Publications by authors named "Tobias Geisler"

187 Publications

Prevention of stroke in patients with chronic coronary syndromes or peripheral arterial disease.

Eur Heart J Suppl 2020 Nov 6;22(Suppl M):M26-M34. Epub 2020 Dec 6.

Cardiovascular Research Unit, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.

Stroke is a common and devastating condition caused by atherothrombosis, thromboembolism, or haemorrhage. Patients with chronic coronary syndromes (CCS) or peripheral artery disease (PAD) are at increased risk of stroke because of shared pathophysiological mechanisms and risk-factor profiles. A range of pharmacological and non-pharmacological strategies can help to reduce stroke risk in these groups. Antithrombotic therapy reduces the risk of major adverse cardiovascular events, including ischaemic stroke, but increases the incidence of haemorrhagic stroke. Nevertheless, the net clinical benefits mean antithrombotic therapy is recommended in those with CCS or symptomatic PAD. Whilst single antiplatelet therapy is recommended as chronic treatment, dual antiplatelet therapy should be considered for those with CCS with prior myocardial infarction at high ischaemic but low bleeding risk. Similarly, dual antithrombotic therapy with aspirin and very-low-dose rivaroxaban is an alternative in CCS, as well as in symptomatic PAD. Full-dose anticoagulation should always be considered in those with CCS/PAD and atrial fibrillation. Unless ischaemic risk is particularly high, antiplatelet therapy should not generally be added to full-dose anticoagulation. Optimization of blood pressure, low-density lipoprotein levels, glycaemic control, and lifestyle characteristics may also reduce stroke risk. Overall, a multifaceted approach is essential to best prevent stroke in patients with CCS/PAD.
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http://dx.doi.org/10.1093/eurheartj/suaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916419PMC
November 2020

Ethnic Difference of Thrombogenicity in Patients with Cardiovascular Disease: a Pandora Box to Explain Prognostic Differences.

Korean Circ J 2021 Mar;51(3):202-221

Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.

Arterial and venous atherothrombotic events are finely regulated processes involving a complex interplay between vulnerable blood, vulnerable vessel, and blood stasis. Vulnerable blood ('thrombogenicity') comprises complex interactions between cellular components and plasma factors (inflammatory, procoagulant, anticoagulant, and fibrinolytic factors). The extent of thrombogenicity may determine the progression of atheroma and the clinical manifestation of atherothrombotic events, with the highest thrombogenicity in African Americans and lowest in East Asians. Inherent thrombogenicity may influence clinical efficacy and safety of specific antithrombotic treatments in high-risk patients, which may in part explain the observation that East Asian patients have reduced anti-ischemic benefits and elevated bleeding risk with antithrombotic therapy compared to Caucasian patients. In this review, we discuss available evidence regarding the racial differences in thrombogenicity and its impact on clinical outcomes among patients with atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.4070/kcj.2020.0537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925962PMC
March 2021

Severe SARS-CoV-2 infection inhibits fibrinolysis leading to changes in viscoelastic properties of blood clot: A descriptive study of fibrinolysis.

Thromb Haemost 2021 Feb 25. Epub 2021 Feb 25.

Universitätsklinikum Tübingen, Transfusion Medicine, Tübingen, Germany.

Background: Accumulating evidence indicates towards an association between SARS-CoV-2 infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis.

Objectives: We investigated the hypothesis that the procoagulatory state in COVID-19 patients is caused by impaired fibrinolysis system.

Methods: COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in the study. Whole blood samples were investigated by thromboelastography. Additionally, global parameters of coagulation and factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and alpha 2-antiplasmin (A2AP) were determined.

Results And Conclusion: A significantly increased lysis-resistance and a significantly longer time of lysis after adding tissue plasminogen activator was observed in blood samples from ICU COVID-19 patients compared to controls (maximal lysis: 3.25% ± 0.56 vs. 6.20% ± 0.89, p=0.0127; lysis time: 365.7s ± 44.6 vs. 193.2s ± 16.3, p=0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92U/ml ± 0.91 vs. 1.28U/ml ± 0.33, p=0.001). Interestingly, a positively correlation between the activity of PAI-1 and the lysis time of the formed clot (r=0.7015, p=0.0006) was observed. Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Future clinical studies should address the contribution of the fibrinolysis system to the procoagulatory state in blood of COVID-19 patients and investigate potential therapeutic targets in this system.
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http://dx.doi.org/10.1055/a-1400-6034DOI Listing
February 2021

Biomarkers of coagulation and fibrinolysis in acute myocardial infarction: a joint position paper of the Association for Acute CardioVascular Care and the European Society of Cardiology Working Group on Thrombosis.

Eur Heart J Acute Cardiovasc Care 2020 Nov 7. Epub 2020 Nov 7.

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Blvd. 161, 8200 Aarhus N, Denmark.

