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Introduction Hypertension is a major cause of premature death worldwide as it is an important risk factor for coronary artery disease, myocardial infarction, heart failure and stroke. Although an estimated 1.3 billion adults suffer from hypertension, less than half of them are diagnosed correctly and therefore receive sufficient treatment. Furthermore, only one fifth of those treated reach the therapy target of normotension. This significant deficit underlines the need for new therapy concepts to improve long-term health outcomes. Several studies have shown positive effects of digital health programmes in the disease management of ambulatory, long-term hypertension treatment. More research is needed to explore the abilities of digital health programmes as an innovative pathway in ambulatory healthcare.The eXPLORE study aims to evaluate the feasibility of a clinical trial on the impact of a supplementary digital therapy programme for the treatment of primary arterial hypertension.Methods and analyses The eXPLORE study collects data in the setting of a prospective randomised controlled trial to evaluate methodological feasibility for larger-scaled follow-up research. The study compares a digital therapy programme using a smartphone application that is based on functions and algorithms creating tasks and recommendations based on individual health data to standard care for the treatment of primary arterial hypertension. The study period is 180 days, with a 90-day in-life phase followed by a 90-day follow-up phase. Baseline and follow-up data (3 months, 6 months follow-up) of all participants included is collected via questionnaire surveys as well as self-administered blood pressure monitoring. Patient inclusion, initial data acquisition and follow-up were carried out in an innovative remote setting. The study was initiated in November 2022 and is currently ongoing. Study outcome measures are changes in mean blood pressure, health literacy and self-sufficient health behaviour.Ethics and dissemination The eXPLORE study is carried out in accordance with all applicable legal regulations. Cost-effectiveness is assured by continuous evaluation and documentation over the course of the study. All health-relevant data from the eXPLORE study will be provided for analyses and publication to the investigators of LMU Hospital. The study was approved by the local ethics committee of LMU Munich (project nr.: 22–0115).Trial registration NCT05580068. Protocol Version: 1.5, 28.08.2023.

Background Right‐sided heart failure (HF) due to severe tricuspid regurgitation (TR) is associated with reduced quality of life (QoL). Here, we analyzed the impact of TR on specific QoL dimensions and the effect of transcatheter tricuspid valve intervention (TTVI) on individual QoL items. Methods and Results In this study, we included 174 patients with HF (49% women; median age, 79 years; 97% New York Heart Association ≥3) with baseline QoL assessment undergoing TTVI by transcatheter edge‐to‐edge‐repair at our center between April 2016 and March 2022. QoL was assessed by the standardized Minnesota Living With HF Questionnaire. QoL change after TTVI and correlation to functional end points were analyzed. In addition, all QoL domains and the 21 individual items of the Minnesota Living With HF Questionnaire were analyzed. TTVI significantly reduced TR (TR ≥3: baseline 95%, 1‐year‐follow‐up 7%; P

Background COVID-19 remains a challenge to individual health and healthcare resources worldwide. Telemedical surveillance might minimise hospitalisation and direct patient–physician contacts. Yet, randomised clinical trials evaluating telemedical management of COVID-19 patients are lacking. Methods COVID-SMART is a randomised, open-label, controlled clinical trial investigating whether telemedicine reduces the primary end-point of hospitalisation or any unscheduled utilisation of an emergency medical service within 30 days of follow-up. Key secondary end-points included mortality and primary end-point components. We enrolled acutely infected SARS-CoV-2 patients suitable for outpatient care. All presented with ≥1 risk factor for an adverse COVID-19 course. Patients were randomised 1:1 into a control group receiving standard of care and an intervention group receiving smartphone-based assessment of oxygen saturation, heart rate and electrocardiogram, and telemedical counselling via a 24/7 emergency hotline. Results Of 607 enrolled patients (mean±sd age 46.7±13.5 years), 304 were randomised into the intervention and 303 into the control group. The primary end-point occurred in 6.9% (n=21) of the intervention and in 9.6% (n=29) of the control group (hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.41–1.26; p=0.24). No deaths occurred during follow-up. Fewer intervention group participants utilised outpatient-based emergency medical services (HR 0.43, 95% CI 0.20–0.90; p=0.03). Conclusions COVID-SMART is the first randomised clinical trial assessing the benefit of telemedicine in an acute respiratory infectious disease. Whereas telemedical management did not reduce the primary end-point of hospitalisation, fewer intervention group patients used outpatient-based emergency services, suggesting a potential benefit for less-acutely infected individuals.

OBJECTIVES:. Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN:. Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING:. Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS:. In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS:. In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS:. HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

BackgroundOpenAI’s ChatGPT is a pioneering artificial intelligence (AI) in the field of natural language processing, and it holds significant potential in medicine for providing treatment advice. Additionally, recent studies have demonstrated promising results using ChatGPT for emergency medicine triage. However, its diagnostic accuracy in the emergency department (ED) has not yet been evaluated. ObjectiveThis study compares the diagnostic accuracy of ChatGPT with GPT-3.5 and GPT-4 and primary treating resident physicians in an ED setting. MethodsAmong 100 adults admitted to our ED in January 2023 with internal medicine issues, the diagnostic accuracy was assessed by comparing the diagnoses made by ED resident physicians and those made by ChatGPT with GPT-3.5 or GPT-4 against the final hospital discharge diagnosis, using a point system for grading accuracy. ResultsThe study enrolled 100 patients with a median age of 72 (IQR 58.5-82.0) years who were admitted to our internal medicine ED primarily for cardiovascular, endocrine, gastrointestinal, or infectious diseases. GPT-4 outperformed both GPT-3.5 (P

Transcatheter tricuspid valve replacement (TTVR) is an increasingly used treatment technique for patients with severe tricuspid regurgitation (TR). Currently, available data from international registries and randomized controlled trials provide outcome data until a maximum follow-up of 2 years after the procedure. This case report presents 4-year follow-up data for an 84-year-old woman who underwent TTVR for torrential TR in 2019. The patient experienced durable TR reduction, symptomatic improvement, right ventricular reverse remodeling, and substantial improvement in liver and kidney function.

