Nikolaus Marx

University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

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Publications (354)

  • [Show abstract] [Hide abstract] ABSTRACT: Patients with CKD on hemodialysis exhibit increased cardiovascular risk. Fibrin clot structure and clot lysis are crucially involved in development of cardiovascular events, but little is known about the influence of clot density on outcome in patients on hemodialysis. We determined fibrin clot structure parameters and effect on mortality in a prospective cohort of 171 patients on chronic hemodialysis (mean±SD age =59±11 years old; 54% men) using a validated turbidimetric assay. Kaplan-Meier analysis revealed that patients on hemodialysis with a denser clot structure had increased all-cause and cardiovascular mortality risks (log rank P=0.004 and P=0.003, respectively). Multivariate Cox regression models (adjusted for age, diabetes, sex, and duration of dialysis or fibrinogen, C-reactive protein, and complement C3) confirmed that denser clots are independently related to mortality risk. We also purified fibrinogen from healthy controls and patients on hemodialysis using the calcium-dependent IF-1 mAb against fibrinogen for additional investigation using mass spectrometric analysis and electron microscopy. Whereas purified fibrinogen from healthy controls displayed no post-translational modifications, fibrinogen from patients on hemodialysis was glycosylated and guanidinylated. Clots made of purified fibrinogen from patients on hemodialysis exhibited significantly thinner fibers compared with clots from fibrinogen of control individuals (mean±SD =63±2 and 77±2 nm, respectively; P<0.001). In vitro guanidinylation of fibrinogen from healthy subjects increased the formation of thinner fibers, suggesting that difference in fiber thickness might be at least partially due to post-translational modifications. Thus, in patients on hemodialysis, a denser clot structure may be a potent independent risk factor for mortality.
    Article · Jan 2017 · Journal of the American Society of Nephrology
  • A. Babler · J. Bernhagen · P. Boor · [...] · Marx N
    Poster · Dec 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Objective: Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which gets secreted in response to nutritional stimuli from the gut mediating glucose-dependent insulin secretion. Interestingly, GLP-1 was recently found to be also increased in response to inflammatory stimuli in an interleukin 6 (IL-6) dependent manner in mice. The relevance of this finding to humans is unknown but has been suggested bythe presence of high circulating GLP-1 levels in critically ill patients that correlated with markers of inflammation. This study was performed to elucidate, whether a direct link exists between inflammation and GLP-1 secretion in humans. Research design and methods: We enrolled 22 non-diabetic patients scheduled for cardiac surgery as a reproducible inflammatory stimulus with repeated blood sampling before and after surgery. Results: Mean total circulating GLP-1 levels significantly increased in response to surgery from 25.5±15.6pM to 51.9±42.7pM which was not found in a control population. This was preceded by an early rise of IL6, which was significantly associated with GLP-1 under inflammatory but not basal conditions. Using repeated measure ANCOVA, IL6 best predicted the observed kinetics of GLP-1, followed by blood glucose concentrations and cortisol plasma levels. Furthermore, GLP-1 plasma concentrations significantly predicted endogenous insulin production as assessed by C-peptide concentrations over time, while an inverse association was found for insulin infusion rate. Conclusion: We found GLP-1 secretion to be increased in response to inflammatory stimuli in humans, which was associated to parameters of glucose metabolism and best predicted by IL6.
