C O E U R A N N U A L R E P O R T C O E U R ANNUAL REPORT

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1 C O E U R A N N U A L R E P O R T C O E U R ANNUAL REPORT

2 COEUR ANNUAL REPORT 2007 Erasmus MC Rotterdam The Netherlands

3 Contents Preface 5 Mission 6 Organization 7 Input of personnel and funds 8 Grants and Awards 10 Education 15 Introduction 15 PhD education program 16 PhD Courses 16 Research Seminars 17 Other educational activities 18 MD Elective program 19 Research themes 20 Theme 1 Cardiovascular Biology and Pharmacology 21 Theme 2 Vascular Medicine, Hemostasis and Stroke 34 Theme 3 Image-guided Cardiovascular Medicine 44 Theme 4 Surgical- Interventional and Device Therapy of Cardiovascular Disease 58 Theme 5 Congenital Heart Disease 68 Theme 6 Neurovascular and Cardiovascular Clinical Epidemiology 76 Doctoral degrees 84 Publications 94 Citation Classics Addendum Colofon 139

4 Preface Cardiovascular Research School Erasmus University Rotterdam (COEUR) Participating institutes Anesthesiology Biochemistry Cardiology Cardiothoracic Surgery Hematology Intensive Care Medicine Internal Medicine (Vascular Medicine) Medical Informatics Neurology (Vascular Neurology) Pediatric Cardiology Pharmacology Radiology Surgery (Vascular Surgery) Board representatives Prof dr Don Poldermans Prof dr Jos MJ Lamers Prof dr Maarten L Simoons, chairman Prof dr Ad JJC Bogers Dr Frank WG Leebeek Prof dr Jan Bakker Dr Anton H van den Meiracker Prof dr Wiro J Niessen Prof dr Peter J Koudstaal Prof dr Wim A Helbing Prof dr AH Jan Danser Prof dr Gabriel J Krestin Prof dr Hence JM Verhagen Prof dr Dirk J Duncker, scientific director Dr Jaap W Deckers, secretary Scientific Advisory Board Prof dr Jos RTC Roelandt, chairman Prof dr Jan HJ Hoeijmakers, Medical Genetics Centre South-West Netherlands Prof dr Albert Hofman, Netherlands Institute for Health Sciences Prof dr MG Myriam Hunink, Erasmus MC Research Committee Prof dr Huib AP Pols, Dean, Erasmus Medical School Prof dr Harry AJ Struijker Boudier, Cardiovasculaire Research School Maastricht Amsterdam Prof dr Wiek H van Gilst, Interuniversity Cardiology Institute Utrecht Preface The year 2007 was - again a good year at COEUR. Scientific output remained high with 450 articles registered in Pubmed, and 30 theses completed in A large part of this output was the result of close collaboration between the different departments, and also with others. Ultimo 2007, a total of 146 PhD candidates were registered. Overall, time from PhD initiation until thesis completion and defence continues to be in the order of five years, although large variation exists between individual projects also saw some personnel changes: Dr Rob Krams moved from Rotterdam via Amsterdam to the UK, while Dr Marc van Sambeek left ErasmusMC to pursue his career at a large nonacademic hospital in Eindhoven. Dr Hence Verhagen joined COEUR as new professor of vascular surgery. We welcome him and wish him success with this task. The education program was continued with a similar format. The attendance of the various courses and research seminars by PhD candidates increased. However, the quantitative assessment of the education received by individual students in other words, how much education do they actually receive in their total PhD trajectory - is not satisfactory, and this is an item that should receive more attention in the coming years. Another issue that we have placed on our wish list for 2008 is a larger number of external, foreign speakers at the Research Seminars. To this end, we have created special funds. Another important activity for 2008 will be preparations for the renewed accreditation (in 2009) for our school by the Royal Netherlands Academy of Arts and Sciences (KNAW). You will appreciate that we have slightly adapted the format of this annual report, and have given more emphasis to the specific scientific themes as well as to individual projects. In this manner, we hope to better highlight the various activities within COEUR and, at the same time, to be more appreciative of the individual contributions of the researchers. We hope that this goal has indeed been achieved and that the information described in this yearbook will be of value to the reader. Jaap W Deckers, secretary Dirk J Duncker, scientific director Maarten L Simoons, chairman Accredited (2003) by the Royal Netherlands Academy of Arts and Sciences 5

5 Mission Organization The mission of COEUR: The mission of COEUR is two-fold: To promote outstanding basic, translational and clinical cardiovascular research, aimed at improving the understanding of the pathophysiology as well as the prognosis and quality of life of patients with cardiovascular disease To train future national and international leaders in the cardiovascular field through a systematic scientific education and training program To achieve this mission, COEUR conducts innovative research and provides high quality training in the cardiovascular research field. The research programs include a wide spectrum of disciplines, including cardiovascular biology and pharmacology, biomedical engineering and informatics, clinical science, clinical epidemiology and health care research. Training involves an individual training program and includes monthly research seminars and an all-encompassing cardiovascular science core curriculum. COEUR recognizes the need for an integrative, multidisciplinary, translational approach and encourages national and international collaboration. COEUR Scientific Advisory Board Graduate School Erasmus MC COEUR Board 13 COEUR departments Anesthesiology Biochemistry Cardiology Cardiothoracic Surgery Hematology Intensive Care Medicine Internal Medicine Biomedical Imaging Executive Committee Neurology Pediatric Cardiology Scientific Director Pharmacology Radiology Scientific Secretariat Vascular Surgery Theme 1 Theme 2 Theme 3 Theme 4 Theme 5 Theme 6 6 7

