AN N UAL R EPORT 2008

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1 COEUR A N N UA L R E P O RT 2008 COEUR AN N UAL R EPORT 2008

2 COEUR ANNUAL REPORT 2008

3 Contents Prefce 4 Mission sttement 5 Orgniztion 7 Grnts nd Awrds 8 Eduction 12 PhD eduction progrm 12 PhD Courses 12 Reserch Seminrs 12 Other eductionl ctivities 14 MD Elective progrm 15 COEUR Reserch themes 28 Theme 1 Crdiovsculr Biology nd Phrmcology 29 Theme 2 Vsculr Medicine Hemostsis nd Stroke 41 Theme 3 Imge-guided Crdiovsculr Medicine 51 Theme 4 Surgicl- Interventionl nd Device Therpy of Crdiovsculr Disese 61 Theme 5 Congenitl Hert Disese 69 Theme 6 Neurovsculr nd Crdiovsculr Clinicl Epidemiology 75 Doctorl degrees 86 Publictions 91 Cittion Clssics 91 PubMed Publictions Colofon 136

4 C O E U R Annul Report 2008 Prefce This yer, we celebrted the fifth nniversry of our Reserch School. In its present form, COEUR ws initited in 2003 nd officil ccredittion from the Royl Netherlnds Society of Science nd Arts (KNAW) ws obtined in tht yer. An overview of the yers is given in seprte chpter in this nnul report. Reccredittion by the KNAW for nother six yer period will be sought in To this end, the School ws visited by n externl evlution committee in October The Committee ws heded by Prof Wlter Pulus from the Free University of Amsterdm, nd its members cme from Mstricht, Belgium, the United Kingdom nd the United Sttes of Americ. The two dy evlution visit ws very fruitful, nd we received mny compliments, but lso vluble recommendtions nd suggestions from our collegues. As result of the committee s dvice, the current six reserch themes will be re-nmed nd re-orgnised in mtrix-like structure. The themes were indeed somewht rbitrry, nd, in prticulr, considerble overlp exists between the vrious clinicl themes. In the new structure, there will be three (horizontl) syndrome defined themes nd one verticl theme Imging intersecting with the other themes. The themes will (probbly) be nmed s follows: Vsculr Medicine, Acute Crdiovsculr Diseses, nd Chronic Diseses. Seprte reserch progrms will be developed within the themes. The overll result, we trust, will be well recognizble progrms nd smoother integrtion of bsic (pthophysiology) nd clinicl (risk strtifiction nd therpy) reserch. The new structure will be formlized in the course of Scientificlly, the yer 2008 ws very good. Scientific output ws higher thn ever before: 567 ppers ppered in PubMed, nd 12 theses were completed. Agin, the gret mjority of this output resulted from voluntry collbortion between the different deprtments benefiting from working together within COEUR. Ultimo 2008, 158 PhD cndidtes were registered in our reserch school. No mjor chnges in personnel were observed in the lst yer with one notble exception: the secretrit of COEUR welcomed new coordintor, Mrs Ern Egelie. Within the deprtment of Internl Medicine, new division ws creted, entitled Phrmcology nd Vsculr nd Metbolic Diseses. The PhD eduction progrm continues to evolve: courses re currently orgnised in two dy formt, much to the plesure of orgnisers nd ttendees. Attendnce rtes keep rising, just s the number of eductionl credit points of individul PhD cndidtes. The nnul report is provided to you in the hope tht you will enjoy the scope of ctivities within COEUR. Finlly we express our grtitude to ll COEUR prticipnts for their contribution to the overll gol of the institute: to promote outstnding bsic, trnsltionl nd clinicl crdiovsculr reserch, nd to trin the future leders in these fields. Jp W Deckers Dirk J Duncker Mrten L Simoons Mission sttement The mission of COEUR is two-fold: - To promote outstnding bsic, trnsltionl nd clinicl crdiovsculr reserch, imed to improve the understnding of the pthophysiology s well s the prognosis nd qulity of life of ptients with crdiovsculr disese - To trin future ntionl nd interntionl leders in the crdiovsculr field through systemtic scientific eduction nd trining progrm To chieve this mission, COEUR conducts innovtive reserch nd provides high qulity trining in the crdiovsculr field. The reserch progrms include wide spectrum of disciplines, including crdiovsculr biology nd phrmcology, biomedicl engineering nd informtics, clinicl science, clinicl epidemiology nd helth cre reserch. Trining involves n individul trining progrm nd includes monthly reserch seminrs nd n ll-encompssing crdiovsculr science core curriculum. COEUR recognizes the need for n integrtive, multidisciplinry, trnsltionl pproch nd encourges ntionl nd interntionl collbortion. C O E U R Annul Report

5 Crdiovsculr Reserch School Ersmus University Rotterdm (COEUR) Prticipting institutes Anesthesiology Biochemistry Crdiology Crdiothorcic Surgery Hemtology Intensive Cre Medicine Internl Medicine (divsion of Phrmcology nd Vsculr nd Metbolic Diseses) Medicl Informtics Neurology (Vsculr Neurology) Peditric Crdiology Rdiology Surgery (Vsculr Surgery) Bord representtives Prof dr Don Poldermns Prof dr Jos MJ Lmers Prof dr Mrten L Simoons, chirmn Prof dr Ad JJC Bogers Dr Frnk WG Leebeek Prof dr Jn Bkker Prof dr AH Jn Dnser, Dr Anton H vn den Meircker Prof dr Wiro J Niessen Prof dr Peter J Koudstl Prof dr Wim A Helbing Prof dr Gbriel J Krestin Prof dr Hence JM Verhgen Grdute School Ersmus MC Orgniztion 13 COEUR deprtments Anesthesiology Biochemistry Crdiology Crdiothorcic Surgery Hemtology Prof dr Dirk J Duncker, scientific director Dr Jp W Deckers, secretry COEUR Scientific Advisory Bord COEUR Bord Intensive Cre Medicine Internl Medicine Divsion of Phrmcology nd Vsculr nd Metbolic Diseses C O E U R Annul Report 2008 Scientific Advisory Bord Prof dr Jos RTC Roelndt, chirmn Prof dr Jn HJ Hoeijmkers, Medicl Genetics Centre South-West Netherlnds Prof dr Albert Hofmn, Netherlnds Institute for Helth Sciences Prof dr MG Myrim Hunink, Ersmus MC Reserch Committee Prof dr Huib AP Pols, Den, Ersmus Medicl School Prof dr Hrry AJ Struijker Boudier, Crdiovsculire Reserch School Mstricht Amsterdm Prof dr Wiek H vn Gilst, Interuniversity Crdiology Institute Utrecht Accredited (2003) by the Royl Netherlnds Acdemy of Arts nd Sciences Scientific Secretrit Executive Committee Scientific Director Biomedicl Imging Neurology Peditric Crdiology Phrmcology Rdiology Vsculr Surgery Theme 1 Theme 2 Theme 3 Theme 4 Theme 5 Theme 6 C O E U R Annul Report

