Publications by authors named "Steffen Massberg"

362 Publications

Point-of-care detection and differentiation of anticoagulant therapy - development of thromboelastometry-guided decision-making support algorithms.

Thromb J 2021 Sep 7;19(1):63. Epub 2021 Sep 7.

Department of Anaesthesiology, University Hospital Munich, LMU Munich, Munich, Germany.

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 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12959-021-00313-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425056PMC
September 2021

Self-sustaining interleukin-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19.

JCI Insight 2021 Aug 17. Epub 2021 Aug 17.

Department of Medicine I, University Hospital, Ludwig-Maximilian University Munich, Munich, Germany.

Neutrophils provide a critical line of defense in immune responses to various pathogens, but also inflict 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 suffering from COVID-19. Here, we utilize state-of-the art mass spectrometry-based proteomics, 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 interleukin-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 SARS-CoV-2 spike protein-induced, hACE2-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 promising therapeutic target in severe SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.150862DOI Listing
August 2021

Percutaneous dilatational tracheotomy in high-risk ICU patients.

Ann Intensive Care 2021 Jul 28;11(1):116. Epub 2021 Jul 28.

Intensive Care Unit, Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.

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 P2Y 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13613-021-00906-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319261PMC
July 2021

Prediction of COVID-19 deterioration in high-risk patients at diagnosis: an early warning score for advanced COVID-19 developed by machine learning.

Infection 2021 Jul 19. Epub 2021 Jul 19.

Institute for Infectious Diseases and Infection Control, RG Systemsbiology, Jena University Hospital, Kollegiengasse 10, 07743, Jena, Germany.

Purpose: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization.

Methods: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16).

Results: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface.

Conclusion: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s15010-021-01656-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287547PMC
July 2021

Interventional Snare Procedure to Lift a Balloon-Expandable TAVR Impeding a Mechanical Bi-Leaflet Mitral Valve.

JACC Cardiovasc Interv 2021 Aug 14;14(15):e189-e190. Epub 2021 Jul 14.

Department of Cardiology, University Hospital, Ludwig-Maximilians-Universität München (LMU Munich), Munich, Germany; German Cardiovascular Research Centre (DZHK), partner site Munich Heart Alliance, Munich, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcin.2021.03.070DOI Listing
August 2021

Cardiac output states in patients with severe functional tricuspid regurgitation: impact on treatment success and prognosis.

Eur J Heart Fail 2021 Jul 16. Epub 2021 Jul 16.

Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany.

Aims: To investigate whether there is evidence for distinct cardiac output (CO) based phenotypes in patients with chronic right heart failure associated with severe tricuspid regurgitation (TR) and to characterize their impact on TR treatment and outcome.

Methods And Results: A total of 132 patients underwent isolated transcatheter tricuspid valve repair (TTVR) for functional TR at two centres. Patients were clustered according to k-means clustering into low [cardiac index (CI) < 1.7 L/min/m ], intermediate (CI 1.7-2.6 L/min/m ) and high CO (CI > 2.6 L/min/m ) clusters. All-cause mortality and clinical characteristics during follow-up were compared among different CO clusters. Mortality rates were highest for patients in a low (24%) and high CO state (42%, log-rank P < 0.001). High CO state patients were characterized by larger inferior vena cava diameters (P = 0.003), reduced liver function, higher incidence of ascites (P = 0.006) and markedly reduced systemic vascular resistance (P < 0.001) as compared to TTVR patients in other CO states. Despite comparable procedural success rates, the extent of changes in right atrial pressures (P = 0.01) and right ventricular dimensions (P < 0.001) per decrease in regurgitant volume following TTVR was less pronounced in high CO state patients as compared to other CO states. Successful TTVR was associated with the smallest prognostic benefit among low and high CO state patients.

Conclusions: Patients with chronic right heart failure and severe TR display distinct CO states. The high CO state is characterized by advanced congestive hepatopathy, a substantial decrease in peripheral vascular tone, a lack of response of central venous pressures to TR reduction, and worse prognosis. These data are relevant to the pathophysiological understanding and management of this important clinical syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.2307DOI Listing
July 2021

Combined extracorporeal membrane oxygenation and microaxial pump-when left ventricular preload is too low to unload in cardiogenic shock.