    Full-text available · Article · Dec 2016 · Cardiovascular Diabetology
  • [Show abstract] [Hide abstract] ABSTRACT: Aims: Hypoglycaemia is associated with increased risk of cardiovascular events and mortality in patients with diabetes, but the extent and mechanisms of this link are ill defined. We here prospectively studied cardiac repolarization abnormalities during insulin-induced hypoglycaemia in humans. Methods: 119 individuals (69 males, age 47.5±13.4years, range 18-82years) were assessed during hypoglycaemia after the injection of 0.1-0.25units/kg human insulin. Corrected QT intervals (QTc) and QT dispersion (QTd) were calculated from serially recorded twelve lead electrocardiograms, and plasma glucose and other endocrine markers were studied. Results: QTc increased from 415.1±21.9ms (mean±standard deviation) at baseline to 444.9±26.5ms during hypoglycaemia (plasma glucose nadir, 1.6±0.5mmol/L, p=0.001), accompanied by an increase of QTd from 45.0±22.7ms to 64.1±40.0ms (p<0.001). Hypoglycaemia-induced abnormal QTc prolongation (defined as ⩾460ms in females and ⩾450ms in males) occurred in 17% (9/54) of females and 26% (17/65) of males. 97 of 119 of individuals (82%) developed transient hypokalaemia (K(+) ⩽3.6mmol/L), and plasma epinephrine increased from 220.4±169.5pmol/L at baseline to 2945.6±2421.4pmol/L during hypoglycaemia. Baseline QTc, but not age or gender, was a significant predictor of hypoglycaemia-induced QTc prolongation (p=0.001). Conclusions: Insulin-induced hypoglycaemia frequently causes abnormal QT prolongation and is associated with hypokalaemia and sympathoadrenal activation, thereby increasing the potential risk for ventricular arrhythmias, particularly in individuals with pre-existing high normal QTc.
    Article · Dec 2016 · Diabetes research and clinical practice
  • [Show abstract] [Hide abstract] ABSTRACT: Aims: The PDE4 inhibitor roflumilast is a clinically approved anti-inflammatory drug used for the treatment of chronic obstructive pulmonary disease. In addition, roflumilast was found to reduce body weight and improve glucose metabolism by a yet unknown mechanism. Materials and methods: Metabolic effects of roflumilast were investigated in C57BL/6J mice on high fat western-type diet treated with or without roflumilast for a period of 12 weeks. Results: Roflumilast led to a marked reduction of body weight gain, which became apparent in the second week following treatment initiation and was attributable to a pronounced increase of energy expenditure. Furthermore, roflumilast improved glucose tolerance, reduced insulin resistance and diminished steatohepatitis of mice. Mechanistically, this was associated with hepatic PKA and CREB-activation leading to PGC-1α-dependent induction of mitochondrial biogenesis. Consistently, roflumilast increased cellular respiratory capacity of hepatocytes in a PKA-dependent manner. Conclusion: Roflumilast dependent PDE4-inhibition is a new target for weight loss strategies especially in conditions of associated co-morbidities like insulin resistance and non-alcoholic steatohepatitis.
    Article · Dec 2016 · Diabetes Obesity and Metabolism
  • Article · Nov 2016 · DMW - Deutsche Medizinische Wochenschrift
  • Vincent Brandenburg · Nadine Kaesler · Rafael Kramann · [...] · Nikolaus Marx
    Article · Oct 2016 · DMW - Deutsche Medizinische Wochenschrift
  • [Show abstract] [Hide abstract] ABSTRACT: Low adherence to cardiac rehabilitation (CR) might be improved by remote monitoring systems that can be used to motivate and supervise patients and tailor CR safely and effectively to their needs. The main objective of this study was to evaluate the feasibility of a smartphone-guided training system (GEX) and whether it could improve exercise capacity compared to CR delivered by conventional methods for patients with coronary artery disease (CAD). A prospective, randomized, international, multi-center study comparing CR delivered by conventional means (CG) or by remote monitoring (IG) using a new training steering/feedback tool (GEx System). This consisted of a sensor monitoring breathing rate and the electrocardiogram that transmitted information on training intensity, arrhythmias and adherence to training prescriptions, wirelessly via the internet, to a medical team that provided feedback and adjusted training prescriptions. Exercise capacity was evaluated prior to and 6 months after intervention. 118 patients (58 ± 10 years, 105 men) with CAD referred for CR were randomized (IG: n = 55, CG: n = 63). However, 15 patients (27 %) in the IG and 18 (29 %) in the CG withdrew participation and technical problems prevented a further 21 patients (38 %) in the IG from participating. No training-related complications occurred. For those who completed the study, peak VO2 improved more (p = 0.005) in the IG (1.76 ± 4.1 ml/min/kg) compared to CG (−0.4 ± 2.7 ml/min/kg). A newly designed system for home-based CR appears feasible, safe and improves exercise capacity compared to national CR. Technical problems reflected the complexity of applying remote monitoring solutions at an international level.