Background: MRI (magnetic resonance imaging) represents the diagnostic image modality of choice in several conditions. With an increasing number of patients requiring MRI for diagnostic purposes, the issue of safety in patients with cardiac implantable electronic devices (CIED) undergoing this imaging modality will play an ever more important role. The purpose of this study was to assess the safety and device function following MRI in an unrestricted real-world cohort of patients with a wide array of cardiac devices. Methods: We conducted a retrospective single-center study including 1010 MRI studies conducted in adult patients (≥18 years) with an implanted CIED treated in the University Hospital of Munich (LMU) between July 2012 and March 2024. Patients with non-MR conditionally labeled leads, abandoned or epicardial leads, as well as lead fragments, were included for analysis. Results: Across a total of 1010 MRIs (920 total MR-conditional device generators) performed in patients with an implanted CIED, there were no deaths, reports of discomfort, palpitations, heating, or ventricular arrythmias in the 24 h following MRI. Only 2/1010 MRIs were followed by a reported atrial arrhythmia within 24 h, both in patients with an MR-conditional pacemaker (PM) device without an abandoned lead. No significant changes in device function following MRI from baseline were observed across all included CIEDs. Lastly, no instances of severe malfunction, such as generator failure, loss of capture, electrical reset, or inappropriate inhibition of pacing, were found in post-MRI interrogation reports across all MRI studies. Conclusions: Based on the analysis of 1010 MRIs undergone by patients with CIEDs, following standardized device interrogation, manufacturer-advised device programming, monitoring of vital function, and manufacturer-advised reprogramming, MRI can be performed safely and without adverse events or changes in device function.

Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin - CD4+ T cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T cell activation, which is initially triggered by IL- 12p40- and MHC-II dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the fibrinolysis inhibitor TAFI with fibrin whereby fibrin deposition is increased by TAFI in the absence but not presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1 dependent T helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee’s individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.

Objective: Acute cardiogenic shock is a life-threatening condition with mortality rates of up to 50%. If conventional therapy fails, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy has emerged to a promising alternative for temporary cardiac and respiratory support in specialized centers. However, it is only a bridge to recovery, final decision, heart transplantation or the permanent implantation of a left ventricular assist device. Therefore, the identification of the optimum weaning time point is challenging, and standardized weaning protocols are rare. Methods: In this explorative pilot study, we evaluated the potential benefit of blood flow measurements in the aortic arch using an ultrasonic cardiac output monitor (USCOM) for the primary endpoint of successful VA-ECMO weaning. 12 patients under VA-ECMO therapy for acute cardiogenic shock and a hemodynamic condition which qualified for a stepwise weaning process were included in this study. Main exclusion criterion was the presence of additional venting therapy for left ventricular unloading, e.g. Impella. Statistical comparisons were performed using the Mann-Whitney test and corrected for multiple testing by the Holm-Sidak method. Results: Peak velocity of flow in the aortic arch showed a positive correlation with weaning success independent of ECMO flow (weaning success vs. failure: 0.75 vs. 0.35 m/s (low ECMO support), p = 0.049), whereas we identified only a trend for mean pressure gradient, minute distance and stroke volume index. Conclusion: We hypothesize, that USCOM might provide an additive benefit to conventional strategies in its ability to predict successful VA-ECMO weaning and prevent pulmonary congestion. Larger upcoming trials are required to address this relevant topic and provide standardized treatment protocols for optimized weaning in the future.

Abstract Background The efficacy and safety of saline versus balanced crystalloid solutions in ICU-patients remains complicated by exceptionally heterogenous study population in past comparative studies. This study sought to compare saline and balanced crystalloids for fluid resuscitation in patients with cardiogenic shock with or without out-of-hospital cardiac arrest (OHCA). Methods We retrospectively analyzed 1032 propensity score matched patients with cardiogenic shock from the Munich University Hospital from 2010 to 2022. In 2018, default resuscitation fluid was changed from 0.9% saline to balanced crystalloids. The primary endpoint was defined as 30-day mortality rate. Results Patients in the saline group (n = 516) had a similar 30-day mortality rate as patients treated with balanced crystalloids (n = 516) (43.1% vs. 43.0%, p = 0.833), but a higher incidence of new onset renal replacement therapy (30.2% vs 22.7%, p = 0.007) and significantly higher doses of catecholamines. However, OHCA-patients with a lactate level higher than 7.4 mmol/L had a significantly lower 30-day mortality rate when treated with saline (58.6% vs. 79.3%, p = 0.013). In addition, use of balanced crystalloids was independently associated with a higher mortality in the multivariate cox regression analysis after OHCA (hazard ratio 1.43, confidence interval: 1.05–1.96, p = 0.024). Conclusions In patients with cardiogenic shock, use of balanced crystalloids was associated with a similar all-cause mortality at 30 days but a lower rate of new onset of renal replacement therapy. In the subgroup of patients after OHCA with severe shock, use of balanced crystalloids was associated with a higher mortality than saline. Trial registration: LMUshock registry (WHO International Clinical Trials Registry Platform Number DRKS00015860).

We present 2 cases of significant mitral regurgitation secondary to pericardial patch avulsion from the anterior mitral valve leaflet after aortic valve replacement with aortic annulus enlargement. Both cases were successfully managed by transcatheter repair with off-label implantation of occluder devices.

Residual and recurrent mitral regurgitation after transcatheter edge-to-edge repair are therapeutically challenging. In the present case report, we describe a simplified, transapical electrosurgical laceration and stabilization of clip procedure that represents an alternative and direct approach for electrosurgical laceration of mitral valve leaflets enabling transcatheter mitral valve replacement for recurrent mitral regurgitation after mitral valve transcatheter edge-to-edge repair.

