Publications by authors named "Ulrike Flierl"

38 Publications

A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction.

Basic Res Cardiol 2021 Mar 15;116(1):17. Epub 2021 Mar 15.

Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The monocyte β-integrin Mac-1 is crucial for leukocyte-endothelium interaction, rendering it an attractive therapeutic target for acute and chronic inflammation. Using phage display, a Designed-Ankyrin-Repeat-Protein (DARPin) was selected as a novel binding protein targeting and blocking the α I-domain, an activation-specific epitope of Mac-1. This DARPin, named F7, specifically binds to activated Mac-1 on mouse and human monocytes as determined by flow cytometry. Homology modelling and docking studies defined distinct interaction sites which were verified by mutagenesis. Intravital microscopy showed reduced leukocyte-endothelium adhesion in mice treated with this DARPin. Using mouse models of sepsis, myocarditis and ischaemia/reperfusion injury, we demonstrate therapeutic anti-inflammatory effects. Finally, the activated Mac-1-specific DARPin is established as a tool to detect monocyte activation in patients receiving extra-corporeal membrane oxygenation, as well as suffering from sepsis and ST-elevation myocardial infarction. The activated Mac-1-specific DARPin F7 binds preferentially to activated monocytes, detects inflammation in critically ill patients, and inhibits monocyte and neutrophil function as an efficient new anti-inflammatory agent.
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http://dx.doi.org/10.1007/s00395-021-00849-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960600PMC
March 2021

Standardized secondary prevention in patients with ST-elevation myocardial infarction.

Eur J Prev Cardiol 2020 Oct 7. Epub 2020 Oct 7.

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.

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http://dx.doi.org/10.1093/eurjpc/zwaa078DOI Listing
October 2020

Neuromarkers and neurological outcome in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia-experience from the HAnnover COoling REgistry (HACORE).

PLoS One 2021 7;16(1):e0245210. Epub 2021 Jan 7.

Cardiac Arrest Centre, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Neuron-specific enolase (NSE) and S-100b have been used to assess neurological damage following out-of-hospital cardiac arrest (OHCA). Cut-offs were derived from small normothermic cohorts. Whether similar cut-offs apply to patients treated with hypothermia remained undetermined.

Methods: We investigated 251 patients with OHCA treated with hypothermia but without routine prognostication. Neuromarkers were determined at day 3, neurological outcome was assessed after hospital discharge by cerebral performance category (CPC).

Results: Good neurological outcome (CPC≤2) was achieved in 41%. Elevated neuromarkers, older age and absence of ST-segment elevation after ROSC were associated with increased mortality. Poor neurological outcome in survivors was additionally associated with history of cerebrovascular events, sepsis and higher admission lactate. Mean NSE was 33μg/l [16-94] vs. 119μg/l [25-406]; p<0.001, for survivors vs. non-survivors, and 21μg/l [16-29] vs. 40μg/l [23-98], p<0.001 for good vs. poor neurological outcome. S-100b was 0.127μg/l [0.063-0.360] vs. 0.772μg/l [0.121-2.710], p<0.001 and 0.086μg/l [0.061-0.122] vs. 0.138μg/l [0.090-0.271], p = 0.009, respectively. For mortality, thresholds of 36μg/l for NSE and 0.128μg/l for S-100b could be determined; for poor neurological outcome 33μg/l (NSE) and 0.123μg/l (S-100b), respectively. Positive predictive value for NSE was 81% (74-88) and 79% (71-85) for S-100b.

Conclusions: Thresholds for NSE and S-100b predicting mortality and poor neurological outcome are similar in OHCA patients receiving therapeutic hypothermia as in those reported before the era of hypothermia. However, both biomarkers do not have enough specificity to predict mortality or poor neurological outcome on their own and should only be additively used in clinical decision making.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245210PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790428PMC
January 2021

Early use of hemoadsorption in patients after out-of hospital cardiac arrest - a matched pair analysis.

PLoS One 2020 3;15(11):e0241709. Epub 2020 Nov 3.

Department of Cardiology and Angiology, Cardiac Arrest Centre, Hannover Medical School, Hannover, Germany.

Background: Pro- and anti-inflammatory mediators are released during and after cardiac arrest, which may be unfavourable. Small case-series and observational studies suggested that unselective hemoadsorption may reduce inadequately high cytokine levels during sepsis or cardiac surgery. We aimed to assess the effect of cytokine adsorbtion on mortality in patients following out-of-hospital cardiac arrest by comparing a patient cohort with hemoadsorption after resuscitation for out-of-hospital cardiac arrest to a control cohort without adsorption within the HAnnover COling REgistry (HACORE).

Methods: We adopted an early routine use of hemoadsorption in patients after out-of-hospital cardiac arrest with increased vasopressor need and performed a 1:2 match according to age, gender, time to return of spontaneous circulation, initial left-ventricular ejection fraction, extracorporeal membrane-oxygenation or left-ventricular unloading by Impella, need for renal replacement therapy, admission lactate, pH, glomerular filtration rate to patients without an adsorber from HACORE. The primary endpoint was 30-day mortality.

Results: Twenty-four patients receiving hemoadsorption were matched to 48 patients without hemoadsorption (mean age 62±13 years, 83% male). While there was no significant difference in baseline parameters, 30-day mortality was higher in patients treated with hemoadsorption than in the matched control group (83% vs 65%, Log rank p = 0.011).

Conclusions: Routine use of hemoadsorption did not reduce, but seems to be associated with higher 30-day mortality in patients after OHCA. Prior to routine adoption in daily practice, hemoadsorption should be evaluated in properly sized randomized controlled trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241709PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608917PMC
January 2021

Anti-thrombotic strategies in patients with atrial fibrillation undergoing PCI.

Clin Res Cardiol 2020 Jul 21. Epub 2020 Jul 21.

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.