6 Input of personnel and funds a a a a a a a a a a a a a a a a a a a a Personnel Funding Ultimo 2007, the research school listed 146 PhD candidates. Details of the project teams and of the individual projects are given elsewhere in this report. Project leaders and staff also amounted to about 150 men and women. Some personnel changes occurred in the course of the past year: Dr Krams went to work in London, and Dr Marc van Sambeek switched from the department of Surgery at ErasmusMC to the Catharina Hospital in Eindhoven. Dr Hence Verhagen was appointed Professor of Vascular Surgery. The number of Departments participating in COEUR still amount to 13. Lastly, Ms Linda Smit, who assisted the secretariat for some years, has left the COEUR secretariat. The distribution of the funding sources of the PhD candidates is given in the figure. About 55% of the projects are funded externally. The education given by COEUR is partially funded by support from ErasmusMC, the so called O&O en van Rijn funds. In addition, there is financial support from the Master of Science program. Lastly, the departments participating in COEUR make regular contributions. In December 2007, special funding was created to invite more foreign speakers at the monthly research seminars. Charity, industry ErasmusMC CIN, NWO, KNAW, STW Funding source of COEUR PhD students (n=146) 8 9

7 Grants and Awards a a a a a a a a a a a a a a a a a a a a A selection of grants and awards is presented below. Nathalie van der Velde The Editors of the British Journal of Clinical Pharmacology awarded the 2007 BJCP Prize to Nathalie van der Velde, for her manuscript in that journal entitled Risk of falls after withdrawall of fall-risk-increasing drugs: a prospective cohort study. Co-authors were Bruno Stricker, Huib Pols and Tischa van der Cammen. The article was published under the following headings: British Journal of Clinical Pharmacology 63(2): Pim J de Feyter The research program Modification of cardiovascular risk and management with MSCT coronary imaging in high risk asymptomatic individuals by professor Pim de Feyter was funded by the Dutch Heart Foundation. The program investigates the value of MSCT for this purpose. The predictive value of traditional risk factors may be increased by direct non-invasive multislice computed tomography. MSCT coronary imaging identifies individual without or with varying degrees of sub clinical atherosclerosis and this may result in a more precise reclassification of high-risk subjects based on traditional risk factors into low, medium or high or very high risk groups. This research program aims to demonstrate that non-invasive CT coronary imaging is efficacious to remodify risk in asymptomatic subjects who are at high risk based on traditional risk factors. Hence JM Verhagen Professor Verhagen was named Principal Investigator of a clinical trial studying a new generation of endografts for the endovascular treatment of abdominal aneurysms. The new stentgraft - called Endurant - is specifically designed to treat challenging anatomy like short and angulated necks and tortuous iliac arteries. This multicentre, international pre-ce mark trial will involve about 100 patients. Kayi Chan During the October meetings of the Netherlands Federation for Innovative Drug Research, Kayi Chan of the Division of Pharmacology received the 2nd prize for the best poster presentation. Her presentation was entitled Investigation of the role of glutamate receptors in migraine using intravital microscopy. The Federation is the integrative platform for innovative drug research in the Netherlands and promotes its mission by enhancing existing initiatives and by actively signaling and encouraging new developments in drug research. Wim Helbing The Department of Paediatric Cardiology, under the leadership of professor Wim Helbing, received financial support by the Dutch Heart Foundation for the project Early diagnosis of right ventricular dysfunction in patients operated for tetralogy of Fallot. A multicenter study with serial follow-up. Danielle Robbers-Visser For her presentation at the occasion of the meetings of the Society of Cardiovascular Magnetic Resonance Imaging, held in Rome, in February 2007, Danielle Robbers-Visser, medical doctor at the Department of Paediatric Cardiology, received the Young Investigator Award. Her presentation was entitled Cardiac MRI combined with low-dose dobutamine stress reveals an abnormal stress response in children and young adults after Fontan operation at young age (J Cardiovasc Magn Res 2007;9:115). Ewout Jan van den Bos In December 2007, Ewout Jan received the so called Hamburgerprijs. This remarkable prize was awarded by the Dutch Society of Physiology to honour the best thesis publised in the year Peter J Koudstaal For exceptional teaching skills, professor Peter Koudstaal received the Vaandrager award. The prize was endowed by the Dutch Society of Neurology Residents. Tischa van der Cammen The research project The [cost]effectiveness of medication withdrawal in older fallers: a randomized controlled trial at the Accident and Emergency Department was funded by the Dutch Healthcare Organization (Zorg Onderzoek Nederland Medische Wetenschappen). The sum associated with the funding ( 400,000) will allow Dr van der Cammen, associate Professor of Geriatric Medicine, to make significant inroads into the prevention and treatment of this frequent but potentially dangerous clinical syndrome

8 Ton van der Steen The Technology Foundation STW is embedded within the Dutch research council ZonMw, and supports research that meets two criteria: it must have high scientific quality and at the same time it must be directed towards practical application. Tenured university staff can apply for a research grant, provided that their proposal includes utilization: the embedding of the results in society. The STW actively supports utilization by involving market parties in the users committee. On October 4, the Foundation awarded the prestigious Simon Stevin Meesterprijs to professor Ton van der Steen, Director of the Department of Biomedical Engineering. The prize enables Ton van der Steen to spend 500,000 Euro on his scientific explorations. The price is named after Simon Stevin, the first ( ) and foremost Dutch engineer. As an engineer, Stevin contributed enourmously to the famous Dutch watersystems, but his achievements in the dissemination of knowledge are perhaps even more remarkable. Patrick Serruys The Arrigo Recordati International Prize for Scientific Research Prize was awarded to the scientist for his contribution to the research in the field of Ischemic Heart Disease. The ceremony took place in Villa D Este, Cernobbio (Lake of Como) during the 17th European Meeting on Hypertension The Arrigo Recordati International Prize for scientific research was established in 2000 in memory of the Italian pharmaceutical entrepreneur Arrigo Recordati. The 2007 edition of the Prize was open to scientists of all nationalities who worked in institutional settings and were not affiliated with a pharmaceutical company. International societies and organizations specializing in the areas of cardiology and internal medicine were invited to nominate candidates that they felt deserved the Lifetime Achievement Award in Ischemic Heart Disease. Professor Bassand, on behalf of the Jury, officially awarded the winner with the following motivation: The Recordati Prize recognizes Patrick W. Serruys for his outstanding achievements in the field of interventional cardiology and ischemic heart disease. On December 3, Patrick Serruys received the prestigious ICI Achievement Award 2007 for his life-long accomplishment in the field of interventional Cardiology. The price was awarded by Shimon Peres, president of Israel, during the meetings Cardiovascular Interventions held in that country. Frank Leebeek Dr Leebeek obtained funding from the Dutch Heart Foundation to the amount of 250,000 to investigate the role of genetic variation in Von Willebrand Factor as well as other genes. He and his group will study the role of these abnormalities on the pathogenesis of arterial thrombosis. In addition, they will investigate how genetic variation in ADAMTS13 and TSP-1 affects VWF concentration and function, and their influence on the relationship between VWF and arterial thrombosis

