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In the reporting year, our senior scientific staff and PhD candidates have worked on 31 research projects. Quantitatively and qualitatively their results are worth mentioning, since altogether more than 750 PubMed/Medline articles were produced. In the latest citation analysis, the mean normalized citation score of COEUR over the period 2010-2013 was 2.00, the highest of all Erasmus MC Research Schools, and meaning that the impact of our publications is twice that of average within the cardiovascular field. A total of 37 PhD candidates successfully defended their thesis and obtained the doctoral degree. The grant funds that have been raised by COEUR investigators totals more than 2.5 million euro’s. Without doing injustice to others, we like to mention Prof. Dirk Jan Duncker and his team, Dr. Mostafa Mokhles, PhD fellow Vivan Baggen and Prof. Wiro Niessen, who obtained prestigious grants from CVON, STW, NOW and EUR, and the Netherlands Heart Foundation, respectively. The reporting year was also memorable for our colleagues Deckers, Van Geuns and Gommers, who delivered their inaugural lectures. We congratulate them with their achievements. Main challenges are lying ahead. Research budgets are under pressure. Scientists are encouraged to demonstrate the value of their work for society, and to involve the lay public in shaping their research agenda. The formation of Academic Centers of Excellence within the Erasmus MC provides opportunities to rethink and restructure existing research programs, and to strengthen collaborations inside and outside our Research School. We are confident that the COEUR Principal Investigators will direct these developments to the benefit of science, society and patients. We trust you will enjoy the presentation of our activities in this annual report. Eric Boersma, scientific director Adrie Verhoeven, secretary Felix Zijlstra, chairman 5 COEUR 6 6 Mission The mission of COEUR is two-fold: ■ To promote 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, such as 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. 7 COEUR Cardiovascular Research School Erasmus University Rotterdam (COEUR) 8 Participating institutes Board representatives Anesthesiology and Vascular Surgery Professor Robert Jan Stolker Cardiology Professor Felix Zijlstra, chairman Cardiothoracic Surgery Professor Ad JJC Bogers Hematology Professor Frank WG Leebeek Intensive Care Medicine Professor AB Johan Groeneveld Internal Medicine, Pharmacology, Vascular and Metabolic Diseases and Division of Nephrology Professor AH Jan Danser Dr Anton H van den Meiracker Professor Bob Zietse Neurology (Vascular Neurology) Professor Diederik WJ Dippel Pediatric Cardiology Professor Wim A Helbing Radiology (including Biomedical Imaging) Professor Aad van der Lugt Professor Wiro J Niessen Surgery (Vascular Surgery) Professor Hence JM Verhagen Professor Eric Boersma, scientific director Dr Adrie JM Verhoeven, secretary Accredited (2003) by the Royal Netherlands Academy of Arts and Sciences. Re-accreditated in 2009 Organization 10 COEUR participants Anesthesiology Cardiology Graduate School Erasmus MC Cardiothoracic Surgery Hematology Intensive Care Medicine COEUR Scientific Advisory Board COEUR Board Internal Medicine Pharmacology, Vascular and Metabolic Diseases and Division of Nephrology 9 Neurology Pediatric Cardiology Executive Committee Scientific Director Radiology Biomedical Imaging Group Vascular Surgery Scientific Secretariat Theme I Vascular Medicine Theme II Acute CV Syndromes Theme III Chronic Cardiac Disease COEUR 10 Grants and Awards A selection of grants and awards obtained by COEUR investigators in 2015 is given below. Cardiology Dr. Jaap Deckers has been appointed as extraordinary professor of Cardiovascular Training and Education, on behalf of ICIN Netherlands Heart Institute. On February 6th he delivered his inaugural lecture titled “The heart attacks that disappeared”. Dr. Robert Jan van Geuns, who has been appointed as endowed professor of “Interventional Cardiology” on behalf of the Vereniging Trustfonds EUR, delivered his inaugural lecture titled “Beyond the boundaries of the stent” on April 17. Professor Dirk-Jan Duncker (Principal Investigator), Dr. Caroline Cheng and Dr. Daphne Merkus (Co-Investigators) obtained a prestigious CVON grant (CVON-2014-11; RECONNECT), totalling M€ 5 of which Erasmus MC receives k€800. CVON, the Netherlands CardioVascular Research Initiative, is an initiative with support of the Dutch Heart Foundation, Dutch Federation of University Medical Centers, The Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Arts and Sciences. In April Professor Dirk-Jan Duncker was promoted from Associate Editor to Deputy Editor of Cardiovascular Research, the Basic Science Journal of the European Society of Cardiology, while Dr. Daphne Merkus was appointed as Associate Editor of Cardiovascular Research in October. Professor DirkJan Duncker, who is presently the Secretary of the Working Group for Coronary Pathophysiology and Microcirculation, organized a two-day Nucleus Meeting of the Working Group in Rotterdam in April. PhD candidate Anouchska Autar presented her work on NETosis at the spring meeting of The Netherlands Society of Cardiology where she received a prize for best oral presentation. With the Thorax Foundation dinner, Professor Jolien Roos raised k€200 for research into the long-term effects of congenital heart diseases. PhD candidate Vivan Baggen received a grant from the Dutch Heart Foundation’s Dekker Program. Dr. Natasja de Groot was elected as board member of the European Heart Rhythm Society where she holds the position of chair website and communication. She is member of a consortium that received an ErasmusMC MRace grant and a grant from the Royal Dutch Society of Pharmacy. PhD candidate Ameeta Yaksh was rewarded for the best poster presentation on ElectroPhysiology Research during the spring meeting of the Dutch Society of Cardiology; the subject of her presentation was Rhythm disturbances after LVAD implantation. PhD candidate Eva Lanters was rewarded 11 COEUR for the best oral presentation during the autumn meeting of the Dutch Society of Cardiology. PhD candidate Pranav Bhagirath was rewarded with a travel grant for the European Arrhythmia meeting in Milan (Europace-Cardiostim). Dr. Caroline Cheng is workproject leader in the above mentioned CVON RECONNECT program. On March 6, PhD candidate Maarten Brandt won the best oral presentation award during the CardioVascular Conference basal session at the Dutch Atherosclerosis Society meeting. 12 Dr. Hans Bosch was awarded with a STW grant for his project on 3D-Intra-Cardiac Echography (STW project 14279). PhD candidate Tianshi Wang caught a lot of media attention of among others the NOS Journaal and The Voice of America for Heartbeat Optical Cohorence Tomography (OCT), the subject of his thesis. It is on micromotor based intravascular OCT that can collect around 5000 images per second. With his catheter a whole coronary can be imaged within a heartbeat. The patents arising from his work have been licensed to Terumo and they are now collaborating with Terumo and Kinetron to productize this spectacular development. On October 30th 2015, Dr. Jasper Brugts finished his two-year fellowship Heart Failure at the University Hospital of Zurich, Switzerland. The programme was organized by the European Society of Cardiology (ESC) and European Heart Academy according to the “Heart Failure Association Heart Failure Specialists Core Curriculum” for training in heart failure, consisting of 300 hours self-study and 300 hours of practical training and courses at the University Hospital of Zurich with final examinations per module. Successful completion resulted in a diploma by ESC for accreditation in heart failure and a certificate of Advanced Studies of the University of Zurich. The programme was organized by Prof Thomas Luscher and Prof Frank Ruschitzka. The diploma was handed to Jasper by Prof Eugene Braunwald (see photo). Annual Report 2015 Cardio-thoracic Surgery PhD candidate Sahar Mokhles was nominated to take part in the Global Young Scientists Summit (GYSS). Young researchers around the world are invited to participate in this program, which is basically one-week of debates, discussions and presentations. Each year there is a new theme, and the theme for 2015 was Global Health. Sahar was there to share insights on joint decision-making in lung cancer patients. Dr. Mostafa Mokhles won a Veni grant for his project “Effective Prediction of Outcome after Congenital Heart Surgery; Combining statistics and clinic for improved patient care”, worth k€250, on behalf of the general board of the Dutch Organization for Scientific Research NWO and the Board of ZonMW. In addition, Dr. Mostafa Mokhles also received an EUR Fellowship worth k€ 135 titled “Reliable predictive models for patients with congenital heart defects”. Today, patients with a congenital heart defect can grow to adulthood. Unfortunately, this does require several heart operations throughout their lives. In these projects, he will develop models to predict the optimum time to perform each operation, in order to be able to minimize the total number of heart operations. Reducing the number of operations will not only lead to improved survival rates and lower disease burden, but also better quality of life. At the 2015 Radiology Society of North Amercia (RSNA) meeting, Marcel Dijkshoorn was awarded with the Certificate of Merit, for his poster “Comprehensive Evaluation of Mechanical Heart Valves with Third Generation Dual Source CT” . 13 COEUR Hemostasis and Thrombosis 14 Professor Frank Leebeek has been appointed as co-chair of the Scientific Subcommittee on Von Willebrand Factor of the International Society for Thrombosis and Haemostasis (ISTH). Dr. Marieke J.H.A. Kruip received an MRace efficiency grant of k€50 for a study on DDAVP in patients with haemophilia who undergo dental intervention (Dental DAVID study). Dr. Moniek de Maat received a research grant of k€30 from the Stichting Jacoba for implementing a Calibrated Thrombin Generation system in research projects on Thrombosis and Haemostasis. Professor Frank Leebeek received a grant of k€100 from the Dutch Haemophilia Foundation for part 3 of the Willebrand in the Netherlands Study, of which he is the PI. PhD candidate Shiraaz Abdul was awarded a travel grant from the International Society on Fibrinolysis and Proteolysis (ISFP). He used it to set up a collaboration with Professor P Declerck and visited the Laboratory for Therapeutic and Diagnostic Antibodies of the Faculty of Pharmaceutical Sciences at the University of Leuven for one month. PhD candidate Michelle Sonneveld received the Prof. Heimburger award worth k€50 for research on Complement factor H, the relation with von Willebrand Factor and ADAMTS13, and the risk of stroke and myocardial infarction, of which Dr. Moniek de Maat is the PI. At the ISTH Congress in Toronto, Canada, PhD candidates Michelle Sonneveld and Johan Boender received a Young Investigator Award. Michelle was awarded for her research on ADAMTS13 and the association with cardiovascular disease. Johan received the award for his presentation on bleeding phenotype in children with von Willebrand disease. PhD candidate Carolien Hazendonk received the Jeanne Stibbe Bokaal of the annual scientific meeting of the Dutch Society for Thrombosis and Haemostasis for the best oral presentation delivered by PhD students. Intensive Care Dr. Diederik Gommers has been appointed as professor of “Intensive Care”. On September 25, he delivered his inaugural lecture entitled “Wu Wei”. PhD candidate and IC-nurse Margo van Mol received the Anna Reynvaan Praktijkprijs on behalf of the Foundation Family and patient Centered Intensive Care (FCIC), for the best nursing initiative to improve patient care. Being admitted to a Intensive Care Unit also greatly affects close relatives. The patient may not be able to make deliberate choices, and family are often overwhelmed by anxiety, grief and confusion. The Foundation has developed several initiatives Annual Report 2015 for counseling and support of close relatives of ICU patients, among others diaries, information leaflets and consultation structures.The award came with a sculpture and sum of k€5. Professor Johan Groeneveld was awarded Honorary membership of the European Society of Intensive Care Medicine (ESICM) at the Berlin meeting in October 2015, for his “outstanding contribution to the field of intensive care medicine”. Internal Medicine: Pharmacology and Nephrology At the European Society of Hypertension meeting in Milan, Professor Jan Danser received the Pieter A. van Zwieten-award for his ‘outstanding contribution to research on clinical pharmacology of drugs acting on RAAS (Renin-Angiotensin-Aldosterone-System)’. Dr. Ton van den Meiracker was honoured with the Willem Birkenhäger Award by the Dutch Hypertension Society during the national hypertension congress in Zeist. Professor Jan Danser was elected Promotor of the year 2015 by the Erasmus MC PhD students. The election was organized by Promeras, the representive body of all Erasmus MC PhD students.Professor Danser earned this election because ‘he is always approachable, even during holidays’, ‘does not think along hierarchical lines’ and ‘leaves space to others’. He is a great motivator, ‘he succeeds to keep up with the many parallel challenges, even in hard times’, and ‘problems seem less complex after a consultation with him’. He was also praised particularly for his language instinct. In april, Professor Jan Danser stepped down as chairman of the Dutch Pharmacology Society. Dr. Antoinette Maassen van den Brink was appointed Member of the Board. She is also member of the Dutch Headache Society and the Medical Advisory Council of the Dutch Society of Headache Patients. Dr. Antoinette Maassen van den Brink is member of the Advisory Council of the Migraine Thrust, which was erected December 9. One of the aims of the fund is to raise funds for migraine research in women. Dr. Antoinette Maassen van den Brink co-authored the ZonMW report Kennisagenda Gender en Gezondheid, which identifies lacunas in knowledge in the field of Gender and Health care, and which offers an agenda for future policy making. The report was offered to Mrs. Schipper, minister of Health on June 16, and to members of Parliament on June 24. Dr. Antoinette Maassen van den Brink is member of the Alliance Gender and Health, which is started by Women Inc together with the Ministry of Health, to gain recognition for gender differences in health care. In this context, she participated in the Dress Red Day talkshows at the VUMc on September 25. 15 COEUR The research of the project group of Antoinette Maassen van den Brink on migraine in women attracted vast media attention. She was interviewed on national TV during the 8 o´clock NOS Journaal on June 16, and interviews appeared in national newspapers AD on June 17 and Telegraaf on December 9. Professor Jan Danser delivered a lecture for the general public titled ‘From poison to pill: poison gives life’ on December 13 during the exhibition ‘The power of poison’ in Rotterdam. 16 PhD candidate Khatera Ibrahimi received the Prof. Dr. Saxena award from the Dutch Headache Society for her research on migraine. At the European Society of Hypertension 2015 meeting in Milan, PhD candidates Lodi Roksnoer and Langeza Saleh were awarded with the Alberto Ferrari Poster Prize. Lodi’s poster was titled “Dual AT1 Receptor/neprilysin inhibition (ARNI) vs AT1 receptor blockade in diabetic TGR(mREN2)27 rats”. Langeza’s poster was ‘The sFlt-1/PlGF ratio associates with adverse outcomes and prolongation of pregnancy’. The prize included free participation and free accommodation at the conference, and a sum of € 500. Langeza Saleh Annual Report 2015 Internal Medicine: Vascular and Metabolic Diseases Professor Eric Sijbrands obtained a grant of k€ 22 from Insuline Medical Ltd, for a study on standardmeal-time subcutaneous injection of rapid-acting insulin. Dr. Monique Mulder was co-applicant of a research proposal on “Restoring memory by activating liver x receptors (LXR)”, which was granted k€ 100 by ISAO/AFI (Internationale Stichting Alzheimer Onderzoek/Alzheimer Forschung Initiative). She also received a k€3 grant from the Erasmus MC SNIP (Support Programme National and International Projects) fund for support in grant preparations. Dr. Jeanine Roeters van Lennep was awarded the Corrie Hermann 2015 prize by the Dutch Society of Female Physicians, for her contribution to advance awareness of gender differences and multidisciplinary collaboration to improve Womens’ Health. The award was handed to her on October 10 during the symposium organized to honour the prize winner. The title of the symposium was “Gender sensitive medicine: from utopia to clinical practice." 