Health Sci Rep 2021 Sep 9;4(3):e321. Epub 2021 Jul 9.

Intensive Care Unit, Medizinische Klinik und Poliklinik I Klinikum der Universität München Munich Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hsr2.321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268316PMC
September 2021

Apixaban versus PhenpRocoumon: Oral AntiCoagulation plus antiplatelet tHerapy in patients with Acute Coronary Syndrome and Atrial Fibrillation (APPROACH-ACS-AF): Rationale and design of the prospective randomized parallel-group, open-label, blinded-endpoint, superiority, multicenter-trial of a triple therapy versus a dual therapy in patients with Atrial Fibrillation and Acute Coronary Syndrome undergoing coronary stenting.

Int J Cardiol Heart Vasc 2021 Aug 1;35:100810. Epub 2021 Jul 1.

Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University Munich (LMU Munich), Munich, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2021.100810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256176PMC
August 2021

Rationale and design of a digital trial using smartphones to detect subclinical atrial fibrillation in a population at risk: The eHealth-based bavarian alternative detection of Atrial Fibrillation (eBRAVE-AF) trial.

Am Heart J 2021 Jul 9;241:26-34. Epub 2021 Jul 9.

Medizinische Klinik und Poliklinik I, LMU University Hospital Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance, Munich, Germany; Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Current guidelines recommend opportunistic screening for subclinical atrial fibrillation (AF) taking advantage of e-health-based technologies. However, the efficacy of a fully scalable e-health-based strategy for AF detection in a head-to-head comparison with routine symptom-based screening is unknown. eBRAVE-AF is an investigator-initiated, digital, prospective, randomized, siteless, open-label, cross-over study to evaluate an e-health-based strategy for detection of AF in a real-world setting. 67,488 policyholders of a large German health insurance company (Versicherungskammer Bayern, Germany) selected by age ≥ 50 years and a CHADS-VASc score ≥ 1 (females ≥2) are invited to participate. Subjects with known AF or on treatment with oral anticoagulation are excluded. After obtaining electronic informed consent, at least 4,400 participants will be randomly assigned to an e-health-based screening strategy or routine symptom-based screening. The e-health-based strategy consists of repetitive one-minute photoplethysmographic (PPG) pulse wave assessments using a certified smartphone app (Preventicus Heartbeats, Preventicus, Jena, Germany), followed by a confirmatory 14-day ECG patch (CardioMem CM 100 XT, Getemed, Teltow, Germany) in case of abnormal findings. After 6 months, participants are crossed over to the other study arm. Primary endpoint is the incidence of newly diagnosed AF leading to oral anticoagulation indicated by an independent physician. Clinical follow-up will be at least 12 months. In both groups, follow-up is performed by 4-week app-based questionnaires, personal contact in case of abnormal findings, and matching with claim-based insurance data and medical reports. At time of writing enrollment is completed. First results are expected to be available in mid-2021.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2021.06.008DOI Listing
July 2021

Transcatheter mitral valve repair may increase eligibility for heart transplant listing in patients with end-stage heart failure and severe secondary mitral regurgitation.

Int J Cardiol 2021 09 19;338:72-78. Epub 2021 Jun 19.

Medizinische Klinik und Poliklinik I, Ludwig-Maximilians University, Munich, Germany; Heart Alliance, Partner Site German Center for Cardiovascular Disease (DZHK), Munich, Germany.

Background: Heart transplantation remains the gold standard for treatment of patients with end-stage heart failure and severely reduced ejection fraction (HFrEF). An increased pulmonary vascular resistance (PVR), which is often prevalent in HFrEF patients with secondary mitral regurgitation (SMR), limits the eligibility for transplantation. Therefore, we evaluated whether transcatheter mitral valve repair (TMVr) improves pulmonary circulatory hemodynamics and increases the eligibility for transplantation in end-stage HFrEF patients with severe SMR.

Methods: We retrospectively analysed the hemodynamics by right heart catheterization (RHC) as well as laboratory and clinical outcomes of end-stage HFrEF patients with SMR that underwent TMVr.

