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The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

The COVID-19 pandemic represents a major public health threat. Risk of death from the infection is associated with age and pre-existing comorbidities such as diabetes, dementia, cancer, and impairment of immunological, hepatic or renal function. It remains incompletely understood why some patients survive the disease, while others do not. As such, we sought to identify novel prognostic factors for COVID-19 mortality. We performed an unbiased, observational retrospective analysis of real world data. Our multivariable and univariable analyses make use of U.S. electronic health records from 122,250 COVID-19 patients in the early stages of the pandemic. Here we show that a priori diagnoses of fluid, pH and electrolyte imbalance during the year preceding the infection are associated with an increased risk of death independently of age and prior renal comorbidities. We propose that future interventional studies should investigate whether the risk of death can be alleviated by diligent and personalized management of the fluid and electrolyte balance of at-risk individuals during and before COVID-19. Nahkuri et al. evaluate potential prognostic factors for COVID-19 mortality in a large US database of electronic health records. They find that fluid, pH and electrolyte imbalances – diagnosed at least one month prior to COVID-19 diagnosis – are associated with mortality. 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.

Background: Central retinal artery occlusion ((C)RAO) is known to be associated with stroke and/or atrial fibrillation (AF). Nevertheless, patients often present at the ophthalmologist initially and it is unknown how many of these receive an adequate cardiological/neurological work-up (CWU/NWU), including a 24 h-Holter-ECG. Hypothesis: Hypothesis of this study was that patients with (C)RAO do not undergo CWU on regular basis and that new-onset AF is more often detected in patients with CWU. Methods and results: We performed a retrospective analysis of n = 292 consecutive patients who presented at an ophthalmology department with the diagnosis of (C)RAO during a 3-year period. After excluding patients with known AF, meeting exclusion criteria, inability to comply with the protocol, missed land phoneline, or death during follow-up a total of 174 patients were enrolled; mean follow-up was 20 ± 12 months. The CHA₂DS₂-VASc score of the cohort was 5.3 ± 1.4. Our analysis revealed that only 50.6% of patients received a CWU including a single Holter-ECG after the index-event. In 12.6% cases new-onset AF was diagnosed, while the rate was higher in patients with CWU compared to patients without CWU (18.2 vs. 7.0%; p = 0.26). Evaluation of oral anticoagulation (OAC) therapy showed that only 66% of patients with AF were treated according to guidelines. Conclusion: Only half of patients with (C)RAO underwent CWU. Despite minimal monitoring, rate of new diagnosed AF was high. Our results confirm that (C)RAO identifies a high-risk population for AF. These results illustrate the importance to implement standardized CWU in (C)RAO patients presenting at the ophthalmologist. OA Förderung 2021

BACKGROUND: The first coronary artery bypass operation (CABG) was performed on May 2, 1960. The first percutaneous coronary intervention (PCI) was performed almost 20 years later. Since then, the invasive treatment of coronary artery disease (CAD) has moved into the spotlight of cardiac medical care. METHODS: We summarize the current status of medical and invasive CAD treatment through a selective review of the literature. RESULTS: More than 800 000 patients currently undergo invasive diagnostic and therapeutic procedures for CAD in Germany each year. The number of coronary artery bypass grafting (CABG) procedures rose to 65 000/year by the turn of the millennium and has been declining since then. In contrast, the number of PCIs in Germany rose to approximately 350 000/year by 2017, and a beginning decline is being observed at present. This development occurred even though, for elective patients, a survival advantage from an invasive procedure compared to medical therapy has been shown in direct comparison only for CABG. CONCLUSION: Conservative treatment is always the baseline treatment and has undergone major advances in the last few decades. Moreover, non-invasive coronary evaluation with computed tomography, as well as non-invasive cardiac stress imaging studies, are increasingly replacing primary invasive coronary evaluations. In this review, we illustrate a mechanistic concept of the appropriate use of CABG and PCI that can improve patient care, while underscoring the importance of interdisciplinary and intersectoral collaboration.

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.

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.

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK–STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk. Accelerated atherosclerosis in a mouse model of clonal haematopoiesis is prevented by genetic interruption of AIM2 inflammasome activation or by inhibition of interleukin-1β.

(1) Herpes simplex virus (HSV) reactivation in critically ill patients can cause infection in the lower respiratory tract, prolonging mechanical ventilation. However, the association of HSV reactivation with cardiogenic shock (CS) is unclear. As CS is often accompanied by pulmonary congestion and reduced immune system activity, the aim of our study was to determine the incidence and outcome of HSV reactivation in these patients. (2) In this retrospective, single-center study, bronchial lavage (BL) was performed on 181 out of 837 CS patients with mechanical ventilation. (3) In 44 of those patients, HSV was detected with a median time interval of 11 days since intubation. The occurrence of HSV was associated with an increase in C-reactive protein and the fraction of inspired oxygen at the time of HSV detection. Arterial hypertension, bilirubin on ICU admission, the duration of mechanical ventilation and out-of-hospital cardiac arrest were associated with HSV reactivation. (4) HSV reactivation could be detected in 24.3% of patients with CS on whom BL was performed, and its occurrence should be considered in patients with prolonged mechanical ventilation. Due to the limited current evidence, the initiation of treatment for these patients remains an individual choice. Dedicated randomized studies are necessary to investigate the efficacy of antiviral therapy.