17 Dr. Jeanine Roeters van Lennep obtained a Investigator initiated grant worth k€34 from Sanofi, for a study on “Goal attainment in primary and secondary prevention in heterozygous FH patients”. Together with T. Vanwolleghem (Gastroenterology and Hepatology), she also obtained a MRace-pilot grant worth k€ 47,6 for the project “Residual cardiovascular disease risk: lessons to learn from an optimal small animal model”. Professor Eric Sijbrands was appointed member of the scientific committee of the Dekker grants of the Netherlands Heart Foundation. Dr. Jeanine Roeters van Lennep was appointed 2015 Editor of “Focus Vasculair”, a multidisciplinary educational journal focussed on cardiovascular medicine. Dr. Jeanine Roeters van Lennep COEUR 18 Neurology Radiology, department Biomedical Imaging The MR CLEAN trial results were published in the NEJM in January 2015. The trial provided convincing proof of the effectiveness and safety of thrombectomy for acute ischemic stroke. The publication led to the early termination of 4 other trials, which all confirmed the positive effect of this treatment. The trial was elected as one of the studies that “changed the face of medicine in 2015” by the NEJM editorial board. The study was already cited more than 600 times in the first year after publication. The trial received several national and international awards. Dr. Puck Fransen, PhD candidates Debbie Beumer and Olvert Berkhemer received young investigator awards from the Neurovascular section of the Dutch Society for Neurology. Further research aimed at improving the intervention and extending the indication for treatment will be done by the newly established consortium CONTRAST (Consortium for new treatments of acute stroke), which is coordinated by Erasmus MC, in collaboration with AMC and MUMC+. Professor Wiro Niessen (BMI) was awarded the STW Simon Stevin Meester 2015 title, the most prestigious prize for technological scientific research in the Netherlands. With this title and the associated lump sum of k€500, professor Niessen is honoured for his research into computer systems that may predict future disease in individuals, and which may lead to more personalized treatment. His research found indications that, for example, signs of Alzheimer’s disease are already detectable ten to fifteen years before symptoms appear. The computer makes predictions based on tens of thousands MRI- and CT-scans of both healthy and affected subjects. This approach enables the identification of pathological patterns that remain unrecognizable otherwise. The prize was awarded to professor Niessen on November 5 during the annual conference of STW. The Erasmus MC Stroke Center has been established and was officially opened on March 9. The center is a cooperation of all departments involved in research, education and patient care concerning stroke. It aims to improve acute treatment, prevention and knowledge of stroke (www.strokecenter.nl). PhD candidate Marisa Lubbers received an award for best oral presentation at the Netherlands Society of Cardiology (NVVC) meeting. PhD candidate Raluca Chelu received a best poster award at the North American Society of Cardiovascular Imaging (NASCI) meeting in San Diego. PhD candidate Adriaan Coenen was awarded for his presentation at the annual meeting of the Society of Cardiovascular Computed Tomography (SCCT) at Las Vegas. Marcel Dijkshoorn received special recognition for his poster presentation at the Radiology Society of North Amercia (RSNA) meeting in Chicago. Annual Report 2015 In 2015 two successful postgraduate cardiac CT courses, one basic and one advanced course, were organized in the Skills Lab of Erasmus MC. Vascular Surgery PhD candidate Frederico Bastos Goncalves obtained his PhD degree ‘cum laude’. His thesis defence was April 1, and the title was Endovascular aortic repair; clarifying risk factors, complications and follow-up strategies. The use of a new type of stent in the treatment of abdominal aortic aneurysmata last year was a world’s first. The new stent is now being evaluated in a large international study led by Professor Hence Verhagen. PhD candidate Bibi van Thiel received an accommodation grant from the European Society of Hypertension for this year’s conference in Milan. At this conference she gave an oral presentation entitled: ‘Involvement of the renin-angiotensin system in a premature aging mouse model’. For the same project, she won the 3rd prize during the annual PhD competition at the FIGON Dutch Medicine Days were she gave on oral presentation. The award also included a price of €500. In addition, she received a travel grant from the North American Vascular Biology Organization NAVBO ($500) and a travel grant from the Trustfonds (€500) to attend the NAVBO Vascular Biology 2015 conference in Cape Cod, Massachusetts, USA. At this meeting she gave an oral presentation entitled: ‘Fibulin-4 Deficiency induces Thoracic and Abdominal Aortic Wall Dilation and Altered Plaque Morphology in Apolipoprotein E Deficient Mice’. 19 COEUR Education PhD Training 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 can become independent researchers, and provides them with a broad basis for their future professional career. Monitoring of the actual education progress of individual PhD candidates is now standard practice, and an overview of the education obtained during the duration of the PhD program is presented elsewhere in this annual report. Importantly, the current education program has received high marks during the external visitation of COEUR late 2014. Contents The curriculum of 2015 comprised the following courses: February 12 & 13, 2015 Cardiovascular Imaging and Diagnostics Coordinators: Professor Aad van der Lugt (Radiology) and Dr Hans Bosch (Cardiology) Number of participants (PhD candidates): 26 April 16 & 17, 2015 Atherosclerosis and Aneurysmal Disease Coordinators: Dr Fop van Kooten (Neurology), Dr Ellen Rouwet (Surgery) and Dr Jeroen Essers (Vascular Surgery) Number of participants (PhD candidates): 13 June 18 & 19, 2015 Congenital Heart Disease Coordinators: Professor Jolien Roos-Hesselink (Cardiology), Professor Wim Helbing (Paediatrics) and Professor Ad Bogers (Cardiothoracic Surgery) Number of participants (PhD candidates): 22 October 8 & 9, 2015 Cardiovascular Pharmacology Coordinators: Professor Jan Danser (Internal Medicine) and Dr Antoinette Maassen van den Brink (Internal Medicine) Number of participants (PhD candidates): 9 December 10 & 11, 2015 Cardiovascular Medicine Coordinators: Professor Frank Leebeek (Hematology) and Dr Ton van den Meiracker (Internal Medicine) Number of participants (PhD candidates): 14 21 COEUR Research Seminars January 16, 2015 Personalized Medicine Organizers: F Zijlstra (Cardiology), E Boersma (Cardiology), A van der Lugt (Radiology), AJM Verhoeven (Internal Medicine) and AH van den Meiracker (Internal Medicine) Speakers: A van der Lugt, A Stiggelbout (LUMC), A IJpma, EJ Sijbrands and RHN van Schaik Number of participants: 30 22 February 25, 2015 Costs, Quality and Value in Cardiovascular Interventions Organizers: RLJ Osnabrugge and AP Kappetein Speakers: AP Kappetein, NMDA Van Mieghem, DJ Cohen (Kansas City MO USA), JB Rich (Norfolk USA), K Isendoorn (Gupta Strategists Amsterdam), EW Steyerberg, AJCW Janssens (Atlanta USA) and MGM Hunink Number of participants: 30 March 27, 2015 Secondary prevention with anti-thrombotics: unraveling the conundrum of bleeding vs efficacy Organizers: FWG Leebeek (Haematology), RJ van Geuns (Cardiology) and M Valgimigli (Cardiology) Speakers: J Versmissen, F Costa, T Yetgin, M Valgimigli, FWG Leebeek and P Vranckx Number of participants: 29 September 11, 2015 Cardiovascular interventions in the Elderly Organizers: JJM Takkenberg (Cardiothoracic Surgery), HJM Verhagen ( Vascular Surgery) and FUS Mattace Raso (Internal Medicine) Speakers: FUS Mattace Raso, TA Winkel, J Goudzwaard, JA Bekkers Number of participants: 20 November 13, 2015 Sex and Gender Differences Organizers: JE Roeters van Lennep (Internal Medicine) and JA Visser (Internal Medicine) Speakers: A Grefhorst, S Schagen, JA Visser, IM Jazet (LUMC), MT Mulder and JE Roeters van Lennep Number of participants: 16 November 27, 2015 Current insights in inherited cardiomyopathies Organizers: M Michels (Cardiology) and RA Oldenburg (Clinical Genetics) Speakers: RA Oldenburg, IMBH van de Laar, HG van Velzen, JI van Waning and J van der Velden (VUMC) Number of participants: 26 Annual Report 2015 December 4, 2015 The role of biomarkers in the pathophysiology of atrial fibrillation Organizers: NMS de Groot (Cardiology) and BJJM Brundel (Cardiology, UMCG) Speakers: D van Marion (UMCG), E Lanters, NMS de Groot and BJJM Brundel Number of participants: 13 The curriculum of 2015 comprised the following Lectures: February 24, 2015 Professor Dulce Casarini, Department of Nephrology, Sao Paulo, Brazil Title: Monitoring of biological processes: identification of biomarkers in renal diseases and new inhibitor of renin angiotensin system Professor Francisco Neves, Department of Pharmaceutical Sciences, Brazil Title: GQ-16, a partial PPARy agonist, improves insulin sensitivity and decreases visceral adiposity. Pharmacological and structural studies March 17, 2015 Dr Eric Stöhr, Cardiff Metropolitan University, Department of Physiology and Health, United Kingdom Title: Cardiac function with a twist – The importance of heart muscle deformation during exercise and hypoxia June 3, 2015 Professor R Dechend, Max-Delbrück-Centrum für Molekulare Medizin Berlin, Germany Title: Integrating hypertension and immunology: view from a cardiologist October 6, 2015 Professor AS Kumar, Department of Cardiothoracic Surgery, AII Institute of Medical Science, India Title: Ross procedure in a rheumatic population & Ross II procedure results November 17, 2015 Dr R Draijer, Department Nutrition & Health, Unilever, The Netherlands Title: Science update on tea and cardiovascular health November 25, 2015 Dr R Boon, Centre of Molecular Medicine, Goethe University Frankfurt, Germany Title: Cardiovascular aging: The role of non-coding RNA 23 COEUR Other educational activities 24 The 20th European symposium on Contrast Imaging, 22-23 January 2015 Contrast echocardiography has evolved dramatically during the last decade, from a clinical and experimental research method to a clinical diagnostic tool. It provides a non-invasive method for imaging the microcirculation of the heart and of many other organs such as the liver, often providing information which could not be found by alternative imaging methods. This Symposium highlighted new directions of research, early experiments and clinical applications by both established faculty and young investigators. One of its strong points was the extensive interaction between different disciplines, including clinicians (cardiologists, radiologists, neurologists and others), physicists and engineers, biologists and chemists, from both academic and industrial backgrounds. Apart from microbubble ultrasound imaging the interaction between microbubbles and ultrasound has been long recognized as having great potential for drug and gene delivery. A detailed understanding of this is vital in exploring the use of this exciting technology. The programme included microbubble technology, molecular imaging and applications for both gene and drug delivery. Since microbubble ultrasound imaging has been crucial into atherosclerotic vasa vasorum imaging, emphasis was directed towards this application including 3D ultrasound vascular technology. The Scientific Board: Mike Averkiou, Folkert ten Cate, Paolo Colonna, David Cosgrove, Eleanor Stride, Edward Leen, Nico de Jong, Arend Schinkel Erasmus Winter Programme February 23 – March 13, 2015 Members of COEUR participated as lecturer in the Erasmus Winter Programme. This annual programme provides participants from all over the world with an invaluable opportunity to bring themselves right up to date in the health sciences in an unequalled academic environment. The Programme focusses on the basics common to all research in clinical medicine, and courses are taught by leading international experts in their field. The Programme emphasizes the understanding of principles and methods of clinical research. It provides courses for those particularly interested in clinical trials, in drug safety research, and in decision making in clinical medicine. It also includes various courses in biostatistics. Venue: Erasmus Expo- & Congress Centre, Rotterdam, The Netherlands Target group: Health professionals interested in clinical trials, drug safety research and decision making in clinical medicine, biostatistics. Number of participants: 212 Annual Report 2015 Optics in Cardiology March 11-13, 2015 The 3rd Optics in Cardiology conference took place in Lantaren Venster Rotterdam. In the past two editions, a meeting place for clinical and technical researchers working with optics for diagnostics and therapy in cardiovascular medicine was created. The program is now complete and features a variety of topics. The conference for scientists, clinicians and engineers on Optics in Cardiology provided a forum for the latest breakthroughs in applications of light in cardiovascular medicine, highlighting clinical, technological and translational advances in this fast-moving field. Part of the Optics in Cardiology program was a special mini-symposium on March 11, 16:00, commemorating the 25th anniversary of intravascular imaging. The distinguished speakers were Patrick Serruys, Klaas Bom, and Jurgen Ligthart, reporting on the development of IVUS in the experimental echo department from prehistory till today. Thereafter, all attendents were invited to the Stadhuis for a reception in honour of this occasion. Number of participants : 191 in Rotterdam. The symposium aimed to bridge the gap between biomechanics, vascular biology and clinical research in order to understand more about cardiovascular disease. A number of internationally renowned speakers with a clinical/biological or technical background were invited to discuss this topic for 2 days. The keynote speakers were Prof. Dr. Chun Yuan, University of Washington, Seattle, USA (On Biomechanical Conditions that Predispose Vasa Vasorum to Rupture and Cause Intraplaque Hemorrhage: An In Vivo Magnetic Resonance Imaging Study”) and Prof. Francesco Migliavacca, Politecnico di Milano, Milan, IT (Stenting and computer modeling), who presented their latest work. Furthermore, 14 excellent researchers were invited to talk about their latest work and more than 68 abstracts (56 posters and 12 orals) were presented. Over 150 visitors from academia and industry from all over Europe and the USA visited the symposium. The reactions of the speakers and the visitors were very positive, indicating that a symposium of this kind fills an important need. The location of the annual conferences alternates between the North-American Continent and Rotterdam, the Netherlands. Shear Stress Symposium on Biomechanics in Vascular Biology and Cardiovascular Disease In April 2015 we celebrated the 10th anniversary of the “International symposium on Biomechanics in Vascular Biology and Cardiovascular Disease’. This year’s meeting was organized in the Hilton hotel Information market for PhD candidates As previously, COEUR participated in the yearly “PhD information market” in cooperation with Erasmus MC, the combined Erasmus MC PhD’s and the other (local) Research Schools. This event took place on June 4. The Research Schools provided 25 COEUR the beginning students with information on their schools and institutes, and last-year Erasmus MC PhD students with information about thesis preparation and future career possibilities. Presentations and workshops were given on practical PhD issues including ethics and medical communication and writing. MD elective program 26 The 4-week course “Introduction into methodologies and measurements” that includes an introduction to ECG and echocardiography as well as cerebrovascular disorders was given to 30 medical students who elected this course as part of their 2nd year curriculum. Under the guidance of COEUR PhD students, couples of two students each wrote a systematic review on a current medical question. The reviews were presented on January 23. The review writing process was supervised by Dr. Ron van Domburg. PhD-training course “Cardiac Function and Adaptation”, “Thrombosis and Haemostasis” and “Vascular Biology”. October 12- October 16, 2015 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. The content of the courses is slightly modified. 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. 5 COEUR PhD candidates were registered. Annual Report 2015 27 COEUR course Cardiovascular Medicine COEUR COEUR day 2015 28 The annual COEUR day was held the 29th of May in ‘het Nieuwe Instituut’ with the inspiring theme: ‘Beyond Excellence’. Of course, we all want to strive towards excellence, but how do we get there? How can we, together, make sure our research organization keeps growing and improving and how can COEUR facilitate this? Many important but hard questions to answer. Last year has been an important year for COEUR. An external assessment committee evaluated our research school which resulted in some recommendations. Following these recommendations but also due to changes in the nationwide policy, the structure and policy of our research schools will change the coming years. During this year’s COEUR day we discussed how these changes will or should be implemented to make sure that, in the future, we will truly go ‘beyond excellence’. The day started with COEUR scientific director Prof. Eric Boersma who explained the recommendations made by the external committee. Did we maintain our level of ‘excellence’ as determined by previous visitations and what are future directions for COEUR? Next, Prof. Diederik Dippel talked us through the role and creation of Academic Centers of Excellence, with the Stroke Center as a good example. Prof. Aart Jan van der Lely enlightened us about the future of PhD and Master education. The research environment in the Netherlands is undergoing changes. Prof. Ewout Steyerberg informed us on the research policy in the Erasmus University Medical Center, while prof. Ton van der Steen gave an inspiring talk about research policy in the Netherlands as a whole. After this, all speakers were invited to join the interactive forum where we discussed how all these changes should be implemented in the Erasmus MC and COEUR, what is excellent science, are we going to win a Nobel prize in science in the coming years with our research lines? The Keynote lecture ‘prize winning science’ was in the hands of Prof. Michel Ferrari (LUMC), who received a Spinoza Price for his groundbreaking research in migraine. He gave a personal talk about his own drives and achievements. Traditionally, the afternoon was dedicated to the PhD students. First, Dr. Maud Vissers explained the soon to be introduced Graduate School Management System. After this, Dr. Gijs Meeusen gave an interactive (and sometimes hilarious) workshop on how to gain and keep the audience’s attention when you present your work. We ended the day with speed-presentations by PhD students of COEUR. This year, the audience had to vote for the best presenter, and decided that for the second time Yanti Octavia went ‘Beyond Excellence’ in presenting her work at the department of Experimental Cardiology. Annual Report 2015 We hope that everyone enjoyed this day as much as we did! COEUR committee 2015 Jelle Schrauwen Ayla Hoogendoorn Kirsten Berk Johan Boender Eric Boersma Erna Egelie Carolien Hazendonk Adrie Verhoeven 29 COEUR 30 Professor Ton van der Steen en Johan Boender Annual Report 2015 31 32 Professor Michel Ferrari 33 COEUR Professor Ewout Steyerberg 34 Professor Aart Jan van der Lely Professor Diederik Dippel Annual Report 2015 35 36 37 COEUR 38 58 Research The original six research themes have been converted in a new, matrix like structure. In the new approach, biological, pathophysiological and clinical entities are now dominant, and the organizational scheme has now moved to the background. The current structure follows the example already given in the annual report of 2006, and results from both internal as well as external recommendations. In the current set-up, the following three major themes have been chosen: I. Vascular Medicine II. Acute Cardiovascular Syndromes III. Chronic Cardiac Disease Within these three major themes, different Research Programs haven been created, while the various disciplines and disease stages are now on the vertical axis. The matrix is outlined in more detail on the following pages, and should provide much better insight into the various research activities within COEUR. 