6 C O E U R Annul Report 2008 Grnts nd Awrds Plese find below selection of grnts nd wrds obtined by COEUR investigtors in Vsculr Neurology Drs Koudstl nd Dippel from the deprtment of Neurology were ble to cquire very significnt (lmost EUR 900,000) funding from vrious sources, including ErsmusMC, phrmceuticl industry, s well s from the Dutch Hert Foundtion nd the Hersenstichting. Internl Medicine Dr Tisch vn der Cmmen ws nmed Fellow of the Royl College of Physicins in the ctegory Distinguished Physicins from the rest of the World. Prof Jn Dnser nd his group were ble to collect the following grnts: Novrtis : ,- (personnel). Project: The renin/receptor system in hypertensive orgn dmge. Collbortive project with dr. Geneviève Nguyen, Collège de Frnce, Pris, Frnce nd drs. Michel Bder nd Dominik Müller, Mx Delbrück Center for Moleculr Medicine, Berlin, Germny. Novrtis : ,- (corelb biochemicl mesurements interntionl trils). Dutch Hert Foundtion: 2007 NHS 2007B019: ,- (2 yr post-doc) Renin inhibition nd (pro)renin receptor blockde in spontneously hypertensive rts: comprison with other renin-ngiotensin blockers. Medivir 2007: , -. Biochemicl mesurements renin inhibitor development. Dutch Renl Foundtion: 2008 NSN C : ,- (2 yr post-doc) The prorenine-(pro)renine receptor-tgf 1 xis: Wht function for inctive renine precursorin dibetic nefropthy? New insights into the efficcy of renl renin inhibition? Dr Anton Roks secured the following project from Biomde Technology Foundtion : , -, entitled: Does cyclic ngiotensin- (1-7) inhibit hert filure fter myocrdil infrction in rts? For her investigtion on tegserod, Dr. Antoinette Mssen vn den Brink obtined ,- from Novrtis For the reserch project with the title Hypertension nd crdic toxicity during ngiogenesis inhibition: mechnistic insights, Dr Kppers received ,- from the Novrtis Foundtion of Crdiovsculr Excellence Dr. Eric Sybrnds hs been very successful in obtining funding from vrious sources ltely. Projects included Whole-genome nd clssicl risk fctors in crdiovsculr disese, Screening for fmilil hypercholesterolemi, s well s studies focussing on the reltionship of personlity nd disese like Does the reltionship between type D personlity nd coronry hert disese (CHD) hve discrimintive bility in prognostic modelling for CHD?. The totl mount thus secured in the lst two yers mounted to bout EUR 2,500,000. Crdiology PhD cndidte Elz vn Deel ws wrded by the Dutch hert Foundtion becuse of her presenttion during the so-clled Ppendl course orgnised by the combined Dutch crdiovsculr reserch institutes. In recognition of his contribution in the field of crdiology, Professor Ptrick Serruys ws nmed Doctor Honoris Cus (right, this is not Greek!) of the Athens University. In ddition, some of his stent ppers in the JAMA, Lncet nd New Englnd Journl of Medicine ended up in the top 10 most cited Dutch ppers of 2006 nd Dr. Croline Cheng hs received the prestigious VENI grnt from the Dutch institute for scientific reserch (NWO). The Veni grnt is wrded to tlented young scientists belonging to the top 10-20% mong their peers in the field of medicl reserch. It consists of funding of 216,000 for her studies of ngiogenesis in the mouse nd zebrfish, which is n integrted prt of the min reserch line in the Moleculr Crdiology lb of Dr. H.J. Duckers. C O E U R Annul Report

7 Dr. Eric Duckers himself ws wrded with the NWO VIDI grnt in 2006, which consists of funding of 680,000 for his studies in the genetic regultion of ngiogenesis nd vsculogenesis in crdiovsculr disese. Both VENI nd VEDI projects re conducted in close coopertion with the group of Dr. Schulte-Merker in the Hubrecht Lbortory in Utrecht. Dr Eric Boersm ws nmed Professor of Clinicl Epidemiology in He ws lso ble to ttrct importnt (lmost EUR 1,400,000) finncil contributions to study (chnges in) Biomrkers to identify the risk of n cute coronry syndrome. Rdiology Dr Ad vn der Lugt ws wrded with vrious grnts, including from ErsmusMC s well s from the Dutch Hert Foundtion. These progrms focus on the genetics of plque vulnerbility, imging of brin neurysms nd of therosclerotic crotid plques. C O E U R Annul Report 2008 Biochemistry Dr Adrie Verhoeven ws chosen s Best Lecturer. This so clled More price ws wrded by the first s well s second yer medicl students

