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Progress Report 2010 > 2012 Circulating matters Institute for Cardiovascular Research VU University Medical Center I C A R -V U m c 1 ailure Hypertrophic Car 2 P r o gr e s s R ep o r t 2010 > 2012 Progress Report P r o gr e s s R ep o r t 2010 / 2011 1 2010 > 2012 ulmonay Arterial Hyper ascular Imaging Focus Circulating matters ronary Syndrome and Reproduction and Va n Diabetis Mellitus and Research Chronic KidI C A R -V U m c 1 P r o gr e s s R ep o r t 2010 > 2012 2 3 Content 6 ICaR-VU the Institute 8 General information 13Research 28 Education Information Colophon Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU) VU University Medical Center (VUmc) Coordination van der Boechorststraat 7 1081 BT Amsterdam Telephone +31-20-4448111 Fax +31-20-4448255 [email protected] www.vumc.com/icar-vu © 2013 ICaR-VU Victor van Hinsbergh Isabelle Vergroesen Jolanda van der Velden Text Scientists of ICaR-VU Editor Lisa Kohn Photography Harry Meijer (pages 4, 8,12, 28, 42, 44, 50, 56, 62, 72, 74, 80, 86, 92, 98, 104, 110) Dirk de Jong (last pages) Design and layout Corina van Riel, Amsterdam 38 44 50 56 62 Theme H 68 Theme V 74 80 86 92 98 104 110 Research Research Research Research Research Research Research Research Research Research Research Group Group Group Group Group Group Group Group Group Group Group Diastolic Heart Failure Hypertrophic Cardiomyopathy Pulmonary Arterial Hypertension Cardiovascular Imaging Coronary Syndrome and Repair Aneurysm Reproduction and Vascular Function Diabetes Mellitus and Obesity Nutrition Research Chronic Kidney Disease Acute and Perioperative Care Print Roto Smeets GrafiServices I C A R -V U m c 3 4 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 5 Preface This is the 2010-2012 Progress Report for the Institute for Cardiovascular Research at VU University Medical Center (ICaR-VU). Over the last 20 years, the ICaR-VU has acquired a solid identity in the field of cardiovascular research in The Netherlands and Europe. Since its foundation in 1992, the Institute has been dedicated to providing better joint research education for basal and clinical PhD students, and promoting the interaction between clinical and basic research. Currently, the majority of research projects falls under two themes ‘Improvement of Cardiac Function in Heart Failure’ and ‘Improvement of Vascular Function in Metabolic Diseases’. A thorough evaluation of the overall research program took place in 2010-2011. This led to the fine-tuning of the relationships between patient care and research, and added support from the participating clinical and preclinical departments. In 2012 three specific programs were defined within the two themes: ‘Heart Failure and Pulmonary Arterial Hypertension’, ‘Circulation and Metabolism’ and ‘Ischemia and Repair’. In the period 2010-2012, the ICaR-VU became coordinator of, and a participant in, various European programs and clinical trials; expanded its external funding and further increased its scientific output. In addition to the PhD program, which has its roots in the Cardiovascular Research School CARMA, a Research Master Program was created in 2010 for excellent students who aim to pursue cardiovascular research. In 2012 the ICaR-VU started participating in the Rembrandt Institute, in collaboration with the Amsterdam Medical Center, Leiden University Medical Center and Sanquin, which has further strengthened our cardiovascular research. I would like to thank all the participants in the ICaR-VU for their enthusiasm and personal contributions to the success of the Institute. Victor W.M. van Hinsbergh Director of the ICaR-VU I C A R -V U m c 5 6 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e The Institute One of the main tasks of the ICaR-VU is to stimulate and promote interdisciplinary research to be able to cover the range from patient to gene 7 1 Profile Organisation Education I C A R -V U m c 7 8 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 9 Profile The Institute for Cardiovascular Research of the VU University (ICaR-VU) was founded in 1992 on the basis of the Dutch University Education Act (WWO). The initial purpose of the research school was the education of graduate students (PhD students) in all aspects of cardiovascular function and cardiovascular diseases. Today the Institute has grown into an internationally recognized platform for high quality interdisciplinary translational research and research education on heart, vessels and related metabolism at the VU University and VU University Medical Center. The ICaR-VU is one of the five research institutes of the VU University Medical Center (VUmc) and participates in Human Health and Life Sciences, one of the four focus areas of the VU University Amsterdam. The ICaR-VU facilitates research groups of clinical and/or pre-clinical investigators from 18 departments in four divisions of VUmc, thus facilitating a multidisciplinary approach to research, patient care and medical education. More than 265 professionals work in the ICaR-VU, and execute research programs in interdisciplinary research teams, bringing together clinical investigators, basal investigators and graduate students. The ICaR-VU stimulates cooperation, aims to create new facilities for clinical and basal research in order to strengthen translational research and to identify opportunities for future improvement of its research and patient care. The network within the Institute enables excellent students to come into contact with top scientists in the PhD education program, and Cardiovascular Research Master program, a teaching program that began in 2009. One of the main tasks of the ICaR-VU is to stimulate and promote interdisciplinary research to enable ‘from patient to gene’ coverage. Therefore, the research is focused on a limited number of cardiovascular diseases with a strong emphasis on translational research and aims to improve patient care. This choice has led to a much better and more coherent program, does away with the traditional barriers between clinical and preclinical departments, and stimulates multidisciplinary research. Thus, it was decided that the Institute would concentrate on heart and blood vessels themes. By integrating patient care and research projects and focusing on selected cardiovascular research niches the ICaR-VU has established an excellent international position at the forefront of international cardiovascular research. I C A R -V U m c 9 10 P r o gr e s s R ep o r t 2010 > 2012 Mission Statement of the ICaR-VU ‘Search for Scientific Solutions for Cardiovascular Suffering’ I C aR -V U / T h e In s tit ut e Strategies The ICaR-VU mission has the following strategies: 1 The management and all members of the ICaR-VU will ensure that the research effort remains focused on the two themes; through high quality basic, applied and clinical research. 2 The management and all members of the ICaR-VU will ensure continuity through a meticulous system of quality assurance and through pursuit of a high degree of financial independence. 3 The management and all members of the ICaR-VU will ensure that graduates of the Institute, in addition to graduating with high quality theses, are sufficiently prepared to successfully join the labor market. An important step towards this goal is to provide excellent education to graduate students. 11 12 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 13 Research The Institute for Cardiovascular Research at VU University Medical Center in Amsterdam offers a first class location for conducting translational cardiovascular research, providing a bridge between the laboratory bench and clinical problems at the bedside. The Institute is dedicated to making advancements in biomedical research and clinical treatment strategies through close collaboration between basic scientists and clinicians. One of the main tasks of The ICaR-VU is to stimulate and promote interdisciplinary research covering the range ‘from patient to gene’. Therefore, the research is focused on a limited number of cardiovascular diseases with a strong emphasis on translational research and the aim of improving patient care. This choice leads to a much better and more coherent program, does away with the traditional barriers between clinical and preclinical departments, and stimulates multidisciplinary research. It was decided that research within the ICaR-VU would concentrate on two themes: Theme H: Improvement of Cardiac Function in Heart Failure (including the activities of the Pulmonary Artery Hypertension Center VUmc). Theme V: Improvement of Vascular Function in Metabolic Diseases Since 2012 has been concentrating on: – Program on Ischemia and Repair – Program on Circulation and Metabolism (including research activities of the Diabetes Center VUmc) The development of improved techniques is an integral aspect of our themes and programs. For example imaging techniques, which play a prominent role in research on heart and vessels. The recent opening of a PET-MRI facility at the VUmc will further boost the existing imaging expertise in the cardiovascular field. The success of the thematic approach with the alignment of patient care and research projects is reflected by an increase in external funding and an improvement in the quality of the output. The current Theme Leaders are: Prof. dr. Jolanda van der Velden (Physiology), Prof. dr. Anton Horrevoets (Molecular Cell Biology and Immunology), Prof. dr. Yvo Smulders (Internal Medicine), Prof. dr. Carlo Gaillard (Nephrology), Prof. dr. Niels van Royen (Cardiology). I C A R -V U m c 13 14 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e Structure ICaR-VU Dean / Board of Directors Think Tank ICaR-VU Directorate Science Committee Theme Heart Heart Failure and Pulmonary Arterial Hypertension Project Project Project Project Project 1 2 3 4 5 ......... ......... ......... ......... ......... 15 External Advisory Board Education Committee Theme Vessels Ischemia and Repair Circulation and Matabolism Project Project Project Project Project 6 7 8 9 10 ......... ......... ......... ......... ......... The Directorate is responsible for the management of the Institute and is supported by the directorate advisor Dr. I. Vergroesen. The directorate is advised and supported by the Theme Leaders and the Science Committee with regard to the research projects and research in general and by the Education Committee with regard to all aspects of PhD, MsC and BSc education covered by the Institute. Furthermore, the External advisory Board and Think Tank, an internal board of upcoming scientists, also advise the Directorate. The research projects in the Institute are under the direct supervision of the project leaders. The Theme Leaders are responsible for coordination and quality of the research themes within the Institute. They coordinate the evaluation of new research project proposals and discuss these with the Project Leaders. The Theme Leaders participate in the Science Committee and advise the Directorate and the other members of the Science Committee on the quality of the projects and their suitability within the Institute and Theme programs. The Education Committee is responsible for the coordination of all education matters of junior scientists, in particular the PhD program. They also advise on the Cardiovascular Research Master program and on the scientific aspects of the cardiovascular research education of medical bachelor students. The External Advisory Board advises the Directorate on general internal and external policy of the Institute as well as its scientific and education programs. In principle, the Advisory Board meets with the Directorate and the Theme Leaders of the ICaR-VU twice a year. The Think Tank was formed in 2005, as an internal board of upcoming scientists by the Directorate. There is a monthly meeting of the Think Tank during which current scientific matters and strategic issues are freely discussed. The Think Tank looks critically at specific research and advises on talent strategy. The Think Tank proposes cutting edge research topics that need attention in colloquia. The Science Committee is made up of Theme Leaders and selected key scientists covering the major expertise and disciplines of the Institute. Monthly, they meet with the Directorate to advise on all scientific matters including general and strategic matters and to approve decisions on newly proposed research projects. I C A R -V U m c 15 16 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e Management Committees DIRECTORATE RESEARCH The Directorate is responsible for the management of the Institute. Theme Leaders The Theme Leaders are responsible for coordination and quality of the research themes. Director prof. dr. V.W.M. van Hinsbergh Department of Physiology Vice-Directors prof. dr. H.W.M. Niessen Department of Pathology prof. dr. A.C. van Rossum, Department of Cardiology Directorate-Advisor dr. I. Vergroesen. 17 The Theme Leaders coordinate the research in the themes and judge new projects and discuss projects with the Project Leaders. The Theme Leaders advise the Science Committee of the Institute on the quality of individual projects before the start. The Theme Leaders as of September 2011: Theme H prof .dr. J. van der Velden prof. dr. N. van Royen Theme V prof. dr. A.J.G. Horrevoets prof. dr. C.A.J.M. Gaillard prof. dr. Y.M. Smulders Project Leaders Within the themes, programs and projects are carried out. The basic research unit is the project. The research projects are under the direct supervision of the Project Leaders. For names of the Project Leaders see the second and third section of this Progress Report, where the themes are explained in more detail. To qualify as a Project Leader, one has to have experience in science (at least PhD), be able to obtain grants, and supervise cardiovascular research projects within the ICaR-VU. The Directorate decides on the appointment of new Project Leaders. ADVISORY COMMITTEE SCIENCE COMMITTEE This Committee advises the Directorate on general policy and other matters. In principle, this Committee meets with the Directorate and Theme Leaders of the ICaR-VU, twice a year. This Committee advises the Directorate on almost all scientific matters, as well as on general and strategic issues. The final approval of projects is their responsibility. This Committee consists of senior scientists from different departments, which participate in the ICaR-VU, and the Theme Leaders, DEC representative and the chair of the Education Committee. prof. dr. A.J.M. Donker Professor emeritus of Internal Medicine VUmc, chair prof. dr. W.G. van Aken Professor emeritus of Internal Medicine, Vice Chair prof. dr. P. Brakman Professor emeritus of Internal Medicine, Leiden University prof. dr. D.J. Duncker Professor Cardiology, EMC prof. dr. W.J. Paulus Physiology, chair prof. dr. H.J. Blom Clinical Chemistry prof. dr. M. Diamant Internal Medicine drs. G.A. van Leijenhorst Medical Director, Merck, Sharp & Dohm, Haarlem prof. dr. R.J.B.J. Gemke Pediatrics prof. dr. C.J.L.M. Meijer Professor emeritus of the Department of Pathology, VUmc prof. dr. C.J.M. de Groot Obstetrics and Gynecology (from March 2012) prof. dr. T.J. Rabelink Professor of Nephrology, LUMC prof. dr. C.B.M. Oudejans Clinical Chemistry dr. W.S. Simonides Physiology prof. dr. A. Vonk Noordegraaf Pulmonology prof. dr. C.A.J.M. Gaillard Nefrology, Theme Leader Vessels (as of September 2011) dr. J.G.F. Bronzwaer Cardiology, chair Education Committee dr. A.A. van Lambalgen Physiology DEC-representative prof. dr. A.B.J. Groeneveld Intensive Care Medicine, Theme Leader Vessels (until July 2011) prof. dr. A.J.G. Horrevoets Molecular Cell Biology and Immunology, Theme Leader Vessels (as of September 2011) prof. dr. N. van Royen Cardiology, Theme Leader Heart (as of September 2011) prof. dr. Y.M. Smulders Internal Medicine, Theme Leader Vessels (as of September 2011) prof. dr. J. van der Velden Physiology Theme Leader Heart (as of September 2011) prof. dr. N. Westerhof Professor emeritus of Physiology, VUmc I C A R -V U m c 17 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e EDUCATION COMMITTEE THINK TANK In the second half of 2005 the Directorate created the so called the ICaR-VU ‘Denktank’ (Think Tank). There is a monthly meeting of the Think Tank during which upcoming scientific matters and occasionally strategic issues are openly discussed. For discussion on specific topics several ad-hoc members can be invited depending on the topic. dr. C. Boer Anesthesiology, chair (as of September 2011) dr. P. Knaapen Cardiology dr. R.A. Bouwman Anesthesiology dr. J.D. Blankensteijn Vascular Surgery dr. P. Krijnen Pathology dr. E.H. Serné Internal Medicine 19 Scientists dr. H.J. Bogaard Pulmonology (as of September 2011) All teaching activities related to Cardiovascular Research falls under the responsibility of the Education Committee. dr. M. van Dijk Clinical Chemistry (as of September 2011) dr. J.G.F. Bronzwaer Chairman Education Committee dr. C.A.C. Ottenheijm Physiology (as of September 2011) dr. G.P. van Nieuw Amerongen prof. dr. J. van der Velden (until January 2012) dr. M.C. de Waard Intensive Care Medicine (as of September 2011) dr. E.H. Serné (as of January 2012) prof. dr. J. van der Velden Physiology, chair. (until September 2011) prof. dr. C.A.J.M. Gaillard Nefrology (until September 2011) drs. J. Aman Representative PhD students (until January 2011) drs. E. R. Paalberends Representative PhD- students (as of January 2011) prof. dr. G.J.M. Stienen Chairman CVR-master 200 Number Committees 180 160 dr. E. Kanters Coordinator CVR-master 140 dr. I. Vergroesen Coordinator WFO, HP and PhD students 100 Shellice Sairras (2009-2011) Mathijs Baart (2010-2011) Stephanie Ragghoe (2011-2012) Chris Happé (2011-2012) Iris van Moort (2012-) Vera Verbruggen (2012-) Students CVR-master Figure 1: Number of persons involved in the Institute related to the Themes. Persons involved in both themes are counted twice, and all researchers involved arriving or leaving within a year count once, as do MD’s who combine clinical duties and research. So, it is only an indication of the maximum number of people involved. *Numbers for 2012 are best value available in January 2013. 120 80 60 40 20 0 2010 2011 Heart 2012* 2010 2011 Vessels 2012* Researchers (clinical and basal) involved in the Institute related to their position 60 FTE 18 50 40 30 dr. A. Beishuizen Intensive Care Medicine 20 dr. G.P. van Nieuw Amerongen Physiology 10 0 2010 2011 Heart 2012* 2010 2011 Vessels 2012* Researchers (full time equivalents) involved in the Institute related to the funding PhD/MD Postdoc/ fellow UHD + UD Full Professor Figure 2: Number of FTE scientific personnel working in the Institute per year and related to the Themes. The different colors correspond to the funding categories. PhD students count for maximal 0.75 FTE, due to educational tasks. Clinical PhD students (MD) count for 0.2-0.75 FTE depending on their clinical and educational tasks. Scientific staff may have educational, clinical and managerial tasks in addition to their research. People arriving or leaving count only for the month they were employed by VUmc. Data are provided by the departments participating in the ICaR-VU. *Numbers for 2012 are best estimates available in January 2013. Industry Funding Charity/Europe Government Research Grants Direct Funding PhD/MD Direct Funding Staff I C A R -V U m c 19 20 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 350 300 250 200 150 Refereed articles Books or bookchapters PhD-theses Professional publications 100 50 0 2009 2010 2011 Heart 2012 2009 2010 2011 Vessels Figure 4: The impact of the published papers, as can be judged from the relative impact of the journal in which the article is published, is shown. All international refereed publications are set to 100% for each year. NB Data for 2012 are not yet available. 80% 60% 18 16 14 12 8 3,100 22 2,900 20 2,700 18 2,500 16 2,300 2,300 14 2,100 2,100 12 1,900 1,900 10 1,700 1,700 Papers Citations PP 1,500 0 1997-2007 1997-2009 1997-2008 1997-2009 1997-2011 1997-2009 1997-2010 1.8 100% 200 Other 50% Top 25 180- 50% Top 11 - 25% 160 Top 10% 20% 2008 2009 2010 Heart Quality of publication 2011 2008 2009 1,500 1997-2010 3,1005: Citation of papers 1997-2010. Figure Papers: number of papers in Web of Science 2,900 published by the ICaR-VU, since 1997. Citations 2,700 PP: average citations per paper excluding self-citations. 2,500 Figure 6: MNCS: Mean Normalized Citation Score (crown indicator), i.e. mean of citations related to the average number of citations in the field of interest. For a group which scores just average of all the groups participating in the same research field the MNCS would be 1.00. VUmc expects its research institutes to score 1.3 or higher. 1.6 1.4 1.2 40% 40% 20 24 The CWTS, Center for Science & Technology Studies, compares the impact of the research of universities and its institutes to the field of science to which it belongs. For the Institute the most recent data are the papers published between 1997-2010. Since the CWTS started the analysis in 1997 the number of papers included in the analysis has increased, For the ICaR-VU the number of citations per paper, excluding self-citations, since 1997 has increased from 14 to 21. 100% 60% 22 10 2012 Overview of number of publications related to type of publication 80% 0% 24 Number of papers Figure 3: The number of publications is shown per year and for each theme. We included 2009 to show the trend over a longer period. The professional publications are mostly in Dutch. *Numbers for 2012 are best estimates available in January 2013.. 400 Number of papers 450 Citations per paper exclusive selfcitationas Citations Citations PP excluding self-citations Number Papers and Impact 21 2010 Vessels 2011 140 120 100 80 60 1.8 2004 - 2007 2005 - 2008 2006 - 2009 2007 - 2010 1 0.8 60 1.6 ICaR-VU 1.4 Heart MNCS (Citation Crown Indicator CWTS) 1.2 50 Vessels 40 30 I C A R -V U m c 20 21 22 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 23 A Selection of Awards in 2010 - 2012 Life Time Achievement Award International Young Investigator Awards Nico Westerhof, the first Director of the ICaR-VU, received the Artery Lifetime Achievement Award from the Artery Society in October 2011. He accepted the Award with a lecture ‘The Tale of Two Circulations’. After retiring as Director of the ICaR-VU he has remained active as a scientist in the Pulmonary Arterial Hypertension group. He is an expert on physics of the aorta and left ventricle and over the past 10 years he has used this expertise to better understand the physics of the right ventricle and pulmonary artery system. Jurjan Aman, PhD student in the Vascular Function in Sepsis Group, received a special award from the European Society of Intensive Care Medicine in October 2011 for studies on imatinib and pulmonary permeability (20,000 euro). Karima Farhat, PhD student in the Nephrology group won a Young Investigator Award for clinical abstracts at International Society of Peritoneal Dialysis (ISPD) in September 2012 in Kuala Lumpur. Nazha Hamdani, postdoc in the Diastolic Heart Failure group won the best Young Scientist Award and the best published manuscript of 2012 of the Deutsche Gesellschaft für Kardiologie (Franz-Maximilian-Groedel-Forschungspreis), the best Poster presentation Award at 77th Annual Meeting of the German Cardiac Society (March 2012) and 2 presentation awards at the 2012 MEDIA- event for her presentations: 1. The pathophysiology of heart failure with preserved ejection fraction. 