9 Education Jan Danser The department of Pharmacology received a grant from the Dutch Heart Foundation Association for their project Renin inhibition and (pro)renin receptor blockade in spontaneously hypertensive rats: comparison with other renin-angiotensin system blockers. Eric Sijbrands In 2007, Dr Sybrands was chosen Best Reviewer by the Dutch Heart Foundation. He was also named Dutch representative in the working group of the European Atherosclerosis Society for cardiovascular disease guidelines. Aart Bootsma Dr Bootsma obtained funding by the Dutch Medical Council (ZonMW) for his project Does early psychological empowerment training improve long-term self-management and metabolic control in diabetes patients starting on insuline therapy. Wim van der Giessen and Ton van den Meiracker The researchers obtained funding to study Microvascular dysfunction in diabetes mellitus type 2 and its relation to metabolic control. Dirk Duncker and Wim van der Giessen Both researchers were able to secure considerable funding from various sources. Profs Duncker and Hoeijmakers obtained grants from ErasmusMC as well as the Dutch Heart Foundation for two projects, entitled Cardiovascular dysfunction in aging, and Cardiovascular aging: role of genomic instability, respectively. Together with other partners within the Medical Delta / Health Science & Technology consortium, Dirk J. Duncker and Wim van der Giessen received a 2.6 million euro grant from the so called Pieken in de Delta programme for the project entitled: Tracking and Targetting in Oncology and Cardiology. Aad van der Lugt It is obvious from the current list of publications that the department of Radiology has seen a lot of activity this year. From this department, Dr van der Lugt obtained funding from the Dutch Heart Foundation for his project Serial CT Angiography of atherosclerotic carotid plaque: Determinants and prognosis of change in volume, position and morphology. Introduction COEUR offers PhD candidates a research and education program tailored towards their individual requirements. This program aims to develop their knowledge and skills such that they will become independent researchers, and should additionally provide them with a sound and broad basis for their future professional career. PhD candidates fill out an individual PhD Training Plan together with their supervisor. Ultimo 2007, a total of 148 PhD candidates were registered. Of these, 30 were also listed as clinician. This latter group mainly consists of medical specialists who perform their research in addition to their clinical activities. The activities of the other PhD candidates are usually entirely research oriented and their PhD trajectory typically is the beginning of their professional career. At the end of 2007, 106 of the young PhD candidates had submitted their individual training program. PhD education program COEUR organizes approximately 10 courses in a two-year cycle format. Most courses comprise two or three consecutive days and require a similar workload in self-study. Each course is concluded with an examination, a certificategiving ceremony and an evaluation. European Credit Transfer System (ECTS) credit is 1.5 points per course. PhD candidates are expected to attend at least six COEUR courses during their PhD trajectory and, additionally, COEUR seminars (credit: 2 ECTS points per 5 seminars), symposia and other lectures. Individual PhD candidates will thus be able to obtain at least 20 ECTS points (of the required 30 ECTS points) by following the COEUR education program during a four year period. In addition to the specific COEUR PhD education program, Erasmus MC offers a set of general courses. These courses are organized centrally, cover topics that are relevant to a large group of PhD candidates, and train general knowledge and basic academic skills. Of course, PhD candidates from COEUR can also attend courses given by other Erasmus MC research schools or courses given elsewhere in the Netherlands or abroad. As from now on, PhD candidates are required to provide details of their education ( portfolio ) in their thesis. Since 2006, monitoring of the actual PhD training program has been given higher priority in the form of regular, yearly, meetings with the PhD s. These group meetings were used to update the individual education plans and to stimulate participation in the various education opportunities. Fortunately, these efforts have paid off: participation in the various courses was considerably higher than in previous years. However, monitoring of the actual education progress of individual PhD candidates is time consuming and efforts will be intensified in the coming years to make this process for both parties students as well as secretariat more efficient