8 C O E U R Annul Report 2008 Eduction PhD Eduction Progrm COEUR offers PhD cndidtes reserch nd eduction progrm tilored towrds their individul requirements. This progrm ims to develop their knowledge nd skills such tht they cn become independent reserchers, nd provides them with brod bsis for their future professionl creer. Developments in these courses nd the eduction of the PhD cndidtes during the lst yers is presented in the chpter COEUR from Monitoring of the ctul eduction progress of individul PhD cndidtes is becoming stndrd prctice, nd n overview of the eduction obtined in the frmework during the durtion of the PhD progrm will be presented in the individul theses from now on. PhD Courses The curriculum of 2008 comprised the following four courses: Februry 14 nd 15, 2008 Crdiovsculr Imging nd Dignostics Coordintors: Dr. Ad vn der Lugt (Rdiology), Prof. Dr. Ton F.W. vn der Steen (Crdiology) nd Dr. R.J.M. vn Geuns(Crdiology) Number of prticipnts (PhD cndidtes): 19 Mrch 19 nd 20, 2008 Crdiovsculr Clinicl Epidemiology Coordintors: Prof Dr. Eric Boersm (Epidemiology) nd Dr. Diederik W.J. Dippel (Neurology) Number of prticipnts (PhD cndidtes): 19 April 25, 2008 Peripherl nd Intrcrnil Aneurysml Disese Coordintors: Dr. Fop vn Kooten (Neurology) nd Prof. Dr. Hence J.M. Verhgen (Vsculr Surgery) Number of prticipnts (PhD cndidtes): 13 October 16 nd 17, 2008 Hert Filure Reserch Coordintors: Dr. Aggie H.M.M. Blk nd Prof Dr. Dirk J. Duncker (Crdiology) Number of prticipnts (PhD cndidtes): 17 Reserch Seminrs COEUR continued its monthly series of reserch seminrs. Seminrs re ttended by scientific stff, PhD cndidtes, Clinicl Reserch Msters nd others. Prticiption vried between 15 nd 45 ttendees. The topics nd orgnizers in 2008 were the following: Jnury 25, 2008 Tetrlogy of Fllot Orgnizers: A.J.J.C. Bogers (Crdiothorcic Surgery), W.A. Helbing (Peditric Crdiology) Spekers: A.J.J.C. Bogers, W.A. Helbing, P.C. vn de Woestijne, M. Witsenburg, J.W. Roos-Hesselink, S.C. Yp, M.W. Wessels Number of prticipnts: 31 Mrch 14, 2008 Phrmcogenetics Orgnizers: M.P.M. de Mt (Hemtology) nd A.G. Uitterlinden (Internl Medicine) Spekers: M.P.M. de Mt, J.J. Brugts, M.Michels, R.H.N. vn Schik, G. Rudez, M. vn Duin, A.L.H.J. Arnoudse, F. Rivdeneir Rmirez Number of prticipnts: 34 Mrch 28, 2008 Crdic nd vsculr remodelling nd repir Orgnizers: H.M.M. vn Beusekom (Crdiology), R.J.M vn Geuns(Crdiology). Spekers: H.M.M. vn Beusekom, Mt Demen (University of Mstricht-CARIM) S.W.M. Kirschbum, O.E. Sorop, R.J.M. vn Geuns, M.N. Gonzlo Lopez, Y. Onum Number of prticipnts: 43 My 23, 2008 Cerebrovsculr disese- Animl Reserch nd Clinicl Applictions Orgnizers: A. Mssen vn den Brink (Division of Phrmcology, Vsculr nd Metbolic Diseses, Dept. of Internl Medicine) nd P.J. Koudstl (Neurology) Spekers: M.H. den Hertog, D.W.J. Dippel, E.G.M. Couturier (Boerhve Medisch Centrum Amsterdm), A. Mssen vn den Brink Number of prticipnts: 15 June 20, 2008 Risk strtifiction nd modelling Orgnizers: H Boersm (Crdiology), D Dippel (Neurology) nd D Poldermns (Vsculr Surgery) Spekers: D. Dippel, H. Lingsm, Y. vn Gestel, E. Boersm, D. Poldermns, M. Dunkelgrun, O. Schouten, M. Dirks. Number of prticipnts: 25 September 12, 2008 Pthophysiology of Crdiovsculr Aging Orgnizers: A.J.M. Roks(Vsculr Medicine nd Phrmcology), D.J. Duncker (Crdiology) nd T.J.M. vn der Cmmen (Geritrics, Internl Medicine) Spekers: G.T.J. vn der Horst, A.J.M. Roks, E. vn Deel, N. vn der Velde, F.U.S. Mttce Rso, T.J.M. vn der Cmmen. Number of prticipnts: 35 November 28, 2008 Gene nd cell bsed therpies of CV disese Orgnizers: H. Duckers (Crdiology), E. vn Dijk (Neurology) Spekers: E. vn Dijk, A.M. Nooordeloos, J. Houtgrf, D. Tempel Number of prticipnts: 32 C O E U R Annul Report

9 December 12, 2008 Imging of crotid bifurction therosclerosis. Improving insight nd foresight by using biomechnics.? Orgnizers: J.J. Wentzel (Crdiology), A vn der Lugt (Rdiology) nd D.W.J. Dippel (Neurology) Spekers: D.W.J. Dippel, S. Rozie, A. vn der Lugt, Q.J.A. vn den Bouwhuijsen, J.J. Wentzel, P.J. Homburg, H.C. Groen, F.J.H. Gijsen. Number of prticipnts: 30 the Europen Society of Crdiology, the COR Foundtion nd COEUR. Thirty experts (minly Europen) presented lectures on numerous spects of clinicl nd interventionl crdiology. The focus ws on new scientific results, their implictions for the prctice of crdiology nd crdiovsculr medicine on recent guidelines nd scientific developments, which my impct prctice in the ner future. More thn 285 prticipnts ttended the meeting. three courses ech yer. An importnt spect of the courses is the interction between PhD students from different Reserch Institutes. To this end, ssignments re discussed in smll groups nd socil ctivities re plnned during the evenings. Prticipnts lso present poster of their own reserch project. MD elective progrm The course Introduction into methodologies nd mesurements tht includes n introduction to ECG nd echocrdiogrphy s well s hemosttic nd bleeding disorders ws given to 30 excellent 2nd yer medicl students. C O E U R Annul Report 2008 Other eductionl ctivities Sher Stress Symposium April 24-25, 2008 The symposium entitled: Biomechnics in Vsculr Biology nd Crdiovsculr Disese covered severl spects of vsculr biology relted to biomechnics, including the vulnerble plque, remodelling nd ngiogenesis, endothelil function nd oxidtive stress, nd stroke. Sessions fetured two interntionl renowned scientists, with technicl s well s with biologicl/clinicl expertise. The Rotterdm Hilton hotel ws the plce of venue. Over 105 prticipnts ttended the symposium. Interntionl Symposium Crdiology nd Vsculr Medicine Updte nd Perspective April 7-9, 2008 The venue for the meeting ws De Doelen in Rotterdm. The fourth of series nnul symposi provided n overview of crdiology nd vsculr medicine. The meeting ws orgnised by the Thorxcenter nd ErsmusMC in collbortion with Informtion mrket for PhD cndidtes As previously, nd in coopertion with Ersmus- MC, the combined ErsmusMC PhD s nd the other (locl) Reserch Schools, COEUR prticipted in the yerly PhD informtion mrket, which took plce on My 21 th. The Reserch Schools provided the students with informtion of their institutes. Presenttions nd workshops were given on prcticl PhD issues including ethics nd medicl communiction nd writing. PhD-trining course Crdic Function nd Adpttion, Thrombosis nd Hemostsis nd Vsculr Biology. October 27-31, The venue of the course ws Ppendl, ner Arnhem. The courses re orgnized under uspices of nd with finncil support from the Netherlnds Hert Foundtion. This yer, the course ws ttended by 15 PhD cndites from COEUR The courses re n integrl prt of the PhDtrining offered by the Dutch Crdiovsculr Reserch Institutes including COEUR. The three courses re tught simultneously, mening tht ech student cn prticipte in only one of the 14 15