While previous reports showed ADP-induced platelet reactivity to be an independent predictor of bleeding after PCI in stable patients, this has never been investigated in patients with cardiogenic shock. The association of bleeding events with respect to ADP-induced platelet aggregation was investigated in patients undergoing primary PCI for acute myocardial infarction complicated by cardiogenic shock and with available on-treatment ADP-induced platelet aggregation measurements. Out of 233 patients, 74 suffered from a severe BARC3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (p

Platelets are generated by specialized cells called megakaryocytes (MKs). However, MK’s origin and platelet release mode have remained incompletely understood. Here, we established direct visualization of embryonic thrombopoiesis in vivo by combining multiphoton intravital microscopy (MP-IVM) with a fluorescence switch reporter mouse model under control of the platelet factor 4 promoter (Pf4CreRosa26mTmG). Using this microscopy tool, we discovered that fetal liver MKs provide higher thrombopoietic activity than yolk sac MKs. Mechanistically, fetal platelets were released from MKs either by membrane buds or the formation of proplatelets, with the former constituting the key process. In E14.5 c-Myb-deficient embryos that lack definitive hematopoiesis, MK and platelet numbers were similar to wild-type embryos, indicating the independence of embryonic thrombopoiesis from definitive hematopoiesis at this stage of development. In summary, our novel MP-IVM protocol allows the characterization of thrombopoiesis with high spatio-temporal resolution in the mouse embryo and has identified membrane budding as the main mechanism of fetal platelet production.

Infection with SARS-COV-2 can result in self-limited upper airway infection or progress to a more systemic inflammatory condition including pneumonic COVID-19. Here the authors utilise a multi-omics approach to interrogate the immune response of patients with self-limiting upper respiratory SARS-CoV-2 infection and reveal a temporal immune trajectory they associate with viral containment and restriction from pneumonic progressive disease.

BackgroundVeno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a valuable treatment option for patients in cardiogenic shock, but complications during decannulation may worsen the overall outcome. Therefore, the aim of this study was to compare the efficacy and safety of suture-based to pure plug-based vascular closure devices for VA-ECMO decannulation.MethodsIn this retrospective study, the procedural outcome of 33 patients with suture-based Perclose ProGlide closure devices was compared to 38 patients with MANTA plug-based closure devices.ResultsRate of technically correct placement of closure devices was 88% in the suture-based group and 97% in the plug-based group (p = 0.27). There was a significant reduction of severe bleeding events during VA-ECMO decannulation in plug-based versus suture-based systems (3% vs. 21%, p = 0.04). Ischemic complications occurred in 6% with suture-based and 5% with plug-based device (p = 1.00). Pseudoaneurysm formation was detected in 3% in both groups (p = 1.00). No switch to vascular surgery due to bleeding after decannulation was necessary in both groups.ConclusionBased on our retrospective analysis, we propose that plug-based vascular closure should be the preferred option for VA-ECMO decannulation. This hypothesis should be further tested in a randomized trial.

Abstract Conduction disorders with need for permanent pacemaker (PPM) implantation remain frequent complications after transcatheter aortic valve implantation (TAVI). Up to 22% of PPM after TAVI are implanted for new onset left bundle branch block (LBBB) and atrioventricular block (AVB) I. However, clinical benefit and predictors of ventricular pacing in TAVI patients receiving PPM for this indication remain unclear. We retrospectively evaluated pacemaker interrogation data of patients who received a PPM post TAVI for new LBBB and new AVB I. The primary endpoint of this study was relevant ventricular pacing (ventricular pacing rate: Vp ≥ 1%) at the first outpatient pacemaker interrogation. Secondary endpoints were predictors for relevant ventricular pacing. At the first pacemaker interrogation (median follow up at 6.23 [2.8–14.8] months), median ventricular pacing frequency was 1.0% [0.1–17.8]. Out of 61 patients, 36 (59%) had Vp rates ≥ 1%. Patients with frequent ventricular pacing showed longer QRS duration (155 ms ± 17 ms vs. 144 ms ± 18 ms, p = 0.018) at the time of PPM implantation and were less likely treated with a balloon-expandable Edwards Sapiens Valve (39% vs. 12%, p = 0.040). Our findings suggest that the majority of patients with new LBBB and new AVB I after TAVI show relevant ventricular pacing rates at follow up. Further prospective studies are necessary to identify patients at higher risk of pacemaker dependency.

Plain language summary The clinical course of patients with COVID-19 is highly variable, with some patients barely affected and others dying. We wanted to better understand why this is the case and identify markers of COVID-19-associated mortality. To this end, we looked into the entire available medical history of more than 100,000 COVID-19 patients from the United States. We found that patients who had experienced a disturbance of electrolyte or fluid levels in the year before they contracted SARS-CoV-2 were more likely to die than patients without such a history. This observation suggests that careful monitoring and balancing of the hydration and electrolyte status during and even before a SARS-CoV-2 infection may be beneficial and possibly reduce the risk of death with COVID-19.

