Marc W Merx

Heinrich-Heine-Universität Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (89)539.4 Total impact

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    ABSTRACT: Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (<35 years) and 20 elderly (50-80 year) healthy, male non-smokers consumed either a CF-containing drink (450 mg CF) or nutrient-matched, CF-free control drink bi-daily for 14 days. The primary endpoint was endothelial function as measured by flow-mediated vasodilation (FMD). Secondary endpoints included cardiac output, vascular stiffness, conductance of conduit and resistance arteries, and perfusion in the microcirculation. Following 2 weeks of CF intake, FMD improved in young (6.1 ± 0.7 vs. 7.6 ± 0.7 %, p < 0.001) and elderly (4.9 ± 0.6 vs. 6.3 ± 0.9 %, p < 0.001). Secondary outcomes demonstrated in both groups that CF intake decreased pulse wave velocity and lowered total peripheral resistance, and increased arteriolar and microvascular vasodilator capacity, red cell deformability, and diastolic blood pressure, while cardiac output remained affected. In the elderly, baseline systolic blood pressure was elevated, driven by an arterial-stiffness-related augmentation. CF intake decreased aortic augmentation index (-9 %) and thus systolic blood pressure (-7 mmHg; Clinicaltrials.gov: NCT01639781). CF intake reverses age-related burden of cardiovascular risk in healthy elderly, highlighting the potential of dietary flavanols to maintain cardiovascular health.
    Age 06/2015; 37(3):9794. DOI:10.1007/s11357-015-9794-9 · 3.45 Impact Factor
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    PLoS ONE 04/2015; 10(4):e0120961. DOI:10.1371/journal.pone.0120961 · 3.53 Impact Factor
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    ABSTRACT: We have recently shown that dipyrone (metamizole), a non-opioid analgesic, can nullify aspirin (acetylsalicylic acid; ASA) antiplatelet effects in patients with coronary artery disease (CAD). In this study, we analysed the aspirin and dipyrone drug-drug interaction in order to identify strategies to prevent the dipyrone induced inhibition of asprin antiplatelet effects. Platelet function was measured by arachidonic acid-induced light-transmission aggregometry, thromboxane (TX) B2- formation by immunoassay. Dipyrone metabolite plasma levels were determined by high-performance-liquid-chromatography (HPLC). In seven healthy individuals, in vitro ASA (30 µM/ 100 µM/ 300 µM/ 1,000 µM) and dipyrone (10 µM) coincubation revealed, that the aspirin and dipyrone interaction can be overcome by increasing doses of aspirin. In 36 aspirin and dipyrone comedicated CAD patients, addition of ASA (30 µM/ 100 µM) in vitro inhibited, but did not completely overcome the dipyrone induced reduction of aspirin antiplatelet effects. Notably, the inhibition of thromboxane formation in aspirin and dipyrone comedicated CAD patients coincided with dipyrone plasma levels. In a cross-over designed study in four healthy individuals, we were able to proof that inhibition of aspirin (100 mg/ day) effects by dipyrone (750 mg/ day) was reversible. Furthermore, aspirin (100 mg/ day) medication prior to dipyrone (750 mg/ day) intake prevented the inhibition of antiplatelet effects by dipyrone in 12 healthy individuals. In conclusion, aspirin medication prior to dipyrone intake preserves antiplatelet effects, circumventing the pharmacodynamic drug-drug interaction at the level of cyclooxygenase-1.