10 C O E U R Annul Report 2008 COEUR from COEUR ws officilly ccredited by the Royl Netherlnds Acdemy of Arts nd Science (KNAW) in Re-ccredittion will be sought in To tht end, n overview of the ctivies nd development of the reserch school during the lst five yers ws prepred. With minor dpttions, the text of tht document is given below. 1. Bckground nd current Mission The Crdiovsculr Reserch School Ersmus University Rotterdm (COEUR) hs been responsible for coordintion of crdiovsculr reserch nd eduction since From 1994 to 1999, COEUR ws prt of the KNAW (Royl Dutch Society of Arts nd Sciences) ccredited reserch school OSCAR, together with its counterprt t the University of Amsterdm. The collbortion with OSCAR ws terminted in The new CŒUR ws ccredited in Within Ersmus MC, COEUR opertes since 2006 under the umbrell orgnistion Ersmus MC Grdute School. The mission of COEUR is two-fold: - To promote outstnding bsic, trnsltionl nd clinicl crdiovsculr reserch, imed t improving the understnding of the pthophysiology s well s the prognosis nd qulity of life of ptients with crdiovsculr disese; - To trin future ntionl nd interntionl leders in the crdiovsculr field through systemtic scientific eduction nd trining progrm. To chieve this mission, COEUR conducts innovtive reserch nd provides high qulity trining in the crdiovsculr field. The reserch progrms include wide spectrum of disciplines, including crdiovsculr biology nd phrmcology, biomedicl engineering nd informtics, clinicl science, clinicl epidemiology nd helth cre reserch. Trining involves n individul trining progrm nd includes monthly reserch seminrs nd crdiovsculr science core curriculum. COEUR recognizes the need for n integrtive, multidisciplinry, trnsltionl pproch nd encourges ntionl nd interntionl collbortion. Ultimo 2007, COEUR registered totl of 148 PhD cndidtes. As of October 1, 2008, the institute hd records of 157 PhD cndidtes. 2. Eduction 2. PhD Eduction Progrm COEUR offers PhD cndidtes reserch nd eduction progrm tilored towrds their individul requirements. This progrm ims to develop their knowledge nd skills such tht they cn become independent reserchers, nd provides them with brod bsis for their future professionl creer. Since 2003, the number of courses orgnized by CŒUR hs incresed from 6 to bout 10 to 12 courses. Currently, COEUR orgnizes 10 courses in two-yer cycle formt. Most courses comprise two or three consecutive dys nd require similr worklod in self-study. Ech course is concluded with n exmintion, certificte-giving ceremony nd n evlution. Europen Credit Trnsfer System (ECTS) credit is 1.5 points per course. PhD cndidtes re expected to ttend t lest six COEUR courses during their PhD trjectory nd, dditionlly, COEUR seminrs (credit: 2 ECTS points per 5 seminrs), symposi nd other lectures. Individul PhD cndidtes will thus be ble to obtin bout 20 ECTS points (of the required 30 ECTS points) by following the COEUR eduction progrm during four-yer period. Additionlly, s n integrl prt of their PhD-trining, set of bsic crdiovsculr courses is offered by the Dutch Crdiovsculr Reserch Institutes including COEUR nd by the Dutch Hert Foundtion. Topics include Crdic Function nd Adpttion, Thrombosis nd Hemostsis nd Vsculr Biology. These weekly courses yerly held in Ppendl ner Arnhem - re tught simultneously, nd ech student cn prticipte in only one of the three courses ech yer. An importnt spect of the courses is interction between PhD cndidtes from different institutes. This is stimulted by smll group meetings s well s by socil ctivities during the evenings. Prticipnts lso present poster of their own reserch project. Next to the specific COEUR PhD eduction progrm, Ersmus MC Grdute School offers set of generl courses. These courses re orgnized centrlly, cover topics tht re relevnt to lrge group of PhD cndidtes, nd trin generl knowledge nd bsic cdemic skills. COEUR PhD cndidtes cn lso ttend courses given by other Ersmus MC reserch schools or courses given elsewhere in the Netherlnds or brod. In the ner future, PhD cndidtes will be required to provide detils of their eduction ( portfolio ) in their thesis. Since 2006, monitoring of the PhD trining progrm prticiption hs high priority. Weekly meetings between the COEUR secretrit nd smll groups of 6-8 PhD students s well s regulr meetings with their supervisors hs rised wreness of the importnce of PhD eduction beyond the scope of their individul reserch project. These efforts hve resulted in incresed course prticiption rtes. Monitoring of the ctul eduction progress of ll individul PhD cndidtes is improving, lthough not quite complete. In the not too distnt future, Ersmus MC Grdute School will provide the mens nd ICT support to fcilitte this. Furthermore, Ersmus MC Grdute School is likely to dopt n eduction policy tht requires minimum eduction prticiption by PhD students in order to obtin their PhD degree. The originl curriculum (of 2003) comprised 6 courses. The current curriculum is s follows: C O E U R Annul Report