10 PhD Courses The curriculum of 2007 comprised the following courses: March 23, 2007 COEUR workshop: Prophylaxis of sudden death Coordinator: Prof Luc JLM Jordaens (Cardiology) Number of participants (PhD candidates): 15 June 7 and 8, 2007 Molecular biology in atherosclerosis and cardiovascular research Coordinators: Dr Rini de Crom (Vascular Surgery/ Cell Biology) and dr Eric J Duckers (Cardiology) Number of participants (PhD candidates): 31 October 11 and 12, 2007 Cardiovascular Medicine Coordinators: Dr Frank WG Leebeek (Hematology) and dr Ton H van den Meiracker (Internal Medicine) Number of participants (PhD candidates): 18 October 18 and 19, 2007 Pathophysiology of Ischemic Heart Disease Coordinators: Prof Wim J van der Giessen and prof Dirk J Duncker (Cardiology) Number of participants (PhD candidates): 21 November 29 and 30, 2007 Cardiovascular Pharmacology Coordinators: Prof Jan Danser and dr Antoinette Maassen van den Brink (both Pharmacology) Number of participants (PhD candidates): 17 PhD-training course Cardiac Function and Adaptation, Thrombosis and Haemostasis and Vascular Biology. October 8-12, 2007 The venue of the course was Papendal, near Arnhem. The courses are organized under auspices of and with financial support from the Netherlands Heart Foundation. The courses are an integral part of the PhDtraining offered by the Dutch Cardiovascular Research Institutes including COEUR. The three courses are taught simultaneously, meaning that each student can participate in only one of the three courses each year. An important aspect of the courses is the interaction between PhD students from different Research Institutes. To this end, assignments are discussed in small groups and social activities are planned during the evenings. Participants also present a poster of their own research project. Research Seminars COEUR continued its monthly series of research seminars. Topics, organizers and attendees in 2007 were as follows: February 2, 2007 Cardiac Hypertrophy and Cardiomyopathies Organisers FJ ten Cate (Cardiology), D Dooijes (Clinical Genetics) Speakers: FJ ten Cate, M Michels, J Hoedemaekers, J Danser, J van der Velden, D Dooijes Number of participants: 45 March 30, 2007 Genetics of Cardiovascular Disease Organisers: E Duckers (Cardiology), E Sijbrands (Vascular Medicine), LJLM Jordaens (Cardiology) Speakers: J Res, L Jordaens, T Smith, A Wilde, M Yazdanpanah, J Houtgraaf Number of participants: 39 April 13, 2007 Novel Strategies for Organ Protection against Ischemia Organisers: PJ Koudstaal (Neurology), D Duncker (Cardiology) Speakers: D Duncker, O Manintveld, R de Bruin, W Dik, P Koudstaal, H den Hertog Number of participants: 30 May 11, 2007 Cardiovascular Imaging Organisers: PJ de Feyter (Cardiology, Radiology), WJ Niessen (Biomedical Imaging) Speakers: B Meijboom, N Mollet, F Pugliese, R Manniesing, M Schaap Number of participants: 32 Juni 15, 2007 Diabetes Mellitus Organisers: WJ van der Giessen (Cardiology), AH Bootsma (Vascular Medicine), JW Deckers (Cardiology) Speakers: M van den Heuvel, H van Beusekom, E de Koning, M Yazdanpanah, A Dehgan Number of participants: 20 November 16, 2007 Hemostasis and arterial thrombosis at young age Organisers: MPM de Maat (Hematology), FWG Leebeek (Hematology) Speakers: F Leebeek, A Canas Guimares, T Bongers, L de Lau, D Dippel, M van Schie, G Rudez Number of participants: 30 December 14, 2007 Cardiopulmonary circulation and RV function Organisers: D Gommers (Anesthesiology), D Merkus (Cardiology) Speakers: I Reiss, M Faber, D Dos Reis Miranda, V de Beer, T Yoong Gan Number of participants:

11 Other educational activities Shear Stress Symposium 19 and 20 February, 2007 The symposium entitled: Biomechanics in Cardiovascular Disease: Shear Stress in Vascular Biology was held for the second time. The program covered several aspects of vascular biology related to shear stress, including vascular adaptation, the vulnerable plaque, endothelial progenitor cells, stroke and mechanotransduction. Sessions featured international renowed scientists, with technical as well as with biological/clinical expertise. The Rotterdam Hilton hotel was the venue. Over 150 participants with very different professional background attended and took part in lively discussions. Hemodyn Satellite Symposium April 20, 2007 Immediately following the 2nd symposium on Biomechanics in Cardiovascular Disease, a satellite symposium was held at which the highlights of the research project Hemodyn were presented. The goal of Hemodyn was to improve diagnosis and treatment by means of patient specific hemodynamic modelling. International Symposium Cardiology and Vascular Medicine Update and Perspective May 6-9, 2007 The venue for the meeting was De Doelen in Rotterdam. The third of a series annual symposia provided an overview of cardiology and vascular medicine. The meeting was organised by the Thoraxcenter and ErasmusMC in collaboration with the European Society of Cardiology, the COR Foundation and COEUR. Thirty experts (mainly European) presented lectures on vascular medicine, preventive cardiology, structural heart disease, acute coronary syndromes and interventional cardiology. They focussed on new scientific results, and their implications for the practice of cardiology and cardiovascular medicine, recent guidelines and scientific developments, which may impact practice in the near future. The meeting was attended by more than 400 participants. Information market for PhD candidates As previously, and in cooperation with ErasmusMC, the combined ErasmusMC PhD s and the other (local) Research Schools, COEUR participated in the yearly PhD information market, which took place on May 24, The Research Schools provided the students with information of their institutes. Presentations and workshops were given on practical PhD issues including ethics and medical communication and writing. MD elective program The course Introduction into methodologies and measurements that includes an introduction to ECG and echocardiography as well as haemostatic and bleeding disorders was given to 30 excellent 2nd year medical students in the months February and November