Abstract Background DOAC detection is challenging in emergency situations. Here, we demonstrated recently, that modified thromboelastometric tests can reliably detect and differentiate dabigatran and rivaroxaban. However, whether all DOACs can be detected and differentiated to other coagulopathies is unclear. Therefore, we now tested the hypothesis that a decision tree-based thromboelastometry algorithm enables detection and differentiation of all direct Xa-inhibitors (DXaIs), the direct thrombin inhibitor (DTI) dabigatran, as well as vitamin K antagonists (VKA) and dilutional coagulopathy (DIL) with high accuracy. Methods Following ethics committee approval (No 17–525-4), and registration by the German clinical trials database we conducted a prospective observational trial including 50 anticoagulated patients (n = 10 of either DOAC/VKA) and 20 healthy volunteers. Blood was drawn independent of last intake of coagulation inhibitor. Healthy volunteers served as controls and their blood was diluted to simulate a 50% dilution in vitro. Standard (extrinsic coagulation assay, fibrinogen assay, etc.) and modified thromboelastometric tests (ecarin assay and extrinsic coagulation assay with low tissue factor) were performed. Statistical analyzes included a decision tree analyzes, with depiction of accuracy, sensitivity and specificity, as well as receiver-operating-characteristics (ROC) curve analysis including optimal cut-off values (Youden-Index). Results First, standard thromboelastometric tests allow a good differentiation between DOACs and VKA, DIL and controls, however they fail to differentiate DXaIs, DTIs and VKAs reliably resulting in an overall accuracy of 78%. Second, adding modified thromboelastometric tests, 9/10 DTI and 28/30 DXaI patients were detected, resulting in an overall accuracy of 94%. Complex decision trees even increased overall accuracy to 98%. ROC curve analyses confirm the decision-tree-based results showing high sensitivity and specificity for detection and differentiation of DTI, DXaIs, VKA, DIL, and controls. Conclusions Decision tree-based machine-learning algorithms using standard and modified thromboelastometric tests allow reliable detection of DTI and DXaIs, and differentiation to VKA, DIL and controls. Trial registration Clinical trial number: German clinical trials database ID: DRKS00015704 .

Cardiac arrest still accounts for a substantial proportion of cardiovascular related deaths and is associated with a tremendous risk of neurological injury and, among the few survivors, poor quality of life. Critical determinants of survival and long‐term functional status after cardiac arrest are timely initiation of cardiopulmonary resuscitation and use of an external defibrillator for patients with a shockable rhythm. Outcomes are still far from satisfactory, despite ongoing efforts to improve cardiac arrest response systems, as well as elaborate postresuscitation algorithms. Targeted temperature management at the wide range between 32 °C and 36 °C has been one of the main therapeutic strategies to improve neurological outcome in postresuscitation care. This recommendation has been mainly based on 2 small randomized trials that were published 20 years ago. Most recent data derived from the TTM2 (Targeted Hypothermia Versus Targeted Normothermia After Out‐of‐Hospital Cardiac Arrest) trial, which included 1861 patients, challenge this strategy. It showed no benefit of targeted hypothermia at 33 °C over normothermia at 36 °C to 37.5 °C with fever prevention. Because temperature management at lower temperatures also correlated with an increased risk of side effects without any benefit in the TTM2 trial, a modification of the guidelines with harmonizing temperature management to normothermia might be necessary.

Since transcatheter edge-to-edge repair (TEER) has become a valuable therapy in the treatment of both, mitral (MR) and tricuspid regurgitation (TR), the question of optimized patient selection has gained growing importance. After years of attributing rather little attention to the right ventricle (RV) and its function in the setting of valvular heart failure, this neglect has recently changed. The present review sought to summarize anatomy and function of the RV in a clinical context and aimed at presenting the current knowledge on how the RV influences outcomes after TEER for atrioventricular regurgitation. The anatomy of the RV is determined by its unique shape, which necessitates to use three-dimensional imaging methods for detailed and comprehensive characterization. Complex parameters such as RV to pulmonary artery coupling (RVPAc) have been developed to combine information of RV function and afterload which is primary determined by the pulmonary vasculature and LV filling pressure. Beyond that, TR, which is closely related to RV function also plays an important role in the setting of TEER. While mitral valve transcatheter edge-to-edge repair (M-TEER) leads to reduction of concomitant TR in some patients, the prognostic value of TR in the setting of M-TEER remains unclear. Overall, this review summarizes the current state of knowledge of the outstanding role of RV function and associated TR in the setting of TEER and outlines the unsolved questions associated with right-sided heart failure.

Abstract Background Percutaneous dilatational tracheotomy (PDT) has become an established procedure in intensive care units (ICU). However, the safety of this method has been under debate given the growing number of critically ill patients with high bleeding risk receiving anticoagulation, dual antiplatelet therapy (DAPT) or even a combination of both, i.e. triple therapy. Therefore, the purpose of this study, including such a high proportion of patients on antithrombotic therapy, was to investigate whether PDT in high-risk ICU patients is associated with elevated procedural complications and to analyse the risk factors for bleeding occurring during and after PDT. Methods PDT interventions conducted in ICUs at 12 European sites between January 2016 and October 2019 were retrospectively analysed for procedural complications. For subgroup analyses, patient stratification into clinically relevant risk groups based on anticoagulation and antiplatelet treatment regimens was performed and the predictors of bleeding occurrence were analysed. Results In total, 671 patients receiving PDT were included and stratified into four clinically relevant antithrombotic treatment groups: (1) intravenous unfractionated heparin (iUFH, prophylactic dosage) (n = 101); (2) iUFH (therapeutic dosage) (n = 131); (3) antiplatelet therapy (aspirin and/or P2Y12 receptor inhibitor) with iUFH (prophylactic or therapeutic dosage) except for triple therapy (n = 290) and (4) triple therapy (DAPT with iUFH in therapeutic dosage) (n = 149). Within the whole cohort, 74 (11%) bleedings were reported to be procedure-related. Bleeding occurrence during and after PDT was independently associated with low platelet count (OR 0.73, 95% CI [0.56, 0.92], p = 0.009), chronic kidney disease (OR 1.75, 95% CI [1.01, 3.03], p = 0.047) and previous stroke (OR 2.13, 95% CI [1.1, 3.97], p = 0.02). Conclusion In this international, multicenter study bronchoscopy-guided PDT was a safe and low-complication airway management option, even in a cohort of high risk for bleeding on cardiovascular ICUs. Low platelet count, chronic kidney disease and previous stroke were identified as independent risk factors of bleeding during and after PDT but not triple therapy.

