AN N UAL R EPORT 2008

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

COEUR ANNUAL REPORT 2008

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 2003-2007 16 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 2008 92 Colofon 136

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 2003-2008 is given in seprte chpter in this nnul report. Reccredittion by the KNAW for nother six yer period will be sought in 2009. To this end, the School ws visited by n externl evlution committee in October 2008. 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 2009. 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 2008 4 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 2008 6 7

C O E U R Annul Report 2008 Grnts nd Awrds Plese find below selection of grnts nd wrds obtined by COEUR investigtors in 2008. 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 2006-2008: 650.000,- (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 2006-2010: 325.000,- (corelb biochemicl mesurements interntionl trils). Dutch Hert Foundtion: 2007 NHS 2007B019: 145.000,- (2 yr post-doc) Renin inhibition nd (pro)renin receptor blockde in spontneously hypertensive rts: comprison with other renin-ngiotensin blockers. Medivir 2007: 15.000, -. Biochemicl mesurements renin inhibitor development. Dutch Renl Foundtion: 2008 NSN C08.2246: 170.000,- (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 2008-2009: 20.000, -, 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 45.000,- from Novrtis 2007. For the reserch project with the title Hypertension nd crdic toxicity during ngiogenesis inhibition: mechnistic insights, Dr Kppers received 90.000,- from the Novrtis Foundtion of Crdiovsculr Excellence 2008-2009. 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 2007. 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 2008 8 9

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 2008. 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. 10 11

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 2003 2007. 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 2008 12 13

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, 2008. 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

C O E U R Annul Report 2008 COEUR from 2003-2007 COEUR ws officilly ccredited by the Royl Netherlnds Acdemy of Arts nd Science (KNAW) in 2003. Re-ccredittion will be sought in 2009. 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 1992. 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 1999. The new CŒUR ws ccredited in 2003. 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, 10-15 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 2008 16 17

C O E U R Annul Report 2008 1. 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 2008 2009 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 2008 18 19

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 2003 2007 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 450 500 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 1998-2005. The number Impct Fctor 100 50 30 10 5 3 1 0.1 Theme 1 Theme 2 Theme 3 Theme 4 Theme 5 Theme 6 1 10 30 50 100 300 500 1000 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 1997-2006. 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 1999-2003 to 1,94 in the yers 2003-2006. 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 2008 20 21

Ersmus MC within the Netherlnds COEUR within Ersmus MC 2.0 2.0 Single deprtment 1.8 1.6 1.8 1.6 Multiple (with vrible COEUR deprtments nd Reserch Schools involved) CPP/FCSm 1.4 1.2 1.0 0.8 0 4 8 12 16 CPP/FCSm 1.4 1.2 1.0 0.8 0 2 4 6 8 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. 1997-2006 2.600 1,86 18% 1997 2000 814 2,23 22% 1998 2001 854 1,95 22% 1999 2002 858 1,87 22% 2000 2003 895 2,00 21% 2001 2004 972 2,10 19% 2002 2005 1.149 2,02 20% 2003 2006 1.359 1,94 20% Pub Med publictions per yer: Number of PhD theses: 2003: 298 2003: 17 2004: 386 2004: 21 2005: 486 2005: 21 2006: 491 2006: 29 2007: 450 2007: 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 2008 22 23

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. 2003 2004 2005 2006 2007 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 10,434,000 7. 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 1999-2003. Cohort No 4 yrs 5 yrs 6 yrs 7+ yrs Not redy Discont d 1999 25 8 7 3 7 n n 2000 23 12 4 4 3 n n 2001 22 11 6 5 n n 2002 24 17 7 n n n 2003 56 11 5 n 40 2004 28 6 n 22 2005 38 2 n 36 2006 38 2 n 36 2007 23 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 1999 2006) 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 2008 24 25

C O E U R Annul Report 2008 8. 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 2008. 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 2009. 9. Distribution of Sexes within COEUR Plese find below the distribution of men nd women in our school s reported in the nnul report 2007. Ctegory Number Men Women Scientific stff 87 71 16 Postdocs 4 2 2 PhD cndidtes 157 101 56 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 2008 26 27

Reserch Reserch Themes COEUR hs six different reserch themes. The themes will undergo mjor chnges s of 2009. 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 2008 3. 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 01-43-01 C O E U R Annul Report 2008 28 29

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)

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 2007. 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, 2006. Expected results We hypothesize tht infrct size reduction will be identicl in cell therpy groups, suggesting prcrine ctivity. 33