12 Research a a a a a a a a a a a a a a a a a a a a Research Themes COEUR has six different research themes. Details and short descriptions of each theme are given on the next pages. Summaries are given below: 1. Cardiovascular Biology and Pharmacology Molecular basis, pathophysiology and therapy of obstructive coronary artery disease, cardiac and coronary remodelling and heart failure 2. Vascular Medicine, Hemostasis and Stroke The clinical complement to the previous theme. Cardiovascular genetics, blood pressure regulation and vascular medicine, thrombotic and bleeding disorders, acute and chronic cardiovascular disease 3. Image-guided Cardiovascular Medicine Fundamental and clinical research of novel diagnostic imaging modalities 4. Surgical,- Interventional and Device Therapy of Cardiovascular Disease Clinical application and implementation of new diagnostic and therapeutic techniques. Local drug delivery, cell therapy, vascular interventions and other device therapy 5. Congenital Heart Disease Small but important theme focussing on major structural congenital cardiac abnormalities and their management 6. Neurovascular and Cardiovascular Clinical Epidemiology Risk modelling, rational predictive thinking and implementation of appropriate diagnostic and therapeutic measures across a wide range of clinical cardiovascular syndromes and procedures. Although adherence to 6 months of clopidogrel in DES-treated patients seems crucial in preventing stent thrombotic events, dedicated large-scale randomized trials are needed to settle the pros and cons of prolonged dual antiplatelet therapy. Circulation 2007;116: Theme 1 Cardiovascular Biology and Pharmacology Program Code: EMC COEUR Coordinators: AHJ Danser, DJGM Duncker, DAMPJ Gommers Theme 1 focuses on the biology and physiology of the normal healthy cardiovascular system, and the molecular basis, patho-physiology and (pharmaco-) therapy of cardiovascular and circulatory disease. The theme covers a wide range of research projects, pertaining to hypertension, migraine, circulatory aspects of general anaesthesia, mechanical ventilation, and of critical care medicine, and several aspects of ischemic heart disease, including atherosclerosis, myocardial infarction, cardiac remodelling and heart failure. Theme 1 encompasses a total of 12 research projects with 31 PhD students. Projects are characterized by a multidisciplinary approach with a strong emphasis on translational research (with several researchers operating at the interface of basic and clinical research), and by the use of state of the art in vivo and in vitro techniques, ranging from molecular and biochemical assays to intact animal models and humans. Consequently, projects within Theme 1 are based on strong collaborations between scientists, both junior and senior, with highly different backgrounds, not only extending beyond the boundaries of individual departments, but also beyond individual COEUR Themes, and even beyond those of the COEUR Research School. Last but not least, several project leaders are actively involved in medical and scientific education, including the medical core curriculum and elective courses, the Research Masters, as well as in the organization of 4 (out of the 10) PhD courses

13 a a a a a a a a a a a a Molecular regulation of vasculogenesis in development and ischemia Mouse genomics and Zebrafish reverse genetics PhD candidates Frank Bos (r) and Robert Herpers (l) Hubrecht Institute and ErasmusMC Vasculogenesis is de novo synthesis of blood vessels through differentiation of angioblast and/ or progenitor cells and later coalescence of endothelial cells. It involves extensive migration of endothelial progenitor cells from their point of origin to the site of vessel formation. The onset of new vessels that arise from already existing vessels is called angiogenesis. These processes have relevance to both embryogenesis and medicine. In this project we combine the strength of two animal models: the mouse and zebrafish. In order gain insight in the genes that are active during vasculogenesis, we have obtained and compared the genomic program during critical time points of vascular development in mouse. The next step is to validate thus further in the zebrafish. First, we have screened for genes that are specifically expressed in angioblasts, the common progenitor of haematopoietic and angiogenic lineages and in developing blood vessels by whole mount in situ hybridisation. Second, we are knocking these genes down by concomitant morpholino injection to further analyze their functional role in vasculogenesis and angiogenesis in the zebrafish. The developing vasculature can be studied particularly well in the zebrafish by taking advantage of its transparency, which allows the use of reporter lines that express GFP in endothelial cells, permitting the observation of vessels in the living embryo. The clinical value of blood lactate measurement in critically ill patients PhD candidate Tim C Jansen, MD Blood lactate measurement is frequently performed in critically ill patients, usually aimed at detecting tissue hypoxia. However, other processes not related to tissue hypoxia and subsequent anaerobic metabolism can also result in increased blood lactate levels, complicating clinical interpretation and therapy. The clinical benefit of blood lactate monitoring in critically ill patients has not yet been subjected to rigorous clinical evaluation and the question therefore remains: should we measure lactate in the critically ill and if so, when should we measure it, what would be the therapeutic action and what would be the clinical impact of this process? This PHD project aims at answering these questions. The most important part of the project involves evaluation of the efficacy of lactate as a resuscitation endpoint in goal-directed therapy to balance oxygen delivery with oxygen demand. We are currently conducting a randomized controlled multi-centre trial, in which 350 patients are randomly allocated to either lactate-guided therapy (lactate group) or nonlactate guided therapy (control group) during the first eight hours of ICU stay. The primary outcome measure is in-hospital mortality. The independent Data Safety Monitoring Board recommended continuing the trial following an interim analysis. Patient recruitment will be finished in March or April