The formation of a thrombus in an epicardial artery may result in an acute myocardial infarction (AMI). Despite major advances in acute treatment using network approaches to allocate patients to timely reperfusion and optimal antithrombotic treatment, patients remain at high risk for thrombotic complications. Ongoing activation of the coagulation system as well as thrombin-mediated platelet activation may both play a crucial role in this context. Whether measurement of circulating biomarkers of coagulation and fibrinolysis could be useful for risk stratification in secondary prevention is currently not fully understood. In addition, measurement of such biomarkers could be helpful to identify thrombus formation as the leading mechanism for AMI. The introduction of biomarkers of myocardial injury such as high-sensitivity cardiac troponins made rule-out of AMI even more precise. However, elevated markers of myocardial injury cannot provide proof of a type 1 AMI, let alone thrombus formation. The combined measurement of markers of myocardial injury with biomarkers reflecting ongoing thrombus formation might be helpful for the fast and correct diagnosis of an atherothrombotic type 1 AMI. This position paper gives an overview of the current knowledge and possible role of biomarkers of coagulation and fibrinolysis for the diagnosis of AMI, risk stratification, and individualized treatment strategies in patients with AMI.
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http://dx.doi.org/10.1093/ehjacc/zuaa025DOI Listing
November 2020

Predicting 1-, 3- and 5-year outcomes in patients with coronary artery disease: A comparison of available risk assessment scores.

Atherosclerosis 2021 02 13;318:1-7. Epub 2020 Dec 13.

Department of Cardiology and Angiology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany. Electronic address:

Background And Aims: Thromboischemic and bleeding events are rare but life-threatening complications after percutaneous coronary intervention (PCI). Various risk assessment models have been established to predict short- and long-term adverse events in patients with chronic and acute coronary syndromes (CCS, ACS). The aim of the present study was to compare available risk assessment systems based on their performance in identifying high-risk patients with symptomatic coronary artery disease (CAD).

Methods: We enrolled 1565 consecutive patients with symptomatic CAD (n = 821 CCS, n = 744 ACS). CALIBER, DAPT, GRACE 2.0, PARIS-CTE, PARIS-MB, PRECISE-DAPT and PREDICT-STABLE scores were calculated in appropriate patient subgroups. All patients were followed-up for 1, 3 and 5 years for all-cause death (ACD), myocardial infarction (MI), ischemic stroke (IS) and bleeding. The primary combined ischemic endpoint (CE) consisted of ACD, MI and/or IS. Secondary endpoints were defined as single occurrence of either ACD, MI, IS, or bleeding.

Results: GRACE 2.0 score showed good discrimination performance (AUC>0.7) for CE in a 3- and 5-year follow-up. CALIBER, GRACE 2.0 and PARIS-CTE showed best performance (AUC>0.7) in predicting ACD throughout the follow-up, whereas IS was best predicted by PARIS-CTE and CALIBER scores. None of the scores performed well (AUC>0.7) in predicting MI or bleeding.

Conclusions: In a consecutive German CAD cohort, CALIBER, GRACE 2.0 and PARIS-CTE scores performed best in predicting CE, ACD and/or IS whereas none of the selected scores could predict MI and bleeding efficiently.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.007DOI Listing
February 2021

The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease.

Thromb Haemost 2021 Apr 10;121(4):422-432. Epub 2020 Nov 10.

Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, South Korea.

East Asian patients have reduced anti-ischemic benefits and increased bleeding risk during antithrombotic therapies compared with Caucasian patients. As potent P2Y receptor inhibitors (e.g., ticagrelor and prasugrel) and direct oral anticoagulants are commonly used in current daily practice, the unique risk-benefit trade-off in East Asians has been a topic of emerging interest. In this article, we propose updated evidence and future directions of antithrombotic treatment in East Asian patients.
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http://dx.doi.org/10.1055/s-0040-1718729DOI Listing
April 2021

Dual Pathway Inhibition for Vascular Protection in Patients with Atherosclerotic Disease: Rationale and Review of the Evidence.

Thromb Haemost 2020 Aug 28;120(8):1147-1158. Epub 2020 Jun 28.

Research and Development Pharmaceuticals, Bayer AG, Wuppertal, Germany.

Despite advances in secondary prevention strategies in patients with cardiovascular disease, the residual risk of recurrent atherothrombotic events remains high. Dual-antiplatelet therapy is the standard of care for secondary prevention in patients with acute coronary syndrome (ACS), whereas single antiplatelet therapy, generally with aspirin, is the standard of care for secondary prevention in stable patients with coronary artery disease (CAD), peripheral artery disease (PAD), or cerebrovascular disease. However, atherosclerotic plaque disruption not only triggers platelet activation but also results in thrombin generation because of tissue factor exposure. Therefore, blocking both pathways by combining antiplatelet therapy with an anticoagulant, or dual pathway inhibition (DPI), has the potential to be more effective than inhibiting either pathway alone. The benefit of DPI has been demonstrated in the ATLAS ACS 2-TIMI 51, COMPASS, and VOYAGER PAD trials, where the combination of rivaroxaban vascular dose (2.5 mg twice daily) plus aspirin significantly reduced the risk of atherothrombotic events compared with aspirin across a broad range of patients, including those with recent ACS, those with chronic CAD and/or PAD, and patients with PAD who have undergone peripheral revascularization. This article provides the rationale for this regimen in more detail, including why the DPI regimen with the rivaroxaban vascular dose was developed for vascular protection in a broad spectrum of patients with atherosclerotic disease.
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http://dx.doi.org/10.1055/s-0040-1713376DOI Listing
August 2020

Risk factors for permanent pacemaker implantation in patients receiving a balloon-expandable transcatheter aortic valve prosthesis.

Heart Vessels 2020 Dec 26;35(12):1735-1745. Epub 2020 Jun 26.

Department of Cardiology and Angiology, University Hospital of Tübingen, Tübingen, Germany.