11 C O E U R Annul Report Pthophysiology of Ischemic Hert Disese (DJ Duncker & WJ vn der Giessen) 2. Crdiovsculr Phrmcology (AHJ Dnser & A Mssen vn den Brink) 3. Vsculr Medicine (FW Leebeek & AH vn den Meircker) 4. Crdiovsculr Imging (PJ de Feyter, P Pttynm & AFW vn der Steen) 5. Design of Crdiovsculr Trils (E Boersm & DW Dippel) 6. Moleculr biology in therosclerosis nd CV reserch (HJ Duckers & MP de Crom) 7. Peripherl- nd neurovsculr disese (H Verhgen, F vn Kooten & E vn Dijk) 8. Congenitl Hert Disese (AJJC Bogers, WA Helbing & JW Roos-Hesselink) 9. Hert Filure Reserch (AHMM Blk & DJ Duncker) 10. Arrhythmi Reserch Methodology LJ Jordens & T Szili Torok) In spring 2009, the progrm will be expnded with n dditionl course Intensive Cre Reserch, orgnised by J Bkker nd DAPM Gommers. 2b. Bchelor nd Reserch Mster The Bchelor Mster structure ws introduced formlly t Ersmus MC in the curriculum. As in previous yers, COEUR will continue to prticipte in the 2nd yer bchelor phse with one-month eduction progrm on vrious spects of crdiovsculr disese nd reserch. As prt of Ersmus MC s policy on scouting, cquiring nd fostering tlented reserchers, the top 10% of medicl students is selected for scholrship. Per yer, bout 5-7 of these students receive trining t COEUR. Their trining consists of substntil mount of course work, nd one yer of reserch tht should result in n rticle in peerreviewed interntionl journl. The overll progrm comprises 70 ECTS. An individul tutor is ppointed who supervises nd mentors the Reserch Mster student during both the course work nd reserch stges. It is expected tht pproximtely hlf of these tlented students will continue scientific trining in subsequent PhD progrm. 3. Reserch Progrmmes nd Ledership COEUR hs six different reserch themes. A short description of ech theme is given. The nmes of the theme coordintors ( leders ) re lso given followed by their Hirsch (h) score (Web of Science). This score specifies the cittion rte of the resercher, nd equls the ith number of publictions cited i times. Theme 1 Crdiovsculr Biology nd Phrmcology Moleculr bsis, pthophysiology nd therpy of obstructive coronry rtery disese, crdic nd coronry remodelling nd hert filure. AHJ Dnser, Professor of Phrmcology (H = 36) DJGM Duncker, Professor of Experimentl Crdiology (H = 30) DAMPJ Gommers, Associte Professor of Anesthesiology (H = 16) Theme 2 Vsculr Medicine, Hemostsis nd Stroke The clinicl complement to the previous theme. Crdiovsculr genetics, blood pressure regultion nd vsculr medicine, thrombotic nd bleeding disorders, cute nd chronic crdiovsculr disese. PJ Koudstl, MD, Professor of Vsculr Neurology (H = 43) FWG Leebeek, MD, Associte Professor of Internl Medicine (H = 17) AH vn den Meircker, MD, Associte Professor of Internl Medicine (H = 25) ML Simoons, MD, Professor of Crdiology (H = 62) Theme 3 Imge-guided Crdiovsculr Medicine Fundmentl nd clinicl reserch of novel dignostic nd therpeutic imging modlities. PJ de Feyter, MD, Professor of Crdiology nd Rdiology (H = 54) WJ Niessen, MSc, Professor of Medicl Informtics (H = 15) PMT Pttynm, MD, Professor of Rdiology (H = 29) AFW vn der Steen, Professor (H = 23) Theme 4 Surgicl- Interventionl nd Device therpy of crdiovsculr disese Clinicl ppliction nd implementtion of new dignostic nd therpeutic techniques. Locl drug delivery, cell therpy, vsculr interventions nd other device therpy. AJJC Bogers, MD, Professor of Crdio-thorcic Surgery (H = 21) WJ vn der Giessen, MD, Professor of Acute Coronry Syndromes (H = 37) LJLM Jordens, MD, Professor of Crdiology (Electrophysiology) (H = 23) PW Serruys, MD, professor of Crdiology (Interventionl Crdiology) (H = 85) Theme 5 - Congenitl Hert Disese Theme focussing on mjor structurl congenitl crdic bnormlities nd their mngement. AJJC Bogers, MD, professor of Crdio-thorcic Surgery (H = 21) WA Helbing, MD, professor of Peditric Crdiology (H = 15) JW Roos, MD, ssocite professor (H = 12) Theme 6: Neurovsculr nd Crdiovsculr Clinicl Epidemiology Risk modelling, rtionl predictive thinking nd implementtion of pproprite dignostic nd therpeutic mesures cross wide rnge of clinicl crdiovsculr syndromes nd procedures. E Boersm, professor of Clinicl Epidemiology (Crdiology) (H = 50) DWJ Dippel, MD, ssocite professor of Vsculr Neurology (H = 18) D Poldermns, MD, professor of Medicine (H = 29) JJM Tkkenberg, ssocite professor (H = 11) C O E U R Annul Report

