• Assoziiertes Institut: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie


    Functional Genomics of familial hypertrophic cardiomyopathy
    The Research focus of Carrier team is "Genetic, Pathophysiology and Therapy of Hypertrophic Cardiomyopathy". Hypertrophic cardiomyopathy (HCM) is a myocardial disease with the major feature of asymmetric septal hypertrophy (ASH). It is the major cause of sudden death in the young and is associated with a significant risk of heart failure without effective treatments. With a prevalence of 1:500 in young adults, HCM is one of the most common monogenic diseases. It involves more than 400 different mutations in 13 genes encoding sarcomeric proteins. Out of them, MYBPC3 encoding cardiac myosin-binding protein C is the most frequently mutated gene in Europe. Our projects are the following:

    1. Screening for mutations in new genes encoding components of the cardiac sarcomere in patients with HCM, and investigation of their consequences in mouse or human cardiac myocytes and engineered heart tissue using adeno-associated virus (AAV).

    2. Evaluation of the role of protein quality controls (ubiquitin-proteasome system, autophagy and unfolded-protein response in cardiac homeostasis, HCM and other cardiac diseases.

    3. Investigation of new cardiac-specific partners for E3 ubiquitin ligases.

    4. Evaluation of gene therapies in HCM. The goal is to suppress the endogenous mutation by different strategies, such as exon skipping, exon inclusion and spliceosome-mediated RNA transplicing or to add exogenous cDNA (in mouse or human cardiac myocytes, engineered heart tissue and in vivo in mice (Mybpc3-targeted knock-in mice) using AAV.

    5. Evaluation of drug-based therapies in Mybpc3-targeted knock-in mice.

    6. Development of a clinical and experimental reference center for hypertrophic cardiomyopathy in Northen Germany: recruitment of patients and relatives with HCM (plus blood sample, septal myectomy, skin biopsy), deciphering of genetic causes, analysis of the pathophysiology and development of personalized therapy concepts (via reprogramming skin fibroblasts into iPS cells and differentiation in cardiac myocytes and engineered heart tissue). Collaborations with Drs Monica Patten and Julia Münch, Cardiology UKE, HEXT-iPS, and EU-FP7-Health-BIG-Heart network, in which biopsies are shared for complementary physiological analyses.

  • Working Group
    Team
    Sharp microelectrode
    Sharp microelectrode
    Contractility
    Contractility
    Patch clamp set up
    Patch clamp set up
    human atrial cardiomyocyte with patch pipette
    Human atrial cardiomyocyte with patch pipette

    Institution
    Institute of Experimental Pharmacology and Toxicology
    University Medical Center Hamburg-Eppendorf

    Working Group
    Kardiale zelluläre Elektrophysiologie
    CVRC PI PD Dr. med Torsten Christ Phone /email 52414 / t.christ@uke.de

    Working group members
    Dr.med. Marc D. Lemoine Phone/email: 56412/m.lemoine@uke.de
    Dr.med. Ahmet Uzun Phone/email: 52387/a.uzun@uke.de
    András Horváth Phone/email: 52466/ahorvath@uke.de
    Marta Lemme Phone/email: 59196/m.lemme@uke.de
    Bernardo Dolce Phone/email: 52466/b.dolce@uke.de
    Zafar Iqbal Phone/email: 52387 z.iqbal@uke.de
    Tobias Krause Phone/email: 56412/tobias.krause@ymail.com
    Anna Steenpaß Phone/email: 52387/steenpas@uke.de

    Brief descriptions of the research focus
    Main interest is regulation of heart function by ion currents and PKA/cAMP activation. Ion channels are still one of the most promising drug targets to stop atrial fibrillation (AF). Block of K+-channels expressed in the atria only may serve as an attractive approach reducing ventricular proarhythmia. We evaluate effects of newly developed blockers of atrial K+-channels on refractoriness in intact human atrial tissue in order to evaluate potential use. Contractile dysfunction in AF is in part related to profound changes in cAMP regulation. Here we study regulation of cAMP in human atrial cardiomyocytes from patients in SR and in AF (in close collaboration with AG Nikolaev). Human induced pluripotent stem-cell derived cardiomyocytes (hIPSC-CM) are a promising tool not only for tissue repair but also to study human heart physiology and pharmacology. However, hIPSC-CM shows some peculiarities (e.g. spontaneous depolarization), questioning how closely they resemble human adult cardiomyocytes. To answer this questions we measure and compare head to head action potentials and ion currents in both hIPSC-CM and adult human CM. Furthermore, we investigate whether hIPSC-CM can serve as a model for human atrial tissue.

    Key techniques/methods
    Key techniques are:

    • Isometric measurements of force in intact cardiac tissue
    • Measurement of action potentials by sharp microelectrodes in intact cardiac tissue
    • Measurement of ion currents in isolated cardiomyocytes

    Recent and relevant publications

    • Wettwer E, Christ T, Endig S, Rozmaritsa N, Matschke K, Lynch JJ, Pourrier M, Gibson JK, Fedida D, Knaut M, Ravens U. The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation. Cardiovasc Res. 2013;98:145-154.
    • Christ T, Rozmaritsa N, Engel A, Berk E, Knaut M, Metzner K, Canteras M, Ravens U, Kaumann A. Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation. Proc Natl Acad Sci U S A. 2014;111:11193-11198.
    • Berk E, Christ T, Schwarz S, Ravens U, Knaut M, Kaumann AJ. In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias. Br J Pharmacol. 2016 Aug;173(16):2478-89.
    • Uzun A, Mannhardt I, Breckwoldt K, Horváth A, Johannsen S, Hansen A, Eschenhagen T, Christ T. Ca2+-currents in human induced pluripotent stem cell-derived cardiomyocytes. Effects of two different culture conditions. Front Pharmacol. 2016 Sep 12;7:300.
    • Horváth A, Lemoine MD. Löser A, Mannhardt I, Flenner F, Uzun AU, Neuber C, Breckwoldt K, Hansen A, Girdauskas E, Reichenspurner H, Willems S, Jost N, Wettwer E, Eschenhagen T, Christ T. Low resting membrane potential and low inward rectifier potassium currents are not inherent features of human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Reports. 2018 Mar 13;10(3):822-833.
    • Lemoine MD, Krause T, Koivumäki JT, Prondzynski M, Schulze M, Girdauskas E, Willems S, Hansen A, Eschenhagen T, Christ T. Engineered Heart Tissue as a Sensitive Test System for QT Prolongation and Arrhythmic Triggers. Circ Arrhythm Electrophysiol. 2018 Jul;11(7):e006035.

    Recent and relevant grants
    Partner within “EU Training Network on Novel Targets and Methods in Atrial Fibrillation” (from 09-2015 to- 08-2019).

  • Assoziierte Klinik : Universitäres Herz- und Gefäßzentrum - Klinik und Poliklinik für Herz- und Gefäßchirurgie

    Cardiac tissue engineering: in vivo application of Engineered Heart Tissue (EHT) The incidence of cardiovascular diseases has increased to become one of the major contributors to morbidity and mortality in the western world today. Therefore, new regenerative treatment strategies are desperately needed. Numerous approaches of stem-cell based myocardial repair have been examined in experimental and clinical settings. However, unequivocal proof of survival and differentiation of transplanted cells into cardiac myocytes or even of improvement of myocardial function remains scarce. In vitro generation of three-dimensional engineered heart tissue constructs and subsequent transplantation onto the failing heart might provide a future option for the therapy of terminal heart failure.

    The technique of generating engineered cardiac muscle tissues from neonatal rat cardiomyocytes has been established and refined at the Institute of Experimental and Clinical Pharmacology and Toxicology during the past 15 years. In recent years the manufacturing process has been adapted and optimized to replace collagen I with fibrin, resulting in a more homogenous distribution of myocytes within the EHT and allowing for miniaturization and standardization of the system. Furthermore recent advantages in stem cell biology allow for the generation of large numbers of human induced pluripotent stem-cell derived cardiomyocytes (hiPS-CM). The production of hiPS-CM EHT constructs has been established in the Institute of Experimental and Clinical Pharmacology and Toxicology.

    The objectives of our group focus on the in vivo application of fibrin-based EHT constructs from neonatal rat- as well as hiPS cell derived cardiomyocytes. After implantation in small animal models, issues like cell survival, electrical- and functional coupling as well as tumor formation (hiPS-CM) will be addressed. Additionally, our group works on the optimization of shape and size of EHT constructs for in vivo application. The presumed potential of EHT to improve myocardial function will be assessed in small animal models of myocardial injury. Furthermore, specific matrix-bound growth factors like VEGF or IGF-1 may be added during construction of EHT, thus creating EHT derivates, that also will be tested, in vivo (EU funded AngioScaff project).

  • Assoziiertes Institut: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie


    Wissenschaftlicher Fokus: Der Fokus der Arbeitsgruppe "Molekulare Pharmakologie" liegt in der Untersuchung der Mechanismen, die zur Veränderung der Signaltransduktion bei kardialer Dysfunktion (z.B. bei kontraktiler Dysfunktion, Myokardinfarkt, Arrhythmie) beitragen, unter Integration physiologischer, pharmakologischer, biochemischer und molekularbiologischer Techniken. Momentane Forschungsprojekte beinhalten die Untersuchung der Auswirkung posttranslationaler Modifikationen wie Phosphorylierung, Dephosphorylierung, oxidative und nitrosative posttranslationale Modifikationen (vermittelt durch Veränderungen des Redox-Gleichgewichtes durch Exposition an H2O2 and/or Nitroxyl; HNO) auf die Myofilamentfunktion.

    Die Projekte beinhalten die komplementäre Anwendung einer Vielzahl unterschiedlicher Techniken wie zum Beispiel die Isolation adulter Kardiomyozyten, Zellkultur, DNA Manipulation, viralen Gentransfer zur Erhöhung oder zum Ausschalten der Expression spezifischer Proteine, Immunofluoreszenz, Konfokale Mikroskopie, Kinase- und Phosphatase-Assays und die Untersuchung der Auswirkungen veränderter Signalwege auf die Myofilamentfunktion in isolierten Zellen, isoliertem Gewebe, und transgenen Tiermodellen.

  • Institution

    Department of Experimental Pharmacology and Toxicology

    Working Group AG Friedrich
    CVRC PI PD Dr. Dr. Felix Friedrich Phone /email +49(0)40/7410-53180, f.friedrich@uke.de

    Working group members
    PD Dr. Dr. Felix Friedrich 040-7410-53180, f.friedrich@uke.de
    Silke Reischmann 040-7410-59770, s.reischmann@uke.de

    Brief descriptions of the research focus
    The scientific focus of the group is on the study of the genetic causes of hypertrophic cardiomyopathy (HCM), the resulting pathological mechanisms and new therapeutic approaches. In this context there is a close collaboration with the research group of Prof. Dr. Lucie Carrier.