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 2008 34 35

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 2008 36 37

Them 1 Crdiovsculr Biology nd Phrmcology Nme Subject Promotor(s) Copromotor(s) Funding VJ de Beer IG Bikker GMJ deboer F Bos KY Chn Coronry nd pulmonry vsculr dpttions fter myocrdil infrction Optimiztion of oxygention nd circultion in criticlly iii ptients Crdic dysfunction in ging: The role of genomic Zebrfish genomics to identify genomic regultion of vsculogenesis The role of femle sex steroids nd ion chnel muttions in migrine DJGM Duncker D Merkus 3 DAMPJ Gommers 1 DJGM Duncker, JHJ Hoeymkers 1 DJGM Duncker HJ Duckers 2 AHJ Dnser A Mssen vn den Brink 1 ED vn Deel WK den Dekker D vn Deursen Pthophysiology nd therpy of pressure overlod induced crdic hypertrophy Moleculr mechnism of the vulnerble plque Regultion of the heptic lipse gene by E-box binding trnscription fctors MD Durik Therpeutic potencil of Angiotensine 1-7 DJGM Duncker D Merkus 1 PW Serruys HJ Duckers 4 H Jnsen, JMJ Lmers AJM Verhoeven 3 AHJ Dnser 1 C O E U R Annul Report 2008 GJ vn Essen F Gembrdt YJ de Groot F Grüne RA Hsdijk F Heldermn RLJM Herpers HJ Houtgrf MJ vn Houwelingen B vn der Hoven TC Jnsen E Klijn Crdivsculr performnce of modern fttening pigs Interction between different peptide systems Bcteril recoloniztion nd resistnce in ICU ptients fter Chnges of effective downstrem pressure in cerebrl perfusion under influence of nesthetics nd vsoctive drugs Moleculr regultion of vsculogenesis nd ngiogenesis Arteril dpttion described by stress model Moleculr regultion of vsculogenesis Cell therpy in myocrdil infrction nd hert filure Assessment of the humn hemodynmic condition by mens of pulse contour nlysis Mesurement of functionl liver blood flow Blood lctte s index for oxygen imblnce in criticlly ill ptients Microcircultion in criticlly ill ptients DJGM Duncker AHJ Dnser 4 J Bkker D Dos Reis Mirnd 1 J Klein 1 DJGM Duncker HJ Duckers 2 AFW vn der Steen R Krms 2 DJGM Duncker HJ Duckers 4 PW Serruys HJ Duckers 4 DJGM Duncker D Merkus 4 J Bkker 1 J Bkker J vn Bommel 1 J Bkker 1 C O E U R Annul Report 2008 38 39

Them 1 Crdiovsculr Biology nd Phrmcology Nme L Klompe M Krop DWD Kuster A Lim BME Mees X Moors MM Noordeloos C Preis TV Scohy D Segers D Tempel DB Uitterdijk Subject Respirtion studies in crdic surgery Renin-ngiotensin receptor Nucler proteins tht discriminte between erly development of dptive nd mldpttive hypertrophy Noninvsive mesurement of peripherl perfusion in criticlly ill ptients Endothelil NO synthse nd ngiogenesis Circultory spects of xenon nesthesi Hemoxygense nd crdiovsculr disese Open lung concept in crdiothorcic surgery Aspects of nesthesi in peditric crdic surgery Inflmmtion nd therosclerosis Mouse genomics to identify the genetic regultion of vsculogenisis / ngiogenesis Prcrine effects of progenitor cells on crdic repir fter myocrdil infrction Promotor(s) Copromotor(s) Funding DAMPJ Gommers, AJJC Bogers 1 AHJ Dnser 3 JMJ Lmers AJM Verhoeven 3 J Bkker 1 H vn Urk R de Crom 1 DAMPJ Gommers, J Klein 1 ML Simoons HJ Duckers 1 DAMPJ Gommers, AJJC Bogers 1 J Klein, AJJC Bogers DAMPJ Gommers 1 AFW vn der Steen R de Crom 3 DJGM Duncker HJ Duckers 1 WJ vn der Giessen H vn Beusekom, B Groenendijk 1 C O E U R Annul Report 2008 Theme 2 Vsculr Medicine, Hemostsis nd Stroke Progrm Code: EMC COEUR 02-43-02 C O E U R Annul Report 2008 40 41