Aims SARS-CoV-2 infection is associated with adverse outcomes in patients with cardiovascular disease. Here, we analyzed whether specific biomarkers predict the clinical course of COVID-19 in patients with cardiovascular comorbidities. Methods and results We enrolled 2147 patients with SARS-CoV-2 infection which were included in the Lean European Open Survey on SARS-CoV‑2 (LEOSS)-registry from March to June 2020. Clinical data and laboratory values were collected and compared between patients with and without cardiovascular comorbidities in different clinical stages of the disease. Predictors for mortality were calculated using multivariate regression analysis. We show that patients with cardiovascular comorbidities display significantly higher markers of myocardial injury and thrombo-inflammatory activation already in the uncomplicated phase of COVID-19. In multivariate analysis, elevated levels of troponin [OR 1.54; (95% CI 1.22–1.96), p p p Conclusion Patients with cardiovascular comorbidities show elevated markers of thrombo-inflammatory activation and myocardial injury, which predict mortality, already in the uncomplicated phase of COVID-19. Starting targeted anti-inflammatory therapy and aggressive anticoagulation already in the uncomplicated phase of the disease might improve outcomes after SARS-CoV-2 infection in patients with cardiovascular comorbidities. Graphic abstract Elevated markers of thrombo-inflammatory activation predict outcome in patients with cardiovascular comorbidities and COVID-19 disease: insights from the LEOSS registry

Europace : the European journal of pacing, arrhythmias and cardiac electrophysiology euac062 (2022). doi:10.1093/europace/euac062, Published by Oxford Univ. Press, Oxford

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.

Supplemental Digital Content is available in the text., 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.

Journal of cardiovascular translational research (2022). doi:10.1007/s12265-022-10281-6, Published by Springer, New York, NY [u.a.]

Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke.We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR.A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site.Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).

In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. Recently, intravascularly adherent leukocytes have been reported to shape the blood flow in their immediate vascular environment. Whether these rheological effects are relevant for microvascular thrombogenesis remains elusive. Employing multi-channel in vivo microscopy, analyses in microfluidic devices, and computational modeling, we identified a previously unanticipated role of leukocytes for microvascular clot formation in inflamed tissue. For this purpose, neutrophils adhere at distinct sites in the microvasculature where these immune cells effectively promote thrombosis by shaping the rheological environment for platelet aggregation. In contrast to larger (lower-shear) vessels, this process in high-shear microvessels does not require fibrin generation or extracellular trap formation, but involves GPIbα-vWF and CD40-CD40L-dependent platelet interactions. Conversely, interference with these cellular interactions substantially compromises microvascular clotting. Thus, leukocytes shape the rheological environment in the inflamed venular microvasculature for platelet aggregation thereby effectively promoting the formation of blood clots. Targeting this specific crosstalk between the immune system and the hemostatic system might be instrumental for the prevention and treatment of microvascular thromboembolic pathologies, which are inaccessible to invasive revascularization strategies.

BACKGROUND. Dose reduction strategies for coronary CTA (CCTA) have been underused in clinical practice given concern that the strategies may lower image quality. OBJECTIVE. The purpose of this study was to explore associations between dose reduction strategies and CCTA image quality in real-world clinical practice. METHODS. This subanalysis of the international Prospective Multicenter Registry on Radiation Dose Estimates of Cardiac CT Angiography in Daily Practice in 2017 (PROTECTION VI) study included 3725 patients (2109 men, 1616 women; median age, 59 years) who underwent CCTA for coronary artery evaluation performed at 55 sites in 32 countries. CCTA image sets were reviewed at a core laboratory. A range of patient and scan characteristics, including use of three dose reduction strategies (prospective ECG triggering, low tube potential, and iterative image reconstruction) and image dose, were recorded. A single core laboratory member reviewed all examinations for quantitative image quality measures, including signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), and reviewed 50% of examinations to assign a qualitative CCTA image quality score and a semiquantitative coronary calcification measure. Multivariable logistic regression models were used to identify predictors of image quality. A second core laboratory member repeated quantitative measures for 100 examinations and the qualitative measure for 383 (approximately 20%) examinations to assess interreader agreement. RESULTS. Independent predictors ( p < .05) of SNR were female sex (effect size, 2.70), lower body mass index (0.38 per 1-unit decrease), stable sinus rhythm (1.71), and scanner manufacturer (variable effect across manufacturers). These factors were also the only independent predictors of CNR. Independent predictors ( p < .05) of CCTA image quality were heart rate (0.17 per 10 beats/min reduction) and coronary calcification (0.15 per coronary calcification grade). None of the three dose-saving strategies or dose-length product was an independent predictor of any image quality measure. Interreader agreement analysis showed intraclass correlation coefficients of 0.874 for SNR and 0.891 for CNR and a kappa value of 0.812 for the qualitative score. CONCLUSION. This large international multicenter study shows that three dose reduction strategies were not associated with decreased CCTA image quality. CLINICAL IMPACT. The dose reduction strategies should be routinely implemented in clinical CCTA.