    Hypertrophic cardiomyopathy is the most common congenital heart muscle disease (1: 500) and is caused in most cases by mutations in genes encoding for sarcomeric proteins. However, (40% ~) of patients may not have mutations in the already established HCM disease genes. Therefore, the identification of other disease-causing genes for a better understanding and treatment of HCM is highly relevant.

    HCM features are hypertrophy, diastolic dysfunction, loss of myocardial fibrosis and orientation. It is the main cause of sudden cardiac death in young adults and is associated with a significant risk of heart failure. Drug therapy remains largely empirical. In addition to the identification of additional disease genes a research focus is based on the evaluation of potential therapies for HCM. Our therapeutic approach is based on the hypothesis that a mutation-induced increased Ca2+ sensitivity of the myofilaments is a central pathomechanism of the disease. One aim of our projects is to evaluate the impact of substances that either directly affect the Ca2+ sensitivity of myofilaments or influence the intracellular Ca2+ homeostasis in HCM mouse models and heart-muscle samples of HCM patients. Target parameters are heart function assessed by echocardiography, cardiac morphology, molecular parameters and the Ca2+ sensitivity of ventricular muscle strips and contractile function of isolated myocytes. In this respect the group highly benefits from the expertise of the Department of Experimental and Clinical Pharmacology and Toxicology in the field of cardiovascular research.

    Key techniques/methods
    Various molecular biology methods, cell culture, analysis of contractile function of mouse, rat and human cardiac tissues and cells, gene sequencing, engineered heart tissue, adeno-associated virus overexpression, in vivo mouse experiments and echocardiography

    Recent and relevant publications
    Stücker S, Kresin N, Carrier L, Friedrich FW. Nebivolol Desensitizes Myofilaments of a Hypertrophic Cardiomyopathy Mouse Model. Front Physiol. 2017 Aug 2;8:558. doi: 10.3389/fphys.2017.00558.

    Flenner F, Geertz B, Reischmann-Düsener S, Weinberger F, Eschenhagen T, Carrier L*, Friedrich FW*. Diltiazem prevents stress-induced contractile deficits in cardiomyocytes, but does not reverse the cardiomyopathy phenotype in Mybpc3-knock-in mice. J Physiol. 2017 Jan 15. doi: 10.1113/JP273769

    Friedrich FW, Flenner F, Nasib M, Eschenhagen T, Carrier L. Epigallocatechin-3-Gallate Accelerates Relaxation and Ca2+ Transient Decay and Desensitizes Myofilaments in Healthy and Mybpc3-Targeted Knock-in Cardiomyopathic Mice. Front Physiol. 2016 Dec 5;7:607.

    Wijnker PJ, Friedrich FW, Dutsch A, Reischmann S, Eder A, Vollert-Mannhardt I, Mearini G, Eschenhagen T, van der Velden J, Carrier L. Comparison of the effects of a truncating and a missense MYBPC3 mutation on contractile parameters of engineered heart tissue. J Mol Cell Cardiol. 2016 Apr 21. pii: S0022-2828(16)30050-5. doi: 10.1016/j.yjmcc.2016.03.003.

    Flenner F*, Friedrich FW*, Ungeheuer N, Christ T, Geertz B, Reischmann S, Wagner S, Stathopoulou K, Söhren K, Weinberger F, Schwedhelm E, Cuello F, Maier LS, Eschenhagen T, Carrier L. Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effects in vivo in a mouse model of hypertrophic cardiomyopathy. Cardiovasc Res. 2015 Nov 3. pii: cvv247

    Thottakara T*, Friedrich FW*, Reischmann S, Braumann S, Schlossarek S, Krämer E, Juhr D, Schlüter H, van der Velden J, Münch J, Patten M, Eschenhagen T, Moog-Lutz C, Carrier L. The E3 ubiquitin ligase Asb2β is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation. J Mol Cell Cardiol. 2015 Sep 3. pii: S0022-2828(15)30052-3. doi: 10.1016/j.yjmcc.2015.08.020.

    Friedrich FW, Reischmann S, Schwalm A, Unger A, Ramanujam D, Münch J, Müller OJ, Hengstenberg C, Galve E, Charron P, Linke WA, Engelhardt S, Patten M, Richard P, van der Velden J, Eschenhagen T, Isnard R, Carrier L. FHL2 expression and variants in hypertrophic cardiomyopathy. Basic Res Cardiol. 2014 Nov;109(6):451. doi: 10.1007/s00395-014-0451-8.

    Stöhr A, Friedrich FW, Flenner F, Geertz B, Eder A, Schaaf S, Hirt MN, Uebeler J, Schlossarek S, Carrier L, Hansen A, Eschenhagen T. Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice. J Mol Cell Cardiol. 2013 Oct;63:189-98. doi: 10.1016/j.yjmcc.2013.07.011.

    Friedrich FW, Wilding BR, Reischmann S, Crocini C, Lang P, Charron P, Müller OJ, McGrath MJ, Vollert I, Hansen A, Linke WA, Hengstenberg C, Bonne G, Morner S, Wichter T, Madeira H, Arbustini E, Eschenhagen T, Mitchell CA, Isnard R, Carrier L. Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. Hum Mol Genet. 2012 Jul 15;21(14):3237-54. doi: 10.1093/hmg/dds157.

    Weinberger F, Mehrkens D, Friedrich FW, Stubbendorff M, Hua X, Müller JC, Schrepfer S, Evans SM, Carrier L, Eschenhagen T. Localization of islet-1-positive cells in the healthy and infarcted adult murine heart. Circ Res. 2012 May 11;110(10):1303-10.

    Friedrich FW, Bausero P, Sun Y, Treszl A, Krämer E, Juhr D, Richard P, Wegscheider K, Schwartz K, Brito D, Arbustini E, Waldenström A, Isnard R, Komajda M, Eschenhagen T, Carrier L; EUROGENE Heart Failure Project. A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. Eur Heart J. 2009 Jul;30(13):1648-55.

    Recent and relevant grants Deutsche Stiftung für Herzforschung F-28-12, F-24-15, F-15-17

  • Assoziiertes Institut: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie

    Engineered heart tissue for drug development and predictive toxicology Drug development is a time consuming and expensive process. One of the major difficulties is the inability of current tests to identify toxic effects of lead compounds early in this process. As a consequence late stage recognition of toxicity leads to enormous costs and delay of the process.

    Aim of this project is the optimization of engineered heart tissue (EHT) technology to serve as a screening tool for cardiac toxicity/arrhythmic potential in early stages of drug development.

    To this end the recent research focused on the establishment of EHTs from neonatal rat cardiac myocytes on the basis of fibrin matrix and the miniaturisation of the tissue constructs. This led to a 24 well EHT-platform, which allows for the robust generation and analysis of force, frequency and rhythm of 8 mm long stripe shaped EHT constructs which are attached to silicon holders. Current focus is directed on the automated analysis and fine-tuning of culture conditions for screening purposes in a medium throughput format.

    A second aspect of this project is employment of cardiomyocytes from human embryonic stem cells (hESC) as a human cell source for fibrin EHTs. Current investigations are focused on the establishment and optimisation of cardiac differentiation of hESCs and the identification of mesodermal/cardiac progenitors at early stages of cardiac differentiation.

  • ..
    ..

    Institution
    Institute of Experimental Pharmacology and Toxicology
    University Medical Center Hamburg-Eppendorf

    Working Group
    Cardiac hypertrophy / non-coding RNAs
    CVRC PI PD Dr. Dr. Marc Hirt Phone /email +49 40 7410 53180 / m.hirt@uke.de

    Working group members
    Jutta Starbatty starbatt@uke.de
    Ann-Cathrin Kunze ann-cathrin.kunze@gmx.de
    Dr. Benjamin Kloth b.kloth@uke.de
    Dr. Sandra Funcke s.funcke@uke.de

    Former but still affiliated members
    Dr. Tessa Werner t.werner@imb.uq.edu.au
    Dr. Marita Rodriguez marita.rodriguez3@gmail.com

    Brief descriptions of the research focus
    Cardiac hypertrophy is the most important risk factor for the development of heart failure which is the leading cause of death in industrialized nations. We aim to decipher some of the molecular mechanisms of cardiac hypertrophy by a model of cardiac hypertrophy which we have developed over the past couple of years. It is based on engineered heart tissue (EHT), a 3-dimensional cell culture format for heart cells, which we subject to enhanced workload thus inducing phenotypical characteristics of cardiac disease. The idea behind our cardiac hypertrophy model is the enhancement of afterload/workload (AE = afterload enhancement) of these small tissue strips by a simple mechanical metal brace. Most fascinating is that engineered heart tissues (EHTs) beat spontaneously. In contrast to simple cell cultures of cardiomyocytes EHTs provide therefore the optimal assay to assess the essential cardiac properties frequency and force, which can be analyzed automatically with technologies developed in our institute. “And it works!” The model of cardiac hypertrophy displays in vitro many aspects of cardiac hypertrophy/heart failure: Cardiomyocyte hypertrophy, fibrosis, metabolic changes towards glycolysis, characteristical changes in coding and noncoding RNAs and many more. Future directions: The next step we are working towards is the transition of this model of cardiac hypertrophy from rat heart cells to human heart cells. For this endeavor, we take advantage of the latest advances in stem cell technology. The discovery of human induced pluripotent stem cells made it – in principal - possible to create all cell types in the human body including all types of human heart cells without ethical concerns or animal experiments. Lately, we have been able to create fluorescently labeled human multi-cell-type EHTs containing blue cardiomyocytes, green endothelial cells, orange smooth muscle cells and red fibroblasts. These EHTs in combination with a magnetics-based device that enables us to modulate stepwise increases in workload enable us to analyze the impact of timing and magnitude of afterload on human heart tissue to deeply investigate pathological cardiac hypertrophy (like in heart failure) and potentially even physiological cardiac hypertrophy (like in an athlete’s heart).