39 COEUR Discipline I Aetiology & Pathogenesis Themes Discipline II Imaging & Diagnos Echo Theme I Vascular Medicine I-A Atherosclerosis MRI Molecular Biology IVUS CAD im Biomechanics Biomechanics Periphe Vascular Damage & Repair I-B Disorders of the microcirculation Role of RAAS Ageing Regulation of Tone I-C Cardiovascular Genetics Genetic regulation of vasculo/angiogenesis Metabolic Diseases I-D Aneurysm disease Molecular biology Aortic imaging Genetic regulation Role of RAAS Aortic remodeling 40 Theme II Acute CV Syndromes II-A Hemostasis & Thrombosis Role of hemostasis in thrombosis II-B Acute Coronary Syndromes Mechanisms of Plaque Vulnerability II-C Stroke & Migraine IVUS CAD im Biomechanics Periphe Causes of Stroke Neurovascular Imaging Pharmacology of migraine II-D Critical Illness and Sepsis Microcirculation Theme III Chronic Cardiac Disease III-A Cardiac Remodeling and Failure III-B Arrhythmias Atrial fibrillation III-C Congenital heart disease Mechanisms of cardiac remodeling and failure Mechanisms of cardiac remodeling and failure 3D echo Cardiac Imaging CV Imaging & Diagnostics Cardiac Imaging Ageing Cardiogenetics Cardiac Imaging Annual Report 2015 Discipline II ging & Diagnostics maging MSCT Discipline III Therapy & Prevention Technology Percutaneous Interventions CAD imaging Image Processing Peripheral Vessels Clinical Decision Making in Surgery Peripheral imaging US Transducers Stents and Restenosis Cardiac Risk Evaluation and Modification US agents CV Surgery & Anesthesiology Risk Stratification & Pharmaco Therapy CABG Role of RAAS Pharmacogenomics Image processing Aortic endografts Medical Manag. of aneurysm disease Molecular imaging 41 Manag. of hemorrhag & thrombc disorders CAD imaging Image Processing Peripheral imaging US Transducers Image Processing Primary PCI for AMI Cardioprotection Biomarkers of acute coronary event Cerebrovasc. Disease Prognosis & Clinical Manag. of Stroke Pharmacology of migraine Image Processing Stem Cell Therapy US Transducers Heart Transplantation Mapping Catheter Ablation Image Processing Cath Based Int. US Transducers Assist-Devices ICD Therapy Stratific. Outcome COEUR Themes Discipline I Aetiology & Pathogenesis Echo 42 Theme I Vascular Medicine I-A Atherosclerosis 2,4,5 I-B Disorders of the microcirculation 1,2,8 I-C Cardiovascular Genetics I-D Aneurysm disease Theme II Acute CV Syndromes II-A Hemostasis & Thrombosis II-B Acute Coronary Syndromes II-C Stroke & Migraine II-D Critical Illness and Sepsis Theme III Chronic Cardiac Disease III-A Cardiac Remodeling and Failure III-B Arrhythmias III-C Congenital heart disease 4,5,19 6,12,24 24 24 14,15 1 19 9,13 3 1,2,8,12 21 17,18 10 Annual Report 2015 Discipline II Imaging & Diagnostics Discipline III Therapy & Prevention MRI MSCT Technology Percutaneous Interventions CV Surgery & Anesthesiology Risk Stratification & Pharmaco Therapy 4,2 4,2 16,18,23 2,19 28 7,31 3 8 20 12 24 24 25 24 14,15 20 20 16,23 22 22 16,23 19 28 9,13,22 43 3,27 20,22 11,29 20,22 16,23 2,29 8,12 17,2 23,26 23 16 4,11 28 30 COEUR Project 1 Cardiac (mal)adaptation to stress and damage 44 Ischemic heart disease, in particular myocardial infarction, and hypertension are major causes of heart failure in western countries. Following myocardial infarction or chronic exposure to pressure-overload, the heart undergoes extensive alterations in muscle mass and geometry. This cardiac remodeling is associated with an increased likelihood of progression towards overt heart failure, particularly in the setting of an aging population. Research within Project Group 1 is aimed at improving our understanding of the mechanisms underlying the progression from ischemic and hypertensive heart disease towards heart failure in order to identify novel targets for therapy. For this purpose, our research focuses on the pathogenesis and therapy of (i) acute myocardial infarction, (ii) the cardiac remodeling and dysfunction that follows in the weeks after an acute myocardial infarction or in the presence of systemic pressure-overload, (iii) myocardial and coronary microvascular dysfunction and in post-infarct remodelled myocardium (iiii) pulmonary hypertension secondary to hypoxia, left ventricular dysfunction or thrombo-embolic events. Furthermore, we study (v) the effects of aging and exercise training on cardiac remodeling and dysfunction following myocardial infarction and chronic pressure overload. Finally, in view of the increasing prevalence of heart failure with preserved ejection fraction and the role therein of multiple co-morbidities we also have recently begun studying the influence of risk factors, such as diabetes, hypercholesterolemia, and renal dysfunction on coronary microvascular-, and cardiac diastolic function. Annual Report 2015 Principal Investigators DJGM Duncker, D Merkus Co-Investigators VJ de Beer, AJJC Bogers, C Cheng, AHJ Danser, RJM van Geuns, IM Heinonen, JH Hoeijmakers, M van Houwelingen, AH van den Meiracker, IKM Reiss, AJM Roks, JW Roos-Hesselink, OE Sorop, D Tibboel, F Zijlstra PhD candidates Name Subject GMJ de Boer Cardiac dysfunction in aging: The role of genomic instability RWB van Duin Pathophysiological mechanisms in pulmonary cardiovascular disease GJ van Essen Does cardiovascular performance in domestic swine obey allometric scaling laws? M van den Heuvel Coronary microvascular dysfunction in diabetes mellitus DPM Meijler Pulmonary hypertension (of the neonate) K Stam Pulmonary Hypertension and associated Right Heart Failure: breaking the vicious circle YJHJ Taverne Reactive oxygen species and the endothelium. Friend or foe of the cardiovascular system? T Yetgin Cardioprotection during primary percutaneous coronary angioplasty 45 COEUR Project 2 Experimental interventional cardiology, vascular injury and repair This interdisciplinary project focuses on percutaneous interventions in the treatment of arteries (coronary and peripheral) and their target tissues in health and disease. 1. Specifically, we study pharmacokinetics and pharmacodynamics of (device-based) pharmacologic interventions such as drug eluting stents and scaffolds on micro- and macro-vasculature. 2. The pathophysiology of arterial thrombosis in acute ischemic syndromes such as stroke and myocardial infarction. This work is performed in collaboration with projects 13 and 15. 3. The role of novel invasive and non-invasive imaging methods to assess these effects over time. 4. The sequelae of- and novel treatment strategies against- ischemia and reperfusion injury in the depending tissues e.g. using biomaterials. This work is performed in collaboration with project 1. 46 Device-based (pharmacological) interventions are performed in different species and disease models, testing various drug-eluting stents, scaffolds and other intravascular devices for their effects on micro- and macro-vasculature. To replace, reduce and refine animal experiments, we use ex-vivo vascular models where possible such as healthy and diseased cadaver arteries with heart-lung machines, organ-baths and lab-on-achip approaches. In addition, we employ a wide range of different disease models in large animals, ranging from simple interventions in healthy young animals to complex dedicated models such as diet- or diabetes induced accelerated atherosclerosis. These are used to unravel important mechanical, pharmacological and pathophysiological effects on the response to vascular injury and repair in both coronary and peripheral arterial beds. We study the diagnostic value of a number of imaging modalities (e.g. OCT, NIRS, IVUS, MSCT and MRI) in order to understand how they can help to characterize the baseline environment and to study the response of the vasculature itself as well as the effects on the depending tissues. In collaboration with TU Delft we are modelling drug transport phenomena in health and disease. We use routine and spectral histology such as mass spectrometry (MS) imaging (financed by NWO through a grant to van Beusekom) to analyze the tissues at high spatial resolution both quantitatively and qualitatively. The pathophysiology of arterial thrombosis in acute ischemic syndromes is studied in collaboration with the clinical cardiac catheterization laboratory, the dept. of Hematology and the depts. of Neurology and Radiology. This has resulted in two biobank projects, one for coronary thrombus aspirates (CorTAsk project) Annual Report 2015 and one for stroke emboli (Mr Clean biobank). One of the aims is to study how thrombus phenotype affects vascular healing, with an emphasis on NETosis, a recently discovered new thrombosis pathway which we hypothesize plays a role in (micro)vascular injury. As such, NETosis and their resultant circulating biomarkers are hypothesized to play a role in no-reflow in the area subjected to ischemia and reperfusion. Principal Investigators HMM van Beusekom, DJGM Duncker, ES Regar Co-Investigators AHJ Danser, DWJ Dippel, ACGM van Es, TM Luider, MPM de Maat, G van Soest, F Zijlstra PhD candidates Name Subject ASA Autar Arterial Thrombosis and Netosis in Acute Myocardial Infarction N van Ditzhuijzen A Karanasos JN van der Sijde Imaging of coronary interventions and early atherosclerosis in a porcine coronary model Optical coherence tomography for guiding coronary interventions and assessing the vascular healing response after coronary stent implantation Retrospective analysis of the Thoraxcenter OCT data on the impact on stent procedure and outcome 47 COEUR Project 3 The circulation, ventilation and ethics during multiple organ failure. Critical illness often results in multiple organ failure. Sepsis is a common source and the syndrome affects the circulation and ventilation among other vital organ functions. The research around this typical intensive care syndrome is thus programmed around these topics, as can be deducted from the individual projects enumerated below. Research on the circulation in the syndrome focuses on peripheral perfusion, among others. New techniques, like side stream dark field (SDF), laser speckle imaging and near-infrared spectroscopy (NIRS) have been studied for assessing microvascular perfusion in septic patients. In order to minimize inflammatory response in mechanically ventilated septic patients, a new lung monitoring device (Electrical Impedance Tomography) is used to optimize ventilator settings. Ultimately, the syndrome can be intractable, raising ethical issues on end-of life decisions. 48 Principal Investigators J Bakker, J van Bommel, DAMPJ Gommers, ABJ Groeneveld, C Ince, EJO Kompanje PhD candidates Name Subject JPC van den Akker P Blankman M Egal PJ van der Geest K de Haan B van der Hoven MMC van Mol S Stads The effect of mechanical ventilation on kidney function Optimizing ventilator settings in order to reduce inflammatory response Acute kidney injury and fluids De ProBic study and other diagnostics of infection Vitamin D in critical illness Measurement of functional liver blood flow Reducing emotional and moral distress among Intensive Care professionals Predicting initiation and discontinuation of continuous renal replacement therapy in the critically ill Improvement of care for ICU patients with delirium by early screening and treatment Z Trogrlic Annual Report 2015 Project 4 Shear-stress related plaque formation & destabilization: from bench to bedside to population studies Shear stress plays an important role in the patho-biology of the endothelium. Among others, it primes the endothelium for atherosclerotic plaque formation, which can be found at the low and oscillatory shear stress regions in the vasculature. However, evidence is accumulating for a role of high shear stress in plaque destabilization. This project focuses on a) the different (molecular) aspects of the role of low or high shear stress in the generation and destabilization of vulnerable plaques and, b) the usage of shear stress in the prediction of plaque destabilization and future events. For that reason studies are performed in animal models of vulnerable plaque formation as well as in patients that are treated for pathological lumen obstruction. For those studies a combination of computational fluid dynamics and advanced catheter based or non-invasive imaging techniques for the assessment of plaque composition is applied. Using the information from the above described studies, we investigate whether shear stress can contribute to prediction models of atherosclerotic plaque growth and events in a population based study. Principal Investigators JJ Wentzel, K van der Heiden Co-Investigators OH Franco, RJ van Geuns, FJH Gijsen, A van der Lugt, ES Regar, AFW van der Steen, MW Vernooij, TH van Walsum, GP Zahnd PhD candidates Name Subject M Cibis Image based wall shear stress measurement K Dilba Non-Invasive assessment of carotid Atherosclerotic Plaques for stroke Risk Prediction A Hoogendoorn Functional, multi-modality imaging of atherosclerotic plaque progression EJ Meester Non-invasive molecular imaging of inflammation to detect atherosclerosis AM Moerman Shear stress and atherosclerotic plaque lipodomics JTC Schrauwen Fusion of imaging parameters for prediction of plaque rupture in human coronary arteries LCJ Winkel Endothelial NOX/ROS contribution to plaque vulnerability R Xing Linking biomechanics to the biology of plaque progression: a non-invasive imaging study 49 COEUR Project 4 - continued Shear-stress related plaque formation & destabilization: from bench to bedside to population studies Calculating wall shear stress in coronary arteries - Jelle Schrauwen 50 The frictional force on the arterial wall caused by flowing of blood is called wall shear stress (WSS). It has been shown that altered WSS patterns are an important factor in the onset and progression of atherosclerosis. It has also been suggested that deviating WSS is associated with atherosclerotic plaque destabilization, which could initialize trombotic events and potentially myocardial infarction. To better understand the role of WSS in this process, it is important to develop tools that can obtain relevant WSS data. My PhD project at EMC was part of a cross-collaboration between the departments of Biomedical Engineering, Cardiology and Biomedical Image Processing, and two industry partners. I focused on computing WSS in coronary arteries of patients suffering of atherosclerosis. I worked on coupling 3D blood flow computations to several medical imaging techniques for example CT or interventional x-ray. Hemodynamic data such as coronary blood pressure or blood flow velocity is required as input for the WSS computations. I developed models to calculate that hemodynamic data and compared that with in vivo measured values. A second part of the project involved coronary OCT which is an intravascular technique that can be used to image the arterial wall in high detail. For this project, Guillaume Zahnd developed software that can automatically detect diseased sections of the coronary wall. For the at-risk regions he developed a method to precisely measure the cap thickness of a plaque, which is directly correlated with plaque rupture. These cap-thickness data from OCT were combined with the WSS data from imaging data. The combination of image-based parameters could give insight in the rupture-risk of coronary plaques, and in the future this might serve as additional information during interventional procedures. These ideas were tested in collaboration with the department of interventional cardiology. Annual Report 2015 51 Jelle Schrauwen COEUR Project 5 Biomechanics of the vascular wall Plaque rupture is in the majority of the cases the underlying cause of cardiovascular events. Plaque rupture occurs at the locations were the stress exceeds the local plaque strength. Plaques are very heterogeneous in composition and local tissue strength. However, not much is known on the biomechanical properties of the different plaque components. In this project we investigate at which pressure and at what location the plaque would rupture by studying the local stress distribution and deformation of the different plaque components under increasing loading. Therefore, in an in vitro setup atherosclerotic plaques from patients or animal models of atherosclerosis are subjected to different pressure loadings and the local deformations are imaged using advanced imaging techniques. This information will be used to validate computations on stress distributions in these plaques. Advances will be made in imaging of plaque deformation and (multiscale) modeling of the different plaque components. 52 Principal Investigators FJH Gijsen, JJ Wentzel Co-Investigators M de Bruijne,C Chiastra, F Iannacconne, A van der Lugt, WJ Niessen, L Speelman, AFW van der Steen PhD candidates Name Subject AM Kok The role of biomechanical factors in plaque progression using image based modeling Annual Report 2015 Project 6 Genetic regulation of vasculogenesis and angiogenesis In this project, we have performed a genome wide expression to identify new molecular regulators of vessel stabilization during development and disease. We have identified a list of candidate genes involved in vessel stabilization in response to endothelial cell and mural cell interaction. A number of these clones were analyzed using an in vitro co-culture approach in which endothelial cells and mural cells can interact to form tubules in a 3D matrix environment. This was followed by in vivo knockdown validation of our findings in zebrafish larvae, using morpholino technology and mutant zebrafish lines. Subsequent studies analyzed in depth the function of the novel proteins using gain-of-function and loss-of-function analysis to determine the molecular signaling cascade and the function of the proteins in vessel formation in development and cardiovascular disease. Principal Investigator C Cheng Co-Investigators DJGM Duncker, F Zijlstra 53 PhD candidates Name Subject MM Brandt I Chrifi C Zhu Molecular Endothelial-Pericyte interaction Effect of mural cell-endothelial cell interaction during new vessel formation CECR1 activity in macrophages regulates tumor angiogenesis 53 COEUR Project 6 - continued Genetic regulation of vasculogenesis and angiogenesis Molecular regulation of angiogenesis - Maarten Brandt 54 Angiogenesis is the process in which endothelial cells and perivascular cells create new vessels under the influence of a broad spectrum of stimuli. This process is tightly regulated and imbalances in signaling can be a causative or progressive factor in many vascular defect associated diseases, including tumor angiogenesis, and diabetes or metabolic risk factors related microvascular disease, leading to organ failure. A thorough insight into the molecular mechanisms involved in angiogenesis and endothelial homeostasis, are therefore essential for maintaining vascular health and subsequent prevention of disease. Potential strategies include manipulation of the (disturbed) angiogenic process by defining the basic mechanisms and changing the activation of key regulators. In our studies we try to unravel the function of several putative target genes that play important roles in angiogenesis. One of the factors that we study is Frizzled receptor 5, which is involved in the Frizzled-Wnt signaling cascade. From literature it is known that this receptor is indispensible in embryonic vascular development. Frizzled 5 knock-out mice show a lethal deficiency in placenta and yolk sac angiogenesis, but the exact molecular mechanism behind this observation still lacks clarification. Using a combination of in vitro and in vivo techniques, we try to decipher the function of this receptor in endothelial cells, and how it is involved in regulating angiogenesis. Besides focusing on specific factors involved in angiogenesis, we also study the interaction between endothelial cells and pericytes. Pericytes are perivascular cells that induce vascular stabilization, endothelial maturation and barrier formation. Besides their well described positive role in the vascular system, detached pericytes are recently implied to act as progenitors of extracellular matrix depositing cells in fibrotic organs. In our study we try to find out whether this differentiation into a scarring cell type is a direct consequence of loss of interaction with the endothelium, and if so, which cellular interaction molecules are important in preventing this trans-differentiation into a disease associated phenotype. With these projects we hope to generate basal knowledge about vascular and perivascular biology, which might eventually serve as a foundation for future therapeutic strategies. Annual Report 2015 55 Maarten Brandt COEUR Project 7 Perioperative care Cardiovascular disease is the major cause of postoperative morbidity and mortality. In Europe, 40.000.000 surgical procedures are performed every year, with a cardiovascular mortality rate of 0.3% (133.000 patients). To improve postoperative outcome, preoperative identification of patients at risk is performed using clinical risk scores, biomarkers for coronary artery disease and heart failure, and cardiac imaging. The preoperative risk assessment is linked to the intraoperative identification of acute coronary syndromes using electrocardiography and cardiac imaging as well as newly identified biomarkers. The follow-up of these patients is performed regularly, for early identification of cardiac events. The identification of a genetic predisposition in relation with biomarkers and subsequent treatment is the research line of this group. 