    Thrombosis and Haemostasis 03/2015; 113(6). DOI:10.1160/TH14-11-0922 · 5.76 Impact Factor
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    ABSTRACT: Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. To investigate associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). Data was available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan-3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Median intake of total flavan-3-ols was 1034mg/d (range: 0-8531mg/d) for men and 970mg/d (0-6695mg/d) for women, median intake of flavan-3-ol monomers was 233mg/d (0-3248mg/d) for men and 217 (0-2712mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow up, there were 8463 cardio-vascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI: 0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 03/2015; 31. DOI:10.1016/j.freeradbiomed.2015.03.005 · 5.71 Impact Factor
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    ABSTRACT: Inflammation is a hallmark of cardiac healing after myocardial infarction and it determines subsequent cardiovascular morbidity and mortality. The aim of the present study was to explore whether inflammation imaging with two perfluorocarbon (PFC) nanoemulsions and fluorine magnetic resonance imaging ((19)F MRI) is feasible at 3.0 T with sufficient signal-to-noise ratio (SNR) using explanted hearts, an (19)F surface coil and dedicated MR sequences. Acute myocardial infarction (AMI) was induced by balloon angioplasty (50 min) of the distal left anterior descending artery in 12 pigs. One day thereafter, PFCs were injected intravenously to label circulating monocytes. Either emulsified perfluoro-15-crown-5 ether or already clinically applied perfluorooctyl bromide (PFOB) was applied. Four days after AMI and immediately after gadolinium administration, hearts were explanted and imaged with a 3.0 T Achieva MRI scanner. (19)F MRI could be acquired with an SNR of >15 using an in-plane resolution of 2 × 2 mm(2) within <20 min for both agents. Combined late gadolinium enhancement (LGE) and (19)F MRI revealed that (19)F signal was inhomogenously distributed across LGE myocardium reflecting patchy macrophage infiltration as confirmed by histology. In whole hearts, we found an apico-basal (19)F gradient within LGE-positive myocardium. The (19)F-positive volume was always smaller than LGE volume. Ex vivo experiments on isolated monocytes revealed that pig and human cells phagocytize PFCs even more avidly than mouse monocytes. This pilot study demonstrates that (19)F MRI at 3.0 T with clinically applicable PFOB is feasible, thus highlighting the potential of (19)F MRI to monitor the inflammatory response after AMI. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    European Heart Journal – Cardiovascular Imaging 03/2015; DOI:10.1093/ehjci/jev008 · 2.65 Impact Factor
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    ABSTRACT: Dual antiplatelet therapy (DAPT) is recommended early after transcatheter aortic valve implantation (TAVI) procedure at the moment despite the lack of evidence. Two small randomized trials failed to demonstrate DAPT to be superior to aspirin alone in TAVI patients. However, it is known that there are substantial response variabilities to antiplatelet medication. We aimed to investigate high on-treatment platelet reactivity (HTPR), respectively low on-treatment platelet reactivity (LTPR) to clopidogrel as well as HTPR to aspirin in patients undergoing TAVI procedure.
    European Journal of Pharmacology 01/2015; 751. DOI:10.1016/j.ejphar.2015.01.028 · 2.68 Impact Factor
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    ABSTRACT: Pulmonary vascular injury is a rare but life-threatening complication of Swan-Ganz catheterization. We report an 82-year old patient who underwent right heart catheterization by a balloon-tipped catheter because of suspected pulmonary hypertension. After deflation of the catheter in the wedge position, hemoptoe appeared associated with acute respiratory insufficiency requiring respiratory support by intubation and mechanical ventilation. Pulmonary angiography showed the formation of a false aneurysm of a segment artery of the left lower lobe. Immediate interventional therapy was performed by the implantation of two coated coronary stent grafts into the injured pulmonary artery thereby excluding the false aneurysm. Bleeding was stopped by this interventional approach while antegrade blood flow was maintained. Long term follow-up after 3 months showed an effective treatment with a completely thrombotic false aneurysm. However, despite oral anticoagulation and dual antiplatelet therapy, graft patency could not be achieved after 3 months. In summary, implantation of coated stents is a feasible and safe approach for the acute and long term treatment of potentially life-threatening condition of a pulmonary artery false aneurysm while treatment to achieve long term patency of the affected vessel still remains an issue to be resolved.
    12/2014; 2014:893647. DOI:10.1155/2014/893647
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    ABSTRACT: Aims: Degenerative aortic valve stenosis (AVS) is independently associated with endothelial dysfunction and increased levels of circulating endothelium-derived microparticles (EMPs) as a marker of compromised endothelial integrity. The aim of this study was to investigate whether therapy for severe AVS by transcatheter aortic valve implantation (TAVI) improves endothelial function and decreases EMPs. Methods and results: Fifty-six patients with indication for TAVI due to symptomatic severe AVS were prospectively enrolled. Brachial wall shear stress (WSS), endothelial function and circulating microparticles (MPs) were measured before and three months following TAVI. Endothelial function was assessed as flow-mediated dilation (FMD) using ultrasound. MP subpopulations were discriminated by flow cytometry according to the expression of established surface antigens: CD31+/CD41-, CD144+ and CD62E+ as EMPs and CD41+ as platelet-derived MPs (PMPs). In patients with severe AVS, decreased brachial WSS was an independent predictor of low FMD. At three-month follow-up after TAVI, WSS and FMD increased along with decreased levels of EMPs as compared to pre TAVI. Decrease of CD31+/CD41-, CD144+ and CD62E+ EMP levels correlated with the increase of FMD. Conclusions: Therapy for AVS by TAVI was associated with improved endothelial function and integrity indicating beneficial effects of TAVI on systemic arterial function.
    EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 10/2014; 10(12). DOI:10.4244/EIJY14M10_02 · 3.76 Impact Factor
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    ABSTRACT: IntroductionThe aim of our study was to develop a reproducible murine model of elastase-induced aneurysm formation combined with aortic transplantation.MethodsAdult male mice (n = 6–9 per group) underwent infrarenal, orthotopic transplantation of the aorta treated with elastase or left untreated. Subsequently, both groups of mice were monitored by ultrasound until 7 weeks after grafting.ResultsMice receiving an elastase-pretreated aorta developed aneurysms and exhibited a significantly increased diastolic vessel diameter compared to control grafted mice at 7 week after surgery (1.11±0.10 mm vs. 0.75±0.03 mm; p≤0,001). Histopathological examination revealed disruption of medial elastin, an increase in collagen content and smooth muscle cells, and neointima formation in aneurysm grafts.ConclusionsWe developed a reproducible murine model of elastase-induced aneurysm combined with aortic transplantation. This model may be suitable to investigate aneurysm-specific inflammatory processes and for use in gene-targeted animals.
    PLoS ONE 07/2014; 9(7):e102648. DOI:10.1371/journal.pone.0102648 · 3.53 Impact Factor
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    ABSTRACT: Aims: Introduction of a novel contrast injection protocol during rotational C-arm CT (RCT) in cardiac catheterisation of patients with aortic stenosis for aortic root assessment. Methods and results: Fifty-two patients underwent RCT imaging with contrast injection performed either into the aorta (Ao-RCT, n=25) or into the left ventricle (LV-RCT, n=27). Aortic annulus diameters were assessed in a multiplanar reconstruction view and compared with corresponding multidetector computed tomography (MDCT). LV contrast injection additionally enabled measurement of the left ventricular outflow tract (LVOT). LV-RCT improved the accuracy of annulus measurements and correlated well with MDCT data in comparison with Ao-RCT and MDCT (r=0.9 r=0.76, respectively). The Bland-Altman analysis showed smaller differences in MDCT and LV-RCT annulus measurements than between MDCT and Ao-RCT (LV-RCT: mean=0.4 mm, limits of agreement -1.5-2.3 mm vs. Ao-RCT: mean=0.1 mm, limits of agreement -3.4-3.6 mm). The inter-observer agreement for the annulus measurements was significantly increased for LV-RCT as calculated by the intra-class coefficient (ICC=0.85) in comparison with Ao-RCT (ICC=0.52). Conclusions: Cardiac catheterisation including LV-RCT offers complementary assessment of left ventricular function, aortic valve anatomy, coronary angiography and arterial access routes. LV-RCT for aortic root measurements shows better correlation to MDCT than standard Ao-RCT protocols.
    EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 04/2014; 10(3). DOI:10.4244/EIJV10I3A60 · 3.76 Impact Factor
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    ABSTRACT: Nitric oxide (NO) derived from endothelial NO synthase (NOS3) plays a central role in myocardial ischemia/reperfusion (I/R)-injury. Subsets of circulating blood cells, including red blood cells (RBCs), carry a NOS3 and contribute to blood pressure regulation and RBC nitrite/nitrate formation. We hypothesized that the circulating blood born NOS3 also modulates the severity of myocardial infarction in disease models. We cross-transplanted bone marrow in wild-type and NOS3−/− mice with wild-type mice, producing chimeras expressing NOS3 only in vascular endothelium (BC−/EC+) or in both blood cells and vascular endothelium (BC+/EC+). After 60-min closed-chest coronary occlusion followed by 24 h reperfusion, cardiac function, infarct size (IS), NOx levels, RBCs NO formation, RBC deformability, and vascular reactivity were assessed. At baseline, BC−/EC+ chimera had lower nitrite levels in blood plasma (BC−/EC+: 2.13 ± 0.27 μM vs. BC+/EC+ 3.17 ± 0.29 μM; *p < 0.05), reduced DAF FM associated fluorescence within RBCs (BC−/EC+: 538.4 ± 12.8 mean fluorescence intensity (MFI) vs. BC+/EC+: 619.6 ± 6.9 MFI; ***p < 0.001) and impaired erythrocyte deformability (BC−/EC+: 0.33 ± 0.01 elongation index (EI) vs. BC+/EC+: 0.36 ± 0.06 EI; *p < 0.05), while vascular reactivity remained unaffected. Area at risk did not differ, but infarct size was higher in BC−/EC+ (BC−/EC+: 26 ± 3 %; BC+/EC+: 14 ± 2 %; **p < 0.01), resulting in decreased ejection fraction (BC−/EC+ 46 ± 2 % vs. BC+/EC+: 52 ± 2 %; *p < 0.05) and increased end-systolic volume. Application of the NOS inhibitor S-ethylisothiourea hydrobromide was associated with larger infarct size in BC+/EC+, whereas infarct size in BC−/EC+ mice remained unaffected. Reduced infarct size, preserved cardiac function, NO levels in RBC and RBC deformability suggest a modulating role of circulating NOS3 in an acute model of myocardial I/R in chimeric mice. Electronic supplementary material The online version of this article (doi:10.1007/s00395-013-0398-1) contains supplementary material, which is available to authorized users.
