions (TRAMI) registry comprises the largest prospectively enrolled cohort of patients treated by MitraClip therapy The current analysis is focusing on long-term mortality rates, cardiac rehospitalization and reintervention. Methods and results: Long-term follow-up (median time 1037 clays) in the TRAMI registry was available for 722 patients treated at 20 German centres. Improvements in New York Heart Association (NYHA) functional class (I/Il long-term: 65% vs. 1-year follow-up: 63.3%) and self-rated health-status (EuroQuol visual analogue scale [EQ VAS] long-term: 60 [50-70] vs. 1-year follow-up: 60 [50; 701) were pertained over time. Estimated mortality rates by Kaplan-Meier method were 19.7% for 1-year, 31.9% for 2-year and 53.1% for 4-year follow-up without differences found for MR aetiology. Multivariable Cox-regression analysis identified previous aortic valve implantation (hazard ratio [HR] 2.21; p < 0.0001), NYHA class IV (HR 1.7S; p < 0.001), prior cardiac decompensation (HR 1.63; p < 0.001), creatinine 1.5 mg/d1 (HR 1.63; p < 0.0001) and left ventricular ejection fraction < 30% (HR 1.60; p < 0.001) as most predictive for long-term mortality. Conclusions: Long-term outcome in the TRAMI registry confirmed lasting clinical improvements and low intervention rates. Long-term mortality was strongly influenced by cardiac and non-cardiac co-morbidities and was found comparable for both MR aetiologies. (C) 2018 Elsevier B.V. All rights reserved.

Objectives To compare baseline characteristics and outcomes in patients treated with either 1 or 2 MitraClips in the German TRAMI (Transcatheter Mitral Valve Interventions) registry. Background The MitraClip community seems to silently assume that results should intrinsically be better after implantation of more than one clip, although data is still sparse. Methods In 2010-2013, 803 patients were enrolled prospectively into TRAMI (461 one-clip and 312 two-clip procedures). Follow-up was performed centrally at 30 days and 1 year. Results Baseline characteristics of TRAMI-patients with two clips differed significantly from single-clip patients regarding constitutional (more men, taller body height) and heart failure-related factors (larger left ventricular dimensions, reduced left ventricular ejection fraction, more severe heart failure). Also, a significant increase in two-clip procedures over time was present. After propensity score matching for differing baseline characteristics, residual moderate mitral regurgitation (MR) occurred more frequently after implantation of two clips, whereas residual severe MR could more frequently be observed after one-clip procedures. However, no or mild residual MR at discharge was present in 71.6% after single-clip and in 70.1% after two-clips implantation (p = .81). After 1 year, no significant differences regarding mortality or New York Heart Association status could be detected in the propensity matched cohorts. However, TRAMI-patients treated with two clips had a significantly higher incidence of cerebral-vascular events (p = .02). Conclusions TRAMI data cannot support the theory that implantation of more than one clip is associated with better clinical outcomes. The finding of more cerebral-vascular events after two-clip procedures might be hypothesis-generating.

Background: Plasma Galeclin-3 is a marker of myocardial inflammation and fibrosis, was associated with left ventricular (LV) reverse remodeling after conventional surgical mitral valve repair (MVR) and predicted clinical events in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to evaluate the association between pre-interventional Galeclin-3 levels and (1) reverse LV remodeling and (2) major adverse cardiovascular events (MACE) in patients undergoing percutaneous MVR. Methods: Forty four consecutive patients (median age 79 years, LV ejection fraction 39.5 +/- 11.4%, 91% in NYHA functional class with symptomatic moderate to severe mitral regurgitation undergoing percutaneous MVR were prospectively included. Plasma Galectin-3 levels were measured before the procedure. Echocardiographic and clinical assessment was performed at baseline and after 3 months. LV reverse remodeling was prospectively defined as a >= 10% increase in global longitudinal strain. MACE included death, myocardial infarction, heart failure related rehospitalization and stroke and was assessed after a mean follow-up time of 2 years. Results: 72.7% of the patients showed LV reverse remodeling. Pre-interventional Galectin-3 < 10 ng/ml was an independent predictor of LV reverse remodeling (OR 10.3, 95% CI 1.2-83.9, p=0.036). 25 patients (56.8%) experienced a MACE. Patients with Galectin-3 levels >= 10 ng/ml had significantly more MACE than patients with Galectin-3 levels < 10 ng/ml (100% vs. 45.5%, p=0.003). Diabetes independently predicted MACE (HR 3.1, 95% CI 1.0-9A, p=0.049); Galectin-3 >= 10 ng/ml was of borderline significance (HR 2.2, 95% CI 0.9-5.4, p=0.038). Conclusions: Pre-interventional plasma Galectin-3 levels are associated with LV reverse remodeling and with clinical outcome after percutaneous MVR. (C) 2013 Elsevier B.V. All rights reserved.