    Key techniques/methods

    • Generation of rat EHT (engineered heart tissue, a 3-dimensional cell culture format for heart cells)
    • Generation of mono-cell-type human EHT with cardiomyocytes from human induced pluripotent stem cells
    • Generation of multi-cell-type human EHT (cardiomyocytes, endothelial cells, smooth muscle cells, fibroblasts, all from human induced pluripotent stem cells)
    • Automated contractility analysis of EHTs including contractile force, frequency, contraction and relaxation velocity, contraction and relaxation time, fractional shortening, arrhythmicity and many more
    • Analysis and modulation of non-coding RNAs (microRNAs, lncRNAs)
    • All standard molecular biology and microscopy techniques

    Recent and relevant publications
    Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. Stenzig J, Schneeberger Y, Löser A, Peters BS, Schaefer A, Zhao RR, Ng SL, Höppner G, Geertz B, Hirt MN, Tan W, Wong E, Reichenspurner H, Foo RS, Eschenhagen T. J Mol Cell Cardiol. 2018 Jul;120:53-63. doi: 10.1016/j.yjmcc.2018. 05.012. Epub 2018 May 21. PMID: 29792884

    Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density. Lemoine MD, Mannhardt I, Breckwoldt K, Prondzynski M, Flenner F, Ulmer B, Hirt MN, Neuber C, Horváth A, Kloth B, Reichenspurner H, Willems S, Hansen A, Eschenhagen T, Christ T. Sci Rep. 2017 Jul 14;7(1):5464. doi: 10.1038/s41598-017-05600-w. PMID: 28710467

    Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation. Barallobre-Barreiro J, Gupta SK, Zoccarato A, Kitazume-Taneike R, Fava M, Yin X, Werner T, Hirt MN, Zampetaki A, Viviano A, Chong M, Bern M, Kourliouros A, Domenech N, Willeit P, Shah AM, Jahangiri M, Schaefer L, Fischer JW, Iozzo RV, Viner R, Thum T, Heineke J, Kichler A, Otsu K, Mayr M. Circulation. 2016 Sep 13;134(11):817-32. doi: 10.1161/CIRCULATIONAHA.115.016423. Epub 2016 Aug 24. PMID: 27559042

    Human Engineered Heart Tissue: Analysis of Contractile Force. Mannhardt I, Breckwoldt K, Letuffe-Brenière D, Schaaf S, Schulz H, Neuber C, Benzin A, Werner T, Eder A, Schulze T, Klampe B, Christ T, Hirt MN, Huebner N, Moretti A, Eschenhagen T, Hansen A. Stem Cell Reports. 2016 Jul 12;7(1):29-42. doi: 10.1016/j.stemcr.2016.04.011. Epub 2016 May 19. PMID: 27211213

    Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia. Schäfer M, Oeing CU, Rohm M, Baysal-Temel E, Lehmann LH, Bauer R, Volz HC, Boutros M, Sohn D, Sticht C, Gretz N, Eichelbaum K, Werner T, Hirt MN, Eschenhagen T, Müller-Decker K, Strobel O, Hackert T, Krijgsveld J, Katus HA, Berriel Diaz M, Backs J, Herzig S. Mol Metab. 2015 Nov 26;5(2):67-78. doi: 10.1016/j.molmet.2015.11.004. eCollection 2016 Feb. PMID: 26909315

    Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. Jacob F, Yonis AY, Cuello F, Luther P, Schulze T, Eder A, Streichert T, Mannhardt I, Hirt MN, Schaaf S, Stenzig J, Force T, Eschenhagen T, Hansen A. PLoS One. 2016 Feb 3;11(2):e0145937. doi: 10.1371/journal.pone.0145937. eCollection 2016. PMID: 26840448

    Spontaneous Formation of Extensive Vessel-Like Structures in Murine Engineered Heart Tissue. Stoehr A*, Hirt MN* (*equal contribution), Hansen A, Seiffert M, Conradi L, Uebeler J, Limbourg FP, Eschenhagen T. Tissue Eng Part A. 2016 Feb;22(3-4):326-35. doi: 10.1089/ten.TEA.2015. 0242. PMID: 26763667

    DNA methylation in an engineered heart tissue model of cardiac hypertrophy: common signatures and effects of DNA methylation inhibitors. Stenzig J*, Hirt MN (*equal contribution), Löser A, Bartholdt LM, Hensel JT, Werner TR, Riemenschneider M, Indenbirken D, Guenther T, Müller C, Hübner N, Stoll M, Eschenhagen T. Basic Res Cardiol. 2016 Jan;111(1):9. doi: 10.1007/s00395-015-0528-z. Epub 2015 Dec 17. PMID: 26680771

    General practitioners' adherence to chronic heart failure guidelines regarding medication: the GP-HF study. Hirt MN, Muttardi A, Helms TM, van den Bussche H, Eschenhagen T. Clin Res Cardiol. 2016 May;105(5):441-50. doi: 10.1007/s00392-015-0939-8. Epub 2015 Nov 9. PMID: 26552905

    Deciphering the microRNA signature of pathological cardiac hypertrophy by engineered heart tissue- and sequencing-technology. Hirt MN, Werner T, Indenbirken D, Alawi M, Demin P, Kunze AC, Stenzig J, Starbatty J, Hansen A, Fiedler J, Thum T, Eschenhagen T. J Mol Cell Cardiol. 2015 Apr;81:1-9. doi: 10.1016/j.yjmcc.2015.01.008. Epub 2015 Jan 26. PMID: 25633833

    Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation. Hirt MN, Boeddinghaus J, Mitchell A, Schaaf S, Börnchen C, Müller C, Schulz H, Hubner N, Stenzig J, Stoehr A, Neuber C, Eder A, Luther PK, Hansen A, Eschenhagen T. J Mol Cell Cardiol. 2014 Sep;74:151-61. doi: 10.1016/j.yjmcc.2014.05.009. Epub 2014 May 19. PMID: 24852842

    Automated analysis of contractile force and Ca2+ transients in engineered heart tissue. Stoehr A, Neuber C, Baldauf C, Vollert I, Friedrich FW, Flenner F, Carrier L, Eder A, Schaaf S, Hirt MN, Aksehirlioglu B, Tong CW, Moretti A, Eschenhagen T, Hansen A. Am J Physiol Heart Circ Physiol. 2014 May;306(9):H1353-63. doi: 10.1152/ajpheart.00705.2013. Epub 2014 Feb 28. PMID: 24585781

    Cardiac tissue engineering: state of the art. Hirt MN, Hansen A, Eschenhagen T. Circ Res. 2014 Jan 17;114(2):354-67. doi: 10.1161/CIRCRESAHA.114.300522. Review. PMID: 24436431

    Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice. Stöhr A, Friedrich FW, Flenner F, Geertz B, Eder A, Schaaf S, Hirt MN, Uebeler J, Schlossarek S, Carrier L, Hansen A, Eschenhagen T. J Mol Cell Cardiol. 2013 Oct;63:189-98. doi: 10.1016/j.yjmcc.2013.07.011. Epub 2013 Jul 26. PMID: 23896226

    Increased afterload induces pathological cardiac hypertrophy: a new in vitro model. Hirt MN, Sörensen NA, Bartholdt LM, Boeddinghaus J, Schaaf S, Eder A, Vollert I, Stöhr A, Schulze T, Witten A, Stoll M, Hansen A, Eschenhagen T. Basic Res Cardiol. 2012 Nov;107(6):307. doi: 10.1007/s00395-012-0307-z. Epub 2012 Oct 26. PMID: 23099820

    Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. Schaaf S, Shibamiya A, Mewe M, Eder A, Stöhr A, Hirt MN, Rau T, Zimmermann WH, Conradi L, Eschenhagen T, Hansen A. PLoS One. 2011;6(10):e26397. doi: 10.1371/journal.pone.0026397. Epub 2011 Oct 20. PMID: 22028871

    Recent and relevant grants
    Grants from DZHK, Werner Otto Stiftung and the German Israeli Foundation (GIF)

  • Assoziierte Klinik: Klinik und Poliklinik für Anästhesiologie

    Der akute Lungenschaden ist eine häufige Komplikation bei Sepsispatienten. Die Gewebeschädigung wird durch die im Rahme der systemischen Entzündungsreaktion freigesetzten Zytokine, Proteasen und Radikale aber auch durch die Bakterien selber hervorgerufen. Die endotheliale Glykokalyx, die Zuckerverbindungen wie Heparansulfate enthält, bildet eine anatomische Schicht zwischen zirkulierenden Entzündungsmediatoren bzw. Bakterien und der Oberfläche des Endothels.

    Da die Rolle der Glykokalyx bei der inflammatorischen Signaltransduktion bisher unklar ist, stellten wir die Hypothese auf, dass die während der Entzündungreaktion freigesetzten Radikale, wie z.B. das H2O2, oder Bakterien eine über die Glykokalyx vermittelte endotheliale Stimulation vermitteln. Hierzu wurde in kapillaren Endothelzellen isoliert perfundierter Mäuselungen sowie in kultivierten Endothelzellen die zytosolische Konzentration des Signalbotenstoffes Calcium mit Hilfe der Fura-2 Videofluoreszenzmikroskopie quantifiziert. Unsere Ergebnisse lassen einen bisher unbekannten rezeptorvermittelten Mechanismus im Rahmen dieses inflammatorischen Geschehens vermuten: H2O2 spaltet aus der endothelialen Glykokalyx Heparansulfat ab, welches konsekutiv über den Oberflächenrezeptor CD44 zu einer intrazellulären Kalzium-Reaktion führt. Darüber hinaus konnten wir zeigen, dass Pneumokokken nur in Verbindung mit Erythrozyten ein endotheliales Calciumsignal induzieren. Die Rolle der Erythrozyten im Rahmen der Infektabwehr wurde bislang nicht beschrieben. Wir vermuten, dass Bakterien die endotheliale Glykokalyx degradieren und die Erythrozyten über die dadurch induzierte Änderung der mikrozirkulatorischen Scherkräfte eine endotheliale Signaltransduktion induzieren

  • Team AG Nikolaev
    Team

    Institution: Institut für Experimentelle Herz-Kreislaufforschung

    Working Group: AG Nikolaev

    CVRC PI: Prof. Dr. Viacheslav O Nikolaev Phone /email: 57095 / v.nikolaev@uke.de

    Working group members

    Dr. Cristina E Molina 57095 / c.molina@uke.de
    Dr. Alexander Froese 51743 / a.froese@uke.de
    Dr. Hariharan Subramanian 57383 / h.subramanian@uke.de
    Dr. Kirstie De Jong 57383 / k.de-jong@uke.de
    Dr. Sergei Rybalkin 57095 / s.rybalkin@uke.de
    Dr. Nadja Bork 51743 / n.bork@uke.de
    Nefeli Grammatika Pavlidou 51743 / nefeligramm@gmail.com
    Nikoleta Pavlaki 57383 / n.pavlaki@uke.de
    Robert Wiegmann 51743 / robert.wiegmann@stud.uke.uni-hamburg.de

    Brief descriptions of the research focus

    The cyclic nucleotides (cAMP and cGMP) regulate cardiac function acting as second messengers for sympathetic and parasympathetic, nitric oxide (NO) and natriuretic peptide systems. Cyclic nucleotides may exert beneficial or deleterious effects on the heart, depending on the duration of the stimulation. Acute elevation of cyclic nucleotides regulates cardiac excitation-contraction coupling. Chronic elevation of cAMP contributes to the development of many cardiac diseases such as cardiac hypertrophy, heart failure and atrial fibrillation, while cGMP seems to covey mostly beneficial effects. The general objective of our laboratory is to understand the molecular mechanisms responsible for the homeostasis of these two second messengers and the functional consequences for cardiac function. By combining biochemical, molecular, genetic, electrophysiological and imaging techniques we aim to elucidate the mechanisms responsible for the temporal and spatial control of cyclic nucleotides signalling and their relevance to both physiological and disease conditions in animal as well as in human models.