2. Myofilament phosphorylation and function in heart failure with preserved ejection fraction. Paul Krijnen, postdoc in the Acute Coronary Syndromes and Repair won The Investigative Pathology in Cardiovascular Diseases Award of the Association for European Cardiovascular Pathology in April 2012 Esther Kuijper, PhD student of the Reproduction and Vascular Function group won Galton Award for Best Student paper at 14th International Congress of Twin studies April 2012. Rick Meijer, PhD student in the Vascular Function in Metabolic diseases Group, received the Young Investigator’s Award of the European Society of Microcirculation and the Gesellschaft für Mikrozirkulation und Vaskuläre Biologie at their joint meeting in München 2011. Thesis Awards Silvia Rain, PhD student in of the pulmonary arterial hypertension group was awarded the ESC First Contact Initiative Grant of European society of Cardiology in April 2012. Vasco Sequeira, PhD student in the Hypertrophic Cardiomyopathy group received a Young Investigator Award at Winter Meeting – Heart Failure Association (European Society of Cardiology) – Les Diablerets, Switzerland; January, 2012. Annemieke Smorenberg, Master student in the group of Vascular Function in Sepsis received The First Prize Poster Award: XIVth Congress of the European Shock Society August 2011. Hari K Thulluru, PhD student in the Reproduction and Vascular Function group won The YW Loke New Investigator Travel Award from The International Federation of Placenta Associations (IFPA) in September 2012. Linda Jufferman, presently a post doc in the Imaging group, received the prof. dr. AA Knoop Award 2010 for Best Physiological Thesis (2008-2009) for her thesis; ‘Ultrasound and microbubble-targeted delivery of drugs and genes, cellular bio-effects’ Frances de Man, presently a postdoc in the Pulmonary Arterial Hypertension group received the Jacob Hamburger Award of the Dutch Physiological Society for the Best Physiological Thesis in 2009-2010. The title of her thesis was: ‘Muscle function, exercise training and beta-blocker treatment in pulmonary arterial hypertension’. Louis Handoko, presently AIOS Cardiology, received the prof. dr. A.A. Knoop Award 2012 for Best Physiological Thesis (2010-2011) with his thesis, entitled ‘Right heart failure in pulmonary hypertension, lessons from the left heart’. Mariëlle van de Veerdonk, PhD student at the Pulmonary Arterial Hypertension Group, received a Young Investigator Award of the European Respiratory Society 2010. Paul Wijnker, PhD student in the Hypertrophic Cardiomyopathy group received a Young Investigator Award for the best oral presentation at Summer School Cardiovascular Science (Basic Science Summer School), Sophia Antipolis (Nice), France, June 2011, a Young Investigator Award at the 41st European Muscle Conference: of the European Society for Muscle Research, Rhodes, Greece, September 2012 and a Best Poster Award + Travel Award 2012 at Frontiers in Cardio Vascular Biology - Second meeting of the ESC Council on Basic Cardiovascular Science, London, United Kingdom, March 2012. I C A R -V U m c 23 24 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 25 Grants 2010 - 2012 In 2010 we obtained 35 grants with an average of 282,000 euro External Grants obtained by the ICaR-VU 2010 in kEuro (selection) Walter Paulus P7, The Metabolic Road to Diastolic Heart Failure (MEDIA) total K of 12,100 kEuro for 20 participating organizations. In 2011 we obtained 45 grants with an average of 196,000 euro 1700 External Grants obtained by the ICaR-VU 2011 in kEuro (selection) Victor van Hinsbergh Pieter Koolwijk FES (NIRM) Cardiovascular WP6 Angiogenesis and hypoxia.1611 Bert van Rossum I ndustry, diverse projects Heart Failure and Ischemic heart disease. CTMM COHFAR prospective CRT study.1200 Walter Paulus and Jolanda van der Velden CVON: Approaching Heart Failure by Translational Research of RNA mechanisms).800 Jolanda van der Velden WO VIDI grant, Sarcomeric dysfunction as a target for treatment in N primary human cardiomyopathy. Bert van Rossum Industry: Estimate of research grants obtained for cardiology projects.867 Hans Niessen, icw H de Wit and Rob Beelen NWO apparatuur middelgroot: Cryo-Electron Microscopy.670 Geerten van Nieuw-Amerongen Netherlands Heart Foundation, Dekker established investigator: Targeting of vulnerable loci in the endothelium.550 800 Hans Niessen and Paul Krijnen Industry, Biomarker detection and therapy development in viral myocarditis.670 Anton Vonk Noordegraaf NWO, translational grant, Betablocker therapy in pulmonary arterial hypertension.500 Judith Huirne and Hans Brölmann NWO, HELLP-syndrome detection.430 Michaela Diamant I ndustry (Investigator initiated grant): The effect of GLP-1 receptor activation on central reward and satiety circuits in response to food stimuli in obesity and diabetes.425 René Musters and Joost Sluijter (UMCU) BMM, P1.05 LUST (FES) Localized Ultra-sound Small RNA Transmittal. Total of 1,164 kEuro. Marie van Dijk NWO, VENI: HELLP-babies: mutations in a novel non-coding RNA.250 Coen Ottenheijm Beatrixfonds, Myofilament-based muscle weakness in faciosca-pulohumeral dystrophy.250 Erik Serné HS junior staff Targeting inflammation-related microvascular dysfunction to N improve cardiometabolic risk in rheumatoid arthritis and obesity.220 Arthur Bouwman Arthur Bouwman 375 ZonMw Clinical Fellowship. Perioperative activation of adenosine monophosphateactivated kinase improves anesthetic cardio protection in type diabetes mellitus: role of cardio protective kinases.160 Young Investigator Dutch society for Anesthesiology. The metabolic profile of the heart modulates its sensitivity to ischemia: an experimental approach to study the impact of lifestyle modification on preservation of perioperative cardiac function. 50 Piet ter Wee, Ed Eringa ‘Nierstichting:’ The FGF23 – klotho – vitamin D axis as a new instrumental target to Rene Musters combat the cardiovascular risk of chronic kidney disease: The NIGRAM Consortium. (Nijmegen, Groningen, Amsterdam) Total 1,500,000 euro.500 Harry Lafeber I ndustry: Studies Towards the Effects of Postdischarge nutrition of preterm infants (STEP I study). The first 6 months after birth. 400 Harry Lafeber I ndustry: Studies Towards the Effects of Postdischarge nutrition of preterm infants (STEP II study). The first seven years after birth.260 Michaela Diamant, icw Miriam Sturkenboom and Judith Huirne P7: SAFEGUARD: Safety of Novel Anti-Diabetic Drugs.330 NWO/ VEMI: Hysteroscopic resection of uterine cesarean scar defect (niche) in patients with abnormal bleeding, a randomized controlled trial.249 Yvo SmuldersEffect of Adalimumab on Inflammatory Activity in Mike Nurmohamed Atherosclerotic lesions in Patients with Reumatoid Arthritis. 220 Tjeerd Germans 170 NHS Dekker grant for AIOS. Energetics in hypertrophic cardiomyopathy: translation between MRI, PET and cardiac myofilament function. I C A R -V U m c 25 26 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 27 Grants 2010 - 2012 In 2012 we obtained 35 grants with an average of 241,000 euro Geerten van Nieuw Amerongen and Peter Hordijk (Sanquin) Rembrandt Research Grant 2012: RhoGTPases in the endothelium: localized activity, cross-talk and relevance for barrier function and inflammation (Total 500).250 Nazha Hamdani PhD Grant, Early Career Researchers of Ruhr University Bochum: The giant titin protein as a novel therapeutic target for diastolic heart failure. 250 Nazha Hamdani PhD Grant, Science and Technology Foundation Germany: The impact of obesity and diabetes mellitus on the pathophysiology of Diastolic Heart Failure.250 M. Bremmer (EMGO) (i.c.w. M. Diamant) EFSD/EASD; ‘Bright light for better mood and metabolic control. The efficacy of Bright Light Treatment in Type 2 Diabetes and comorbid Major Depression’ Richard G. IJzerman (i.c.w. NCA) ZonMw (VENI); ‘The role of central reward and satiety centers in the etiology of obesity: genetic and environmental influences’.250 Paul Knaapen Abbot Vascular ‘Impact of Vascular Reparative Therapy on Vasomotor Function and Myocardial Perfusion’.225 External Grants obtained by the ICaR-VU 2012 in kEuro (selection) Coen OttenheijmNWO VIDI Grant ‘Muscle weakness in Nemaline Myopathy: what is the cause and can it be treated?’800 Bert van Rossum Industry: Estimate of research grants obtained for cardiology projects.750 Hans van Goudoever Danish Government ‘Neo Immune’ coordinator. Total group: 5000.500 Hans van Goudoever FP7: European network Early Nutrition. Total group: 11000.450 Hans van Goudoever Nutricia Foundation: Long term impact of nutritional management.440 Christa Boer, and Evert Verhagen (EMGO+) NWO prevention Fund ‘Increasing habitual physical activity to reduce the surgical risk of hyperglycemia and complications in patients with metabolic syndrome (POSITIVE study)’.435 Hans van Goudoever FP7: Prevent ROP total of group: 4000.400 Yvo Smulders Identifying the right patient to treat, by estimating absolute treatment effect for individual patients based on randomized clinical trial data. ZonMw Programma Goed Gebruik Geneesmiddelen 2012-2016 (co-applicant).374 Christianne De Groot (i.c.w. dr. C. Wagner, EMGO) ZonMw Improving obstetrical care by multidisciplinary team training for patient referral situations. The LOCOMOTIVE Study: Local Obstetrical Collaboration Multidisciplinary On-site Team training effectIVEness Study.372 Harry Lafeber Industry: Step study’s funding for 2012.320 Henk Blom FP7: European network and registry for homocystinurias and methylation defects VUmc coordinator (total 700). Michaela Diamant Eli Lily: ‘The effects of real-time continuous glucose monitoring in patient with type 1 diabetes mellitus and impaired hypoglycemia awareness (IN CONTROL STUDY)’.260 Harm-Jan Bogaard and Geerten van Nieuw Amerongen Lung Foundation: ’The pulmonary endothelium fails to adapt to increasing shear stress: Role of blood flow velocity in the development of pulmonary arterial hypertension‘.250 Christianne de Groot (principal investigator) ZonMw: Regional perinatal network within the education and training region (OOR) of VUmc.250 300 250 The ICaR-VU was successful in obtaining research grants in 2010-2012. In 2010 all types of funding increased compared to prior years. Researchers of the ICaR-VU were active in European consortia, national research platforms, charity research funds and industry competitions. Figure 7: External grants obtained by researchers of the ICaR-VU in 2004-2012. Government grants include: Dutch organizations for research supported by the government like NWO/ZonMw/STW/FES. Charity organizations include: Netherlands Heart Foundation, Dutch Kidney Foundation, Dutch Diabetic Society, Asthma-Fund. Data were provided by the project leaders participating in the ICaRVU. More details are published in the year reports. 2012 is the best available estimate at the end of January 2013. 12,00 Euro’s *10 6 10,00 8,00 6,00 4,00 2,00 0,00 2003 2004 2005 External Funding Research 2006 2007 2008 2009 2010 2011 2012 Year Funding by NWO/ZonMw/STW/FES Funding by Industry Funding by Charity Organizations/FP7 Total external funding I C A R -V U m c 27 28 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 29 Education The ICaR-VU, started with an educational focus on its PhD students; now the ICaR-VU provides challenging educational programs for Bachelor, Master and PhD students in medical and life science research. Bachelor-education Master-education The ICaR-VU participates in research education in the medical bachelor program. Each year, 40 medical bachelor students choose Cardiovascular Research for their scientific training. They write a bachelor thesis in small groups under the supervision of PhD students. A workshop program on the research within the Institute is organized to help them to choose their practical research training. Theoretical education is tested by an oral examination. The Cardiovascular Research Master provides an international education program for excellent students who are looking for a career in cardiovascular research. It was accredited by the NVAO in 2008 and provides a structured 2-year program within cardiovascular sciences for a limited number (up to 25) of students. The first curriculum of the Cardiovascular Research Master was in September 2009. This Research Master Program preselects for bright and motivated students with a life-science or related bachelor degree. Each year, as a part of a special honors program, 3-6 medical bachelor students start specialized cardiovascular research projects (during their medical bachelor education), in order to gain research experience and to write their first scientific paper. They continue the data acquisition and analysis at the start of their master program and finish writing the paper in the second year of their master-education. Most of these students combine research and medical training and start a PhD education after their MD graduation. PhD training program The ICaR-VU offers PhD students a research and education program that is tailored to individual needs. Research training at the front-line of cardiovascular research in the laboratory and the clinic is the primary goal for a PhD student, who will spend most of their time on a research training project collaborating with the ICaR-VU scientists. At the start of their research training, an agreement is made to follow highly specialized topical and/or complementary courses taught by senior scientists at the ICaR-VU, including visiting senior scientists, or other highly qualified teachers. I C A R -V U m c 29 30 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e PhD Training Program The PhD-curriculum consists of five categories of activities: 1Courses contributing to the PhD students general scientific education (i.e. statistics, scientific English, animal research, clinical research regulations, writing grant proposals). 2 Participation in weekly progress meetings of the research team; supported by PhD-supervisor. 3Participation in cardiovascular knowledge transfer (colloquia, symposia, lectures, presentation of own papers and posters). 4Special courses training students to become independent researchers and widening the scope of their knowledge (organized for PhD students in Cardiovascular Research by the ICaR-VU or by the Netherlands Heart Foundation). 5Visits to other labs to enhance cooperation between groups and learn new technical skills. PhD Students and Projects In addition to the monthly scientific colloquia organized by the Institute, symposia are organized by the participating research groups on special occasions, as well as lectures by visiting scientists. 45 40 35 30 PhD students 25 The PhD students in the Institute have a basic life science or medical background. The majority follow the regular full-time PhD project and program. They include comparable numbers of students with an MD background, who will specialize after their research training, and basic science PhD students (from Medical Biology, Epidemiology, Physics or Technology backgrounds). Many international students are among this latter group. In addition a number of clinicians combine clinical duties and research; these projects are embedded in the Institute. 20 15 10 5 0 2009 2010 2011 2012 Twice a year a special themed afternoon is organized by the education committee for all PhD students in ICaR-VU: Figure 9: The number of PhD students active within the ICaR-VU is gradually increasing as is reflected by the number of PhD projects in progress. The average duration of the regular PhD research project is 4 years. The duration of combined specialization and research is more variable. In Theme Vessels more clinical research is combined with a specialist training program. 90 80 70 ‘Ethical dilemma’s in clinical and preclinical research’ by prof. dr. Tjard de Cock Buning, dr. Christa Boer (member METC VUmc), December 2011. ‘Posterworkshop’ How do you get the attention of your public, by Catriona Ester VU University Language Center, April 2012. ‘Good science vs Fraud’ How can you be sure that all your papers are based on solid data by prof. dr. Nico Westerhof and prof. dr. Henk de Regt, December 2012. Figure 8: Education background of the PhD students who are ICaR-VU graduates. The Basic science group has a MSc background and follow a regular 4 year PhD program. The MD regular group represents Medical Doctors that follow the regular 3-4 year PhD program, the MD special group members combine clinical training and research. The MD external group combines clinical work outside VUmc with research under the supervision of an ICaR-VU scientist. In the external group the work and graduation took place outside VUmc under co-supervision of ICaR-VU scientists. Basic Science MD regular MD special MD external (B) External (D) PhD graduations ICaR-VU 100 ‘Meet the criticasters’ How is your paper judged, before it is accepted for publication? by prof. dr. Anton J.G. Horrevoets and prof. dr. Walter J. Paulus, March 2010. ‘PhD graduation in perspective’ What will you do after graduating for your PhD? by dr. ir. Roel G.M. Breuls, and dr. Erik H. Serné, November 2010. ‘Successful writing’ How do you prepare your paper and how did others before you? by prof. dr. Nico Westerhof and prof. dr. Jolanda van der Velden, April 2011. 31 60 50 40 30 20 10 Theme H Theme V 0 2009 2010 2011 2012 Number of PhD projects in progress I C A R -V U m c 31 32 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 33 PhD Degrees Awarded in 2010 DATE CANDIDATE PROMOTOR(ES) CO-PROMOTOR(ES) TITLE THESIS V 28-10 Cathelijne Snijders W.P.F. Fetter T.W. Schaaf H.A. Molendijk R.A. Lingen Sources and consequences of reactive oxygen species in right ventricular hypertrophy and right ventricular failure. Voluntary reporting and systematic analysis of incidents in neonatal intensive care: the Neosafe study. V 17-11 Iris J.G. Ketel C.B. van Lambalk C.D.A. Stehouwer E.H. Serné R. van Homburg Vascular function and insulin sensitivity in lean and obese PCOS. DATE CANDIDATE PROMOTOR(ES) CO-PROMOTOR(ES) TITLE THESIS V 22-01 Cora M.L. Beckers V.W.M. van Hinsbergh G.P. van Nieuw Amerongen Spatial-temporal signalling controlling endothelial permeability. H 25-01 Everaldo M. Redout W.J. Paulus W.S. Simonides R.J.P. Musters theme theme H 04-03 Barbara M.A. Schout L.H.B. Bemelmans A.J.J.A. Scherpbier A. Hendrikx F. Scheele Training in Urology: from virtual to reality. V 23-11 Annemarie M.C. Simonis-Bik M.H.H. Kramer J.C.N. Geus E.W.M. Eelhoff Genetic influences on β-cell function. H 19-03 Martijn A. Bekedam A.C. van Rossum W.J. van der Laarse Skeletspieren bij hartfalen. V 24-11 Margo N. Schilte J. v.d. Born V 26-03 Kirsti S.S. Steen B.A.C. Dijkmans W.F. Lems M. Boers M.T. Nurmohamed Decline of NSAID gastropathy in rheumatoid arthritis. R.H.J. Beelen P.M. ter Wee Anti-inflammatory therapy and biomarker analysis during peritoneal dialysis. V 10-12 Vincent Jongkind W. Wisselink V 29-03 Melanie van der Heijden A.B.J. Groeneveld V.W.M. van Hinsbergh G.P. van Nieuw Amerongen Determinants of vascular leakage in sepsis and acute lung injury. New techniques in minimal invasive and open surgery of the aorta. V 03-12 Floor Remmers A.C. van Rossum R.M. Heethaar M.J.W. Götte Myocardial strain, torsion and untwisting in the normal and failing heart measured with magnetic resonance tagging. Developmental programming of energy balance. Iris K. Russel H.A. Delemarrevan der Waal R.A.H. Adan V 14-12 Leonard P. van der Zwan C.A.J.M. Jacobs P.G. Scheffer T. Teerlink The interplay of oxidative stress and inflammation in atherosclerosis: an epidemiologic approach. P.A.F.M. Doevendans M.C. Verhaar C.A.J.M. Gaillard B. Braam Circulating cells in heart and renal failure. J.H. Beijen M. Diamant D.P.M. Brandjes Chubby children: weighing the risk. J.L.H.R. Bosch R.M. Verdaasdonk F.P. van Swol R.J.A. van Moorselaar Towards improved bladder cancer diagnosis using fluorescence imaging and Raman spectroscopy. H 14-04 V 15-04 Rose-Marieke B.G.E. Breukers A.B.J. Groeneveld A.R.J. Girbes J.R.C. Jansen Preload and cardiac output in the critically ill. V 20-05 Wineke Bakker V.W.M. van Hinsbergh C.D.A. Stehouwer E.C. Eringa P. Sipkema Vascular insulin resistance through fat. V 10-06 Marieke G. Peetsold R.J.B.J. Gemke H.A. Heij H 14-06 M. Louis Handoko W.J. Paulus A. Vonk Noordegraaf Right Heart failure in pulmonary Hypertension, lessons from the left Heart. H 14-06 Frances S. de Man P.E. Postmus W.J. van der Laarse A. Vonk Noordegraaf Muscle function, exercise training and beta-blocker treatment in pulmonary arterial hypertension. V 23-06 Koen L. Deurloo J.M.G. van Vugt M.A. Blankenstein A.C. Bolte Early prediction of pre-eclampsia and intrauterine growth restriction in pregnancy. V 08-09 Annemone van Zwol W.P.F. Fetter V 06-10 Fleur M.F. Rosiervan Dunne J.I.P. de Vries H.J. Odendaal G. van Wezel-Meijler H.P. van Geijn Fetal brain imaging in pregnancies at risk for preterm birth. V 07-10 Wiebe de Vries J.J.L.M. Bierens K. Monsieurs R.W. Kosterd Remember fast - Act skillfully. Training methods for Basic Life Support: an analysis from educational perspective. Long term results after repair of congenital diaphragmatic hernia and esophageal atresia. Glutamine-enriched enteral nutrition in very low birth weight infants, six years of follow-up. EXTERNAL DEFENCES H UU 08-04 Kim E. Jie V UU 15-09 Mariska vanVliet H UU 28-10 Matthijs C.M. Grimbergen All theses listed here had a Promotor or co-Promotor from the ICaR-VU, although some were defended at other universities, as mentioned in the section external defences. I C A R -V U m c 33 34 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 35 PhD Degrees Awarded in 2011 DATE CANDIDATE PROMOTOR(ES) V 06-01 Ingeborg H. Linskens J.M.G. van Vugt M.A. Blankenstein V 27-01 Laura Vroling V.W.M. van Hinsbergh H.M.W. Verheul H.J. Broxterman theme CO-PROMOTOR(ES) TITLE THESIS theme DATE CANDIDATE PROMOTOR(ES) CO-PROMOTOR(ES) TITLE THESIS Pathophysiology of impaired glucose metabolism: the role of the renin angiotensin system. Prenatal screening in twin pregnancies. V 06-07 Nynke van der Zijl M. Diamant E.E. Blaak Circulating endothelial and progenitor cells during anti-angiogenic treatment in cancer patients. V 08-07 Thomas J. Cramer H.W.M. Niessen V 09-09 Mark S. Fineman M. Diamant R.J. Heine Development of immediate and sustainedrelease formulations of the glucagon-like peptide-1 receptor agonist exenatide for the treatment of patients with type 2 diabetes. V 09-09 Mathijs C.M. Bunck M. Diamant R.J. Heine Clinical effects of the GLP-1 receptor agonist exenatide in patients with type 2 diabetes. H 15-02 Viola Kooij G.J.M. Stienen J. van der Velden Contractile Function of the Human Myocardium. Impact of Troponin Phosphorylation. V 16-02 Yolanda M. de Mooij J.M.G. van Vugt AC Gittenbergerde Groot M.N. Bekker Increased nuchal translucency. Lymphatic development and blood flow alterations in fetuses with nuchal edema. A.J. Gale Inactivation of coagulation factors Va and VIIIa by activated protein C. H 09-03 Serge A. van Wolferen A. Vonk Noordegraaf A. Boonstra J.T. Marcus Monitoring the right ventricle in pulmonary arterial hypertension. A non-invasive approach. V 28-09 Ester M. Weijers V.W.M. van Hinsbergh P. Koolwijk V 01-04 Lukas B. Uittenbogaard J.M.G. van Vugt M.C. Haak The Fetal Heart. Critical appraisal of three-dimensional echocardiography. Fibrin matrices for tissue engineering. Naturally occurring fibrinogen variants alter cellular characteristics. V 26-10 Ilse E.A.M. Westerbeek R.M. van Elburg V 21-04 Izhar C. van Eijk B.A.C. Dijkmans Y.M. Smulders M.T. Nurmohamed D. v. Schaardenburg Modulation of cardiovascular risk factors and inflammation in rheumatic diseases. H.N. Lafeber W.P.F. Fetter Enteral supplementation of neutral and acidic oligosaccharides in preterm infants. H 18-11 Katja van den Hurk 26-04 Sabine J. van Dijk G.J.M. Stienen J. van der Velden Sarcomeric function and protein changes in human cardiomyopathy: mutation or phenotype. O. Kamp M.J. Alssema Diabetes and the Heart. H J.M. Dekker M.G.A.A.M. Nijpels V 30-11 Adrie Seldenrijk B.W.J.H. Penninx M. Diamant H.P.J. v. Hout H.W.J. v. Marwijk Depression, Anxiety and Subclinical Cardiovascular Disease. V 18-05 G. Margret Bartelds B.A.C. Dijkmans L.A. Aarden M.T. Nurmohamed G.J. Wolbink Clinical implications of immunogenicity. V 02-12 Mark van Heerde J.J. Roord D.G. Markhorst Preservation of spontaneous breathing during high-frequency oscillatory ventilation. V 24-05 Susan Collins W.W.A. Zuurmond S.A. Loer R.S.G.M. Perez Complex Regional Pain Syndrome type 1 Assessment and treatment targeting central sensitization. V 16-12 Koen J. Hartemink A.B.J. Groeneveld A. Beishuizen Cardiovascular markers and mediators in human septic shock. H 19-12 Gert Jan Mauritz A. Vonk Noordegraaf J.T. Marcus V 25-05 G. Frederiek Estourgie-van Burk D.I. Boomsma H.A. Delemarrevan der Waal W.P.F. Fetter M. Bartels Variation in growth and the influence of early growth in later life: a twin-sibling study. Insights into the progression of right ventricular failure in pulmonary arterial hypertension. V 22-12 Michel E. Weijerman R.J.B.J. Gemke A.M. van Furth V 27-05 Berbel J.R. Sluijter R.J. Scheper P.A.M van Leeuwen D. de Gruijl M.P van der Tol Cutaneous Melanoma: Predictors of Patient Survival and the Potential of Priming of the Sentinel Lymph Node. V 30-05 Robert E. Verloop V.W.M. van Hinsbergh A.J. van Zonneveld P. Koolwijk Progenitor Cells and Hypoxia in Angiogenesis. V 31-05 Ilse A.C. Vermeltfoort G.J.J. Teule P.G.H.M. Raymakers Diagnosis and prognosis of cardiac syndrome X. H 04-07 Luuk-Jon Rijzewijk M. Diamant A.A. Lammertsma Metabolic Imaging in Gluco-Lipotoxic Heart and Liver Disease in Type 2 Diabetes. Consequences of Down syndrome for patient and family. EXTERNAL DEFENCES In 2011, C.J.M de Groot, H.J Blom, P.A.M. van Leeuwen and V.W.M. van Hinsbergh were Promotors for a total of 6 individual thesis defenses at other universities. The details of these can be found in the annual report of the ICaR-VU 2011 at www.vumc.com/branch/icar-vu/infoicarvu/AR/ I C A R -V U m c 35 36 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h e In s tit ut e 37 PhD Degrees Awarded in 2012 DATE CANDIDATE PROMOTOR(ES) CO-PROMOTOR(ES) TITLE THESIS H 03-07 Marijn P. Rolf R.M. Verdaasdonk A.C. van Rossum M.B.M. Hofman Velocity Measurements in Cardiac Magnetic Resonance Imaging. Myocardial O2 supply and O2 utilization of the right ventricle in pulmonary arterial hypertension. H 04-07 Sebastiaan A. Kleijn A.C. van Rossum O. Kamp Novel aspects of left ventricular quantification with three-dimensional echocardiography. Validation and clinical applications. R. Nieuwland Postprandial dysmetabolism and cell-derived microparticles as cardiovascular risk factors in metabolic syndrome and type 2 diabetes mellitus. V 05-09 Neelke C. v.d. Weerd P.M. ter Wee M.L. Bots M.P.C. Grooteman P.J. Blankestijn Hemodiafiltration and Hepcidin. Effects on renal anemia and cardiovascular disease in hemodialysis patients. V 19-09 Daan v. Abel C.B.M. Oudejans M. van Dijk A. Vonk Noordegraaf Th.C.J. Faes Towards a better description of cardiovascular function in pulmonary hypertension. Modeling and clinical practice. The role of transcription factor STOX1A in transcriptional networks associated with neurodegeneration. H 21-09 Nabil Saouti A. Vonk Noordegraaf A. Boonstra The Load of Pulmonary Hypertension. Annemieke v. Dijk H.W.M. Niessen A.C. van Rossum F.J. van Milligen New therapies for myocardial infarction: inflammation inhibitors and adipose stem cells. H 27-09 Christine J. Pol W.J. Paulus W.S. Simonides Milan C. Richir P.A.M. v. Leeuwen Th.P.G.M. de Vries T. Teerlink The importance of the arginine/ADMA ratio on the bioavailability of nitric oxide and organ function in critically ill patients. Impaired cardiac thyroid hormone signaling during heart failure.The role of type III deiodinase. V 28-09 Jessica Sipkens H.W.M. Niessen V.W.M. van Hinsbergh C.D.A. Stehouwer J.A. Rauwerda Homocysteine as a risk factor for the development of cardiovascular disease the role of NOX proteins. V 10-10 Fleur Schouten J.W.R. Twisk Y.M. Smulders M.R. de Boer I. Ferreira Fat Distribution and Arterial Stiffness. The Amsterdam Growth and Health Longitudinal study. V 01-11 Milou P.H. Busard C. van Kuijk J.H.T.M. van Waesberghe V. Mijatovic Advances of MR imaging in endometriosis. V 23-11 Daniël H. v. Raalte M. Diamant V 26-11 Ronald J. Trof A.B.J. Groeneveld A.R.J. Girbes A. Beishuizen Optimizing fluid management in critically ill patients. V 07-12 Daniëlle M.E. v. Assema A.A. Lammertsma Ph. Scheltens B.N.M. van Berckel M. Lubberink Blood-brain barrier P-glycoprotein function in aging and Alzheimer’s disease. DATE CANDIDATE PROMOTOR(ES) CO-PROMOTOR(ES) TITLE THESIS V 24-02 Eelco v. Duinkerken M. Diamant F.J. Snoek M. Klein F. Barkhof Type 1 Diabetes and the Brain: A Bittersweet Relationship? H 21-03 Yeun Ying Wong A. Vonk Noordegraaf P.G.H.M. Raijmakers W.J van der Laarse V 26-03 Maarten E. Tushuizen M. Diamant A. Sturk H 27-03 Taco Kind H 17-04 V 20-04 theme On the pathological remodeling of large arteries. 