Triple anti-thrombotic therapy combining oral anticoagulation and dual anti-platelet therapy following percutaneous coronary intervention in patients with atrial fibrillation was considered as standard and recommended by guidelines. While bleeding risk is considerable with that approach, data for efficacy are scare. Several trials assessed the possibility of reducing anti-thrombotic treatment by mainly shortening the exposure to acetylsalicylic acid. Dropping one of the anti-platelet components might increase the risk of stent thrombosis, myocardial infarction or stroke. Despite that fear, the recent trials' primary endpoint was major and/or clinically-relevant non-major bleeding. We review data on major bleedings, intracranial bleedings and major adverse cardiovascular events from the published reports. We demonstrate that Non-Vitamin K oral anticoagulant (NOAC)-based strategies compared to VKA-based triple therapies significantly reduce the risk for TIMI-major bleedings by 39% and for intracranial bleedings by 66%, while they did not increase the risk for overall ischemic or embolic events. However, recent meta-analyses indicate an increased risk for stent thrombosis with less intense anti-thrombotic therapy. While the overall incidence rate for stent thrombosis is rather low, relative increases by about 30-60% are reported, but they did not translate into adverse clinical net-benefit ratios. This review highlights that using certain NOAC regimens proven effective for stroke prevention in AF can reduce the rate of bleeding without increasing ischemic or embolic events. Furthermore, additive ASA in triple anti-thrombotic regimens should be limited to 1 month and individual weighing of ischemic versus bleeding risk during the first 30 days seems to be reasonable.
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http://dx.doi.org/10.1007/s00392-020-01708-8DOI Listing
July 2020

Mechanical circulatory support in refractory cardiogenic shock due to influenza virus-related myocarditis.

Eur Respir J 2020 09 3;56(3). Epub 2020 Sep 3.

Cardiac Arrest Center and Advanced Heart Failure Unit, Dept of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: There is scarce evidence for mechanical circulatory support (MCS) in patients with influenza-related myocarditis complicated by refractory cardiogenic shock (rCS). We sought to investigate the impact of MCS using combined veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and micro-axial flow pumps (the ECMELLA concept) in influenza-related myocarditis complicated by rCS.

Methods: This is a prospective, observational analysis from the single centre HAnnover Cardiac Unloading REgistry (HACURE) from two recent epidemic influenza seasons. We analysed patients with verified influenza-associated myocarditis complicated by rCS who were admitted to our intensive care unit (ICU) on MCS. Subsequently, we performed a propensity score (PS) matched analysis to patients with acute myocardial infarction (AMI) complicated by rCS and non-ischaemic cardiomyopathy (DCM) related rCS.

Results: We describe a series of seven patients with rCS-complicated influenza-related myocarditis (mean age 56±10 years, 58% male, influenza A (n=2)/influenza B (n=5)). No patient had been vaccinated prior to the influenza season. MCS was provided using combined VA-ECMO and Impella micro-axial flow pump. In two patients with out-of-hospital cardiac arrest, VA-ECMO had been implanted for extracorporeal cardiopulmonary resuscitation. All patients died within 18 days of hospital admission. By PS-based comparison to patients with AMI- or DCM-related rCS and combined MCS, 30-day mortality was significantly higher in influenza-related rCS.

Conclusion: Despite initial stabilisation with combined MCS in patients with rCS-complicated influenza-related myocarditis, the detrimental course of shock could not be stopped and all patients died. Influenza virus infection potentially critically affects other organs besides the heart, leading to irreversible end-organ damage that MCS cannot compensate for and, therefore, results in a devastating outcome.
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http://dx.doi.org/10.1183/13993003.00925-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469974PMC
September 2020

Anticoagulants for Stroke Prevention in Atrial Fibrillation in Elderly Patients.

Cardiovasc Drugs Ther 2020 08;34(4):555-568

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30659, Hannover, Germany.

Ischaemic stroke and systemic embolism are the major potentially preventable complications of atrial fibrillation (AF) leading to severe morbidity and mortality. Anticoagulation using vitamin K antagonists (VKA) or non-vitamin K oral anticoagulants (NOACs) is mandatory for stroke prevention in AF. Following approval of the four NOACs dabigatran, rivaroxaban, apixaban, and edoxaban, the use of VKA is declining steadily. Increasing age with thresholds of 65 and 75 years is a strong risk factor when determining annual stroke risk in AF patients. Current recommendations such as the "2016 Guidelines for the management of atrial fibrillation" of the European Society of Cardiology and the "2019 AHA/ACC/HRS Focused Update" by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society strengthen the importance of anticoagulation and detection of bleeding risks, of which older age is an important one. While patients aged ≥ 75 years are usually underrepresented in randomised clinical trials, they represent almost 40% of the trial populations in the large NOAC approval studies. Therefore, a sufficient amount of data is available to assess the efficacy and safety for this patient cohort in that specific indication. In this article, the evidence for stroke prevention in AF using either VKA or NOACs is summarised with a special focus on efficacy compared to bleeding risk in patients aged ≥ 75 years. Specifically, we used a model of increased weighing of intracranial bleeding to illustrate the potential benefit of NOACs over VKA in the elderly population. In brief, there are at least two tested strategies with apixaban and edoxaban which even confer an additional clinical net benefit compared with VKA. Furthermore, elderly subgroups of trials for combined antithrombotic treatment following percutaneous coronary interventions in anticoagulated patients are analysed.
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http://dx.doi.org/10.1007/s10557-020-06981-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334273PMC
August 2020

Early Escalation of Mechanical Circulatory Support Stabilizes and Potentially Rescues Patients in Refractory Cardiogenic Shock.

Circ Heart Fail 2020 03 13;13(3):e005853. Epub 2020 Mar 13.

Departments of Cardiology and Angiology (J.T., J.-T.S., L.C.N., U.F., P.R., J.B., A.S.), Hannover Medical School, Germany.

Background: Limited progress has been made in the management of cardiogenic shock (CS). Morbidity and mortality of refractory CS remain high. The effects of mechanical circulatory support (MCS) are promising, although many aspects are elusive. We evaluated efficacy and safety of early combined MCS (Impella microaxial pump + venoarterial extracorporeal membrane oxygenation [VA-ECMO]) in refractory CS and aimed to determine factors for decision-making in combined MCS.

Methods And Results: We analyzed 69 consecutive patients with refractory CS from our registry requiring combined MCS. In 12 cases, therapy was actively withdrawn according to patient's will. Patients were severely sick (Survival After Venoarterial ECMO score mean±SD, -8.9±4.4) predicting 30% in-hospital survival; ventilation 94%, dialysis 56%. Impella pumps and VA-ECMO were combined early (duration of combined MCS: median 94 hours; interquartile range, 49-150 hours). Early MCS escalation stabilized patients rapidly, reducing number and doses of catecholamines (<0.05 versus baseline) while hemodynamics improved. Reflecting an improved microcirculation, lactate levels normalized within 24 hours (<0.05 versus baseline). Despite refractory CS and disease severity, survival was favorable (on MCS 61%, 30 days 49%, 6 months 40%). In multivariate Cox-regression, duration of shock-to-first device (hours, hazard ratio, 1.05 [95% CI, 1.01-1.08]; =0.007) and lactate levels after 12 hours of MCS (hazard ratio, 1.28 [95% CI, 1.09-1.51]; =0.002) independently predicted survival. Additional right ventricular failure predisposed to futility (hazard ratio, 8.48 [95% CI, 1.85-38.91]; =0.006).