14 a a a a a a a a a a a a a Cardioprotection PhD candidate Olivier C Manintveld, MD The application of pre- and postconditioning in limiting myocardial infarction is the topic of the thesis of Olivier Manintveld. He will defend his work on October 8, Currently, Olivier Manintveld is involved in setting up a clinical research proposal involving postconditioning in patients with an acute myocardial infarction. A summary of his research topic is presented below. Ischemic heart disease, in particular myocardial infarction, is the main cause of heart failure in western societies. Myocardial infarct size is an important predictor of the development of heart failure. Hence, developing novel research strategies to reduce the irreversible damage produced by myocardial ischemia-reperfusion remains an important therapeutic goal. Ischemic preconditioning by brief episodes of ischemia, preceding a sustained period of ischemia, limits myocardial infarct size and represents the strongest endogenous cardioprotective mechanism known to date. From a clinical standpoint, preconditioning has a limitation that pharmacological mimicry of this cardioprotective phenomenon requires application prior to infarction. Since it is difficult to predict which patients will encounter a myocardial infarction, the single most effective therapy to date remains early reperfusion of the jeopardized ischemic myocardium. However, despite its merits, the process of reperfusion may itself result in some lethal injury, thereby attenuating its benefit. Indeed it was recently shown that intermittent reperfusion (called postconditioning ) following a prolonged period of ischemia could limit infarct size, thereby further optimizing the benefits of early reperfusion. This observation is particularly important since, in contrast to preconditioning, postconditioning can be applied at the onset of reperfusion. Hence gradual or intermittent reperfusion would be applicable in all patients with a pending myocardial infarction that undergo primary coronary intervention for reperfusion therapy. Experimental data indicate that cardioprotection by pre- or postconditioning against myocardial infarction is mediated by activation of the RISK signaling pathway. Presently, Biochemistry and Experimental Cardiology perform studies to further elucidate the mechanisms of postconditioning, and to determine the optimal cardioprotective algorithm of postconditioning in relation to the duration of index ischemia. Cell therapy in myocardial infarction and heart failure PhD candidate Jaco Houtgraaf, MD Many patients with myocardial infarction will develop heart failure. Established drug therapy with ACE-inhibitors and β-blockers can delay the development of heart failure, but post-mitotic myocardium is not able to regenerate. Stem cell therapy could be a promising method to establish improvement of cardiac function. As the use of embryonic stem cells raises practical and ethical concerns, it would be preferable to treat cardiovascular patients with autologous adult stem cells. Mesenchymal stem cells (MSC s) are an example of autologous stem cells that can be derived from adult patients (rather than from embryonic tissue). These cells have shown pluripotency (ability to differentiate into multiple cell lineages including endothelial cells, (cardio)myocytes, neurons, osteocytes, and chondrocytes). More important, these cells are able to secrete a wide range of growth factors and cytokines including IGF-1, VEGF, FGF and various interleukins. In addition to bone-marrow and umbilical cord blood, adipose tissue also is an abundant source of MSC s. The major advantage of adipose tissue, is that it is easily accessible in an adequate amount (via liposuction). Transplantation of these MSC s into the heart by intra-coronary or intra-myocardial injection led to an improvement of cardiac function in various large animal models. In the APOLLO and the PRECISE clinical trial, we will, for the first time in man, investigate the therapeutic value of these adipose-tissue derived MSC s in patients with respectively acute myocardial infarction or chronic ischemic heart failure. Patients will first undergo a liposuction. The autologous stem cells will be isolated using special cell preparation and separation steps. After the isolation, the MSC s will be transplanted into the patient; by intra-coronary delivery (APOLLO) in the culprit coronary artery or by intra-myocardial NOGA facilitated delivery (PRECISE) following endoventricular electromechanical mapping. Cardiac function, cardiac dimensions and myocardial perfusion will be assessed and followed up with various imaging modalities. Holter-analyses will uncover the possible development of inadvertent arrhythmias. After the completion of both trials, we will know whether treatment of patients with a myocardial infarction or ischemic heart failure with adipose-tissue derived MSC s is safe and feasible

15 Research groups Renin-angiotensin system blockade with renin inhibitors PhD candidate Joep HM van Esch, MSc The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure and body fluid homeostasis. The RAS is not only active in the circulation ( circulating RAS ) but also in many tissues, functioning as so-called local RAS. Angiotensin (Ang) II, the main effector peptide of the RAS, when generated from Ang I at tissue sites, stimulates both Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors. AT1 receptors mediate the wellknown vasoconstrictor, inotropic, chronotropic,aldosterone-releasing, noradrenaline-releasing and growth-stimulatory effects of Ang II, and AT2 receptors are generally assumed to counteract these actions. Angiotensin-converting enzyme (ACE), required to convert Ang I into Ang II, is generated locally whereas angiotensinogen and (pro)renin are taken up from blood. The uptake of (pro)renin possibly involves the recently discovered (pro)renin receptor. Under pathological conditions excessive RAS activity may lead to a rise in blood pressure and cardiac/renal hypertrophy, resulting in end-organ damage. It is now possible to block the RAS at three different levels. ACE inhibitors and the AT1 receptor blockers already have been proven to be successful in the treatment of hypertension and cardiovascular disease. We currently investigate the cardiovascular efficacy of the newly developed renin inhibitors. Our working hypothesis is that, for a given decrease in blood pressure, these drugs exert better organ-protective effects than the existing RAS blockers as they provide a more complete suppression of the RAS, by targeting the initial rate-limiting step. Research Groups theme 1 Cardiac (mal)adaptation to stress and damage Project leaders DJGM Duncker, D Merkus R de Crom, AJM Verhoeven, W Sluiter WJ van der Giessen, HJ Duckers, JMJ Lamers, AH van den Meiracker PhD candidates VJ de Beer, MC de Waard, OC Manintveld, ED van Deel Circulatory aspects of anesthesia Project leader DAMPJ Gommers J van Bommel, J Hofland, J Klein PhD candidates F Grüne, X Moors Circulatory aspects of mechanical ventilation Project leader DAMPJ Gommers J Klein, D Dos Reis Miranda, A Struijs, J van Bommel J Hofland, J Bakker, AJJC Bogers, B Lachmann PhD candidates IG Bikker, L Klompe, C Preiss, TV Scohy Experimental atherosclerosis: Shear-stress related gene expression and inflammation in plaque progression Project leaders R Krams, JJ Wentzel R de Crom AJJC Bogers, F Grosveld, PW Serruys, AFW van der Steen, DJGM Duncker PhD candidates F Helderman, D Segers Genetic regulation of vasculogenesis and angiogenesis Project leader HJ Duckers DJGM Duncker, PW Serruys JHJ Hoeijmakers, S Schulte-Merker Postdocs C Cheng PhD candidates F Bos, RLJM Herpers, HJ Houtgraaf, D Tempel 26 27