23-04 Frank Helderman A. Vonk Noordegraaf R. Krams 25-04 Stefan A.J. Timmer A.C. v. Rossum A.A. Lammertsma V 09-05 Shaikh A. Nurmohamed A.B.J. Groeneveld P.M. ter Wee V 09-05 Matteus A.M. Linsen W. Wisselink A.W.F. Vos Endovascular aortic aneurysm repair: alternative strategies. V 14-05 Jan Willem Kuiper A.B.J. Groeneveld R.J.B.J. Gemke F.B. Plötz Mechanical Ventilation and Acute Kidney Injury. V 16-05 Mark G. Vervloet P.M. ter Wee 01-06 Georgios F. Giannakopoulos H.J. Bonjer F.C. Bakker Triage and assessment of injuries in early trauma care. 14-06 Johannes A. v.d. Heide A. C van Rossum O. Kamp Three-dimensional echocardiography for left ventricular quantification in heart failure. 19-06 Olga Bondarenko A.C. van Rossum A.M. Beek Myocardial Viability in Patients With Chronic Ischemic Myocardial Dysfunction: Evaluation by Cardiovascular Magnetic Resonance. 21-06 Lonneke Smeding A.B.J. Groeneveld M.C.J. Kneyber F.B. Plötz Sepsis, mechanical ventilation and the heart. V H V H H V P. Knaapen M. Lubberink Myocardial Perfusion and Metabolic Imaging in Hypertrophic Cardiomyopathy. Unraveling the Pathophysiology. theme Optimizing continuous renal replacement therapy in the ICU. Managing disorders of bone and mineral metabolism in chronic kidney disease. Diabetogenic effects of glucocorticoid drugs:the knowns and the unknowns. EXTERNAL DEFENCES In 2012 J.B. van Goudoever, R.J.B.J. Gemke, M. Diamant, C.A.J.M. Gaillard, H.J. Blom, R.M. Verdaasdonk, M.P.C. Grooteman and C. Boer were (co-)Promotors for a Promovendus at another university. A total of 11 external theses were defended in 2012. Details will be available April 2013 at www.vumc.com/branch/icar-vu/infoicarvu/AR/ I C A R -V U m c 37 38 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H Theme H Improvement of Cardiac Function in Heart Failure The studies in Theme H aim to unravel pathomechanisms underlying myocardialand pulmonary remodeling and impaired cardiac function 39 2 Introduction Toptalents Research Groups I C A R -V U m c 39 40 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 41 Theme H / Heart Failure Ischemia and Repair Circulation and Metabolism Imaging Heart Failure and Pulmonary Arterial Hypertension Heart failure is the most frequent cause of hospitalization in Western societies. Despite advances in treatment, the prognosis of heart failure patients remains poor. Progressive deterioration of myocardial function is a key feature of chronic heart failure and is the result of many different pathological processes affecting the myocardium. Heart failure studies within the ICaR-VU Theme H aim to unravel cellular pathomechanisms underlying myocardialand pulmonary remodeling and impaired cardiac function. The main research areas of Theme H are Heart Failure and Pulmonary Arterial Hypertension. Our research activities include clinical and preclinical collaborations at both a national and an international level. There are three research groups focusing on: diastolic heart failure, hypertrophic cardiomyopathy and right ventricular failure in pulmonary arterial hypertension (PAH). Cardiovascular Imaging studies play a prominent role in all three. Within these research groups the patients form the basis of clinical and basic studies, which sets the stage for a translational research approach. There are many interrelationships amongst Theme H research groups as well as with Theme V of the ICaR-VU. Recent studies have indicated that diastolic heart failure is a common feature in different patient groups and suggest that diastolic dysfunction is a significant determinant of disease outcome. The research groups aim to unravel the pathomecha- nisms underlying diastolic dysfunction. In addition to this, studies on cardiac metabolism is a common research subject for all three groups including: deranged metabolism as risk factor in diastolic heart failure; impaired efficiency of cardiac contraction caused by mutant sarcomeric proteins in inherited forms of cardiomyopathies and perturbations in oxygen supply and utilization in the hypertrophied heart as observed in PAH-induced right heart failure. Studies in the heart are paralleled by studies in Theme V, which focus on vascular remodeling and dysfunction caused by increased metabolic risk (diabetes) and pulmonary hypertension. A classic example of the collaboration between themes H and V is represented in the study of pulmonary hypertension patients. While pulmonary arterial hypertension causes vascular remodeling and as such represents a primary pulmonary disease, mortality in pulmonary arterial hypertension patients is strongly associated with right ventricular dysfunction. The research group right heart failure in PAH aims to develop specific treatments targeted at the right ventricle and/or pulmonary circulation to intervene in the vicious circle triggered by high arterial pressures. Likewise, cardiac and vascular studies on diastolic heart failure and hypertrophic cardiomyopathy are combined to improve diagnostics and to develop preventive and curative measures for the treatment of heart failure. I C A R -V U m c 41 42 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 43 Focus on Toptalent Nebulin, a multi-functional giant Coen Ottenheijm (VIDI Grant 2012) Muscles function through a delicate interplay between innumerable proteins. Defects in these proteins cause this interplay to crash, resulting in life-threatening muscle diseases. Coen Ottenheijm’s research aims to provide insights into how one defective protein - the giant protein nebulin – leads to impeded contractility of the muscle causing nemaline myopathy, a debilitating muscle disease. It is expected that these insights will open new therapeutic windows for patients with nemaline myopathy, a disease for which no effective therapy currently exists. Perioperative cardio-vascular function in cardiometabolic disease Arthur Bouwman (ZonMw Clinical Fellowship 2010 & Young Investigator Dutch society for Anesthesiology 2010) Patients with cardiometabolic disease are prone to perioperative cardiovascular complications. Anesthetic agents protect against ischemic injury by the activation of protective signaling pathways. Diabetes mellitus and obesity reduce the efficacy of anesthetic-induced cardioprotection. Here we are focusing on interventions (insulin-sensitizing medication and lifestyle modification) that have the potential to restore cardioprotective signaling. These insights will provide new perioperative strategies for patients with cardiometabolic disease who undergo anesthesia and surgery. The giant titin protein as novel therapeutic target for diastolic heart failure Nazha Hamdani (Early Career Researchers Grant, Mercator foundation Germany, 2012) Heart failure with preserved ejection fraction (HFpEF) is a major clinical problem for which there is currently no established therapy. The elastic protein titin represents a novel target for intervention, given that there are significant titin-mediated changes in elasticity associated with HFpEF. We are investigating the effect of potential pharmacological interventions on cGMP-PKG signaling, titin isoform expression, phosphorylation and passive stiffness. Our studies will improve understanding of HFpEF pathophysiology and may (even) lead to new effective therapies. ENGINE of the muscle in hypertrophic cardiomyopathy Tjeerd Germans (Netherlands Heart Foundation, Dekker Grant 2011) The mechanism underlying the development of maladaptive hypertrophy in inherited hypertrophic cardiomyopathy (HCM) is poorly understood. Mutant sarcomeric proteins may impair myocardial energetics and trigger disease development. We are combining in-vitro determination of myocardial energetics in cardiac tissue with non-invasive data on myocardial metabolism and function with hybrid MRI/PET of the same patients. Our studies will enhance our knowledge of HCM pathogenesis and form the basis of new therapeutic strategies for the prevention and reversal of disease progression. I C A R -V U m c 43 44 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 45 Research Group Diastolic Heart Failure ‘Our extensive collaborative research endeavor will achieve a better understanding of diastolic heart failure, improved diagnostic algorithms, and novel therapeutic inroads’ Focus The focus of our studies is on diastolic heart failure (DHF). Over the last two decades it has become evident that more than 50% of all heart failure patients suffer from impaired diastolic function with preserved left ventricular ejection fraction (HFpEF). Despite modern heart failure therapy, prognosis of HFpEF has not improved in recent years. This epidemiological finding has confirmed the neutral result of numerous large clinical trials testing modern pharmacotherapy in patients with DHF. HFpEF is of heterogeneous etiology but usually occurs in patients suffering from obesity, arterial hypertension and type 2 diabetes. The vast majority (~80%) of HFpEF patients are exposed to metabolic risk factors and the rising incidence of DHF, therefore, mirrors current epidemics of obesity and type 2 diabetes. Collaboration We collaborate in order to explore the involvement of metabolic risk in the pathogenesis of DHF using a multidisciplinary approach. Studies on cellular pathomechanisms are combined with clinical trials based on existing national and international collaborations. In vivo assessment of left ventricular structure, perfusion, metabolism and contractile function using echocardiography, cardiovascular magnetic resonance imaging, positron emission tomography and multi-detector computed tomography form an essential part of our diastolic heart failure research. In vivo clinical characteristics are combined with cellular studies in human cardiac preparations. In addition to this, several large- and small-animal models are being used to unravel the pathomechanisms underlying impaired diastolic function. Unique Our research group is unique as our in vitro and in vivo observations in humans are a crucial basis for the subsequent targeted approaches in mice and a largeanimal model. An excellent example of the success and impact of these approaches was the observation of increased cardiomyocyte passive stiffness in diastolic heart failure patients, which until then, had never been observed in any animal model. This observation has set the stage for many follow-up studies in animal models and forms the basis for clinical treatment strategies. I C A R -V U m c 45 46 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 47 Diastolic Heart Failure Present and Future Research Prominent clinical features of myocardial dysfunction in HFpEF are slow relaxation and high diastolic stiffness. In recent years, we have shown that intrinsic cardiomyocyte stiffness is a major cause underlying diastolic stiffness. The high cardiomyocyte stiffness is largely determined by the giant cytoskeletal protein titin, whose phosphorylation pattern is altered during cardiac disease. Our most recent studies suggest that hypophosphorylation of titin is the underlying cause of high passive stiffness. With our cellular studies we aim to define the contribution of passive stiffness, myofilament calcium-sensitivity and perturbations in intracellular calcium-handling to cardiomyocyte stiffness. In addition to this, extensive studies of the extracellular matrix are being performed in the Department of Pathology to assess its role in disease pathogenesis. Our current research projects are part of the large collaborative MEDIA project sponsored by the European Commission. In 2009 the committee on diastolic heart failure (founded by the Heart Failure Association of the European Society of Cardiology) chaired by Walter Paulus created MEDIA (the MEtabolic road to DIAstolic heart failure). The focus is on the interaction between metabolic risk and diastolic heart failure, and in January 2011 the project began with funding of €12.1 million divided among seven work packages, 20 universities and small-medium enterprises. Investigators in work package one, are creating novel animal models of diastolic heart failure by exposing rodents or pigs to a high metabolic risk. Three of the work packages cover cardiomyocyte, extracellular matrix, and systems biology, respectively. The remaining three work packages are clinically oriented and deal with biomarkers, imaging, and small proof-of-concept trials whereby modulation of metabolic risk is tested as a cure for diastolic heart failure. Recent advances in the field of microRNAs have provided a novel research field, which may be explored to identify targets for future clinical application. The surprising stability of circulating microRNAs has created the possibility for developing next-generation biomarkers. Inhibition of selected microRNAs is powerful and holds great promise of becoming the next generation therapeutics. With recent funding from CVON (Cardiovascular Research in the Netherlands) we will evaluate whether specific RNA based candidate mechanisms (microRNAs, lncRNA, RNA binding proteins) are of particular relevance in diastolic heart failure. Within the ARENA (Approaching Heart Failure by Translational Research of RNA Mechanisms) consortium several research groups in the Netherlands (see National collaborations) have joined forces to explore the relevance of novel crucial RNA molecules in systolic and diastolic heart failure in the context of diastolic dysfunction, ageing, diabetes and gender. We aim to establish the role of RNA-based regulation in the contractile dysfunction of the failing heart. Identified microRNAs and their target genes will be linked to modifications of extracellular matrix and of myofilament proteins and to contractile properties of isolated cardiomyocytes. Participants Project leaders Physiology Nazha Hamdani Alice Muller Walter Paulus Warner Simonides Ger Stienen Jolanda van der Velden Internal Medicine Michaela Diamant Pathology Paul Krijnen Hans Niessen Cardiology Jean Bronzwaer PhD students Physiology Constantijn Franssen Loek van Heerebeek Rob Janssen Christine Pol Everaldo Redout Internal Medicine Weena Chen Renate van Genugten Diane de Goede Larissa van Golen Susanne Kleijer Luuk-Jon Rijzewijk Mark Smits Collaborations National EMC, Rotterdam Vincent de Beer Dennis Dooijes Dirk Jan Duncker Ellen Kaptein Daphne Merkus Theo Visser MUMC, Maastricht Stephane Heymans Casper Schalkwijk Leon de Windt Marc van Bilzen AMC, Amsterdam Jan Baan Jr Bas de Mol Jan Piek Yigal Pinto Jan Tijssen UMCU, Utrecht Cees van Echteld Cees van de Kolk Annette van den Toorn UMCG, Groningen Maarten van den Berg Jan Jongbloed Adriaan Voors OLVG, Amsterdam Aernout Somsen Freek Verheugt International Antwerpen, Belgium Marc Demolder Leni van der Kerkhoven Nancy, France Romain Eschalier Berlin, Germany Carsten Tschöpe Bochum, Germany Wolfgang Linke Heidelberg, Germany Johannes Backs Pavia, Italy Stefano Perlini Francesco Salinaro Perugia, Italy Giuseppe Ambrosio Emilia Biscottini Pisa, Italy Maja Marchini Alessandro Saba Riccardo Zucchi Porto, Portugal Ines Falcão-Pires Cristina Gavina Adelino Leite-Moreira Daniela Miranda-Silva Daniel Moreira-Goncalves Debrecen, Hungary Zoltán Papp Attila Borbely Oslo, Norway Svend Aakhus William Louch Gabor Kunszt Ole Sejersted Dublin, Ireland Mark Ledwige Kenneth McDonald Atlanta, USA Tsukasa Kawahara Rochester, USA Barry Borlaug Support staf Physiology Edwin Kanters Wies Lommen Ruud Zaremba Marian Zuidwijk I C A R -V U m c 47 48 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 49 Research Highlight Diastolic Heart Failure Data from PhD/post-doc projects: Loek van Heerebeek (Physiology), Nazha Hamdani (Physiology Amsterdam & Bochum) Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality, and is found in up to 50% of all patients with the clinical features of chronic heart failure. Diastolic left ventricular (LV) dysfunction due to high LV stiffness and slow LV relaxation are important contributing factors in HFpEF. Most HFpEF patients are exposed to metabolic risk factors, and the increasing incidence of HFpEF, therefore, reflects the current epidemics of obesity and type 2 diabetes. Despite the clinical importance of HFpEF, its pathophysiology remains poorly understood and treatment options remain limited. Our recent studies in a large-animal model of HFpEF (Hamdani et al. 2011) and HFpEF patients (van Heerebeek et al. 2012) have highlighted the important phenomenon of elevated intrinsic cardiomyocyte stiffness (Figure A). We demonstrated that elevated intrinsic cardiomyocyte stiffness is caused by phosphorylation deficits of the giant sarcomeric protein titin (Borbely et al. 2005/2009; Hamdani et al. 2011; van Heerebeek et al. 2012) and that these alterations contribute to high diastolic LV stiffness. In addition to this, endomyocardial biopsies of HFpEF patients showed increased nitrosative/oxidative stress and impaired nitric oxide bioavailability, which down-regulates myocardial cyclic GMP/protein kinase G (PKG) signaling. This causes hypophosphorylation of titin, which enhances cardiomyocyte and LV diastolic stiffness. Both the in vitro (Figure B) administration of PKG and in vivo administration of sildenafil raised PKG activity and reduced cardio-myocyte and LV stiffness. Our studies clearly show the importance of cGMP-PKG signaling for myocardial remodeling in HFpEF and strongly suggest that readily available, low-toxicity pharmaceutical agents that influence the cGMP/PKG pathway may represent a novel therapeutic opportunity in HFpEF patients. Δ F passive after PKG (kN/m2) A p<0.05 4.5 p<0.01 3.0 1.5 0.0 HFPEF HFREF p<0.001 B AS p<0.001 p<0.001 F passive (kN/m2) Treatment Challenges and Novel Therapeutic Targets Selected Publications 2010-2012 8 p<0.01 6 p<0.01 4 2 0 HF RE HF F R + EF PK G HF PE HF F P + EF PK G AS AS +P KG Figure A: Larger fall in cardiomyocyte Fpassive after PKG administration in HFPEF than in HFREF or AS. HFPEF indicates heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; AS, aortic stenosis; and PKG, protein kinase G. Figure B: Higher cardiomyocyte Fpassive in HFPEF than in HFREF or AS with a significant fall in Fpassive after PKG administration in all 3 conditions. eerebeek L, Hamdani N, Falcão-Pires I, H Leite-Moreira AF, Begieneman MPV, Bronzwaer JGF, van der Velden J, Stienen GJM, Laarman GJ, Somsen A, Verheugt FW, Niessen, HWM Paulus WJ. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012; 126:830-39. F alcão-Pires I, Palladini G, Gonçalves N, van der Velden J, Moreira-Gonçalves D, Miranda-Silva D, Salinaro F, Paulus WJ, Niessen HW, Perlini S, Leite-Moreira AF. Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Research in Cardiology 2011; 106:801-04. amdani N*, Bishu GK*, Ogut O, Kruger H M, Mohammed SF, Ohtani T, Ahmed A, Brozovich FV, Burnett JR, Linke WA, Redfield MM. Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. *Both authors contributed equally. Circulation 2011; 124:2882-91. arluccio E, Biagioli P, Alunni G, Murrone C A, Leonelli V, Pantano P, Biscottini E, Paulus WJ, Ambrosio G. Advantages of deformation indices over systolic velocities in assessment of longitudinal systolic function in patients with heart failure and normal ejection fraction. European Journal of Heart Failure 2011; 13:292-302. F alcão-Pires I, Hamdani N, Borbély A, Gavina C, Schalkwijk CG, van der Velden J, van Heerebeek L, Stienen GJM, Niessen HWM, Leite-Moreira AF, Paulus WJ. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness Circulation 2011; 124:1151-59. P ol CJ, Muller A, Zuidwijk MJ, van Deel ED, Kaptein E, Saba A, Marchini M, Zucchi R, Visser TJ, Paulus WJ, Duncker DJ, Simonides WS. Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology 2011; 152:669-69. Krijnen PAJ, Sipkens JA, Molling JW, Rauwerda JA, Stehouwer CDA, Muller A, Paulus WJ, van Nieuw Amerongen GP, Hack CE, Verhoeven AJ, van Hinsbergh VWM, Niessen HWM. Inhibition of Rho-ROCK signaling induces apoptotic and non-apoptotic PS exposure in cardiomyocytes via inhibition of flippase. Journal of Molecular and Cell Cardiology 2010; 49:781-90. Kroon MH, van den Hurk K, Alssema M, Kamp O, Stehouwer CD, Henry RM, Diamant M, Boomsma F, Nijpels G, Paulus WJ, Dekker JM. Prospective Associations of B-Type Natriuretic Peptide With Markers of Left Ventricular Function in Individuals With and Without Type 2 Diabetes: An 8-year follow-up of the Hoorn Study. Diabetes Care 2012; 35 12:2510-4. v an den Hurk K, Alssema M, Kamp O, Henry RM, Stehouwer CD, Smulders YM, Nijpels G, Paulus WJ, Dekker JM. Independent associations of glucose status and arterial stiffness with left ventricular diastolic dysfunction: an 8-year follow-up of the Hoorn Study. Diabetes Care 2012; 35:1258-64. I C A R -V U m c 49 50 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 51 Research Group Hypertrophic Cardiomyopathy ‘It is of the utmost clinical and societal importance to identify the cause of transition from mutation to cardiac remodeling and failure’ Focus Collaboration Unique The focus of our studies is on inherited hypertrophic cardiomyopathy (HCM), as it represents a major cause of morbidity and mortality with a prevalence of ~1:500 people worldwide; in the Netherland HCM affects ~50,000 people. Individuals with HCM die of sudden cardiac arrest or develop cardiac disease at a young age. Mutations are most frequently found in genes encoding sarcomeric proteins. Due to improved genetic screening, many mutation carriers at risk of developing HCM are identified, but at present the pathomechanisms underlying onset and progression of cardiac dysfunction, remodeling, and the occurrence of arrhythmias are still unidentified. It is of the utmost clinical and societal importance to identify the cause of cardiac remodeling and failure. We collaborate because an integrated in vitro (preclinical) – in vivo (clinical) research approach is essential for unraveling the early HCM disease process and identifying novel points of clinical intervention in order to interrupt the progression of this complex and currently untreatable disorder. Longitudinal studies of early stage and manifest patient cohorts on the clinical side are coupled with advanced basic methodologies to establish the mechanistic links between mutations on the one hand, and the pathogenic molecular and cellular mechanisms that cause cardiomyopathy on the other. Our research group is unique as we are the first to directly link cellular energetic and contractile properties with in vivo energetic and contractile cardiac performance in human. I C A R -V U m c 51 52 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H Present and Future Research By definition, the mechanism of HCM begins with the defective mutant protein. Our research aims to unravel the complex road from the initial insult (genotype) to the end-stage remodeled phenotype. Follow-up studies of in vivo left ventricular structure, perfusion, metabolism and contractile function using echocardiography, CMR and PET are performed in mutation carriers without cardiac disease and patients with manifest HCM to delineate changes in cardiac performance and structure during disease progression. As a first step in understanding the pathophysiology of HCM, functional assays and proteomics are performed in human myocardium to reveal sarcomeric changes specific for inherited cardiomyopathies. Newly developed protein exchange experiments are used to prove causality between the mutant protein and cellular dysfunction. In vitro data on cardiac performance are linked to in vivo measurements of cardiac performance. Within our translational research we will identify cellular changes that are causative for the transition from mutation to cardiac remodeling and failure. This knowledge will be used to enable treatment of HCM at an earlier stage of the disease. It has been suggested that sarcomeric mutations lead to inefficient ATP utilization of sarcomeres, which leads to a higher energy demand. Increased sarcomeric ATP utilization causes oxidative metabolism to be increased relative to cardiac work, rendering the heart less efficient. Indeed, in a recent study we observed reduced myocardial efficiency in mutation carriers compared to controls. At present, a translational approach including PET/CMR studies is being used to establish whether impaired energy utilization is a primary defect of mutant sarcomeres and leads to deficits in energy utilization in human cardiomyopathy (ENGINE study). In the future, PET studies will be expanded to include mutation carriers and involve analysis of glucose and lipid metabolism. Importantly, metabolic agents, which are already used in clinical practice as antianginal agents, may be used as an adjunctive therapy to improve cardiac energetics. We aim to investigate whether add-on metabolic therapy prevents cardiac dysfunction in mutation carriers and improves myocardial energetics and contractility in manifest HCM patients. Our clinical studies are run in parallel with basic studies using cardiac samples from late stage manifest HCM patients. More advanced basic methodologies are crucial for investigating the initial pathomechanisms triggered by the mutation during the early stage of cardiomyopathy. We aim to optimize a heart muscle system based on human pluripotent stem cells that resemble both the early and more advanced stages of HCM in order to study the initial and progressive cellular changes in cardiomyopathy development. Recent studies have suggested that the level of toxic mutant sarcomeric protein is an important determinant of disease onset and progress, and that regulation of mutant protein expression most likely resides, at least partially, at the RNA level. As part of the CVON-funded ARENA project, RNA mechanisms involved in hypertrophy and cardiac dysfunction will be investigated in the HCM patient group in close collaboration with Yigal Pinto (AMC) and Leon de Windt (MUMC). 