Genetic polymorphisms in in the the Renin- Angiotensin-Aldosteron-System in in reltion to to hypertension JJ JJ Brugts 1, M. 1, M. de de Mt Mt 2, E 2, E Boersm 1, 1, J.Wittemn 3, C. 3, C. vn vn Duijn 3, A. 3, A. Uitterlinden 3,4, 3,4, J.Dnser 5, ML 5, ML Simoons 1 1 From From the the Deprtments of of Crdiology (1); (1); Hemetology (2); (2); Epidemiology & & Biosttistics (3); (3); Internl Medicine (4); (4); nd nd Phrmcology (5) (5) of the of the Ersmus Medicl Centre, Rotterdm, The The Netherlnds COEUR Bckground The The renin-ngiotensin-ldosteron-system regultes blood blood pressure nd nd wter wter blnce. We We hypothesized tht tht specific genetic polymorphisms in the in the renin-ngiotensin-ldosteron-system re re relted relted to hy- to hypertension. Methods Blood Blood smples from from prticipnts of the of the EUROPA tril tril were were collected nd nd stored stored t t centrl centrl core core lbortory. For For the the current current study, study, SNP- SNPselection ws ws bsed bsed on on hplotype tgging, functionlity or or loction in in the the gene. gene. For For the the ngiotensinogen gene, gene, genotype ws ws determined by by Tqmn llelic llelic discrimintion. Hplotype structure ws ws gted gted using using HploStt nd nd R R softwre. Hypertension ws ws defined investi- by by study study protocol s s blood blood pressure bove bove 160/90 160/90 mmhg mmhg or or the the use use of of ntihypertensives. All All nlyses re re multivritely djusted for for ge, ge, gender, hypercholesterolemi, dibetes mellitus, smoking, prior prior myocrdil infrction, prior prior PCI, PCI, prior prior CABG, CABG, use use of of bet-blockers, sttins, nti-pltelet gents gents nd nd ACE-inhibitors. Results Men Men ge ge ws ws 60 60 (Sd (Sd 9) yers, 9) yers, nd nd 85.7% 85.7% were were mle. mle. Hypertension ws ws present in 27.9% in 27.9% of the of the ptients. Severl genotypes were were sig- significntly ssocited with with hypertension, which which were were ll ll confirmed in in the the hplotype nlysis s s presented in Figure in Figure 1. As 1. As compred to the to the reference ctegory with with ll ll norml norml lleles lleles (frequency 22.4%), four four hplotypes were were significntly nd nd independently ssocited with with hy- hypertension. Figure Figure 1. 1. Hplotype nlysis of the of the Angiotensinogen Gene Gene in in Reltion to to Hypertension in in Ptients with with Stble Stble Cornry Artery Artery Disese rs5049 rs5049rs5051 rs5051 rs10864770 rs943580 rs699 rs699rs4762 rs4762rs7079 rs7079 rs247854 Hplotype Freq Freq OR OR (95%CT) P. P. vlue vlue Ref. Ref. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 22.4% 22.4% 1.00 1.00 H.1 H.1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 1 1 30,4% 30,4% 1.14 1.14 (1.04-1.25) < 0.01 < 0.01 H.2 H.2 1 1 2 2 1 1 2 2 2 2 2 2 1 1 2 2 12,7% 12,7% 1.29 1.29 (1.18-1.42) <0.001 <0.001 H.3 H.3 2 2 2 2 1 1 2 2 2 2 1 1 1 1 1 1 12.1% 12.1% 1.28 1.28 (1.17-1.41) <0.001 <0.001 H.4 H.4 1 1 2 2 1 1 2 2 2 2 1 1 1 1 2 2 9.9% 9.9% 1.13 1.13 (1.01-1.25) 0.0453 0.0453 H.5 H.5 1 1 2 2 2 2 2 2 2 2 1 1 1 1 1 1 7.0% 7.0% 1.08 1.08 (0.94-1.22) 0.28 0.28 Conclusions Genotype nd nd hplotype nlysis of the of the ngiotensinogen gene gene reveled strong strong nd nd independent ssocition with with hypertension in in ptients with with stble stble coronry rtery rtery disese 44 Supported by by NHS NHS grnt grnt 2005B219