Results: Seventeen patients (age: 55 ± 10 yrs) underwent TMVr and repeat RHC at a mean follow-up of 5.7 ± 7.9 months. TMVr decreased PVR (3.5 ± 2.2 to 2.3 ± 1.2 wood units, p = 0.02) and systolic pulmonary artery pressure (55.4 ± 15 mmHg to 45.6 ± 9.8 mmHg, p = 0.02) from baseline to follow-up, respectively, while cardiac output was increased (3.7 ± 0.9 l/min to 4.6 ± 1.3 l/min, p = 0.02). In addition, transpulmonary gradient decreased significantly (12.0 ± 7.5 mmHg to 9.7 ± 5.3 mmHg, p = 0.04). The prevalence of New York Heart Association functional class ≥III at follow-up was reduced from 88% (15/17 patients) to 47% (8/17 patients, p = 0.01). All five patients with initially too high PVR (>3.5 WU) showed a significant decrease in PVR and three of them became potential candidates for heart transplantation after TMVr.

Conclusion: TMVr is associated with reduction in PVR which may increase eligibility for transplantation in some HFrEF patients with severe SMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2021.06.031DOI Listing
September 2021

Impact of Dose Reduction Strategies on Image Quality of Coronary CTA in Real World Clinical Practice: A Subanalysis of PROTECTION VI Registry Data.

AJR Am J Roentgenol 2021 Jun 16. Epub 2021 Jun 16.

Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany.

Dose reduction strategies for coronary CTA (CCTA) have been underutilized in clinical practice given concern that the strategies may lower image quality. To explore associations between dose reduction strategies and CCTA image quality in real world clinical practice. This subanalysis of the PROTECTION VI (International Prospective Multicenter Registry on Radiation Dose Estimates of Cardiac CT Angiography in Daily Practice in 2017) study included 3725 patients (2109 male, 1616 female; median age 59 years) who underwent CCTA for coronary artery evaluation, performed at 55 sites from 32 countries. CCTA image sets were reviewed at a central core lab. A range of patient and scan characteristics, including use of three dose reduction strategies (prospective ECG triggering, low tube potential, and iterative image reconstruction) as well as image dose were recorded. A single core lab member reviewed all examinations for quantitative image quality measures, including signal-to-noise ratio (SNR) and contrast-tonoise (CNR) ratio, 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 lab member repeated quantitative measures in 100 patients and the qualitative measure in 383 (approximately 20%) patients to assess interreader agreement. Independent predictors (p<.05) of SNR were female sex (+2.70), lower body mass index (+0.38 per 1 kg/m2 decrease), stable sinus rhythm (+1.71), and scanner manufacturer (variable effect across manufacturers). These same factors were also the only independent predictors of CNR. Independent predictors (p<.05) of CCTA image quality were heart rate (+0.17 increase per 10 beat per minute reduction) and coronary calcification (+0.15 per coronary calcification grade). None of the three dose savings strategies, nor dose length product, were independent predictors of any image quality measure. Interreader agreement analysis demonstrated intraclass correlation coefficient of 0.874 for SNR and 0.891 for CNR and kappa of 0.812 for the qualitative score. This large international multicenter study demonstrates that three dose reduction strategies were not associated with decreased CCTA image quality. The dose reduction strategies should be routinely implemented in clinical CCTA imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.21.26007DOI Listing
June 2021

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial.

Lancet Respir Med 2021 08 11;9(8):863-872. Epub 2021 Jun 11.

Department of Internal Medicine I (Cardiology), University Hospital Aachen, Aachen, Germany.

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 (AUC), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596.

Findings: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUC (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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(21)00214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195495PMC
August 2021

Cardiac 18F-FDG Positron Emission Tomography: An Accurate Tool to Monitor Metabolic and Functional Alterations in Murine Myocardial Infarction.

Front Cardiovasc Med 2021 25;8:656742. Epub 2021 May 25.

Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.

Cardiac monitoring after murine myocardial infarction, using serial non-invasive cardiac 18F-FDG positron emissions tomography (PET) represents a suitable and accurate tool for 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.656742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185215PMC
May 2021

Differences in Cardiac Magnetic Resonance Imaging Markers Between Patients With COVID-19-associated Myocardial Injury and Patients With Clinically Suspected Myocarditis.

J Thorac Imaging 2021 Sep;36(5):279-285

Departments of Radiology.