56 Principal Investigators RJ Stolker Co-Investigators SE Hoeks, F van Lier, EG Mik, HJM Verhagen PhD candidates Name Subject GM Balestra Mitochondrial function in critical illness SIA Bodmer Measuring of mitochondrial and microvascular oxygenation W Galal Correlation of pre- and perioperative ischemia in vascular surgery F Grüne L Khajeh Changes of effective downstream pressure in cerebral perfusion under influence of anaesthetics and vasoactive drugs Benzodiazepines in perioperative care Subject Study of hemostatic and intra arterial treatment in acute ischemic stroke Surgical outcome; aparameters fresh perspective (SMARTIS) The making of the ‘MPA-16’ Genetic and non-genetic causes of dementia Measuring mitochondrial function in sepsis MR CLEAN Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke Hypopituitarism in patients after subarachnoid hemorrhage: screening and treatment CP Mendez-Orellana Mechanism of language recovery after brain damage F Nouwens Randomized trial of speech and language therapy in aphasia after stroke E Osei Treatment and prognostic value of prediabetes and newly diagnosed diabetes in patients with a TIA or minor stroke Body temperature and prognosis in acute ischemic stroke HJ Mijderwijk Name D Beumer EKM Tjeertes MHN van Velzen RFAG de Bruijn MA Wefers Bettink PSS Fransen IR de Ridder Annual Report 2015 57 Dr. Sanne Hoeks COEUR Project 8 Hypertension, the kidney and vascular ageing: focus on the renin-angiotensinaldosterone system This project focuses on hypertension, capitalizing on four pathways to discover novel intervention pathways, namely: - the role of aldosterone in difficult-to-treat hypertensive subjects, - hypertension induced by angiogenesis inhibition in patients with cancer, - the impact of genomic instability on hypertension, and vascular and renal function, and - the regulation of volume and osmoregulation in kidneys by WNKs and exosomes 58 An important unifying aspect in all the above topics, apart from the common relationship with hypertension, is the involvement of the renin-angiotensin-aldosterone system (RAAS), resulting in projects that investigate angiotensin/aldosterone interaction in the kidney, the function of the (pro)renin receptor in intercalated cells, the vasodilator effects of endothelial angiotensin II type 2 receptors (with an emphasis on gender-related aspects), the angiotensin-(1-7) / Mas receptor axis, the non-genomic effects of aldosterone in the vessel wall, and the role of RAAS- and related interventions on genomic instability-related vascular and renal dysfunction. The studies concerning genomic instability involve transgenic mice with decreased DNA repair function, and are performed in close collaboration with the Departments of Genetics and of Vascular Surgery. Studies on the importance of nucleotide phosphodiesterases in ageing occur in collaboration with the Department of Epidemiology. Annual Report 2015 Principal Investigators AHJ Danser, EJ Hoorn, AH van den Meiracker, AJM Roks, R Zietse Co-Investigators A Dehghan, DJGM Duncker, J Essers, OH Franco, JHJ Hoeijmakers, GJ van der Horst, I van der Pluijm PhD candidates Name Subject P Bautista Niño Cyclic nucleotide phosphodiesterases in vascular aging S Lankhorst Hypertension and Renal Toxicity during Angiogenesis Inhibition: Salt Dependency and Treatment Options AD Moes When salt turns sour: from kidney salt transport to hypertension LCW Roksnoer Urinary biomarkers in humans and rats: focus on diabetes and aldosteronism L Saleh The predictive value of the sFit-1/PIGF ratio for the diagnosis of preeclampsia M Salih Exosomal research on ADPKD D Severs The immune system and sodium balance 59 Name JS Biedermann Name JS Biedermann J Boender Subject Treatment with anticoagulants Subject Treatment In search ofwith newanticoagulants causes of Von Willebrand disease JHCAM Boender Hazendonk HCAM Hazendonk I van Moort LM Schütte SCM Stoof In search of Peri-Operative new causes of PharmacokineTIc-guided Von Willebrand disease dosing of CLOTting factor in hemophilia OPTI-CLOT: OPTI-CLOT: Peri-Operative PharmacokineTIc-guided dosing ofof CLOTting “OPTI-CLOT”:Peri-Operative PharmacokineTIc-guided dosing CLOTingfactor factorininhemophilia Clotting Factor Disorders Moderate and Severe Von Willebrand Disease in the Netherlands Moderate and Severe Von Willebrand Disease in the Netherlands "OPTI-CLOT":Peri-Operative PharmacokineTIc-guided dosing of CLOTing factor in Clotting DDAVPDisorders treatment combIneD with FVIII clotting factor concentrates in patients with nonFactor severe haemophilia A-DAVIDwith studyFVIII clotting factor concentrates in patients with nonDDAVP treatment combIneD Optimization of treatment of inherited bleeding disorders severe haemophilia A-DAVID study SCM Stoof Optimization of treatment of inherited bleeding disorders YV Sanders YV Sanders I van Moort LM Schütte COEUR Project 8 - continued Hypertension, the kidney and vascular ageing: focus on the renin-angiotensinaldosterone system 60 Lodi Roksnoer Annual Report 2015 ‘Targeting the renin-angiotensin-system in hypertension and diabetes’ Lodi Roksnoer Blockers of the renin-angiotensin-system (RAS) are the cornerstone in the treatment of hypertension, heart failure and diabetic nephropathy. Yet, morbidity and mortality of these diseases remain high, despite near-complete suppression of the RAS. Therefore, we need new therapeutic strategies. Neprilysin inhibitors (NEPi) prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. We studied the effects of NEPi combined with angiotensin receptor blockade (ARB) on blood pressure, vascular reactivity, and cardiac hypertrophy in hypertensive rats. We observed that rats treated with ARB plus a low dose of NEPi (ARNI) had a significantly lower blood pressure than animals treated with ARB alone. The low dose of NEPi counterbalanced the slow rise in blood pressure during prolonged RAS blockade, rather than enhancing its immediate hypotensive effect. This beneficial effect of ARNI was abolished when a ten-fold higher dose of NEPi was used, and this was associated with higher endothelin-1 levels. Therefore, apparently optimal dosing rather than maximal dosing is crucial. Next, we studied the effects of ARNI on diabetic nephropathy in hypertensive rats with diabetes. To our surprise, the slow rise in blood pressure during ARB treatment did not occur, and, therefore, ARNI was unable to exert an additional beneficial effect on blood pressure compared to ARB treatment alone. However, ARNI-treated animals did have less proteinuria, glomerulosclerosis, and cardiac hypertrophy. We conclude that these favorable, blood pressure-independent effects of ARNI versus ARB, support the application of NEPi in ARB-treated diabetic patients in future clinical trials. 61 COEUR Project 9 Pharmacology of migraine Migraine is a paroxysmal neurovascular disorder, which is 2-3 times more prevalent in women than in men. Currently available drugs for the acute treatment of migraine all constrict cranial blood vessels, which most likely mediates their therapeutic action. However, since these drugs may also constrict peripheral blood vessels, including the coronary artery, there is a concern about cardiac side effects and these drugs are thus contraindicated in patients with cardiovascular disease. We are investigating the neurovascular properties of prospective antimigraine drugs. In addition, since migraine is a major cardiovascular risk factor, we focus on the (endothelial) vascular properties of migraine patients. Because migraine occurs more often in women and depends on hormonal fluctuations such as occurring around the menstruation, we focus on the effects of (changing levels of) female sex hormones on mechanisms implied in the pathophysiology of migraine. 62 Principal Investigator A Maassen van den Brink Co-Investigators AJJC Bogers, AJ van den Bogaerdt, AHJ Danser, MF Dirven, MD Ferrari, AMJM van den Maagdenberg, GM Terwindt, AG Uitterlinden Postdocs KY Chan, KA Haanes PhD candidates Name Subject ALR Labastida KM Linstra AERB Rubio Beltrán Relation between CGRP and cardiovascular disease Migraine as determinant of stroke risk in reproductive age Peripheral microvascular function in murine models of migraine Annual Report 2015 CREW-MIST: Cardiovascular risk profile in women: microvascular status Katie Linstra The CREW-MIST study is part of the national CREW project aimed at investigating the female specific cardiovascular risk profile. Current cardiovascular risk prediction models rarely include factors exclusive to women, such as polycystic ovary syndrome (PCOS) and pregnancy-related events, such as pre-eclampsia. An important example of a female-specific cardiovascular risk factor is migraine, a neurovascular headache disorder with a high prevalence among young women (~25%). It is associated with an increased risk of cardiovascular morbidity, including a twofold increased stroke risk. Endothelial dysfunction is likely to play a pivotal role in the pathophysiology behind the association between migraine and cardiovascular disease. The pathophysiology of cardiovascular disease might be related to microvascular ischemia and endothelial dysfunction in women more so than in men. For this study, 500 women between 45 and 55 years old with a medical history associated with cardiovascular disease (PE, PCOS or stroke) will be invited. Three different parameters of microvascular health will be assessed in equal groups of women diagnosed with migraine and without migraine. Firstly, white matter hyperintensities (WMHs) on brain MRI will be quantified. WMHs are a sign of cerebral microvascular damage and are associated with cardiovascular morbidity and migraine. In addition, MRI of the heart and carotid arteries will be performed. Secondly, peripheral endothelial dysfunction will be assessed using local thermal hyperaemia (LTH), an elegant method using heating of the skin of the arm to induce changes in the dermal blood flow. Thirdly, peripheral vascular function will be evaluated using EndoPAT by measuring changes in finger pulse amplitude after occlusion of the brachial artery. We expect to gain insight into the additional impact of migraine on the vascular health of women with pre-existing cardiovascular disease and the role of endothelial dysfunction in this process. 63 COEUR Project 9 - continued Pharmacology of migraine 64 Katie Linstra Annual Report 2015 Project -10 Translational and Clinical Electrophysiology Our research projects are aimed at developing innovative diagnostic tools and therapies by implementing basic electrophysiology into daily clinical practice. Main research topics are mechanisms of (post-operative) atrial fibrillation, dysrhythmias in patients with congenital heart disease, channelopathies and development of electro-anatomical mapping techniques. Atrial fibrillation (AF) is associated with significant morbidity and mortality. The prevalence of AF will continue to rise and AF will persist to pose a major burden on public health costs. Anti-arrhythmic drugs are often not effective in eliminating AF episodes and ablative therapy is also not so successful as first assumed. The expected epidemic of AF necessitates research in order to develop preventive strategies, to improve existing treatment modalities and design novel therapies. After the discovery that paroxysms of AF can be triggered by pulmonary vein foci, isolation of the pulmonary veins was introduced as a potential curative treatment modality. It is in general assumed that in patients with persistent AF, AF has progressed from a triggerdriven to a substrate mediated arrhythmia. In these patients, persistence of AF no longer depends on the presence of a trigger (‘true fibrillation’) but is maintained by an arrhythmogenic substrate. Although animal studies have provided extensive insights into the various mechanisms that can explain perpetuation of AF, it is unknown which specific electropathological changes are relevant for the development of a substrate of persistent AF in humans. Also, it is unknown whether different cardiac diseases result in different electropathological alterations. Particularly in patients with congenital heart disease, there are no mapping data available. Clinical mapping data of AF are scarce and the available studies are often limited to parts of the atria or a small number of beats. Theoretically, multi-site high density mapping can be used to localize sources generating AF in patients with trigger-driven AF and to identify areas perpetuating AF in patients with substrate mediated-AF. Based on the premise that AF can be eliminated by ablation of either the trigger or the substrate perpetuating AF it is expected that multi-site high density mapping is a suitable tool to diagnose AF thereby allowing individualization of AF treatment. The mechanism of early post-operative dysrhythmias is studied by correlating continuous rhythm registrations with hemodynamic alterations. 65 COEUR Project 10 - continued Translational and Clinical Electrophysiology Principal Investigator NMS de Groot Co-Investigators M Götte, BJJM Brundel, AJJC Bogers, F Zijlstra PhD candidates 66 Name Subject P Bhagirath Cardiac imaging and electrophysiology (Haga) L van der Does Morphology of atrial unipolar electrograms: does it reflect the arrhythmogenic substrate underlying atrial fibrillation ? M de Graaf Cardiac imaging and electrophysiology (Haga) CA Houck Cardiac arrhythmias in patients with congenital heart disease and channelopathies P Knops The arrhythmogenic substrate of atrial fibrillation E Lanters The role of biological markers in the pathophysiology of atrial fibrillation. D de Marion The role of biomarkers in the pathophysiology of atrial fibrillation. EMJP Mouws Development of post-operative atrial and ventricular tachycardias A Rhagab Cardiac arrhythmias in patients with channelopathies TTTK Ramdjan Mechanisms underlying dysrhythmias in patients with congenital heart disease C Teuwen Cardiac arrhythmias in patients with congenital heart disease and the role of Bachman’s Bundle in development of atrial fibrillation Post-Operative Atrial Fibrillation in the 21st century A Yaksh 66 Annual Report 2015 The role of biological markers in the pathophysiology of atrial fibrillation Eva Lanters Atrial Fibrillation (AF) often progresses from a trigger dependent to a substrate mediated arrhythmia. The exact characteristics of this arrhythmogenic substrate are not completely understood. Since AF tends to recur in 40% of the patients after electrical cardioversion or isolation of the pulmonary veins, optimal understanding of the pathophysiology is of utmost importance. Persistence of AF induces atrial remodeling on an electrical, structural and contractile level. The combination of electrical and structural remodeling is also referred to as electropathology. Our novel, high-resolution intra-operative epicardial mapping procedure allows localization and quantification of electropathology in the individual patient. Biomarkers of the Heat Shock Protein (HSP) family potentially reflect the degree of atrial electropathology, as is present in patients with AF. The main focus of my research is to identify the extensiveness of atrial electropathology in patients undergoing cardiothoracic surgery, pulmonary vein isolation (PVI) or electrical cardioversion (ECV) for AF, with our mapping approach and HSPs. Epicardial mapping procedures have been performed in 600 patients undergoing cardiac surgery for ischemic, valvular or congenital heart disease, with or without AF. So far, we quantified the extensiveness of atrial electropathology during sinus rhythm in CABG patients with electrically non-remodeled (“healthy”) atria. The results of this analysis will serve as a reference dataset for all future mapping studies. Tissue samples, including blood samples and atrial appendages have been obtained from almost 200 cardiothoracic surgery, PVI or ECV patients included in the HALT & REVERSE project. The samples are currently being investigated at the VU Medical Center by our colleagues on this project. These studies will increase our understanding of the pathophysiology of AF and are steps towards the development of patient tailored treatment of AF and novel treatment strategies. Eva Lanters 67 COEUR Project 10 - continued Translational and Clinical Electrophysiology Clinical Electrophysiology Part I Principal Investigators NMS de Groot, T Szili-Torok Co-Investigator F Zijlstra PhD candidate Name Title R Bhagwandien Outcome of catheter ablation of atrial fibrillation Clinical Electrophysiology Part II 68 Principal Investigator T Szili-Torok Co-Investigators F Zijlstra Clinical outcomes of catheter ablation procedures for the treatment of cardiac arrhythmias Many patients are suffering from cardiac arrhythmias which could lead to life-threatening conditions. Catheter ablation is a well-established therapy and has been introduced in the 1980s for the treatment of these arrhythmias. During the past decades, it became a first-line therapy for several types of arrhythmias. With an increasing eligible population suffering from arrhythmias, the safety of procedures is crucial to determine which patients should be considered for ablation. Further developments are necessary to minimize complications as much as possible. In the past significant improvements have been made to increase safety and efficacy of ablation procedures, such as the introduction of irrigated-tip catheters, the use of intracardiac echocardiography, and cryo-energy ablation. New technological developments are currently available and could potentially improve the safety and outcome of ablation procedures. One of the innovations is the remote magnetic navigation system that allows remote manipulation of the catheter in the heart. It has been suggested that this system improves patient safety and offers advantages for targeting complex cardiac arrhythmias. Another development is the introduction of catheters that could measure the force that the catheter applies to the myocardium. This provides crucial information for appropriate lesion formation and improves the efficacy of the ablation procedures. Annual Report 2015 Project 10 - continued Translational and Clinical Electrophysiology The clinical electrophysiology department at the Erasmus MC aims to investigate novel innovations to improve safety and efficacy of catheter ablation procedures. The Erasmus MC plays an important role in the international publications on the remote magnetic navigation