Common vrition in in the the pltelet receptor P2RY12 gene is is determinnt of of the the wide vribility in in on-clopidogrel pltelet rectivity Gorn Gorn Rudež Rudež,, Heleen Heleen J. J. Boumn Boumn b, b, Jochem Jochem W. W. vn vn Werkum Werkum b, b, Frnk Frnk W.G. W.G. Leebeek Leebeek,, Adrin Adrin Kruit Kruit c, c, Hendrik Hendrik J.T. J.T. Ruven Ruven c, c, Jürien Jürien M. M. ten ten Berg Berg b, b, Moniek Moniek P.M. P.M. de de Mt Mt,, Christin Christin M. M. Hckeng Hckeng c c Deprtment Deprtment of of Hemtology, Hemtology, Ersmus Ersmus University University Medicl Medicl Center, Center, Rotterdm, Rotterdm, the the Netherlnds Netherlnds b b Deprtment Deprtment of of Crdiology, Crdiology, St. St. Antonius Antonius Hospitl, Hospitl, Nieuwegein, Nieuwegein, the the Netherlnds Netherlnds c c Deprtment Deprtment of of Clinicl Clinicl Chemistry, Chemistry, St. St. Antonius Antonius Hospitl, Nieuwegein, the Netherlnds Hospitl, Nieuwegein, the Netherlnds COEUR A lrge vribility ws found in 20 µmol/l ADP-induced pltelet ggregtion A lrge vribility ws found in 20 µmol/l ADP-induced pltelet ggregtion nd VerifyNow P2Y12 Assy, despite clopidogrel tretment (Figure 2A nd nd VerifyNow P2Y12 Assy, despite clopidogrel tretment (Figure 2A nd B). B). Men pltelet rectivity ws significntly higher in ptients who received Men pltelet rectivity ws significntly higher in ptients who received clopidogrel ccording to the dosing regimen B compred to other groups. clopidogrel ccording to the dosing regimen B compred to other groups. In both ssys, the vribility in residul on-clopidogrel pltelet rectivity In both ssys, the vribility in residul on-clopidogrel pltelet rectivity ws similr cross the 3 clopidogrel loding dose regimens. ws similr cross the 3 clopidogrel loding dose regimens. Introduction Introduction The clinicl efficcy of clopidogrel is hmpered by lrge The clinicl efficcy of clopidogrel is hmpered by lrge interindividul vribility in response. Polymorphisms in the interindividul vribility in response. Polymorphisms in the P2RY12 receptor gene hve been suggested to contribute to this P2RY12 receptor gene hve been suggested to contribute to this phenomenon, but previous studies were reltively smll nd did not phenomenon, but previous studies were reltively smll nd did not cover the common vrition in the P2RY12 gene completely. cover the common vrition in the P2RY12 gene completely. Aim Aim of of the the study study The im of this study ws to comprehensively investigte the The im of this study ws to comprehensively investigte the possible ssocition between common vrition in the entire possible ssocition between common vrition in the entire P2RY12 locus nd the mgnitude of on-clopidogrel pltelet P2RY12 locus nd the mgnitude of on-clopidogrel pltelet rectivity in lrge cohort of elective PCI ptients using multiple rectivity in lrge cohort of elective PCI ptients using multiple pltelet function ssys. pltelet function ssys. Methods Methods A totl of 1031 consecutive ptients with coronry rtery disese A totl of 1031 consecutive ptients with coronry rtery disese who were scheduled for elective PCI were enrolled in the study. who were scheduled for elective PCI were enrolled in the study. These ptients were on one of the following 3 clopidogrel dosing These ptients were on one of the following 3 clopidogrel dosing regimens: regimens: A. chronic mintennce therpy of 75 mg dily for >5 dys (n=659) A. chronic mintennce therpy of 75 mg dily for >5 dys (n=659) B. clopidogrel loding dose of 300 mg t lest 24 h before PCI, B. clopidogrel loding dose of 300 mg t lest 24 h before PCI, followed by chronic mintennce therpy of 75 mg dily (n=314) followed by chronic mintennce therpy of 75 mg dily (n=314) C. clopidogrel loding dose of 600 mg t lest 6h before PCI, C. clopidogrel loding dose of 600 mg t lest 6h before PCI, followed by chronic mintennce therpy of 75 mg dily (n=58) followed by chronic mintennce therpy of 75 mg dily (n=58) Pltelet function ws ssessed by mens of: Pltelet function ws ssessed by mens of: ADP-induced light-trnsmittnce ggregometry (LTA) ADP-induced light-trnsmittnce ggregometry (LTA) VerifyNow P2Y12 ssy VerifyNow P2Y12 ssy PFA-100 Collgen/ADP ssy. PFA-100 Collgen/ADP ssy. 6 hplotype-tgging single nucleotide polymorphisms (ht-snps) 6 hplotype-tgging single nucleotide polymorphisms (ht-snps) were crefully selected in order to cover 88% of the totl common were crefully selected in order to cover 88% of the totl common vrition in the P2RY12 gene nd its flnking regultory regions vrition in the P2RY12 gene nd its flnking regultory regions bsed on the HpMp dt (Figure 1). bsed on the HpMp dt (Figure 1). Figure 1. Schemtic representtion of the P2RY12 gene nd the linkge Figure 1. Schemtic representtion of the P2RY12 gene nd the linkge disequilibrium mp of the P2RY12 locus. disequilibrium mp of the P2RY12 locus. The P2RY12 gene consists of 3 exons (E1, E2 nd E3) nd two intervening The P2RY12 gene consists of 3 exons (E1, E2 nd E3) nd two intervening sequences (IVS1 nd IVS2), together 47kb. Only E3 is coding. According sequences (IVS1 nd IVS2), together 47kb. Only E3 is coding. According to the HpMp linkge disequilibrium (LD) mp of the P2RY12 locus, 4 LD to the HpMp linkge disequilibrium (LD) mp of the P2RY12 locus, 4 LD blocks cn be discerned (blck-white brs) within which there is little or no blocks cn be discerned (blck-white brs) within which there is little or no recombintion between SNPs. recombintion between SNPs. 6 common hplotypes with llele frequency >5% cn be inferred from these 6 common hplotypes with llele frequency >5% cn be inferred from these 6 ht-snps (Tble). 6 ht-snps (Tble). Hplotype SNP llele Allele frequency Hplotype SNP llele Allele frequency composition (%) composition (%) A (ref.) ttcggt 10 A (ref.) ttcggt 10 B ttcagt 6 B ttcagt 6 C CTCAGc 15 C CTCAGc 15 D CTAT 15 D CTAT 15 E CcCgGT 21 E CcCgGT 21 F CcCAGT 22 F CcCAGT 22 Figure 2. Mximl 20 µmol/l ADP-induced LTA nd VerifyNow P2Y12 Figure 2. Mximl 20 µmol/l ADP-induced LTA nd VerifyNow P2Y12 ssy in the totl study popultion nd ccording to the 3 clopidogrel ssy in the totl study popultion nd ccording to the 3 clopidogrel dose regimens. p-vlues: one-wy ANOVA with Tukey s post-hoc multiple dose regimens. p-vlues: one-wy ANOVA with Tukey s post-hoc multiple comprisons test comprisons test Figure 3. The effect of P2RY12 hplotypes on pltelet rectivity ssessed Figure 3. The effect of P2RY12 hplotypes on pltelet rectivity ssessed by LTA. by LTA. 5 µmol/l ADP-induced mximl ggregtion (A), lte ggregtion t 6 min 5 µmol/l ADP-induced mximl ggregtion (A), lte ggregtion t 6 min (B), 20 µmol/l ADP-induced mximl ggregtion (C) nd lte ggregtion (B), 20 µmol/l ADP-induced mximl ggregtion (C) nd lte ggregtion t 6 min (pnel D). Totl study popultion (squres), the subgroup of t 6 min (pnel D). Totl study popultion (squres), the subgroup of ptients on clopidogrel dosing regimen A (tringles) nd dosing regimen ptients on clopidogrel dosing regimen A (tringles) nd dosing regimen B (circles). Vlues re expressed s men differences from the reference B (circles). Vlues re expressed s men differences from the reference hplotype A in percent of bsolute ggregtion per hplotype llele, with hplotype A in percent of bsolute ggregtion per hplotype llele, with error brs corresponding to the stndrd errors of the estimtes. Results error brs corresponding to the stndrd errors of the estimtes. Results re djusted for ge, sex, BMI, dibetes nd smoking. In the nlysis of the re djusted for ge, sex, BMI, dibetes nd smoking. In the nlysis of the totl group of ptients, dditionl djustment for clopidogrel loding-dose totl group of ptients, dditionl djustment for clopidogrel loding-dose ws performed. *p<0.05, **p<0.001 ws performed. *p<0.05, **p<0.001 Hplotype F ws ssocited with significntly lower 5 nd 20 µmol/l Hplotype F ws ssocited with significntly lower 5 nd 20 µmol/l ADP-induced mximl nd lte ggregtion (both -4% per hplotype ADP-induced mximl nd lte ggregtion (both -4% per hplotype llele, p<0.05, Figure 3) compred to the reference hplotype A. Under llele, p<0.05, Figure 3) compred to the reference hplotype A. Under ssumption of n dditive effect of the hplotype lleles, the net effect in n ssumption of n dditive effect of the hplotype lleles, the net effect in n individul would be 8% lower pltelet ggregtion. individul would be 8% lower pltelet ggregtion. Similr differences between the hplotype F nd the reference hplotype A Similr differences between the hplotype F nd the reference hplotype A were seen in the subgroup nlysis of ptients from the clopidogrel dosing were seen in the subgroup nlysis of ptients from the clopidogrel dosing regimens A nd B. regimens A nd B. Similr results were obtined for 2 nd 10 µmol/l concentrtions of ADP Similr results were obtined for 2 nd 10 µmol/l concentrtions of ADP (dt not shown). (dt not shown). Figure 4. The effect of P2RY12 hplotypes on pltelet rectivity ssessed by Figure 4. The effect of P2RY12 hplotypes on pltelet rectivity ssessed by VerifyNow P2Y12 ssy nd PFA-100 Collgen/ADP. VerifyNow P2Y12 ssy nd PFA-100 Collgen/ADP. Totl study popultion (squres) nd the subgroups of ptients on Totl study popultion (squres) nd the subgroups of ptients on clopidogrel dosing regimen A (tringles) nd dosing regimen B (circles). clopidogrel dosing regimen A (tringles) nd dosing regimen B (circles). Error brs re stndrd errors. Results re djusted for ge, sex, BMI, Error brs re stndrd errors. Results re djusted for ge, sex, BMI, dibetes nd smoking. In the nlysis of the totl group of ptients, dibetes nd smoking. In the nlysis of the totl group of ptients, dditionl djustment for clopidogrel loding-dose ws performed. *p<0.05, dditionl djustment for clopidogrel loding-dose ws performed. *p<0.05, **p<0.001 **p<0.001 Hplotype F ws ssocited with lower number of PRU when mesured Hplotype F ws ssocited with lower number of PRU when mesured with the VerifyNow P2Y12 Assy (-11 PRU, p<0.05, Figure 4A) compred with the VerifyNow P2Y12 Assy (-11 PRU, p<0.05, Figure 4A) compred to the reference hplotype A. to the reference hplotype A. However, these differences were less pronounced nd sttisticlly not However, these differences were less pronounced nd sttisticlly not significnt for clopidogrel dosing regimens A nd B (Figure 4A). significnt for clopidogrel dosing regimens A nd B (Figure 4A). A stronger nd significnt ssocition ws observed for hplotype E, which A stronger nd significnt ssocition ws observed for hplotype E, which ws consistently ssocited with sttisticlly lower number 27 PRU in the ws consistently ssocited with sttisticlly lower number 27 PRU in the VerifyNow P2Y12 Assy for both the totl study popultion nd for the two VerifyNow P2Y12 Assy for both the totl study popultion nd for the two clopidogrel dosing regimens (p<0.05, Figure 4A). clopidogrel dosing regimens (p<0.05, Figure 4A). No significnt differences between the P2RY12 hplotypes were observed No significnt differences between the P2RY12 hplotypes were observed when pltelet function ws mesured with the PFA-100 collgen/adpcrtridge (Figure 4B). when pltelet function ws mesured with the PFA-100 collgen/adpcrtridge (Figure 4B). Conclusion Conclusion Common vrition in the P2RY12 gene is significnt determinnt Common vrition in the P2RY12 gene is significnt determinnt of the wide interindividul vribility in on-clopidogrel pltelet of the wide interindividul vribility in on-clopidogrel pltelet rectivity in ptients with CAD. rectivity in ptients with CAD. milto: milto: g.rudez@ersmusmc.nl g.rudez@ersmusmc.nl 45