Permanent pacemaker implantation (PPI) is a widely recognized complication associated with TAVI (incidence up to 20%). Smaller registries have identified several variables associated with PPI. The objective was to validate patient- and transcatheter aortic valve implantation (TAVI)-related procedural variables associated with PPI. We performed a retrospective analysis of patients from six European centers undergoing TAVI with the Edwards SAPIEN 3 prosthesis. Baseline variables and pre-procedural ECG characteristics and CT-scans were taken into account. Data for 1745 patients were collected; 191 (10.9%) required PPI after TAVI. The baseline variables pulmonary hypertension (OR 1.64; 95% CI 1.01-2.59), QRS duration > 117 ms (OR 2.58; 95% CI 1.73-3.84), right bundle branch block (RBBB; OR 5.14; 95% CI 3.39-7.72), left anterior hemi block (OR 1.92; 95% CI 1.19-3.02) and first-degree atrioventricular block (AVB, OR 1.63; 95%CI 1.05-2.46) were significantly associated with PPI. RBBB (OR 8.11; 95% CI 3.19-21.86) and first-degree AVB (OR 2.39; 95% CI 1.18-4.66) remained significantly associated in a multivariate analysis. Procedure-related variables included access site (TF; OR 1.97; 95% CI 1.07-4.05), implanted valve size (29 mm; OR 1.88; 95% CI 1.35-2.59), mean TAVI valve implantation depth below the annulus > 30% (OR 3.75; 95% CI 2.01-6.98). Patients receiving PPI had longer ICU stays and later discharges. Acute kidney injury stage 2/3 was more common in patients with PPI until discharge (15.2 vs. 3.1%; p = 0.007), but was not statistically significant thereafter. Further differences in outcomes at 30 days did not reach significance. The data will aid pre- and post-procedural patient management and prevent adverse long-term outcomes.Clinical Trial: NCT03497611.
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http://dx.doi.org/10.1007/s00380-020-01653-6DOI Listing
December 2020

Optimal antiplatelet and anticoagulation strategies in acute coronary syndromes.

Herz 2020 Sep;45(6):528-536

Department of Cardiology and Angiology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany.

Antithrombotic therapy has become increasingly challenging due to the thrombotic and bleeding risk of patients presenting with acute coronary syndrome (ACS) today. Contributing factors include increasing age, underlying comorbidities (e.g., renal failure, atrial fibrillation [AF]), or concomitant interventions including transcatheter valve procedures requiring individualized antithrombotic strategies. Thanks to the development of novel stent platforms with biocompatible polymers and thin strut design allowing for a more rapid endothelialization, shortening or de-escalation of antiplatelet therapies is an attractive option for reducing bleeding events. In fact, several trials have been recently published or are currently underway that address the issue of early monotherapy after short-term dual antiplatelet therapy in ACS patients. Patients with AF and ACS are at a particularly high risk for thromboembolic and bleeding events. An individualized combination approach of antiplatelet therapy plus non-vitamin K oral anticoagulants should be favored in these patients to reduce bleeding risk according to recent randomized trials and guidelines. In contrast to de-escalation strategies in ACS patients at high bleeding risk, in patients with myocardial infarction in whom the long-term risk for ischemic events prevails, prolongation of an intensified antithrombotic therapy on top of acetylsalicylic acid is recommended. This review summarizes the recent evidence and offers practical recommendations to determine patients' bleeding versus thrombo-ischemic risk in order to tailor early and late antithrombotic therapy after ACS.
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http://dx.doi.org/10.1007/s00059-020-04947-7DOI Listing
September 2020

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Clin Pharmacol Ther 2020 Nov 9;108(5):1067-1077. Epub 2020 Jul 9.

Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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http://dx.doi.org/10.1002/cpt.1911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689744PMC
November 2020

Usefulness of the updated logistic clinical SYNTAX score after percutaneous coronary intervention in patients with prior coronary artery bypass graft surgery: Insights from the GLOBAL LEADERS trial.

Catheter Cardiovasc Interv 2020 Nov 15;96(5):E516-E526. Epub 2020 Apr 15.

Department of cardiology, National University of Ireland Galway (NUIG), Galway, Ireland.

Objectives: We aimed to investigate the prognostic utility of the anatomical CABG SYNTAX and logistic clinical SYNTAX scores for mortality after percutaneous coronary intervention (PCI) in patients with prior coronary artery bypass grafts (CABG).

Background: The anatomical SYNTAX score evaluated the anatomical complexity of coronary artery disease and helped predict the prognosis of patients undergoing PCI. The anatomical CABG SYNTAX score was derived from the anatomical SYNTAX score in patients with prior CABG, whilst the logistic clinical SYNTAX score was developed by incorporating clinical factors into the anatomical SYNTAX score.

Methods: We calculated the anatomical CABG SYNTAX score and logistic clinical SYNTAX score in 205 patients in the GLOBAL LEADERS trial. The predictive abilities of these scores for 2-year all-cause mortality were evaluated.

Results: Using the median scores as categorical thresholds between low and high score groups, the logistic clinical SYNTAX score was able to discriminate the risk of 2-year mortality, unlike the anatomical CABG SYNTAX score. The logistic clinical SYNTAX was significantly better at predicting 2-year mortality, compared to the anatomical CABG SYNTAX score, as evidenced by AUC values in receiver-operating characteristic curve analysis (0.806 vs. 0.582, p < .001) and integrated discrimination improvement (0.121, p < .001).