Conclusions: The early and consequent combination of MCS by Impella microaxial pumps and VA-ECMO enables stabilization and may rescue high-risk patients with refractory CS at low overall risk. Independent predictors of survival may guide prognostication, decision-making, and allocation of medical resources.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005853DOI Listing
March 2020

Response to: Antithrombotic therapy for elderly patients with acute coronary syndrome: reasons to be cautious.

Eur Heart J Cardiovasc Pharmacother 2020 01;6(1):70

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover D-30659, Germany.

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http://dx.doi.org/10.1093/ehjcvp/pvz043DOI Listing
January 2020

Anti-thrombotic strategies in elderly patients receiving platelet inhibitors.

Eur Heart J Cardiovasc Pharmacother 2020 01;6(1):57-68

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, D Hannover, Germany.

Acetyl-salicylic acid is the basic anti-thrombotic therapy used for single anti-platelet therapy in primary as well as secondary prevention of atherosclerotic disease. Dual anti-platelet therapy (DAPT) is the cornerstone of maintenance medication following elective percutaneous coronary intervention or acute coronary syndromes (ST elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina). DAPT duration has been frequently discussed. Currently, guideline recommendations strengthen the importance of individualized treatment to reduce bleeding risk based on clinical predictors, of which older age is an important one. Patients aged ≥75 years are often underrepresented in randomized clinical trials, but present a patient cohort deemed both at heightened ischaemic as well as bleeding risk. We aimed to summarize the evidence or the lack of evidence for anti-platelet treatment strategies in patients aged ≥75 years including combinations with anticoagulants in secondary prevention or coronary interventions in elderly patients with atrial fibrillation. This review article represents the author's interpretation of available data and is not discussed by a formal task force; it is intended to point out missing evidence and to provide age-specific data for individualized decision making, which is currently encouraged by the guidelines.
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http://dx.doi.org/10.1093/ehjcvp/pvz032DOI Listing
January 2020

Successful renal denervation decreases the platelet activation status in hypertensive patients.

Cardiovasc Res 2020 01;116(1):202-210

Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.

Aims: To determine whether renal denervation (RDN) in hypertensive patients affects the platelet activation status.

Methods And Results: We investigated the effect of RDN on the platelet activation status in 41 hypertensive patients undergoing RDN. Ambulatory blood pressure (BP), plasma sympathetic neurotransmitter Neuropeptide Y, and platelet activation markers were measured at baseline, at 3 months, and 6 months after RDN. RDN significantly decreased BP at 3 months (150.6 ± 11.3/80.9 ± 11.4 mmHg to 144.7 ± 12.0/77.1 ± 11.1 mmHg; P < 0.01) and at 6 months (144.3 ± 13.8/78.3 ± 11.1 mmHg; P < 0.01). Plasma levels of the sympathetic neurotransmitter Neuropeptide Y, an indicator of sympathetic nerve activity, were significantly decreased at 3 months (0.29 ± 0.11 ng/mL to 0.23 ± 0.11 ng/mL; P < 0.0001) and at 6 months (0.22 ± 0.12 ng/mL; P < 0.001) after RDN. This was associated with a reduction in platelet membrane P-selectin expression (3 months, P < 0.05; 6 months, P < 0.05), soluble P-selectin (6 months, P < 0.05), circulating numbers of platelet-derived extracellular vesicles (EVs) (3 months, P < 0.001; 6 months, P < 0.01), and phosphatidylserine expressing EVs (3 months, P < 0.001; 6 months, P < 0.0001), indicative of a reduction in platelet activation status and procoagulant activity. Only patients who responded to RDN with a BP reduction showed inhibition of P-selectin expression at 3 months (P < 0.05) and 6 months (P < 0.05) as well as reduction of glycoprotein IIb/IIIa activation at 3 months (P < 0.05). Notably, 13 patients who took aspirin did not show significant reduction in platelet P-selectin expression following RDN.

Conclusion: Our results imply a connection between the sympathetic nervous system and the platelet activation status and provide a potential mechanistic explanation by which RDN can have favourable effects towards reducing cardiovascular complications.
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http://dx.doi.org/10.1093/cvr/cvz033DOI Listing
January 2020

Safe Exchange of a Transfemoral Impella Pump.

Cardiovasc Revasc Med 2019 09 19;20(9):827-828. Epub 2018 Dec 19.

Cardiac Arrest Center, Advanced Heart Failure Unit, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Mechanical circulatory support with the Impella pump is established in many centers treating patients with cardiogenic shock. While Impella pumps usually run very stable, it may still be possible that one needs to remove the pump for using the same vascular access for different reasons. Unfortunately, until now it had been nearly impossible to remove the pump while preserving arterial access without severe bleeding. Here we describe a prototypical approach of exchanging an Impella pump in a 47-year-old female supported with veno-arterial ECMO for cardiogenic shock from myocarditis. The dysfunctional Impella pump was safely removed and replaced by a new one through the same arterial access site. Continuation of active LV unloading resolved pulmonary edema, and the patient was finally bridged to ventricular assist device surgery with favorable outcome. In general, the described approach is applicable for virtually all large-bore devices with arterial access.
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http://dx.doi.org/10.1016/j.carrev.2018.12.006DOI Listing
September 2019

Mortality in Patients With Out-of-Hospital Cardiac Arrest Undergoing a Standardized Protocol Including Therapeutic Hypothermia and Routine Coronary Angiography: Experience From the HACORE Registry.

JACC Cardiovasc Interv 2018 09;11(18):1811-1820

Cardiac Arrest Centre, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. Electronic address:

Objectives: This study sought to analyze the impact of mandatory therapeutic hypothermia and cardiac catheterization in the absence of overt noncardiac cause of arrest as part of the Hannover Cardiac Resuscitation Algorithm before intensive care admission.