    Key techniques/methods

    Cardiomyocytes isolation, Förster resonance energy transfer (FRET) biosensors, scanning ion conductance microscopy (SICM), patch-clamp, confocal imaging, immunostaining, western blot, qPCR

    Recent and relevant publications

    • De Jong KA, Nikolaev VO. Multifaceted remodelling of cAMP microdomains driven by different aetiologies of heart failure FEBS J. 2021 Jan 8. doi: 10.1111/febs.15706. Online ahead of print. PMID: 33415835 Review.
    • Garnier A, Bork NI, Jacquet E, Zipfel S, Muñoz-Guijosa C, Baczkó I, Reichenspurner H, Donzeau-Gouge P, Maier LS, Dobrev D, Girdauskas E, Nikolaev VO, Fischmeister R, Molina CE. Garnier A, et al. Mapping genetic changes in the cAMP-signaling cascade in human atria. J Mol Cell Cardiol. 2021 Feb 22;155:10-20. doi: 10.1016/j.yjmcc.2021.02.006. Online ahead of print.J Mol Cell Cardiol. 2021. PMID: 33631188
    • Iqbal Z, Ismaili D, Dolce B, Petersen J, Reichenspurner H, Hansen A, Kirchhof P, Eschenhagen T, Nikolaev VO, Molina CE, Christ T. Regulation of basal and norepinephrine-induced cAMP and ICa in hiPSC-cardiomyocytes: Effects of culture conditions and comparison to adult human atrial cardiomyocytes. Cell Signal. 2021 Mar 4:109970. doi: 10.1016/j.cellsig.2021.109970. Online ahead of print.Cell Signal. 2021. PMID: 33677066
    • Dolce B, Christ T, Grammatika Pavlidou N, Yildirim Y, Reichenspurner H, Eschenhagen T, Nikolaev VO, Kaumann AJ, Molina CE. Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation
      Naunyn Schmiedebergs Arch Pharmacol. 2021 Feb;394(2):291-298. doi: 10.1007/s00210-020-01968-1. Epub 2020 Sep 19.Naunyn Schmiedebergs Arch Pharmacol. 2021.PMID: 32949251
    • Li X, Li J, Martinez EC, Froese A, Passariello CL, Henshaw K, Rusconi F, Li Y, Yu Q, Thakur H, Nikolaev VO, Kapiloff MS. Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy
      Circulation. 2020 Sep 8;142(10):948-962. PMID: 32611257
    • Schobesberger S, Wright PT, Poulet C, Sanchez Alonso Mardones JL, Mansfield C, Friebe A, Harding SE, Balligand JL, Nikolaev VO, Gorelik J. β 3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes Elife. 2020 Mar 31;9:e52221. PMID: 32228862
    • Špiranec Spes K, Chen W, Krebes L, Völker K, Abeßer M, Eder Negrin P, Cellini A, Nickel A, Nikolaev VO, Hofmann F, Schuh K, Schweda F, Kuhn M. Heart-Microcirculation Connection: Effects of ANP (Atrial Natriuretic Peptide) on Pericytes Participate in the Acute and Chronic Regulation of Arterial Blood Pressure Hypertension. 2020 Nov;76(5):1637-1648. doi: 10.1161/HYPERTENSIONAHA.120.15772. Epub 2020 Sep 21. PMID:32951468
    • Diering S, Stathopoulou K, Goetz M, Rathjens L, Harder S, Piasecki A, Raabe J, Schulz S, Brandt M, Pflaumenbaum J, Fuchs U, Donzelli S, Sadayappan S, Nikolaev VO, Flenner F, Ehler E, Cuello F. Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase signaling in cardiac myocytes by oxidizing agents J Biol Chem. 2020 Nov 6;295(45):15342-15365. PMID: 32868295
    • Eiringhaus J, Wünsche CM, Tirilomis P, Herting J, Bork N, Nikolaev VO, Hasenfuss G, Sossalla S, Fischer TH. Sacubitrilat reduces pro-arrhythmogenic sarcoplasmic reticulum Ca 2+ leak in human ventricular cardiomyocytes of patients with end-stage heart failure ESC Heart Fail. 2020 Oct;7(5):2992-3002. doi: 10.1002/ehf2.12918. PMID: 32710603
    • Hofhuis J, Bersch K, Wagner S, Molina C, Fakuade FE, Iyer LM, Streckfuss-Bömeke K, Toischer K, Zelarayán LC, Voigt N, Nikolaev VO, Maier LS, Klinge L, Thoms S.Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy Europace. 2020 Jul 1;22(7):1119-1131. PMID: 32572487
    • Bastug-Özel Z, Wright PT, Kraft AE, Pavlovic D, Howie J, Froese A, Fuller W, Gorelik J, Shattock MJ, Nikolaev VO. Heart failure leads to altered β2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain. Cardiovasc Res. 2019 Mar 1;115(3):546-555.
    • Subramanian H, Froese A, Jönsson P, Schmidt H, Gorelik J, Nikolaev VO. Distinct submembrane localisation compartmentalises cardiac NPR1 and NPR2 signalling to cGMP. Nat Commun. 2018 Jun 22;9(1):2446.
    • Bork NI, Nikolaev VO. cGMP Signaling in the Cardiovascular System-The Role of Compartmentation and Its Live Cell Imaging. Int J Mol Sci. 2018 Mar 10;19(3). pii: E801.
    • Pavlaki N, Nikolaev VO. Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes. J Cardiovasc Dev Dis. 2018 Jan 19;5(1). pii: E4.
    • Jungen C, Scherschel K, Eickholt C, Kuklik P, Klatt N, Bork N, Salzbrunn T, Alken F, Angendohr S, Klene C, Mester J, Klöcker N, Veldkamp MW, Schumacher U, Willems S, Nikolaev VO, Meyer C. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias. Nat Commun. 2017 Jan 27;8:14155. doi: 10.1038/ncomms14155.
    • Kraft AE, Nikolaev VO. FRET Microscopy for Real-Time Visualization of Second Messengers in Living Cells. Methods Mol Biol. 2017;1563:85-90.
    • Froese A, Nikolaev VO. Imaging alterations of cardiomyocyte cAMP microdomains in disease. Front Pharmacol. 2015 Aug 25;6:172.
    • Sprenger JU, Perera RK, Steinbrecher JH, Lehnart SE, Maier LS, Hasenfuss G, Nikolaev VO. In vivo model with targeted cAMP biosensor reveals changes in receptor-microdomain communication in cardiac disease. Nat Commun. 2015 Apr 28;6:6965.
    • Perera RK, Sprenger JU, Steinbrecher JH, Hübscher D, Lehnart SE, Abesser M, Schuh K, El-Armouche A, Nikolaev VO. Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ Res. 2015 Apr 10;116(8):1304-11.
    • Götz KR, Sprenger JU, Perera RK, Steinbrecher JH, Lehnart SE, Kuhn M, Gorelik J, Balligand JL, Nikolaev VO. Transgenic mice for real-time visualization of cGMP in intact adult cardiomyocytes. Circ Res. 2014 Apr 11;114(8):1235-45.
    • Froese A, Breher SS, Waldeyer C, Schindler RF, Nikolaev VO, Rinné S, Wischmeyer E, Schlueter J, Becher J, Simrick S, Vauti F, Kuhtz J, Meister P, Kreissl S, Torlopp A, Liebig SK, Laakmann S, Müller TD, Neumann J, Stieber J, Ludwig A, Maier SK, Decher N, Arnold HH, Kirchhof P, Fabritz L, Brand T. Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest. 2012 Mar;122(3):1119-30.
    • Börner S, Schwede F, Schlipp A, Berisha F, Calebiro D, Lohse MJ, Nikolaev VO. FRET measurements of intracellular cAMP concentrations and cAMP analog permeability in intact cells. Nat Protoc. 2011 Apr;6(4):427-38.
    • Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science. 2010 Mar 26;327(5973):1653-7.
    • Nikolaev VO, Gambaryan S, Lohse MJ. Fluorescent sensors for rapid monitoring of intracellular cGMP. Nat Methods. 2006 Jan;3(1):23-5.

    Recent and relevant grants

    Prof. Nikolaev and the Institute of Experimental Cardiovascular Research are funded by the Gertraud and Heinz Rose Foundation and several national and international grants.

    Our institute participates in the DFG research group 2060 “cGMP in cell growth and survival” with a subproject "cGMP microdomains in cardiomyocyte hypertrophy and heart failure". Moreover, we have subprojects in the newly funded Collaborative Research Center SFB1328 “Adenine nucleotides in immunity and inflammation” as well as in the European Research Area (ERANet) program called ERA-CVD.

    As part of the DZHK Hamburg/Kiel/Lübeck partner site, a scientific project entitled "Modulation of cAMP microdomains" is being purused. Its goal is the preclinical development of new therapeutic approached in the field of specific modulation of subcellular cAMP signals.

  • Forschungsfokus der Arbeitsgruppe

    Molekulare Pathogenese des Diabetes mellitus Typ 2 und seiner Komplikationen
    Diabetes mellitus gehört zu den weltweit am stärksten zunehmenden Erkrankungen. Mikro- und makrovaskuläre Komplikationen mit Erkrankungen des kardiovaskulären Systems zählen zu den Folgeerkrankungen von Diabetes. Neben der peripheren Insulinresistenz führt der Verlust der Funktion und der Masse der Insulin produzierenden pankreatischen beta-Zellen zu Diabetes Typ 2. Unsere eigenen Untersuchungen zeigen, dass die dual leucine zipper kinase (DLK) beta-Zellapoptose und damit beta-Zellverlust induziert. Wir untersuchen jetzt die Rolle der DLK für die Entstehung von Diabetes und wie diese Kinase reguliert wird.

    Rolle des transkriptionellen Koaktivators CRTC1 für die Entwicklung maladaptiver Herzhypertrophie.
    Cyclic AMP regulated transcriptional co-activator 1 (CRTC1) wird in Kardiomyozyten durch beta-adrenerge Signale reguliert. In humanen und murinen Herzen mit HCM findet sich ein erhöhter Gehalt an CRTC1. Wir untersuchen jetzt die Rolle von CRTC1 in der Entwicklung der kardialen Hypertrophie.

    Beschreibung der Methoden

    Reportergenassays, Immunoblotanalysen und biochemische und molekularbiologische Methoden.