system and other technological developments for catheter ablation procedures. PhD candidates Name Title J de Heide Improving the pre-, peri-and postprocedural care of electrophysiology patients with the nurse practitioner a casemanager Z Kis The role of rotors in atrial fibrillation treatment LJ de Vries Etiology of Idiopathic Ventricular Tachycardia 69 COEUR Project 11 Percutaneous Interventions in Structural Heart Disease 70 Catheter-based treatment of structural heart disease is a recent but rapidly evolving treatment modality. At present it is primarily reserved for patients with aortic stenosis who are considered poor candidate for surgical valve replacement. As a result of ongoing research and innovations in catheter technology, bioprosthetic materials (scaffolding frame and tissue), imaging (3-4D, co-registration) in addition to operator experience, it is expected that catheter-based treatment will also be available for other forms of structural heart disease such as mitral – and aortic regurgitation, left ventricular systolic dysfunction in addition to the application of these techniques in patients who are candidate for surgical treatment. Research in this domain will encompass 1] clinical cohort research examining the safety and efficacy, the evaluation of responder and non-responder by the definition of determinants of (clinical and technical) outcome by means of single- and multicenter collaborative efforts, 2] pathophysiologic assessment of the effects of treatment on the morphology, function and haemodynamics of various cardiac components (myocardium, valves, ascending aorta) in collaboration with the department of radiology and experimental cardiology, 3] randomised clinical comparison between catheter-based and surgical treatment of structural heart disease, 4] advanced imaging allowing 3D and eventually 4D co-registration of the anatomy during treatment (collaboration with experimental cardiology, radiology and industry) Principal Investigator PPT de Jaegere Co-Investigators RPJ Budde, RT van Domburg, MJ Lenzen, FUS Mattace Raso, NMDA Van Mieghem, JJM Takkenberg, YJHJ Taverne, HJM Verhagen PhD candidates Name Subject N El Faquir Advanced imaging in planning and evaluation of TAVI L van Gils Stroke during TAVI; aetiology and preventive measures JA Goudzwaard Transcatheter Aortic Valve Replacement and the elderly Z Rahhab Innovation in mitral valve therapy R Rodriguez-Olivares Paravalvular aortic regurgitation after TAVI MJAG de Ronde-Tillmans Influence of TAVI on quality of life in elderly patients with Aortic Stenosis Annual Report 2015 Project 12 Cardiovascular genetics and metabolic diseases At the Erasmus outpatient clinic for cardiovascular genetics, family based approaches are employed to study inherited cardiovascular diseases: cardiomyopathies, congenital heart malformations, arrhythmias, dyslipidemias, diabetes mellitus, hypertension and severe premature coronary artery disease. Technical innovation is a hall mark of this research: for example, novel imaging modalities are used to identify new phenotypes and high-throughput molecular analyses are performed to identify modifier genes in addition to major locus effects. We have identified a large number of novel genes that are associated with cardiovascular disease and related traits. We perform molecular and biochemical studies to get a better understanding of the mechanisms underlying the diseases and the complications. Our clinical research is performed in patients with very rare diseases, like ßβ-myosin heavy chain defects in noncompaction cardiomyopathy, but also more common disorders of synthesis and processing of insulin in families with type 2 diabetes. 71 COEUR Project 12 - continued Cardiovascular genetics and metabolic diseases Principal Investigators EJG Sijbrands, F Zijlstra Co-Investigators CM van Duijn, ECH Friesema, M van Hoek, FUS Mattace Raso, M Michels, MT Mulder, JE Roeters van Lennep, FWM de Rooij, JW Roos-Hesselink, AFL Schinkel, AG Uitterlinden, AJM Verhoeven, MW Wessels PhD candidates 72 Name Subject KAC Berk Cognitive behavioral therapy after very low calorie diet in overweight patients with type 2 diabetes S Bos Improvement of risk stratification in patients with familial dyslipidaemia TTW van Herpt Genetic and Environmental Risk Factors of Type 2 Diabetes SM den Hoedt Functional defects of lipid metabolism in Alzheimer’s disease S Jainandunsing Pancreatic beta-cell function and type 2 diabetes RFH Lemmers HDL and vascular complications in Diabetes Mellitus type 2 M Licona-Rashid Vascular function and microalbuminuria RA Neeleman Optimizing treatment and follow-up for acute porphyric patients B Özcan Glycemic control in type 2 diabetes B Spoto Inflammatory balance and cardiovascular risk HG van Velzen Hypertrophic Cardiomyopathy R Vongpromek Lipid composition in heart and brain diseases PA Vriesendorp Risk stratification in hypertrophic cardiomyopahty R Yahya Novel diagnostic test to improve CVD risk reduction in subjects with DMII, increasing cost effectiveness and quality of life Annual Report 2015 Project 12 - continued Cardiovascular genetics and metabolic diseases Improvement of risk stratification in patients with familial hypercholesterolemia Sven Bos Familial Hypercholesterolemia (FH) is the most common metabolic disorder that is associated with premature cardiovascular disease (CVD). FH can be diagnosed by clinical criteria or genetically by identification of a pathogenic mutation in the LDLR gene, APOB gene or PCSK9 gene. These mutations cause the clinical phenotype in which LDL-Cholesterol levels are severely elevated and subsequently lead to the higher CVD risk. To lower CVD risk in FH patients cholesterol lowering agents, mainly statins, are used. The impact of statins on the life expectancy of FH patients can hardly be overestimated. Before the statin era half of men with FH and 12% of women with FH suffered from a myocardial infarction before the age of fifty. However, despite statin therapy 39% of FH patients still develop CVD. The classical risk factors: age, male sex, body mass index (BMI), hypertension, diabetes mellitus, smoking and reduces high-density lipoprotein (HDL) levels all clearly contribute to CVD risk in FH patients. But even in the absence of these classical risk factors some patients still develop cardiovascular events. The research in my project focussed on identification of FH patients who are still at increased risk despite statin treatment. For identification we investigated the non-traditional risk factor Lipoprotein (a) (Lp(a)), and used cardiovascular imaging. We found that Lp(a) was not associated with subclinical atherosclerosis in statin-treated FH patients measured by carotid ultrasonography. Interestingly Lp(a) was associated with aortic valve calcification measured by CT scanning in our FH patients. We also found that the presence and severity of aortic valve calcification are increased in FH patients compared to controls. Currently, we are investigating the clinical applicability of carotid ultrasonography in the statin-treated FH patient, and are trying to find novel biomarkers related to CVD in FH patients by using proteomic techniques. AC van Dijk QJA van den Bouwhuijsen MJ Berghout- van Gils Name Imaging atherosclerotic plaque in ischemic stroke coronary heart disease and stroke The predictive value of vulnerable plaques in the carotid arteries for risk of determinants and prognosis of change in volume composition and morphology Serial CT Angiography of atherosclerotic carotid plaque: Subject 73 COEUR Project 13 Stroke: risk factors and etiology, prognosis and treatment 74 Stroke is a heterogeneous disease; it comprises ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage. Stroke is a high-ranking cause of death and the most common cause of acquired disability in The Netherlands and Western Europe. Causes of disability include motor dysfunction and disturbances of language, memory and cognition. Etiologic studies within this project include genetics, hemostasis (von Willebrand factor, fibrinogen), glucose metabolism, cardioembolic disorders, and carotid plaque morphology (PARISK). New translational research will be aimed at microvascular obstruction after thrombectomy in acute ischemic stroke. Intervention studies include a series of multicenter RCT’s of the effect of prevention of high body temperature and fever (PAIS). Also, we conducted a large national multicenter study of the effect of intra-arterial treatment for acute ischemic stroke (MR CLEAN), which is now extended into a national registry of thrombectomy interventions, and includes a database with thrombus material and neuro-imaging. Furthermore, we evaluate early cognitive linguistic treatment of aphasia in a series of multicenter RCT’s (RATS) and the value of functional imaging (FIAT) in patients with aphasia caused by stroke. Data for genetic, prognostic and etiologic studies are derived from the Erasmus Stroke Study, an ongoing hospital based registry, and from the Rotterdam study, a large population based cohort study. Annual Report 2015 Principal Investigators DWJ Dippel, PJ Koudstaal Co-Investigators HMM van Beusekom, CM van Duijn, BJ Emmer, MH den Hertog, MA Ikram, F van Kooten, LML de Lau, FWG Leebeek, HF Lingsma, A van der Lugt, MPM de Maat, M Smits, PhD candidates EW Steyerberg, EJG Sijbrands, MW Vernooij, EG Visch-Brink Name Subject D Beumer Study of hemostatic parameters and intra arterial treatment in acute ischemic stroke (SMARTIS) PSS Fransen MR CLEAN Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke L Khajeh Hypopituitarism in patients after subarachnoid hemorrhage: screening and treatment MJHL Mulder MR CLEAN REGISTRY F Nouwens Randomized trial of speech and language therapy in aphasia after stroke E Osei Treatment and prognostic value of prediabetes and newly diagnosed diabetes in patients with a TIA or minor stroke IR de Ridder Body temperature and prognosis in acute ischemic stroke 75 COEUR Project 13 - continued Stroke: risk factors and etiology, prognosis and treatment RATS-3: Rotterdam Aphasia Therapy Study; a randomized controlled trial on early intensive treatment for aphasia due to stroke - Femke Nouwens 76 Aphasia, one of the possible consequences of stroke, affects language-processing and can have a large impact on everyday life. Hence, most patients with aphasia receive speech and language treatment (SLT). In the prior Rotterdam Aphasia Therapy Studies (RATS-1 and RATS-2) we studied one particular type of SLT: cognitive-linguistic treatment (CLT). It has been hypothesized that CLT positively interacts with poststroke spontaneous neural recovery, as CLT supposedly triggers specific neural pathways for language processing. Since neural recovery occurs temporarily after stroke, supposedly CLT should be initiated as soon as possible. In RATS-3 we tested the hypothesis that early initiated intensive CLT is more effective than deferred regular SLT for the recovery of aphasia due to stroke. Over 80 Dutch institutions participated in this multi-center randomized controlled trial. Between January 2012 and December 2014 we have included 153 patients with aphasia caused by stroke, and randomly allocated them within two weeks after stroke to either four weeks of intensive CLT or no language treatment, followed by usual care. Although early intensive treatment is widely promoted in rehabilitation-medicine, it appeared very difficult to reach the intended treatment intensity of 28 hours in 4 weeks. We found no statistically significant differences on the primary outcome (everyday verbal communication) between the intervention group and control group. Our findings show that an early boost of CLT is not more effective than later initiated usual care for the recovery of post-stroke aphasia. Hence, there appears no urgency to start impairment-based treatment as soon as possible after stroke. We expect that our results will raise a sturdy discussion in the field of rehabilitation-medicine, as early treatment is currently highly stimulated. However, we now know that a later start is not detrimental, and in the light of budgetary limitations in health-care, reorganization of aphasia rehabilitation may be considered. Annual Report 2015 77 Femke Nouwens COEUR Project 14 Management of hemorrhagic and thrombotic disorders Clinical studies on bleeding disorders, including von Willebrand disease (VWD) are currently performed within this theme. The Von Willebrand disease in the Netherlands (WiN) study is a nation-wide study coordinated by the ErasmusMC (PI Prof dr Frank W.G. Leebeek) on the clinical aspects of VWD. In this study more than 800 patients with moderate and severe VWD are included. We have studied the impact of the disease on quality of life and obtained more insight in diagnosis and disease burden. In addition we focus on optimal treatment of this bleeding disorder. In the future we will focus on the genotype-phenotype association. The etiology, diagnosis and treatment of various clinical entities of venous thrombosis are also focus of our research. One of our interests is the site specificity of venous thrombosis, for instance hepatic and portal vein thrombosis. In collaboration with other partners we have initiated studies on prevention and treatment of arterial and venous thrombosis using new oral anticoagulant drugs, including direct factor IIa and Xa inhibitors. 78 Principal Investigators FWG Leebeek, MJHA Kruip, MH Cnossen Co-Investigators MPM de Maat, DC Rijken PhD candidates Name Subject JS Biedermann Treatment with anticoagulants J Boender In search of new causes of Von Willebrand disease HCAM Hazendonk OPTI-CLOT: Peri-Operative PharmacokineTIc-guided dosing of CLOTting factor in hemophilia EJ Huisman Trombocytopathy in children I van Moort "OPTI-CLOT": Peri-Operative PharmacokineTIc-guided dosing of CLOTing factor in Clotting Factor Disorders LM Schütte DDAVP treatment combIneD with FVIII clotting factor concentrates in patients with nonsevere haemophilia A-DAVID study SCM Stoof Optimization of treatment of inherited bleeding disorders CSB Veen Unexplained bleeding tendency - new diagnostic options Annual Report 2015 Project 15 Role of hemostasis in arterial thrombosis The studies performed in this theme are focusing on the role of coagulation factors and platelets in the development of arterial thrombosis. Several case-control studies have been initiated to investigate the role of hemostatic or inflammatory factors in determining the risk of first and recurrent arterial thrombotic events, including stroke and acute coronary syndrome. Our special interest is on von Willebrand factor and fibrinolysis. Several genetic approaches are used, including GWAS, SNP and haplotype analysis. We have obtained more insight in the mechanism of fibrin formation and fibrinolysis by identifying new proteins binding to fibrin using plasma proteomics techniques. In the coming years we will also focus on the role of alpha-2-antiplasmin in arterial thrombosis. The effect of fibrin structure on the risk of thrombosis and the relationship with atherosclerosis and angiogenesis, is studied using recombinant and plasma-purified fibrinogen forms. Principal Investigators FWG Leebeek, MPM de Maat, DC Rijken Co-Investigators JW Deckers, DWJ Dippel, PJ Koudstaal Post-doc S Uitte de Willige PhD candidates Name Subject S Abdul Regulation of fibrinolysis by alpha-2-antiplasmin MAH Sonneveld Von Willebrand factor, ADAMTS13 and the risk of stroke 79 COEUR Project 15- continued Role of hemostasis in arterial thrombosis Regulation of fibrinolysis by alpha-2-antiplasmin- Shiraaz Abdul 80 Cardiovascular thrombotic disease, a major cause of morbidity and mortality, is characterized by partial or complete occlusion of an artery by a thrombus or blood clot. Blood clots, mainly composed of fibrin, can be dissolved by the fibrinolytic system via plasmin which on its turn is tightly regulated by its main natural inhibitor alpha-2-antiplasmin (a2AP or Plasmin Inhibitor). In the circulation, a2AP exists in different molecular forms by undergoing N- and C-terminal proteolytic cleavages. This heterogeneity has a huge impact on the functionality of a2AP. My project aims to fully elucidate the role of a2AP and its heterogeneity in pathological thrombus formation and dissolution and will include the biochemical characterization of a2AP N- and C-terminal variation and functionality and further evaluation of the clinical relevance of a2AP heterogeneity. Studies have already elucidated the N-terminal cleavage site and responsible protease, which affects a2AP crosslinking to fibrin. Crosslinking of a2AP to fibrin renders fibrin less sensitive for breakdown by plasmin. In contrast, the exact C-terminal cleavage site(s) and protease(s) responsible for this cleavage are still unknown. Recently, we have identified a candidate C-terminal cleavage area at an interesting location in the a2AP C-terminus. This candidate region will be used to further identify the responsible protease by using a2AP recombinant mutants proteins. We will assess the relevance of this cleavage site by measuring antigen levels of the different a2AP molecular forms and the protease in patient samples. These studies, focusing on N- and C-terminal variation, will improve our knowledge of the mechanisms that regulate a2AP function and eventually will help us identify novel therapeutic targets for treatment of thrombotic disorders like Myocardial infarction, Ischemic Stroke and Venous Thromboembolism. Annual Report 2015 81 Shiraaz Abdul COEUR Project 16 Ultrasound Contrast agents Ultrasound contrast agents (UCA) consist of gas microbubbles (1 – 10 µm) that are coated by a protein, lipid or polymer. In addition to their diagnostic value, microbubbles have great potential as local drug delivery systems. In project 16 we investigate the clinical and the more fundamental/ future use of UCA and targeted UCA. The clinical use includes the left ventricle opacification and myocardial perfusion during normal and stress echocardiography. Further, a clinical study (ParisK) is running to detect the presence and properties of atherosclerotic plaques in the carotid artery after administration of UCA. 82 Future use of UCA lies in ultrasound molecular imaging by using targeted microbubbles that bind to cellular disease processes. These targeted microbubbles are functionalized using specific ligands and injected into the human body. Upon excitation by an appropriate ultrasonic field the microbubbles start to vibrate thereby acting as an ultrasound source. This source shows a very specific signature which differs to a great extent from the scattering by normal/pathological tissue. For therapy the bubble can be either loaded with the drug of choice where the drug can be locally released upon ultrasound and/or the vibrating bubble is used to enhance the uptake of the drug. Essential in this whole process is the knowledge of the vibrating bubble, the ultrasound field, and the imaging capabilities of the ultrasound system. Principal Investigator N de Jong Co-Investigators FJ ten Cate, K Kooiman, AFL Schinkel, AFW van der Steen Postdoc HJ Vos PhD candidates Name Subject DI Beekers Microbubble-mediated Drug Delivery T van Rooij Molecular Ultrasound Imaging IV Skachkov Sonodrugs J Viti Ultrasound contrast imaging methods for perfusion measurements Annual Report 2015 Project 17 Echocardiography: Transducers and image processing Research