Purpose: Coronavirus 2019 disease (COVID-19) has been shown to affect the myocardium, resulting in a worse clinical outcome. In this registry study, we aimed to identify differences in cardiac magnetic resonance imaging (CMRI) between COVID-19 and all-cause myocarditis.

Materials And Methods: We examined CMRI of patients with COVID-19 and elevated high-sensitivity serum troponin levels performed between March 31st and May 5th and compared them to CMRI of patients without SARS-CoV-2 infection with suspected myocarditis in the same time period. For this purpose, we evaluated Lake-Louise Criteria for myocarditis by determining nonischemic myocardial injury via T1-mapping, extracellular volume, late gadolinium enhancement, and myocardial edema (ME) by T2-mapping and fat-saturated T2w imaging (T2Q).

Results: A total of 15 of 18 (89%) patients with COVID-19 had abnormal findings. The control group consisted of 18 individuals. There were significantly fewer individuals with COVID-19 who had increased T2 (5 vs. 10; P=0.038) and all-cause ME (7 vs. 15; P=0.015); thus, significantly fewer patients with COVID-19 fulfilled Lake-Louise Criteria (6 vs. 17; P<0.001). In contrast, nonischemic myocardial injury was not significantly different. In the COVID-19 group, indexed end-diastolic volume of the left ventricle showed a significant correlation to the extent of abnormal T1 (R2=0.571; P=0.017) and extracellular volume (R2=0.605; P=0.013) and absolute T1, T2, and T2Q (R2=0.644; P=0.005, R2=0.513; P=0.035 and R2=0.629; P=0.038, respectively); in the control group, only extracellular volume showed a weak correlation (R2=0.490; P=0.046).

Conclusions: Cardiac involvement in COVID-19 seems to show less ME than all-cause myocarditis. Abnormal CMRI markers correlated to left ventricle dilation only in the COVID-19 group. Larger comparative studies are needed to verify our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RTI.0000000000000599DOI Listing
September 2021

Isolation and Culture of Resident Cardiac Macrophages from the Murine Sinoatrial and Atrioventricular Node.

J Vis Exp 2021 05 7(171). Epub 2021 May 7.

University Hospital Munich, Department of Medicine I, Ludwig-Maximilian-Unversity Munich (LMU); Walter Brendel Center of Experimental Medicine (WBex), LMU Munich; German Center for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA).

Resident cardiac macrophages have been demonstrated to facilitate the electrical conduction in the heart. The physiologic heart rhythm is initiated by electrical impulses generated in sinoatrial node (SAN) and then conducted to ventricles via atrioventricular node (AVN). To further study the role of resident macrophages in cardiac conduction system, a proper isolation of resident macrophages from SAN and AVN is necessary, but it remains challenging. Here, we provide a protocol for the reliable microdissection of the SAN and AVN in murine hearts followed by the isolation and culture of resident macrophages. Both, SAN which is located at the junction of the crista terminalis with the superior vena cava, and AVN which is located at the apex of the triangle of Koch, are identified and microdissected. Correct location is confirmed by histologic analysis of the tissue performed with Masson's trichrome stain and by anti-HCN4. Microdissected tissues are then enzymatically digested to obtain single cell suspensions followed by the incubation with a specific panel of antibodies directed against cell-type specific surface markers. This allows to identify, count, or isolate different cell populations by fluorescent activated cell sorting. To differentiate cardiac resident macrophages from other immune cells in the myocardium, especially recruited monocyte-derived macrophages, a delicate devised gating strategy is needed. First, lymphoid lineage cells are detected and excluded from further analysis. Then, myeloid cells are identified with resident macrophages being determined by high expression of both CD45 and CD11b, and low expression of Ly6C. With cell sorting, isolated cardiac macrophages can then be cultivated in vitro over several days for further investigation. We, therefore, describe a protocol to isolate cardiac resident macrophages located within the cardiac conduction system. We discuss pitfalls in microdissecting and digesting SAN and AVN, and provide a gating strategy to reliably identify, count and sort cardiac macrophages by fluorescence-activated cell sorting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/62236DOI Listing
May 2021

Cardiac surgery following transcatheter aortic valve replacement.

Eur J Cardiothorac Surg 2021 May 21. Epub 2021 May 21.

Department of Cardiac Surgery, LMU University Hospital, Munich, Germany.