53 Participants Project leaders Cardiology Aernout Beek Tjeerd Germans Paul Knaapen Bert van Rossum Physiology Coen Ottenheijm Ger Stienen Jolanda van der Velden Pathology Hans Niessen Medical Physics Tim Marcus Mark Hofman Cardiac Surgery Alexander Vonk Radiology & Nuclear Medicine Adriaan Lammertsma Clinical chemistry Cees Oudejans PhD students Cardiology Stefan Timmer Wessel Brouwer Ahmet Güçlü Sebastiaan Kleyn Thelma Konings Physiology Viola Kooij Sabine van Dijk Rosalie Paalberends Josine de Winter Aref Najafi Paul Wijnker Vasco Sequeira Louise Nijenkamp Saskia Lassche Barbara Joureau Support staf Physiology Nicky Boontje Max Goebel Michiel Helmes Ruud Zaremba Clinical Chemistry Joyce Mulders Postdoctoral fellows Physiology Diederik Kuster Rob Wüst Visiting scientist Tucson, USA Jessica Regan Florence, Italy Benedetta Tosi Sydney, Australia Michaela Kreissl Collaborations National Erasmus, MC Rotterdam Folkert ten Cate Dirk Duncker Daphne Merkus Michelle Michels Arend van Schinkel Marjon van Slegtenhorst Antonius Hospital, Nieuwegein Jurrien ten Berg Aladin Yilmaz MUMC, Maastricht Stephane Heymans RU, Nijmegen Baziel van Engelen Richard Dekhuijzen Leo Heunks Johannes van der Hoeven AMC, Amsterdam Jacques de Bakker Imke Christiaans Maarten Groenink Yigal Pinto Hanno Tan Arthur Wilde UMCG, Groningen Bart de Smet Dirk van Veldhuisen UMCU, Utrecht Cees van Echteld Pieter Doevedans VU, Amsterdam Martijn Heijmans Jaap Seidel International Florence, Italy Corrado Poggesi Hamburg, Germany Lucie Carrier Manheim, Germany Siegfried Labeit Oxford, UK Charles Redwood Hugh Watkins London, UK Steve Marston Boston, USA Alan Beggs Elizabeth DeChene Michael Lawlor Chicago, USA Thomas Irving Sakthivel Sadayappan Baltimore, USA Anne Murphy Jennifer van Eyk Tucson, USA Henk Granzier Sydney, Australia Cris dos Remedios Egypt Hossam Kandil Khalid Sorour Yasser Abd El-Hady Japan Atsu Aiba Hiroyuki Sorimachi I C A R -V U m c 53 54 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 55 Research Highlight Hypertrophic Cardiomyopathy Selected Publications 2010-2012 Time Impaired cardiac relaxation at early stage of HCM Diastolic circumferential strain rate Peak shortening 160 D carriers controls † peak DCSR (%.s-1) To investigate the effect of a genetic disorder a study in familial hypertrophic cardiomyopathy patients with founder mutations in the gene (MYBPC3) encoding cardiac myosin binding protein C (cMyBP-C) was initiated in 2007 in collaboration with Folkert ten Cate and Michelle Michels of the Thorax Center at the Erasmus MC in Rotterdam. Our study in the HCM patients carrying a MYBPC3 founder mutation revealed depressed cardiomyocyte function and reduced expression of cMyBP-C (i.e. haploinsufficiency) (van Dijk et al. 2009; Circulation – heart failure 2012). Moreover, cardiac magnetic resonance studies have revealed that MYBPC3 mutation carriers with normal wall thickness were already exhibiting regional systolic and diastolic dysfunction, indicating that abnormal intrinsic myocardial properties underlie reduced cardiac function and precede cardiac hypertrophy (Germans et al. 2010). Most evident were the perturbations in diastolic function of the heart muscle as indicated by a high calciumsensitivity of myofilaments in cardiac tissue from patients with manifest HCM and the decreased diastolic circumferential strain rate in mutation carriers (see figure). Moreover, the healthy mutation carriers were already showing enlargement of the left atrium, which is an important indicator of diastolic dysfunction. Overall, our studies suggest that diastolic dysfunction of the mutant sarcomeric protein may trigger development of cardiac hypertrophy and failure. Strain (Ecc) Data from PhD projects: Sabine van Dijk (Physiology), Tjeerd Germans (Cardiology), Wessel Brouwer (Cardiology), Stefan Timmer (Cardiology) 120 † ✽ † † 80 0 IS AS AN AL IL IN Segmental comparison of basal left ventricular segments between carriers and controls. Data are presented as mean ± standard error of the mean as indicated by the red bars (carriers) and blue bars (controls). Peak diastolic circumferential strain rate is reduced in almost every segment in carriers compared to controls. IS = inferoseptal, AS = anteroseptal, AN = anterior, AL = anterolateral, IL = inferolateral, IN = inferior, peak DCSR = peak diastolic circumferential strain rate, *= p<0.05, †= p<0.01. rouwer WP, van Dijk SJ, Stienen GJM, B van Rossum AC, van der Velden J, Germans T. The development of familial hypertrophic cardiomyopathy; from mutation to bedside. European Journal of Clinical Investigation 2011; 41:568-78. opeland O, Sadayappan S, Messer AE, C Stienen GJM, van der Velden J, Marston SB. Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. Journal of Molecular and Cellular Cardiology 2010; 49:1003-11. v an Dijk SJ, Paalberends ER, Najafi A, Michels M, Sadayappan S, Carrier L, Boontje NM, Kuster D, van Slegtenhorst M, Dooijes D, dos Remedios C, ten Cate FJ, Stienen GJM, van der Velden J. Contractile dysfunction irrespective of the mutant protein in human hypertrophic cardiomyopathy with normal systolic function. Circulation – Heart Failure 2012; 5:36-46. ermans T, Götte MJW, Rüssel IK, G Spreeuwenberg MD, Doevendans PA, van der Geest RJ, Pinto YM, van der Velden J, Wilde AAM, van Rossum AC. How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance 2010; 12:13. K ooij V, Saes M, Jaquet K, Zaremba R, Foster DB, Murphy AM, dos Remedios C, van der Velden J, Stienen GJM. Effect of troponin I Ser23/24 phosphorylation on calcium-sensitivity in human myocardium depends on the phosphorylation background. Journal of Molecular and Cellular Cardiology 2010; 48:954-63. K ooij V, Boontje NM, Zaremba R, Jaquet K, dos Remedios C, Stienen GJM, van der Velden J. Protein kinase C α and ε phosphorylation of troponin and myosin binding protein C reduce calcium-sensitivity in human myocardium. Basic Research in Cardiology 2010; 105:289-300. Ottenheijm CAC, Hooijman P, DeChene ET, Stienen GJM, Beggs AH, Granzier H. Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2). Journal of Structural Biology 2010; 170: 334-43. üssel IK, Brouwer WP, Germans T, R Knaapen P, Marcus JT, van der Velden J, Götte MJW, van Rossum AC. Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness. Journal of Cardiovascular Magnetic Resonance 2011; 13:3. T immer SAJ, Germans T, Brouwer WP, Lubberink M, van der Velden J, Wilde AAM, Lammertsma AA, Knaapen P, van Rossum AC. Carriers of the hypertrophic cardiomyopathy MYBPC3 mutation are characterized by reduced myocardial efficiency in the absence of hypertrophy and microvascular dysfunction. European Journal of Heart Failure 2011; 13:1283-89. I C A R -V U m c 55 56 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 57 Research Group Right Ventricular Failure in PAH ‘Our studies focus on the mechanisms and treatment of right ventricular failure and pulmonary arterial hypertension, and as such bridge the two main the ICaR-VU themes H & V’ Focus Collaboration The primary focus of our research is to increase life expectancy and improve quality of life of patients with right ventricular (RV) failure due to pulmonary arterial hypertension (PAH). PAH is a rare and fatal disease with a 3-year life expectancy of 58%. Although PAH is primarily a lung disease, the majority of PAH-patients die as a result of RV failure. Progressive pulmonary vascular remodeling in PAH results in an increase in pressure in the pulmonary circulation. To cope with an almost 4-fold increase in pressure, the right ventricle enlarges (RV hypertrophy). Ultimately, the RV fails to keep up with its increased after-load and RV failure develops. The VUmc pulmonary hypertension clinic is tertiary referral center for the diagnosis of PAH and chronic thromboembolic pulmonary hypertension in the Netherlands. To date more than 2000 patients have been seen. In 2005 the VUmc Pulmonary Hypertension Knowledge Center was founded, with the aim to improving survival and quality of life in PAH. Our collaborative studies focus on the mechanisms and treatment of RV failure and PAH, and as such bridge the two main the ICaR-VU themes H & V. Studies in PAH patients combine cardiovascular imaging of the RV and pulmonary circulation, pulmonary haemodynamics and clinical trials. Data obtained at the bedside are translated into basic research questions and form the basis of our studies at the bench. Animal models have been developed that enable us to investigate changes at the different stages of RV failure and test (therapeutic) interventions. The translational collaborations are aimed at dissecting the pathomechanisms underlying cardiac and vascular failure in PAH and represent a true bedside-bench-to-bedside approach. Unique Based on our central position as tertiary referral center and well-structured clinical and basic experimental research, we are able to immediately implement experimental observations in the clinical setting. A good example of our bench-to-bedside approach is the ZonMw-funded translational research, in which we are investigating the efficacy of β-blocker therapy in a randomized clinical trial. I C A R -V U m c 57 58 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 59 Hypertrophic Cardiomyopathy Present and Future Research Understanding the mechanisms underlying RV failure in PAH begins with clinical observations. All our PAH-patients have been followed using MRI since 1997, which has led to an extensive database of more than 1000 patients and more than 100 peer reviewed publications. These studies have provided fundamental insight into the mechanisms of RV failure (van de Veerdonk et al. 2011). By means of hemodynamic modeling we are able to give an accurate description of the load and RV work of pulmonary hypertension (Saouti et al. 2010). We are now focusing on the correct assessment of RV-arterial coupling and its clinical application. By comparing PAH-patients with similar RV loading conditions, but a difference in survival (long versus short term), we expect to reveal the mechanisms of the disease progression. In future studies we will investigate whether a genetic predisposition determines the outcome of PAH-induced RV failure through genetic screening of stable and progressive PAH-patients. In addition to the genetic characteristics, we will determine morphological characteristics and load-independent measures of RV contractility and relaxation in this patient cohort. Research to develop treatment strategies for the prevention of RV failure is highly translational and based on clinical and animal studies. In rat studies we have shown that β-blocker therapy effectively reversed RV remodeling and failure in PAH (Research highlight). At present the efficacy of β-blockers is being studied in a randomized clinical trial. Moreover, we have shown that exercise improved exercise capacity and muscle function in stable PAH-patients, due to improved oxygen handling of the quadriceps muscle (de Man et al. 2009). Rat studies have revealed that exercise can improve RV function in stable PAH, while it exerts a detrimental effect in progressive PAH (Handoko et al. 2009). During development of PAH-induced RV disease, there is a transition from right myocardial hypertrophy to RV failure. One of the underlying causes of this transition may be development of hypoxia in hypertrophied cardiomyocytes. Studies in papillary RV muscles have revealed increased rate of oxygen consumption, together with increased diffusion distances for oxygen and reduced myoglobin concentration and capillary density in PAH compared to control rats. This may lead to a condition where oxygen supply to the cardiomyocytes is limiting cardiac output (Wong et al. 2010; Ruiter et al. 2011). Similar findings have been obtained in PAH-patients (Wong et al. 2011; Ruiter et al. 2012). Current studies are investigating the role of disturbed cardiolipin metabolism, which may cause oxidation of cytosolic NADH by cytochrome c and is the underlying cause of reduced mitochondrial efficiency. Our studies on pulmonary vascular remodeling and RV failure are highly interrelated and form the basis for our future studies. Regardless of the primary cause, an elevated pressure in the pulmonary circulation almost invariably leads to RV failure and death. We hypothesize that an imbalance in TGFβ and BMP signaling and a vicious circle of alterations in pulmonary blood flow velocity and pressure, are at the basis of progressive pulmonary vascular remodeling and RV heart failure. Our aim is to break the vicious circle and identify key factors that increase the probability of developing pulmonary hypertension, pulmonary vascular remodeling and RV dysfunction. Participants Project leaders Internal Medicine Erik Serné Medical Physics Theo Faes Tim Marcus Physiology Willem van der Laarse Geerten van Nieuw-Amerongen Coen Ottenheijm Jolanda van der Velden Nico Westerhof Pulmonology Harm Jan Bogaard Anco Boonstra Frances de Man Piet Postmus Anton Vonk Noordegraaf Radiology & Nuclear Medicine Adriaan Lammertsma PhD students Pulmonology Karin de Boer Bart Boerrigter Jasmijn van Campen Herman Groepenhoff Frank Helderman Wouter Jacobs Taco Kind Gert-Jan Mauritz Esther Nossent Nabil Saouti Onno Spruijt Pia Trip Marielle van der Veerdonk Pim Welvaart Serge van Wolferen Pulmonology & Physiology Chris Happé Emmy Manders Michiel de Raaf Silvia Rain Gerrina Ruiter Robert Szulcek Yeun Ying Wong Postdoctoral fellows Cardiology Louis Handoko Support staf Physiology Silvia Bogaards Pulmonology Ingrid Schalij Visiting scientist Åarhus, Denmark Stine Andersen Jacob Gammelgaard Schultz Collaborations National EMC, Rotterdam Dirk Duncker Daphne Merkus LUMC, Leiden Peter ten Dijke Marie-José Goumans Berend Hierck Hubert Vliegen Ernst van der Wall UMCG, Groningen Rolf Berger Beatrijs Bartelds International Åarhus, Denmark Stine Andersen Jacob Gammelgaard Schultz Brussels, Belgium Robert Naeije Cambridge, UK Nick Morrell London, UK Martin Wilkens Paris, France Marc Humbert Christophe Guignabert Stanford, USA Marlene Rabinovitch Sydney, Australia Cris dos Remedios Tucson, USA Henk Granzier Virginia, USA Norbert Voelkel I C A R -V U m c 59 60 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 61 Research Highlight Right Ventricular Failure in PAH A % right heart failure Based on PhD/postdoc studies by Frances de Man, Louis Handoko and Harm-Jan Bogaard * 100 PH 50 0 20 B PH+biso 25 30 Time (days) RV Afterload mmHg/ml 1500 n.s. 1000 500 0 Control C PH PH+biso RV Contractility *** 1500 mmHg/ml Whether neurohormonal dysregulation represents a compensation to maintain cardiac output and systemic blood pressure or a mediator contributing to development of right heart failure, was previously unclear. To demonstrate that neurohormonal up-regulation may not be harmless, we investigated the contribution of increased sympathetic nerve activation in our PAH rat model. Previous studies had already demonstrated that sympathetic overstimulation by means of exercise training could precipitate right heart failure (Handoko et al. 2009). Therefore, we hypothesized that inhibiting sympathetic activation with a cardiac-specific β-blocker (bisoprolol) could have beneficial effects on disease progression (de Man et al. 2012). At the same time, Bogaard et al. (2011) investigated effects of the a-selective β-blocker carvedilol. Both rat studies revealed that interference in the sympathetic nerve activation reduced disease progression and improved RV function and morphology in PAH (figure). The renin-angiotensin-aldosteron-system (RAAS) is another important neurohormonal system. Compared to the recognized detrimental effects of sympathetic activity, little was known about the role of RAAS in PAH. In collaboration with Marc Humbert and Christophe Guignabert (Paris), we were able to reveal severe systemic and local RAAS up-regulation. More importantly, RAAS-inhibition by means of angiotensin receptor blocker (losartan) could delay disease progression, restore arterial-ventricular coupling and reduce pulmonary vascular remodeling in our rat PAH model (de Man et al. 2012). Our studies suggest that neurohormonal up-regulation in PAH is not harmless. In order to translate these findings to the clinic, we initiated a safety and efficacy study for the use of β-blockers in patients financed by a ZonMw translational research grant. A similar study will be initiated to investigate usefulness of angiotensin receptor blockers. Manifest right heart failure 500 0 Control D PH PH+biso RV relaxation 60 mmHg/ml Neurohormonal dysregulation in patients with pulmonary arterial hypertension Selected Publications 2010-2012 Bogaard HJ, Mizuno S, Guignabert C, Al Hussaini AA, Farkas D, Ruiter G, Kraskauskas D, Fadel E, Allegood JC, Humbert M, Vonk-Noordegraaf A, Spiegel S, Farkas L, Voelkel NF. Copper Dependence of Angioproliferation in Pulmonary Arterial Hypertension in Rats and Humans. American Journal of Cellular Molecular Biology 2012; 46: 582-91. Bogaard HJ, Natarajan R, Mizuno S, Abbate A, Chang PJ, Chau VQ, Hoke NN, Kraskauskas D, Kasper M, Salloum FN, Voelkel NF. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. American Journal of Respiratory and Critical Care Medicine 2010; 182:652-60 de Man FS, Handoko ML, van Ballegoij JJ, Schalij I, Bogaards SJ, Postmus PE, van der Velden J, Westerhof N, Paulus WJ, Vonk-Noordegraaf A. Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension. Circulation Heart Failure 2012; 5:97-105. de Man FS, van Hees HW, Handoko ML, Niessen HWM, Schalij I, Humbert M, Dorfmüller P, Mercier O, Bogaard HJ, Postmus PE, Westerhof N, Stienen GJM, van der Laarse WJ, Vonk-Noordegraaf A, Ottenheijm CAC. Diaphragm muscle fiber weakness in pulmonary hypertension American Journal of Respiratory and Critical Care Medicine 2011; 15;183:1411-18. Ruiter G, Lankhorst S, Boonstra A, Postmus PE, Zweegman S, Westerhof N, van der Laarse WJ, Vonk-Noordegraaf A. Iron deficiency is common in idiopathic pulmonary arterial hypertension. European Respiratory Journal 2011; 37:1386-91. Saouti N, Westerhof N, Helderman F, Marcus JT, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Right ventricular oscillatory power is a constant fraction of total power irrespective of pulmonary artery pressure. American Journal of Respiratory and Critical Care Medicine 2010; 182:1215-1320. van der Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. Journal of the American College of Cardiology 2011; 58:2511-19. Wong YY, Ruiter G, Lubberink M, Raijmakers PG, Knaapen P, Marcus JT, Boonstra A, Lammertsma AA, Westerhof N, van der Laarse WJ, Vonk-Noordegraaf A. Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization. Circulation Heart Failure 2011; 4:700-06. Wong YY, Handoko ML, Mouchaers KT, de Man FS, Vonk-Noordegraaf A, van der Laarse WJ. Reduced mechanical efficiency of rat papillary muscle related to degree of hypertrophy of cardiomyocytes. American Journal of Physiology Heart and Circulatory Physiology 2010; 298:H1190-97. ** 40 20 0 Control PH PH+biso I C A R -V U m c 61 62 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 63 Research Group Cardiovascular Imaging ‘Advanced imaging is essential for non-invasive diagnosis of cardiovascular diseases and for monitoring response to therapy’ Focus Collaboration Unique The focus of our studies is on the development, implementation and clinical validation of novel imaging methods in various groups of cardiovascular patients. In order to combine anatomical, functional and molecular information; there is strong emphasis on hybrid imaging equipment, in particular PET/CT and, more recently, PET/ MRI. With respect to functional and molecular processes, measurements of myocardial perfusion and flow reserve, oxygen and glucose consumption, fibrosis, and cardiac innervation are now available for clinical research and/or patient care, whilst methods for measuring unstable plaques and, more generally, inflammatory processes are under development. We collaborate with various groups (e.g. from Cardiology, Physiology, Pulmonology, Endocrinology, Vascular Surgery, etc) within the ICaR-VU, for a variety of reasons: to test new (or existing) imaging methods in specific patient populations, to gain new pathophysiological information based on validated non-invasive imaging procedures, and to assess the value of an imaging method for diagnostic purposes. In addition to this, there is an international collaboration on the diagnostic use of oxygen-15 labelled water for measuring myocardial blood flow. Our research group is unique because of its truly translational character. New tracers and methods are being developed, evaluated in preclinical studies, used in clinical pathophysiological research studies, and finally assessed as potential diagnostic tools. The group is multidisciplinary and is made up of clinicians, chemists, physicists, biologists, pharmacologists and others. I C A R -V U m c 63 64 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 65 Hypertrophic Cardiomyopathy Present and Future Research Cardiovascular imaging provides a unique and noninvasive means for obtaining information in both healthy controls and various groups of cardiovascular patients. Based on a range of imaging modalities (ultrasound, CT, MRI, SPECT, PET) many anatomical, physiological and molecular parameters can be measured and related to clinical characteristics. Imaging research can be divided into three interconnecting lines. First, there is extensive research in the development of new imaging methods. This is especially true for PET, where new radiotracers together with appropriate tracer kinetic models for quantification of the resulting PET data are being developed. To a lesser extent this is also true for other imaging modalities, e.g. the development of new sequences for MRI and the application of kinetic models to MRI or CT data. The second line of research is the use of validated imaging methods in selected groups of patients. These studies are always in collaboration with and based on relevant research questions from clinical ‘user’ groups. Input from the imaging group remains important, as the validity of an imaging procedure under pathophysiological conditions must always be considered. This is even more important if studies are performed before and after an intervention (e.g. a drug study). Once a method has been developed and it has been shown to provide valuable information about disease, the final line of research is to assess whether the method could lead to improved diagnostic accuracy. This often entails large patient groups and linking (blind) reading of the images with final outcome of the patients. In recent years, hybrid equipment has become available, providing the opportunity to measure multiple parameters in a single scanning session. In particular, there has been extensive research on the PET/CT combining CT angiography with PET measurements of myocardial perfusion and flow reserve. It is expected that the recent installation of a PET/MRI scanner will provide a similar stimulus for multimodality imaging. Participants Projectleaders Cardiology Cor Allaart Carel de Cock Otto Kamp Paul Knaapen Bert van Rossum Gerrit Veen Nuclear Medicine and PET Research Ronald Boellaard Otto Hoekstra Adriaan Lammertsma Physiology Rene Musters Linda Juffermans Physics and Medical Technology Tim Marcus Mark Hofman Ruud Verdaasdonk PhD students Pathology Benno Naaijkens Cardiology Farid Afsharzada Frank Bernink Ibrahim Danad Ahmed Güçlü Johannes van der Heide Sebastiaan Kleijn Tessa Konings Lourens Robbers Iris Russel Stefan Timmer Lina Wu Karin de Boer Sebastiaan Roos Sven Brinkman Physics and Medical Technology Marijn Rolf Nuclear Medicine and PET Research Danielle van Assema Hans Harms Collaborations National AMC, Amsterdam Bart Biemond Berthe van Eck Jan Piek Arthur Wilde EMC, Rotterdam Folkert-Jan ten Cate Wim van der Giessen Felix Zijlstra UMCG, Groningen Bart de Smet René Tio Dirk van Veldhuisen International Turku, Finland Juhani Knuuti Essen, Germany Thomas Buck Milan, Italy Eustachio Agricola Paolo Camici Osaka, Japan Hidehiro Lida Uppsala, Sweden Mark Lubberink London, UK Mark Monaghan Petros Nihoyannopoulos Dudley Pennell Boston, USA, Stanton Shernan Durham, USA Robert Judd, Raymond Kim Michele Parker New haven, USA Lissa Sugeng Omaha, USA Thomas Porter Postdoctoral fellows Nuclear Medicine and PET Research Marc Huisman Cees van Kuijk Pieter Raijmakers Bert Windhorst I C A R -V U m c 65 66 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e H 67 Research Highlight Cardiovascular Imaging Selected Publications 2010-2012 Cardiac PET/CT: Advanced hybrid imaging for the diagnosis of coronary artery disease Danad I, Raijmakers PG, Appelman YE, Harms HJ, de Haan S, Marques KM, van Kuijk C, Allaart CP, Hoekstra OS, Lammertsma AA, Lubberink M, van Rossum AC, Knaapen P. Quantitative relationship between coronary artery calcium score and hyperemic myocardial blood flow as assessed by hybrid O-15-water PET/CT imaging in patients evaluated for coronary artery disease. Journal of Nuclear Cardiology 2012; 19: 256-64. Clinical research from the departments of Cardiology and Nuclear Medicine and Radiology Coronary artery disease (CAD) is the leading cause of death in Western countries. Invasive coronary angiography (ICA), in combination with invasive coronary pressure measurements, is considered the gold standard for CAD diagnosis. The invasive nature of this procedure with potential hazardous complications, limits its application for initial diagnostic purposes. Noninvasive imaging techniques to evaluate the severity of CAD are needed. Computed tomography coronary angiography (CTCA) has emerged as alternative for ICA. CTCA has proven its value in clinical cardiology for accurately ruling out CAD due to an excellent sensitivity and negative predictive value. Unfortunately, observed epicardial coronary lesions require further functional testing given the low specificity and positive predictive value of CTCA (Groothuis et al. 2012). Positron emission tomography (PET) allows for noninvasive quantification of myocardial perfusion. Although [15O]-water is considered the ideal perfusion tracer and we have a long track record of evaluating myocardial perfusion for research purposes (Knaapen et al. 2004, 2009), until recently this tracer was considered unsuitable for clinical purposes given its low count statistics, elaborate post-processing, and poor image quality for diagnostic evaluation. However, clinical software has been developed by our group to generate high quality parametric myocardial perfusion and viability images in a quantitative manner (Harms et al. 2011). These technical in-house developments have propelled a clinical cardiac hybrid PET/CT imaging program that allows for comprehensive evaluation of both anatomy and function in patients suspected of CAD within a single session of 30 minutes at low radiation burden (figure). This hybrid approach yields excellent diagnostic accuracy that is superior to single modality imaging (Danad et al. 2013). At present, prospective investigations are ongoing to compare the hybrid imaging approach with more conventional methods to assess myocardial perfusion, such as single photon computed tomography. Example of a hybrid cardiac PET/CT image of a patient evaluated for coronary artery disease. The combined perfusion images, obtained with [15O]-water PET during vasodilator stress, are fused with CT based coronary angiography. This patient displayed a coronary lesion in the proximal LAD. Hemodynamic significance was subsequently confirmed by regional perfusion impairment in the vascular territory of the LAD and the patient was referred for invasive coronary angiography and percutaneous coronary intervention. Groothuis JGJ, Beek AM, Meijerink MR, Brinckman SL, Heymans MW, van Kuijk C, van Rossum AC. Positive predictive value of computed tomography coronary angiography in clinical practice. International Journal of Cardiology 2012; 156: 315-19. Harms HJ, Knaapen P, de Haan S, Halbmeijer R, Lammertsma AA, Lubberink M. Automatic generation of absolute myocardial blood flow images using [O-15]H2O and a clinical PET/CT scanner. European Journal of Nuclear Medicine and Molecular Imaging 2011; 38: 930-39. Kleijn SA, Brouwer WP, Aly MFA, Russel IK, de Roest GJ, Beek AM, van Rossum AC, Kamp O. Comparison between three-dimensional speckle-tracking echocardiography and cardiac magnetic resonance imaging for quantification of left ventricular volumes and function. European Heart Journal: Cardiovascular Imaging 2012; 13: 834-39. Timmer SAJ, Germans T, Gotte MJW, Russel IK, Lubberink M, Ten Berg JM, Ten Cate FJ, Lammertsma AA, Knaapen P, van Rossum AC. Relation of Coronary Microvascular Dysfunction in Hypertrophic Cardiomyopathy to Contractile Dysfunction Independent from Myocardial Injury. American Journal of Cardiology 2011; 107: 1522-28. Kleijn SA, Aly MFA, Terwee CB, van Rossum AC, Kamp O. Comparison Between Direct Volumetric and Speckle Tracking Methodologies for Left Ventricular and Left Atrial Chamber Quantification by Three-Dimensional Echocardiography. American Journal of Cardiology 2011; 108: 1038-44. Vermeltfoort IA, Raijmakers PG, Lubberink M, Germans T, van Rossum AC, Lammertsma AA, Knaapen P. Feasibility of subendocardial and subepicardial myocardial perfusion measurements in healthy normals with O-15-labeled water and positron emission tomography. Journal of Nuclear Cardiology 2011; 18: 650-56. Lubberink M, Harms HJ, Halbmeijer R, de Haan S, Knaapen P, Lammertsma AA. Low-Dose Quantitative Myocardial Blood Flow Imaging Using O-15Water and PET Without Attenuation Correction. Journal of Nuclear Medicine 2010; 51: 575-80. Rolf MP, Hofman MBM, Gatehouse PD, Markenroth-Bloch K, Heymans MW, Ebbers T, Graves MJ, Totman JJ, Werner B, van Rossum AC, Kilner PJ, Heethaar RM. Sequence optimization to reduce velocity offsets in cardiovascular magnetic resonance volume flow quantification - A multi-vendor study. Journal of Cardiovascular Magnetic Resonance 2011; 13: a18. Wong YY, Ruiter G, Lubberink M, Raijmakers P, Knaapen P, Marcus TJ, Boonstra A, Lammertsma AA, Westerhof N, van der Laarse WJ, Vonk-Noordegraaf A. Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization. Circulation Heart Failure 2011; 4: 700-6. I C A R -V U m c 67 68 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Theme V Improvement of Vascular Function in Metabolic Diseases Studies in Theme V aim to unravel pathomechanisms underlying acute and chronic vascular disorders 3 Introduction Toptalents Research Groups 69 70 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Theme V / Vascular Failure Circulation and Metabolism Ischemia and Repair Imaging Heart Failure and Pulmonary Arterial Hypertension Vascular failure lies at the heart of many of the pathologies encountered in a multitude of large patient groups who visit our Medical Center. Because of this diversity our research groups are focused on selected aspects of vascular disorders of specific pathologies seen in several large patient groups. This research is done from both a clinical and basic science angle, in a translational approach to advance insights into underlying mechanisms, to improve diagnosis and to find innovative treatments. The main research programs that form the basis of Theme V are centered on two subthemes: Ischemia and Repair and Circulation and Metabolism. The first program, Ischemia and Repair, focuses on beneficial and pathological remodeling of the vasculature. It is comprised of research groups that study effects of: ischemia-induced angiogenesis and acute coronary syndromes, the life-threatening aneurysms of the aorta, and vascular aspects surrounding human reproduction and complications of pregnancy. Within this research program we define relevant pathways in a clinical bedside-to-bench genomics approach, which we aim to translate into innovative approaches to patient care via a sound basal laboratory research line. The second program, Circulation and Metabolism, focuses on the aspect of the general circulation in multiple organs and how it is affected by metabolic and acute challenges. Here the research groups study effects of metabolic derangements like diabetes, effects of nutrition on vascular health, the vascular complications of kidney disease and life-threatening cardiovascular complications in the perioperative setting. The studies in these research areas range from: clinical trials, vascular and cellular physiology in humans and animal models, cell and molecular biology laboratory studies to large genomic and genetic studies. They all have strong clinical-preclinical collaborations. The majority of the groups are based in the clinical departments of Cardiology, Internal Medicine, Nephrology, Gynecology, Pediatrics and Surgery and the preclinical departments of Physiology, Pathology, Clinical Chemistry and Molecular Cell Biology and Immunology. There are many interrelationships between the research topics of Theme V as well as between these and the topics covered by Theme H the second ICaR-VU theme, as heart and vascular systems are closely related. 71 72 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Focus on Toptalent Stopping leaky blood vessels Geerten van Nieuw-Amerongen (Established Investigator 2011 – Netherlands Heart Foundation) The FGF23 – klotho – vitamin D axis as a new instrumental target to combat the cardiovascular risk of chronic kidney disease Marc Vervloet (Dutch Kidney Foundation, 2011) Just like a bursting dike, one weak spot in the vascular wall is enough to cause problems for a large area. Leaking blood vessels cause complications such as edema (tissue swelling) and worsening of atherosclerosis, and may become life threatening when they affect the heart or the lungs. The research of Geerten van Nieuw Amerongen aims to unravel how weak spots in the blood vessels originate and expects to find new leads for sealing the dangerous little holes in the vessel wall. HELLP-babies: mutations in a novel non-coding RNA Marie van Dijk ( VENI, ZonMw, 2010) The HELLP-syndrome occurs in approximately 1 in 200 pregnancies and, although the symptoms start in the third trimester in the mother, the origin of the disease is found in the first trimester fetal placenta. Indeed, the chromosomal region genetically linked to this disease contains mutations in children born from HELLP-pregnancies. This region consists of a novel long non-coding RNA with an unknown function. Marie van Dijk aims to characterize the function of this noncoding RNA and its dysfunction in the HELLP-syndrome. This knowledge will be used to develop a test for early disease detection. In the last few years the circulating proteins fibroblast growth factor 23 and klotho have emerged as modulators of mineral metabolism and, independent from that, to be involved in cardiovascular structure and function. In the translational research plan, in collaboration with the department of Physiology of UMCN and Nephrology UCMG, the regulation of expression, shedding into the circulation, biological effects at the tissue level and clinical aspects of these proteins are being studied. There are two PHD students at each university. How does red wine help treat type 2 diabetes and hypertension? Erik Serné (Netherlands Heart Foundation, Dekker Junior Staff Grant, 2010) Epidemiological data suggest that moderate red wine consumption reduces the incidence of diabetes by an impressive 40-60% and has beneficial effects on blood pressure. The underlying mechanisms are far from clear, but are thought to involve improvement of insulin resistance and endothelium-dependent vasodilatation by red wine polyphenols. Erik Serné is investigating whether shared insulin-signaling pathways in metabolic and vascular tissues may provide a target for red wine polyphenols and explain the beneficial effects on insulin resistance and blood pressure. 73 74 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Acute Coronary Syndrome and Repair ‘A unique feature is the use of porcine models combined with MRI imaging, which allows us to closely mimic the procedures encountered in the hospital’ Focus Our studies focus on understanding the molecular and cellular mechanisms that drive perfusion of poorly vascularized tissues that are at risk of necrosis from a deficit of oxygen and nutrients. This can be encountered e.g. in the heart after an Acute Myocardial Infarction (AMI) due to a blocking of the coronary circulation, in peripheral tissues as a result of metabolic disorders like diabetes, and during the implantation of tissue engineered scaffolds. Two intertwined research lines are being pursued on the patient groups we study. The first focuses on acute coronary syndrome (ACS), in which we would like to preserve the microvasculature of the heart after successful treatment of AMI with percutaneous coronary intervention (PCI) and stimulate arteriogenesis. The second focuses on establishing perfusion in artificial tissues and grafts as part of a program on regenerative medicine. Collaboration In a multi-disciplinary approach, we combine clinical trials and resulting physical and imaging measurements from Intervention Cardiology, with pathological insights, cellular analysis and genomics in order to establish the molecular profiles that distinguish individual patients. By linking cellular and molecular data to patient characteristics, we can establish underlying mechanisms and key molecular switches that we validate in a variety of animal models ranging from small rodents (mice and rats) to pigs. These models are used to test effects of revascularization after artificially induced AMI in the heart, arteriogenesis after obstruction of blood supply in the hindlimb and angiogenesis in artificial tissues (fibrin and matrigel plugs). In addition to the well studied endothelial cells, we have set up a unique collaboration centered around a number of bone marrow-derived and peripheral blood cell types that have recently been established to play important roles in angiogenesis. Unique Our research group is unique in its combination of complementary expertise, which allows us to establish a strong translational research program from gene to protein to cell to tissues to animal models and patients. Another unique feature is the use of porcine models combined with MRI imaging, which allows us to closely mimic the procedures encountered in the catheterization room of the hospital. 75 76 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Hypertrophic Cardiomyopathy Present and Future Research Participants Acute coronary syndrome We have collected a large number of genomic profiles of circulating cells, most notably monocytes, as well as blood samples from patients undergoing PCI. By linking these profiles to physical data such as pressure-flow profiles (CFI) and imaging data (CMR) we have identified immunological pathways that correlate to patient outcome. A well-established collateral vasculature in patients was modulated by molecules like interferonbeta and galectin-2 from circulating monocytes, which were validated in small animal models (Highlight). Our current focus is on understanding the underlying signal transduction pathways of these proteins, which should yield innovative targets for intervention that can be translated to the clinic. We participated in a number of clinical trials like the ICIN-initiated HEBE stem cell trial, the EXAMI trial and the ongoing PREDICT-MVO trial. Here, we found genomic and cellular profiles that correlate with acute microvascular obstruction (MVO) and late left ventricular remodeling at 3-4 months after successful PCI, which may lead to the development of heart failure. Using culture models and state-of-the-art immunological approaches, we are establishing the exact phenotype of monocyte subtypes and their role in both scarring and angiogenesis/arteriogenesis. This is done in collaboration with the department of Vascular Medicine at LUMC. The role of coagulation in intramyocardial hemorrhage as a driving force for MVO is studied in close collaboration with the department of Vascular Medicine of the AMC. The role of reactive oxygen species in ischemia and reperfusion injury from a variety of cell types is studied through analysis of the role of NOX-enzymes from endothelial cells, monocytes Projectleaders Cardiology Niels van Royen Yolande Appelman MCBI Anton Horrevoets Tineke van der Pouw-Kraan Pathology Paul Krijnen Hans Niessen Physiology Pieter Koolwijk Victor van Hinsbergh and cardiomyocytes. Our recent studies have yielded innovative insights into the role of actin fibers and newly identified small molecules in vascular remodeling induced by shear stress. Tissue engineering In recent years we have participated in the Dutch Program of Tissue Engineering and the Netherlands Institute of Regenerative medicine. Here, our focus lies in the establishment of novel angiogenesis-stimulating approaches in order to achieve proper vascularization of tissue-engineered scaffolds/constructs, to obtain adequate function and maintenance of long-term viability. It is important to understand how the molecular interaction between angiogenic factors, vascular cells, matrix proteins (e.g. different variants of fibrinogen) and hypoxia-inducible factors is organized in time and space to guide the formation of new blood vessels. As an example, the vascularization of skin grafts is optimized in collaboration with the department of Dermatology. Human endothelial cells are established from healthy donors and patients using either circulating endothelial progenitor cells or adipose-derived mesenchymal stem cells. The role of the latter cell type is also studied in myocardial regeneration after differentiation into cardiomyocytes. Current approaches aim to evaluate the role of hypoxic preconditioning of the endothelial cells and mesenchymal stem cells in order to make them more resistant to long term hypoxic conditions that occur in the body after implantation of the constructs. Using genomic approaches, protein chemistry, a unique hypoxia culture chamber and animal models of vascularization we are establishing a number of molecular targets for improving vascularization. PhD students Cardiology Paul Teunissen Maurits Hollander Elise Eerenberg MCBI Thomas Leyen Sylvia Nieuwenhuis Cansu Yildirim Anja van der Laan Pathology Benno Naaijkens Umit Baylan Nynke Hahn Ellis ter Horst Physiology Dimitri Tasev Tessa Nauta Robert Verloop Postdoctoral fellows MCBI Julie Favre Physiology Ester Weijers Supportstaf MCBI Josefien Baggen Marloes van den Broek Ruud Fontijn Pathology Mark Begieneman Physiology Jan van Bezu Michiel van Wijhe Collaborations National AMC, Amsterdam Ed van Bavel Chantal van der Horst Jan Mekkes Jan Piek Allard van der Wal Menno de Winther CWI, Amsterdam Roeland Merks EMC, Rotterdam Moniek de Maat Jean-Luc Murk LUMC, Leiden Paul Quax Tom Rabelink MUMC, Maastricht Stephane Heymans Sanquin, Amsterdam Peter Hordijk Sander Tas Jan Voorberg UMCU, Utrecht Imo Hoefer International Frankfurt, Germany Reinier Boon Stefanie Dimmeler Patras, Greece Lily Papadimitriou Jeruzalem, Israel Eli Keshet Sendai, Japan Yasufumi Sato Bern, Switzerland Christian Seiler Lund, Sweden Anna Blom Bristol, UK Andrew Newby Stephen White Leeds, UK Robert Ariens London, UK Rob Krams Manuel Mayr Boston, USA Mathias Nahrendorf 77 78 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Angiogenesis Galectin-2 expression is dependent on the rs7291467 polymorphism and acts as an inhibitor of arteriogenesis Selected Publications 2010-2012 Placebo A Galectin-2 Pre-OK By Anja van der Laan, Niels van Royen and Anton Horrevoets Post-OK Day-2 Day-7 120 B Perfusion restoration (%) In patients with obstructive coronary artery disease (CAD), the growth of collateral arteries (arteriogenesis) can preserve myocardial tissue perfusion and function. Monocytes modulate this process, by locally supplying the necessary growth factors and degrading enzymes. Knowledge on the factors involved in human arteriogenesis is scarce. The aim of the present study is to identify targets in monocytes that are critical for arteriogenesis in patients with CAD. A total of 50 patients with a chronic total coronary occlusion were dichotomized according to their collateral flow index. From each patient, RNA was isolated from unstimulated peripheral blood monocytes, monocytes stimulated by lipopolysaccharide (LPS) or interleukin-4, and from macrophages. Transcriptomes were analyzed by full genome microarray analysis, comparing good to bad collateral patients, dichotomized on median Collateral Flow Index, as measured during PCI. Increased mRNA expression of galectin-2 was found in three (unstimulated and LPS-stimulated monocytes, and macrophages) out of four monocytic cell types of patients with a low capacity of the collateral circulation. Additionally, galectin-2 mRNA expression was significantly associated with the rs7291467 polymorphism in LGALS2 encoding galectin-2 in all four monocytic cell types. Patients with the rs7291467 CC genotype displayed the highest galectin-2 expression, and tended to have a lower arteriogenic response. In order to evaluate the effect of galectin-2 on arteriogenesis in vivo, we used a murine hindlimb model. Treatment with galectin-2 markedly impaired the perfusion restoration at Day 7. Collectively, these results identify galectin-2 as a novel inhibitor of arteriogenesis. Modulation of galectin-2 may constitute a new therapeutic strategy for stimulation of arteriogenesis in patients with CAD. 100 0.002 80 60 40 Boon RA, Urbich C, Fischer A, Fontijn RD, Seeger FH, Koyanagi M, Horrevoets AJG, Dimmeler S. Kruppel-like factor 2 improves neovascularization capacity of aged proangiogenic cells. European Heart Journal 2011; 32:371-77. 0.08 20 0 Boon RA, Leyen TA, Fontijn RD, Fledderus JO, Baggen JM, Volger OL, van Nieuw Amerongen GP, Horrevoets AJG. KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium. Blood 2010; 25;115:2533-42. Pre-OK Post-OK Day 2 Day 7 C Galectin-2 impairs arteriogenesis in the murine hindlimb model The effect of galectin-2 treatment on arteriogenesis in a murine hindlimb model was investigated using laser-Doppler perfusion imaging (A, B). Paraffin sections from left adductor muscle were stained for macrophages using Mac-3 (C). Counterstaining was performed with hematoxylin, visualizing nuclei in blue. van Dijk A, Naaijkens BA, Jurgens WJ, Nalliah K, Sairras S, van der Pijl RJ, Vo K, Vonk ABA, van Rossum AC, Paulus WJ, van Milligen FJ, Niessen HWM. Reduction of infarct size by intravenous injection of uncultured adipose derived stromal cells in a rat model is dependent on the time point of application. Stem Cell Research 2011; 7:219-29. Hahn NE, Meischl C, Kawahara T, Musters RJ, Verhoef VM, van der Velden J, Vonk ABA, Paulus WJ, van Rossum AC, Niessen HWM, Krijnen PAJ. NOX5 expression is increased in intramyocardial blood vessels and cardiomyocytes after acute myocardial infarction in humans. American Journal of Pathology 2012; 180:2222-29. Krijnen PAJ, Hahn NE, Kholová I, Baylan U, Sipkens JA, van Alphen FP, Vonk ABA, Simsek S, Meischl C, Schalkwijk CG, van Buul JD, van Hinsbergh VWM, Niessen HWM. Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients. Basic Research in Cardiology 2012; 107:233. van der Laan AM, Schirmer SH, de Vries MR, Koning JJ, Volger OL, Fledderus JO, Bastiaansen AJ, Hollander MR, Baggen JM, Koch KT, Baan J Jr, Henriques JP, van der Schaaf RJ, Vis MM, Mebius RE, van der Pouw-Kraan TCTM, Quax PHA, Piek JJ, Horrevoets AJG, van Royen N. Galectin-2 expression is dependent on the rs7291467 polymorphism and acts as an inhibitor of arteriogenesis. European Heart Journal 2012; 33:1076-84. Schirmer SH, Bot PT, Fledderus JO, van der Laan AM, Volger OL, Laufs U, Böhm M, de Vries CJ, Horrevoets AJG, Piek JJ, Hoefer IE, van Royen N. Blocking interferon {beta} stimulates vascular smooth muscle cell proliferation and arteriogenesis. Journal of Biological Chemistry. 2010; 5;285:34677-85. Weijers EM, van Wijhe MH, Joosten L, Horrevoets AJG, de Maat MP, van Hinsbergh VWM, Koolwijk P. Molecular weight fibrinogen variants alter gene expression and functional characteristics of human endothelial cells. Journal Thrombosis and Haemostasis 2010; 8:2800-09. Weijers EM, van den Broek LJ, Waaijman T, van Hinsbergh VWM, Gibbs S, Koolwijk P. The influence of hypoxia and fibrinogen variants on the expansion and differentiation of adipose tissuederived mesenchymal stem cells. Tissue Engineering Part A 2011; 17:2675-85. 79 80 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Aneurysm ‘Our translational studies have resulted in the implementation of a new surgical technique for our standard patient care’ Focus Our studies focus on the identification of the underlying causes of initiation, progression and rupture of aortic aneurysms, because of its high prevalence (8% of males older than 65) and devastating hemodynamic and physiological consequences. Mortality rates after an abdominal aortic aneurysm (AAA) rupture are exceptionally high (80%), and in the event of survival, neurological complications and multi-organ failure are common. If an AAA ruptures, only 50% will reach the hospital alive and even if they reach the hospital alive the mortality rate increases to 80%. Moreover, 30% to 50% will not survive the acute repair. The most important predictive value of an aneurysm rupture is the growth of the aneurysm in diameter. According to the Dutch consensus, surgical intervention is indicated when: the diameter exceeds 5.5 cm in men and 5.0 cm in women; the diameter expands more than 1 cm per year or when a patient experiences symptoms. Regardless of these criteria aneurysms still rupture and the pathophysiology of AAAs remains unclear. Even though there have been surgical advances, the prognosis of ruptured AAAs remains poor and the overall mortality high. Therefore, it is of the utmost importance to improve current therapeutic possibilities and to develop new surgical techniques. To do so, we need to investigate the pathophysiology of the development of aortic aneurysms and other large arterial diseases. We are also focusing on updating current treatments like endovascular/ laparoscopic repair of aortic aneurysms. Collaboration Vascular diseases are associated with both cardiac and renal disease. Identification of the pathophysiology of aortic aneurysms requires intensive collaborations between the departments of Physiology, Cardiology, Nephrology, Pathology, General Surgery, Cardio Thoracic Surgery and Clinical Genetics. Unique We are unique as we provide translational research, which can lead to the elucidation of pathomechanisms underlying vascular pathologies and the best treatment options for the patients. Our translational studies have already resulted in the implementation of a new surgical technique for our standard patient care. 81 82 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Hypertrophic Cardiomyopathy Present and Future Research The pathological etiology of aneurysms may be associated with a focal atherosclerotic presentation of systemic vascular disease in which massive vascular wall degradation leads to aortic dilation. Alternatively, genetic mutations can lead to errors in cell signaling and result in mutated vascular collagen and extracellular matrix production. A third possible cause is infection of the aorta that leads to a weakening of the vascular wall and the development of an aneurysm. Our research projects are divided into three areas. First there are the experimental studies in which the department of Vascular Surgery collaborates with the departments of Nephrology and Physiology, which is of great importance for sharing knowledge and use of central facilities. New surgical techniques for decreasing kidney damage triggered by inflammation factors and oxidative stress, as a result of suprarenal aortic clamping in aneurysm repair surgery, have been investigated in a rat model. This study has resulted (Research highlight) in the implementation of a new surgical technique for our standard patient care. Together with the departments of Pathology and Clinical Genetics a tissue bank has been established that contains frozen vascular tissue samples of over 125 patients, blood samples and live cell cultures. This database is used to investigate genetic factors and intracellular signaling pathways associated with the decrease of vascular wall strength and aneurysm development. The second area involves clinical studies. In a prospective study we investigate possibilities for minimal invasive surgical techniques by endovascular and (robot-assisted) laparoscopic aortic repair surgery. A retrospective study on infections in aortic grafts has led to a prospective clinical study investigating the possibilities of Positron Emission Tomography (PET) as a new diagnostic imaging tool for aortic graft infection. The third area involves our participation in multi-center randomized controlled trials: The AJAX-trial is a collaboration between AMC, OLVG and VUmc in order to improve the outcome of ruptured aorto-iliac aneurysm repair surgery. In 2011 the trial was completed and the results have been submitted to The Lancet. Together with the LUMC the medical treatment of small aneurysms is being investigated in a randomized controlled trial. In collaboration with the St. Antonius Hospital in Nieuwegein a randomized controlled trial is examining the changes in renal amino acid metabolism after renal ischemia reperfusion injury in patients undergoing open AAA repair using amino acid stable isotope tracers. Furthermore, we are using these amino acid tracers to study the possible protective effect of a perioperative supplement of alanyl-glutamine on renal metabolism after ischemia reperfusion injury. Minimal invasive surgery is a key point for the department of Vascular Surgery. In future studies we will investigate the possibilities of minimal invasive techniques in surgical repair of dilating and occlusive arterial disease. A new region of interest for our group, in collaboration with the departments of Cardiology and Radiology, will be the treatment of occlusive arterial disease using micro bubble enhanced ultrasound. We will also continue our search on biomarkers of AAA development and investigate the pathophysiology of AAA in close collaboration with the departments of Physiology, Cardiology, Pathology and Clinical Genetics. Participants Projectleaders Clinical Genetics Gerard Pals Petra Zwijnenburg Physiology Rene Musters Geert Jan Tangelder Vascular Surgery Jan Blankensteijn Paul van Leeuwen Willem Wisselink PhD students Clinical Genetics Dimitra Micha Physiology Rick Kwekkeboom Vascular Surgery Saskia Brinkmann Nikki Buijs Harm Ebben Vincent Jongkind Menno Groeneveld Matteus Linsen Hillian Nederhoed Wouter Niepoth Joyce Struik Mechteld Vermeulen Kak-khee Yeung Postdoctoral fellows Vascular Surgery Arjan Hoksbergen Support staf Physiology Sylvia Bogaards Vascular Surgery Laura van Wieringen Collaborations National AMC, Amsterdam Ron Balm Dink Legemate Bas de Mol EMC, Rotterdam Aida Bertoli-Avella Marc van Sambeek UMCG, Groningen Eric Verhoeven Cisca Wijmenga UMCM, Maastricht Petra Boelens Cornelis Dejong Marcel van de Poll UNCN, Nijmegen Sebastian Bredie UMCU, Utrecht Monique Prinssen Annette Baas Diederick Grobbee Edwin Cuppen Catharina Hospital, Eindhoven Jaap Buth Philippe Cuypers Joep Teijink International Reykjavik, Iceland Stefansson, Kari Unnur Thorsteinsdottir Warsaw, Poland Elzbieta KompanowskaJezierska Leicester, UK Nilesh Samani Robert Sayers London, UK Rob Krams Australia Jonathan Golledge Joseph Moxon New ealand Andre van Rij Gregory Jones 83 84 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Selected Publications 2010-2012 A Data from PhD project KK Yeung Cold perfusion through the arteries during renal ischemia has been suggested to diminish postoperative renal damage after juxtarenal aortic aneurysm repair. As the kidneys play a key role in dimethylarginine metabolism, which in turn is associated with renal hemodynamics, we hypothesized that the protective effect of cold perfusion is associated with preserved renal extraction of dimethylarginines. Renal ischemia was induced in 3 groups of anesthetized Wistar rats, which underwent suprarenal aortic clamping (45 min) with no perfusion (group 1), renal perfusion with 37°C saline (group 2), and renal perfusion with 4°C saline (group 3), followed by 90 min of renal reperfusion in all groups. The sham group had no clamping. In group 3 (renal ischemia with cold perfusion), postoperative serum creatinine levels as well as the presence of luminal lipocalin-2 and its associated brush-border damage were lower compared to groups 1 and 2. Furthermore, renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine as well as the arginine/ADMA ratio, which defines the bioavailability of nitric oxide, remained intact in group 3 only. The arginine/ADMA ratio correlated with cortical flow, lipocalin-2, and creatinine rises. Warm and cold renal perfusion (groups 2 and 3) during ischemia were similarly effective in lowering protein nitrosylation levels (i.e. oxidative stress), plasma creatinine levels (Figure A), renal leukocyte accumulation (Figure B), neutrophil gelatinase-associated lipocalin (NGAL) expression in distal tubules, and urine NGAL. These data support the clinical use of cold renal perfusion during renal ischemia in situations where renal ischemia is inevitable, as it reduces tubular damage and preserves renal extraction of dimethylarginines. Renal perfusion with saline per se during renal ischemia is effective in diminishing renal leukocyte accumulation and oxidative stress. 0.6 0.6 P=0.002 P=0.002 0.4 0.4 P=0.007 P=nsP=0.007 P=ns P=0.047 P=0.047 0.2 0.2 0.0 0.0 sham sham no warm cold perfusion perfusion perfusion no warm cold perfusion perfusion perfusion Figure A. Absolute rise in creatinine level (mg/dL) in the 4 groups (see text). Ns = 0.084. B Number Number of CD45 of CD45 positive positive cellcell nuclei nuclei per per cellcell image image Clinical use of cold renal perfusion during suprarenal aortic clamping Absolute Absolute riserise in creatinine in creatinine levellevel (mg/dL) (mg/dL) Aneurysm 300 300 250 250 200 200 150 150 100 100 50 50 0 0 sham no perfusion sham warm perfusion no perfusion cold perfusion warm perfusion cold perfusion cortex cortex * * * * cortico- lis of Henle medulla medullary cortico- lis of Henle medulla medullary Figure B. Number of leukocytes per full microscopic image in 4 kidney areas of the 4 groups. Significant differences (P < 0.05) between the perfusion groups and the group without renal perfusion during renal ischemia are shown at the top of the boxes marked with an asterisk (*). de Bruin JL, Baas AF, Buth J, Prinssen M, Verhoeven EL, Cuypers PW, van Sambeek MR, Balm R, Grobbee DE, Blankensteijn JD; DREAM Study Group. Long-term outcome of open or endovascular repair of abdominal aortic aneurysm. New England Journal of Medicine 2010; 20:362:1881-89. Jongkind V, Yeung KK, Linsen MA, Heidsieck D, Coveliers HM, Hoksbergen AW, Wisselink W. Direct videoscopic approach to the thoracic aorta for aortic endograft delivery: evaluation in a human cadaver circulation model. Journal of Endovascular Therapy 2010; 17:12-18. de Bruin JL, de Jong S, Pol J, van der Jagt M, Prinssen M and Blankensteijn JD. Residual Infrarenal Aortic Neck following Endovascular and Open Aneurysm Repair. European Journal of Vascular and Endovascular Surgery 2012; 43: 415-18. van de Laar IMBH, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JMA, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collee M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IME, Micha D, Timmermans J, Hilhorst-Hofstee Y, BiermaZeinstra SM, Willems PJ, Kros JM, Oei EHG, Oostra BA, Wessels MW, Bertoli-Avella AM. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nature Genetics 2011; 43: 121-26. Buijs N, van Bokhorst-de van der Schueren MA, Langius JA, Leemans CR, Kuik DJ, Vermeulen MA, van Leeuwen PAM. Perioperative arginine-supplemented nutrition in malnourished patients with head and neck cancer improves long-term survival. American Journal of Clinical Nutrition 2010; 92:1151-56. Jongkind V, Diks J, Yeung KK, Cuesta MA, Wisselink W. Mid-term results of robot-assisted laparoscopic surgery for aortoiliac occlusive disease. Vascular 2011;19:1-7. Linsen MAM, Jongkind V, Nio D, Hoksbergen AWJ and Wisselink W. Pararenal aortic aneurysm repair using fenestrated endografts. Journal of Vascular Surgery 2012; 56: 238-46. Vermeulen MAR, Ligthart-Melis GC, Buijsman R, Siroen MPC, van de Poll MCG, Boelens PG, Dejong CHC, van Schaik C, Hofman MBM, van Leeuwen PAM. Accurate perioperative flow measurement of the portal vein and hepatic and renal artery: A role for preoperative MRI? European Journal of Radiology 2012; 81: 2042-48. Yeung KK, De Gouyon Matignon C, Renwarin L, Tjon-A-Fat MR, Teerlink T, van Leeuwen PA, Musters RJ, Wisselink W, Tangelder GJ. Hypothermic renal perfusion during aortic surgery reduces the presence of lipocalin-2 and preserves renal extraction of dimethylarginines in rats. American Journal of Physiology; Renal Physiology 2011; 301:F1231-41. 85 86 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Reproduction and Vascular Function ‘Pregnancy provides a unique window of opportunity for exposing the hidden risks of vascular disease in women at the earliest stage possible’ Focus Our studies focus on cardiovascular disease in women by using pregnancy as a unique predictor for cardiovascular events occurring later in life. Cardiovascular disease is the single leading cause of death for women in developed countries, and claims the lives of more women than all forms of cancer combined. All women face the threat of cardiovascular disease. However, symptoms of cardiovascular disease tend to occur about 10 years later in women than in men, while women often have different symptoms of coronary artery disease than men. Pregnancy allows a unique opportunity to challenge these gender-specific differences. The physiological demands of pregnancy on the maternal cardiovascular system and the need to establish a connection between the maternal and fetal vascular systems can catapult a woman into a metabolic syndrome that predisposes to vascular endothelial dysfunction and atherosclerosis. By focusing on pregnancy as a cardiovascular stress test for later life and by focusing on the shared pathophysiology of hypertensive disorders before, during and after pregnancy with cardiovascular disease later in life, pregnancy provides a unique window of opportunity for exposing the hidden risks of vascular disease in women at the earliest stage possible. Collaboration Vascular homeostasis during pregnancy is maintained by highly dynamic multi-level, multi-organ, and multi-pathway interactions. Consequently our collaborative clinical and preclinical research is multidisciplinary, multi-methodological and addresses all stages (before, during and after pregnancy). Unique Our research group is unique as we combine state-of-the art molecular methods, e.g. genomewide sequencing permitting the exploration of novel layers of biological information with well-defined patient cohorts to deliver clinical milestones from bench-to-bedside. An excellent example of the success and impact of these approaches was the identification of the gene responsible for the HELLP syndrome, the first large noncoding gene linked to a Mendelian disorder with autosomal recessive inheritance. 87 88 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Hypertrophic Cardiomyopathy Present and Future Research Currently our ongoing multi-disciplinary studies are researching the underlying functional mechanistic defect of the HELLP syndrome with a focus on the novel non-coding RNA. There are ongoing functional studies to improve understanding of the interaction between maternal and fetal genes, found in genetic screens and a mouse model in order to identify the cause of reduced spiral artery remodeling in pre-eclampsia. Multicenter follow-up studies are being performed to investigate the relationships between microcirculation, vascular insulin resistance and ß-cell function in a cohort of PCOS patients. Women with a twin pregnancy after IVF are being studied for their neovascularization profile. Observational cohort studies are being performed to look at the role of niche- and fibroid-related vascularity in bleeding- and implantation disorders using innovative diagnostic methods. Long-lasting disease-causing changes that persist years after a previous challenge are by definition epigenetic in nature. The hypothesis-free identification of these epigenetic changes will be tackled by methyl-C sequencing. The phenotypic consequences as reflected in the RNA of endothelial-derived microparticles will be analyzed by RNA sequencing. We will study discordant monozygotic twin sisters and epigenetic profiling of children born from (un)complicated pregnancies. In addition, we will include the well-documented cohorts of the Hypitat and Hyras studies. We will explore the hypothesis that both hypertension in pregnancy and cardiovascular disease in later life share pathophysiological features of cardiac, (micro) vascular and metabolic perturbations. Generalized (micro) vascular dysfunction is a predictor of cardiovascular disease. In women with severe hypertension in prior pregnancy we will look at local and systemic vascular dysfunction leading to an increased prevalence of the metabolic syndrome, arterial stiffness, impaired microcirculation and altered microparticle levels. Additionally, these women will be tested on systemic level for diastolic heart dysfunction, one of the earliest signs of cardiac failure, especially in ‘asymptomatic’ women. In collaboration with the EMGO institute we will develop lifestyle intervention studies. We collaborate in national studies to expand this knowledge through in-depth evaluations of large well-phenotyped patient groups with PCOS, early menopause and pregnancy related hypertension. The specific role of the hyperandrogenic condition, as present in PCOS patients, in relation to CVD will be explored in collaboration with the University of Gent. The etiology of impaired implantation and pregnancy outcome in women with benign uterine disorders is still unclear. Nevertheless, we expect abnormal vascularity and neovascularisation to play a key role. Participants Project leaders Clinical Chemistry Marie van Dijk Cees Oudejans Obstetrics and Gynecology Annemiek Bolte Hans Brölmann Christianne de Groot Peter Hompes Judith Huirne Velja Mijatovic Nils Lambalk Marieke Lambers Hanneke de Vries John van Vugt PhD Students Clinical Chemistry Daan van Abel Hari Thulluru Obstetrics and Gynecology Bauke Adriaanse Heleen Betjes Noortje van den Boogaard Eva Bouwsma Nicole Burger Milou Busard Kim Dreyer Koen Deurloo Leonoor van Eerden Wietske Hermes Lisette van der Houwen Floortje van Kesteren Iris Ketel Dorrit Kieslinger Els Groeneveld Petra Janssen Tamar König Esther Leushuis Ingeborg Linskens Marjolein Louwerse Marleen Nahuis Lotte van Nieuwenhuis Melanie van Os Barbara Stoelinga Maaike Tasma Chantal Tromp Lucas Uittenbogaard Marjolein Bij de Vaate Griet Vandenberghe Christine van Velzen Carlijn Vergouw Lucet van der Voet Sanne Visser Machteld Witmer Support staf Clinical Chemistry Omar Michel Joyce Mulders Ankie Poutsma Allerdien Visser Collaborations National AMC, Amsterdam Ben Mol Patrick Bossuyt Suzanne Geerlings EMC, Rotterdam Hans Duvekot LUMC, Leiden Kitty Bloemenkamp UMCG, Groningen Annemieke Hoek Mariëlle van Pampus UMCM, Maastricht Jan Nijhuis Christine Willekes UMCN, Nijmegen Mallory Woiski UMCU, Utrecht Frank Broekmans Bart Fauser Martijn Oudijk Anneke Kwee International Adelaide, Australia Robert Norman Brussels, Belgium Olivier Donnez Jacques Donnez Montreal, Canada Daniel Dufort Toronto, Canada Steve Lye Aarhus, Denmark Margit Dueholm Copenhagen, Denmark Olav Istre Le Kremlin Bicêtre, France Herve Fernandez Shatin, Hong Kong Dennis Lo Tel Hashomer, Israel Motti Goldenberg Pamplona, Spain Juan Alcazar Malmö, Sweden Lil Valentin London, UK Tom Bourne Pittsburgh, USA Mirka Jones Wakeforest, USA Robert Taylor 89 90 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Pre-Eclampsia Selected Publications 2010-2012 HELLP-babies link a novel lincRNA to the trophoblast cell cycle Burger NB, Einarsson JI, Brolmann HAM, Vree FEM, McElrath TF, Huirne JAF. Preconceptional laparoscopic abdominal cerclage: a multicenter cohort study. American Journal of Obstetrics and Gynecology 2012; 207:273.e1. By Marie van Dijk, Hari Thulluru and Cees Oudejans The HELLP syndrome is a pregnancy-associated disease inducing Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) in the mother. Although HELLP symptoms occur in the third trimester in the mother, the origin of the disease can be found in the first trimester fetal placenta. An essential connection between the maternal and fetal circulations is made during the first trimester, by the fetal genesmediated mechanism of trophoblast invasion into the maternal placental bed. Failure of this local early process by (epi)genetic defects leads to aberrant trophoblast differentiation with incomplete maternal vessel wall adaptation in the placental bed. This local defect is followed by compensatory mechanisms of the hypoxic placenta. Changes in the release of PlGF, sEng and sFlt trigger maternal TGFß-dependent NOSmediated vasodilation. Finally, months after the initial event, maternal endothelial cell damage with systemic symptoms (hypertension, proteinuria, convulsion, elevated liver enzymes, low platelets) results. By multipoint non-parametric linkage, pedigree structure allele sharing and haplotype association analysis of affected sisters and cousins, we have demonstrated that the HELLP locus resides in an intergenic region on 12q23.2 between PMCH and IGF1. By strand-specific RT-PCR complemented with RACE and FISH, a novel non-coding RNA transcript of 205,012 bases with (peri)nuclear expression in the extravillous trophoblast was identified. By siRNA-mediated knockdown followed by RNA-sequencing, the HELLP lincRNA was found to classify as an activator affecting a large set of genes involved in the cell cycle. Furthermore, by blocking potential mutation sites as identified in HELLP, families decreased the invasion capacity of extravillous trophoblasts. This large non-coding gene is the first underlying Mendelian disorder with autosomal recessive inheritance. Our data demonstrate that pregnancy exposes hidden risks of vascular disease in women involving biological mechanisms that have not been previously described. Expression (green) in perivascular extravillous trophoblast cells of the long intergenic noncoding RNA (lincRNA) associated with the HELLP syndrome. In normal pregnancy, these fetal cells actively modify the vessel wall of the maternal spiral arteries to establish a connection between the maternal and fetal vascular systems. In pre-eclampsia and the HELLP syndrome, by a fetal gene defect, this process fails to trigger a cascade of events ultimately leading to maternal endothelial cell damage with systemic symptoms of hypertension and proteinuria. van Dijk M, van Bezu J, van Abel D, Dunk C, Blankenstein MA, Oudejans CBM, Lye SJ. The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by αT-catenin upregulation. Human Molecular Genetics 2010; 19: 2658-67. van Dijk M, Thulluru HK, Mulders J, Abdul-Hamid O, Poutsma A, Windhorst S, Kleiverda G, Sie D, Lachmeijer AMA, Oudejans CBM. HELLP-babies link a novel lincRNA to the trophoblast cell cycle. Journal of Clinical Investigation 2012; 122: 4003-11. Gaugler-Senden IPM, Tamsma JT, van der Bent C, Kusters R, Steegers EAP, de Groot CJM. Angiogenic Factors in Women Ten Years after Severe Very Early Onset Preeclampsia. Plos One 2012: 7; e43637. Groeneveld E, Lambers MJ, Stakelbeek ME, Mooij TM, van den Belt-Dusebout AW,Heymans MW, Schats R, Hompes PG, Hoek A, Burger CW, van Leeuwen FE, Lambalk CB; on behalf of the OMEGAproject group. 2012. Factors associated with dizygotic twinning after IVF treatment with double embryo transfer. Human Reproduction 2012; 12:2966-70. de Groot CJM, van der Mast BJ, Visser W, De Kuiper P, Weimar W, Van Besouw NM. Preeclampsia is associated with increased cytotoxic T-cell capacity to paternal antigens. American Journal of Obstetrics and Gynecology 2010; 203:496.e1-6. Ketel IJ, Serné EH, Ijzerman RG, Korsen TJ, Twisk JW, Hompes PG, Smulders YM, Homburg R, Vorstermans L, Stehouwer CD, Lambalk CB. Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS. Human Reproduction 2011; 6:3130-37. bij de Vaate AJ, Brölmann HA, van der Voet LF, van der Slikke JW, Veersema S, Huirne J. Ultrasound evaluation of the caesarean scar: relation between a niche and postmenstrual spotting. Ultrasound in Obstetrics and Gynecology 2011; 37:93-99. Vergouw CG, Kieslinger DC, Kostelijk EH, Botros LL, Schats R, Hompes PG, Sakkas D and Lambalk CB. Day 3 embryo selection by metabolomic profiling of culture medium with near-infrared spectroscopy as an adjunct to morphology: a randomized controlled trial. Human Reproduction 2012; 27:2304-11. 91 92 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Diabetis Mellitus and Obesity ‘Only a multi-disciplinary approach can fully explore the most promising pathways to prevent, treat and cure diabetes and its cardiometabolic complications’ Focus Our research efforts focus on the pathophysiology of type 2 diabetes (T2DM) and its metabolic and cardiovascular complications. The obesity and diabetes (‘diabesity’) pandemic as well as the ensuing cardiovascular disease incidence rates, are leading threats to public health in the 21st century. Our group explores novel pathophysiologic mechanisms underlying insulin resistance and β-cell dysfunction, the two key defects in T2DM, as well as pathways leading to the development of cardiovascular disease. This integrative approach may enable us to identify novel targets for the development of future preventive and therapeutic strategies. Collaboration Research into the pathophysiology of diabetes requires solid multi-disciplinary collaborations. Epidemiological and pathophysiological aspects of T2DM, and its cardiovascular and microvascular complications have been an internationally successful research focus of the VUmc for more than 20 years (The Hoorn Study, multiple clinical/pathophysiology and intervention studies). Currently, interdisciplinary collaborations between the Diabetes Center and the departments of Vascular Medicine, Cardiology, Radiology and Nuclear Medicine & PET Research enable interactions amongst investigators with complementary interests and expertise, as well as the use of cutting edge phenotyping imaging modalities. Collaborations with surrounding interfaculty research institutes, including the Institute for Research in Extramural Medicine and the Neuroscience Campus Amsterdam enable research in innovative management and care strategies to improve metabolic control, self-management and quality of life, as well as research into the causes and consequences of diabetes in relation to the brain. These collaborations offer opportunities to create out-of-the-box approaches that may lead to significant advances in the field. Unique Our research group is unique as it provides a facilitating framework for conducting multi-disciplinary basic and clinical research and encourages the scientific development of young investigators. Our clinical research unit, a joint initiative of the Diabetes Center and department of Vascular Medicine, offers researchers specialized technical assistance as well as a network of colleagues from across the medical and scientific community. 93 94 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Hypertrophic Cardiomyopathy Present and Future Research Our research has been focusing on several aspects of the pathogenesis of key-defects of T2DM, i.e. beta-cell dysfunction and insulin resistance, as well as diabetesrelated microvascular and cardiovascular pathologies: postprandial hyperlipidemia, effects of ectopic fat, and shared insulin-signaling pathways in metabolic and vascular target tissues. In addition, several studies are focusing on incretin biology and pleiotropic effects of incretin-based therapies, including those on the heart, vasculature, beta-cell function, kidney and gastrointestinal system. Postprandial hyperglycemia and hyperlipidemia have been associated with increased cardiovascular risk. We demonstrated that postprandial increases in glucose and triglycerides, especially in T2DM, are accompanied by pro-atherosclerotic functional changes in HDL and LDL particles and oxidative stress. Recent experimental studies show that incretin-based therapies, i.e. glucagon-like peptide-1 receptor agonists (GLP-1RA) and inhibitors of the incretin degrading enzyme dipeptidyl peptidase 4, may decrease postprandial hyperlipidemia by reducing intestinal lipoprotein formation. We were able to confirm these findings in T2DM patients, showing that both therapies significantly reduced postprandial glycemic excursions, triglycerides, triglyceride-rich lipoproteins, as well as oxidative stress variables. In ongoing studies we will further explore possible pleiotropic effects of incretins on vascular function, kidney and cardiovascular health. T2DM is a progressive disease due to a relentless decline in beta-cell function. Investigators at the Diabetes Center showed that 3-year treatments with GLP-1RA versus basal insulin conferred beta-cell protection in T2DM patients. Current findings from an extensive international collaboration suggest a link between genetic factors and incretin biology, including the response to incretin-based therapies. The brain may be regarded as a target organ of diabetes-related (micro)vascular complications, whereas the brain, in its role as key regulator organ of cardiometabolic functions, has also been implicated in the development of cardiometabolic abnormalities in high-risk populations. Therefore, current and future research will focus on the interactions among diabetes, the brain, metabolism and cognition. Obesity is associated with adipose tissue accumulation in ectopic locations that may disturb organ function. In both pre-diabetic and T2DM populations we have found increased ectopic fat accumulation. Ectopic fat, particularly liver fat, was associated with insulin resistance, but also with impaired myocardial perfusion and metabolism. Adipose tissue is also located around blood vessels, so called perivascular adipose tissue (PVAT). We have demonstrated that metabolic insulin resistance is characterized by pathway-specific impairment in PI3-kinase–dependent signaling, which in endothelium may cause imbalance between NO production and secretion of endothelin-1, limiting nutritive blood flow, and thus insulin and substrate delivery to target tissues and possibly increasing vascular resistance. PVAT-derived cytokines may contribute to impairment of insulin’s metabolic and vascular actions by modulating insulin signaling (Highlight). Recent funding from the Netherlands Heart Foundation (Serné) is enabling us to further characterize impaired vascular insulin signaling and whether it can be targeted by red wine polyphenols. Participants Projectleaders Clinical Chemistry Rien Blankenstein Henk Blom Peter Scheffer Tom Teerlink Internal Medicine Michiel van Agtmael Michaela Diamant Mark Kramer Mike Nurmohamed Erik Serné Yvo Smulders Ophthalmology Annette Moll Physiology Etto Eringa Geert-Jan Tangelder PhD students Clinical chemistry Mariska Davids Ruben Essen Monica Rocha Milan Richir Leonard van der Zwan Internal medicine Liselotte Bloemendaal Michiel de Boer Marije Bomers Mathijs Bunck Stieneke Doornweerd Nalini Elmont-Radhakishun Mark Fineman Renate van Genugten Tibor Hajos Herman Hofstee Jacqueline Hornstra Katja van den Hurk Judith Kuenen Jennifer ten Kulve Rick Meijer Linde Morsink Marcel Muskiet Daniël van Raalte Fleur Schouten Alper van Sijl Jorn Woerdeman Nienke Wijnstok Nynke van der Zijl Ophthalmology Huang-Ton Nguyen Physiology Wineke Bakker Erik van Poelgeest Support staf Internal Medicine Jennifer Benit Jeannette Boerop Sandra Gassman Ingrid Knufman Physiology Caro-Lynn Alta Sophie Luikinga Collaborations National LUMC, Leiden Marie-Jose Goumans Leen ‘t Hart Hildo Lamb Albert de Roos MUMC, Maastricht Ellen Blaak Jan Glatz Joost Luiken Coen Stehouwer Hans Vink UMCG, Groningen Bert Groen Bruce Wolffenbuttel AMC, Amsterdam John Karemaker Rienk Nieuwland Mireille Serlie Guus Sturk WU, Wageningen Sander Kersten Willem de Vos Slotervaart zh, Amsterdam Ines von Rosenstiel Jos Beijnen Dees Brandjes EMC, Rotterdam Eric Sijbrands Miriam Sturkenboom UMCN, Nijmegen Jan Smit UMCU, Utrecht Harold de Valk International Aarhus, Denmark Allan Flyvbjerg Copenhagen, Denmark Carolyn Deacon Jens Juul Holst Erik Richter Praag, Czech Republic Martin Haluzik Helsinki, Finland Marja-Riitta Taskinen Hannele Yki-Järvinen Paris, France Bernard Viollet Dusseldorf, Germany Hobart, Australia Margriet Ouwens Steve Rattigan Tübingen, Germany Andreas Fritsche Hans-Ulrich Häring Padua, Italy Andrea Mari Glasgow, Scottland Naveed Sattar Göteburg, Sweden Ulf Smith London, UK John Yudkin Charlottesville, USA Eugene Barrett Chapel Hill, USA John Buse 95 96 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Metabolic Vascular Disease baseline capillary density (n/mm2) A 70 50 30 -30 0 60 meal peak reactive hyperaemia (n/mm2) Hyperinsulinemia-induced whole-body glucose uptake during a euglycemic-hyperinsulinemic clamp is partly mediated by increased capillary density. We hypothesized that physiological insulinema in response to a mixed meal may also enhance microvascular function, which, however, may be impaired in insulin resistant individuals and patients with type 2 diabetes (T2DM). Twelve men with uncomplicated T2DM, 13 with metabolic syndrome (MetS) and 12 age-matched healthy normoglycemic controls, mean age 57±6 years, underwent skin capillary video-microscopy before and 60 and 120 min following a standardized mixed-meal to measure capillary density at baseline and during post-occlusive peak reactive hyperemia (PRH), also termed capillary recruitment. Oral glucose insulin sensitivity (Matsuda-Index) and postprandial hyperglycemia (2h-AUCglucose) were calculated. Fasting baseline capillary density (BCD) was similar among groups, but fasting PRH was lowest in T2DM (p<0.05). Postprandially, both BCD and PRH increased linearly in all groups (p<0.001), however, the meal-related increase in BCD was significantly lower in T2DM and MetS versus controls (both p<0.05). At all time points, postprandial PRH was lower in both T2DM and MetS versus controls (both p<0.05). In pooled analysis, postprandial mean PRH correlated with MatsudaIndex (r=0.386, p=0.018) and inversely with 2h-AUCglucose (r=-0.336, p=0.042). In conclusion, gradual deterioration of meal-related capillary recruitment was paralleled by decreasing insulin sensitivity and postprandial hyperglycemia, as assessed in healthy normoglycemic men, men with the MetS and those with overt T2DM. These findings suggest that in both pre-diabetic conditions and in overt T2DM microvascular dysfunction might contribute to postprandial dysglycemia. (Diabetologia 2012; in press). 120 Time (min) B Bunck MC, Corner A, Eliasson B, Heine RJ, Shaginian RM, Wu Y, Yan P, Smith U, Yki-Jarvinen H, Diamant M, Taskinen MR. One-year treatment with exenatide vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and oxidative stress. Atherosclerosis 2010; 212:223-29. Rocha MS, Teerlink T, Janssen MCH, Kluijtmans LAJ, Smulders YM, Jakobs C, de Almeida IT, Rivera I, Castro R, Blom HJ. Asymmetric dimethylarginine in adults with cystathionine beta-synthase deficiency. Atherosclerosis 2012; 222: 509-511. Diamant M, van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, Trautmann M. DURATION-3: Exenatide once weekly resulted in significant reductions in HbA1c compared to insulin glargine titrated to target in patients with type 2 diabetes. Lancet 2010; 375:2234-43. van Sijl AM, van den Oever IAM, Peters MJL, Boers M, Dijkmans BAC, van Halm VP, Smulders YM, Voskuyl AE, Nurmohamed MT. Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRE Study. Annals of the Rheumatic Diseases 2012; 71: 341-344. 70 50 30 -30 0 60 120 Time (min) meal AUC Glucose (mmol l -1 2h-1) By Michaela Diamant and Erik Serné (supported by the Netherlands Heart Foundation) C 1500 1000 500 0 r - 0.336 p =0.042 0 40 60 80 100 mean PRH (n/mm2) 50 40 Matsuda Index Diabetes Mellitus, Obesity and Cardiovascular Complications Selected Publications 2010-2012 D r 0.386 p = 0.018 30 20 10 0 0 40 60 80 100 mean PRH (n/mm2) Postprandial course of baseline capillary density (fig. A and B) and peak reactive hyperemia (fig. B and C) in men with type 2 diabetes (red line), men with the metabolic syndrome (broken line) and healthy normoglycemic controls (blue line). Pooled linear regression analysis of mean postprandial peak reactive hyperemia (PRH) with (C) 2h-AUC for glucose as a measure of postprandial glucose disposal, and (D) Matsuda Index as a measure of insulin sensitivity. van Duinkerken E, Schoonheim MM, Sanz-Arigita EJ, IJzerman RG, Moll AC, Snoek FJ, Ryan CM, Klein M, Diamant M, Barkhof F. Resting-State Brain Networks in Type 1 Diabetic Patients With and Without Microangiopathy and Their Relation to Cognitive Functions and Disease Variables. Diabetes 2012; 61: 1814-21. Meijer RI, Serne EH, Smulders YM, van Hinsbergh VWM, Yudkin JS, Eringa EC. Perivascular Adipose Tissue and Its Role in Type 2 Diabetes and Cardiovascular Disease. Current Diabetes Reports 11: 211-17, 2011. den Uyl D, van Raalte DH, Nurmohamed MT, Lems WF, Bijlsma JWJ, Hoes JN, Dijkmans BAC, Diamant M. Metabolic effects of high-dose prednisolone treatment In early rheumatoid arthritis: diabetogenic effects and inflammation reduction on the balance. Arthritis Rheumatism 2012; 64:639-46. van der Zijl NJ, Moors ,CCM, Goossens GH, Hermans MH, Blaak EE, Diamant M. Valsartan improves beta-cell function and insulin sensitivity in normotensive subjects with impaired fasting glucose and/or impaired glucose tolerance (PancREatic betacell dySfunction rEstoRed by Valsartan Effects – PRESERVE Study). Diabetes Care 2011; 34:845-51. van der Zijl NJ, Serné EH, Goossens GH, Moors CC, IJzerman RG, Blaak EE, Diamant M. Valsartan-induced improvement in insulin sensitivity is not paralleled by changes in microvascular function in individuals with impaired glucose metabolism. Journal of Hypertension 2011; 29:1955-62. 97 98 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Nutrition Research ‘Optimization of nutritional support during the first postnatal weeks may reduce occurrence of metabolic syndrome and associated cardiovascular disease’ Focus In recent years nutritional research in very low birth weight preterm infants (VLBW) has focused on the prevention of protein malnutrition during the first postnatal weeks. At this early age, the nutritional protein fortification depends on amino acid infusion via a central vein due to the immature gastrointestinal tract. In 2010 the ESPGHAN nutrition committee proposed new guidelines on nutrition. In particular, the relative increase of the protein fraction in the nutrition of these infants is aimed at preventing early postnatal weight loss to reduce morbidity, and to stimulate neurodevelopment. On the other hand, an increasing number of follow-up studies in VLBW infants indicate that specifically in the infants that show rapid growth after preterm birth, there is already a development of clinical signs of a metabolic syndrome during early infancy, leading to cardiovascular disease later in life. Our research is focused on the effects of early modifications of nutritional support on growth, metabolism and body composition in VLBW and small for gestational age infants. Collaboration The departments of Pediatrics, Neonatology and Vascular Surgery join their efforts to investigate effects of infantile nutritional support on early growth, and development of vascular disease in later life. Unique Our research group is the only center in The Netherlands where nutrition related research is performed with a focus on clinical studies in a high risk perinatal population. We have world renowned experts known for the development of very special customized infant formulas. Full expertise is available for neonatal intensive care, pediatric follow-up into adulthood with laboratory technology on growth and metabolism, anthropometry, bodycomposition and stable isotope mass spectrometry. 99 100 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Hypertrophic Cardiomyopathy Present and Future Research Fetal growth is characterized by the interaction of the fetal genome and its environment. The fetal environment, in turn, is influenced by the mother’s environment, metabolism and by the placenta. Intra-uterine growth is regulated by genetic factors, essential substrates, and endocrine factors. In utero, important growth-regulating hormones are insulin and thyroxin, and insulin-like growth factors (IGFs) that are regulated independent of growth-hormone. After birth the regulation of IGFs becomes increasingly growth hormone dependent. It is suggested that growth regulation may be permanently altered, i.e. programmed, in utero and even during infancy. By changes in the nutritional, hormonal and/or metabolic factors afforded by the mother during critical periods of development, reprogramming imposes lasting or lifelong changes in the structure and physiology of her offspring. Low birth weight, as a proxy of intrauterine growth retardation is associated with chronic diseases in adulthood, such as hypertension, cardiovascular disease, insulin resistance, and type 2 diabetes. Comparable mechanisms are suggested from the long-term observational studies of the Dutch famine that describe the onset of type 2 diabetes at later age in the offspring of mothers that were malnourished during the winter of 1944 -45. In particular the third trimester of pregnancy is considered to be a critical phase for the programming of body functions. Hence, a shortage of nutrients during this phase followed by an abundance of nutrients after birth results in the onset of the metabolic syndrome, as demonstrated by a more than 25 percent rise in body mass index. This condition has been associated with obesity, insulin resistance, glucose intolerance, and hypertension followed by vascular disease. In long-term follow-up studies of preterm infants born in 1983 in the Netherlands (Project On Preterm and SGA birth [POPS cohort]) signs of the appearance of the metabolic syndrome at 19 years of age were observed, when growth was (too) rapid during the first postnatal months. From these observations it may be suggested that nutritional interventions in VLBW preterm infants are only possible if they are performed during the golden window of programming after preterm birth. In ongoing studies we investigate effects of postdischarge nutrition of preterm infants during the first 6 months after birth (STEP I study) and the first seven years after birth (STEP II study). The latter study was initiated in March 2011. A total of 120 infants will have been investigated at age 7 by 2013. Studies by the Pediatrics department, hosted by the ICaR-VU and EMGO, focus on the relationship of fetal and infantile growth with anthropometry, insulin sensitivity and cardiovascular function at age 5 in a multi-ethnic birth cohort (ABCD study; funded by ZonMw). In addition, we investigate determinants of early programming of cardiometabolic profile; we study the relationship between birth weight and (accelerated) growth, and physical activity and physical fitness at primary school age. Ethnic differences in metabolic and cardiovascular function are studied in 5-year-old children. Participants Project leaders Clinical Chemistry Tom Teerlink Internal medicine Abel Thijs Pediatrics Ruurd van Elburg Reinoud Gemke Hans van Goudoever Harrie Lafeber Joost Rotteveel Mirjam van Weissenbruch Vascular surgery Paul van Leeuwen PhD students Clinical Chemistry Mariska Davids Internal medicine Floor Neelemaat Pediatrics neonatology Eline Amesz Jolice van den Berg Jorrit de Kieviet Monique van de Lagemaat Ilse Westerbeek Annelies van Zwol Dutch human milk bank Willemijn Corpeleijn Stefanie Kouwenhoven Pediatrics general Marieke de Beer Gerrit van den Berg Arend van Deutekom Marieke Peetsold Michel Weijerman University of Amsterdam Aimee van Dijk Marieke de Hoog Research nurses Pediatrics Anneke Cranendonk Sandra Diepenhorst Annemiek de Lange Coördinator Dutch human milk bank Ineke van Vliet Collaboration National AMC, Amsterdam Elvira van Dalen Bas de Mol Karien Stronks Rien de Vos Tanja Vrijkotte Bascule, Amsterdam Theo Doreleijers EUR, Rotterdam Guenther Boehm Onno Helder Anita Hokken-Koelega Marijn Vermeulen GGD, Amsterdam Manon van Eijsden UMCU, Utrecht Frank van Bel VU, Amsterdam Jaap Oosterlaan International Auckland, New Zealand. Jane Harding Cambridge, UK. David Dunger Southampton, UK Caroline Fall Clive Osmond Yogyakarta, Indonesia. Achmad Surjono 101 102 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Nutrition Selected Publications 2010-2012 How optimal early postnatal nutrition in very low birth weight infants may reduce the risk of metabolic syndrome in adult life Special VUmc-designed high protein/normal energy ‘postdischarge’ formula for infants successfully reduces rise in body fat Over the last three years we have published the results of our Study Towards the Effects of Postdischarge nutrition (STEP study) using our unique formula (Amesz et al. 2010; van de Lagemaat M et al. 2011, 2012A). Only limited effects of calcium, phosphorus and vitamin D supplementation in special preterm formula, fortified human milk and postdischarge formula could be observed on bone development in small for gestational age (SGA) born preterm infants, suggesting that prenatal conditions for bone accretion cannot simply be replicated after birth (van de Lagemaat, 2012B). Long-term follow-up studies investigating body composition in our cohort of infants are now in progress. The ICaR-VU equipment investment award for Human Milk Bank in VUmc Recently the first scientific study of the first Dutch human milk bank began. In this early nutrition study (ENS) the possible beneficial role of donor milk in the prevention of necrotizing enterocolitis and enhancement of proper growth and development of extremely preterm infants is being investigated. This study received an ICaR-VU equipment investment award to enable the purchase of a body composition measuring plethysmography device for infants 95 % Cl sds weight About 30 years ago, after observing the rapid decline in growth velocity when preterm infants were discharged from the hospital with nutrition that was equal to that given to term infants, a specially composed nutrition for preterm infants (preterm formula) was introduced. However, this special nutrition not only led to rapid growth but also to a sharp rise in body fat, resulting in an increased risk of type 2 diabetes and cardiovascular disease in later life. 0,50 0,00 -0,50 -1,00 -1,50 0 PDF 3,00 6,00 corrected age in months TF Length 0,50 95 % Cl sds length By H.N. Lafeber Bodyweight 0,00 -0,50 -1,00 -1,50 0 PDF 3,00 6,00 corrected age in months TF Effects of PDF (post discharge formula) or TF (term formula) on Body Weight and Length expressed as 95% confidence interval of standard deviation score normalized for Dutch preterm infants. Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN. Optimal growth and lower fat mass in preterm infants fed a protein-enriched post discharge formula. Journal of Pediatric Gastroenterololgy & Nutrition 2010; 50:200-07. van den Berg G, van Eijsden M, Vrijkotte TG, Gemke RJBJ Educational inequalities in perinatal outcomes: the mediating effect of smoking and environmental tobacco exposure. PLoS One 2012; 7:e37002. Corpeleijn WE, Kouwenhoven SMP, Paap MC, van Vliet I, Scheerder I, Muizer Y, Helder OK, van Goudoever JB , Vermeulen MJ. Intake of Own Mother’s Milk during the First Days of Life Is Associated with Decreased Morbidity and Mortality in Very Low Birth Weight Infants during the First 60 Days of Life. Neonatology 2012; 102: 276-281. Davids M, Richir MC, Visser M, Ellger B, van den Berghe G, van Leeuwen PAM, Teerlink T. Role of dimethylarginine dimethylaminohydrolase activity in regulation of tissue and plasma concentrations of asymmetric dimethylarginine in an animal model of prolonged critical illness. Metabolism-Clinical and Experimental 2012; 61: 482-490. van Dijk AE, Van Eijsden M, Stronks K, Gemke RJBJ, Vrijkotte TG. Maternal depressive symptoms, serum folate status, and pregnancy outcome: results of the Amsterdam Born Children and their Development study. American Journal Obstetrics Gynecology 2010; 203:563.e1-7. Weijerman ME, van Furth AM, van der Mooren MD, van Weissenbruch MM, Rammeloo L, Broers CJM and Gemke RJBJ. Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome. European Journal of Pediatrics 2010; 169: 1195-99. de Hoog ML, van Eijsden M, Stronks K, Gemke RJBJ, Vrijkotte TG Ethnic differences in cardiometabolic risk profile at age 5-6 years: the ABCD study. PLoS One 2012;7:e43667. Westerbeek EA, van den Berg JP, Lafeber HN, Fetter WP, Boehm G, Twisk JW, van Elburg RM. Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial. American Journal of Clinical Nutrition 2010; 91:679-86. de Kieviet JF, Oosterlaan J, Vermeulen RJ, Pouwels PJ, Lafeber HN, van Elburg RM. Effects of glutamine on brain development in very preterm children at school age. Pediatrics 2012; 130,1121-27. van de Lagemaat M, Rotteveel J, Muskiet FA, Schaafsma A, Lafeber HN. Post term dietary-induced changes in DHA and AA status relate to gains in weight, length, and head circumference in preterm infants. Prostaglandins Leukot Essent Fatty Acids 2011; 85:311-16. van de Lagemaat M, Rotteveel J, van Weissenbruch MM, Lafeber HN. Small-for-gestational-age pretermborn infants already have lower bone mass during early infancy. Bone 2012; 51:441-46. 103 104 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Chronic Kidney Disease ‘Cardiorenal interaction and related metabolic pathophysiological mechanisms are being studied in newly developed animal and cellular experimental models and multicenter intervention studies’ Focus Collaboration Unique Chronic kidney disease (CKD) is associated with markedly increased cardiovascular risk and, on the other hand, renal function is the major determinant of the outcome of heart failure. We focus on the underlying pathophysiological mechanisms relevant for the cardiorenal interaction and the burden of cardiovascular disease in CKD. More specifically we are interested in mechanisms such as CKD-associated cardiomyopathy, vascular calcification, and anemia and iron metabolism in patients with heart and/or renal failure. We collaborate in order to study mechanisms that are associated in the outcome of CKD patients, such as vascular calcification and the red cell-iron axis. We use cell-cultures, animal models and human intervention studies, for our translational research program. On a therapeutic level, based on the assumption that the high incidence of cardiovascular disease is related to the retention of uremic toxins, we co-initiated the first prospective randomized multicenter trial, comparing two distinct renal replacement strategies, on-line hemodiafiltration and hemodialysis. The main study outcome has recently been published, further analyses are being performed and a follow-up study is being designed. Our concept of cardiorenal interaction creates a unique platform to study the pathophysiology behind the complications in renal and cardiac disorders. We study cardiorenal interaction and related metabolic pathophysiological mechanisms in newly developed animal experimental models, cell studies and multicenter intervention studies. This approach allows for delineation of mechanisms pivotal in both heart and renal failure and the development of relevant therapeutic approaches. A novel area of study in this respect is our interest in the molecular circadian clock that regulates appropriate timing of metabolic processes in almost all organs, including the heart and kidney. 105 106 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Present and Future Research Disturbances in the fibroblast growth factor 23 (FGF23)- klotho-vitamin D axis lead to vascular dysfunction, calcification and left ventricular hypertrophy and are associated with cardiovascular morbidity and mortality in CKD patients. In a consortium program the role of vitamin D, klotho and FGF23 on the handling of minerals and cardiovascular function and structure is studied. In prospective clinical studies the modifiability of both FGF23 and klotho is assessed. To further study the FGF23-Klotho hypothesis we have shifted the focus of our peritoneal dialysis research to the actions of vitamin D. As part of a 7th Marie Curie European framework grant we are studying the influence of active vitamin D on inflammation and peritoneal membrane function in peritoneal dialysis. Similarly, anemia and iron deficiency are strongly associated with cardiovascular outcomes in patients with heart and/or kidney failure. In our view these non-hemodynamic mechanisms are paramount in the deleterious interaction between the heart and the kidney. Although iron compounds are widely used some basic data and clinical hard endpoint studies are missing. The department has the Dutch lead for an international, multicenter, randomized study to investigate the comparative efficacy and safety of an intravenous iron compound. The molecular circadian clock regulates appropriate timing of metabolic processes in almost all organs, including the heart and kidney. Previously we have shown that in CKD a markedly disturbed circadian sleep-wake rhythm exists in conjunction with impaired secretion of melatonin. Now we are studying the effect of renal replacement therapy including renal transplantation on circadian rhythm and the molecular make-up of the peripheral clock. We are investigating quality of life and cardiovascular parameters related to circadian disturbances before and after the living donor renal transplantation procedure in both the kidney donor and acceptor. We also aim to connect, our previously published, circadian disturbances in CKD to molecular changes in the peripheral cell clock gene expression in CKD patients. The goal of the department of Nephrology is to further focus research on the cardiorenal interaction including diastolic dysfunction and on the two non-hemodynamic cardiorenal connectors that are currently being studied, the fibroblast growth factor 23 (FGF23)-klotho-vitamin D axis and the red cell-iron axis. With respect to arterial calcification, the role of vitamin K binding by phosphate binder therapy will be a subject of future studies. Since vitamin K deficiency leads to a deficiency of MGP, an important inhibitor of vascular calcification, this research line will complement the fibroblast growth factor 23 (FGF23)-klotho-vitamin D axis research that focuses more on vascular function and cellular trans differentiation, instead of calcification. Participants Project leaders Clinical Chemistry Peter Scheffer Tom Teerlink Internal Medicine Erik Serné Pediatrics Michiel Schreuder Joanna van Wijk MCBI Rob Beelen Nephrology Carlo Gaillard Muriel Grooteman Marc Vervloet Piet ter Wee Physiology Ed Eringa René Musters Geert-JanTangelder PhD students Aaltje Adema Annet Bouma Fenna van Breda Isabelle Chapdelaine Mireille Emans Karima Farhat Evelina Ferrantelli Tom Foster Claire den Hoedt Aegida Neradova Albert Mazairac Kaatje Le Poole Marije Russcher Andrea Stavenuiter Oanh Thang Melissa Verkaik Neelke van der Weerd Rik Westland Support staf Adry Bakker Diepenbroek Eelco Keuning Nanne Paauw Dennis Schooneman Marjon van Vliet Hiske Wellink Visiting Scientist Cecilia Giachelli Denis Fouque Gerard Friedlander Makoto Kuro-O Leon Schurgers Catherine Shanahan Myles Wolf Collaboration National UMCM, Maastricht Leon Schurgers UMCN, Nijmegen René Bindels Joost Hoenderop UMCG, Groningen Gerard Navis Jeroen Hillebrands UMCU, Utrecht Pieter Doevedans Marianne Verhaar MCA, Alkmaar Menso Nubé International Montreal, Canada Renée Lévesque Lyon, France Denis Fouque Paris, France Gerard Friedlander Aachen, Germany Vincent Brandenburg Milano, Italy Mario Cozzolino Barcelona, Spain Jordi Bover Stockholm, Sweden Tobias Larsson London, UK Catherine Shanahan Dallas, USA Makoto Kuro-O Miami, USA Myles Wolf Seattle, USA Cecilia Giachelli 107 108 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Nefrology and Cardiovascular Diseases 100 lowflux HD online HDF 80 survival (%) In hemodialysis (HD) patients the high incidence of cardiovascular disease is, at least partially, related to the retention of uremic toxins in the middle and large-middle molecular range. During hemodiafiltration clearance of such middle molecular weight substances is achieved by convection, while standard hemodialysis provides only small molecule clearance. Indeed, in observational studies treatments with hemodiafiltration was related to improved survival. In CONTRAST (the CONvective TRAnsport Study), the first prospective, randomized multicenter trial comparing hemodiafiltration with hemodialysis, patients were followed for more than 3 years. Disappointingly, all-cause mortality and a composite of fatal and non-fatal cardiovascular events were not influenced by treatment assignment (figure A). However, a reduction of all-cause mortality was observed in patients who received high volume hemodiafiltration (hazard ratio upper tertile [›21.95 liters/treatment] 0.62; 95% CI 0.41-0.93), even after correction for confounders and dialysis facility (figure B). As this finding results from an ‘on-treatment’ analysis, it might be explained by dose-targeting-bias (the ‘best’ patients achieving highest convection volumes). However, the effect remained after correction for a large number of confounders. Furthermore, the fact that a huge (up to 2-fold) difference in mean convection volumes existed between the different participating centers suggests that convection volumes were not the result of patient factors. A follow-up study is being designed to compare high volume hemodiafiltration to standard therapy in patients in which high volume hemodiafiltration is feasible. Also, intermediate endpoints are currently being analyzed, such as ESA resistance, cardiac dysfunction, and markers of atherosclerotic disease burden and vascular stiffness. Lastly, this well characterized and prospectively followed cohort of 715 chronic HD patient will be used to study the impact and course of specific biomarkers (e.g. hepcidin, markers of protein energy wasting and inflammation). A 60 40 20 0 B 0 1 2 3 4 time (years) 5 6 1,2 1,0 Hazard Ratio Cardiovascular outcome and renal replacement therapy Does dialysis treatment modality affect hard endpoints? Selected Publications 2010-2012 0,8 p=0.016 0,6 de Borst MH, Vervloet MG, ter Wee PM, Navis GJ. Cross Talk Between the ReninAngiotensin-Aldosterone System and Vitamin D-FGF-23-klotho in Chronic Kidney Disease. Journal of the American Society of Nephrology 2011; 22:1603-09. Braam B, Cupples WA, Joles JA, Gaillard CAJM. Systemic arterial and venous deter-minants of renal hemodynamics in congestive heart failure. Heart Failure Reviews 2011; 17:161-75. 0,4 0,2 0 LFHD low medium high online HDF Figure A: survival curve for time to death from any cause, based on life table analyses using 3 month time periods. HD= hemodialysis. HDF= hemodiafiltration Figure B: Risk of all-cause mortality by tertiles of achieved convection volume (liters per treatment) as compared to lowflux HD (LFHD); adjusted for determinants of mortality and center differences. Online HDF: low = <15.5 L, medium = 15.5-20.3 L, high= >20.3 L. Brandenburg VM, Vervloet MG, Marx N. The role of vitamin D in cardiovascular disease - from present evidence to future perspectives. Atherosclerosis 2012; 225:253-63. Grooteman MP, van den Dorpel MA, Bots ML, Penne EL, van der Weerd NC, Mazairac AH, den Hoedt CH, van der Tweel I, Lévesque R, Nubé MJ, ter Wee PM, Blankestijn PJ; CONTRAST Investigators. Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. Journal of the American Society of Nephrology 2012; 23:1087-96. Ronden RA, Houben AJ, Teerlink T, Bakker JA, Bierau J, Stehouwer CDA, de Leeuw PW, Kroon AA. Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency. American Journal of Physiology Renal Physiology 2012; 303:F149-56. Russcher M, Koch B, Nagtegaal E, van der Putten K, Ter Wee P, Gaillard CAJM. The role of melatonin treatment in chronic kidney disease. Frontiers in Bioscience 2012; 17:2644-56. Thang OH, Serné EH, Grooteman MP, Smulders YM, Ter Wee PM, Tangelder GJ, Nubé MJ. Capillary rarefaction in advanced chronic kidney disease is associated with high phosphorus and bicarbonate levels. Nephrology Dialysis and Transplantation 2011; 26:3529-36 Vervloet MG, van Ittersum FJ, Buttler R, Heijboer A, Blankenstein MA, ter Wee PM. Effects of dietary phopshate intake on fibroblast growth factor 23. Clinical Journal of American Society of Nephrology 2011; 6:383-89. van der Weerd NC, Grooteman MPC, Bots ML, van den Dorpel MA, den Hoedt CH, Mazairac AHA, Nube MJ, Penne EL, Gaillard CAJM, Wetzels JFM, Wiegerinck ET, Swinkels DW, Blankestijn PJ, ter Wee PM. Hepcidin-25 in Chronic Hemodialysis Patients Is Related to Residual Kidney Function and Not to Treatment with Erythropoiesis Stimulating Agents. Plos One 2012; 7:e39783. Westland R, Wijk JAE van, Schreuder MF. The reason why mother nature provided us with two kidneys: the risks of a congenital solitary functioning kidney. Nephrology Dialysis and Transplantation 2012; 27:2603-04. 109 110 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Group Acute and Perioperative Care ‘The acute and perioperative setting requires intensive collaboration between involved specialties, as most patients are treated by a multidisciplinary team’ Focus The acute care for patients with life-threatening conditions and perioperative and postoperative management of surgical patients requires an integrative knowledge of cardiovascular physiology and the function of vital organs. In particular, the anesthetic regime, surgery, fluid resuscitation, shock, bleeding and metabolic alterations induce a generalized stress response that may contribute to deterioration of patient outcome. In the research line Acute & Perioperative Care we focus on novel strategies for the diagnosis, prevention and treatment of complications due to tissue hypoperfusion in the acute and perioperative setting. We particularly emphasize the interaction between tissue hypoperfusion and ischemia/reperfusion injury, hemostatic abnormalities and vascular dysfunction by exploring underlying mechanisms using a translational approach. Collaboration Research in the acute and perioperative setting requires close collaboration between involved specialties, as most patients are treated by a multidisciplinary team. Therefore, our research lines adhere to existing chains of care in order to achieve a high level of agreement between our scientific interests and routine clinical practice. The Acute & Perioperative Care research group involves activities of the departments of Anesthesiology, Cardio-Thoracic Surgery, Emergency Medicine, General Surgery, Intensive Care Medicine and Physiology. Unique We are unique in our multidisciplinary research approach that translates physiological research into clinical practice, and the fact that our research lines are closely related to the clinical chain of care. 111 112 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Present and Future Research The department of Anesthesiology mainly focuses on acute and perioperative disturbances in organ perfusion, with specific attention to ischemia-reperfusion injury, hypoperfusion-related shock, microcirculatory dysfunction, hemostatic alterations and endothelial activation. The concept of tissue hypoperfusioninduced abnormalities in the coagulation cascade and micro-circulation can be transferred to different patient categories, including surgical and trauma patients, and patients with cardiopulmonary arrest. However, as treatment strategies are not easily generalized among distinct patient categories, more insight is required into the exact mechanisms that lead to tissue hypoperfusion and damage in different clinical settings. Our research areas involve close collaboration with other ICaR-VU specialties. Most of our research is translational in nature and consists of clinical and parallel preclinical studies. In the department of Cardio-Thoracic Surgery, most studies are focused on perioperative blood management and the effect of cardiopulmonary bypass on (impaired) hemostasis. In close collaboration with the department of Pathology we additionally investigate the relationship between valve disease and inflammation. Scientific research in the Emergency Department has blossomed over the last few years and mainly focuses on three topics: hemodynamic monitoring in the emergency setting, delirium prevention in the emergency setting and improvement of patient flow. Our investigations contribute to improvement of healthcare strategies in the acute setting. The research in the department of Intensive Care Medicine (ICU) is comprised of clinical trials and investigator-initiated research. The main areas of interest are hypothermia, infection diseases, sepsis, nutrition & metabolism and pharmacokinetics. We are aiming to build a preclinical research line to allow from-bed-to-bench and from–bench-to-bed investigations. In close collaboration with the departments of Anesthesiology and Cardiology a translational research program has been initiated that includes studies in critically ill patients, in animal models of critical illness, as well as molecular and biochemical studies of patient samples. One of the research lines in the department of Physiology is aiming to identify the mechanisms that underlie the remarkable sensitivity of the diaphragm muscle to mechanical unloading during mechanical ventilation, which has recently been shown by our group. This diaphragm weakness is now considered a major contributor to weaning failure in the ICU and has been suggested to be contributing to postoperative pulmonary complications. We use unique diaphragm biopsies from mechanically ventilated patients in combination with novel KO mouse models to identify the pathways that trigger these rapid changes in the diaphragm following unloading. In our research we specifically focus on the role of titin, a giant mechanosensing protein. These recent studies on diaphragm dysfunction illustrate the interaction between vascular and muscle studies within the ICaR-VU. Participants Project leaders Anesthesiology Christa Boer Arthur Bouwman Stephan Loer Patrick Schober Lothar Schwarte Cardio-thoracic Surgery Alexander Vonk Hans Niessen Emergency Medicine Jaap Bonjer Leo Geeraedts Prabath Nanayakkara Intensive Care Medicine Albertus Beishuizen Armand Girbes Johan Groeneveld Angelique Spoelstra Monique de Waard Pediatric Intensive Care Dick Markhorst Pediatric Surgery Hugo Heij Physiology Geerten van Nieuw Amerongen Coen Ottenheijm Ger Stienen PhD students Anesthesiology Chantal Boly Bas Bossers Charissa van den Brom Carolien Bulte Simone Dekker Gaby Franschman Sander Keet Nick Koning Michael Meesters Victor Viersen Cardio-thoracic surgery Dennis Veerhoek Daan van Velzen Emergency Medicine Nadia Alam Mahi Dzelili Durk Linzel Edmee Schrijver Irene Vegting General Surgery Koen Hartemink Intensive Care Medicine Evelien de Jong Jan Krul Physiology Jurjan Aman Melanie van der Heiden Pleuni Hooijman Lonneke Smeding Support staff Anesthesiology Rob van den Akker Silwana Arensma Intensive Care Medicine Erna Alberts, Ingrid van den Hull Physiology Jan van Bezu Collaboration National AMC, Amsterdam Marcus Hollmann Janneke Horn Can Ince Benedict Preckel Rienk Nieuwland Marcus Schultz UMCN, Nijmegen Nico Hoogerwerf Lizzy van Pampus Pieter Vos EMC, Rotterdam Frank Leebeek Dick Rijken WFG, Hoorn Jens Peter Hering RKZ, Beverwijk David Mackie UMCG, Groningen Martin Kneyber Thomas Scheeren MUMC, Maastricht Hans Vink International Sydney, Australia Nigel Clarke Angers, France Christophe Baufreton Daniel Henrion Berlin, Germany Michael Gotthardt Dusseldorf, Germany Artur Fournell Olaf Picker Ingo Schwartges Frankfurt, Germany Kaij Zacharowski Rome, Italy Salvatore Disomma Tokyo, Japan Hiroyuki Sorimachi London, UK Louella Vaughan Boston, USA Alan Beggs Joseph Brain James Butler Jeffrey Fredberg Chicago, USA Stephan Huveneers Thomas Irving Richard Minshall Heidelberg, Germany Siegfried Labeit Detroit, USA Richard Novak Rochester, USA Gary Sieck 113 114 P r o gr e s s R ep o r t 2010 > 2012 I C aR -V U / T h em e V Research Highlight Peri Operative Patients Endothelial barrier function and microcirculatory perfusion during extracorporeal circulation Selected Publications 2010-2012 Aman J, van Bezu J, Damanafshan A, Huveneers S, Eringa EC, Vogel SM, Groeneveld ABJ, Vonk Noordegraaf A, van Hinsbergh VWM, van Nieuw Amerongen GP. Effective treatment of edema and endothelial barrier dysfunction with imatinib. Circulation 2012; 126:2728-38. A Data from Nick Koning (Anesthesiology), Christa Boer (Anesthesiology), Geerten van Nieuw-Amerongen (Physiology), Martijn Overmars (Anesthesiology/ Physiology), Alexander Vonk (Cardio-Thoracic Surgery). B Perfused vessel density 8 C Atasever B, van der Kuil M, Boer C, Vonk A, Schwarte L, Girbes AR, Ince C, Beishuizen A, Groeneveld ABJ. Red blood cell transfusion compared with gelatin solution and no infusion after cardiac surgery: effect on microvascular perfusion, vascular density, hemoglobin, and oxygen saturation. Transfusion 2012; 52:2452-58. 6 4 2 CPB + 60’ CPB + 10’ 60’ CPB 10’ CPB 30’ CPB 0 Pre-CPB Perfused vessel density (vessels / recording) 10 1800 Resistance (ohm) In a rat model for cardiopulmonary bypass (CPB) we have shown that extracorporeal circulation is associated with reduced microcirculatory perfusion through a decrease in perfused vascular density. This observation is paralleled by disturbed tissue oxygenation. Subsequently, we investigated the effects of pulsatile flow on these microcirculatory alterations and have shown that restoration of pulsatility during extracorporeal circulation preserves microcirculatory perfusion during surgery, as well as improves postoperative microvascular recovery, irrespective of system hemodynamics. Patient and animal studies have further shown that hemodilution and low hematocrit, which are considered to be important mediators of microcirculatory perfusion abnormalities, could only partially explain the observed reduction in microvascular perfusion during extracorporeal circulation. Furthermore, exposure to extracorporeal circulation was associated with increased heterogeneity of microcirculatory flow. We also exposed endothelial cell cultures to plasma from patients subjected to cardiopulmonary bypass and assessed the barrier function of these cells by Electrical Cell-substrate Impedance Sensing (ECIS). The figure C shows a typical example of the overall resistance as a measure of barrier function of endothelial cells exposed to plasma obtained prior to CPB (Pre-CPB), following CPB (Post-CPB) and upon admission to the ICU. The addition of plasma induced a transient rise in resistance, followed by a steady state. The steady-state values were further used to define the effect of cardiopulmonary bypass on endothelial barrier function. Exposure to cardiopulmonary bypass reduced the overall resistance of endothelial cells as measured by ECIS. Furthermore, we could not attribute this loss of resistance to the hemodilution component that is associated with extracorporeal circulation. 1600 1400 Pre-CPB Post-CPB ICU 1200 1000 800 0 A 1 B 2 Time (hours) 3 4 Figure A: Example of the sublingual microcirculation in a patient undergoing surgery. Figure B: Microcirculatory perfusion disturbances in a rat CPB model can only partially be explained by hemodilution. Data represent mean ± SD. Circles: hemodilution group. Squares: CPB group. Figure C: Plasma obtained following CPB (post-CPB; ICU) decreases endothelial barrier function when compared to pre-CPB values. Biere SS, van Berge Henegouwen MI, Maas KW, Bonavina L, Rosman C, Garcia JR, Gisbertz SS, Klinkenbijl JH, Hollmann MW, de Lange ES, Bonjer HJ, van der Peet DL, Cuesta MA. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. The Lancet 2012; 379:1887-92. Bulte CSE, Slikkerveer J, Meijer RI, Gort D, Kamp O, Loer SA, de Marchi SF, Vogel R, Boer C, Bouwman RA. Contrast-enhanced ultrasound for myocardial perfusion imaging. Anesthesia Analgesia 2012; 114:938-45. Trof RJ, Beishuizen A, Cornet AD, de Wit RJ, Girbes AR, Groeneveld AB. Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock. Critical Care Medicine 2012; 40:1177-85. Franschman G, Boer C, Andriessen TM, van der Naalt J, Horn J, Haitsma I, Jacobs B, Vos PE. Multicenter evaluation of the course of coagulopathy in patients with isolated traumatic brain injury: relation to CT characteristics and outcome. Journal of Neurotrauma 2012; 29:128-36. Viersen VA, Greuters S, Korfage AR, van der Rijst C, Van Bochove V, Nanayakkara PWB, Vandewalle E, Boer C. Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion. Resuscitation 2012; 83:1451-55. Koning NJ, Vonk AB, van Barneveld LJ, Beishuizen A, Atasever B, van den Brom CE, Boer C. Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics. Journal of Applied Physiology 2012; 112:1727-34. Krishnan R, Klumpers DD, Park CY, Rajendran K, Trepat X, van Bezu J, van Hinsbergh VWM, Carman CV, Brain JD, Fredberg JJ, Butler JP, van Nieuw-Amerongen GP. Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces. American Journal of Physiology-Cell Physiology 2011; 300: C146-54. Welvaart WN, Paul MA, Stienen GJM, van Hees HW, Loer SA, Bouwman RA, Niessen HWM, de Man FS, Witt CC, Granzier H, Vonk-Noordegraaf A, Ottenheijm CAC. Selective diaphragm muscle weakness after contractile inactivity during thoracic surgery. Annals of Surgery 2011; 254:1044-49. 115 P r o gr e s s R ep o r t 2010 / 2011 117 Those who matter It is the people of the Institute who are at the heart of the research accomplishments. We are proud to introduce them and to present their recent achievements and plans for the future. I C A R -V U m c 117 I C A R -V U m c 119 VU University Medical Center ICaR-VU