Supplemental Digital Content is available in the text., 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.

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.

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.

Funding Acknowledgements Type of funding sources: None. Purpose Intracranial hemorrhage (ICH) is one of the most serious complications of adult patients treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO) and is associated with increased morbidity and mortality. However, the prevalence and risk factors of ICH in this cohort are still insufficiently understood. Therefore, the purpose of this study was to further investigate prevalence, associated mortality and predictors of ICH in VAECMO patients. Methods We conducted a retrospective multicenter study including adult patients (≥18 years) treated with VA-ECMO in cardiac intensive care units (ICUs) at five clinical sites between January 2016 and March 2020, excluding patients with ICH upon admission. Differences in baseline characteristics and clinical outcome between VA-ECMO patients with and without ICH were analysed. Predictors of ICH were identified by uni- and multivariable regression models. Results Among 598 patients included, 70 (12%) developed ICH during VA-ECMO treatment with mean duration of 82 ± 84h between ECMO initiation and ICH diagnosis. Out of these ICH, 23% were intraparenchymal, 20% subarachnoid, 10% subdural, 3% intraventricular and 44% combined hemorrhage. In-hospital mortality in the ICH cohort was 81% and 1-month mortality 86%, compared to 63% (p = 0.002) and 64% (p Conclusion ICH occurred frequently in VA-ECMO patients and was associated with a significantly higher mortality rate. Diabetes mellitus, low platelet count and low fibrinogen level are independent predictors of ICH. These findings may help to develop effective strategies to prevent and treat ICH and build the basis for further investigations to optimize clinical outcome in patients on VA-ECMO.

Funding Acknowledgements Type of funding sources: None. Background 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 (CS). Methods 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 (AMI-CS) and with available on-treatment ADP-induced platelet aggregation measurements. Results Out of 233 patients, 74 suffered from a severe BARC 3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (10 AU [IQR 3 - 13] vs. 15 AU [IQR 9 - 25], p

Funding Acknowledgements Type of funding sources: None. Objectives (Background): The feasibility and hemodynamic effects of isoflurane sedation in cardiogenic shock in the presence of extracorporeal membrane oxygenation (VA-ECMO) treatment is currently unknown. Design Retrospective single-center study Patients/subjects: Cardiogenic shock patients with VA-ECMO treatment under sedation with volatile isoflurane between November 2018 and October 2019 have been enrolled in this study and were matched by propensity score in a 1:1 ratio with intravenously (IV) sedated patients treated between January 2013 and November 2018 from the cardiogenic shock registry of our university hospital. Measurements and Main Results: Isoflurane sedation was used in 32 patients with cardiogenic shock and VA-ECMO treatment. The mean age of conventionally sedated patients was 58.4 ± 13.8 years and 56.3 ± 11.5 years for patients with isoflurane sedation (p = 0.51). Administration of isoflurane was associated with lower IV sedative drug use during VA-ECMO treatment (86% vs. 32%, p = 0.01). Mean systolic arterial pressure was similar (94.3 ± 12.6 mmHg versus 92.9 ± 10.5 mmHg, p = 0.65), but mean heart rate was significantly higher in the conventional sedation group, when compared to the isoflurane group (85.2 ± 20.5 /min vs. 74.7 ± 15.0 /min; p = 0.02). Catecholamine doses, VA-ECMO blood and gas flow, ventilation time (304 ± 143 h vs. 398 ± 272 h,p = 0.16), bleeding complications BARC3a or higher (59.3% vs. 65.3%, p = 0.76) and 30 day-mortality (59.2% vs. 63.4%, p = 0.80) were similar in both groups. The overall sedation costs per patient were significantly lower in the conventional group, when compared to the isoflurane group (537 ± 624 € vs. 1280 ± 837 €, p Conclusions Volatile sedation with isoflurane is feasible – albeit at higher costs - in patients with cardiogenic shock and VA-ECMO treatment and was not associated with higher catecholamine dosage or ECMO flow rate compared to IV sedation.

Graphical abstract, Highlights • Pseudoaneurysm is a rare but life-threatening complication after thoracic surgery. • Standard therapy is surgical occlusion and excision of the aneurysm. • Interventional closure with ASD occluder is an alternative for patients deemed inoperable.