    Assoziierte Klinik: Universitäres Herz- und Gefäßzentrum Hamburg - Kardiologie

    Institution
    Universitäres Herz- und Gefäßzentrum Hamburg GmbH (UHZ), Klinik für Kardiologie

    Working Group
    Kardiovaskuläre Forschung, Epidemiologie, Biostatistik und Datenmanagement- Cardiovascular Research, Epidemiology, Biostatistics and Data Management

    CVRC PI
    Prof. Dr. med. Renate Schnabel Phone /email: +49 (0) 40 7410 - 53979 /r.schnabel@uke.de

    Working group members
    Dr. Francisco Ojeda +49 (0) 40 7410 – 28287 / f.ojeda-echevarria@uke.de
    M. Sc. Nicole Rübsamen +49 (0) 40 7410 -28286 / n.ruebsamen@uke.de
    M. Sc. Nargiz Rzayeva +49 (0) 40 7410 - 28279 / n.rzayeva@uke.de
    Dr. Nataliya Makarova +49 (0) 40 7410 - 28289 / n.makarova@uke.de B. Sc.
    Adil Ghrib +49 (0) 1522/2897424 / a.ghrib@uke.de
    M. Sc. Ngoc Anh Sprünker +49 (0) 40 7410 - 28279 / n.spruenker@uke.de
    M. Sc. Daniel Engler +49 (0) 40 7410- 28276 / d.engler@uke.de
    B. Sc. Mareike Kallweit +49 (0) 40 7410- 59339 / m.kallweit@uke.de
    Peter Lasch +49 (0) 40 7410- 39126 / lasch@uke.de
    M. Sc. Alina Goßling +49 (0) 40 7410- 28288 / a.gossling@uke.de
    Dr. Bastiaan Geelhoed +49 (0) 1522/2810149 / b. geelhoed@uke.de
    M. Sc. Thiess Lorenz +49 (0) 40 7410- 28285 / t.lorenz@uke.de

    Brief descriptions of the research focus

    Kardiovaskuläre Forschung, Epidemiologie, Biostatistik und Datenmanagement
    Ziel unserer Arbeitsgruppe ist es, die Prädisposition für kardiovaskuläre Erkrankungen sowie frühe, reversible Stadien der Erkrankung zu erfassen, um eine Prävention und frühe Intervention zu ermöglichen. Wir nutzen hierzu Biomarker und genetische Analysen der nicht-invasiv erfassten Gefäßfunktion in prospektiven Kohortenstudien sowohl bei initial Gesunden als auch bei Patienten mit manifester kardiovaskulärer Erkrankung.

    Kardiovaskuläre Erkrankungen sind weltweit die häufigste Ursache für Tod und Morbidität. Wir fangen erst an, die Pathophysiologie und Suszeptibilität in der Allgemeinbevölkerung zu verstehen.

    Die Integration von Daten neu entdeckter und klassischer Risikofaktoren und die Assoziation mit inzidenter Erkrankung sollen die aktuellen Risikoalgorithmen verbessern, um eine präventive, personalisierte kardiovaskuläre Medizin zu erlauben und Interventionsmöglichkeiten aufzuzeigen. Internationale Kollaborationen u.a. mit der Framingham Heart Study, MORGAM Kohorten und dem BiomarCaRE Projekt unterstützen dieses Vorhaben.

    Risikoprädiktion bei Vorhofflimmern
    Vorhofflimmern ist die häufigste anhaltende Herzrhythmusstörung mit erheblicher Komorbidität und Mortalität. Die Prävalenz nimmt weltweit zu – mit entsprechenden Implikationen in der Klinik und für das Gesundheitssystem. Präventive Maßnahmen sind erforderlich, aber verhältnismäßig wenig ist bekannt über Risikofaktoren, außer einer Handvoll etablierter Risikofaktoren, die vor kurzem von uns in einem Risikoscore zusammengefasst wurden. Gemeinsam erklären diese Risikofaktoren jedoch lediglich 60% des attributablen Risikos in der Population. Neue Ansätze zur Verbesserung der Risikoprädiktion sind dringend erforderlich.

    Vorhofflimmern wird durch das Elektrokardiogramm (EKG) diagnostiziert. In einer epidemiologischen Studie untersuchen wir elektrokardiographische Veränderungen, die zu Vorhofflimmern führen können. Zudem werden innovative Methoden zur Biomarkerbestimmung, genetische und Genexpressionsanalysen in Querschnittsuntersuchungen und auch prospektiv durchgeführt, um neue Risikofaktoren zu identifizieren. Eine enge Kooperation zwischen Epidemiologen, Elektrophysiologen und Kardiochirurgen ist hierzu essentiell. Unsere Daten werden neue Einblicke in die Epidemiologie und Prävention geben sowie das pathophysiologische Verständnis der Erkrankung erweitern und möglicherweise therapeutische Optionen aufzeigen. Dazu verwenden wir u.a. folgende Methoden:

    • Epidemiologische Kohortenstudien
    • Biobanking
    • Nicht-invasive Gefäßfunktionsmessung der flussmediierten Dilatation (FMD) und peripheren arteriellen Tonometrie (PAT)
    • Digitale Oberflächen-Elektrokardiographie

    Key techniques/methods
    Um epidemiologische Fragestellungen zu beantworten, ist es entscheidend, die richtigen Methoden für diese Fragestellungen auszuwählen. Unsere Arbeitsgruppe verfügt daher über ein breites Spektrum an statistischer Expertise.

    Regressionsanalysen erlauben es, Beziehungen zwischen einer abhängigen und einer oder mehreren unabhängigen Variablen zu modellieren. Sie zählen daher zu den statistischen Standardmethoden. Unsere Arbeitsgruppe hat Erfahrung in der Anwendung unterschiedlichster Regressionsanalysen, z.B. der Cox-Regression. Diese Methode wird typischerweise in der Analyse von Kohortenstudien angewandt, um Überlebenszeiten (d.h. die Zeit bis zum Eintritt eines bestimmten Ereignisses wie Tod, erneute Erkrankung o.Ä.) zu modellieren und dadurch Risikofaktoren für Tod und Morbidität zu identifizieren. Für Fall-Kontroll-Studien wenden wir dagegen meist die logistische Regression an.

    Wenn eine Messung nicht nur einmalig durchgeführt, sondern mehrmals wiederholt wird (egal ob zum selben Zeitpunkt oder im Abstand mehrerer Jahre), benötigt man Regressionsmethoden für longitudinale Daten. Unsere Arbeitsgruppe verwendet für solche Analysen sogenannte „gemischte Modelle“ (die Benennung verweist darauf, dass diese Modelle sowohl „fixed effects“ als auch „random effects“ enthalten) und GEE-Modelle (generalized estimating equation). Wenn longitudinale Daten mit Überlebenszeiten in Beziehung gesetzt werden sollen, sind „Joint Models“ die Methode der Wahl.

    In allen Analysen, die die krankheitsspezifische Mortalität oder die Neuerkrankung an einer bestimmten Krankheit betrachten, es ist zu empfehlen, konkurrierende Risiken zu beachten. Wenn z.B. Risikofaktoren für die Inzidenz des Vorhofflimmerns identifiziert werden sollen, dann muss Tod als konkurrierendes Risiko betrachtet werden, da für Probanden, die während des Studienzeitraums sterben, nicht bekannt ist, ob sie Vorhofflimmern entwickelt hätten, wenn sie nicht gestorben wären. Wir verwenden für solche Analysen unter anderem die Regressionsmethode von Fine und Gray. Auch für andere als die oben genannten Fragestellungen verfügen wir über die nötige Expertise, um passende Analysemethoden anzuwenden.

    Recent and relevant publications

    Adherence to Mediterranean diet, high-sensitive C-reactive protein, and severity of coronary artery disease: Contemporary data from the INTERCATH cohort.
    Waldeyer C, Brunner FJ, Braetz J, Ruebsamen N, Zyriax BC, Blaum C, Kroeger F, Kohsiack R, Schrage B, Sinning C, Becher PM, Karakas M, Zeller T, Westermann D, Sydow K, Blankenberg S, Seiffert M, Schnabel RB.
    Atherosclerosis. 2018 Jun 22;275:256-261. doi: 10.1016/j.atherosclerosis.2018.06.877.

    Multi-ethnic genome-wide association study for atrial fibrillation
    Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM, Almgren P, Alonso A, Anderson CD, Aragam KG, Arking DE, Barnard J, Bartz TM, Benjamin EJ, Bihlmeyer NA, Bis JC, Bloom HL, Boerwinkle E, Bottinger EB, Brody JA, Calkins H, Campbell A, Cappola TP, Carlquist J, Chasman DI, Chen LY, Chen YI, Choi EK, Choi SH […] Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA […]Ellinor PT.

    Sex and Stroke Risk in Atrial Fibrillation: More Work to Be Done.
    Schnabel RB, Pecen L, Rzayeva N, Lucerna M, Purmah Y, Ojeda FM, De Caterina R, Kirchhof P.
    J Am Heart Assoc. 2018 May 18;7(11). pii: e007559. doi: 10.1161/JAHA.117.007559.

    Symptom Burden of Atrial Fibrillation and Its Relation to Interventions and Outcome in Europe.
    Schnabel RB, Pecen L, Rzayeva N, Lucerna M, Purmah Y, Ojeda FM, De Caterina R, Kirchhof P.J Am Heart Assoc. 2018 May 18;7(11). pii: e007559. doi: 10.1161/JAHA.117.007559.

    Relations of Sex to Diagnosis and Outcomes in Acute Coronary Syndrome.
    Sörensen NA, Neumann JT, Ojeda F, Schäfer S, Magnussen C, Keller T, Lackner KJ, Zeller T, Karakas M, Münzel T, Blankenberg S, Westermann D, Schnabel RB.
    J Am Heart Assoc. 2018 Mar 10;7(6). pii: e007297. doi: 10.1161/JAHA.117.007297.

    Atrial Fibrillation Manifestations Risk Factors and Sex Differences in a Population-Based Cohort (From the Gutenberg Health Study).
    Magnussen C, Ojeda FM, Wild PS, Sörensen N, Rostock T, Hoffmann BA, Prochaska J, Lackner KJ, Beutel ME, Blettner M, Pfeiffer N, Rzayeva N, Sinning CR, Blankenberg S, Münzel T, Zeller T, Schnabel RB.
    Am J Cardiol. 2018 Jul 1;122(1):76-82. doi: 10.1
    16/j.amjcard.2018.03.028. Epub 2018 Mar 29.

    Atrial fibrillation patterns are associated with arrhythmia progression and clinical outcomes.
    B Schnabel R, Pecen L, Engler D, Lucerna M, Sellal JM, Ojeda FM, De Caterina R, Kirchhof P. Heart. 2018 Mar 17. pii: heartjnl-2017-312569. doi: 10.1136/heartjnl-2017-312569. [Epub ahead of print]

    Lipid Management After First Diagnosis of Coronary Artery Disease: Contemporary Results From an Observational Cohort Study.
    Waldeyer C, Seiffert M, Staebe N, Braetz J, Kohsiack R, Ojeda , Schofer N, Karakas M, Zeller T, Sinning C, Schrage B, Westermann D, Sydow K, Blankenberg S, Brunner FJ, Schnabel RB.
    Clin Ther. 2017 Nov;39(11):2311-2320.e2. doi: 10.1016/j.clinthera.2017.10.005. Epub 2017 Nov 2.

    Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe)
    Christina Magnussen, Teemu J. Niiranen, Francisco Ojeda, Francesco Gianfagna, Stefan Blankenberg, […] Ellisiv B. Mathiesen, Torben Jørgensen, Stefan Söderberg, Kari Kuulasmaa, Tanja Zeller, Licia Iacoviello, Veikko Salomaa, Renate B. Schnabel.
    Circulation. 2017;CIRCULATIONAHA.117.028981 Volume 136, Issue 20.

    Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System.
    Zeller T, Seiffert M, Müller C, Scholz M, Schäffer A, Ojeda F, Drexel H, Mündlein A, Kleber ME, März W, Sinning C, Brunner FJ, Waldeyer C, Keller T, Saely CH, Sydow K, Thiery J, Teupser D, Blankenberg S, Schnabel R.
    Front Cardiovasc Med. 2017 Sep 20;4:57. doi: 10.3389/fcvm.2017.00057. eCollection 2017.

    Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.
    Freedman B, Camm J, Calkins H, Healey JS, Rosenqvist M, Wang J, Albert CM, Anderson CS, Antoniou S, Benjamin EJ, Boriani G, […] , Schnabel RB, Siu CW, Steinhubl S, Svendsen JH, Svennberg E, Themistoclakis S, Tieleman RG, Turakhia MP, Tveit A, Uittenbogaart SB, Van Gelder IC, Verma A, Wachter R, Yan BP; AF-Screen Collaborators.
    Circulation. 2017 May 9;135(19):1851-1867. doi: 10.1161/CIRCULATIONAHA.116.026693.

    Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation.
    Schnabel RB, Pecen L, Ojeda FM, Lucerna M, Rzayeva N, Blankenberg S, Darius H, Kotecha D, Caterina R, Kirchhof P.
    Heart. 2017 Jul;103(13):1024-1030. doi: 10.1136/heartjnl-2016-310406. Epub 2017 Feb 22.

    Left Ventricular Assist Devices
    Baum C, Bernhardt A, Schnabel R 2016. Percutaneous Treatment of Cardiovascular Diseases in Women. Presbitero P, Mehilli J, Petronico A (Hrsg.). 1. Aufl. Springer, 263-275

    ADMA and arginine derivatives in relation to non-invasive vascular function in the general population
    Baum C, Johannsen S, Zeller T, Atzler D, Ojeda Echevarria F, Wild P, Sinning C, Lackner K, Gori T, Schwedhelm E, Böger R, Blankenberg S, Münzel T, Schnabel R
    ATHEROSCLEROSIS. 2016;244:149-56.

    Subclinical impairment of lung function is related to mild cardiac dysfunction and manifest heart failure in the general population
    Baum C, Ojeda Echevarria F, Wild P, Rzayeva N, Zeller T, Sinning C, Pfeiffer N, Beutel M, Blettner M, Lackner K, Blankenberg S, Münzel T, Rabe K, Schnabel R
    INT J CARDIOL. 2016;218:298-304.

    A roadmap to improve the quality of atrial fibrillation Management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference
    Kirchhof P, Breithardt G, Bax J, Benninger G, Blomstrom-Lundqvist C, Boriani G, Brandes A, Brown H, […] Schnabel R, Schotten U, Schwichtenberg L, Sinner M, Steinbeck G, Stoll M, Tavazzi L, Themistoclakis S, Tse H, Van Gelder I, Vardas P, Varpula T, Vincent A, Werring D, Willems S, Ziegler A, Lip G, Camm A
    EUROPACE. 2016;18(1):37-50.

    Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study)
    Ko D, Riles E, Marcos E, Magnani J, Lubitz S, Lin H, Long M, Schnabel R, McManus D, Ellinor P, Ramachandran V, Wang T, Gerszten R, Benjamin E, Yin X, Rienstra M
    AM J CARDIOL. 2016;118(10):1493-1496.

    Recent and relevant grants

    • EU-BiomarCaRE Project (Framework Programme 7) http://www.biomarcare.eu/
    • DZHK (German Center for Cardiovascular Research) http://dzhk.de/
    • e:Med SymAtrial (BMBF, Federal Ministry of Education and Research)
    • ERC consolidator grant 2015

  • Assoziierte Klinik:Klinik und Poliklinik für Anästhesiologie

    Institution
    Department of Anesthesiology
    Center of Anesthesiology and Intensive Care Medicine
    University Medical Center Hamburg-Eppendorf

    Working Group
    Personalized hemodynamic management
    CVRC PI Prof. Dr. med. Bernd Saugel Phone /email 18866 / b.saugel@uke.de

    Working group members
    Dr. med. Julia Nicklas (geb. Wagner) 18867 / j.nicklas@uke.de

    Brief descriptions of the research focus

    • "Personalized hemodynamic management" based on advanced innovative hemodynamic monitoring
    • Personalized goal-directed optimization of cardiovascular dynamics (anesthesiology, intensive care medicine)
    • Intraoperative hypotension, perioperative blood pressure management
    • Innovative technologies for less- and non-invasive advanced hemodynamic monitoring
    • Coherence/decoupling between global cardiovascular dynamics (macrocirculation) and the microcirculation

      Our research group focuses on concepts of "personalized hemodynamic management" (Saugel B, Vincent JL, Wagner JY. Curr Opin Crit Care. 2017. 23:334-341) using advanced innovative hemodynamic monitoring methods in anesthesiology and intensive care medicine.
      We evaluate and establish strategies for the personalized goal-directed optimization of cardiovascular dynamics in the perioperative care of high-risk surgical patients.
      In addition, we investigate the pathophysiology of "intraoperative hypotension" and concepts of personalized perioperative blood pressure management. We perform clinical studies to evaluate innovative technologies for less- and non-invasive advanced hemodynamic monitoring methods that might in the future be used for personalized hemodynamic management of high-risk surgical patients and critically ill patients treated in the intensive care unit. Another main research topic is to investigate the coherence/decoupling between global cardiovascular dynamics (macrocirculation) and the microcirculation

    Key techniques/methods

    • - clinical (multicenter) randomized-controlled trials (anesthesiology, intensive care medicine)
    • - innovative less- and non-invasive hemodynamic monitoring (pulse wave analysis, transpulmonary thermodilution, applanation tonometry, vascular unloading technology)
    • - assessment of microcirculatory blood flow: incident dark field (IDF) imaging with automated image analysis

    Recent and relevant publications
    https://www.ncbi.nlm.nih.gov/pubmed/?term=saugel+b

    Recent and relevant grants
    Personalized perioperative blood pressure management
    Grant: Else Kröner-Fresenius-Stiftung (Bad Homburg, Germany)
    Year: 2017 (duration: 24 month)
    Main applicant: Dr. med. Julia Nicklas

  • Assoziierte Klinik: Universitäres Herz- und Gefäßzentrum - Klinik und Poliklinik für Herz- und Gefäßchirurgie
    Assoziiertes Labor: TSI- Lab: Transplant and Stem Cell Immunobiology Lab Regenerative cell therapy Immunobiology and Transplant Immunology of Solid Organ Transplantation and Stem Cell Transplantation

    Congestive heart failure is the leading cause of death in the United States and Western Europe. Therapeutic options for end-stage heart failure include heart transplantation as well as stem cell transplantation to regenerate the damaged myocardium. The main focus of our transplant immunology studies is to investigate mechanisms of immune tolerance, such as immunotolerance windows, the role of Th17 cells in cellular and humoral rejection and specific T cell modulation as well as gene therapy for modulating the immunogenicity of transplanted organs.

    We are further interested to transfer the knowledge of heart transplantation into the field of stem cell transplantation. A variety of cell types including skeletal myoblasts, neonatal cardiac myocytes and adult stem cells have been investigated for the regeneration of injured myocardium by cellular transplantation. However, there is little reproducible evidence that any of these cells differentiate into cardiac myocytes or significantly improve myocardial function. We have investigated cellular transplantation of adult mouse stem cells for the treatment of congestive heart failure following myocardial infarction and have observed limited cell survival and non-relevant improvement in myocardial function. Embryonic stem cells (ESC) theoretically hold the most promise for the treatment of heart failure since they are the most pluripotent precursor cells known. However, there is a need to better understand how immunologically mediated rejection and non-immunological factors such as ischemia and inflammation affect survival and differentiation of ESCs. Importantly, factors that may effect the survival of intramyocardially delivered cells is a fundamental issue that has not been adequately assessed. The tracking and assessment of cell survival with novel in vivo imaging modalities must be correlated with changes in myocardial function following transplantation. We aim to characterize the type and intensity of the recipient immune response to transplanted stem cells, correlate this immune response with changes in cardiac function, establish the influence of innate immunity on transplanted cell survival and determine the effects of antigen independent factors (such as ischemia, non-specific inflammation and apoptosis) that effect stem cell survival following transplantation.

  • Assoziertes Institut: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie

    Institution
    UKE/UHZ

    Working Group
    Vasoactive Biomarker
    CVRC PI Edzard Schwedhelm 040-7410-54891 /schwedhelm@uke.de

    Working group members
    Chi-un Choe 040-7410-22389/c.choe@uke.de
    Kathrin Cordts 040-7410-53887/k.cordts@uke.de
    Günter Daum 040-7410-58173/g.daum@uke.de

    Brief descriptions of the research focus
    Function and integrity of the vasculature is controlled by diverse mediators. In addition to the well known vasoconstrictors catecholamines, endothelin-1, and angiotensin-2, our research interest focusses on sphingosin-1-phosphate (S1P) and the vasodilator nitric oxide (NO). The sphingolipid S1P is involved in the regulation of pathophysiologic changes underlying atherosclerosis such as intimal hyperplasia, but also neurodegenerative diseases. We investigate which of the S1P receptors contribute and if pharmacological intervention can modulate the progression of intimal hyperplasia and vascular restenosis. Furthermore, S1P receptor agonists like fingolimod confer neuroprotective effects in cell and mouse models of multiple sclerosis and Parkinson’s disease. On the other hand, NO biosynthesis can be impaired by endogenous L-arginine derivatives, i.e. asymmetric dimethylarginine (ADMA) or symmetric dimethylarginine (SDMA). Investigations revealed that genetically modified mice lacking the ADMA-degrading enzyme dimethylarginine dimethylamine hydrolase (DDAH) are suffering from high blood pressure and endothelial dysfunction. In contrast, the naturally occurring amino acid homoarginine is protective in cardio- and neurovascular disease. In line with clinical data, disruption of the homoarginine generating enzyme L-arginine:glycine-amidinotransferase (AGAT) in mice results in different cardio- and neurovascular phenotypes, which can be resolved upon homoarginine-supplementation.

    Key techniques/methods
    Arterial injury mouse models, clinical trials and cohort studies, mass spectrometry, neurodegenerative mouse models

    Recent and relevant publications
    https://www.ncbi.nlm.nih.gov/pubmed/?term=Schwedhelm+E%5BAuthor%5D+arginine https://www.ncbi.nlm.nih.gov/pubmed/?term=Daum+G%5BAuthor%5D+sphingosine https://www.ncbi.nlm.nih.gov/pubmed/?term=Choe+CU%5BAuthor%5D+agat

    Recent and relevant grants
    DZHK, NIH, Werner-Otto-Stiftung

  • Assoziiertes Institut: Institut für Zelluläre und Integrative Physiologie


    Zelluläre Wirkmechanismen einer linksventrikulären Entlastung

    Ventrikuläre Entlastung von insuffizienten Herzen durch implantierbare Pumpensysteme hat sich zu einer erfolgreichen therapeutischen Option bei der Behandlung von Patienten mit fortgeschrittenem Herzversagen entwickelt. Die meisten Pumpensysteme werden derzeit zur Überbrückung der Wartezeit auf eine Herztransplantation implantiert. Eine solche, zeitlich begrenzte, Unterstützung des Herzens ermöglicht somit akut das Überleben des Patienten. Interessanterweise kann darüber hinaus bei bestimmten Patientenkollektiven ein zellulärer Umbauprozess in Gang gesetzt werden, der zu einer deutlichen Verbesserung der kardialen Pumpfunktion führt. Hieraus hat sich eine neue klinische Indikation für die Implantation dieser Pumpen entwickelt.