Abstract Background Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. Methods This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). Results 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p

Abstract Background In this descriptive study of male and female mice at different weeks of age, we use serial non-invasive cardiac 18F-FDG-PET scans to follow up on metabolic alterations, heart function parameters, and the ECG of both sexes in early to mid-adulthood. Methods ECG-gated 18F-FDG-PET scans were performed in mice on 10, 14, and 18 weeks of age, using a dedicated small-animal PET scanner. The percentage of the injected activity per gram (%IA/g) in the heart, left ventricular metabolic volume (LVMV), myocardial viability and left ventricular function parameters: end-diastolic (EDV), end-systolic (ESV), stroke volume (SV), and the ejection fraction (EF%) were estimated. Results Compared to their age-matched female counterpart, male mice showed a constant increase in LVMV and ventricular volume during the follow-up. In contrast, female mice remain stable after ten weeks of age. Furthermore, male mice showed lower heart rates, positive correlation with cardiac %IA/g, and negative correlation with LVMV. Conclusion In this study of serial cardiac PET scans, we provide insight for basic murine research models, showing that mice gender and age show distinct cardiac metabolisms. These physiologic alterations need to be considered when planning in vivo injury models to avoid potential pitfalls.

Breakdown of vascular barriers is a major complication of inflammatory diseases. However, the mechanisms underlying platelet recruitment to inflammatory micro-environments remains unclear. Here, the authors identify haptotaxis as a key effector function of immune-responsive platelets

Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.

Summary: Background: Cardiac autonomic dysfunction after myocardial infarction identifies patients at high risk despite only moderately reduced left ventricular ejection fraction. We aimed to show that telemedical monitoring with implantable cardiac monitors in these patients can improve early detection of subclinical but prognostically relevant arrhythmic events. Methods: We did a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial at 33 centres in Germany and Austria. Survivors of acute myocardial infarction with left ventricular ejection fraction of 36–50% had biosignal analysis for assessment of cardiac autonomic function. Patients with abnormal periodic repolarisation dynamics (≥5·75 deg2) or abnormal deceleration capacity (≤2·5 ms) were randomly assigned (1:1) to telemedical monitoring with implantable cardiac monitors or conventional follow-up. Primary endpoint was time to detection of serious arrhythmic events defined by atrial fibrillation 6 min or longer, atrioventricular block class IIb or higher and fast non-sustained (>187 beats per min; ≥40 beats) or sustained ventricular tachycardia or fibrillation. This study is registered with ClinicalTrials.gov, NCT02594488. Findings: Between May 12, 2016, and July 20, 2020, 1305 individuals were screened and 400 patients at high risk were randomly assigned (median age 64 years [IQR 57–73]); left ventricular ejection fraction 45% [40–48]) to telemedical monitoring with implantable cardiac monitors (implantable cardiac monitor group; n=201) or conventional follow-up (control group; n=199). During median follow-up of 21 months, serious arrhythmic events were detected in 60 (30%) patients of the implantable cardiac monitor group and 12 (6%) patients of the control group (hazard ratio 6·33 [IQR 3·40–11·78]; p

Background. The development and progression of cardiac allograft vasculopathy documented by coronary angiography (CAVangio) after heart transplantation (HTx) has prognostic relevance. Yet there are limited data regarding the role of concomitant intracoronary imaging in the presence CAVangio. In particular, atherosclerotic plaques might represent a potential target for prevention, but their impact on stenosis is understudied. Methods. We used high-resolution intracoronary optical coherence tomography (OCT) to quantify and compare findings of intimal hyperplasia (IH) and plaque morphologies in HTx patients (fibrotic plaque, lipid plaque, and calcified plaque). OCT findings were related to the presence of CAVangio as well as to the severity of stenosis. Results. We included 65 consecutive patients into analysis (66% with CAVangio, posttransplant interval 9.9 ± 7.6 y). Fibrotic, lipid, and calcified plaques were present in 41 (63.1%), 39 (60%), and 18 (27.7%) patients, respectively. In addition to IH, the presence of fibrotic, lipid, and calcified plaques was found to be associated with CAVangio. The prevalence of lipid plaque and quantitative measurements of fibrotic plaque increased with stenosis severity (lipid plaque, P < 0.001, maximal and mean fibrotic arc, P = 0.05 and P = 0.001, respectively). Receiver operating characteristic analysis showed that area under the curve of the fibrotic plaque parameter mean fibrotic arc (0.87, 95% confidence interval [0.76-0.99]; P = 0.002) was superior to area under the curve of intima parameters regarding CAVangio. The effect of mean fibrotic arc (r = 0.52, P < 0.001) was relevant regarding stenosis severity. Conclusions. After a longer posttransplant interval, CAV findings in OCT included a combination of IH and atherosclerotic plaques. In addition to IH, the presence of fibrotic, lipid, and calcified plaques is associated with CAVangio. Further studies are warranted to evaluate if the in vivo screening for plaque progress, particularly of fibrotic plaque, could improve individual secondary prevention and outcome in HTx patients.