Selbstexpandierende Koronarstents stellen eine eigenständige Option in der Behandlung von Koronarstenosen dar. Aufgrund der speziellen elastischen Materialeigenschaften ihres Nitinolgerüsts werden sie aktuell bevorzugt zur Therapie von großlumigen Bifurkations- (z. B. distale Hauptstammstenosen), ektatischen und aneurysmatischen Gefäßen, venösen Bypassgrafts sowie Koronardissektionen eingesetzt. Nachteilig sind eine schwierigere Handhabung im Vergleich zu ballonexpandierenden Stents sowie eine erhöhte Rigidität, welche die Freisetzung in stark gewundenen oder verkalkten Gefäßen erschwert. Limitierend ist zudem der aktuell hohe Stückpreis, der im deutschen DRG-System noch unzureichend refinanziert wird. Im Einzelfall kann der Einsatz eines selbstexpandierenden Koronarstents jedoch eine schwierige Koronarpathologie meistern und ist daher eine Bereicherung für das Portfolio eines Katheterlabors.

Introduction: Cyclophilin A (CyPA) is a ubiquitously expressed chaperon protein that contains PPIase activity and regulates intracellular functions, like protein folding and Ca2+ signaling.Upon activation CyPA is released into the extracellular space and binds to the Ig superfamily member CD147.Platelets are a major source of CyPA and the binding of CyPA to its receptor promotes platelet activation.CyPA is involved in the development of cardiovascular diseases including myocardial infarction, cardiac hypertrophy and atherosclerosis.Till know there is no specific inhibitor targeting extracellular CyPA.Purpose: The known inhibitors are also affecting other extracellular cyclophilins or also the intracellular cyclophilins including CyPA.The aim of this study is to design a specific antibody that only affects extracellular CyPA.Methods: For the generation of a specific extracellular CyPA antibody mice and rats were immunized with a peptide containing the CD147 binding site.The antibodies were screened for their binding ability in a Western Blot SDS page and in a CyPA-binding-ELISA.For the functional test the inhibitory effects were tested in in vitro and in vivo migration assay.For the anti-thrombotic experiments platelets were stimulated with CyPA and the inhibitory effects were analyzed by measuring CD62P surface expression in flow cytometry.Next the anti-thrombotic properties were analyzed in an in vitro thrombus formation model and in vivo in a FeCl3 model.Next the anti-thrombotic effects of the antibody were tested in trauma/ hemorrhagic shock model.Moreover the effect of the antibody on hemostasis was measured by tail bleeding time.Results: Form the developed antibodies the antibody, 8H7, which had the best performance in the binding assays were used for further experiments.8H7 reduce significantly the CyPA-induced migration in vitro.Moreover also in vivo in a CyPA-induced peritonitis model there is a reduction in infiltrating CD3+ cells (5.1±0.67 vs. 2.1±0.37) and F4/80+ cells (4.7±0.67 vs. 1.9±0.43)compared to IgG.Moreover 8H7 reduces the CyPA-induced CD62P expression compared to IgG (35.72±2.65 vs. 26.76±2.1).The CyPA-induced thrombus formation is significantly reduced by 8H7 in vitro and in vivo in a FeCl3 model (1948±183.9vs. 775.4±67.63).The CyPA antibody 8H7 is able to decrease the aggregation of circulating platelets and platelet aggregates in the liver significantly of mice exposed to trauma and hemorrhagic shock. Conclusion:This study provides evidence that it is possible to counteract the pro-thrombotic and pro-inflammatory effects of CyPA using our antibody 8H7 and that there is no effect of 8H7 on general hemostasis.

Aims Intracoronary infusion of autologous nucleated bone marrow cells (BMCs) enhanced the recovery of left ventricular ejection fraction (LVEF) after ST-segment elevation myocardial infarction (STEMI) in the randomised-controlled, open-label BOOST trial. We reassessed the therapeutic potential of nucleated BMCs in the randomised placebo-controlled, double-blind BOOST-2 trial conducted in 10 centres in Germany and Norway. Methods and results Using a multiple arm design, we investigated the dose-response relationship and explored whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on BMC efficacy. Between 9 March 2006 and 16 July 2013, 153 patients with large STEMI were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose (hi)BMCs, low-dose (lo)BMCs, irradiated hiBMCs, or irradiated loBMCs 8.1 ± 2.6 days after percutaneous coronary intervention (PCI) in addition to guideline-recommended medical treatment. Change in LVEF from baseline (before cell infusion) to 6 months as determined by MRI was the primary endpoint. The trial is registered at Current Controlled Trials (ISRCTN17457407). Baseline LVEF was 45.0 ± 8.5% in the overall population. At 6 months, LVEF had increased by 3.3 percentage points in the control group and 4.3 percentage points in the hiBMC group. The estimated treatment effect was 1.0 percentage points (95% confidence interval, -2.6 to 4.7; P = 0.57). The treatment effect of loBMCs was 0.5 percentage points (-3.0 to 4.1; P = 0.76). Likewise, irradiated BMCs did not have significant treatment effects. BMC transfer was safe and not associated with adverse clinical events. Conclusion The BOOST-2 trial does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF treated according to current standards of early PCI and drug therapy.