    Die zugrundeliegenden Mechanismen sind derzeit unklar. Überraschenderweise induziert eine mechanische Entlastung von gesunden Herzen sehr ähnliche Genexpressionsmuster wie eine Überlastung des Herzens. Ein Abweichen der tatsächlichen Herzarbeit von der "normalen" Belastung scheint somit unabhängig von der Richtung der Abweichung gemeinsame zelluläre Antworten zu provozieren.

    Unsere Arbeitsgruppe verwendet Tiermodelle, um molekulare Mechanismen zu identifizieren, die letztendlich den positiven Effekten einer Entlastungstherapie zu Grunde liegen. In Bezug auf die zelluläre Elektrophysiologie konnten wir bereits zeigen, dass eine mechanische Entlastung identische Konsequenzen hat wie eine mechanische Überlastung. Wir konnten ebenfalls nachweisen, dass eine Entlastung Veränderungen in der zellulären Kinasen-Phosphatasen-Balance verursacht, die die Phosphorilierung zentraler Phospho-Proteine deutlich verändert. Diese Befunde haben komplexe Implikationen für die zelluläre Erregbarkeit und Kontraktilität. Derzeit werden darüber hinaus translationale und posttranslationale Prozesse untersucht, um die zellulären Regulatoren von Zellwachstum zu identifizieren.

  • Institution
    Institut für Zelluläre und Integrative Physiologie
    Department of Cellular and Integrative Physiology

    Working Group Seniuk
    CVRC PI Dr. med Anika Seniuk Phone /email +4940 74105 5855 / a.seniuk@uke.de

    Working group members
    Isabel Meyer, MSc. +4940 74105 7701 isa.meyer@uke.de
    Philipp Tessmer +4940 74105 6443 philipp.tessmer@stud.uke.uni-hamburg.de
    Torben Neuss +4940 74105 7701 torben.neuss@stud.uke.uni-hamburg.de

    Brief descriptions of the research focus

    Physiologische Blutdruckregulation und Arterielle Hypertonie
    Die kardiovaskuläre Forschung in unserer Arbeitsgruppe hat zum Ziel, neue Erkenntnisse über die physiologische Regulation des Blutdrucks sowie über die pathophysiologischen Mechanismen, die an der Entstehung der arteriellen Hypertonie beteiligt sind, zu gewinnen. Als einer der wichtigsten Risikofaktoren für Erkrankungen des Herz-Kreislauf-Systems wie Schlaganfall, Herzinfarkt und chronischem Nierenversagen steht die arterielle Hypertonie schon lange im Fokus der Wissenschaft. Obgleich der arterielle Blutdruck pharmakologisch mit Hilfe zahlreicher Medikamente gesenkt werden kann, sind die der arteriellen Hypertonie ursächlich zugrunde liegenden Prozesse immer noch unverstanden.

    An der Regulation des arteriellen Blutdrucks sind mehrere Organsysteme mit komplexen Regelkreisen beteiligt, unter anderem die Nieren, Hormone, das Gefäßsystem, das Herz, das Nervensystem und auch dem Immunsystem werden Einflüsse zugesprochen. Mit neuen Erkenntnissen in diesem Bereich könnten sich neue kausale therapeutische Optionen zur Behandlung der arteriellen Hypertonie und somit eine Verhinderung ihrer Folgeerkrankungen ergeben. Aktuelle Projekte befassen sich mit dem Einfluss des angeborenen oder erworbenen Immunsystems auf die Entstehung hypertoniebedingter Endorganschädigung, der Rolle spezifischer Ionentransportproteine in der glatten Gefäßmuskulatur auf den peripheren Gefäßwiderstand sowie mit den Effekten einer Salzbelastung bzw. Salzrestriktion auf den Wasser- und Elektrolythaushalt. Außerdem soll der Einfluss der Ernährung in der perinatalen Phase auf die spätere Anfälligkeit für die Entwicklung einer arteriellen Hypertonie herausgearbeitet werden.

    Blood pressure regulation and hypertension
    The aim of our cardiovascular research is to gain new insight into the physiological regulation of blood pressure and into pathophysiological mechanisms leading to arterial hypertension. Arterial hypertension is a main risk factor for cardiovascular disease, apparent e.g. in stroke, myocardial infarction and renal insufficiency. Although many pharmacological as well as more invasive interventions are clinically used for the therapy of arterial hypertension, the causes for the development of this disease are still unknown. Renal function, hormones, the vascular system, the central nervous system, the heart as well as the immune system affect the complex regulation of blood pressure. A better understanding of this regulation may help to develop novel causal therapeutic options for the treatment of arterial hypertension and the prevention of cardiovascular disease. Our current projects focus on the influence of the innate and acquired immune system on the development of hypertensive end organ damage, the role of specific vascular ion transporters in vascular smooth muscle cells for regulation of the peripheral resistance, and the effects of salt restriction and salt depletion on water- and electrolyte homeostasis. Furthermore, we focus on how the perinatal period might influence the risk for the development of hypertension in later life.

    Recent and relevant publications

    Reference List

    1. Heinze,C., Seniuk,A., Sokolov,M.V., Huebner,A.K., Klementowicz,A.E., Szijarto,I.A., Schleifenbaum,J., Vitzthum,H., Gollasch,M., Ehmke,H. et al 2014. Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. J. Clin. Invest.

    2. Mesirca,P., Alig,J., Torrente,A.G., Muller,J.C., Marger,L., Rollin,A., Marquilly,C., Vincent,A., Dubel,S., Bidaud,I. et al 2014. Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nat. Commun. 5:4664.

    3. Rudolph,V., Andrie,R.P., Rudolph,T.K., Friedrichs,K., Klinke,A., Hirsch-Hoffmann,B., Schwoerer,A.P., Lau,D., Fu,X., Klingel,K. et al 2010. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat. Med. 16:470-474.

    4. Sachse,G., Faulhaber,J., Seniuk,A., Ehmke,H., and Pongs,O. 2014. Smooth muscle BK channel activity influences blood pressure independent of vascular tone in mice. J. Physiol 592:2563-2574.

    5. Vitzthum,H., Seniuk,A., Schulte,L.H., Muller,M.L., Hetz,H., and Ehmke,H. 2014. Functional coupling of renal K+ and Na+ handling causes high blood pressure in Na+ replete mice. J. Physiol.

  • Team

    Institution
    Institute of Experimental Pharmacology and Toxicology
    University Medical Center Hamburg-Eppendorf

    Working Group
    Cardiac Regeneration
    CVRC PI Dr. Florian Weinberger Phone /email +49-40.7410-53180 / f.weinberger@uke.de

    Working group members
    Dr. Marina Reinsch 7410-52466 /m.reinsch@uke.de
    Dr. Liesa Castro 7410-52466 /li.castro@uke.de
    Birgit Geertz 7410-54707 / b.geertz@uke.d

    Brief descriptions of the research focus
    Myocardial damage following myocardial infarction or other cardiac diseases results in the loss of working myocardium and subsequent heart failure. Despite new therapies prognosis for heart failure remains poor, and new therapeutic options are urgently needed. In this context, regenerative approaches have gained increasing attention.
    The possibility of generating unlimited numbers of human cardiomyocytes from human embryonic as well as human induced pluripotent stem cells has opened the door for pluripotent stem cell based therapeutic strategies. We are using cardiomyocytes derived from pluripotent stem cells to generate human engineered heart tissue (hEHT) and have recently shown that the transplantation of hEHTs can remuscularize an injured heart in a myocardial injury model. We are currently working on different projects to further evaluate the possibility for regenerative tissue replacement therapy to advance this concept from a “proof of principle“-study towards a clinical application.

    Key techniques/methods

    • Stem cell culture
    • Cardiac differentiation from pluripotent stem cells
    • Animal models Histology
    • Confocal microscopy

    Recent and relevant publications

    • Reinsch M, Weinberger F. Stem cell-based cardiac regeneration after myocardial infarction. Herz. 2018 Mar;43(2):109-114.
    • Weinberger F, Mannhardt I, Eschenhagen T. Engineering Cardiac Muscle Tissue: A Maturating Field of Research. Circ Res. 2017 Apr 28;120(9):1487-1500.
    • Weinberger F, Breckwoldt K, Pecha S, Kelly A, Geertz B, Starbatty J, Yorgan T, Cheng KH, Lessmann K, Stolen T, Scherrer-Crosbie M, Smith G, Reichenspurner H, Hansen A, Eschenhagen T. Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells. Sci Transl Med. 2016 Nov 2;8(363):363ra148.
    • Weinberger F, Mehrkens D, Friedrich FW, Stubbendorff M, Hua X, Müller JC, Schrepfer S, Evans SM, Carrier L, Eschenhagen T. Localization of Islet-1-positive cells in the healthy and infarcted adult murine heart. Circ Res. 2012 May 11;110(10):1303-10.

    Recent and relevant grants
    DFG-Einzelförderung „Untersuchung der Bedeutung der aktiven Kraftentwicklung von implantiertem Herzmuskelgewebe auf die linksventrikuläre Funktion“ 2018-2021

  • Team
    Key techniques / Methods

    Assoziierte Klinik:III. Medizinische Klinik und Poliklinik

    Institution
    Medical Clinic and Policlinic III
    Center of Internal Medicine
    University Medical Center Hamburg-Eppendorf

    Working Group AG Wenzel
    Hypertension, Inflammation and the Renin Angiotensin System
    CVRC PI Prof. Dr. med. Ulrich Wenzel Phone /email +49 40 7410-50062 / wenzel@uke.de

    Working group members
    Prof. Dr. Ulrich Wenzel 040 7410 50062, wenzel@uke.de
    Dr. Alva Rosendahl 040 7410 59220, a.rosendahl@uke.de
    Stefan Gatzemeier 040 7410 58704, s.gatzemeier@uke.de
    Marlies Bode 040 7410 59220, ma.bode@uke.de
    Lennard Prüssner 040 7410 58704, lennard_pruessner@web.de
    Anna Cai 040 7410 58704, anna.cai0197@gmail.com

    Brief descriptions of the research focus
    Increasing evidence indicates that inflammation contributes to the deleterious consequences of arterial hypertension and its end-organ damage of this disease. Renal inflammation results in injury and impaired urinary sodium excretion. Modulation of the immune response can reduce the severity of blood pressure elevation and hypertensive end-organ damage in several animal models. The underlying mechanisms are incompletely understood. We wish to address the role of the innate and the adaptive immune system in hypertension and hypertensive end organ damage by examining the following points:
    1. Role of complement in arterial hypertension
    2. Role of dendritic cells in arterial hypertension
    3. Role of the renin angiotensin system in inflammatory cells
    In addition, we are working on new models of arterial hypertension with hypertensive cardiac and renal injury in mice. In addition, we are examining the role of the soluble (pro)renin receptor in hypertension and chronic kidney disease.