Background. The impact of devices for vessel closure on the safety and efficacy of cannula removal in VA-ECMO patients is unknown. Methods. We retrospectively analyzed 180 consecutive patients weaned from VA-ECMO after cardiac arrest or cardiogenic shock from January 2012 to June 2020. In the first period (historical technique group), from January 2012 to December 2018, primary decannulation strategy was manual compression. In the second period (current technique group), from January 2019 to June 2020, decannulation was performed either by a conventional approach with manual compression or by a suture-mediated closure device technique. Results. A femoral compression system was necessary in 71% of patients in the historical group compared to 39% in the current technique group (p

OBJECTIVES:. Venoarterial extracorporeal membrane oxygenation treatment in patients with severe cardiogenic shock can cause or aggravate acute lung injury. In our retrospective analysis, we aimed at identifying markers for acute lung injury after arrival on ICU, which predict mortality of those patients. DESIGN:. Observational, monocentric, retrospective analysis. SETTING:. Cardiac ICU of Ludwig Maximilian University Hospital, Munich, Germany. PATIENTS:. Two-hundred eleven patients undergoing venoarterial extracorporeal membrane oxygenation treatment for severe cardiogenic shock were included into this analysis. Patients who died within 24 hours after venoarterial extracorporeal membrane oxygenation implantation were excluded. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. To determine lung injury, we investigated the influence of Pao2/Fio2 ratio (Horowitz index). The lowest Horowitz index was measured on ICU 6–12 hours after venoarterial extracorporeal membrane oxygenation implantation. An optimal cutoff value of less than 126 for Horowitz index to predict mortality was identified via receiver operating characteristic analysis (area under the curve, 0.62). Patients with Horowitz index less than 126 had a 30-day mortality rate of 67.5% compared to 37.5% with a Horowitz index greater than or equal to 126 (p < 0.001). Multivariate analysis identified Horowitz index less than 126 as an independent risk factor of ICU mortality (odds ratio, 3.6; 95% CI, 1.8–7.3; p < 0.001). CONCLUSIONS:. In this hypothesis-generating analysis, a Horowitz index less than 126 is associated with increased mortality in patients with cardiogenic shock and venoarterial extracorporeal membrane oxygenation, which may serve as a threshold for further therapeutic interventions.

Visualizing cell behavior and effector function on a single cell level has been crucial for understanding key aspects of mammalian biology. Due to their small size, large number and rapid recruitment into thrombi, there is a lack of data on fate and behavior of individual platelets in thrombosis and hemostasis. Here we report the use of platelet lineage restricted multi-color reporter mouse strains to delineate platelet function on a single cell level. We show that genetic labeling allows for single platelet and megakaryocyte (MK) tracking and morphological analysis in vivo and in vitro, while not affecting lineage functions. Using Cre-driven Confetti expression, we provide insights into temporal gene expression patterns as well as spatial clustering of MK in the bone marrow. In the vasculature, shape analysis of activated platelets recruited to thrombi identifies ubiquitous filopodia formation with no evidence of lamellipodia formation. Single cell tracking in complex thrombi reveals prominent myosin-dependent motility of platelets and highlights thrombus formation as a highly dynamic process amenable to modification and intervention of the acto-myosin cytoskeleton. Platelet function assays combining flow cytrometry, as well as in vivo, ex vivo and in vitro imaging show unaltered platelet functions of multicolor reporter mice compared to wild-type controls. In conclusion, platelet lineage multicolor reporter mice prove useful in furthering our understanding of platelet and MK biology on a single cell level.

Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry–based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8–CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8–like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein–induced, human ACE2–dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil–IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.

Abstract Purpose Severe cardiogenic shock is the major driver of mortality on cardiologic intensive care units. Novel therapeutic options like extracorporeal membrane oxygenation (ECMO) or the combination of ECMO and a percutaneous microaxial pump like Impella CP (ECMELLA) are promising Options. Here we want to focus on the question what happens when left ventricular preload is too low to unload in cardiogenic shock in patients with ECMELLA and this aspect is illustrated by transesophageal echocardiography. Methods We detail a case of a 43‐year‐old active smoker who was admitted for acute myocardial infarction causing severe cardiogenic shock and who was finally treated with ECMELLA. Transesophageal echocardiography is used to illustrate what happens when left ventricle (LV) preload is too low to unload. Results Transesophageal echocardiography demonstrates complete collapse of LV and LA as consequence of increased but still low flow rate of the coaxial pump. Conclusion Novel therapeutic options like ECMO and percutaneous microaxial pumps like Impella CP, 5.0 or the combination of both (ECMELLA), are promising options. Whether these approaches reduce mortality has to be evaluated in urgently needed randomized trials but results will not be available in the next few years.

Background: A regimen of dual (DAT) vs. triple (TAT) antithrombotic therapy reduces bleeding in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, recent evidence suggests that DAT may be associated with an increased ischemic risk. This raises the question whether DAT rather than TAT should be recommended to AF patients that undergo PCI for acute coronary syndrome (ACS), carrying a particularly high risk of both bleeding and ischemic events, studied only as subgroups of previous trials. Methods and design: The APPROACH-ACS-AF-(DZHK-7) trial is a multicenter prospective, randomized, open-label, blinded endpoint (PROBE) trial which will include patients presenting with an ACS managed by PCI and requiring oral anticoagulation (OAC) due to AF. The trial will test, whether a DAT-regimen comprising clopidogrel plus the non-Vitamin-K-antagonist oral anticoagulant (NOAC) apixaban is superior to a TAT-regimen of vitamin-K-antagonist (VKA) plus dual anti-platelet therapy (APT) with respect to bleeding. A total of 400 patients will be randomized 1:1 to a control-arm with guideline-recommended TAT with VKA plus clopidogrel and acetylsalicylic-acid and a study arm receiving DAT comprising apixaban plus clopidogrel. Patients will be followed-up for 6 months. The primary endpoint of the study is the cumulative incidence of BARC type ≥2 bleeding, secondary endpoints include a composite clinical ischemic outcome and net clinical outcome. Conclusions: APPROACH-ACS-AF is the first trial dedicated to ACS patients, testing whether in terms of bleeding a DAT with NOAC is superior to a TAT regimen with VKA in high-risk ACS patients with AF.