12 4. Orgnistionl Structure 5. The Position of COEUR Impct Fctor per Publiction C O E U R Annul Report 2008 COEUR is decentrlised, virtul institute in which crdiovsculr reserch nd eductionl ctivities from different Ersmus MC deprtments hve joined forces. The Bord consists of representtives from ech of the (currently) 13 deprtments prticipting in COEUR. The Bord meets t lest twice yer. The Executive Bord hs four members. The Scientific Director of COEUR, currently Prof Duncker, is lso prt of the Executive Bord. There is smll centrl, dministrtive orgnistion tht consists of coordintor nd secretry. The registrtion of PhD cndidtes nd Resech Msters, s well s the orgnistion of their eduction, is the min ctivity of the secretrit. Since 2007, COEUR opertes within the so-clled Ersmus Grdute School. Within COEUR itself, however, no mjor orgnistionl chnges hve occurred since its inception nd the grphic presenttion of its structure s in the vrious nnul reports - is still vlid. In the ner future, the scientific dvisory bord of COEUR will be composed by members of the bord of the Ersmus MC Grdute School. Ersmus MC deprtments nd/or institutes currently prticipting in COEUR: Anesthesiology, Biochemistry, Crdiology, Crdiothorcic Surgery, Hemtology, Intensive Cre Medicine, Internl Medicine (Vsculr Medicine), Medicl Informtics, Neurology (Vsculr Neurology), Peditric Crdiology, Phrmcology, Rdiology nd Surgery (Vsculr Surgery). Currently, there re two (of 16 currently ccredited medicl reserch schools) crdiovsculr reserch schools in the Netherlnds. COEUR hs pre-dominnt clinicl (nd imging) focus, while CARIM hs stronger bsic orienttion. Although these institutes hve very different orgnistionl structure, it is probbly fir to sy tht both re quite successful in chieving their missions. In 2008, informl s well s forml discussions hve tken plce between CARIM nd COEUR regrding mens of coopertion, specificlly on externl funding, PhD eduction nd (combined) invittion of foreign spekers t symposi nd reserch seminrs. We expect tht this will ber fruit in the ner future. The ntionl nd interntionl position of COEUR cn best be described by the qulity of the scientific output. Totl output in the yers is given in the figure below. The dotted line indictes the impct fctor in the Crdic & Crdiovsculr Systems ctegory tht constitutes the top 25% (used s n output prmeter by the Bord of Ersmus MC). In the lst two yers, totl scientific output is in the rnge of publictions per yer (lmost 10 rticles per week). The scientific merits of the vrious crdiovsculr reserch institutes were compred in report of 2002 by the combined Dutch universities. According to tht publiction, crdiovsculr reserch performed t Ersmus MC ws considered outstnding. Overll Dutch scientific output hs been compred over the period The number Impct Fctor Theme 1 Theme 2 Theme 3 Theme 4 Theme 5 Theme of publictions from ErsmusMC ws (by fr) the highest in tht period, mounting to 6,74% of the totl output. The verge cittion rte from ErsmusMC in the sme time ws 1,60 (figure next pge, left pnel). Scientific output from the Dutch universities ws lso compred in nother, more recent report. The Centre for Science nd Technology Studies from the Leiden University nlyzed scientific output in the lst ten yers, from Cittion scores of reserch performed t most Reserch Schools t Ersmus MC re higher thn of reserch t other ErsmusMC institutes or deprtments. Publiction number Top 25% Among the six Reserch Schools within Ersmus MC, COEUR hs the highest score, with lmost two cittions per publiction over the entire ten yer period studied (next pge, right pnel in the figure below). Over the yers, cittions scores re stble, lthough the score incresed from 1,87 in the time period to 1,94 in the yers Within COEUR, theme 4 nd 6 re the most successful over the entire time period. However, scores of themes 2 nd 3 hve incresed with time (both score > 2 in the lst three yers). C O E U R Annul Report

13 Ersmus MC within the Netherlnds COEUR within Ersmus MC Single deprtment Multiple (with vrible COEUR deprtments nd Reserch Schools involved) CPP/FCSm CPP/FCSm Multiple reserch Schools within Ersmus MC Multiple deprtments within COEUR Totl Publictions (x1000) Totl Publictions (x1000) C O E U R Annul Report 2008 Period Number of publictions Cittion score CPP / FCSm Self cittions The scientific output of COEUR cn lso be summrised s follows ,86 18% ,23 22% ,95 22% ,87 22% ,00 21% ,10 19% ,02 20% ,94 20% Pub Med publictions per yer: Number of PhD theses: 2003: : : : : : : : : : 30 In order to investigte whether the scientific output t COEUR is bsed on mono-disciplinry or other forms of collbortion, we hve clssified the most recent (yer 2007) COEUR output into one of the four following ctegories: resulting from 1) single deprtment (within COEUR); 2) resulting from coopertion of multiple COEUR deprtments ;3) in coopertion with other Ersmus- MC Reserch Schools, nd 4) multicentre. According to tht nlysis, less thn 25% of our scientific output resulted from reserch performed t only single deprtment. Over 75% of the output resulted from collbortion within COEUR deprtments or with other deprtments or institutes. C O E U R Annul Report

14 Type of funding 6. Funding Ersmus MC nd thus COEUR - is orgnised long deprtmentl lines. With the exception of Crdiology nd Crdiothorcic surgery, ll other deprtments tke only prtilly prt in COEUR. This, in combintion with centrlised finncil dministrtive system, mkes it chllenging to obtin proper insight into the overll finncil sitution of our (decentrlised) institute. This topic lso cught the ttention of our externl peer reviewers. Non-trivil dministrtive chnges on centrl - Ersmus MC - level will be needed to remedy this. We will contemplte these when the findings of the externl peer review committee will be reviewed with the Den of Ersmus MC. Globlly, the distribution of funding hs been reltively stble over the yers, with Internl (Ersmus MC) funding ccounting for lmost 60%, nd externl funding contributing to over 40% of totl expenditure Direct 4,400,000 4,150,000 4,450,000 4,150,000 4,540,000 Indirect 893,000 2,220,000 4,680,000 2,175,790 2,815,000 Other 2,317,000 3,085,000 4,861,000 1,590,000 3,079,000 Totl 7,610,000 9,455,000 13,991,000 7,915,790 10,434, PhD cndidtes 7. PhD Projects Success Rte Most theses completed in the yers 2003 until now originted from reserch initited prior to the forml recognition of COEUR. So fr, 120 theses hve been defended. The verge time from reserch strt to thesis completion ws 4 yers nd 6 months, with rnges of 1-11 nd medin of 4 yers. No forml evlution of thesis trjectories ws vilble before COEUR ws ccredited, so the ctul numbers of filed ttempts to obtin PhD degree prior to 2003 re unknown. The PhD filure rte the number of PhD cndidtes dropping out premturely hs since remined in the order of 10%. In the tble right, PhD projects strting before 2003 hve been rnked ccording to the yer the reserch commenced. Not surprisingly, the forml strt of COEUR in 2003 ws ssocited with lrger thn usul forml PhD strt-up s. However, considerble number of these erly PhD cndidtes comprised clinicins nd clinicl stff members, who combine reserch nd clinicl work. PhD students with such profile were lmost exclusively responsible for the reltively long PhD trjects, e.g. lsting longer thn 6 yers, in the time period Cohort No 4 yrs 5 yrs 6 yrs 7+ yrs Not redy Discont d n n n n n n n n n n n n n n 23 PhD initition nd completed theses 7b. Future Prospects Alumni The working sttus of the COEUR lumni is presented in the grph below. The current employment of the lumni (cohorts ) who completed their theses cn be summrized s follows: still working s resercher or employed Non-cdemic MD specilist Helth Cre generl Acdemic MD specilist in cdemic institution: lmost 60%. Not included: one subject (senior clinicin) who retired following her PhD, nd one scientist who ws temporrily unemployed while witing visum requirements for subsequent scientific creer in the USA. In trining Reserch C O E U R Annul Report