Aims Automated coronary total plaque volume (TPV) quantification derived from coronary computed tomographic angiography (CTA) datasets provide exact and reliable assessment of calcified and non-calcified coronary atherosclerosis burden. The aim of this analysis was to investigate the long-term predictive value of TPV. Methods and results TPV was quantified in 1577 patients undergoing coronary CTA and cardiovascular events were collected during 10.5 years (interquartile range 6.0–11.4) of follow-up. The study endpoint comprised cardiac death and acute coronary syndrome and occurred in 59 (3.7%) patients. Coronary TPV provided additive prognostic value over clinical risk assessed with the Morise Score and coronary artery disease severity (rise in C-index from 0.744 to 0.769, P = 0.03). A category-based reclassification approach combining the Morise Score and TPV revealed superior risk stratification (categorical net reclassification improvement: 0.48 with 95% CI 0.13–0.68, P Conclusion Quantification of TPV from coronary CTA permits an improved 10-year cardiovascular risk stratification.

Highlights • Acute cardiac tamponade is a highly relevant complication in modern cardiology. • Continuous pericardial drainage is safe and does not increase total drainage volume. • Continuous drainage associates with lower rates of open-heart surgical interventions. • Continuous drainage associates with reduced re-tamponades and mortality on day 5., 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.

Purpose SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury. Methods We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography. Results A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037). Conclusion In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up. Trial registration COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.

Summary 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 II receptor blockers (ARBs) mitigates the course o\f recent-onset 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 (AUCSOFA), 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 AUCSOFA (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 [10–90th 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. Funding Austrian Science Fund and German Center for Cardiovascular Research.

BACKGROUND Although mitral valve transcatheter edge-to-edge repair (M-TEER) achieves symptomatic benefit for a broad spectrum of patients with relevant secondary mitral regurgitation, conflicting data exist on its prognostic impact. OBJECTIVES Adapted enrollment criteria approaching those used in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart��Failure Patients With Functional Mitral Regurgitation) and MITRA-FR (Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation) trials were retrospectively applied to a European real-world registry to evaluate the influence of the respective criteria on outcomes. METHODS A total of 1,022 patients included in the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry and treated with M-TEER (November 2008 to September 2019) were stratified into COAPT-eligible (n��=��353 [34.5%]) and COAPT-ineligible (n��=��669 [65.5%]) as well as MITRA-FR-eligible (n��=��408 [48.3%]) and MITRA-FR-ineligible (n��=��437 [51.7%]) groups. RESULTS Although the stratification of patients according to adapted MITRA-FR criteria led to comparable outcomes regarding all-cause mortality (P��=��0.19), the application of adapted COAPT enrollment criteria demonstrated lower mortality rates in COAPT-eligible compared with COAPT-ineligible patients (P��< 0.001). Multivariable Cox regression analysis identified New York Heart Association functional class IV (hazard ratio [HR]: 2.29; 95% confidence interval [CI]: 1.53-3.42; P��< 0.001), logarithmic N-terminal pro-brain natriuretic peptide (HR: 1.47; 95%��CI: 1.24-1.75; P��< 0.001), and right ventricular-to-pulmonary arterial coupling (HR: 0.10; 95%��CI: 0.02-0.57; P��=��0.009) as independent predictors of outcome. Yet improvement of functional outcome was demonstrated in a subset of patients irrespective of COAPT eligibility status. CONCLUSIONS In this real-world cohort of patients with secondary mitral regurgitation undergoing M-TEER, the retrospective application of adapted COAPT enrollment criteria successfully identified a specific phenotype demonstrating lower mortality rates. On the contrary, stratification according to adapted MITRA-FR criteria resulted in comparable outcomes.

Journal of thrombosis and haemostasis : JTH 19(2), 574-581 (2021). doi:10.1111/jth.15179, Published by Wiley-Blackwell, Oxford

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. CA extern

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides temporary cardiac and respiratory support and has emerged as an established salvage intervention for patients with hemodynamic compromise or shock. It is thereby used as a bridge to recovery, bridge to permanent ventricular assist devices, bridge to transplantation, or bridge to decision. However, weaning from VA-ECMO differs between centers, and information about standardized weaning protocols are rare. Given the high mortality of patients undergoing VA-ECMO treatment, it is all the more important to answer the many questions still remaining unresolved in this field Standardized algorithms are recommended to optimize the weaning process and determine whether the VA-ECMO can be safely removed. Successful weaning as a multifactorial process requires sufficient recovery of myocardial and end-organ function. The patient should be considered hemodynamically stable, although left ventricular function often remains impaired during and after weaning. Echocardiographic and invasive hemodynamic monitoring seem to be indispensable when evaluating biventricular recovery and in determining whether the VA-ECMO can be weaned successfully or not, whereas cardiac biomarkers may not be useful in stratifying those who will recover. This review summarizes the strategies of weaning of VA-ECMO and discusses predictors of successful and poor weaning outcome.