The efficacy of thrombolysis is inversely correlated with thrombus age. During early thrombogenesis, activated factor XIII (FXIIIa) cross-links α2-AP to fibrin to protect it from early lysis. This was exploited to develop an α2-AP-based imaging agent to detect early clot formation likely susceptible to thrombolysis treatment. In this study, this imaging probe was improved and validated using 111In SPECT/CT in a mouse thrombosis model. In vitro fluorescent- and 111In-labelled imaging probe-to-fibrin cross-linking assays were performed. Thrombus formation was induced in C57Bl/6 mice by endothelial damage (FeCl3) or by ligation (stenosis) of the infrarenal vena cava (IVC). Two or six hours post-surgery, mice were injected with 111In-DTPA-A16 and ExiTron Nano 12000, and binding of the imaging tracer to thrombi was assessed by SPECT/CT. Subsequently, ex vivo IVCs were subjected to autoradiography and histochemical analysis for platelets and fibrin. Efficient in vitro cross-linking of A16 imaging probe to fibrin was obtained. In vivo IVC thrombosis models yielded stable platelet-rich thrombi with FeCl3 and fibrin and red cell-rich thrombi with stenosis. In the stenosis model, clot formation in the vena cava corresponded with a SPECT hotspot using an A16 imaging probe as a molecular tracer. The fibrin-targeting A16 probe showed specific binding to mouse thrombi in in vitro assays and the in vivo DVT model. The use of specific and covalent fibrin-binding probes might enable the clinical non-invasive imaging of early and active thrombosis.

Cardiac monitoring after murine myocardial infarction, using serial non-invasive cardiac 18F-FDG positron emissions tomography (PET) represents a suitable and accurate tool for in vivo studies. Cardiac PET imaging enables tracking metabolic alterations, heart function parameters and provides correlations of the infarct size to histology. ECG-gated 18F-FDG PET scans using a dedicated small-animal PET scanner were performed in mice at baseline, 3, 14, and 30 days after myocardial infarct (MI) by permanent ligation of the left anterior descending (LAD) artery. The percentage of the injected dose per gram (%ID/g) in the heart, left ventricular metabolic volume (LVMV), myocardial defect, and left ventricular function parameters: end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and the ejection fraction (EF%) were estimated. PET assessment of the defect positively correlates with post-infarct histology at 3 and 30 days. Infarcted murine hearts show an immediate decrease in LVMV and an increase in %ID/g early after infarction, diminishing in the remodeling process. This study of serial cardiac PET scans provides insight for murine myocardial infarction models by novel infarct surrogate parameters. It depicts that serial PET imaging is a valid, accurate, and multimodal non-invasive assessment.

This study assessed the basic working principle to measure aortic annulus resistance during balloon inflation for transcatheter aortic valve implantation (TAVI), by acquisition of pressure-volume curve for a guided semi-automatic implantation. A modular bench-system was used which allows the incremental inflation of valvuloplasty balloons by means of a stepper-motor driven linear axis with simultaneous recording of the pressure changes inside the system. Different porcine aortic xenografts were assessed by use of a non-compliant valvuloplasty balloon. In a second step transcatheter aortic stents were implanted inside target sized xenografts. The recorded pressure volume-curves showed that the system can accurately differentiate between different xenografts and assess the quality of the tissue rendering real-time analysis of pressure-volume curves during balloon-inflation possible, which has the potential to optimize the implantation procedure by direct adaptation to the patient specific anatomy and characteristics. Further investigations and development are warranted.

Background: Acute cardiac tamponade is a life-threatening pathology in modern cardiology as catheter-based interventions become increasingly relevant. Pericardiocentesis is usually the primary treatment of choice. However, protocols for handling of draining pigtail catheters are very variable due to limit data and require further investigation. Methods: We retrospectively analyzed 52 patients with acute cardiac tamponade requiring immediate pericardiocentesis from January 2017 to August 2020. Patients were treated with a classical approach of intermittent manual aspiration or continuous pericardial drainage using a redon drainage system. Results: Mean age of patients was 74 years in both groups. Most common causes for cardiac tamponade were percutaneous coronary interventions in about 50% and transaortic valve implantations in 25% of all cases. 28 patients were treated with classic intermittent drainage from 2017 to 2020. 24 patients were treated with continuous drainage from December 2018–2020. Compared to classical intermittent drainage treatment, continuous drainage was associated with a lower rate of a surgical intervention or cardiac re-tamponade and a lower mortality at 5 days (HR 0.2, 95% CI 0.1–0.9, log-rank p = 0.03). Despite a longer total drainage time under continuous suction, drainage volumes were comparable in both groups. Conclusion: Acute cardiac tamponade can be efficiently treated by pericardiocentesis with subsequent continuous negative pressure drainage via a pigtail catheter. Our retrospective analysis shows a significantly lower mortality, a decreased rate of interventions and lower rates of cardiac re-tamponade without any relevant side effects when compared to classical intermittent manual drainage. These findings require further investigations in larger, randomized trials.

Background: Atherosclerosis has been shown to result from chronic inflammation caused by constitutive activation of the pattern recognition receptors (PRR), which are principle effectors of the innate immune system. PRR are present in the endosome or on the cellular membrane and can sense the aberrant release of nucleic acids, which is often a sign of acute or chronic cellular damage. Absent in melanoma 2 (AIM2) is a PRR that is expressed by vascular cells and specializes in detecting cytoplasmic double-stranded DNA (dsDNA). Activation of AIM2 leads eventually to activation of the inflammasome, but the role of AIM2 in vascular disease and atherosclerosis has not been well-studied. Therefore, in this study we took advantage of acute and chronic models of vascular injury to determine the biological role of AIM2 in atherogenesis.Methods and Results: We were able to induce significant release of proinflammatory cytokines in mice through the intravenous injection of a synthetic ligand for AIM2, double-stranded poly dA:dT. This cytokine release was shown to impair reendothelialization of the carotid artery and increase the number of circulating endothelial microparticles (EMP) after acute denudation, compared to treatment with vehicle. We saw an increase in the production of reactive oxygen species in the aorta, the number of circulating EMP, and, most interestingly, atherosclerotic plaque formation in apolipoprotein E-deficient (ApoE−/−) mice when they received continual subcutaneous poly dA:dT, in contrast to vehicle-treated animals. Finally, treatment with poly dA:dT did not impair vascular reendothelialization in AIM2−/− mice compared to vehicle controls in the carotid artery injury model.Conclusion: Overall, our data suggest that AIM2, as a known regulator of the inflammasome, is an active participant in atherogenesis, and highlight the importance of fully understanding the pathological mechanisms involved. It seems to be worth of further exploration as a therapeutic target, and future studies focusing on the effects of AIM2 activation as well as its pharmacological inhibition may reveal promising new therapeutic concepts for the treatment of atherosclerosis.