15 C O E U R Annul Report Mesures tken following Accredittion nd externl Peer Review The following ctions were tken on the bsis of the recommendtions mde t the time of ccredittion: - The eductionl progrm hs been further developed, refined nd expnded. Since 2003, the number of courses orgnized by CŒUR hs incresed from 6 to bout 10 to 12. We re in the process of developing Reserch Mster in Clinicl Reserch progrm. - Monitoring of PhD entry nd progress is completely functionl. Monitoring of PhD (overll) eductionl ctivities, in prticulr of eduction received outside Ersmus MC, needs to be improved, however. In ddition, we need to set up counselling system to mke sure tht PhD students re supervised in comprble mnner cross our institute. Most likely, such system will be developed within the Ersmus MC Grdute School. - COEUR is now represented by one of its PhD s in the so-clled Ersmus PhD committee. - There hs been semless trnsition of PhD cndidtes from the time period before COEUR ws ccredited to the new, ccredited COEUR. Another recommendtion mde by ECOS in 2003 relted to the six reserch themes. Since then, the chosen themtic pproch hs been discussed internlly on number of occsions. The nnul report of 2006 (pge 19) reflects this debte. The originl themtic choices were lso criticized by the externl peer group review committee during the site visit of October It hs now been decided tht, from 2009 onwrds, the scientific themes will be the following: Theme 1: Vsculr Medicine Theme 2: Acute CV Syndromes Theme 3: Chronic Crdic Disese nd Theme 4: (verticl, mtrix structure): Imging Horizontl, syndrome centered, progrms will be developed within these themes, including (but not limited to) therosclerosis, hypertension nd vsculr tone, hemostsis nd thrombosis, cute coronry syndromes, stroke nd migrine, nd crdic remodelling nd hert filure. Other remrks mde by our colleques were relted to the overll mngement structure nd overview ssocited with the finnces of COEUR, including the lloction of specific budgets for scholrships, nd the lck of reserch in hert filure to nme the most importnt. Addressing the first issue will certinly not be esy since it is inherently ssocited with the existing deprtmentl structure of Ersmus MC. These topics will be discussed both within COEUR s well s with the Den of our institution in the yer Distribution of Sexes within COEUR Plese find below the distribution of men nd women in our school s reported in the nnul report Ctegory Number Men Women Scientific stff Postdocs PhD cndidtes The verge COEUR PhD cndidte is < 30 yers of ge, hs femle to mle rtio of 3 to 7, is medicl doctor nd externlly finnced. C O E U R Annul Report

16 Reserch Reserch Themes COEUR hs six different reserch themes. The themes will undergo mjor chnges s of The themes cn be summrized s follows: 1. Crdiovsculr Biology nd Phrmcology Moleculr bsis, pthophysiology nd therpy of obstructive coronry rtery disese, crdic nd coronry remodelling nd hert filure 2. Vsculr Medicine Hemostsis nd Stroke The clinicl complement to the previous theme. Crdiovsculr genetics, blood pressure regultion nd vsculr medicine, thrombotic nd bleeding disorders, cute nd chronic crdiovsculr disese 5. Congenitl Hert Disese Smll but importnt theme focussing on mjor structurl congenitl crdic bnormlities nd their mngement 6. Neurovsculr nd Crdiovsculr Clinicl Epidemiology Risk modelling rtionl, predictive thinking nd implementtion of pproprite dignostic nd therpeutic mesures cross wide rnge of clinicl crdiovsculr syndromes nd procedures. On the following pges, project groups, PhD cndidtes nd reserch titles re summrized for ech theme. In ddition, detiled informtion is presented on some individul PhD projects. C O E U R Annul Report Imge-guided Crdiovsculr Medicine Fundmentl nd clinicl reserch of novel dignostic imging modlities 4. Surgicl- Interventionl nd Device Therpy of Crdiovsculr Disese Clinicl ppliction nd implementtion of new dignostic nd therpeutic techniques. Locl drug delivery cell therpy vsculr interventions nd other device therpy Theme 1 Crdiovsculr Biology nd Phrmcology Progrm Code: EMC COEUR C O E U R Annul Report

17 enos enos overexpression fils fils to to protect ginst pressure overlod induced LV LV hypertrophy nd nd dysfunction Elz Elz vn vn Deel Deel 1, Mrtine 1, Mrtine de Boer de Boer 1, Rien 1, Rien vn vn 1 Div. 1 Div. of of Experimentl Crdiology, Hperen Hperen 2, Rini 2, Rini de Crom de Crom 2, Dphne 2, Dphne Merkus Merkus 1, 1, Dept. Dept. of of Crdiology, Thorxcenter, Dirk Dirk J. Duncker J. Duncker 1 1 COEUR, COEUR, 2 Genetics 2 Genetics nd nd Cell Cell Biology, Biology, Ersmus Ersmus MC, MC, Rotterdm, The The Netherlnds COEUR 30 Funded Funded by the by Netherlnds Netherlnds Hert Hert Foundtion Foundtion (grnt (grnt 2007B024) 2007B024)