    Article · Oct 2016 · Heart and Vessels
  • Katharina Schütt · Nikolaus Marx
    Article · Sep 2016 · Kardiologie up2date
  • [Show abstract] [Hide abstract] ABSTRACT: Background: It is not clear whether patients entering a specialized, interdisciplinary weaning unit from surgical or medical intensive care units (ICU) distinguish substantially. The purpose of the present study was to assess differences in patients with prolonged weaning being referred from surgical and medical ICU. Methods: Data collected from April 2013 to April 2014 was conducted for retrospective analysis. Mortality rates, demographic data, clinical, and microbial differences in 150 patients with prolonged weaning were assessed (80 surgical and 70 medical). Results: Surgical ICU referrals tended to be older (70.7 ± 11.3 vs. 67.3 ± 12.3, P = 0.051) and had fewer underlying pulmonary diseases (45% vs. 60%, P = 0.067). Sodium values at the time of referral to the weaning unit were significantly higher in surgical (147.1 ± 9.6) vs. medical (141.3 ± 6.7 mmol/l) patients (P < 0.001). Each 10-unit increase in sodium at the time of referral to the weaning unit was associated with a 2.5-day (95% CI -0.4, 5.4; P = 0.09) prolongation of stay in the weaning unit. Although significant differences in microbiological agents from tracheal aspiration were seen, the infection rate on the weaning unit was similar in both groups. There was no difference in weaning unit mortality between surgical and medical ICU patients (18% vs. 23%; P = 0.41). Conclusion: Few differences were found between patients being referred to a specialized weaning unit from surgical vs. medical ICUs. Besides differences in microbiological characteristics of tracheal secretions, there were also differences in sodium levels, which appear to influence on treatment duration.
    Article · Aug 2016 · Acta Anaesthesiologica Scandinavica
  • Nikolaus Marx
    Article · Jun 2016 · DMW - Deutsche Medizinische Wochenschrift
  • Martin Berger · Katharina Schütt · Katharina Lysaja · [...] · Nikolaus Marx
    [Show abstract] [Hide abstract] ABSTRACT: Aims/hypothesis Clot properties are altered in acute coronary syndromes (ACS). However, data on clot properties and the impact of concomitant disease and medication in patients with diabetes in ACS are incomplete. Therefore, the present study investigates clot parameters in stable and unstable coronary artery disease (SCAD and UCAD respectively). Methods Hundred-eighty patients were included in a consecutive manner based on their diabetes and CAD status between March 2012 and December 2014. Clot properties were determined by a turbidimetric assay in 90 controls (noCAD N=39; SCAD N=29;, UCAD N=22) and 90 patients with diabetes (noCAD N=21; SCAD N=41; UCAD N=28). Results Clot structure was not affected by CAD status. However, clot lysis time was significantly increased in UCAD compared to SCAD and absence of CAD in control patients (1414 ± 703, 915 ± 461 and 1069 ± 414 respectively; p = 0.003). In contrast, in patients with DM clot lysis time did not differ between UCAD, SCAD and absence of CAD (1260 ± 649, 1304 ± 658 and 1318 ± 675 respectively; p = 0.947). Interestingly, clot lysis time in diabetes patients without CAD was comparable to UCAD control patients (p = 0.654). In an adjusted multiple regression model clot lysis time was significantly predicted by PAI-1 (p = 0.023), CRP (p = 0.042) and presence of UCAD (NSTEMI p = 0.010, STEMI p = 0.002) in control patients. Strikingly, in diabetes patients solely PAI-1 (p = 0.004) predicted clot lysis time. Conclusions Unstable coronary artery disease leads to an increase in clot lysis time in control patients. In contrast, clot lysis time in patients with diabetes is not affected by UCAD. Strikingly, clot lysis time in diabetes patients without CAD is comparable to control patients with UCAD indicating their increased prothrombotic risk already present in a stable situation.
    Article · Jun 2016 · Heart (British Cardiac Society)
  • [Show abstract] [Hide abstract] ABSTRACT: Recently, glucagon-like peptide-1 (GLP-1) was found to be increased in response to inflammatory stimuli leading to insulin secretion and prevention of hyperglycemia during endotoxemia in mice. We here study the relevance of the other incretin hormone, glucose-dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found Lipopolysaccharide (LPS) to increase GIP secretion in a time- and dose-dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP significantly increased in response to IL-1β but not IL-6 or TNF-α administration. Using respective knockout mice we found LPS-mediated GIP secretion to selectively dependent on IL-1 signaling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP-receptor antagonist (Pro3)GIP. This blunted LPS-induced TNF-α and IL-6 secretion but did not affect LPS-induced insulin secretion or blood glucose lowering. In conclusion GIP provides a novel link between the immune system and the gut with proinflammatory-immune modulatory function but minor glucose regulatory relevance in context of acute endotoxemia.