    Key techniques/methods

    • Mouse models of hypertension and kidney desease
    • Mouse models of inflammation
    • FACS analysis heart, aorta, kidney
    • Hemodynamic measurements

    Recent and relevant publications

    Wenzel UO, Bode M, Kurts C, Ehmke H. Salt, inflammation, IL-17 and hypertension. Br J Pharmacol. 2018 [Epub ahead of print]

    Wenzel UO, Bode M, Kohl J, Ehmke H. A pathogenic role of complement in arterial hypertension and hypertensive end organ damage. Am J Physiol Heart Circ Physiol 2017; 312: H349-H354.

    Hoxha E, Wiech T, Stahl PR, Zahner G, Tomas NM, Meyer-Schwesinger C, Wenzel U, Janneck M, Steinmetz OM, Panzer U, Harendza S, Stahl RA. A Mechanism for Cancer-Associated Membranous Nephropathy. N Engl J Med 2016; 374:1995-6.

    Weiss S, Rosendahl A, Czesla D, Meyer-Schwesinger C, Stahl RA, Ehmke H, Kurts C, Zipfel PF, Kohl J, Wenzel UO. The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension. Am J Physiol Renal Physiol 2016; 310: F1356-1365.

    Wenzel U, Turner JE, Krebs C, Kurts C, Harrison DG, Ehmke H. Immune Mechanisms in Arterial Hypertension. J Am Soc Nephrol 2016; 27: 677-686.

    Lehners A, Lange S, Niemann G, Rosendahl A, Meyer-Schwesinger C, Oh J, Stahl R, Ehmke H, Benndorf R, Klinke A, Baldus S, Wenzel UO. Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice. Am J Physiol Renal Physiol 2014; 307: F407-417.

    Rosendahl A, Niemann G, Lange S, Ahadzadeh E, Krebs C, Contrepas A, van Goor H, Wiech T, Bader M, Schwake M, Peters J, Stahl R, Nguyen G, Wenzel UO. Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice. Lab Invest 2014; 94: 863-872.

    Krebs CF, Lange S, Niemann G, Rosendahl A, Lehners A, Meyer-Schwesinger C, Stahl RA, Benndorf RA, Velden J, Paust HJ, Panzer U, Ehmke H, Wenzel UO. Deficiency of the interleukin 17/23 axis accelerates renal injury in mice with deoxycorticosterone acetate+angiotensin ii-induced hypertension. Hypertension 2014; 63: 565-571.

    Krebs C, Fraune C, Schmidt-Haupt R, Turner JE, Panzer U, Quang MN, Tannapfel A, Velden J, Stahl RA, Wenzel UO. CCR5 deficiency does not reduce hypertensive end-organ damage in mice. Am J Hypertens 2012; 25: 479-486.

    Fraune C, Lange S, Krebs C, Hölzel A, Baucke J, Divac N, Schwedhelm E, Streichert T, Velden J, Garrelds IM, Danser AH, Frenay AR, van Goor H, Jankowski V, Stahl R, Nguyen G, Wenzel UO: AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease. Am J Physiol Renal Physiol 2012; 303:F1037-48.

    Recent and relevant grants

    • DFG 2014 We 1688/17-1 Reninabhängige und -unabhängige Funktionen des (Pro)renin Rezeptors
    • 2016-2019 SFB 1192, Projekt B7: The innate immune response in hypertensive glomerular injury

  • Assoziiertes Institut: Universitäres Herz- und Gefäßzentrum Hamburg - Kardiologie

    Brief descriptions of the research focus:

    Our research group is focused on the extracellular matrix remodelling and the regulation of cardiac inflammation in different types of heart failure. Therefore, animal models were used to induce experimental viral myocarditis, myocardial infarction, cardiac hypertrophy or diabetic cardiomyopathy. Furthermore, we combine in vivo animal models with in vitro cell culture experiments to describe molecular mechanisms involved in heart failure pathology.

    Key techniques/methods:

    Animal models:

    • hemodynamic measurements
    • myocardial infarction (surgical ligation of the coronary artery) Viral myocarditis (Coxsackievirus B3)
    • Cardiac hypertrophy (AngII pumps)
    • Diabetic cardiomyopathy (STZ model)

    Cell culture:

    • primary cardiac fibroblasts
    • primary cardiomyocytes
    • Flexercell-System to apply mechanical stretch to cells
    • Cytokine stimulation

    Molecular biology:

    • gene expression analysis
    • Western blot

    Assoziiertes Institut: Universitäres Herz- und Gefäßzentrum Hamburg – Kardiologie

    Institution
    Cardiovascular Research Center (CVRC) University Medical Center Hamburg-Eppendorf
    Clinic for Cardiology

    Working Group
    Molecular Cardiology - Genomics and Systems Medicine

    CVRC PI
    Prof. Dr. rer. nat. Tanja Zeller Phone /email: +49 (0) 40 7410 - 56575 / t.zeller@uke.de

    Working group members
    Dr. Olga Schweigert +49 (0) 40 7410 – 58860 / o.schweigert@uke.de
    Christian Müller +49 (0) 40 7410 - 56575 / ch.mueller@uke.de
    Dylan Aissi +49 (0) 40 7410 - 58860 / d.aissi@uke.de
    Henri Weidmann +49 (0) 40 7410 - 58860 / h.weidmann@uke.de
    Tina Haase +49 (0) 40 74 10 - 54864/ t.haase@uke.de
    Julia Krause +49 (0) 40 7410 - 35330/ j.krause@uke.de
    Apurva Shrivastava +49 (0) 40 7410- 54233
    Kirstin Geppert +49 (0) 40 7410- 58753 / k.geppert@uke.de
    Claudia Winkelmann +49 (0) 40 7410- 58753 / c.winkelmann@uke.de
    Tim Hartmann +49 (0) 40 7410- 58866 / t.hartmann@uke.de
    Alexander Haschke +49 (0) 40 7410- 58864 / a.haschke@uke.de
    Martina Peter +49 (0) 40 7410- 58753/53909 / mar.peter@uke.de
    Sarah Dünger +49 (0) 40 7410-53909 / s.duenger@uke.de
    Sabine Gerth +49 (0) 40 7410-53909 / s.gerth@uke.de
    Dr. Satya Bhowmik +49 (0) 40 7410-28273 / s.bhowmik@uke.de
    Simone Schnella +49 (0) 40 7410-54864 / s.schnella@uke.de
    Sibylle Koerner +49 (0) 40 7410-28274 / s.koerner@uke.de

    Brief descriptions of the research focus

    Molekulare Kardiologie
    Genomik und Systembiologie

    Durch intensive Forschungsarbeiten der letzten Jahre wurde deutlich, dass genetische Varianten eine große Rolle bei kardialen Erkrankungen spielen. Modernste Technologien ermöglichen es, krankheitsrelevante, genetische Varianten durch genom-weite Analysen zu identifizieren und deren Einfluss auf das Expressionsmuster einer Vielzahl an Genen zu untersuchen. Die so identifizierten genetischen Varianten und Gene bilden die Grundlage für die weiterführende molekulare Charakterisierung.

    Der Schwerpunkt im Bereich "Molekulare Kardiologie" ist die Erforschung der Pathophysiologie und der molekularen Mechanismen kardiovaskulärer Erkrankungen unter Zuhilfenahme genetisch-molekularbiologischer, zellbiologischer, bioinformatischer und statistischer Methoden. Eine große Rolle spielen dabei die Identifizierung regulatorischer Netzwerke, die molekulare Charakterisierung von Kandidatengenen sowie Sequenzierungsanalysen.

    In groß angelegten, genom-weiten Assoziations- und Expressionsanalysen untersuchen wir den Zusammenhang von genetischen Varianten (so genannte single nucleotide polymorphisms -SNPs-) und kardiovaskulären Phänotypen/Biomarkern sowie der Genexpression.
    So konnte unsere Arbeitsgruppe SNPs identifizieren, welche einen Zusammenhang zur koronaren Herzerkrankung und dem Myokardinfarkt zeigen und die Expression krankheitsrelevanter Gene beeinflussen. Die molekulare Funktion diese Krankheitsgene wird mit Hilfe molekularer und zellbiologischer Methoden untersucht.

    Weiterhin beschäftigt sich die Arbeitsgruppe mit der Identifizierung kardiovaskulärer microRNAs. microRNAs sind kleine, nicht-kodierende RNA Moleküle, welche regulatorisch auf die Genexpression wirken. Wir untersuchen in populations-basierten Studien und Studien zur sekundär Prävention das Expressionsprofil von microRNAs und den Nutzen von zirkulierenden microRNAs als Biomarker. Im Rahmen des BiomarCaRE Projekt, einem EU-FP7 geförderten Projekt untersuchen wir den Zusammenhang von zirkulierenden microRNAs und kardiovaskulären Erkrankungen.

    Recent and relevant grants

    • Else Kröner Fresenius Stiftung “G-protein coupled receptor GPR15 – a novel candidate Receptor for cardiovascular disease. Molecular characterization of GPR15”. 2014-2016, 131.700 €
    • BMBF e:Med Förderung "Juniorverbünde in der Systemmedizin"
      symAtrial (Systems Medicine of Atrial Fibrillation)
      2014-2018 1.500.000 €
    • Deutsche Stiftung für Herzforschung - Novel Biomarkers in heart failure with reduced and preserved ejection fraction in the general population 2013-2014, 50,000€
    • Deutsche Stiftung für Herzforschung "Die Bedeutung des NLRC4 Inflammasoms in der Pathogenes der koronaren Herzkrankheit: Molekulare Untersuchungen des Einflusses genetischer Varianten"
      Laufzeit: 2013-2014
    • EU FP7 HEALTH.2011.2.4.2-2 (Evaluation and validation studies of clinically useful biomarkers in prevention and management of cardiovascular diseases). Projekt "BiomarCaRE - Biomarkers for Cardiovascular Risk Assessment in Europe"
      Laufzeit 2011 - 2015
    • BMBF Deutsch/Französische Kollaborationen im Bereich Genomics and Physiopathology of Cardiovascular and Metabolic Diseases, Projekt "CARDomics"
      Laufzeit 2010-2013
    • BMBF Nationale Genom Forschungs Netzwerks NGFNplus, Projekt "AtheroGenomics"
      Laufzeit 2008 - 2013
    • Biomarker Messungen im Rahmen des IMI-SUMMIT Projekts (Surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools)
      Laufzeit 2012 - 2013