Objectives: The objective of this study was to retrospectively analyse surgical outcomes of patients undergoing secondary cardiac surgery after initial transcatheter aortic valve replacement (TAVR).

Methods: Between December 2012 and February 2020, a total of 41 consecutive patients underwent cardiac surgery after a TAVR procedure at our institution. Patients who underwent emergency operations due to periprocedural complications such as ventricular rupture and TAVR dislocation were excluded from this study (n = 12). Thus, 29 patients were included in the analysis. Data are presented as medians (25th-75th quartiles) or as absolute numbers (percentages).

Results: The median age was 76 years (68-80); 58.6% were men. The median time to a secondary conventional procedure was 23 months (8-40), with 8 patients requiring surgical intervention within the first year post TAVR. The indications for secondary conventional procedures were prosthesis endocarditis (n = 15), prosthesis degeneration or dysfunction (n = 7) and progression of valvular, aortic or coronary artery disease (n = 7). Surgical redo aortic valve replacement was performed in 24 patients (82.8%). No complications involving the aortic root or the aortomitral continuity were observed. The operative mortality was 10.3%. Extracorporeal life support was required in 3 patients (10.3%) for a median duration of 3 days (3-3 days). No adverse cerebrovascular events were observed postoperatively. Postoperatively, 4 patients (13.8%) required a pacemaker and 7 patients (24.1%) required renal replacement therapy. Overall survival at 1 year was 83.0%.

Conclusions: Conventional cardiac surgical procedures following TAVR are feasible with reasonable results and a low complication rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ejcts/ezab217DOI Listing
May 2021

Clopidogrel vs. prasugrel vs. ticagrelor in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis.

Clin Res Cardiol 2021 Sep 17;110(9):1493-1503. Epub 2021 May 17.

Department of Medicine I, University Hospital, Ludwig-Maximilians-University, Munich, Germany.

Aims: The aim of this pooled sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated either with clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor.

Methods And Results: For the current analysis the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. 856 patients were eligible for analysis. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ significantly between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60-1.09, p = 0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65-1.15, p = 0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20 -0.69, p = 0.002) and not significantly different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43 -1.24, p = 0.24).

Conclusion: This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that acute therapy with either clopidogrel, prasugrel or ticagrelor is no independent predictor of 1-year mortality. Treatment with ticagrelor seems independently associated with less in-hospital moderate and severe bleeding events compared to clopidogrel. This finding might be due to selection bias and should be interpreted with caution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-021-01866-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405498PMC
September 2021

Proof of Concept: Measuring Aortic Annulus Resistance by Means of Pressure-Volume Curves During Balloon Inflation to Guide Transcatheter Aortic Valve Implantation.

Front Cardiovasc Med 2021 30;8:665029. Epub 2021 Apr 30.

Department of Cardiology & Intensive Care Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.665029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119645PMC
April 2021

Impact of Residual Mitral Regurgitation on Survival After Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation.

JACC Cardiovasc Interv 2021 Jun 12;14(11):1243-1253. Epub 2021 May 12.

Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany; Munich Heart Alliance, Partner Site German Center for Cardiovascular Disease, Munich, Germany. Electronic address:

Objectives: The aim of this study was to assess the impact of residual mitral regurgitation (resMR) on mortality with respect to left ventricular dilatation (LV-Dil) or right ventricular dysfunction (RV-Dys) in patients with secondary mitral regurgitation (SMR) who underwent mitral valve transcatheter edge-to-edge repair (TEER).

Background: The presence of LV-Dil and RV-Dys correlates with advanced stages of heart failure in SMR patients, which may impact the outcome after TEER.

Methods: SMR patients in a European multicenter registry were evaluated. Investigated outcomes were 2-year all-cause mortality and improvement in New York Heart Association functional class with respect to MR reduction, LV-Dil (defined as LV end-diastolic volume ≥159 ml), and RV-Dys (defined as tricuspid annular plane systolic excursion-to-systolic pulmonary artery pressure ratio of <0.274 mm/mm Hg).

Results: Among 809 included patients, resMR ≤1+ was achieved in 546 (67%) patients. Overall estimated 2-year mortality rate was 32%. Post-procedural resMR was significantly associated with mortality (p = 0.031). Although the improvement in New York Heart Association functional class persisted regardless of either LV-Dil or RV-Dys, the beneficial treatment effect of resMR ≤1+ on 2-year mortality was observed only in patients without LV-Dil and RV-Dys (hazard ratio: 1.75; 95% confidence interval: 1.03 to 3.00).