    Article · Jun 2016 · Diabetes Obesity and Metabolism
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    Winfried März · Nikolaus Marx · Ralf Kinscherf · [...] · Stefan Lorkowski
    [Show description] [Hide description] DESCRIPTION: Schriftliche Stellungnahme der Deutschen Gesellschaft für Arterioskleroseforschung e.V. (DGAF) zum Beschluss des Gemeinsamen Bundesausschusses zur Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage III – Übersicht über Verordnungseinschränkungen und -ausschlüsse: Alirocumab
    File available · Research · May 2016
  • Nikolaus Marx · Darren K McGuire
    [Show abstract] [Hide abstract] ABSTRACT: Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk for cardiovascular (CV) events. Hyperglycaemia itself contributes to the pathogenesis of atherosclerosis and heart failure (HF) in these patients, but glucose-lowering strategies studied to date have had little to no impact on reducing CV risk, especially in patients with a long duration of T2D and prevalent CV disease (CVD). Sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic medications that increase urinary glucose excretion, thus improving glycaemic control independent of insulin. The recently published CV outcome trial, EMPA-REG OUTCOME, demonstrated in 7020 patients with T2D and prevalent CVD that the SGLT2-inhibitor empagliflozin significantly reduced the combined CV endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke vs. placebo in a population of patients with T2D and prevalent atherosclerotic CVD. In addition and quite unexpectedly, empagliflozin significantly and robustly reduced the individual endpoints of CV death, overall mortality, and hospitalization for HF in this high-risk population. Various factors beyond glucose control such as weight loss, blood pressure lowering and sodium depletion, renal haemodynamic effects, effects on myocardial energetics, and/or neurohormonal effects, among others may contribute to these beneficial effects of SGLT2-inhibition. The present review summarizes known and postulated effects of SGLT2-inhibition on the CV system and discusses the role of SGLT2-inhibition for the treatment of high-risk patients with T2D and CVD.
    Article · May 2016 · European Heart Journal
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    [Show abstract] [Hide abstract] ABSTRACT: Objective To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes.
    Full-text available · Article · Apr 2016 · Metabolism
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Cardiac magnetic resonance imaging (CMR) has been established as a powerful tool for predicting mortality. However, its application is limited by availability and various contraindications. The aim of this study was to evaluate the predictive value of layer-specific myocardial deformation analysis as assessed by strain echocardiography for cardiac events in patients with chronic ischemic left ventricular dysfunction in comparison with CMR. Methods: Three hundred ninety patients (mean age, 63 ± 4 years; 69% men; mean left ventricular ejection fraction [LVEF], 41 ± 7%) with chronic ischemic cardiomyopathy were prospectively enrolled and underwent strain echocardiography and CMR within 3 ± 1 days. LVEF, wall motion score index, and circumferential strain (CS), longitudinal strain, and radial strain for total wall thickness and for three myocardial layers (endocardial, midmyocardial, and epicardial) were determined by echocardiography. The extent of total myocardial scar (TMS) was determined by CMR. Follow-up was obtained for a mean of 4.9 ± 2.2 years. Cardiac events were defined as readmission for worsening of heart failure, ventricular arrhythmias, or death of any cause. The incremental value of LVEF, strain parameters, and TMS to relevant clinical variables was determined in nested Cox models. Results: There were 133 cardiac events (34%). Baseline clinical data associated with outcomes were age (hazard ratio [HR], 1.27; P = .04), diabetes mellitus (HR, 1.52; P = .001), and renal insufficiency (HR, 1.77; P = .001) by multivariate analysis. The addition of LVEF, global and endocardial strain parameters, and TMS increased the predictive power, but endocardial CS (HR, 1.52; P < .01) caused the greatest increment in model power (χ(2) = 39.2, P < .001). Endocardial CS < -20% was found to be the optimal predictor of prognosis. Conclusions: Endocardial CS is a powerful predictor of cardiac events and appears to be a better parameter than LVEF, TMS by CMR, and other strain variables by echocardiography.