Conclusions: The logistic clinical SYNTAX score was superior to the anatomical CABG SYNTAX score in predicting 2-year mortality.
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http://dx.doi.org/10.1002/ccd.28898DOI Listing
November 2020

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb.

Nat Commun 2020 03 11;11(1):1315. Epub 2020 Mar 11.

Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.

Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Platelet-neutrophil interaction is a crucial process during inflammation, yet its consequences are not fully understood. Here, we show that platelet-neutrophil complexes (PNCs) are increased in patients with acute myocardial infarction and that this is associated with increased levels of neuronal guidance protein semaphorin 7A (SEMA7A). To investigate this further, we injected WT animals with Sema7a and found increased infarct size with increased numbers of PNCs. Experiments in genetically modified animals identify Sema7a on red blood cells to be crucial for this condition. Further studies revealed that Sema7a interacts with the platelet receptor glycoprotein Ib (GPIb). Treatment with anti-Sema7a antibody protected from myocardial tissue injury. In summary, we show that Sema7a binds to platelet GPIb and enhances platelet thrombo-inflammatory activity, aggravating post-ischemic myocardial tissue injury.
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http://dx.doi.org/10.1038/s41467-020-14958-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066172PMC
March 2020

Platelet Inhibition in Acute Coronary Syndrome and Percutaneous Coronary Intervention: Insights from the Past and Present.

Thromb Haemost 2020 Apr 19;120(4):565-578. Epub 2020 Feb 19.

Department of Cardiology and Angiology, University Hospital, Eberhard-Karls-University Tuebingen, Tuebingen, Germany.

Platelet activation and aggregation have a pivotal role in arterial thrombosis and in the pathogenesis of both acute coronary syndromes (ACS) and in the thrombotic complications that occur in patients undergoing percutaneous coronary intervention (PCI). The past 30 years has seen the progress from early trials of clopidogrel and glycoprotein IIb/IIIa inhibitors to the application of more potent P2Y inhibitors prasugrel and ticagrelor. Early enthusiasm for newer and more potent antiplatelet agents, which could reduce ischemic events, has led to the understanding of the importance of bleeding and a desire to individualize and optimize treatment. It has increasingly become apparent that the potency and duration of dual antiplatelet therapy (DAPT) has to reflect the balance between ischemic and bleeding risk. Recently, multiple strategies have been proposed to individualize DAPT intensity and duration to reduce the bleeding and ischemic risks. Strategies of de-escalation of DAPT intensity, as well as shorter (less than a year) or more prolonged (beyond a year) treatment have been proposed, as well as platelet function test and genotype guidance of P2Y inhibitor therapy. Herein, we provide an overview of the progress in the field of antiplatelet therapy for ACS and PCI over the years, showing the current directions of travel. Ongoing studies focusing on personalized antiplatelet treatment will hopefully yield further insight into ways of optimizing outcomes for the individual.
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http://dx.doi.org/10.1055/s-0040-1702920DOI Listing
April 2020

Long-term outcome after thrombus aspiration in non-ST-elevation myocardial infarction: results from the TATORT-NSTEMI trial : Thrombus aspiration in acute myocardial infarction.

Clin Res Cardiol 2020 Oct 6;109(10):1223-1231. Epub 2020 Feb 6.

Department of Internal Medicine/Cardiology, Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute, Strümpellstr. 39, 04289, Leipzig, Germany.

Aims: To investigate the long-term prognostic value of aspiration thrombectomy in conjunction with primary percutaneous coronary intervention (PCI) compared to conventional PCI in patients with non-ST-elevation myocardial infarction (NSTEMI).

Methods: In the randomized TATORT-NSTEMI (Thrombus aspiration in thrombus containing culprit lesions in non-ST-elevation myocardial infarction) trial, NSTEMI patients with thrombus containing culprit lesions were randomized to either PCI with aspiration thrombectomy or conventional PCI. The endpoint was a combination of all-cause death, reinfarction and new congestive heart failure.

Results: From 440 patients initially randomized, outcome data were available in 432 (98.2%) patients at a median follow-up of 4.9 (interquartile range [IQR] 4.4-5.0) years. Thrombectomy was associated with a significant reduction of the combined endpoint compared to conventional PCI (19.9% vs. 30.7%, p = 0.01). This finding was primarily driven by a reduced rate of reinfarction with thrombectomy (3.4% vs. 10.3%, p = 0.01). Thrombectomy was still independently associated with the combined endpoint after multivariable adjustment (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.30-0.76, p = 0.002). Findings were consistent across all analyzed subgroups (p values for interaction all > 0.05).

Conclusions: In NSTEMI, thrombus aspiration is associated with favorable clinical outcome during long-term follow-up.

Clinical Trial Registration: NCT01612312.
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http://dx.doi.org/10.1007/s00392-020-01613-0DOI Listing
October 2020

Performance of two Methods for Cardiac MRI Edema Mapping: Dual-Contrast Fast Spin-Echo and T2 Prepared Balanced Steady State Free Precession.

Rofo 2020 Jul 4;192(7):669-677. Epub 2020 Feb 4.

Diagnostic and Interventional Radiology, University of Tübingen, Germany.

Purpose:  To compare true positive and false negative results of myocardial edema mapping in two methods. Myocardial edema may be difficult to detect on cardiac MRI.