16 Immunoregulatory mechanisms in atherosclerosis Project leader HJ Duckers PW Serruys, DJGM Duncker B Lambrecht, J Laman, M Soares Postdocs C Cheng PhD candidates MM Noordeloos, T Soullie Microcirculation in critical illness Project leader J Bakker C Ince, J LeNoble, DAMPJ Gommers J van Bommel PhD candidates TC Jansen, A Lima, B van der Hoven, E Klijn Molecular biology of atherosclerosis Project leaders R de Crom, HJ Duckers JF Hamming F Grosveld, H van Urk PhD candidates W Dekker, BME Mees Pathogenesis and therapy of hypertension and heart failure, with emphasis on the renin-angiotensin system Project leader AHJ Danser MADH Schalekamp, JMJ Lamers Postdocs WW Batenburg PhD candidates F Gembardt, M Krop, JHM van Esch Pharmacology of migraine: The role of serotonin, calcitonin gene-related peptide and noradrenaline receptors Project leader A Maassen van den Brink AHJ Danser, AJJC Bogers, CMF Dirven PhD candidate KY Chan Stem-cell and growth-factor therapy in ischemic heart disease Project leaders DJGM Duncker, WJ van der Giessen HMM van Beusekom, HJ Duckers, RJM van Geuns E Braakman, GP Krestin, ML Simoons PhD candidates DB Uitterdijk Molecular biology of heart failure: Genomic and proteomic analysis of disease-related proteins as basis for development of novel therapeutic strategies Project leaders JMJ Lamers, AJM Verhoeven W Sluiter, M Dalinghaus, D Merkus DJGM Duncker, WA Helbing, J van der Velden PhD candidates DWD Kuster, D van Deursen Our data suggest that high wall shear stress influences plaque vulnerability and therefore may become a potential parameter for predicting future events. Stroke 2007;38:

17 Thema 1 Name VJ de Beer IG Bikker F Bos KY Chan ED van Deel W Dekker D van Deursen JHM van Esch F Gembardt F Grüne F Helderman RLJM Herpers HJ Houtgraaf B van der Hoven TC Jansen E Klijn L Klompe M Krop DWD Kuster A Lima OC Manintveld Cadiovascular Biology and Pharmacology Subject Coronary and pulmonary vascular adaptations after myocardial infarction Optimization of oxygenation and circulation in critically ill patients Zebrafish genomics to identify genomic regulation of vasculogenesis The role of female sex steroids and ion chanel mutations in migraine Pathophysiology and therapy of pressure overload induced cardiac hypertrophy Molecular mechanism of the vulnerable plaque Regulation of the hepatic lipase gene by E-box binding transcription factors Renin-angiotensin system and oxidative stress Interaction between different peptide systems Changes of effective downstream pressure in cerebral perfusion under influence of anesthetics and vasoactive drugs Arterial adaptation described by a stress model Molecular regulation of vasculogenesis Cell therapy in myocardial infarction and heart failure Measurement of functional liver blood flow Blood lactate as index for oxygen imbalance in critically ill patients Microcirculation in critically ill patients Respiration studies in cardiac surgery Renin-angiotensin receptor Nuclear proteins that discriminate between early development of adaptive and maladaptive hypertrophy Noninvasive measurement of peripheral perfusion in critically ill patients Cardioprotection by postconditioning Funding source: ErasmusMC (1); ICIN, NWO, KNAW, STW (2); Charity (3); Industry etc. (4) Promotor(s) Copromotor(s) Funding DJGM Duncker D Merkus 3 DAMPJ Gommers 1 DJGM Duncker HJ Duckers 2 AHJ Danser A Maassen van den Brink 1 DJGM Duncker D Merkus 1 PW Serruys HJ Duckers 2 H Jansen, JMJ Lamers AJM Verhoeven 3 AHJ Danser 1 AHJ Danser 4 J Klein 1 AFW van der Steen R Krams 2 DJGM Duncker HJ Duckers 4 WJ van der Giessen HJ Duckers 4 J Bakker 1 J Bakker J van Bommel 1 J Bakker 1 DAMPJ Gommers, AJJC Bogers 1 AHJ Danser 3 JMJ Lamers AJM Verhoeven 3 J Bakker 1 DJGM Duncker, JMJ Lamers

18 BME Mees X Moors MM Noordeloos C Preiss TV Scohy D Segers T Soullie D Tempel DB Uitterdijk MC de Waard Endothelial NO synthase and angiogenesis Circulatory aspects of xenon anesthesia Hemoxygenase and cardiovascular disease Circulatory aspects of mechanical ventilation in cardiac surgery Aspects of anesthesia in pediatric cardiac surgery Inflammation and atherosclerosis The role of Dendritic cells in atherosclerosis and the role of EPC s in ischemia Mouse genomics to identify the genetic regulation of vasculogenisis and angiogenesis Paracrine effects of progenitor cells on cardiac repair after myocardial infarction The effects of NO and exercise training on cardiac function in health and disease H van Urk R de Crom 1 DAMPJ Gommers, J Klein 1 DJGM Duncker HJ Duckers 1 DAMPJ Gommers, AJJC Bogers 1 J Klein, AJJC Bogers DAMPJ Gommers 1 AFW van der Steen R de Crom 3 DJGM Duncker HJ Duckers 4 DJGM Duncker HJ Duckers 1 WJ van der Giessen 1 DJGM Duncker R de Crom

19 a a a a a a a a a a a a a a a a a a a a Theme 2 Vascular Medicine, Hemostasis and Stroke Program Code: EMC COEUR Coordinators: PJ Koudstaal, FWG Leebeek, AH van den Meiracker, ML Simoons This theme has a predominately clinical focus, and complements the basic research of COEUR theme 1. Departments working together in this theme are the following: Clinical Genetics, Hematology, Internal Medicine, specifically Vascular Medicine, Neurology, and Cardiology. Therefore the theme covers a wide range of subjects: hypertension, thrombosis and hemostasis, stroke, acute coronary syndromes, cardiovascular genetics and, new this year, pharmaco-genetics. Research is aimed at identifying mechanisms involved in: blood pressure regulation, specifically the renin-angiotensin system, the role of coagulation factors and platelets in the development of arterial as well as venous thrombosis, inherited structural cardiac abnormalities and the prevention and treatment of acute and chronic clinical cardiovascular syndromes. In 2007, theme 2 encompassed a total of 10 scientific projects with 26 PhD students. Some examples of individual projects are given on the next pages. Natriuretic peptides: Biomarkers of cardiovascular disease PhD candidate Joost HW Rutten, MD B-type natriuretic peptide (BNP) and its aminoterminal counterpart NT-proBNP are synthesized and secreted by cardiomyocytes in response to stretch. Recently both natriuretic peptides have been identified as markers for cardiac disease. Especially in patients presenting to an emergency department with shortness of breath BNP and NT-proBNP may be useful to exclude or diagnose heart failure. The costs of natriuretic peptide measurement are relatively high compared to other biomarkers, but it was hypothesized that introduction of NT-proBNP testing would improve diagnostics in patients with dyspnea ultimately leading to cost-reduction. This was tested in acute dyspneic patients presenting at the Erasmus MC emergency department in a prospective randomized clinical trial. Introduction of NT-proBNP reduced median time to discharge by 2 days and resulted in a trend towards cost reduction without negatively affecting mortality (Figure 1). In the near future we will investigate the diagnostic value of natriuretic peptides in various subpopulations, i.e dialysis, preeclampsia, intensive care. Also, we will study the prognostic value of NT-proBNP for cardiovascular morbidity and mortality in the population of the Rotterdam Study. The figure shows the cost-effectiveness plane of introduction of NT-proBNP in the emergency department. The right lower quadrant of the graph represents the proportion of bootstrap samples in which a reduction in costs coincides with a reduction in mortality, while ellipses represent 50 and 90% confidence intervals