Background: Despite advanced therapies, out-of-hospital cardiac arrest (OHCA) is still associated with high mortality rates. Recently, the TTM (Target Temperature Management 33°C Versus 36°C After Out-of-Hospital Cardiac Arrest)-trial caused severe uncertainty about the efficacy of and need for therapeutic hypothermia. Furthermore, the role of early coronary angiography in OHCA survivors without ST-segment elevation remains undetermined.

Methods: In the HACORE (HAnnover Cooling REgistry) we investigated 233 consecutive patients (median age 64 [interquartile range: 53 to 74] years) with OHCA admitted to our institution between January 2011 and December 2015 who were treated according to the algorithm.

Results: A total of 73% had ventricular fibrillation as primary rhythm. Return of spontaneous circulation was achieved after 20 (interquartile range: 10 to 30) min. Immediate percutaneous coronary angiography was performed in 96% and coronary angioplasty in 59% of all cases. ST-segment elevation was present in 47%. Critical coronary stenosis requiring percutaneous coronary intervention was present in 67% of patients with and 52% of patients without ST-segment elevation. Overall 30-day intrahospital mortality in this real-world registry was 37%. Patients in our local registry who matched the inclusion/exclusion criteria of the TTM-trial (n = 145) had a markedly lower 30-day mortality (27%) compared with the published trial (44%).

Conclusions: Standardized treatment of patients with OHCA following a strict protocol incorporating computed tomography, cardiac catheterization and revascularization, liberal use of active hemodynamic support in presence of shock, and mandatory therapeutic hypothermia results in mortality rates lower than previously reported.
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http://dx.doi.org/10.1016/j.jcin.2018.06.022DOI Listing
September 2018

The effect of oxygen in Sirt3-mediated myocardial protection: a proof-of-concept study in cultured cardiomyoblasts.

J Thromb Thrombolysis 2018 Jul;46(1):102-112

Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Ramistr. 100, 8098, Zurich, Switzerland.

Sirtuin 3 is a nicotinamide adenine dinucleotide dependent mitochondrial deacetylase that governs mitochondrial metabolism and oxidative defense. The demise in myocardial function following myocardial ischemia has been associated with mitochondrial dysfunction. Sirt3 maintains myocardial contractile function and protects from cardiac hypertrophy. The role of Sirt3 in ischemia is controversial. Our objective was to understand, under what circumstances Sirt3 is protective in different facets of ischemia, using an in vitro proof-of-concept approach based on simulated ischemia in cultured cardiomyoblasts. Cultured H9c2 cardiomyoblasts were subjected to hypoxia and/or serum deprivation, the combination of which we refer to as simulated ischemia. Apoptosis, as assessed by Annexin V staining in life-cell imaging and propidium-iodide inclusion in flow cytometry, was enhanced following simulated ischemia. Interestingly, serum deprivation was a stronger trigger of apoptosis than hypoxia. Knockdown of Sirt3 further increased apoptosis upon serum deprivation, whereas no such effect occurred upon additional hypoxia. Similarly, only upon serum deprivation but not upon simulated ischemia, silencing of Sirt3 led to a deterioration of mitochondrial function in extracellular flux analysis. In the absence of oxygen these Sirt3-dependent effects were abolished. These data indicate, that Sirt3-mediated myocardial protection is oxygen-dependent. Thus, mitochondrial respiration takes center-stage in Sirt3-dependent prevention of stress-induced myocardial damage.
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http://dx.doi.org/10.1007/s11239-018-1677-3DOI Listing
July 2018

Mortality in patients with cardiogenic shock treated with the Impella CP microaxial pump for isolated left ventricular failure.

Eur Heart J Acute Cardiovasc Care 2020 Mar 6;9(2):138-148. Epub 2018 Feb 6.

Cardiac Arrest Centre and Advanced Heart Failure Unit, Department of Cardiology and Angiology, Hannover Medical School, Germany.

Aims: Cardiogenic shock is still associated with high mortality rates of around 50%. Intra-aortic counterpulsation had been frequently used in cardiogenic shock, but was previously found to provide no mortality benefit. We investigated the effect of an interdisciplinary and multiprofessional routine strategy of early invasive haemodynamic support in combination with complete revascularization in patients with cardiogenic shock before admission to our intensive care unit.

Methods And Results: We analysed all cardiogenic shock patients (mean age 62±13 years) presenting at our institution between 2013 and mid 2016, who received an Impella CP microaxial pump for isolated left ventricle support (=61). Sixty-one per cent (=37) had been resuscitated before Impella insertion. Overall mortality was 48% (=29/61) at 30 days. Thirty-day mortality was higher in resuscitated patients (resuscitated: 65% (=24/37); non-resuscitated: 21% (=5/24)). When applying the inclusion/exclusion criteria of the SHOCK-II trial, eligible patients (=25) had a markedly lower mortality (24% (=6/25) at 30 days) compared with the published trial (~40% in both arms). The observed mortality of SHOCK-II-like patients in the registry was also lower compared with their predicted mortality using IABP-Shock II score (49%) and CardShock score (36%).

Conclusion: The results of this registry suggest that using a standardized protocol including early active haemodynamic support with Impella CP in cardiogenic shock in patients with isolated left ventricle failure may be associated with improved outcomes and lower than previously reported or predicted mortality rates. Pre-implantation cardiac arrest critically influences observed mortality. The results support the case for a randomized trial.
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http://dx.doi.org/10.1177/2048872618757393DOI Listing
March 2020

One symptom, two arrhythmias: the rare and the even rarer.

BMC Cardiovasc Disord 2017 Sep 12;17(1):244. Epub 2017 Sep 12.

Department of Cardiology & Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany.

Background: Wolff-Parkinson-White (WPW) syndrome and idiopathic left ventricular tachycardia (ILVT) are rare and up to now the coexistence of both entities has rarely been reported. In patients with ventricular preexcitation the underlying mechanism of paroxysmal tachycardia most likely is atrioventricular reentrant tachycardia (AVRT). However, without ECG documentation of the tachycardia diagnosis of the underlying mechanism cannot be made due to similar clinical presentation of AVRT and ILVT.

Case Presentation: We report a case of a two-staged occurrence of two rare arrhythmias in a young adult, who was admitted to our hospital twice within 6 months because of paroxysmal tachycardia. WPW syndrome and ILVT as underlying arrhythmias have been diagnosed and were ablated successfully.