18 Prcrine- nd cytotherpeutic effects of bone mrrow-derived cells on myocrdil infrction in porcine model André Uitterdijk 1, Binc Groenendijk 1, Robert-Jn vn Geuns 1, Dirk Duncker 1, Wim vn der Giessen 1, 2 1 Thorxcenter, Ersmus MC, Rotterdm nd 2 ICIN-KNAW Utrecht, The Netherlnds COEUR Bckground Animl experiments Mny cell therpeutic studies in niml models of myocrdil infrction (MI) demonstrted tht cell therpy is sfe nd modertely effective. In 1998, Doris Tylor lredy showed tht myocrdil performnce of cryoinfrcted herts in rbbits improved fter utologous cell trnsplnttion (Nt Med 1998). The gret interest of cell therpy for the regenertion of infrcted myocrdium ws initited in murine model of MI (Orlic et l., Nture, 2001). Severl preclinicl studies of MI in porcine nd cnine models further ccentuted the huge potentil of cell therpy (Moelker et l. Eur Hert J, 2006; Perin et l. J Mol Cell Crdiol, 2008). Clinicl Trils Prllel to preclinl work, the first rndomized clinicl trils were initited. Rndomized clinicl trils of bone mrrow-derived cell therpy for cute MI show tht the modlity is sfe nd my hve the potentil to improve crdic function (Tble 1). However, mny procedurl nd experimentl prmeters re suboptiml nd need to be further studied. In order to obtin better results the mode of ction of cell therpy lso remins to be elucidted. Tble 1. Results of 5 rndomized clinicl trils LVEF Infrct Size Boost = n.. Repir-AMI n.. Astmi = n.. Jnssens = Regent n.. : increse, : decrese, =: unchnged, n..: not vilble Previous Preclinicl Results Previous cell therpy experiments in our lb with bone mrrow-derived mononucler cells showed significnt reduction in infrct size from 14.3% to 8.2% of the left ventricle in porcine model, this is 42% reduction (Fig 1) Intrcoronry dministrtion of umbilicl cord-derived stem cells in n immunosuppressed swine model of MI cused microinfrctions (Fig 2). A B Fig. 2 A. Helthy myocrdium B. Arrows denote micro-infrctions. From: Moelker et l. J Moll Cell Crdiol Current Project Prcrine effects of bone mrrow-derived mononucler cells (BM-MNCs) in porcine model of MI. The current project ims to elucidte whether cells in cell therpy must hve prolifertion- or differentition potentil to exert positive effect on crdic function. To this extend we will induce growth-rrest in cells using irrdition. Cell numbers remin unchnged from 7.5 Gy upwrds (Fig. 3). Fig. 3 Effect of different doses of irrdition on totl cell number. Study design Prt 1. Chrcteristion Flowcytometric chrcteristion of (irrdited) BM- MNCs Stte of the cells, with nd without irrdition poptosis,necrosis, cell-cycle) Anlysis of prcrine fctors Prt 2. Experimentl groups Control group; 15 swine with experimentl MI Untreted cell group; 15 swine with MI + BM-MNC therpy Irrdited cell group; 15 swine with MI + growth- rrested BM-MNC therpy Primry endpoint t 4 weeks follow-up A. Infrct size B. Regionl function by MRI 32 Fig. 1 Reduction in infrct size 4 weeks fter cell trnsplnttion From: Moelker et l. Eur Hert J, Expected results We hypothesize tht infrct size reduction will be identicl in cell therpy groups, suggesting prcrine ctivity. 33

19 Reserch groups Reserch Groups theme 1 Crdic (ml)dpttion to stress nd dmge Project leders DJGM Duncker, D Merkus Stff AJM Verhoeven, W Sluiter, WJ vn der Giessen JH Hoeijmkers, GJ vn der Horst, J vn der Velden PhD cndidtes VJ de Beer, GMJ de Boer, ED vn Deel, GJ vn Essen, MJ vn Houwelingen Circultory spects of nesthesi Project leder DAMPJ Gommers Stff J vn Bommel, J Hoflnd, J Klein PhD cndidtes F Grüne, X Moors Circultory spects of mechnicl ventiltion Project leder DAMPJ Gommers Stff J Klein, D Dos Reis Mirnd, A Struijs, J vn Bommel J Hoflnd, J Bkker, AJJC Bogers, B Lchmnn PhD cndidtes IG Bikker, YJ de Groot, L Klompe, C Preiss, TV Scohy C O E U R Annul Report 2008 Experimentl therosclerosis: Sher-stress relted gene expression nd inflmmtion in plque progression Project leders JJ Wentzel Stff R de Crom AJJC Bogers, F Grosveld, PW Serruys, AFW vn der Steen, DJGM Duncker PhD cndidtes F Heldermn, D Segers Genetic regultion of vsculogenesis nd ngiogenesis Project leder HJ Duckers Stff DJGM Duncker, PW Serruys J Hoeijmkers, S Schulte-Merker Postdocs C Cheng PhD cndidtes F Bos, RA Hsdijk, RLJM Herpers, HJ Houtgrf, D Tempel C O E U R Annul Report

20 Microcircultion in criticl illness Project leder J Bkker Stff C Ince, J LeNoble, DAMPJ Gommers J vn Bommel PhD cndidtes B vn der Hoven, TC Jnsen, E Klijn, A Lim Moleculr biology of therosclerosis Project leders HJ Duckers, R de Crom Stff PW Serruys, DJGM Duncker, JF Hmming B Lmbrecht, J Lmn, F Grosveld, H vn Urk Postdocs C Cheng PhD cndidtes WK den Dekker, BME Mees, MM Noordeloos Stem-cell nd growth-fctor therpy in ischemic hert disese Project leders WJ vn der Giessen, DJGM Duncker Stff HMM vn Beusekom, HJ Duckers, RJM vn Geuns E Brkmn, GP Krestin, ML Simoons Postdocs BCW Groenendijk PhD cndidtes DB Uitterdijk Moleculr biology of hert filure: Genomic nd proteomic nlysis of disese-relted proteins s bsis for development of novel therpeutic strtegies Project leders AJM Verhoeven Stff W Sluiter, M Dlinghus, D Merkus, DJGM Duncker WA Helbing, J vn der Velden PhD cndidtes DWD Kuster, D vn Deursen Pthogenesis nd therpy of hypertension nd hert filure: novel pthwys nd interventions in the rennin-ngiotensin system nd the role of genomic instbility Project leder AHJ Dnser MADH Schlekmp Postdocs WW Btenburg, JHM vn Esch PhD cndidtes MD Durik, F Gembrdt, M Krop C O E U R Annul Report 2008 Phrmcology of migrine: The role of serotonin clcitonin gene-relted peptide nd nordrenline receptors Project leder A Mssen vn den Brink AHJ Dnser, AJJC Bogers, CMF Dirven PhD cndidte KY Chn C O E U R Annul Report

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