Reserch Groups theme 2 Acute coronry syndromes Project leder ML Simoons Stff H Boersm, FWG Leebeek PhD cndidte CA den Uil Crdiovsculr Aging Project leder TJM vn der Cmmen, FUS Mttce Rso AH vn den Meircker, JCM Wittemn PhD cndidte GC Verwoert, KA Hrtholt Crdiovsculr genetics nd metbolic diseses Project lederss EJG Sijbrnds, DF Mjoor-Krkuer, FJ ten Cte Stff AH Bootsm, GM Dlling-Thie, JG Lngendonk, D Dooijes, MW Wessels SWJ Lmberts, JP Mckenbch, BA Oostr PhD cndidtes IPG Botden, K Cliskn, TTW vn Herpt, YM Hoedemekers, M vn Hoek, IMBH de Grf-vn de Lr, M Michels, JB vn der Net, DM Oosterveer, J Versmissen Cuses nd consequences of stroke Project leders PJ Koudstl, MMB Breteler Stff EG Visch-Brink, DWJ Dippel CM vn Duijn, FWG Leebeek Postdocs LML de Lu PhD cndidtes M de Jong Hgelstein, EG vn den Herik, EMC Schrijvers, RG Wieberdink Mngement of hemorrhgic nd thrombotic disorders Project leder FWG Leebeek Stff MJHA Kruip P Sonneveld, B Löwenberg, MPM de Mt, DC Rijken PhD cndidtes EM de Wee Pthogenesis of hypertension Project leder F Boomsm, AH vn den Meircker PhD cndidtes AM Birkenhäger, PM Jnsen, JHW Rutten Phrmcogenomics in crdiovsculr disese Project leder MPM de Mt, ML Simoons Stff EJG Sijbrnds, AHJ Dnser, AG Uitterlinden JCM Wittemn, CM vn Duijn PhD cndidte JJ Brugts Role of hemostsis in rteril thrombosis Project leder FWG Leebeek, MPM de Mt Stff DC Rijken PJ Koudstl, B Löwenberg, DWJ Dippel PhD cndidtes TN Bongers, ELE de Bruijne, YL Kwok-Cheung, JE vn Loon, G Rudež, MC vn Schie, S Tlens C O E U R Annul Report 2008 Circultory spects of kidney trnsplnttion Project leder DAMPJ Gommers Stff J Klein, JNM IJzermns PhD cndidte vcncy Mngement nd prevention of stroke Project leder DWJ Dippel, PJ Koudstl DJGM Duncker PhD cndidte MH den Hertog C O E U R Annul Report 2008 46 47