Conclusions: This case highlights the diagnostic defiance of rare tachycardia entities and the paramount importance of ECG documentation and analysis of all available tachycardia ECGs.
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http://dx.doi.org/10.1186/s12872-017-0679-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596476PMC
September 2017

Acquired von Willebrand syndrome in cardiogenic shock patients on mechanical circulatory microaxial pump support.

PLoS One 2017 14;12(8):e0183193. Epub 2017 Aug 14.

Hannover Medical School, Department of Cardiology and Angiology, Cardiac Arrest Center and Advanced Heart Failure Unit, Hannover, Germany.

Early use of mechanical circulatory support, e.g. veno-arterial extracorporeal membrane oxygenation (ECMO) or left ventricular unloading by microaxial pump in refractory cardiogenic shock is recommended in current guidelines. Development of acquired von Willebrand Syndrome (AVWS) in patients with left ventricular assist devices (LVADs) and ECMO has been reported. There is an increasing number of patients treated with the Impella® CP microaxial pump for left ventricular unloading. However, the prevalence of AVWS in these high risk patients is unknown and needs to be determined. We therefore screened 21 patients (68 ± 11years) treated with Impella® (17 for cardiogenic shock, 4 for protected PCI) for the presence of AVWS by determining von Willebrand factor multimers, VWF collagen binding capacity and VWF antigen. During the time course of Impella® support, 20/21 patients (95%) developed AVWS (mean duration of support: 135 ± 114 hours, mean time from device implantation to first diagnosis of AVWS: 10.6 ± 10.8 hours). Our data indicate that AVWS is a common phenomenon during left ventricular unloading via microaxial pump support. Thus, AVWS has to be considered as contributing factor for potential bleeding complications in this high risk patient population, especially in the context of dual antiplatelet therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183193PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555672PMC
October 2017

A Unique Recombinant Fluoroprobe Targeting Activated Platelets Allows Detection of Arterial Thrombosis and Pulmonary Embolism Using a Novel Three-Dimensional Fluorescence Emission Computed Tomography (FLECT) Technology.

Theranostics 2017 26;7(5):1047-1061. Epub 2017 Feb 26.

Atherothrombosis & Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

Progress in pharmaceutical development is highly-dependent on preclinical animal studies. Small animal imaging is invaluable for the identification of new disease markers and the evaluation of drug efficacy. Here, we report for the first time the use of a three-dimensional fluorescence bioimager called FLuorescence Emission Computed Tomography (FLECT) for the detection of a novel recombinant fluoroprobe that is safe, easily prepared on a large scale and stably stored prior to scan. This novel fluoroprobe (Targ-Cy7) comprises a single-chain antibody-fragment (scFv), which binds exclusively to activated-platelets, conjugated to a near-infrared (NIR) dye, Cy7, for detection. Upon mouse carotid artery injury, the injected fluoroprobe circulates and binds within the platelet-rich thrombus. This specific binding of the fluoroprobe to the thrombus, compared to its non-targeting control-fluoroprobe, is detected by the FLECT imager. The analyzed FLECT image quantifies the NIR signal and localizes it to the site of vascular injury. The detected fluorescence is further verified using a two-dimensional IVIS Lumina scanner, where significant NIR fluorescence is detected at the thrombotic site, and , at the injured carotid artery. Furthermore, fluorescence levels in various organs have also been quantified for biodistribution, with the highest fluoroprobe uptake shown to be in the injured artery. Subsequently, this live animal imaging technique is successfully employed to monitor the response of the induced thrombus to treatment over time. This demonstrates the potential of using longitudinal FLECT scanning to examine the efficacy of candidate drugs in preclinical settings. Besides intravascular thrombosis, we have shown that this non-invasive FLECT-imaging can also detect pulmonary embolism. Overall, this report describes a novel fluorescence-based preclinical imaging modality that uses an easy-to-prepare and non-radioactive recombinant fluoroprobe. This represents a unique tool to study mechanisms of thromboembolic diseases and it will strongly facilitate the testing of antithrombotic drugs. Furthermore, the non-radiation nature, low-cost, high sensitivity, and the rapid advancement of optical scanning technologies make this fluorescence imaging an attractive development for future clinical applications.
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http://dx.doi.org/10.7150/thno.18099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399575PMC
January 2018

Leukocytoclastic vasculitis associated with endocarditis in a patient with transposition of the great arteries and mechanical valve replacement.

Cardiovasc Pathol 2017 Mar - Apr;27:68-70. Epub 2017 Jan 24.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Immunological vascular phenomena can be the initial manifestation of bacterial infection and endocarditis. Here, we report a rare case of leukocytoclastic vasculitis without immune complexes or cryoglobulinemia in a patient with infective endocarditis, congenital heart disease, and a prior mechanical valve replacement. The patient completely recovered following antibiotic therapy, and skin lesions disappeared without immune suppression, which suggested infection-mediated vasculitis. While the treatment of leukocytoclastic vasculitis typically involves immunosuppressive therapy, the treatment for infection-mediated vasculitis is eradication of the infection.
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http://dx.doi.org/10.1016/j.carpath.2017.01.005DOI Listing
March 2017

Renal Denervation Reduces Monocyte Activation and Monocyte-Platelet Aggregate Formation: An Anti-Inflammatory Effect Relevant for Cardiovascular Risk.

Hypertension 2017 02 12;69(2):323-331. Epub 2016 Dec 12.

From the Atherothrombosis and Vascular Biology (M.T.K.Z., J.R., B.L., N.M.H., S.U.E., U.F., K.P.) and Neurovascular Hypertension and Kidney Disease Laboratory (D.H., P.M., Y.S., N.E., R.L., G.W.L., M.D.E., J.D., L.H., M.P.S.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Melbourne (M.T.K.Z., N.M.H., M.P.S., K.P.); Dobney Hypertension Centre, School of Medicine and Pharmacology-Royal Perth Hospital Unit, University of Western Australia, Australia (D.H., P.M., M.P.S.); and Department of Plastic and Hand Surgery, University Medical Centre, Freiburg, Germany (S.U.E.).