OBJECTIVES The purpose of this paper was to evaluate the impact of proportionality of secondary mitral regurgitation (SMR) in a large real-world registry of transcatheter edge-to-edge mitral valve repair (TMVr) BACKGROUND: Differences in the outcomes of recent randomized trials of TMVr for SMR may be explained by the proportionality of SMR severity to left ventricular (LV) volume. METHODS The ratio of pre-procedural effective regurgitant orifice area (EROA) to LV end-diastolic volume (LVEDV) was retrospectively assessed in patients undergoing TMVr for severe SMR between 2008 and 2019 from the EuroSMR registry. A recently proposed SMR proportionality scheme was adapted to stratify patients according to EROA/LVEDV ratio in 3 groups: MR-dominant (MD), MR-LV-co-dominant (MLCD), and LV-dominant (LD). All-cause mortality was assessed as a primary outcome, secondary heart failure (HF) outcomes included hospitalization for HF (HHF), New York Heart Association (NYHA) functional class, N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-min-walk distance, quality of life and MR grade. RESULTS A total of 1,016 patients with an EROA/LVEDV ratio were followed for 22 months after TMVr. MR was reduced to grade ≤2+ in 92%, 96%, and 94% of patients (for MD, MLCD, and LD, respectively; p = 0.18). After adjustment for covariates including age, sex, diabetes, kidney function, body surface area, LV ejection fraction, and procedural MR reduction (grade ≤2+), adjusted rates of 2-year mortality in MD patients did not differ from those for MLCD patients (17% vs. 18%, respectively), whereas it was higher in LD patients (23%; p = 0.02 for comparison vs. MD+MLCD). The adjusted first HHF rate differed between groups (44% in MD, 56% in MLCD, 29% in LD; p = 0.01) as did the adjusted time for first death or HHF rate (66% in MD, 82% in MLCD, 68% in LD; p = 0.02). Improvement of NYHA functional class was seen in all groups (p

Introduction Approximately 20% of patients with atrial fibrillation (AF) are suffering from coronary artery disease (CAD), requiring percutaneous coronary intervention (PCI) and stenting over time. These patients are in need of a so-called “triple therapy” (TT) for prevention of stent thrombosis and stroke. Prospective and randomized trials examined risk for bleeding in TT and compared it to a dual regimen, but in majority excluded elderly patients. Moreover, in all to date presented triple therapy trials women represent a minority of included patients (mostly Methods The objective of our retrospective cohort study was to determine the number of women and elderly patients with the indication for TT and to evaluate the differences in medical treatment. Furthermore, we evaluated safety, represented by bleeding (BARC ≥2 bleedings) and efficacy endpoints (composite clinical endpoint: all-cause-death, myocardial infarction, stent thrombosis, stroke and other systemic thromboembolism) in women vs. men, and elderly vs. younger patients. Moreover, we investigated the influence of NOAC (new oral anticoagulant) vs. VKA (vitamin K antagonist) treatment. Follow-ups were performed via phone-calls or in-hospital visits. Results In total, we included 928 patients with AF, that underwent PCI and stenting. Mean follow-up was 464 days. 627 patients were Conclusion In our real-life cohort female sex represents around a quarter of TT patients in line with large RCTs. But, unlike the large RCTs, 1/3 of our included patients were older then 80 years and seem to be underrepresented in randomized TT trials. TT seems to be safe in elderly as well as in female patients. As they both represent an important group, future trials should focus more on including a well balanced patient cohort to improve the applicability of the results. Funding Acknowledgement Type of funding source: None

Objective: Percutaneous dilatational tracheotomy has become a routine procedure in ICUs. However, given the high and steadily growing number of patients receiving anticoagulation, dual antiplatelet therapy, or even a combination of both (also known as “triple therapy”), there are concerns about the safety of the procedure, in particular for critically ill patients with a high risk of bleeding. In this retrospective study, we investigated whether percutaneous dilatational tracheotomy in this high-risk population was associated with elevated procedural complications. Design: Retrospective single-center study with analysis of all percutaneous dilatational tracheotomies performed in our cardiac ICU from January 2018 to May 2019. Setting: Munich university hospital’s cardiac ICU. Patients and Interventions: A total of 34 patients who underwent percutaneous dilatational tracheotomy according to Ciaglia technique with accompanying bronchoscopy in our cardiac ICU from January 2018 to May 2019 were included. Patients were stratified into clinically relevant risk groups based on anticoagulation and antiplatelet therapy considering standard laboratory coagulation parameters, that is, activated partial thromboplastin time, international normalized ratio, and platelet count with differentiated analysis of procedure-related complications in each risk group until hospital discharge. Measurements and Main Results: A total of 34 patients who underwent percutaneous dilatational tracheotomy were included and assigned to five clinically relevant treatment groups: IV unfractionated heparin (prophylactic dosage) (n = 4), IV unfractionated heparin (therapeutic dosage) (n = 4), aspirin and IV unfractionated heparin (therapeutic dosage) (n = 7), dual antiplatelet therapy with IV unfractionated heparin (prophylactic dosage) (n = 5), and dual antiplatelet therapy with IV unfractionated heparin (therapeutic dosage) (n = 14). Three bleedings without surgical intervention or blood transfusion were documented in the whole cohort, but no single bleeding did occur in the triple therapy group. These were exclusively caused by skin bleedings at the immediate puncture site—each of which could be easily treated with one or two single stitches. There were no severe bleeding complications or potentially life-threatening procedure-related complications. Additionally, the rate of complications in patients with elevated body mass index was not increased. Conclusions: Bronchoscopy-guided percutaneous dilatational tracheotomy according to Ciaglia technique with careful consideration of all potential indications and contraindications may be a safe and low-complication procedure for airway management, even in patients receiving dual antiplatelet therapy and therapeutic anticoagulation simultaneously in our cohort with a high risk of bleeding.