    Archiv für Kreislaufforschung 01/2014; 109(1):398. DOI:10.1007/s00395-013-0398-1 · 5.96 Impact Factor
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    ABSTRACT: Dietary interventions with flavan-3-ols have shown beneficial effects on vascular function. The translation of these findings into the context of the health of the general public requires detailed information on habitual dietary intake. However, only limited data are currently available for European populations. Therefore, in the present study, we assessed the habitual intake of flavan-3-ol monomers, proanthocyanidins (PA) and theaflavins in the European Union (EU) and determined their main food sources using the EFSA (European Food Safety Authority) Comprehensive European Food Consumption Database. Data for adults aged 18-64 years were available from fourteen European countries, and intake was determined using the FLAVIOLA Flavanol Food Composition Database, developed for the present study and based on the latest US Department of Agriculture and Phenol-Explorer databases. The mean habitual intake of flavan-3-ol monomers, theaflavins and PA ranged from 181 mg/d (Czech Republic) to 793 mg/d (Ireland). The highest intakes of flavan-3-ol monomers and theaflavins were observed in Ireland (191/505 mg/d) and the lowest intakes in Spain (24/9 mg/d). In contrast, the daily intake of PA was highest in Spain (175 mg/d) and lowest in The Netherlands (96 mg/d). Main sources were tea (62 %), pome fruits (11 %), berries (3 %) and cocoa products (3 %). Tea was the major single contributor to monomer intake (75 %), followed by pome fruits (6 %). Pome fruits were also the main source of PA (28 %). The present study provides important data on the population-based intake of flavanols in the EU and demonstrates that dietary intake amounts for flavan-3-ol monomers, PA and theaflavins vary significantly across European countries. The average habitual intake of flavan-3-ols is considerably below the amounts used in most dietary intervention studies.
    The British journal of nutrition 12/2013; DOI:10.1017/S0007114513003930 · 3.34 Impact Factor
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    ABSTRACT: Pulmonary vein isolation (PVI) as a cornerstone for catheter ablation of atrial fibrillation (AF) remains a complex and time consuming procedure. The purpose of this study was to assess feasibility, safety and acute efficacy of a novel irrigated multielectrode ablation catheter guided by an electroanatomical mapping system for PVI in patients with paroxysmal AF. 25 consecutive patients (60 ± 10 years) with paroxysmal AF underwent PVI by using a novel decapolar mapping and ablation catheter (NMARQ). Ablation was guided by electroanatomical mapping allowing radiofrequency (RF) energy delivery in the antral region of pulmonary veins (PV) from 10 irrigated electrodes simultaneously. The day after ablation, cardiac magnetic resonance imaging (MRI) was performed routinely in order to assess for potential acute PV-stenosis. Overall, 97 of 97 targeted PV (100 %) could be isolated with a mean of 27 ± 11 RF applications and a mean total burning time of 15 ± 6 minutes per patient. The total procedure time from femoral vein access to catheter withdrawal was 110 ± 31 minutes including a mean total fluoroscopy time of 23 ± 9 minutes. On average, 6 ± 3 RF impulses with a maximum of 25 Watt were applied per vein. After a short learning curve procedure, fluoroscopy and total burning time decreased to 94 ± 16 minutes, 16 ± 3 minutes and 9 ± 2 minutes respectively (p<0.05). Entrance and exit block could be verified by placing the ablation catheter into 90 of 97 (93%) PVs in 18 of 25 (72%) patients. No procedure-related complications were observed, especially no acute PV stenosis could be detected. Use of a novel irrigated multielectrode ablation system for PVI is feasible and safe, resulting in acute isolation of all targeted PVs with no complications and short procedure times. Sustainability of these initial results has to be confirmed in long term efficacy and follow up trials.