focuses on novel ultrasound transducers and image processing for ultrasound, with a strong accent on novel 3D and high-framerate cardiovascular imaging. This includes matrix transducers, electronics and new beam forming for 2D and 3D imaging of the heart, the carotid artery etc. Cardiac shear wave elastography is an important topic. Moreover, image processing approaches for 3D image generation, 2D and 3D image analysis and quantification by segmentation, tracking and classification are pursued. Current applications include improved real-time 3D TEE and 3D ICE imaging, 3D echocardiography analysis, myocardial stiffness assessment for diastolic heart failure, 4D mapping of flow in the heart, 3D imaging and analysis of plaque in carotid arteries, and monitoring and procedure guidance of electrophysiological interventions with 3D ultrasound. This COEUR project currently includes the MICA, PUMA, Heartin4D, 4DFlow, 3DICE and IMAGIC projects. All of these are embedded within the Medical Delta framework and involve cooperation with TU Delft and/or Leiden University Medical Center. The research is strongly aimed at fast clinical translation. The projects are all strongly governed by the demands and feedback of (tentative) clinical users within the Thoraxcenter and beyond. New technology is mostly developed on experimental research scanners, tested on phantom, ex-vivo and preclinical material, and tested on volunteers and patients with clinical systems as soon as this is feasible and allowed. Good contacts with ultrasound machine and transducer manufacturers assure a fast transition into commercially available equipment. Principal Investigators JG Bosch, N de Jong, AFW van der Steen, HJ Vos Co-Investigators ML Geleijnse, A van der Lugt, T Szili-Torok, MD Verweij Postdocs BM van Dalen, P Kruizinga PhD candidates Name Subject D Bera Miniature ultrasound probe for real-time three-dimensional imaging and monitoring of Cardiac interventions JD Voorneveld Heart Failure and 4D Flow 83 COEUR Project 17- continued Echocardiography: Transducers and image processing 84 Deep Bera Annual Report 2015 Miniature ultrasound probe for real-time three-dimensional imaging and monitoring of cardiac interventions - Deep Bera Transesophageal echocardiography (TEE) produces high quality ultrasound images of the heart. Unlike a standard transthoracic echocardiogram, the transducer is mounted on a tube that passes through the patient’s mouth, into patient’s esophagus. Currently, 3D TEE is used for real time diagnostic imaging and image guidance in adults. There is no real time 3D imaging device for babies and infants because of the relatively large diameter of the probe. TEE procedures in adults fail in 5-10 % of cases due to the high level of discomfort (or intolerance) caused by the large probe in the throat. Real time 3D imaging for visual feedback in electrophysiology procedures and valve replacements in adults is becoming increasingly important. Rhythm disorder treatments are life-saving but lengthy interventions that last up to 4-6 hours. The patient should be awake in many cases, so the discomfort of a large 3D probe is prohibitive. Therefore, one possible solution could be a miniature 3D TEE probe which is suitable for small children and can be inserted via patient’s nose (which is also unpleasant) causing less discomfort to the patient. The aim of this project is to design a miniature 3D TEE probe with dimensions similar to a pediatric 2D TEE probe (head volume approx. 1cm³, tube 5mm). Such a probe should contain built-in electronics to accommodate the large number of elements (approx. 900) with a very limited number of cables (approx. 200) in the tube. The heat dissipation should be very low to prevent tissue heating. Very recently we have successfully built the first of its kind low power (approx. 250mW) prototype 3D TEE transducer with the dimensions as mentioned earlier, in collaboration with our partner research groups in TUDelft and partner company Oldelft. This transducer includes a custom-designed integrated circuit to achieve the functionalities we have in mind. At this moment we are characterizing the properties of the probe and doing 3D imaging experiments with it. We are also developing the signal processing tools needed to produce 3D images using this probe. Later we will realize the real-time monitoring and fusion with multimodality applications e.g. CT or MRI. With the integrated position sensor and full control of the 3D beamforming, a unique device for interventional monitoring can be realized. We are very hopeful that this will lead us to a new era of 3D TEE usage. 85 COEUR Project 18 Intravascular ultrasound techniques Intravascular imaging is momentarily highly focusing on characterizing the composition of the atherosclerotic plaque. Characterizing lipid content, plaque vascularization and thickness of thin caps are of particular interest. These characteristics discriminate a stable plaque from a rupture prone or vulnerable plaque. The latter one can cause myocardial infarctions or stroke. Plaque vascularization is measured by intravascular ultrasound in combination with ultrasound contrast agents. Several strategies are developed to characterize lipid content. These are based on optical coherence tomography or combination catheters where light and sound are combined. 86 Principal Investigator AFW van der Steen Co-Investigators G van Soest, ES Regar Postdocs V Daechin, T Wang PhD candidates Name Subject M Gnanadesigan Tissue characterization of the atherosclerotic plaque using optical coherence tomography S Iskander-Rizk Photoacoustic guidance of RF ablation for atrial fibrillation J Janjic Image-guided Interventions and Therapy-Chronic Total Occlusions (IGIT-CTO) A Karanasos Innovations in the use of clinical OCT R Pakdaman Intelligent catheters in advanced systems for interventions M Pekar Endovascular devices for intracardiac application M Visscher Imaging Atheromics M Wu Intravascular photoacoustic imaging Annual Report 2015 Project 19 Intravascular imaging and interventional cardiology The decision making process for patients with obstructive coronary artery disease requiring revascularization is evolving. Historically, patients with the most complex coronary artery disease were preferentially treated by surgical revascularization: however technological advances in percutaneous therapy have ensured that many of these patients can now receive equally effective treatment with percutaneous coronary intervention (PCI). Intertwined with these developments are a lower threshold to investigate patients with symptoms suggestive of coronary artery disease, an increasingly elderly population in need of revascularization, the changing dynamics of the doctor-patient relationship, and a greater emphasis on guideline driven patient care. Consequently decisions regarding revascularization are now more complex than ever before. The advent of drug eluting stents (DES), which consist of a drug (immunosuppressive or antiproliferative drug), a polymer and a metallic platform, has revolutionized the practice of interventional cardiology by significantly reducing the rates of restenosis and repeat revascularization as compared to bare metal stents. The latest development includes the development of a bioresorbable platform eluting similar antiproliferative drugs trying to reduce the long-term negative impact of a permanent implant. Within this project, this subject is studied in detail while taking into account evolvement in stent development, as well as secular trends in acute and chronic benefits of percutanuous coronary interventions. Principal Investigators RJM van Geuns, PW Serruys Co-Investigators H Boersma, J Daemen , RT van Domburg, HM Garcia Garcia, PPT de Jaegere, ES Regar, AFW van der Steen, F Zijlstra PhD candidates Name Subject FC Costa RD Diletti Bleeding and Thrombosis during percutaneous coronary intervention Coronary Artery Atherosclerosis and Restoration Therapy in Bioresorbable Vascular Scaffold Era Bioresorbable Absorb scaffolds in complex lesions Bioresorbable vascular scaffold (BVS) in real world patients Renal Sympathetic Denervation Prognostic Impact of Left Main Coronary Artery Anatomy Upper Extremity Dysfunction Post TR-PCI J Fam CM Felix L Feyz CHD Girasis EM Zwaan 87 COEUR Project 19 - continued Intravascular imaging and interventional cardiology BVS in real-world patients - Cordula Felix 88 Drug-eluting stents (DES) currently form the mainstay of coronary devices used in percutaneous coronary interventions (PCI) in many parts of the world. Despite advantages in clinical outcomes such as reduction in target lesion revascularization rates within the first year, shortcomings related to the use of DES still exist such as delayed arterial healing, late stent thrombosis and hypersensitivity reactions to the polymer. In addition, from a physiological point of view, a vessel that is indefinitely caged in a metal stent may not be desirable with long-term implications and adverse consequences such as impaired endothelial function, the reduced potential for vessel remodeling, interference with the normal arterial healing process and the risk of occlusion of covered side branches by neointima hyperplasia. Follow-up after one year post implantation has shown a consistent late re-intervention rate where even some of the initial benefit is lost. Furthermore, interference with non-invasive imaging (cardiac computed tomography or magnetic resonance imaging) during patient follow-up and possible impairment of future treatment options (re-PCI or coronary artery bypass surgery) are drawbacks of metallic stents. To overcome these limitations, bioresorbable scaffolds (BRS) were developed. The BRS most studied is the Absorb bioresorbable vascular scaffold (BVS). The BVS provides transient vessel support and gradually elutes the anti-proliferative drug everolimus. After degradation of the polymer no foreign material remains. Multiple studies have proven safety and feasibility of the BVS. However, in- and exclusion criteria were rather strict and extrapolation to a more complex population is limited. The aim of my research is investigating the performance of the BVS in a more real-world patient population, including specific subsets as long lesions, bifurcation lesions and thrombotic lesions in the setting of an acute coronary artery syndrome. Annual Report 2015 89 Cordula Felix COEUR Project 20 Cardiac Imaging (MRI and CT) 90 The advanced cardiac imaging group is a joint initiative by the departments of cardiology and radiology and collaborates with several (pre-) clinical departments within the Erasmus MC. In 2015 research activities included assessment of several technological innovations and new clinical applications, i.e. computational fluid dynamics and stress myocardial perfusion imaging to assess the hemodynamic significance of obstructive coronary disease. Results from an on-site CT derived FFR algorithm were published this year, and participation in an international registry on the value of CT derived FFR will start in 2016. Together with the University of Tübingen the Erasmus MC will lead a multicentre validation study (SPECIFIC trial) of dynamic stress perfusion CT, which will start enrolment early 2016. Ongoing investigation into the implementation of cardiac CT in clinical practice includes the use of cardiac CT in patients with stable angina (fast-track chest pain clinic), to exclude coronary disease in patients with congestive heart failure, and as a tool for triage of acute chest pain in the emergency ward. Two clinical multicenter trials (CRESCENT and BEACON), a collaboration between a total of ten Dutch centers, were completed in 2015. The CRESCENT 2 trial (with Albert Schweitzer Hospital, Maasstad Hospital and Maastricht UMC) completed enrolment, and enrolment in the IsoCOR trial, which compares the effectiveness of two different contrast media for coronary imaging, started enrolment. The results of the CAMPER trial, into the potential role of cardiac CT in high-risk populations, were accepted for publication. Combined with positron emission tomography, the value of CT imaging is investigated in the context of prosthetic valve endocarditis. For cardiac MRI, 4D flow imaging has been investigated in particular for patients with congenital heart disease. The group also supports research projects focussed on reduction of the myocardial infarct size and the treatment of systemic and pulmonary hypertension. In an international multicentre registry the use of T1-mapping for the quantification of diffuse myocardial fibrosis is applied in patients with hypertrophic cardiomyopathy. Annual Report 2015 Principal Investigators K Nieman, RPJ Budde, RJM van Geuns Co-Investigators M Dijkshoorn, MGM Hunink, WJ Niessen, M Ouhlous, JW Roos-Hesselink, PA Wielopolski PhD candidates Name Subject RG Chelu Advanced MRI techniques A Coenen Imaging in advanced coronary artery disease A Dedic Clinical application of CT coronary angiography AS Dharampal Cardiac CT GJR ten Kate Imaging of coronary arteries by MSCT M van Kranenburg CMR of acute myocardial infarction MM Lubbers Clinical implementation of cardiac CT SL Papadopoulou Coronary atherosclerotic plaque imaging with MSCT T Springeling Acute myocardial infarction and MRI 91 COEUR Project 20 - continued Cardiac Imaging (MRI and CT) Clinical use of CARDIAC CT - Marisa Lubbers Stable angina is a common and disabling disorder, characterized by discomfort to the chest, typically provoked by exertion or stress. It is caused by atherosclerotic degeneration of the coronary artery wall, resulting in vessel lumen narrowing limiting the ability to increase blood flow and supply of oxygen to the myocardium at instances of increased demand. The current guidelines still recommend stress tests as first line diagnostic test for patients with stable chest pain. While considered cost effective, the functional stress test is also known for its modest diagnostic accuracy, which in practice often leads to multiple testing. 92 Cardiac CT is an alternative modality for diagnosing coronary artery disease. Its high sensitivity and negative predictive value makes it an excellent diagnostic examination to rule out coronary artery disease. In the multicenter CRESCENT trial, conducted in 4 hospitals in the Rotterdam region, 350 patients with stable angina were prospectively randomized between cardiac CT and standard functional testing. The tiered cardiac CT protocol included a calcium scan followed by CT-angiography if the Agatston calciumscore was between 1-400. We found that one year after a cardiac CT scan, more patients were free of angina compared to patients in the functional testing group. Furthermore, after cardiac CT additional tests were required less frequently, the final diagnosis was established sooner, resulting in lower cumulative diagnostic costs. This trial is followed by the CRESCENT-2 trial, in which we added myocardial perfusion imaging to the CT algorithm. As CT-angiography has a relatively low specificity, the addition of adenosine-stress myocardial perfusion CT imaging, assessing the functional relevance of coronary narrowing, completes the non-invasive cardiac CT evaluation. If >50% obstructive coronary disease is found on CT angiography, it is followed by perfusion imaging: after coronary vasodilation by adenosine infusion CT images of the myocardium will be acquired during injection of iodine contrast medium. Reduced opacification of myocardium indicates myocardial ischemia. The effectiveness and (cost-)efficiency of this comprehensive cardiac CT workup of suspected coronary artery disease will be evaluated in comparison to standard functional testing. Annual Report 2015 93 Marisa Lubbers COEUR Project 21 Cardiac imaging (ultrasound) Echocardiography is one of the most important diagnostic tools in cardiology. Recent advances in ultrasound hardware and software have made 3-dimensional echocardiography and speckle tracking echocardiography possible. These techniques are used for estimation of left ventricular function according to the classically defined volumes and ejection fractions but also deformation and rotation imaging. Finally, plane-wave imaging is a new research tool to investigate stiffness of the heart. Principal Investigator ML Geleijnse Co investigators RT van Domburg, AFL Schinkel PhD candidates 94 Name Subject HJ Boiten Long-term outcome after cardiac stress imaging F Kauer Speckle Tracking Echocardiography in hypertrophic cardiomyopathy M Strachinaru Diagnosing diastolic heart failure by myocardial stiffness with ultrasound shear wave technique Annual Report 2015 Project 22 Neurovascular imaging (MRI and CT) Ischemic cerebral infarcts are related to the presence of atherosclerotic disease in the carotid artery. Severity of the stenosis is a predictor of clinical symptoms and is used as parameter in the therapeutic decision as to which patients will benefit from carotid intervention. Next to stenosis, plaque morphology is thought to be a major determinant of cerebrovascular events. Within this project, imaging of the atherosclerotic plaque in the carotid bifurcation with multidetector CT and MRI is evaluated. We focus on 1) the validation of imaging parameters by comparison of images with histology, 2) development of new structural and haemodynamic parameters of atherosclerotic disease, 3) development and validation of automated measurements, 4) prospective studies in patients and healthy volunteers to prove the additional value of plaque parameters in risk prediction, 5) serial imaging studies to evaluate the natural course of the atherosclerotic disease, 6) studies into the relationship between atherosclerotic plaque parameters and brain infarcts and white matter lesions on CT and MRI. 95 Principal Investigator A van der Lugt Co-Investigators D Bos, DWJ Dippel, OH Franco, PJ Koudstaal, WJ Niessen, HJ Verhagen, MW Vernooij PhD candidates Name Subject MJ Berghout- van Gils Serial CT Angiography of atherosclerotic carotid plaque: determinants and prognosis of change in volume composition and morphology QJA van den Bouwhuijsen The predictive value of vulnerable plaques in the carotid arteries for risk of coronary heart disease and stroke AC van Dijk Imaging atherosclerotic plaque in ischemic stroke T Zadi Silent MR Angiography COEUR Project 23 Image processing (Cardiovascular) Cardiovascular imaging has gone beyond the traditional depiction of vascular luminal morphology. Stateof-the art imaging techniques have the potential to provide detailed information on the vessel wall, such as plaque composition, elastic wall properties, and even biochemical processes that take place in the plaque. In addition, dynamic and perfusion imaging can provide functional information, e.g. for determining the perfusion or motion of the heart, or to study tumor activity. Owing to the growing complexity and sheer size of cardiovascular data, in combination with the large increase in the number of studies in clinical practice and biomedical research, there is a strong and increasing interest in robust, automated processing tools to aid in the analysis of these data. This research line aims to develop and evaluate novel image processing techniques for visualization, quantification, and integrated analysis of multimodal anatomical and functional cardiovascular imaging data. 96 Principal Investigator WJ Niessen Co-Investigators M de Bruijne, RJM van Geuns, S Klein, GP Krestin, A van der Lugt, AFW van der Steen, Th van Walsum, JJ Wentzel PhD candidates Name Subject A Arias Lorza Image analysis of the carotid artery for assessment of biomechanical stress on atherosclerotic plaques G Dibildox Computer Aided Image Guidance for Percutaneous Treatment of Coronary Chronic Total Occlusions Hua Ma IMAGIC - intelligent image guidance in cardiac interventions EMM Santos Automated Intracranial Thrombus Quantification and Characterization in Computed Tomography Annual Report 2015 Influences of clot permeability on treatment success and functional outcome in patient with acute ischemic stroke - Emilie Santos Acute ischemic stroke (AIS) is a medical emergency and requires fast accurate diagnosis and optimal treatment decisions to prevent lifelong disability or death. To identify patients with a higher likelihood of response to a particular treatment, imaging biomarkers reflecting pivotal clots characteristics from baseline imaging is essential. AIS diagnosis and treatment decisions are often supported by Computed Tomography (CT) imaging. Non-contrast CT and CT angiography (CTA) are attractive due to their speed and wide availability as their protocols are in current acute care practice in many clinical centers. Based on a combination of CT and CTA imaging and simple manual measures, “thrombus perviousness” was developed. This biomarker reflects the permeability of the occulting clot by measuring the contrast penetration in CTA images. It is expected that clot permeability may increase downstream tissue oxygenation, improve thrombus dissolution, and augment treatment success. The clinical relevance of the thrombus perviousness was recently confirmed in the MRCLEAN population, where strong relationships were found between the measured perviousness and patient functional outcome and recanalization rate. Similar analysis on the DUST dataset demonstrated strong association with intra-venous (IV-rtPA) treatment efficiency, making this measure an excellent candidate for AIS patient stratification in acute clinical diagnosis settings. However, in CT angiography, the quality of the image is strongly affected by the timing of imaging such that variations in contrast agent arrival in these CTA images may result in suboptimal perviousness measurement. Furthermore, the use of manual assessment of the contrast agent penetration in the clot is observer dependent and prone to bias. Current researches focus on the resolution of potential delayed filing from CTA images and the uses of automated measures based on computer vision. 