Aims Vessel maturation involves the recruitment of mural cells such as pericytes and smooth muscle cells. Laminar shear stress is a major trigger for vessel maturation, but the molecular mechanisms by which shear stress affects recruitment of pericytes are unclear. MicroRNAs (miRs) are small non-coding RNAs, which post-transcriptionally control gene expression. The aim of the present study was to unveil the mechanism by which shear stress-regulated microRNAs contribute to vessel maturation. Methods and results Here, we show that laminar shear stress increased miR-27a and miR-27b expression in vitro and in ex vivo in mouse femoral artery explants. Overexpression of miR-27b in endothelial cells increased pericyte adhesion and pericyte recruitment in vitro. In vitro barrier function of endothelial-pericyte co-cultures was augmented by miR-27b overexpression, whereas inhibition of miR-27a/b reduced adhesion and pericyte coverage and decreased barrier functions. In vivo, pharmacological inhibition of miR-27a/b by locked nucleic acid antisense oligonucleotides significantly reduced pericyte coverage and increased water content in the murine uterus. MiR-27b overexpression repressed semaphorins (SEMA), which mediate repulsive signals, and the vessel destabilizing human but not mouse Angiopoietin-2 (Ang-2). Silencing of SEMA6A and SEMA6D rescued the reduced pericyte adhesion by miR-27 inhibition. Furthermore, inhibition of SEMA6D increased barrier function of an endothelial-pericyte co-culture in vitro. Conclusion The present study demonstrates for the first time that shear stress-regulated miR-27b promotes the interaction of endothelial cells with pericytes, partly by repressing SEMA6A and SEMA6D.

This article contains errors in Figs. 5 and 6, for which we apologize. In Fig. 5f, the image ‘E12.5 tail’ was inadvertently replaced with a duplicate of the image ‘E12.5 trunk’ from the same panel. In Figure 6d, the image ‘E9.5/OH-TAM E8.5, embryo’ was inadvertently replaced with a duplicate of the image ‘E10.5/ OH-TAM E8.5, embryo’ from Fig. 6b. The corrected versions of these figures appear in the Author Correction associated with this Article.

Background: To investigate the impact of diabetes on coronary artery total plaque volume (TPV) and adverse events in long-term follow-up.Methods: One-hundred-and-eight diabetic patients were matched to 324 non-diabetic patients, with respect to age, sex, body-mass index, hypertension, smoking habits, LDL and HDL cholesterol, family history for CAD as well as aspirin and statin medication. In all patients, TPV was quantified from coronary CT angiographies (CTA) using dedicated software. All-cause mortality, acute coronary syndrome and late revascularisation ( > 90 days) served as combined endpoint.Results: Patients were followed for 5.6 years. The endpoint occurred in 18 (16.7%) diabetic and 26 (8.0%) nondiabetic patients (odds ratio 2.3, p = 0.03). Diabetic patients had significantly higher TPV than non-diabetic patients (55.1 mm 3 [IQR: 6.2 and 220.4 mm(3)] vs. 24.9 mm 3 [IQR: 0 and 166.7 mm(3)], p = 0.02). A TPV threshold of 110.5 mm(3) provided good separation of diabetic and non-diabetic patients at higher and lower risk for adverse events. Noteworthy, diabetic and non-diabetic patients with a TPV < 110.5 mm(3) had comparable outcome (hazard ratio: 1.3, p = 0.59), while diabetic patients with TPV > 110.5 mm(3) had significantly higher incidence of adverse events (hazard ratio 2.3, p = 0.03) compared to non-diabetic patients with TPV > 110.5 mm(3). There was incremental prognostic value in diabetic and non-diabetic patients over the Framingham Risk Score (Integrated Discrimination Improvement: 0.052 and 0.012, p for both < 0.05).Conclusion: Diabetes is associated with significantly higher TPV, which is independent of other CAD risk factors. Quantification of TPV improves the identification of diabetic patients at higher risk for future adverse events.