    Heart rhythm: the official journal of the Heart Rhythm Society 12/2013; 11(3). DOI:10.1016/j.hrthm.2013.12.008 · 4.92 Impact Factor
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    ABSTRACT: Endothelial nitric oxide synthase (NOS)3-derived nitric oxide (NO) modulates inotropic response and diastolic interval for optimal cardiac performance under non-inflammatory conditions. In sepsis, excessive NO production plays a key role in severe hypotension and myocardial dysfunction. We aimed to determine the role of NOS3 on myocardial performance, NO production, and time course of sepsis development. NOS3−/− and C57BL/6 wildtype mice were rendered septic by cecum ligation and puncture (CLP). Cardiac function was analyzed by serial echocardiography, in vivo pressure and isolated heart measurements. Cardiac output (CO) increased to 160 % of baseline at 10 h after sepsis induction followed by a decline to 63 % of baseline after 18 h in wildtype mice. CO was unaltered in septic NOS3−/− mice. Despite the hyperdynamic state, cardiac function and mean arterial pressure were impaired in septic wildtype as early as 6 h post CLP. At 12 h, cardiac function in septic wildtype was refractory to catecholamines in vivo and respective isolated hearts showed impaired pressure development and limited coronary flow reserve. Hemodynamics remained stable in NOS3−/− mice leading to significant survival benefit. Unselective NOS inhibition in septic NOS3−/− mice diminished this survival benefit. Plasma NOx- and local myocardial NOx- and NO levels (via NO spin trapping) demonstrated enhanced NOx- and bioactive NO levels in septic wildtype as compared to NOS3−/− mice. Significant contribution by inducible NOS (NOS2) during this early phase of sepsis was excluded. Our data suggest that NOS3 relevantly contributes to bioactive NO pool in developing sepsis resulting in impaired cardiac contractility. Electronic supplementary material The online version of this article (doi:10.1007/s00395-013-0330-8) contains supplementary material, which is available to authorized users.
    Archiv für Kreislaufforschung 03/2013; 108(2):330. DOI:10.1007/s00395-013-0330-8 · 5.96 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). DOI:10.1186/1532-429X-15-S1-P277 · 5.11 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). DOI:10.1186/1532-429X-15-S1-E39 · 5.11 Impact Factor
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    ABSTRACT: Introduction Murine arterial graft models are being used to uncover the inflammatory reactions of the vessel wall after surgery and the herein involved mediators. The aim of this study was to establish a model of transplantation-induced atherosclerosis after aortic transplantation. Methods Mice on a C57BL/6-background (n = 14) underwent infrarenal, orthotopic aortic transplantation. A group of sham animals (n = 10) served as controls. These groups of mice were kept on normal chow. In addition, apolipoprotein E-deficient (ApoE-/-) mice were employed (n = 5) that were fed a high fat diet immediately after surgery for 4 weeks. Results Ultrasound analyses and immunohistochemical analyses of the transplanted aorta revealed no major changes in morphology and function of C57BL/6 mice. In contrast, ApoE-/- mice developed marked intimal hyperplasia, with signs of monocyte/macrophage and smooth muscle cell infiltrations. Conclusion While C57BL/6 mice showed no significant changes in the aorta after transplantation, ApoE-/- mice on a high fat diet displayed signs of transplant atherosclerosis. Hence, this model provides an experimental basis for studying the pathogenesis of chronic atherosclerotic vessel wall remodeling after transplantation. This may also be useful for elucidating new therapeutic targets for the treatment of this disease.
    Gefässchirurgie 12/2012; DOI:10.1007/s00772-012-1084-6 · 0.24 Impact Factor
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    Free Radical Biology and Medicine 11/2012; 53:S13. DOI:10.1016/j.freeradbiomed.2012.10.025 · 5.71 Impact Factor
  • Free Radical Biology and Medicine 11/2012; 53:S129-S130. DOI:10.1016/j.freeradbiomed.2012.10.324 · 5.71 Impact Factor
  • Marc Merx, Malte Kelm
    Free Radical Biology and Medicine 11/2012; 53:S11. DOI:10.1016/j.freeradbiomed.2012.10.022 · 5.71 Impact Factor

Publication Stats

2k Citations
539.40 Total Impact Points

Institutions

  • 2001–2015
    • Heinrich-Heine-Universität Düsseldorf
      • • Faculty of Medicine
      • • Nuklearmedizinische Klinik
      • • Institute of Heart and circulatory physiology
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2014
    • Robert Koch Institut
      Berlín, Berlin, Germany
  • 2010–2014
    • Universitätsklinikum Düsseldorf
      • Klinik für Kardiologie, Pneumologie und Angiologie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1999–2012
    • University Hospital RWTH Aachen
      • Department of Neurology
      Aachen, North Rhine-Westphalia, Germany
  • 1995–2011
    • RWTH Aachen University
      • • Department of Cardiology, Pneumology, Angiology and Intensive Care (Internal Medicine I)
      • • Institute of Medical Statistics
      • • Institute for Molecular Cardiovascular Research
      Aachen, North Rhine-Westphalia, Germany