    Article · Mar 2016 · Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography
  • D Tschöpe · N Marx · R Dörr
    Article · Feb 2016 · Herz
  • F. Kahles · N. Marx
    [Show abstract] [Hide abstract] ABSTRACT: Background Patients with type 2 diabetes are at increased risk of dying from cardiovascular (CV) complications despite optimal lipid-reducing and blood pressure-lowering treatments. Studies ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Trial), VADT (Veterans Affairs Diabetes Trial), and ACCORD (Action to Control Cardiovascular Risk in Diabetes) have shown intensive glucose lowering to reduce risk of diabetes-related microvascular disease. However, these studies failed to show CV risk reduction by intensive glucose lowering. Only the 20-year follow-up data of UKPDS (UK Prospective Diabetes Study) suggest a long-term beneficial effect on macrovascular outcome in patients with newly diagnosed diabetes without prior CV disease. Since 2008 the Federal Drug Administration requires that new antidiabetes drugs undergo testing for CV outcomes to show cardiovascular safety. As a consequence many cardiovascular outcome trials with noninferiority designs have been initiated. Various trials with DDP-4 inhibitors (DPP: dipeptidylpeptidase) and GLP-1 agonists (GLP: glucagon-like peptide) could prove cardiovascular safety but did not show CV risk reduction. The very recently published landmark trial EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes Trial) could show for the first time that the antidiabetic drug SGLT-2 inhibitor empagliflozin (SGLT: sodium-dependent glucose transporter) reduces CV mortality in patients with type 2 diabetes at high risk for CV events after 3 years. Conclusions From the results of the EMPA-REG OUTCOME trial, the underlying mechanisms are still not completely understood, since reduction of glucose, blood pressure, and body weight by empagliflozin cannot completely explain the beneficial effect on CV outcomes. Further studies are required to clarify this question.
    Article · Feb 2016 · Der Diabetologe
  • [Show abstract] [Hide abstract] ABSTRACT: Aims Electromagnetic interferences (EMIs) with cardiovascular implantable electronic devices (CIEDs) are associated with potential risk for patients. Studies imply that CIED sensitivity setting and lead's tip-to-ring spacing determine the susceptibility of CIEDs with bipolar leads to electric and magnetic fields (EMFs); however, little is known about additional decisive parameters affecting EMI of CIEDs. We therefore investigated the influence of different patient-, device-, and lead-depending variables on EMIs in 160 patients. Methods and results We ran numerical simulations with human models to determine lead-depending variables on the risk of EMI by calculating the voltage induced in bipolar leads from 50/60 Hz EMF. We then used the simulation results and analysed 26 different patient-, device-, and lead-depending variables with respect to the EMI threshold of 160 CIED patients. Our analyses revealed that a horizontal orientation and a medial position of the bipolar lead's distal end (lead-tip) are most beneficial for CIED patients to reduce the risk of EMI. In addition, the effect of CIED sensitivity setting and lead's tip-to-ring spacing was confirmed. Conclusion Our data suggest that in addition to the established influencing factors, a medial position of the lead-tip for the right ventricular lead as achievable at the interventricular septum and a horizontal orientation of the lead-tip can reduce the risk of EMI. In the right atrium, a horizontal orientation of the lead-tip should generally be striven independent of the chosen position. Still important to consider remains a good intrinsic sensing amplitude during implant procedure.
    Article · Feb 2016 · Europace

Publication Stats

11k Citations

Institutions

  • 2012-2016
    • University Hospital RWTH Aachen
      • Clinic of Cardiology, Pneumology, Angiology and Internal Medicine Intensive Care (Internal Medicine I )
      Aachen, North Rhine-Westphalia, Germany
    • Deutsche Gesellschaft für Internistische Intensivmedizin und Notfallmedizin
      Aachen, North Rhine-Westphalia, Germany
  • 2014
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
  • 2005
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2003
    • Universität Ulm
      • Clinic of Internal Medicine II
      Ulm, Baden-Wuerttemberg, Germany