Theme 2 Vsculr Medicine Hemostsis nd Stroke Nme Subject Promotor(s) Copromotor(s) Funding AM Birkenhäger Mechnism of diurnl blood pressure vrition HAP Pols AH vn den Meircker 3 TN Bongers ADAMTS13: new fctor in the development of stroke B Löwenberg FWG Leebeek 1 IPG Botden Red wine nd resvertrol: crosstlk between endothelil prcrine function nd energy metbolism AHJ Dnser JG Lngendonk, EJG Sijbrnds 1 JJ Brugts Phrmcogenomics of ACE-inhibition in stble coronry rtery disese: The EUROPA-tril ML Simoons MPM de Mt, E Boersm 2 ELE de Bruijne Thrombin-ctivtble fibrinolysis inhibitor nd rteril thrombosis B Löwenberg FWG Leebeek 1 K Cliskn Non-compction crdiomyopthy ML Simoons 1 KA Hrtholt (Cost)effectiveness of mediction withdrw in older fllers: rndomized controlled tril t the Accident nd Emergency Deprtment TJM vn der Cmmen 1 E vn den Herik Etiologicl fctors in stroke PJ Koudstl 2 TTW vn Herpt Genetic nd Environmentl Risk Fctors of Type 2 Dibetes SWJ Lmberts EJG Sijbrnds 1 MH den Hertog Tretment of cute stroke PJ Koudstl DWJ Dippel 3 YM Hoedemekers The genetic epidemiology of non-compction crdiomyopthy BA Oostr 3 M vn Hoek Genes in dibetic environment HAP Pols EJG Sijbrnds 3 PM Jnsen Aldosterone in hypertension HAP Pols AH vn den Meircker 3 M de Jong-Hgelstein The efficcy of cognitive linguistic therpy in the cute stge of phsi: rndomized controlled tril PJ Koudstl EG Visch-Brink 3 YL Kwok- Cheung The role of fibrinogen vrints in wound heling B Löwenberg 2 IMBH de Grfvn de Lr Identifiction of genes involved in humn congenitl hert mlformtions BA Oostr MW Wessels 3 C O E U R Annul Report 2008 JE vn Loon M Michels JB vn der Net DM Oosterveer G Rudež JHW Rutten Von Willebrnd Fctor in the pthogenesis of myocrdil infrction nd stroke Genetics of hypertrophic crdiomyopthies Discrimintive bility of genetic risk fctors in fmilil hypercholesterolemi The whole-genome nd clssicl risk fctors in CVD Pltelet gene polymorphisms nd rteril thrombosis Ntriuretic peptides: biomrkers of crdiovsculr disese B Löwenberg, FWG Leebeek FWG Leebeek 3 ML Simoons 1 HAP Pols, JPMckenbch EJG Sijbrnds, GM Dlling-Thie 1 HAP Pols EJG Sijbrnds 2 B Löwenberg FWG Leebeek, MPM de Mt HAP Pols AH vn den Meircker 1 C O E U R Annul Report 2008 48 49