SummaryAtopaxar, also known as E 5555 is a novel reversible protease-activated receptor-1 (PAR-1) thrombin receptor antagonist. To date, Atopaxar has been investigated in phase II trials with focus on safety and tolerability in patients with acute coronary syndromes or stable coronary artery disease on top of standard antiplatelet therapy. Atopaxar was generally well tolerated, however a rise in liver enzymes and prolongation of the QTcF interval were observed. The data suggest, that atopaxar administration may promote some minor bleeding complications, but does not seem to significantly increase the risk of major bleeding. Although not powered for efficacy, the currently available data suggest potential benefits in patients at high risk for recurrent ischemic events on top of standard antiplatelet therapy. In conclusion, more studies (e.g. phase III) are needed to evaluate efficacy and safety of atopaxar.

Apart from their intracellular function as chaperones in protein folding, cyclophilins have been found to play important roles in the pathogenesis of thrombosis as well as inflammation. With liberation of cyclophilin A (CyPA) into the extracellular space (eCyPA), it acts as a danger-associated molecular pattern. Following interaction with its primary extracellular receptor CD147, eCyPA facilitates platelet activation with subsequent adhesion to the endothelium, degranulation as well as shape change. Furthermore, the eCyPA-CD147 interaction induces leucocyte adhesion and has strong chemotactic effects on leucocytes. In this chapter, we review the effects of cyclophilins in the context of thrombo-inflammation and give insight into current pharmacological strategies targeting cyclophilins.

AIMS Factors predicting outcomes after MitraClip implantation are not well defined. We aimed to report the influence of baseline renal function on short-term outcomes of patients enrolled in the investigator-initiated German transcatheter mitral valve interventions (TRAMI) registry. METHODS AND RESULTS Twenty participating German centres prospectively included 778 patients (mean age 76.0 years [71-81], 38.8% female gender) at high surgical risk (mean logistic EuroSCORE 20% [12-32%]) undergoing TMVR with the MitraClip for the treatment of symptomatic functional (70%) or degenerative (30%) mitral valve regurgitation (FMR, DMR). The patients were stratified according to renal function before clip implantation. The prevalence of moderate to severe renal impairment (glomerular filtration rate [GFR] <60 ml/min) was 62.7% (37.3%, normal renal function [GFR >60 ml/min]; 49.6%, moderate renal impairment [GFR 30-60 ml/min]; 13.1%, severe renal impairment [GFR <30 ml/min]). TMVR was successfully completed in 98.2% of cases; acute procedural failure, in-hospital and 30-day mortality rates were 1.8%, 2.3% and 4.4%, respectively. Acute procedural failure and mortality rates (in-hospital, 30-day) were significantly higher in patients with severe renal impairment (5.9%, 7.8%, 14.1%), as compared to patients with moderately (1%, 1.3%, 3.0%) or mildly impaired to normal (1.4%, 1.7%, 2.9%) renal function (p<0.0001). Following Cox regression analysis, the prevalence of severe renal impairment at the time of TMVR was the only predictor for increased 30-day mortality rates (hazard ratio 3.42, 95% confidence interval 1.88-6.2; p<0.0001). CONCLUSIONS Renal function at the time of interventional mitral valve repair with the MitraClip system is a strong predictor for procedural outcomes. Patients with severe renal impairment have a more than threefold increased risk for acute procedural failure, in-hospital death and 30-day mortality.