Overactivation of renal sympathetic nervous system and low-grade systemic inflammation are common features of hypertension. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been examined. We prospectively investigated the effect of RDN on monocyte activation and inflammation in patients with uncontrolled hypertension scheduled for RDN. Ambulatory blood pressure, monocyte, and monocyte subset activation and inflammatory markers were assessed at baseline, 3 months, and 6 months after procedure in 42 patients. RDN significantly lowered blood pressure at 3 months (150.5±11.2/81.0±11.2 mm Hg to 144.7±11.8/77.9±11.0 mm Hg), which was sustained at 6 months (144.7±13.8/78.6±11.0 mm Hg). Activation status of monocytes significantly decreased at 3 months (P<0.01) and 6 months (P<0.01) after the procedure. In particular, classical monocyte activation was reduced at 6 months (P<0.05). Similarly, we observed a reduction of several inflammatory markers, including monocyte-platelet aggregates (3 months, P<0.01), plasma monocyte chemoattractant protein-1 levels (3 months, P<0.0001; 6 months, P<0.05), interleukin-1β (3 months, P<0.05; 6 months, P<0.05), tumor necrosis factor-α (3 months, P<0.01; 6 months, P<0.05), and interleukin-12 (3 months, P<0.01; 6 months, P<0.05). A positive correlation was observed between muscle sympathetic nerve activity and monocyte activation before and after the procedure. These results indicate that inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08373DOI Listing
February 2017

Efficacy of prasugrel administration immediately after percutaneous coronary intervention in ST-elevation myocardial infarction.

Thromb Haemost 2017 01 13;117(1):99-104. Epub 2016 Oct 13.

Prof. Dr. Andreas Schäfer, Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany, Tel.: +49 511 532 5240, Fax: +49 511 532 8244, E-mail:

Prasugrel, a potent thienopyridine, achieves stronger inhibition of platelet activation than clopidogrel. However, onset of inhibition is significantly delayed in patients with acute ST-elevation myocardial infarction (STEMI), as haemodynamic instability and morphine application seem to exhibit significant influence. Since rapid onset of effect was demonstrated in non-STEMI patients when prasugrel was administered only after percutaneous coronary intervention (PCI) without increasing cardiovascular event rates we assessed the efficacy of prasugrel loading immediately after PCI for STEMI instead of pre-loading before revascularisation. We investigated 50 consecutive patients with acute STEMI (mean age 56 ± 10 years) admitted for primary PCI. Prasugrel efficacy was assessed by platelet reactivity index (PRI; VASP assay) before, 1, 2, 4, 6, 12, and 24 hours following an oral loading dose of 60 mg immediately after PCI. High on-treatment platelet reactivity (HTPR) was defined as PRI>50 %. Prasugrel significantly and rapidly reduced platelet reactivity in acute STEMI patients (p<0.0001 at each time point vs control). Morphine application resulted in a significantly higher HTPR rate among patients having received morphine less than 1 hour before prasugrel loading (p<0.001) while concomitant metoclopramide (MCP) treatment did not significantly affect prasugrel efficacy. In conclusion, in contrast to previous reports describing a significant delay in onset of prasugrel-mediated P2Y inhibition in acute STEMI, we observed a rapid onset with low HTPR rates comparable to those observed in stable non-STEMI patients. Prasugrel administered directly after primary PCI might therefore be a useful therapeutic strategy in patients with STEMI to provide strong and effective P2Y inhibition.
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http://dx.doi.org/10.1160/TH16-07-0569DOI Listing
January 2017

Platelet inhibition with prasugrel in patients with acute myocardial infarction undergoing therapeutic hypothermia after cardiopulmonary resuscitation.

Thromb Haemost 2016 05 21;115(5):960-8. Epub 2016 Jan 21.

Prof. Dr. Andreas Schäfer, Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Carl Neuberg Straße 1, 30625 Hannover, Germany, Tel: +49 511 532 5240; Fax: +49 511 532 8244, E-mail:

Acute myocardial infarction (AMI) is the leading cause for out-of-hospital cardiac arrest. Therapeutic hypothermia improves neurological outcome in combination with early revascularisation, but seems to affect clopidogrel responsiveness. The more potent thienopyridine prasugrel has not yet been sufficiently evaluated during therapeutic hypothermia. We investigated 23 consecutive AMI patients (61 ± 11 years) following out-of-hospital resuscitation undergoing revascularisation and therapeutic hypothermia. Prasugrel efficacy was assessed by the platelet-reactivity-index (PRI) before and 2, 4, 6, 12, 24, 48, and 72 hours (h) following a loading dose of 60 mg via a gastric tube. Mean PRI (± SD) was 70 ± 12 % prior to loading and 60 ± 16 % (2 h, ns), 52 ± 21 % (4 h, p< 0.01), 42 ± 26 % (6 h, p< 0.01), 37 ± 21 % (12 h, p< 0.01), 27 ± 23 % (24 h, p< 0.01), 18 ± 14 % (48 h, p< 0.01), and 13 ± 10 % (72 h, p< 0.01) after loading. Sufficient platelet inhibition occurred later compared to stable AMI patients (6 h vs 2 h); however, high on-treatment platelet reactivity significantly decreased over time and was non-existent after 72 h (PRI> 50 %: 2 h: 72 %, 4 h: 52 %, 6 h: 43 %, 12 h: 29 %, 24 h: 17 %, 48 h: 5 %, 72 h: 0 %). There was no relation between 30-day mortality rate (26 %) and PRI values. Prasugrel significantly reduced platelet reactivity even during vasopressor use, analgosedation and therapeutic hypothermia. Despite a significant delay compared to stable AMI patients, sufficient platelet inhibition was reached in 83 % of patients within 24 h. Therefore, prasugrel administration via gastric tube might be a useful therapeutic strategy in these patients at high risk, providing potent and effective P2Y12 inhibition.
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http://dx.doi.org/10.1160/TH15-07-0599DOI Listing
May 2016

The nitric oxide donor pentaerythritol tetranitrate reduces platelet activation in congestive heart failure.

PLoS One 2015 30;10(4):e0123621. Epub 2015 Apr 30.

Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.

Background: Platelet activation associated with endothelial dysfunction and impaired endogenous platelet inhibition is part of the cardiovascular phenotype of congestive heart failure (CHF) and contributes to the increased risk for thromboembolic complications. Pentaerythritol tetranitrate (PETN) has been shown to release nitric oxide without development of nitrate tolerance. We investigated the effect of chronic PETN treatment on platelet activation and aggregation in an experimental CHF model.