Materials And Methods:  76 patients (age 59 ± 11 years, 15 female) with acute myocardial infarction (MI) and 10 healthy volunteers were prospectively included in this single-center study. 1.5 T cardiac MRI was performed in patients 2.5 days after revascularization (median) for edema mapping: Steady State Free Precession (SSFP) mapping sequence with T-preparation pulses (Tprep); and dual-contrast Fast Spin-Echo (dcFSE) signal decay edema mapping. Late gadolinium enhancement (LGE) was used as the reference for expected edema in acute MI.

Results:  311 myocardial segments in patients were acutely infarcted with mean T 73 ms for Tprep SSFP vs. 87 ms for dcFSE edema mapping. In healthy volunteers the mean T was 56 ms for Tprep SSFP vs. 50 ms for dcFSE edema mapping. Receiver operating characteristic (ROC) curve for Tprep SSFP show area under the curve (AUC) 0.962, p < 0.0001, Youden index J 0.8266, associated criterion > 60 ms, sensitivity 94 %, specificity 89 %. dcFSE ROC AUC 0.979, p < 0.0001, J 0.9219, associated criterion > 64 ms, sensitivity 93 %, specificity 99 %.

Conclusion:  Both edema mapping methods indicate high-grade edema with high sensitivity. Nevertheless, edema in acute infarction may be focally underestimated in both mapping methods.

Key Points:   · Sensitivity for edema detection is high for both methods.. · Edema may be focally underestimated by T2prep SSFP edema mapping and dcFSE mapping..

Citation Format: · Krumm P, Martirosian P, Rath D et al. Performance of two Methods for Cardiac MRI Edema Mapping: Dual-Contrast Fast Spin-Echo and T2 Prepared Balanced Steady State Free Precession. Fortschr Röntgenstr 2020; 192: 669 - 677.
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http://dx.doi.org/10.1055/a-1088-3478DOI Listing
July 2020

Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease.

Nat Rev Cardiol 2020 04 17;17(4):242-257. Epub 2020 Jan 17.

Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA.

Advances in antiplatelet therapies for patients with cardiovascular disease have improved patient outcomes over time, but the challenge of balancing the risks of ischaemia and bleeding remains substantial. Moreover, many patients with cardiovascular disease have a residual risk of ischaemic events despite receiving antiplatelet therapy. Therefore, novel strategies are needed to prevent clinical events through mechanisms beyond platelet inhibition and with an acceptable associated risk of bleeding. The advent of non-vitamin K antagonist oral anticoagulants, which attenuate fibrin formation by selective inhibition of factor Xa or thrombin, has renewed the interest in dual-pathway inhibition strategies that combine an antiplatelet agent with an anticoagulant drug. In this Review, we highlight the emerging pharmacological rationale and clinical development of dual-pathway inhibition strategies for the prevention of atherothrombotic events in patients with different manifestations of cardiovascular disease, such as coronary artery disease, cerebrovascular disease and peripheral artery disease.
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http://dx.doi.org/10.1038/s41569-019-0314-yDOI Listing
April 2020

Smoking and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients: a substudy from the randomized TROPICAL-ACS trial.

Eur Heart J Cardiovasc Pharmacother 2020 11;6(6):372-381

Department of Cardiology, Ludwig-Maximilians University, Marchioninistraße 15, 81377 Munich, Germany.

Aims: Prior analyses disclosed variations in antiplatelet drug response and clinical outcomes between smokers and non-smokers, thus the safety and efficacy of any dual antiplatelet therapy (DAPT) de-escalation strategy may differ in relation to smoking status. Hence, we assessed the impact of smoking on clinical outcomes and adenosine diphosphate-induced platelet aggregation following guided de-escalation of DAPT in invasively managed acute coronary syndrome (ACS) patients.

Methods And Results: The multicentre TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to standard treatment with prasugrel for 12 months (control group) or a platelet function testing guided de-escalation of DAPT. Current smokers (n = 1182) showed comparable event rates between study groups [6.6% vs. 6.6%; hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.64-1.56, P > 0.99]. In non-smokers (n = 1428), a guided DAPT de-escalation was associated with a lower 1-year incidence of the primary endpoint [cardiovascular death, myocardial infarction, stroke, or bleeding ≥ Grade 2 according to Bleeding Academic Research Consortium (BARC) criteria] compared with control group patients (7.9% vs. 11.0%; HR 0.71, 95% CI 0.50-0.99, P = 0.048). This reduction was mainly driven by a lower rate of BARC ≥ Grade 2 bleedings (5.2% vs. 7.7%; HR 0.68, 95% CI 0.45-1.03, P = 0.066). There was no significant interaction of smoking status with treatment effects of guided DAPT de-escalation (Pint = 0.23). Adenosine diphosphate-induced platelet aggregation values were higher in current smokers [median 28 U, interquartile range (IQR: 20-40)] vs. non-smoker [median 24 U (16-25), P < 0.0001] in the control group and in current smokers [median 42 U, IQR (27-68)] vs. non-smoker [median 37 U, IQR (25-55), P < 0.001] in the monitoring group.

Conclusion: Guided DAPT de-escalation appears to be equally safe and effective in smokers and non-smokers. Regardless of smoking status and especially for those patients deemed unsuitable for 1 year of potent platelet inhibition this DAPT strategy might be used as an alternative antiplatelet treatment regimen.
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http://dx.doi.org/10.1093/ehjcvp/pvz084DOI Listing
November 2020

Ticagrelor monotherapy beyond one month after PCI in ACS or stable CAD in elderly patients: a pre-specified analysis of the GLOBAL LEADERS trial.