Theme 2 Vsculr Medicine Hemostsis nd Stroke Nme MC vn Schie EMC Schrijvers S Tlens CA den Uil J Versmissen GC Verwoert EM de Wee RG Wieberdink Subject Elucidting the hplotype structure of von Willebrnd fctor nd its ssocition with rteril thrombosis Glucose metbolism nd Risk of (vsculr) dementi Identifiction nd chrcteriztion of new fibrin-binding Crdiogenic shock nd the microcircultion investigtion with sidestrem drk-field imging. The whole-genome nd clssicl risk fctors in CVD Genetic determinnts nd consequences of rteril stiffness nd blood pressure Severe von Willebrnds disese in the Netherlnds Determinnts of stroke Promotor(s) Copromotor(s) Funding B Löwenberg FWG Leebeek, MPM de Mt 2 P Koudstl, MM Breteler 4 B Löwenberg DC Rijken 1 ML Simoons WK Lgrnd 1 HAP Pols EJG Sijbrnds 2 JCM Wittemn FUS Mttce Rso 1 B Löwenberg FWG Leebeek 3 P Koudstl, MM Breteler 1 C O E U R Annul Report 2008 Lisn Vermunt-Neefjes Theme 3 Imge-guided Crdiovsculr Medicine Progrm Code: EMC COEUR 03-43-03 C O E U R Annul Report 2008 50 51

Automted Anlysis for for Three-Dimensionl Stress Echocrdiogrphy K.Y.E. Leung, G. G. vn vn Burken, M. M. vn vn Crdiology, Thorxcenter, Ersmus MC MC Strlen, N. N. de de Jong, Jong, A.F.W. vn vn der der Steen, Rotterdm, the the Netherlnds J.G. J.G. Bosch, Biomedicl Engineering, Thorxcenter, Ersmus MC MC Rotterdm, the the Netherlnds I m I m involved the in the project clled clled Automted mesures of of crdic motion. Our Our methods re re minly minly nlysis for for three-dimensionl stress stress bsed bsed on on modeling of these of these contours vi vi sttisticl echocrdiogrphy models. Here Here you you see see n n exmple of the of the typicl typicl vritions in the in the ppernce of the of the left left ventricle cross 3D 3D Echocrdiogrphy is is reltively new new imging set set of of ptients. Such Such models re re then then used used to detect to detect modlity which which llows llows the the rel-time visuliztion of of contours, by by fitting fitting the the model model to the to the imge. We We hve hve crdic structures, s s shown shown here. here. Imges re re mde mde investigted detection in in ntomicl views, views, but but lso lso trnsthorciclly using using device device such such s s this this one. one. 3D 3D detection. A A second ppliction of of modeling is is The The min min dvntge of 3D of 3D versus trditionl 2D 2D shown shown here: here: model model of the of the typicl typicl crdic motion is is imging is tht is tht the the hert hert is of is of course 3D 3D structure. constructed, nd nd used used for for trcking contour in the in the Stress Stress echocrdiogrphy is is commonly used used end-distolic frme frme throughout the the crdic cycle. cycle. technique for for dignosing left left ventriculr dysfunction. Imges re re cquired in in different stges of of stress, A third A third prt prt of the of the project involves the the nlysis of the of the brought on on by by exercise, for for exmple. The The motion of of wll wll motion. We We lso lso use use modeling techniques here. here. the the crdic wll wll is then is then nlyzed by by crdiologist. In In For For the the utomtic clssifiction of of segmentl wll wll this this project, we we im im to to develop utomted nlysis motion, we we used used n n dpted version of the of the trditionl methods for for more more objective, quntittive, nd nd fst fst principl component nlysis modeling technique, wy wy of of interpreting stress stress echoes. clled clled orthomx rottions to get to get more more loclized vritions. During clssifiction, subset of these of these soclleclled modes is is selected s clssifiers for for segmentl so- A min A min prt prt of the of the project involves the the lignment of of imges in in different stges of of stress. This This is wll wll motion. We We found found tht tht using using these these orthomx necessry becuse these these imges my my be be imged rotted models, fewer fewer modes re re needed to to chieve from from slightly different ngles. For For this, this, we we hve hve the the sme sme clssifiction ccurcy. developed n n utomtic registrtion method to detect to detect stndrd ntomicl plnes in the in the stress stress imge, Finlly, we we hve hve lso, lso, in in coopertion with with our our clinicl given given the the mnully selected views views in rest. in rest. This This n is n prtners, developed clinicl ppliction for for viewing exmple of of registrtion results. You You cn cn see see the the 4C, 4C, 3D 3D stress stress imges side-by-side. This This progrm lso lso 2C, 2C, nd nd short-xis views. views. The The registrtion improves fetures esy esy mnul lignment of of imges. This This lignment of the of the crdic structures, s s cn cn be be seen. seen. is n is importnt step step in the in the ppliction of 3D of 3D stress stress echocrdiogrphy, becuse previously, no no dedicted A A second prt prt of the of the project involves contour tools tools existed. We We re re in the in the process of of incorporting detection methods. Contours of the of the left left ventriculr our our utomted nlysis methods into into the the ppliction. endocrdium cn cn give give us us more more quntittive Supported Supported by the by Dutch the Dutch Technology Technology Foundtion Foundtion STW STW (grnt (grnt 06666), 06666), pplied pplied science science division division of NWO of NWO nd the nd Technology the Technology Progrm Progrm of the of Ministry the Ministry of Economic of Economic Affirs Affirs