Methods And Results: Chronic ischemic heart failure was induced in male Wistar rats by coronary artery ligation. Starting 7 days thereafter, rats were randomised to placebo or PETN (80 mg/kg twice daily). After 9 weeks, activation of circulating platelets was determined measuring platelet bound fibrinogen, which requires activated glycoprotein IIb/IIIa on the platelet surface. Binding was quantified by flow-cytometry using a FITC-labelled anti-fibrinogen antibody. Platelet-bound fibrinogen was significantly increased in CHF-Placebo (mean fluorescence intensity: Sham 88±4, CHF-Placebo 104±6, p<0.05) and reduced following treatment with PETN (89±7, p<0.05 vs. CHF-Placebo). Maximal and final ADP-induced aggregation was significantly enhanced in CHF-Placebo vs. Sham-operated animals and normalized / decreased following chronic PETN treatment. Moreover, platelet adhesion was significantly reduced (number of adherent platelets: control: 85.6±5.5, PETN: 40±3.3; p<0.001) and VASP phosphorylation significantly enhanced following in vitro PETN treatment.

Conclusion: Chronic NO supplementation using PETN reduces platelet activation in CHF rats. Thus, PETN may constitute a useful approach to prevent thromboembolic complications in CHF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123621PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415973PMC
April 2016

Modulation of platelet and monocyte function by the chemokine fractalkine (CX3 CL1) in cardiovascular disease.

Eur J Clin Invest 2015 Jun 24;45(6):624-33. Epub 2015 Apr 24.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: The chemokine fractalkine, CX3CL1, bears unique features within the chemokine family: it exists in a membrane bound form acting as an adhesion molecule and surface receptor; however, when cleaved by ADAM 10, it functions as a soluble chemokine. Fractalkine and its chemokine receptor CX3CR1 are known to have multiple roles in diverse human diseases, for example inflammatory diseases, rheumatoid arthritis, renal diseases and atherosclerosis.

Materials And Methods: This review is based on the material obtained via PubMed up to November 2014. The key search terms used were 'fractalkine', 'CX3CL1', 'CX3CR1', 'cardiovascular disease', 'platelets', 'monocytes' and 'platelet-monocyte complexes'.

Results: Atherosclerosis is recognized as a highly inflammatory disease, and it has become increasingly evident that the immune system plays an important role in atherogenesis and atheroprogression. Two blood cell populations are crucially involved in the early development of atherosclerotic lesions: monocytes and platelets. They are detected at vascular sites of endothelial dysfunction and are involved in inflammatory immune responses. These cells directly interact with each other, forming platelet-monocyte complexes that are increased in cardiovascular diseases. During the development of atherosclerosis, fractalkine mediates leukocyte recruitment to the inflamed endothelium, which promotes early formation of lesions. This process only effectively works in the presence of activated platelets. It has been suggested that fractalkine and its receptor contribute to platelet-monocyte aggregate formation underlining the two important impacts of this chemokine for platelets as well as monocytes.

Conclusion: Interesting data hint at a role of fractalkine for platelet activation, adhesion and subsequent monocyte recruitment to activated endothelial cells in cardiovascular diseases. However, the exact mechanisms remain to become unravelled.
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http://dx.doi.org/10.1111/eci.12443DOI Listing
June 2015

Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators.

J Exp Med 2015 Feb 2;212(2):129-37. Epub 2015 Feb 2.

Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.
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http://dx.doi.org/10.1084/jem.20140391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322051PMC
February 2015

A comprehensive analysis of primary acute myeloid leukemia identifies biomarkers predicting susceptibility to human allogeneic Vγ9Vδ2 T cells.

J Immunother 2014 Jul-Aug;37(6):321-30

*Medizinische Klinik und Poliklinik II †Institut für Klinische Transfusionsmedizin und Hämotherapie, University of Würzburg, Würzburg §Medizinische Klinik V, Klinikum Nürnberg Nord, Nürnberg, Germany ‡Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia.

Allogeneic innate lymphocytes such as Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy as they provide MHC-unrestricted antitumor activity without clinical evidence for inducing graft-versus-host disease (GvHD). However, current cellular immunotherapy approaches lack predictive biomarkers identifying patient cohorts most susceptible to immune attack. For this purpose we performed a comprehensive analysis of clinical, genetic, metabolic, and immunophenotypic features of 19 primary acute myeloid leukemia (AML) samples and correlated these factors with AML blast recognition by allogeneic Vγ9Vδ2 T cells. We show that 36% of primary AML samples were intrinsically susceptible to allogeneic Vγ9Vδ2 T cells. Among several evaluated features, only UL-16 binding protein 1 (ULBP1) expression (P<0.01) determines intrinsic AML susceptibility to allogeneic Vγ9Vδ2 T cells. Within the intrinsically resistant AML samples, pretreatment of AML blasts with nitrogen-containing bisphosphonates (NBP) significantly induced Vγ9Vδ2 T-cell cytotoxicity in 50% of AML samples, whereas 50% of AML samples were consistently refractory to γδ T-cell cytolysis. Activity of the mevalonate pathway (P<0.05) and myelomonocytic differentiation of AML (P<0.05) correlated with sensitivity of primary AML samples toward NBP pretreatment. In conclusion, this study identifies subsets of AML patients most likely to benefit from allogeneic Vγ9Vδ2 T-cell-mediated immunotherapy.
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http://dx.doi.org/10.1097/CJI.0000000000000043DOI Listing
April 2015

Fractalkine promotes platelet activation and vascular dysfunction in congestive heart failure.

Thromb Haemost 2014 Apr 12;111(4):725-35. Epub 2013 Dec 12.

Prof. Dr. Andreas Schäfer, Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany, Tel.: +49 511 532 5240, Fax: +49 511 532 8244, E-mail:

Unlabelled: Endothelial dysfunction and enhanced platelet reactivity in congestive heart failure (CHF) contribute to poor prognosis. CHF patients display an impaired responsiveness to clopidogrel. Fractalkine activates platelets and elevated plasma levels of this chemokine are a feature of CHF. We here addressed the interrelation of fractalkine, platelet reactivity and clopidogrel efficacy in humans and rats with CHF. Fractalkine serum levels determined by ELISA were increased in CHF patients (CHF: 1548 ± 650 pg/ml;