EuroIntervention 2020 Apr 3;15(18):e1605-e1614. Epub 2020 Apr 3.

Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands.

Aims: Antiplatelet treatment in the elderly post percutaneous coronary interventions (PCI) remains a complex issue. Here we report the results of the pre-specified subgroup analysis of the GLOBAL LEADERS trial evaluating the long-term safety and cardiovascular efficacy of ticagrelor monotherapy among patients categorised according to the pre-specified cut-off value of 75 years of age.

Methods And Results: This was a pre-specified analysis of the randomised GLOBAL LEADERS trial (n=15,991), comparing 23-month ticagrelor monotherapy (after one month of DAPT) with the reference treatment (12-month DAPT followed by 12 months of aspirin). Among elderly patients (>75 years; n=2,565), the primary endpoint (two-year all-cause mortality or new Q-wave core lab-adjudicated myocardial infarction [MI]) occurred in 7.2% and 9.4% of patients in the ticagrelor monotherapy and the reference group, respectively (hazard ratio [HR] 0.75, 95% confidence interval [CI]: 0.58-0.99, p=0.041; pint=0.23); BARC-defined bleeding type 3/5 occurred in 5.2% and 4.1%, respectively (HR 1.29, 95% CI: 0.89-1.86; p=0.180; pint=0.06). The elderly with stable CAD had a higher rate of BARC 3/5 type bleeding (HR 2.05, 95% CI: 1.18-3.55) with ticagrelor monotherapy versus the reference treatment (pint=0.02). Elderly patients had a lower rate of definite or probable stent thrombosis (ST) with ticagrelor monotherapy (0.4% vs 1.4%, p=0.015, pint=0.01), compared with the reference group.

Conclusions: In this pre-specified, exploratory analysis of the overall neutral trial, there was no differential treatment effect of ticagrelor monotherapy (after one-month dual therapy with aspirin) found in elderly patients undergoing PCI with respect to the rate of the primary endpoint of all-cause death or new Q-wave MI. The lower rate of ST in the elderly with ticagrelor monotherapy is hypothesis-generating. ClinicalTrials.gov identifier: NCT01813435.
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http://dx.doi.org/10.4244/EIJ-D-19-00699DOI Listing
April 2020

Pivotal role of PDK1 in megakaryocyte cytoskeletal dynamics and polarization during platelet biogenesis.

Blood 2019 11;134(21):1847-1858

Department of Cardiology, Angiology, and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany.

During thrombopoiesis, megakaryocytes (MKs) form proplatelets within the bone marrow (BM) and release platelets into BM sinusoids. Phosphoinositide-dependent protein kinase-1 (PDK1) is required for Ca2+-dependent platelet activation, but its role in MK development and regulation of platelet production remained elusive. The present study explored the role of PDK1 in the regulation of MK maturation and polarization during thrombopoiesis using a MK/platelet-specific knockout approach. Pdk1-deficient mice (Pdk1-/-) developed a significant macrothrombocytopenia as compared with wild-type mice (Pdk1fl/fl). Pdk1 deficiency further dramatically increased the number of MKs without sinusoidal contact within the BM hematopoietic compartment, resulting in a pronounced MK hyperplasia and a significantly increased extramedullary thrombopoiesis. Cultured Pdk1-/- BM-MKs showed impaired spreading on collagen, associated with an altered actin cytoskeleton structure with less filamentous actin (F-actin) and diminished podosome formation, whereas the tubulin cytoskeleton remained unaffected. This phenotype was associated with abrogated phosphorylation of p21-activated kinase (PAK) as well as its substrates LIM domain kinase and cofilin, supporting the hypothesis that the defective F-actin assembly results from increased cofilin activity in Pdk1-deficient MKs. Pdk1-/- BM-MKs developed increased ploidy and exhibited an abnormal ultrastructure with disrupted demarcation membrane system (DMS). Strikingly, Pdk1-/- BM-MKs displayed a pronounced defect in DMS polarization and produced significantly less proplatelets, indicating that PDK1 is critically required for proplatelet formation. In human MKs, genetic PDK1 knockdown resulted in increased maturity but reduced platelet-like particles formation. The present observations reveal a pivotal role of PDK1 in the regulation of MK cytoskeletal dynamics and polarization, proplatelet formation, and thrombopoiesis.
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http://dx.doi.org/10.1182/blood.2019000185DOI Listing
November 2019

Platelet surface expression of cyclophilin A is associated with increased mortality in patients with symptomatic coronary artery disease.

J Thromb Haemost 2020 01 20;18(1):234-242. Epub 2019 Oct 20.

Department of Cardiology, University Hospital Tübingen, Tübingen, Germany.

Background: Cyclophilin A (CyPA) is an important intracellular molecule mediating essential cellular functions such as signaling and protein folding. Enhanced CyPA platelet surface expression is associated with hypertension and hypercholesterolemia in patients with stable coronary artery disease (CAD). In patients with acute myocardial infarction CyPA platelet surface expression is significantly decreased. The aim of this study was to investigate possible associations of CyPA platelet surface expression and a clinically relevant CyPA single-nucleotide polymorphism (CyPA PPIA rs6850) with prognosis in patients with symptomatic cardiovascular disease.