97 COEUR Project 23 - continued Image processing (Cardiovascular) 98 Emilie Santos Annual Report 2015 Project 24 Molecular biology of aneurysm formation In the basic research line ‘Molecular biology of aneurysm formation‘ of the Laboratory for Experimental Vascular Surgery (LEVAS), the molecular processes that underlie aneurysm formation are investigated through close collaboration between the department of Genetics & Cell Biology and the department of Vascular Surgery. The goal of this translational research line is to decrease aneurysm related mortality and reduce the need for surgical intervention. Consequently, we focus on two research areas: 1) early detection of degenerative changes in the aortic wall, and 2) pharmacological intervention to treat aortic wall degeneration. To this end we make use of the scientific expertise and state-of-the-art infrastructure of our research institute as well as the practical implications, anonymous patient data and bio-bank of the clinical research group. This intensive collaboration ensures innovative basic research based on clear clinical relevance. This research line is embedded in the Erasmus MC research schools Medical Genetics Centre South-West Netherlands (MGC) and COEUR in collaboration with among others the departments of pharmacology, cardiology, clinical genetics, bioinformatics and biochemistry. Principal Investigator J Essers Co-Investigators K Caliskan, AH Danser, DJGM Duncker, R Kanaar, DF Majoor-Krakauer, JW Roos-Hesselink, EV Rouwet, PJ van der Spek, HJM Verhagen, MW Wessels, WFJ van IJcken Postdoc I van der Pluijm PhD candidates Name Subject L te Riet Dilating versus stenosing arterial disease; identification of the genetic factors involved in aortic aneurysm formation BS van Thiel Characterization of aortic aneurysm disease and the development of therapeutic strategies JI van Waning NCCM (noncompaction cardiomyopathy) 99 COEUR Project 25 Endovascular Management of Aortic Aneurysms Aortic pathology like aneurysms, dissections and traumatic ruptures were traditionally treated by open surgery repair. In the last decade, endovascular technology became available as a minimally invasive alternative. Like with all other new and innovative treatment modalities, results, especially long-term, are unknown and it remains unclear whether this minimal invasive treatment is beneficial for all patients or only for the ones declared “unfit for surgery”. Furthermore, many uncertainties remain on the best indications for stentgraft placement: is it only advisable for aneurysmal disease or should it be used for all aortic pathology known to eventually lead to life-threatening dilatation of the aorta. If so, in what stage of the disease should it be used: as treatment or as prevention? Can it be seen as definitive treatment or will it turn out to be just a “bridge to surgery”? Within this project, many sides of this new treatment are being investigated. 100 Principal Investigator HJM Verhagen Co-Investigators JA Bekkers, B Muhs, E Rouwet, F Schlosser, O Schouten PhD candidates Name Subject SA Cornelissen Advances in imaging after EVAR JMW Donker Modern outcomes in Vascular Surgery FHW Jonker Thoracic Aortic Catastrophies, towards an endovascular solution J van Keulen Endovascular management of Aortic Pathology JH van Laanen Long-term CAS KM vd Luijtgaarden Familial Aneurysms NF Gomes Oliveira Controversies in endovascular aortic repair KHJ Ultee Clinical Outcome of Endovascular Treatment for Elective and Ruptured Abdominal Aortic Aneurysms Annual Report 2015 Project 26 Improvement and risk modeling in the prevention of sudden cardiac death Heart failure (HF) remains an important issue in cardiology because of its high mortality and morbidity. Sudden cardiac death is responsible for up to 50% of the reported mortality. The implantable defibrillator (ICD) has proven to be effective in reducing arrhythmic death in selected patients with ischemic or nonischemic cardiomyopathy and reduced left ventricular function. Despite the efficacy in terminating ventricular arrhythmias, there is an on-going debate on further risk stratification of patients who will benefit most from ICD implantation. The benefit of the ICD is attenuated by the presence of comorbidities. Identification of those patients at high risk for mortality who may not derive benefit from ICD implantation is important for optimal patient selection of this therapy. Erasmus MC has a cooperation with the University Hospital Basel and Seattle University for further development of risk estimation models in primary prevention of sudden death for better patient identification. Next to risk modeling and clinical aspects of patients at risk for sudden death, efforts are made to incorporate patient-reported outcomes in clinical practice and decision-making. Erasmus MC has a cooperation with Tilburg University and University of South-Denmark Odense for research focusing on patient-reported outcomes. In addition, Erasmus MC has played a role in the development of new innovative technologies in the prevention of sudden death, like implementation of remote monitoring and the development of subcutaneous defibrillator. Principal Investigator DAMJ Theuns Co-Investigators MGM Hunink, LMJL Jordaens, SS Pedersen PhD candidates Name Subject L Dabiri Abkenari Actual Insights on Prophylactic ICD Therapy SDA Valk Approaches to ventricular tachycardia and sudden death 101 COEUR Project 27 Surgical aspects and clinical decision making in cardio-thoracic (including pulmonary) interventions 102 This project concerns outcomes research, risk modelling, decision making, innovative statistical analysis and health technology assessment of appropriate diagnostic and therapeutic measures in the area of cardiothoracic interventions. Technological developments in surgery (and interventional cardiology as well) and peri-operative/ peri-procedural care continue to evolve at a rapid pace. In particular, the field evidence with regard to the treatment of coronary artery disease and cardiac valvular disease is rapidly expanding. The treatment evidence in thoracic and pulmonary disease (including transplantion) is moving as well. One of the challenges for contemporary medicine is to apply evidence-based medicine and to rationally implement the available therapies in clinical practice, in the appropriate patients at the appropriate time. Current research includes outcomes research of complex aortic valve and lung cancer surgery, longitudinal statistical modeling on serial data such as cardiac biomarkers and echocardiographic measurements over time for the purpose of outcome prediction, the optimization of individualized prognosis prediction through the development of novel risk models, shared decision making studies in prosthetic heart valve selection, pediatric LVOT and RVOT surgery and NSCLC treatment selection, and cost-effectiveness studies of novel cardio-thoracic interventions. The results should support clinical decision making. Annual Report 2015 Principal Investigators AJJC Bogers, JJM Takkenberg Co-Investigators H Boersma, AP Kappetein PhD candidates Name Subject B Arabkhani Aortic aneurysm and aortic valve disease: Treatment options LE de Groot-de Laat Three-dimensional echocardiography in mitral regurgitation SA Huygens Health Technology Assessment of Heart Valve Prostheses NM Korteland Optimizing clinical decision-making in prosthetic aortic valve selection WJ van Leeuwen Clinical results of mitral valve surgery APMW Maat Surgical aspects of mesothelioma treatment S Mokhles Prognostication and decision making in non-small cell lung carcinoma R van Valen Quality improvement in the management cardio-surgical perioperative care 103 COEUR Project 27 - continued Surgical aspects and clinical decision making in cardio-thoracic (including pulmonary) interventions Prognosis and Treatment decision making in early stage Non-Small Cell Lung Cancer - Sahar Mokhles 104 Lung cancer remains a global health problem, accounting for 18% of all cancer deaths. The treatment options for non-small cell lung cancer (NSCLC) are based on cancer stage and patient overall health. Although surgery is still considered standard therapy for early stage lung cancer, stereotactic ablative radiotherapy (SABR) is a less invasive option for the treatment of NSCLC in patients with comorbidities. In our previous studies, we identified the clinical baseline parameters that can help to determine survival of early stage NSCLC and illustrated that both patient characteristics and survival of patients undergoing surgical treatment or SABR differ considerably. In the absence of a randomized trial we performed a propensity score matching analysis to create two similar groups in order to compare clinical outcomes. We developed a nomogram for overall survival by using a large-intuitional cohort of NSCLC patients, and described quality of life during the five years after treatment with SABR. The focus of our research is also patient participation in treatment decision making and practice variation between individual lung cancer clinicians (e.g. cardio-thoracic surgeons, lung physicians and radiation oncologists) concerning shared decision making (SDM). In lung cancer SDM has not been widely incorporated into routine clinical practice due to lack of familiarity with SDM. Our studies highlights the need to improve the implementation of SDM in clinical practice as clinicians report that doctors are not properly trained to implement SDM, and there is not enough consultation time to properly engage the patient with limited health literacy in treatment decision making. Whereas, patient involvement will result in better knowledge of disease and treatment options and allow for informed decision making. Our research can contribute to the goal of improving SDM in the treatment of early stage NSCLC, and it will be another step towards personalized cancer treatment. Annual Report 2015 105 Sahar Mokhles COEUR Project 28 Surgery for congenital heart disease Surgical management of congenital heart disease has improved significantly in the last decades and has resulted in improved survival into adulthood. Thus the number of adult patients is growing. While the number of patients to be operated at young age is more or less constant, the number of patients needing an operation at adult age is increasing, both the number of primary operations as well as the number of reoperations due to residual cardiac abnormalities. In particular, an abnormal load is commonly imposed on the right ventricle or on single ventricular hearts. Residual abnormalities may cause heart failure, rhythm disturbances and may affect quality of life. Evidence-based treatment is often lacking. Guidelines for timing of catheter intervention and surgical therapy also may lack sufficient evidence. This project aims at outcome research with emphasis on assessment of cardiac function in the right ventricle and in structurally abnormal hearts with conventional imaging techniques. An important part of this theme concerns these imaging techniques on one hand and improvement of clinical decision-making and therapy on the other. 106 Principal Investigator AJJC Bogers Co-Investigators WA Helbing, AP Kappetein, JW Roos-Hesselink, JJM Takkenberg PhD candidates Name Subject JRG Etnel Decision-making in Paediatric LVOT and RVOT Surgery A Mookhoek Changing Roots: remodelling after the Ross procedure A van Saet Pharmacokinetics and pharmacodynamics of drugs in neonates and children during cardiopulmonary bypass PC van de Woestijne Pulmonary atresia with ventricular septal defect and systemic-pulmonary collateral arteries GA Zeilmaker Pharmacokinetics and pharmacodynamics of drugs in neonates and children during cardiopulmonary bypass Annual Report 2015 107 COEUR Project 28 - continued Surgery for congenital heart disease Decision-making in congenital ventricular outflow tract surgery Jonathan R.G. Etnel 108 Evidence-based medicine remains difficult to universally attain in congenital cardiac surgery due to the rarity, complexity and variability of congenital heart disease and the associated surgical procedures. The subsequent scarcity of data and lack of treatment guidelines causes clinical decision-making in congenital cardiac surgery to be largely based on expert opinion of the patient’s clinical state and the available treatments. Especially the field of congenital ventricular outflow tract surgery requires many difficult decisions to be made as each treatment option has its own inherent advantages and limitations. Consequently, there is substantial inter-institutional practice variation as well as an ongoing discussion on optimal patient care. In response to this major clinical practice gap, this PhD project employs advanced methods of meta-analysis, predictive modeling, microsimulation and longitudinal data analysis to synthesize high quality evidence on outcome after congenital ventricular outflow tract surgery. This information is vital in clinical decision-making and will aid clinicians in deciding on the optimal selection and timing of treatment for each patient. Besides the clinical consequences of the advantages and limitations of each treatment option, the choice for a certain treatment has a major impact on many non-clinical aspects of patients’ lives such as education, career, personal finances, pregnancy and sports. Additionally, the value of each risk and benefit to the patient varies strongly among individual patients. This makes patient preferences a crucial element in the decision-making process. It is therefore essential to use the available evidence to optimally inform not only clinicians, but also patients and their caregivers and to involve them in decision-making. In this light we have developed and tested a pilot nationwide evidence-based online information portal for patients with aortic and pulmonary valve abnormalities and their caregivers. This information portal contains multidisciplinary information on all aspects of aortic and pulmonary valve abnormalities, including diagnosis, treatment and implications for daily life and life planning. The information portal will soon be implemented in daily clinical practice, which will allow us to study its effect on patient knowledge, involvement, anxiety and quality of life. The portal will subsequently be expanded to all common types of congenital heart disease. Annual Report 2015 109 Jonathan Etnel COEUR Project 28 - continued Surgery for congenital heart disease Pharmacokinetics and pharmacodynamics in children during and after cardiac surgery - Gerdien Zeilmaker 110 We also have little evidence on pain treatment after cardiac surgery in children. Morphine is the analgesic of first choice in guidelines, but these are based on small, non-randomized trials and Parmacokinetics (PK) is lacking. We performed an international survey on type and dosing of analgesics in children after cardiac surgery. Morphine was the drug of first choice but the dosing could differ tenfold depending on local protocol. These high morphine doses can lead to unwanted drug reactions, such as respiratory depression and hypotension. Starting 2016 we will perform a multi-center prospective RCT to compare morphine intravenous with paracetamol intravenous in children after cardiac surgery (PACS study). A previous study comparing paracetamol iv with morphine iv after major noncardiac surgery in children found that paracetamol iv is as good as morphine iv as primary analgesic. The PACS study aims to decrease the cumulative morphine consumption in the first 48 hours after cardiac surgery by 30% in children aged 0-36 months. During the PACS study blood-samples for PK analysis of morphine and paracetamol will be collected. The results of the PACS study will be used to write a national PK-based guideline on the treatment of pain in children after cardiac surgery. Annual Report 2015 111 Gerdien Zeilmaker COEUR Project 29 Determinants of outcome of pediatric (congenital) heart disease Treatment of congenital heart disease in early childhood has resulted in excellent survival in the pediatric age range. However, residual cardiac loading abnormalities and the effects of pre-treatment hypoxaemia may impair long term survival and quality of life. The project aims to identify early (bio)markers of suboptimal outcome following treatment in childhood and to develop new treatment modalities to improve outcome. Novel imaging methods and animal experiments are used for these purposes. Principal Investigator WA Helbing Co-Investigators M Dalinghaus, DJGM Duncker, LP Koopman, IKM Reis, JW Roos-Hesselink, JJM Takkenberg, M Witsenburg PhD candidates 112 Name Subject SL den Boer Heart failure in children with cardiomyopathy. Which markers can be used to predict outcome? COBRA3: Congenital Heart defects: Bridging the gap between Growth, Maturation, Regeneration, Adaption, late Attrition and ageing Cardiomyopathy in children, CARS 2 E van den Bosch MH van der Meulen Annual Report 2015 CArdiomyopathy Registry Study (CARS) - Suzanne den Boer Our research project focused on the identification of prognostic factors measured during follow-up in children with dilated cardiomyopathy (DCM). In this prospective study we followed children with DCM from 7 pediatric cardiology departments in the Netherlands. Over a study period of four years, we included almost 100 children, who were seen at 3-6 months intervals. Outcome analysis of the pediatric DCM population in the Netherlands demonstrated that the heart transplantation rate early after diagnosis was relatively low compared to other cohorts, with similar 1- and 5-year survival rates and heart transplantation rates after the first year of diagnosis. This suggests that a conservative approach of listing for heart transplantation early after diagnosis may be justified in a considerable amount of children, except for those who were admitted to the intensive care unit at diagnosis, and who needed mechanical circulatory support during first hospitalization, since these were risk factors for death within the first year of diagnosis. Age > 6 years at diagnosis was a risk factor for reaching an endpoint > 1 year after diagnosis, which was mainly transplantation. Furthermore, this is the first study in children with DCM that demonstrated that the following markers were associated with a higher risk of death or transplantation: lower mean global longitudinal peak strain on echocardiography, higher New York University Pediatric Heart Failure Index, lower physical functioning score on health-related quality of life questionnaire, higher NT-proBNP, increasing NT-proBNP over time, and a lower distance walked in 6 minutes. Suzanne den Boer 113 COEUR Project 30 Adult congenital heart disease In the Netherlands, 8 out of 1000 children are born with a congenital heart defect. Due to improved diagnostics, the introduction of the heart lung machine and open heart surgery, more than 85% of these patients reach adulthood and nowadays there are 30.000 adults living in the Netherlands. Many of them have late complications, such as valvular dysfunction, arrhythmias or heart failure. In addition often surgical or catheter reintervention is necessary. Research in project 30 focuses on long-term outcome in these patients, both after surgical correction, interventional treatment or natural history. Special emphasis on psychological outcome, pregnancy and sports participation is important in this specific group of young adults. Also genetic research, imaging of the complex cardiac anatomy and biomarker studies are being conducted. 