Conclusions: Achieving optimal MR reduction by TEER is associated with improved survival in SMR patients, especially if the progress in heart failure is not too advanced. In SMR patients with advanced stages of heart failure, as evidenced by LV-Dil or RV-Dys, the treatment effect of TEER on symptomatic improvement is maintained, but the survival benefit appears to be reduced.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcin.2021.03.050DOI Listing
June 2021

New challenges in cardiac intensive care units.

Clin Res Cardiol 2021 Sep 9;110(9):1369-1379. Epub 2021 May 9.

Cardiac Intensive Care Unit, Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.

Critical care cardiology is a steadily and rapidly developing sub-specialization within cardiovascular medicine, since the first emergence of a coronary care unit in the early 1960s. Today, modern cardiac intensive care units (CICU) serve a complex patient population with a high burden of cardiovascular and non-cardiovascular critical illnesses. Treatment of these patients requires a multidisciplinary approach, with a combination of highly specialized knowledge and skills in cardiovascular diseases, as well as emergency, critical-care and internal medicine. The CICU has always posed special challenges to both experienced intensivists as well as fellows-in-training (FIT) and is certainly one of the most demanding training phases. In recent years, these challenges have grown significantly owing to technological innovations, with new and steadily rising numbers of complex interventional procedures and new options for temporary circulatory support for critically ill patients, such as venoarterial extracorporeal membrane oxygenation (VA-ECMO). Herein, we focus on the successful CICU management of these special patient cohorts, which must become an integral part of critical-care training.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-021-01869-0DOI Listing
September 2021

Interplay between inflammation and thrombosis in cardiovascular pathology.

Nat Rev Cardiol 2021 09 6;18(9):666-682. Epub 2021 May 6.

Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany.

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41569-021-00552-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100938PMC
September 2021

ADP-induced platelet reactivity and bleeding events in patients with acute myocardial infarction complicated by cardiogenic shock.

Platelets 2021 May 3:1-10. Epub 2021 May 3.

Department of Medicine I, University Hospital, LMU Munich, Munich, Germany.

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 ( < .001). Multivariate analysis identified on-treatment ADP-induced platelet aggregation as an independent risk factor for bleeding (HR = 0.968 per AU). An optimal cutoff value of <12 AU for ADP-induced platelet aggregation to predict BARC≥3 bleedings was identified via ROC analysis. Moreover, the use of VA-ECMO (HR 1.972) or coaxial left ventricular pump (HR 2.593), first lactate (HR 1.093 per mmol/l) and thrombocyte count (HR 0.994 per G/l) were independent predictors of BARC≥3 bleedings. In conclusion, lower on-treatment ADP-induced platelet aggregation was independently associated with severe bleeding events in patients with AMI-CS. The value of platelet function testing for bleeding risk prediction and guidance of anti-thrombotic treatment in cardiogenic shock warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09537104.2021.1913577DOI Listing
May 2021

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.

Nat Rev Immunol 2021 05 6;21(5):319-329. Epub 2021 Apr 6.

Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41577-021-00536-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023349PMC
May 2021

Sex-Related Clinical Characteristics and Outcomes of Patients Undergoing Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation.

JACC Cardiovasc Interv 2021 Apr 31;14(8):819-827. Epub 2021 Mar 31.

Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany; Munich Heart Alliance, Partner Site German Center for Cardiovascular Disease (DZHK), Munich, Germany. Electronic address:

Objectives: The authors sought to assess sex-based differences in characteristics and outcomes of patients undergoing transcatheter edge-to-edge mitral valve repair (TMVR) for secondary mitral regurgitation (SMR).

Background: Subgroup analysis from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial indicated potential sex-related differences in outcomes after TMVR. The impact of sex on results after TMVR in a real-world setting is unknown.

Methods: The authors assessed clinical outcomes and echocardiographic parameters in women and men undergoing TMVR for SMR between 2008 and 2018 who were included in the large, international, multicenter real-world EuroSMR registry (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation).