20 Willebrand in the Netherlands: the WiN study. PhD candidate Eva M de Wee, MD This year we initiated a study on moderate and severe von Willebrand disease (VWD) in the Netherlands Willebrand in the Netherlands the WiN study. VWD is the most frequent inherited bleeding disorder with a highly variable clinical presentation. Some patients have severe bleeding problems while others have never experienced a bleeding episode although they have similar levels of von Willebrand factor (VWF). The mechanism of this variability is unknown. Consequently, the treatment of VWD varies significantly between individuals. This study aims to register and investigate all patients in the Netherlands with moderate and severe VWD, to gain insight in their clinical presentation, treatment and the complications of treatment. Another goal is to investigate the influence of VWD on quality of life. It is expected that at least patients currently treated in the 12 Dutch haemophilia treatment centres will be included. Inclusion criteria are as follows: VWF antigen or activity 30% and/or FVIII:C 40%. There is no restriction in age or type of VWD. The patients will be questioned in a standard fashion and a blood sample will be obtained. So far, 921 patients have been included. Their characteristics are as follows: mean age 34 (range 0-79) years in males and 40 (range 1-88) years in females. Of these, 147 are below 18 years of age. Sixty percent is female. In this population of moderate and severe VWD patients 63% has type 1 disease, 27% has type 2 disease, 4% type 3 disease while the disease type is non-specified in 6%. Our centre has already included 150 patients. This cohort will be valuable for various sub-studies in the future and will provide additional insight in the clinical course and disease burden of Von Willebrand Disease

21 Causes and risks of stroke PhD candidate Michiel J Bos, MD Stroke is an often disabling and fatal disease. Although the onset of a stroke is sudden, the underlying processes can take decades before the first symptoms are experienced. Our research, embedded within the large population-based cohort of the Rotterdam Study, is aimed at identifying differences between persons who will develop stroke and those who will not. These differences may help to target preventive treatment, particularly for those at highest risk. Differences with limited predictive value, however, may still be useful because they can reveal causal pathways leading to stroke. Some insights from our recent studies highlight the importance of renal function. We found that tubular sodium re-absorption under the influence of the renin-angiotensinogen-system, and renal glomerular filtration are important players in the pathophysiology of stroke. Furthermore, we have very recently shown the importance of a transient neurological attack (TNA), an attack with neurological symptoms with a sudden onset and duration of seconds to hours. We identified three types of TNA: (1) Focal TNAs, also called transient ischemic attacks (TIAs), with focal neurological symptoms, i.e. symptoms that can be linked to the dysfunction of one single brain artery, and since decades have been recognized as important harbingers of future stroke; (2) Nonfocal TNAs, with symptoms localized diffusely within the brain (e.g. loss of consciousness, unsteadiness, confusion, amnesia); and (3) Mixed TNAs, with both focal and nonfocal symptoms within one attack. We discovered that nonfocal TNAs are not as benign as generally assumed, but denote a high risk of stroke and dementia, and that mixed TNAs are associated with a very high risk of stroke, dementia, as well as coronary heart disease. Pharmacogenetics in stable coronary artery disease: towards individualized medicine PhD candidate Jasper J Brugts, MD MSc Clinical treatment guidelines recommend considering the use of ACE-inhibitors in the routine secondary prevention treatment of the broad group of patients with coronary artery disease (CAD). The efficiency and cost-effectiveness of this prolonged prophylactic treatment would be significantly enhanced if only those patients would be treated who benefit most from ACE-inhibitor therapy. Until now, subgroup-analyses of large ACE-inhibitor trials have shown a strong consistency. Simple clinical patient characteristics are therefore not sufficient to guide ACE-inhibitor therapy and more specific methods need to be developed. Pharmacogenetic profiling may be a new way to achieve significant advances in tailored-therapy. We will investigate whether genetic polymorphisms in the renin-angiotensin-aldosteron-system (RAAS) predict the effects of ACE-inhibitor treatment on blood pressure and cardiovascular risk. These relationships will be studies in stable CAD patients randomized for ACE-inhibitor therapy who participated in the EUROPA-trial. This project is the first large pharmacogenetic study on the effects of ACE-inhibitors in CAD patients. Blood samples of the participants in the EUROPA-trial have been stored and, during the first year of this project, DNA has been isolated and prepared for genetic analysis. The analysis of the first genetic polymorphisms using the Taqman high-throughput allelic discrimination equipment has started at the end of The genetic polymorphisms in this project have been selected to comprehensively cover the total common genetic variation in multiple RAAS-genes that may determine the effect of ACE-inhibitor treatment. The aim of the project is to compose a genetic profile that advances individualized therapy and improves risk prediction models in cardiovascular medicine

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