114 Principal Investigator JW Roos-Hesselink Co-Investigators H Boersma, AJJC Bogers, AE van den Bosch, RT van Domburg, WA Helbing, JJM Takkenberg, EMWJ Utens, M Witsenburg PhD candidates Name Subject VJM Baggen Predicting outcome in adult congenital heart disease IM van Hagen Pregnancy and Cardiac Disease AT van den Hoven Aortic Pathology MJG Leening Epidemiologic aspects of cardiovascular disease. A population-based approach ME Menting Echocardiography in congenital heart disease Annual Report 2015 Project 30 - contunued Adult congenital heart disease (Project30) Mindfulness in heart disease: a randomized controlled trial John Younge Increased attention is being paid to potential beneficial mind-body practices. These practices such as meditation, mindfulness training, relaxation exercises and yoga are increasingly popular in the general population and more commonly used in the western world. In recent years, mindfulness training has gained more attention in healthcare. By doing mindfulness, one is taught to live with an open and non-judgmental awareness towards all experiences within the present moment. Mindfulness puts the focus on the true needs of the body and mind and therefore also promotes a healthy lifestyle. Mindfulness therapy has been found to positively affect psychological outcomes in a variety of clinical conditions. However, effects on physiological outcomes are limited. We randomized 324 patients with structural heart disease to either an online mindfulness training or to usual care. We investigated several physiological and psychological outcome parameters. After 12 weeks, we found a borderline significant but clinically small effect in favor of mindfulness. Heart rate also decreased significantly more with mindfulness training. Remarkably, no significant improvements were found on subjective outcome measures, although anxiety and depressive symptoms did decrease. Our results may indicate that online mindfulness training may be used in patients with limitations in physical functioning, but whether it can address clinically important physiological distress factors needs to be determined. Mindfulness training may be considered a good alternative treatment option when other modalities have limited effect or are less feasible as a result of personal interests or clinical motives. 115 COEUR Project 30 - contunued Adult congenital heart disease 116 Dr. John Younge Annual Report 2015 Project 31 Clinical epidemiology of cardiovascular diseases In the past decades, significant improvement has been achieved in the management and outcome of patients with cardiovascular disease (CVD). Despite these developments, CVD still is a major cause of the loss of healthy years in The Netherlands: the annual number of fatal events is as high as 40,000. The burden of CVD is expected to increase in the decades ahead, and it is crucial to develop and improve CVD risk prediction instruments, and implement appropriate preventive and therapeutic measures. Traditionally, the assessment of CVD risk is based on global risk models. However, these models fall short, as they do not utilize contemporary knowledge on the pathophysiology of CVD. Project 31 is designed to improve CVD risk assessment and risk reduction in individual patients. Several concepts are currently studied: (multiple) CVD biomarkers, repeated biomarker assessment, cardiac imaging and dynamic risk modelling. Principal Investigator H Boersma Co-Investigators KM Akkerhuis, RT van Domburg, RJ van Geuns, JL Hillege, I Kardys, MJ Lenzen, MD Levin, V Umans PhD candidates Name Subject SS Anroedh Biomarker measurements in coronary disease and heart failure SJ Baart CREW: Dutch national consortium to promote Cardiovascular Healthy Aging in Women V van den Berg Blood biomarkers and cholesterol metabolism in coronary artery disease and heart failure N van Boven Serial Biomarker measurements and new echocardiographic techniques in chronic Heart Failure patients result in Tailored prediction of prognosis (Bio-SHiFT) M Brankovic Biomarkers to evaluate renal function in coronary artery disease and chronic heart failure N Buljubasic Dynamic aspects of associations between blood biomarkers and coronary artery disease C Liesting Cardiotoxicity of treatment in patients with HER2Neu positive breast cancer RM Oemrawsingh Prognostic value of biomarkers in patients with chronic CAD M Sunamura Opticare: optimal cardiac rehabilitation following acute coronary syndrome LC van Vark Epidemiological validation and clinical implementation of candidate biomarkers in patients with acute heart failure 117 COEUR Project 30 - continued Adult congenital heart disease 118 Dr. Judith Cuypers Annual Report 2015 The “unnatural history” of congenital heart disease: outcome up to 40 years after surgical repair - Judith Cuypers The milestone successes since the early years of surgical congenital heart defect repair have led to dramatic improvements in the prognosis of patients with congenital heart disease. Most patients now survive well into their adult years and focus has shifted from mere survival to late complications and quality of life. We need to learn which patients are at increased risk of developing serious adverse events. Outcome in patients that were treated in the earliest era of congenital heart surgery cannot thoughtlessly be extrapolated to patients that are treated later on. New insights and developments continuously lead to new adaptations in surgical techniques. Nevertheless, prospectively studying the long-term outcome of patients that were operated in earlier eras, as we do in the Rotterdam Quality of Life study, remains the only way to improve our knowledge and will provide important information and feedback for both patients and their treating physicians. This thesis describes the outcome beyond 30 years of follow-up in patients operated for ASD, VSD, pulmonary stenosis, tetralogy of Fallot and transposition of the great arteries (TGA). Survival is nearly normal in the milder defects, but clearly impaired in the more complex defect, especially the patients with TGA, who all received an atrial switch operation and consequently have a right ventricle supporting the systemic circulation. Late morbidity is substantial in all groups studied, varying from mainly atrial arrhythmias in the milder defects to re-interventions, ventricular arrhythmias and heart failure in the more complex defects. Ventricular dysfunction was expected and confirmed in the more complex defects, but not entirely absent in the mild defects. Trying to identify predictors of outcome, we found that arrhythmias in the early postoperative period were associated with adverse late outcome in nearly all groups. Nevertheless, most patients are leading satisfactory and fairly normal lives, fully participating in society: they have a job, get married, have children and do everything that healthy people do. 119 COEUR Doctoral degrees In the year 2015, 37 COEUR PhD candidates successfully defended their PhD thesis and obtained a doctoral degree. Details of their achievements are given on the next pages. Apart from scientific accomplishments, PhD candidates are required to document their educational activities (courses, meetings and teaching) in their portfolio, which is integral part of their thesis. Thirty ECTS (European Credit Transfer Score) points are required. In 2015, out of the doctorates 31 had included a detailed portfolio. Missing portfolios were exclusively associated with foreign PhD candidates. The median number of ECTS points scored was 33. The time to PhD degree varied between three and six years with a median time of 4 years and six months. COEUR currently lists 190 PhD candidates. In 2015, 11 candidates discontinued their PhD trajectory. The drop-out rate in 2015 was therefore about 6%. 40 121 35 30 25 20 15 10 5 0 2003 2004 2005 2006 Doctoral degrees 2003 - 2015 2007 2008 2009 2010 2011 2012 2013 2014 2015 COEUR January 13, 2015 Christos V Bourantas Early Detection and Invasive Sealing of Future Culprit Lesions Promotores: professor Patrick WJC Serruys (Cardiology) and professor Eric Boersma (Cardiology) Copromotor: dr Hector M Garcia-Garcia (Cardialysis) January 14, 2015 Michiel Th Voûte Medical & Technical Considerations in Vascular Surgery Promotores: professor Hence JM Verhagen (Vascular Surgery) and professor Robert Jan Stolker (Anaesthesiology) 122 January 16, 2015 Jannet A Eindhoven Cardiac Biomarkers in Adult Congenital Heart Disease Promotores: professor Jolien W Roos-Hesslink (Cardiology) and professor Eric Boersma (Cardiology) Copromotor: dr Annemien E van den Bosch (Cardiology) January 20, 2015 Michael Magro Percutaneous Coronary Interventions in Stable and Acute Coronary Syndromes Promotores: professor Patrick WJC Serruys (Cardiology) and professor Robert Jan van Geuns (Cardiology) Annual Report 2015 123 Dr. Jannet Eindhoven COEUR January 21, 2015 Verya Daeichin Micro-Ultrasound Molecular Imaging Promotores: professor Ton AFW van der Steen (Cardiology/Biomedical Engineering) and professor Nico de Jong (Cardiology) Copromotor: dr Hans JG Bosch (Cardiology) February 25, 2015 Ruben LJ Osnabrugge Cost, Quality and Value in Cardiovascular Interventions Promotor: professor Arie Pieter Kappetein (Cardiothoracic Surgery) 124 February 25, 2015 Bruno Sevá Pessôa The Alternative Renin-Angiotensin System: Exploration of its Therapeutic Potential Promotor: professor AH Jan Danser (Internal Medicine) Copromotor: dr Anton JM Roks (Internal Medicine) Maart 5, 2015 Sjoerd T Nauta Myocardial infarction: temporal trends over the past three decades Promotor: professor Jaap W Deckers (Cardiology) Copromotor: dr Martijn Akkerhuis (Cardiology) Annual Report 2015 Maart 10, 2015 Pieter Kruizinga Acoustic images of the carotid artery Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical Engineering) Copromotor: dr Gijs van Soest (Cardiology/Biomedical Engineering) Maart 10, 2015 Tianshi Wang Heartbeat optical coherence tomography Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical Engineering) Copromotor: dr Gijs van Soest (Cardiology/Biomedical Engineering) 125 Maart 13, 2015 Michel E. van Genderen Peripheral perfusion in relation to systemic hemodynamics and its importance in critically ill patients Promotor: professor Jan Bakker (Intensive Care) Copromotor: dr Jasper van Bommel (Intensive Care) April 1, 2015 Frederico Bastos Goncalves - CUM LAUDE Endovascular aortic repair, clarifying risk factors, complications and follow-up Promotores: professor Hence JM Verhagen (Vascular Surgery) and professor Robert Jan Stolker (Anaesthesiology) COEUR April 22 2015 Harm A. Nieuwstadt MRI-based biomechanical modeling of carotid atherosclerotic plaques the stable plaque paradigm Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical Engineering) Copromotor: dr Frank JH Gijsen (Cardiology) 126 Mei 12, 2015 Jin Ming Cheng Coronary artery disease from atherosclerosis to cardiogenic shock Promotor: professor Eric Boersma (Cardiology) Copromotores: dr K Martijn Akkerhuis (Cardiology) and dr Isabella Kardys (Cardiology) Mei 12, 2015 Helena J Heuvelman Aortic Stenosis in Adults Promotores: professor Ad JJC Bogers (Cardiothoracic Surgery) and professor Hanneke JJM Takkenberg (Cardiothoracic Surgery) Mei 13, 2015 Ido G Bikker Optimization Mechanical Ventilation by Bedside Lung Monitoring Systems in Critically iII Patients Promotor: professor Diederik AMP Gommers (Intensive Care) Annual Report 2015 Mei 19, 2015 John O Younge Lifestyle in Cardiovascular Disease Promotores: professor Jolien W Roos-Hesselink (Cardiology) and professor Myriam GM Hunink (Radiology/Epidemiology) Mei 22, 2015 Takashi Muramatsu Multi-modality Imaging and Clinical Implications of Bioresorbable Scaffolds in Complex Coronary Artery Disease Promotor: professor Patrick WJC Serruys (Cardiology) Copromotor: dr Yoshi Onuma (Cardiology) Mei 27, 2015 Renée FAG de Bruijn Emerging Determinants of Dementia Promotores: professor Peter J Koudstaal (Neurology) and professor Bert Hofman (Epidemiology) Copromotor: dr Yoshi Onuma (Cardiology) June 3, 2015 Koen Verdonk Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond Promotores: professor AH Jan Danser (Internal Medicine) and professor Eric AP Steegers (Gynecology) Copromotores: dr Ton AH van den Meiracker and dr Willy Visser (Gynecology) 127 COEUR June 9, 2015 Sandra H Hoeboer Biomarkers of infection and its complications in the critically ill Promotores: professor AB Johan Groeneveld (Intensive Care) and professor Heleen M Oudemans-van Straaten (IC-VUmc) 128 June 30, 2015 Carolina Méndez Orellana Functional MRI of Language Processing and Recovery Promotores: professor Aad van der Lugt (Radiology) and professor Peter J Koudstaal (Neurology) Copromotores: dr Marion Smits (Radiology) and dr Evy G Visch-Brink (Neurology) September 2, 2015 Alexander Haak Augmenting Electrophysiology Interventions with Advanced 3D Transesophageal Echocardiographeal Echocardiography Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical Engineering) Copromotor: dr Hans JG Bosch (Cardiology) September 16, 2015 Jelle L Epker Death and Dying in the intensive care unit Promotor: professor Jan Bakker (Intensive Care) Copromotor: dr Erwin JO Kompanje (Intensive Care) Annual Report 2015 September 16, 2015 André Uitterdijk Experimental Approaches to Acute Myocardial Infarction Promotores: professor Dirk J Duncker (Cardiology) and professor Wim van der Giessen († 2011) Copromotores: dr Daphne Merkus (Cardiology) and dr Heleen MM van Beusekom (Cardiology) 129 COEUR September 16, 2015 Ferdi Akca Optimizing Safety and Efficacy of Catheter Ablation Procedures Promotor: professor Felix Zijlstra (Cardiology) Copromotor: dr Tamas Szili – Torok (Cardiology) October 8, 2015 Teresa Mary Kieser Building a better bypass with emphasis on bilateral internal mammary grafting Promotor: professor Arie Pieter Kappetein (Cardiothoracic Surgery) 130 October 9, 2015 Eva Klijn The additional value of microcirculatory imaging in critically ill patients Promotores: professor Jan Bakker (Intensive Care) and professor AB Johan Groeneveld (Intensive Care) Copromotor: dr Jasper van Bommel (Intensive Care) October 14, 2015 Khatera Ibrahimi Microvasculature, the Trigeminal System and Migraine; A focus on female seks hormones Promotor: professor AH Jan Danser (Internal Medicine) Copromotores: dr Antoinette Maassen van den Brink (Internal Medicine) and dr Anton H van den Meiracker (Internal Medicine) Annual Report 2015 131 Dr. Ferdi Akca COEUR 132 Annual Report 2015 October 20, 2015 Sjoerd SM Bossers Outcomes after Contemporary Fontan Operation: Step by step Promotor: professor Wim A Helbing (Pediatrics) October 20, 2015 Nienke Duppen Exercise training in children and young adults with congenital heart disease Promotores: professor Wim A Helbing (Pediatrics) and professor Maria TE Hopman (Radboud Nijmegen) 133 COEUR October 21, 2015 Saloua Akoudad Cerebral microbleeds: a marker of vascular brain disease Promotores: professor Peter J Koudstaal (Neurology) and professor Aad van der Lugt (Radiology) Copromotores: dr Meike W Vernooij (Radiology) and dr M Arfan Ikram (Radiology) November 11, 2015 Yvonne Veroni Sanders Von Willebrand Disease in the Netherlands; from genetic variation to phenotypic variability Promotor: professor Frank WG Leebeek (Hematology) 134 December 1, 2015 Carlos M Campos Risk Assessment in Coronary Artery Disease Promotor: professor Patrick WJC Serruys (Cardiology) December 8, 2015 Diego Dias Bispo Carvalho Nonrigid Registration Methods for Multimodal Carotid Artery Imaging Promotor: professor Wiro J Niessen (Radiology) Copromotor: dr ir Stephan Klein (Radiology) Annual Report 2015 December 15, 2015 Judith AAE Cuypers The unnatural history of congenital heart disease; outcome up to 40 years after surgical repair Promotores: professor Jolien W Roos-Hesslink (Cardiology) and professor Ad JJC Bogers (Cardiothoracic Surgery) December 16, 2015 Yanti Octavia Endothelial Nitric Oxide Synthase in Heart Failure Dr Jekyll and Mr Hyde Promotores: professor Dirk Jan Duncker (Cardiology) and professor Harry J Crijns (Cardiology Maastricht) 135 COEUR Citation Classics (2015) 136 1. 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Revealing the Impact of Local Access-Site Complications and Upper Extremity Dysfunction Post Transradial Percutaneous Coronary Procedures. Neth Heart J. 2015;23(11):514-24. 186 Annual Report 2015 187 COEUR Colofon Edited by: Erna Egelie Photography: Levien Willemse Lay out: Maud van Nierop Production and publication: COEUR Secretariat, Erasmus MC Printing: Mediajoenit BV, Rotterdam Contact: 188 Thoraxcentre Erasmus MC P.O. 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