Materials And Methods: Blood was obtained from 335 consecutive patients with symptomatic CAD. All patients were followed up for 1080 days for endpoints all-cause death, myocardial infarction (MI), ischemic stroke, and bleeding. The primary combined endpoint was defined as a composite of all-cause death and/or MI and/or ischemic stroke. Cyclophilin A platelet surface expression levels less than or equal to the median were significantly associated with a worse prognosis (combined endpoint and all-cause death) when compared to CyPA greater than the median. Genotyping for CyPA PPIA rs6850 was performed in 752 patients with symptomatic CAD. Homozygous carriers of the minor allele showed a significantly worse cumulative event-free survival for both combined endpoint and MI when compared to carriers of the major allele.

Conclusion: The CyPA platelet surface expression is associated with mortality whereas CyPA PPIA rs6850 is associated with recurrent MI in patients with symptomatic CAD. Cyclophilin A might offer a new biomarker for risk stratification and tailoring therapies in patients with cardiovascular disease.
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http://dx.doi.org/10.1111/jth.14635DOI Listing
January 2020

Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.

Eur Heart J Cardiovasc Pharmacother 2020 07;6(4):203-210

Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA.

Aims: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.

Methods And Results: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.

Conclusion: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
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http://dx.doi.org/10.1093/ehjcvp/pvz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363022PMC
July 2020

Thrombogenicity and Antithrombotic Strategies in Structural Heart Interventions and Nonaortic Cardiac Device Therapy-Current Evidence and Practice.

Thromb Haemost 2019 10 17;119(10):1590-1605. Epub 2019 Aug 17.

Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands.

As the number of, and the indications for, structural heart interventions are increasing worldwide, the optimal secondary prevention to reduce device thrombosis is becoming more important. To date, most of the recommendations are empiric. The current review discusses mechanisms behind device-related thrombosis, the available evidence with regard to antithrombotic regimen after cardiac device implantation, as well as providing an algorithm for identification of risk factors for device thrombogenicity and for management of device thrombosis after implantation of patent foramen ovale and left atrial appendage occluders, MitraClips/transcatheter mitral valve replacement, pacemaker leads, and left ventricular assist devices. Of note, the topic of antithrombotic therapy and thrombogenicity of prostheses in aortic position (transcatheter aortic valve replacement, surgical, mechanical, and bioprostheses) is not part of the present article and is discussed in detail in other contemporary focused articles.
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http://dx.doi.org/10.1055/s-0039-1694751DOI Listing
October 2019

Atrial fibrosis and its implications on a revised ESUS concept.

Neurology 2019 07 25;93(4):141-142. Epub 2019 Jun 25.

From the Department of Neurology With Focus on Neurovascular Diseases and Neurooncology (S.P., P.B.), Hertie Institute for Clinical Brain Research (S.P., P.B.), and Department of Cardiology (T.G.), University Hospital Tübingen, Germany.

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http://dx.doi.org/10.1212/WNL.0000000000007823DOI Listing
July 2019

Gender and Outcomes following Guided De-Escalation of Antiplatelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Gender Substudy.

Thromb Haemost 2019 Sep 21;119(9):1527-1538. Epub 2019 Jun 21.

Department of Cardiology and Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany.

Objectives:  This prespecified analysis of the TROPICAL-ACS trial aimed to assess the impact of gender on clinical outcomes and platelet reactivity (PR) following guided de-escalation of dual antiplatelet treatment (DAPT) in acute coronary syndrome (ACS) patients.

Background:  Guided de-escalation of DAPT was recently identified as an effective alternative treatment strategy in ACS.

Methods:  We used Cox proportional hazards models and linear regression analysis to assess the interaction of gender with clinical endpoints and PR.

Results:  In both male ( = 2,052) and female ( = 558) patients, the 1-year incidence of the primary endpoint did not differ in guided de-escalation versus control group patients (male: 7.0% vs. 9.0%; hazard ratio [HR], 0.78, 95% confidence interval [CI], 0.57-1.06,  = 0.11; female: 8.4% vs. 9.2%; HR, 0.92, 95% CI, 0.53-1.62,  = 0.76, = 0.60). The 1-year incidence of combined ischemic events (male: 2.5% vs. 3.3%; HR, 0.76, 95% CI, 0.46-1.26,  = 0.29; female: 2.2% vs. 2.8%; HR, 0.78,95% CI, 0.27-2.25,  = 0.65, = 0.96) as well as Bleeding Academic Research Consortium ≥ 2 bleeding (male: 4.6% vs. 6.0%; HR, 0.77, 95% CI, 0.52-1.12,  = 0.17; female: 6.2% vs. 6.4%; HR, 0.99, 95% CI, 0.51-1.92,  = 0.97, = 0.51) was similar in the guided de-escalation versus control group for both male and female patients. Interaction testing revealed no significant impact of gender on PR levels (prasugrel or clopidogrel) across treatment groups ( = 0.72).

Conclusion:  Guided de-escalation of DAPT appears to be equally safe and effective in women and men. Especially in patients with increased bleeding risk and independent from gender, a guided DAPT de-escalation strategy may be used as an alternative treatment strategy.

Clinical Trial Registration:  URL: https//www.clinicaltrials.gov. Unique Identifier: NCT: 01959451.
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http://dx.doi.org/10.1055/s-0039-1692441DOI Listing
September 2019

Platelet reactivity and clinical outcomes in acute coronary syndrome patients treated with prasugrel and clopidogrel: a pre-specified exploratory analysis from the TROPICAL-ACS trial.