Corneal immune privilege is integral in maintaining the clear avascular window to the foreign world. The presence of distinct populations of corneal leukocytes (CLs) in the normal cornea has been firmly established. However, their precise function and kinetics remain, as of yet, unclear. Through intravital multiphoton microscopy (IV-MPM), allowing themeans to accumulate critical spatial and temporal cellular information, we provide details for long-term investigation of CL morphology and kinetics under steady state and following inflammation. Significant alterations in size and morphology of corneal CD11c+ dendritic cells (DCs) were noted following acute sterile inflammation, including cellvolume(4364.4±489.6 vs. 1787.6±111.0mm3,P

Tumor microvesicles are a peculiar type of extracellular vesicles that circulate in the blood of patients with metastatic cancer. The itineraries and immune cell interactions of tumor microvesicles during the intravascular and extravascular stages of metastasis are largely unknown. We found that the lipid receptor CD36 is a major mediator of the engulfment of pancreatic tumor microvesicles by myeloid immune cells in vitro and critically samples circulating tumor microvesicles by resident liver macrophages in mice in vivo. Direct nanoscopic imaging of individual tumor microvesicles shows that the microvesicles rapidly decay during engulfment whereby their cargo is targeted concomitantly to the plasma membrane and the cytoplasm excluding lysosomal compartments. CD36 also promotes internalization of blood cell (nontumor) microvesicles, which involves endolysosomal pathways. A portion of tumor microvesicles circulating in the liver microcirculation traverses the vessel wall in a CD36-dependent way. Extravasated microvesicles colonize distinct perivascular Ly6C(-) macrophages for at least 2 wk. Thus, the microvesicles are increasingly integrated into CD36-induced premetastatic cell clusters and enhance development of liver metastasis. Hence, promotion of metastasis by pancreatic tumor microvesicles is associated with CD36-regulated immune cell invasion and extravasation of microvesicles and persistent infiltration of specific tissue macrophages by microvesicle cargo.Pfeiler, S., Thakur, M., Grunauer, P., Megens, R. T. A., Joshi, U., Coletti, R., Samara, V., Muller-Stoy, G., Ishikawa-Ankerhold, H., Stark, K., Klingl, A., Frohlich, T., Arnold, G. J., Wormann, S., Bruns, C. J., Algul, H., Weber, C., Massberg, S., Engelmann, B. CD36-triggered cell invasion and persistent tissue colonization by tumor microvesicles during metastasis.

Arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality. The underlying pathophysiology of arrhythmias is complex and remains incompletely understood, which explains why mostly only symptomatic therapy is available. The evaluation of the complex interplay between various cell types in the heart, including cardiomyocytes from the conduction system and the working myocardium, fibroblasts and cardiac immune cells, remains a major challenge in arrhythmia research because it can be investigated only in vivo. Various animal species have been used, and several disease models have been developed to study arrhythmias. Although every species is useful and might be ideal to study a specific hypothesis, we suggest a practical trio of animal models for future use: mice for genetic investigations, mechanistic evaluations or early studies to identify potential drug targets; rabbits for studies on ion channel function, repolarization or re-entrant arrhythmias; and pigs for preclinical translational studies to validate previous findings. In this Review, we provide a comprehensive overview of different models and currently used species for arrhythmia research, discuss their advantages and disadvantages and provide guidance for researchers who are considering performing in vivo studies.

To investigate the safety and efficacy of an early platelet function testing (PFT)-guided de-escalation of dual antiplatelet treatment (DAPT) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with bioresorbable vascular scaffolds (BVS). Early DAPT de-escalation is a new non-inferior alternative to 12-months DAPT in patients with biomarker positive ACS treated with stent implantation. In this post-hoc analysis of the TROPICAL-ACS trial, which randomized 2610 ACS patients to a PFT-guided DAPT de-escalation (switch from prasugrel to clopidogrel) or to control group (uniform prasugrel), we compared clinical outcomes of patients (n = 151) who received a BVS during the index PCI. The frequency of the primary endpoint (cardiovascular death, myocardial infarction, stroke or BARC ≥ 2 bleeding) was 8.8% (n = 6) in the de-escalation group vs. 12.0% (n = 10) in the control group (HR 0.72, 95% CI 0.26-1.98, p = 0.52) at 12 months. One early definite stent thrombosis (ST) occurred in the control group (day 19) and 1 possible ST (sudden cardiovascular death) in the de-escalation group (day 86), both despite prasugrel treatment and in a background of high on-treatment platelet reactivity assessed at day 14 after randomization (ADP-induced platelet aggregation values of 108 U and 59 U, respectively). A PFT-guided DAPT de-escalation strategy could potentially be a safe and effective strategy in ACS patients with BVS implantation but the level of platelet inhibition may be of particular importance. This hypothesis-generating post-hoc analysis requires verification in larger studies with upcoming BVS platforms. peerReviewed