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-to-human porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF.

Background and Objectives: Mitral stenosis with extensive mitral annular calcification (MAC) remains surgically challenging in respect to clinical outcome. Prolonged surgery time with imminent ventricular rupture and systolic anterior motion can be considered as a complex of causal factors. The aim of our alternative hybrid approach was to reduce the risk of annual rupture and paravalvular leaks and to avoid obstruction of the outflow tract. A review of the current literature was also carried out. Materials and Methods: Six female patients (mean age 76 ± 9 years) with severe mitral valve stenosis and severely calcified annulus underwent an open implantation of an Edwards Sapien 3 prosthesis on cardiopulmonary bypass. Our hybrid approach involved resection of the anterior mitral leaflet, placement of anchor sutures and the deployment of a balloon expanded prosthesis under visual control. Concomitant procedures were carried out in three patients. Results: The mean duration of cross-clamping was 95 ± 31 min and cardiopulmonary bypass was 137 ± 60 min. The perioperative TEE showed in three patients an inconspicuous, heart valve-typical gradient on all implanted prostheses and a clinically irrelevant paravalvular leakage occurred in the anterior annulus. In the left ventricular outflow tract, mild to moderately elevated gradients were recorded. No adverse cerebrovascular events and pacemaker implantations were observed. All but one patient survived to discharge. Survival at one year was 83.3%. Conclusions: This “off label” implantation of the Edwards Sapien 3 prosthesis may be considered as a suitable bail-out approach for patients at high-risk for mitral valve surgery or deemed inoperable due to extensive MAC.

Cathelicidins are antimicrobial peptides that eliminate pathogens and contribute to the innate immune response. Here the authors show that neutrophil-derived LL-37/CRAMP induces platelet activation and promotes arterial thrombosis and thrombo-inflammation.

Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (cag-T4SS) into host cells is a hallmark of infection with Hp and a major risk factor for severe gastric diseases, including gastric cancer. To mediate the injection of CagA, Hp uses a membrane-embedded syringe-like molecular apparatus extended by an external pilus-like rod structure that binds host cell surface integrin heterodimers. It is still largely unclear how the interaction of the cag-T4SS finally mediates translocation of the CagA protein into the cell cytoplasm. Recently certain carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), acting as receptor for the Hp outer membrane adhesin HopQ, have been identified to be involved in the process of CagA host cell injection. Here, we applied the CRISPR/Cas9-knockout technology to generate defined human gastric AGS and KatoIII integrin knockout cell lines. Although confocal laser scanning microscopy revealed a co-localization of Hp and β1 integrin heterodimers on gastric epithelial cells, Hp infection studies using the quantitative and highly sensitive Hp β-lactamase reporter system clearly show that neither β1 integrin heterodimers (α1β1, α2β1 or α5β1), nor any other αβ integrin heterodimers on the cell surface are essential for CagA translocation. In contrast, deletion of the HopQ adhesin in Hp, or the simultaneous knockout of the receptors CEACAM1, CEACAM5 and CEACAM6 in KatoIII cells abolished CagA injection nearly completely, although bacterial binding was only reduced to 50%. These data provide genetic evidence that the cag-T4SS-mediated interaction of Hp with cell surface integrins on human gastric epithelial cells is not essential for CagA translocation, but interaction of Hp with CEACAM receptors is facilitating CagA translocation by the cag-T4SS of this important microbe.

Blood platelets are critical for hemostasis and thrombosis, but also play diverse roles during immune responses. We have recently reported that platelets migrate at sites of infection in vitro and in vivo. Importantly, platelets use their ability to migrate to collect and bundle fibrin (ogen)-bound bacteria accomplishing efficient intravascular bacterial trapping. Here, we describe a method that allows analyzing platelet migration in vitro, focusing on their ability to collect bacteria and trap bacteria under flow.

Medical treatment of arterial thrombosis is mainly directed against platelets and coagulation factors, and can lead to bleeding complications. Novel antithrombotic therapies targeting immune cells and neutrophil extracellular traps (NETs) are currently being investigated in animals. We addressed whether immune cell composition of arterial thrombi induced in mouse models of thrombosis resemble those of human patients with acute myocardial infarction (AMI).In a prospective cohort study of patients suffering from AMI, 81 human arterial thrombi were harvested during percutaneous coronary intervention and subjected to detailed histological analysis. In mice, arterial thrombi were induced using two distinct experimental models, ferric chloride (FeCl3) and wire injury of the carotid artery. We found that murine arterial thrombi induced by FeCl3 were highly concordant with human coronary thrombi regarding their immune cell composition, with neutrophils being the most abundant cell type, as well as the presence of NETs and coagulation factors. Pharmacological treatment of mice with the protein arginine deiminase (PAD)-inhibitor Cl-amidine abrogated NET formation, reduced arterial thrombosis and limited injury in a model of myocardial infarction.Neutrophils are a hallmark of arterial thrombi in patients suffering from acute myocardial infarction and in mouse models of arterial thrombosis. Inhibition of PAD could represent an interesting strategy for the treatment of arterial thrombosis to reduce neutrophil-associated tissue damage and improve functional outcome.