Eur Heart J 2019 06;40(24):1942-1951

Department of Cardiology, LMU München, Munich, Germany.

Aims: The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel.

Methods And Results: Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2-5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57-1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47-1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01-4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18-2.56), P = 0.005], without interaction (Pint = 0.76) between study groups.

Conclusion: Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.
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http://dx.doi.org/10.1093/eurheartj/ehz202DOI Listing
June 2019

Time-Dependent Myocardial Necrosis in Patients With ST-Segment-Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI-SCAR Project.

J Am Heart Assoc 2019 06 11;8(12):e012429. Epub 2019 Jun 11.

5 Department of Cardiology Robert Bosch Medical Center Stuttgart Germany.

Background Acute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction ( MI ) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with  high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST -segment-elevation MI with <12 hours of symptom onset. We sought to visualize time-dependent necrosis in a population with ST -segment-elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI-SCAR project). Methods and Results ST -segment-elevation MI patients with single-vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset <12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0-50%, 51-75%, 76-100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom-to-balloon time of 121 minutes: patients with >121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P<0.01) and decreased myocardial salvage index ( P<0.001) versus patients with symptom-to-balloon times ≤121 minutes. Conclusions In MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom-to-balloon time of >121 minutes causes a high grade of transmural necrosis. In this pure ST -segment-elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.
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http://dx.doi.org/10.1161/JAHA.119.012429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645633PMC
June 2019

Effect of Bruton's tyrosine kinase inhibitors on platelet aggregation in patients with acute myocardial infarction.

Thromb Res 2019 Jul 24;179:64-68. Epub 2019 Apr 24.

Norwich Medical School, University of East Anglia and Norfolk and Norwich University Hospital, Norwich, Norfolk, United Kingdom; Norfolk and Norwich University Hospital, Colney Lane, Norwich, Norfolk, United Kingdom. Electronic address:

Aims: Despite widespread use of dual antiplatelet therapy in acute myocardial infarction, there remains a residual risk of morbidity and mortality. Bruton's Tyrosine Kinase inhibitors have been found to inhibit platelet aggregation through the Glycoprotein VI collagen-mediated pathway. The Bruton's Tyrosine Kinase inhibitor, Ibrutinib is used in the management of haematological malignancies and another Bruton's Tyrosine Kinase inhibitor, ONO-4059 (also known as tirabrutinib), is in clinical development. This is an observational study to evaluate the effects of Ibrutinib and ONO-4059 on platelet aggregation after acute myocardial infarction.

Methods And Results: Twenty patients with a confirmed diagnosis of acute myocardial infarction were enrolled and blood samples obtained within 48 h of hospital admission. All patients were on dual antiplatelet therapy; aspirin plus a P2Y12 inhibitor (clopidogrel or ticagrelor). Blood samples were treated ex vivo with increasing concentrations of Ibrutinib (0, 0.5, 1, 2 μM) and ONO-4059 (0, 0.2, 0.5, 1 μM). Platelet aggregation was measured in response to collagen using a Multiplate analyser to estimate the area under the curve, with lower values indicating lower platelet aggregation. The median age was 63 years and 80% were male. The median area under the curve values for Ibrutinib concentrations 0 (control), 0.5, 1 and 2 μM were 18.5, 8 (P = 0.0004), 4.5 (P < 0.0001) and 2 (P < 0.0001) units and for ONO-4059 concentrations 0 (control), 0.2, 0.5 and1μM, median area under the curve values were 13, 12 (P = 0.7), 6.5 (P = 0.0001) and 5.5 (P = 0.0004 compared to control).

Conclusion: The Bruton's Tyrosine Kinase inhibitors, Ibrutinib and ONO-4059, show further inhibition of platelet aggregation in blood samples from patients with acute myocardial infarction, receiving dual antiplatelet therapy in a dose dependent manner. These results provide a rationale for Bruton's Tyrosine Kinase inhibitors to be tested as a potential new antiplatelet strategy for acute myocardial infarction.
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http://dx.doi.org/10.1016/j.thromres.2019.04.024DOI Listing
July 2019

Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.

Nat Med 2019 04 1;25(4):641-655. Epub 2019 Apr 1.

Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
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http://dx.doi.org/10.1038/s41591-019-0379-5DOI Listing
April 2019

Dual Antiplatelet or Dual Antithrombotic Therapy for Secondary Prevention in High-Risk Patients with Stable Coronary Artery Disease?

Thromb Haemost 2019 10 5;119(10):1583-1589. Epub 2019 Mar 5.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.

Antithrombotic treatment is a key component of secondary prevention following acute coronary syndromes (ACS). Although dual antiplatelet therapy is standard therapy post-ACS, duration of treatment is the subject of ongoing debate. Prolonged dual antiplatelet therapy in high-risk patients with history of myocardial infarction reduced the risk of recurrent myocardial infarction, stroke or cardiovascular death. Similarly, in patients with stable coronary artery disease, two-thirds of whom had a history of myocardial infarction, dual antithrombotic therapy with very-low-dose rivaroxaban and aspirin also resulted in improved ischaemic outcomes. In the absence of head-to-head comparison, choosing the most appropriate treatment strategy can be challenging, particularly when it comes to balancing the risks of ischaemia and bleeding. We aim to review the evidence for currently available antithrombotic treatments and provide a practical algorithm to aid the decision-making process.
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http://dx.doi.org/10.1055/s-0039-1679903DOI Listing
October 2019