Aims: Advances of cardiac computed tomography angiography (CTA) have been developed for dose reduction, but their efficacy in clinical practice is largely unknown. This study was designed to evaluate radiation dose exposure and utilization of dose-saving strategies for contrast-enhanced cardiac CTA in daily practice.Methods and results: Sixty one hospitals from 32 countries prospectively enrolled 4502 patients undergoing cardiac CTA during one calendar month in 2017. Computed tomography angiography scan data and images were analysed in a central core lab and compared with a similar dose survey performed in 2007. Linear regression analysis was performed to identify independent predictors associated with dose. The most frequent indication for cardiac CTA was the evaluation of coronary artery disease in 89% of patients. The median dose-length product (DLP) of coronary CTA was 195 mGy*cm (interquartile range 110-338 mGy*cm). When compared with 2007, the DLP was reduced by 78% (P Conclusion: This large international radiation dose survey demonstrates considerable reduction of radiation exposure in coronary CTA during the last decade. However, the large inter-site variability in radiation exposure underlines the need for further site-specific training and adaptation of contemporary cardiac scan protocols.

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., Author summary The Cag Type IV secretion system of Helicobacter pylori (Hp) interacts with host cell integrins and injects the bacterial oncoprotein CagA into host cells thereby contributing to inflammation and carcinogenesis during chronic infection. Binding of β1 integrin receptors by the CagA protein and the type IV secretion system is well described by many research groups, but its function for CagA translocation is not well understood. We report here that this interaction is not essential for the function of the secretion system and for CagA injection into the gastric epithelial cells lines AGS and KatoIII. However, the bacterial binding to a set of specific receptors called carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) by the Hp outer membrane protein HopQ is a prerequisite for CagA translocation. Interestingly, other bacterial adhesins and the mediated binding events do not have a similar effect on CagA translocation, suggesting a specific feature associated with HopQ mediated binding.

Severe tricuspid regurgitation (TR) has long been neglected despite its well-known association with mortality. While surgical mortality rates remain high in isolated tricuspid valve surgery, interventional TR repair is rapidly evolving as an alternative to cardiac surgery in selected patients at high surgical risk. Currently, interventional edge-to-edge repair is the most frequently applied technique for TR repair even though a device has not been developed for this particular indication. Due to the inherent differences in tricuspid and mitral valve anatomy and pathology, percutaneous repair of the tricuspid valve is challenging due to a variety of factors including the complexity and variability of tricuspid valve anatomy, echocardiographic visibility of the valve leaflets, and device steering to the tricuspid valve. Furthermore, it remains to be clarified which patients are suitable for a percutaneous tricuspid repair and which features predict a successful procedure. On the basis of the available experience, we describe criteria for patient selection including morphological valve features, a standardised process for echocardiographic screening, and a strategy for clip placement. These criteria will help to achieve standardisation of valve assessment and the procedural approach, and to develop interventional tricuspid valve repair further, using either currently available devices or dedicated tricuspid edge-to-edge repair devices in the future. In summary, this manuscript will provide guidance for patient selection and echocardiographic screening when considering edge-to-edge repair for severe TR.

Leukocyte-released antimicrobial peptides contribute to pathogen elimination and activation of the immune system. Their role in thrombosis is incompletely understood. Here we show that the cathelicidin LL-37 is abundant in thrombi from patients with acute myocardial infarction. Its mouse homologue, CRAMP, is present in mouse arterial thrombi following vascular injury, and derives mainly from circulating neutrophils. Absence of hematopoietic CRAMP in bone marrow chimeric mice reduces platelet recruitment and thrombus formation. Both LL-37 and CRAMP induce platelet activation in vitro by involving glycoprotein VI receptor with downstream signaling through protein tyrosine kinases Src/Syk and phospholipase C. In addition to acute thrombosis, LL-37/CRAMP-dependent platelet activation fosters platelet–neutrophil interactions in other inflammatory conditions by modulating the recruitment and extravasation of neutrophils into tissues. Absence of CRAMP abrogates acid-induced lung injury, a mouse pneumonia model that is dependent on platelet–neutrophil interactions. We suggest that LL-37/CRAMP represents an important mediator of platelet activation and thrombo-inflammation., 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.

Background: To investigate the incremental prognostic value of low-attenuation plaque volume (LAPV) from coronary CT angiography datasets.Methods: Quantification of LAPV was performed using dedicated software equipped with an adaptive plaque tissue algorithm in 1577 patients with suspected CAD. A combination of death and acute coronary syndrome was defined as primary endpoint. To assess the incremental prognostic value of LAPV, parameters were added to a baseline model including clinical risk and obstructive coronary artery disease (CAD), a baseline model including clinical risk and calcium scoring (CACS) and a baseline model including clinical risk and segment involvement score (SIS).Results: Patients were followed for 5.5 years either by telephone contact, mail or clinical visits. The primary endpoint occurred in 30 patients. Quantified LAPV provided incremental prognostic information beyond clinical risk and obstructive CAD (c-index 0.701 vs. 0.767, p