Vasileia Ismini Alexaki1; Andreas E. May2,3; Chika Fujii1; Saskia N. I. v. UngernSternberg2; Christine Mund1; Meinrad Gawaz2; Triantafyllos Chavakis1*; Peter Seizer2* 1Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany; 2Medizinische Klinik III, Universitätsklinikum Tübingen, Tübingen, Germany; 3Medizinische Klinik I, Klinikum Memmingen, Memmingen, Germany

There is a tendency to match the age of donor and recipient in lung transplantation (LuTx). The aim of this study was to examine whether this is justified. All double LuTx recipients in Denmark and Norway were included. Donor/recipient age and post LuTx outcomes were registered. Of 589 patients included, 94 (16%) had received lungs from a donor ≥10 years older than the recipient (age∆≥10 group) and of these, 45 (8%) from a donor ≥20 years older (age∆≥20 group). Compared to non age mismatched recipients, recipients in the age∆≥10 group and age∆≥20 group were younger (51 vs. 32 and 26 years respectively, p<0.001). Moreover, the donors for the age mismatched were more often female (52% vs. 27% and 29% respectively) and for the age∆≥20 group the donors were less likely to have a smoking history (p=0.002). Although there were no differences between the groups in absolute lung function 1 year after LuTx, both FEV1, FVC and DLCO in % of reference values were lower in age mismatched. At 3 years post LuTx, the absolute values and the % of reference values were all significantly lower in the age mismatched groups (figure 1). In contrast, when calculating reference values using donor age, there were no differences between groups at 3 years post LuTx. Although lung function was lower at 3 years post LuTx, 6MWT was better and survival was not inferior in age mismatched groups (see figure 1). Recipient age but not donor age significantly predicted survival (Cox regr. p=0.015). Although lower spirometric values occurred in age-mismatched patients, we found no differences in survival between recipients who had received lungs from ≥10 or ≥20 years older donors in the complete national cohorts of double lung transplanted patients in Denmark and Norway. Lung function post LuTx seems to reflect donor age, and recipients who receive older lungs may have lower lung function at 3 years post LuTx compared to others. Survival, however, was related to recipient, not donor age. suggesting that it may be safe to give older lungs to younger donors.

Objective: Recently, we reported that extracellular cyclophilin A (CyPA) is an important agonist for platelets. Whereas soluble CyPA-levels have been associated with cardiovascular risk factors, cell-bound CyPA has not been investigated yet. In this study, we analyzed for the first time platelet-bound CyPA in patients with symptomatic coronary artery disease (CAD). Methods and results: blood was obtained from 388 consecutive patients: 204 with stable CAD and 184 with acute coronary syndrome (76 with unstable angina, 78 with non ST-elevation myocardial infarction (NSTEMI), and 30 with STEMI). In vitro stimulation of platelets with classical agonists revealed an enhanced expression of CyPA on the platelet surface. In patients with stable CAD, platelet-bound CyPA correlated excellently with platelet activity measured by P-selectin exposure in flow cytometry. The analysis of classical risk factors for atherosclerosis revealed that patients with hypertension and hypercholesterolemia had significantly enhanced platelet-bound CyPA, whereas diabetes and smoking were not associated with enhanced CyPA-binding to the platelet surface. In multivariate analysis, hypercholesterolemia was the only significant predictor of enhanced platelet-bound CyPA. Interestingly, in patients with acute myocardial infarction (AMI) platelet-bound CyPA was significantly decreased compared with patients with stable CAD. Conclusions: Enhanced platelet-bound CyPA is associated with hypertension and hypercholesterolemia in stable CAD patients. In patients with AMI platelet-bound CyPA is significantly decreased.

BACKGROUND There are 60,000 to 100,000 new cases of borreliosis in Germany each year. This infectious disease most commonly affects the skin, joints, and nervous system. Lyme carditis is a rare manifestation with potentially lethal complications. METHODS This review is based on selected publications on the clinical manifestations, diagnosis, and treatment of Lyme carditis, and on the authors' scientific and clinical experience. RESULTS Lyme carditis is seen in 4% to 10% of all patients with Lyme borreliosis. Whenever the clinical suspicion of Lyme carditis arises, an ECG is mandatory for the detection or exclusion of an atrioventricular conduction block. Patients with a PQ interval longer than 300 ms need continuous ECG monitoring. 90% of patients with Lyme carditis develop cardiac conduction abnormalities, and 60% develop signs of perimyocarditis. Borrelia serology (ELISA) may still be negative in the early phase of the condition, but is always positive in later phases. Cardiac MRI can be used to confirm the diagnosis and to monitor the patient's subsequent course. The treatment of choice is with antibiotics, preferably ceftriaxone. The cardiac conduction disturbances are usually reversible, and the implantation of a permanent pacemaker is only exceptionally necessary. There is no clear evidence at present for an association between borreliosis and the later development of a dilated cardiomyopathy. When Lyme carditis is treated according to the current guidelines, its prognosis is highly favorable. CONCLUSION Lyme carditis is among the rarer manifestations of Lyme borreliosis but must nevertheless be considered prominently in differential diagnosis because of the potentially severe cardiac arrhythmias that it can cause.