Control: 968 ± 575 pg/ml, p<0.01) and following CHF induction in rats (CHF: 1509 ± 753 pg/ml; Sham: 1181 ± 275 pg/ml, p<0.05). Expression of fractalkine and its receptor CX3CR1 was enhanced in aortas of CHF rats as determined by immunofluorescence microscopy and molecular analysis. Fractalkine significantly aggravated endothelial dysfunction and augmented P-selectin expression on platelets from CHF rats. Platelet surface expression of CX3CR1 was increased in CHF rats, who displayed an impaired response to clopidogrel (platelet reactivity to ADP: CHF 30 ± 22%; Sham: 8 ± 5%, p<0.05). Similarly in humans with CHF, elevated fractalkine levels were accompanied by reduced clopidogrel responsiveness. Patients with high on-clopidogrel treatment platelet P2Y12 reactivity displayed higher fractalkine levels (1525 ± 487 pg/ml) than those with sufficient clopidogrel response (684 ± 315 pg/ml, p<0.01). In conclusion, in CHF fractalkine was increased on the endothelium and in blood serum, and platelet surface-expression of CX3CR1 was enhanced. Fractalkine diminished endothelial function beyond the impairment already observed in CHF and was associated with a reduced responsiveness to the platelet inhibitor clopidogrel. These findings may indicate a novel pathophysiological mechanism contributing to impaired clopidogrel responsiveness in CHF.
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http://dx.doi.org/10.1160/TH13-08-0640DOI Listing
April 2014

The direct factor Xa inhibitor Rivaroxaban reduces platelet activation in congestive heart failure.

Pharmacol Res 2013 Aug 25;74:49-55. Epub 2013 May 25.

Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.

Background: Platelet activation in congestive heart failure (CHF) contributes to an increased risk for thromboembolic complications. Rivaroxaban, the first oral direct FXa inhibitor is approved in Europe for prevention and treatment of venous thrombosis, pulmonary embolism, and prevention of thromboembolic events in atrial fibrillation. As heart failure is an important risk factor for thromboembolism and increased platelet activation is common in heart failure, we investigated the potential effect of Rivaroxaban treatment on platelets in an experimental CHF model.

Methods And Results: Chronic myocardial infarction was induced in male Wistar rats by coronary ligation. Rats were randomized to placebo or Rivaroxaban (3 and 10mg/kg once daily). After 10 weeks platelet activation was assessed. Platelet-bound fibrinogen, detected by flow-cytometry, was significantly increased in CHF-Placebo (p<0.05) and reduced following treatment with Rivaroxaban (p<0.05 vs. CHF-Placebo). ADP-induced aggregation was significantly enhanced in CHF-Placebo vs. sham-operated animals (p<0.05) and normalized following chronic FXa inhibition (p<0.05 vs. CHF-Placebo). In separate in vitro experiments, attenuated platelet aggregation was present after incubating whole blood directly with Rivaroxaban but absent when the experiment was performed in platelet-rich plasma only. Thus, a direct effect on platelets could be excluded.

Conclusion: Chronic direct factor Xa inhibition using Rivaroxaban reduces platelet activation in CHF rats by attenuating the secondary phase of ADP-induced platelet aggregation. Thus, Rivaroxaban may constitute a useful approach to prevent thromboembolic complications and reduce platelet activation in CHF at the same time.
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http://dx.doi.org/10.1016/j.phrs.2013.05.002DOI Listing
August 2013

Fractalkine--a local inflammatory marker aggravating platelet activation at the vulnerable plaque.

Thromb Haemost 2012 Sep 28;108(3):457-63. Epub 2012 Jun 28.

Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.

Chemokines play an important role in inducing chemotaxis of cells, piloting white blood cells in immune surveillance and are crucial parts in the development and progression of atherosclerosis. Platelets are mandatory players in the initiation of atherosclerotic lesion formation and are susceptible targets for and producers of chemokines. Several chemokine receptors on platelets have been described previously, amongst them CX(3)CR1, the receptor for fractalkine. The unique chemokine fractalkine (CX(3)CR1, FKN) exists as a soluble as well as a membrane-anchored glycoprotein. Its essential role in the formation of atherosclerotic lesions and atherosclerosis progression has been impressively described in mouse models. Moreover, fractalkine induces platelet activation and adhesion via a functional fractalkine receptor (CX(3)CR1) expressed on the platelet surface. Platelet activation via the FKN/CX(3)CR1-axis triggers leukocyte adhesion to activated endothelium, and fractalkine-induced platelet P-selectin is mandatory for leukocyte recruitment under arterial flow conditions. This review summarises the role of fractalkine as a potential local inflammatory mediator which influences platelet activation in the setting of atherosclerosis. Beyond that, aspects of a potential interaction between fractalkine and platelet responsiveness to antiplatelet drugs are described. Furthermore, the possible impact of high-density lipoprotein cholesterol (HDL-C) on atherosclerosis progression, platelet activation and fractalkine signalling are discussed.
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http://dx.doi.org/10.1160/TH12-04-0271DOI Listing
September 2012

Fractalkine activates a signal transduction pathway similar to P2Y12 and is associated with impaired clopidogrel responsiveness.

Arterioscler Thromb Vasc Biol 2012 Aug 31;32(8):1832-40. Epub 2012 May 31.

Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Objective: Fractalkine (FKN) activates a G(αi) protein-coupled signaling pathway similar to the one activated by ADP via P2Y(12), which is the drug target of clopidogrel. FKN levels are increased under several disease conditions associated with impaired clopidogrel responsiveness.

Methods And Results: Blood samples were obtained from healthy volunteers and from 40 patients under chronic clopidogrel treatment. FKN reduced prostaglandin E1-induced vasodilator-stimulated phosphoprotein phosphorylation by ≈ 25% (P<0.01) at least partially mimicking the effect of ADP via P2Y(12). In vitro, FKN increased platelet reactivity index in clopidogrel-treated patients indicating potential activation of downstream targets of P2Y(12). When stratifying patients by their FKN levels, patients within the highest quartile of FKN (2042 ± 25 pg/mL) had the weakest response to clopidogrel (platelet reactivity index, 68 ± 4%), and patients within the lowest quartile (479 ± 50 pg/mL) had the strongest response (platelet reactivity index, 48 ± 7%; P=0.0106). FKN by itself induced phosphoinositide 3-kinase activation leading to Akt phosphorylation at Ser(473) (P<0.01 versus basal).

Conclusions: In addition to desensitizing platelets to prostaglandin E1 via G(αi), FKN induces phosphoinositide 3-kinase-dependent Akt phosphorylation via a G(βγ) protein similar to ADP signaling through P2Y(12). FKN increased the platelet ADP response in clopidogrel-treated patients. Once released from an atherosclerotic lesion, this mechanism could contribute locally to impaired clopidogrel responsiveness at the vulnerable plaque.
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http://dx.doi.org/10.1161/ATVBAHA.112.250720DOI Listing
August 2012