Results: A total of 1,233 patients, including 445 women (36%) and 788 men (64%), were analyzed. Although women were significantly older and had fewer comorbidities than men, TMVR was equally effective in women and men (mitral regurgitation [MR] grade ≤2+ at discharge: 93.2% vs. 94.6% for women vs. men; p = 0.35). All-cause mortality at 1 year (17.9% vs. 18.9%, adjusted hazard ratio: 0.806; p = 0.46) and at 2-year follow-up (26.5% vs. 26.4%, adjusted hazard ratio: 0.757; p = 0.26) were similar in women versus men after multivariate regression analysis. Durability of MR reduction, improvement in symptoms, quality of life, and functional capacity did also not differ during follow-up.

Conclusions: Results from the EuroSMR registry confirmed effective and similar MR reduction with TMVR in women and men. There were no sex-related differences in clinical outcomes up to 2 years of follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcin.2020.12.042DOI Listing
April 2021

Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial.

JAMA Cardiol 2021 Jul;6(7):753-761

Department of Cardiology, Medizinische Klinik und Poliklinik I, Munich University Clinic, Ludwig-Maximilian University of Munich, Munich, Germany.

Importance: The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant.

Objective: To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI.

Design, Setting, And Participants: A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).

Interventions: Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy.

Main Outcomes And Measures: The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days.

Results: Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5'-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36).

Conclusions And Relevance: Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.

Trial Registration: ClinicalTrials.gov Identifier: NCT03312855.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.0475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014195PMC
July 2021

Percutaneous edge-to-edge repair of severe mitral regurgitation using the MitraClip XTR versus NTR system.

Clin Cardiol 2021 May 24;44(5):708-714. Epub 2021 Mar 24.

Medizinische Klinik und Poliklinik I, University Hospital Munich Campus Grosshadern, Marchioninistraße, München, Deutschland, Germany.

Background: Transcatheter mitral valve repair (TMVR) has shown to improve symptoms and functional capacity in patients with severe mitral valve regurgitation (MR). Novel device developments provide the technology to treat patients with complex anatomies and large coaptation gaps. Nevertheless, the question of superiority of one device remains unanswered. We aimed to compare the MitraClip XTR and MitraClip NTR system in a real world setting.

Hypothesis: TMVR with the MitraClip XTR system is equally effective, but associated with a higher risk of leaflet injury.

Methods: We retrospectively analyzed peri-procedural and mid-term clinical and echocardiographic outcomes of 113 patients treated for severe MR between March 2018 and August 2019 at the University Hospital of Munich.

Results: Postprocedural MR reduction to ≤2+ was comparable in both groups (XTR: 96.1% vs. NTR: 97.6%, p = .38). There was a significant difference in a composite safety endpoint of periprocedural Major adverse cardiac and cerebrovascular events (MACCE) including leaflet injury between groups (XTR 14.6% vs. NTR 1.7%, 95% CI [2.7, 24.6], p = .012). After a median follow-up of 8.5 (4.4, 14.0) months, durable reduction of MR was confirmed (XTR: in 91.9% vs. NTR: 96.8%, p = .31) and clinical and symptomatic improvement was comparable in both groups accordingly.

Conclusion: While efficacy was comparable in both treatment groups, patients treated with the MitraClip XTR systems showed more events of acute leaflet tear and single leaflet device attachment (SLDA). A detailed echocardiographic assessment should be done to identify risk candidates for acute leaflet injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/clc.23599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119798PMC
May 2021

The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.

Nature 2021 04 17;592(7853):296-301. Epub 2021 Mar 17.

Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

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 factors. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2 (JAK2) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2 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. Jak2 lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2 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 Jak2 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03341-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038646PMC
April 2021

Viscoelastometry for detecting oral anticoagulants.

Thromb J 2021 Mar 16;19(1):18. Epub 2021 Mar 16.

Department of Anaesthesiology, University Hospital Munich, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.

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 (CT) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CT was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CT in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CT compared to controls (median 307 vs 73 s; p < 0.0001). CT correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CT (r = 0.7998; p < 0.0001), and CT provided 83% sensitivity and 64% specificity for detecting FXa inhibitors.

Conclusions: In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking.

Trial Registration: German clinical trials database ID: DRKS00015302 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12959-021-00267-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962229PMC
March 2021
-->