Modifiction of of risk with MSCT-coronry ngiogrphy in in high-risk crdic symptomtic ptients Lisn A A Neefjes 1, Mrk 1, Mrk M M Boogers 2, 2, Mrten-Jn M M Crmer 3, 3, Jeroen J Bx J Bx 4, 4, Pim Pim J de J de Feyter 5 5 1+5: 1+5: Deprtment of of crdiology nd nd rdiology, Ersmus Medicl Center Center Rotterdm, 2+4: 2+4: Deprtment of of crdiology, Leiden Leiden University Medicl Center, 3: 3: Deprtment of of crdiology, University Medicl Center Center Utrecht COEUR Bckground Crdiovsculr disese disese the is the leding leding cuse cuse of of mortlity nd nd morbidity in the in the USA USA nd nd Europe Europe nd nd cute cute crdic crdic deth deth or or nonftl myocrdil infrction is the is the first first clinicl clinicl mnifesttion of of coronry therosclerosis which which occurs occurs in 40% in 40% to 50% to 50% of of cses.[1] Nowdys usully usully trditionl riskfctors re re used used to define to define the the sttisticl likelihood of of progression of n of n dverse coronry event, event, but but they they provide provide no no direct direct evidence of the of the presence or degree or degree of of coronry therosclerosis.[2-4] Ptients who who re re ctegorized s s high-risk following these these prediction models, models, should should be be optiml optiml mediclly treted treted for for intense intense globl globl risk risk mngement (spirin, lipid-lowering, ntihypertensives or or glucosemodultion). Multi-slice computed tomogrphy (MSCT) (MSCT) is ble is ble to detect to detect therosclerosis in in non-invsive, ptient ptient friendly, friendly, inexpensive nd nd fst fst wy[5, wy[5, 6]. 6]. A A non-enhnced CT CT is is performed to detect to detect coronry clcium. A A contrst enhnced CT CT coronry ngiogrphy (CTCA) (CTCA) permits permits evlution of both of both the the coronry lumen lumen nd nd coronry vessel vessel wll[5, wll[5, 8]. 8]. Figure Figure 3. cmpr 3. cmpr CT CT imge, imge, 3, 3, nd nd cross cross section section (inly), (inly), 3b, 3b, showing showing the the LAD LAD with with mixed mixed plque. plque. Figure Figure 4. cmpr 4. cmpr CT CT imge, imge, 4, 4, nd nd cross cross section section (inly), (inly), 4b, 4b, showing showing significnt stenosis stenosis in the in the LAD. LAD. Figure Figure 6. 6. ECG-synchroniztion: Dt Dt is used is used of of consecutive hert hert bets bets when when the the hert hert is reltively is reltively in rest in rest (for (for exmple exmple end-systolic or or mid mid to end-distolic phse) phse) to minimize to minimize coronry coronry motion motion rtefcts. Methods Our Our study study is is prospective, multicenter blinded blinded observtionl study study of of high-risk ptients ptients undergoing CT-coronry imging imging with with long-term (5-yers) follow-up. The The study study popultion will will consist consist of 700 of 700 crdic crdic symptomtic high-risk ptients ptients defined defined s s hving: hving: dibetes mellitus, peripherl vessel vessel disese disese or fmilil or fmilil hypercholesterolemi. These These ptients ptients will will be be enrolled t 3 t UMC s: 3 UMC s: the the Ersmus Medicl Medicl Center Center Rotterdm (400), (400), the the Leiden Leiden University Medicl Medicl Center Center (200) (200) nd nd the the University Medicl Medicl Center Center Utrecht Utrecht (100). (100). They They will will ll ll undergo non non contrst enhnced scn, scn, followed by by contrst enhnced CTCA. CTCA. The The non-enhnced scn scn provides: 1. 1. the the totl totl clcium clcium score score of the of the coronry tree tree 2. 2. the the per per vessel vessel score score 3. 3. the the per per lesion lesion score. score. Quntifiction of of coronry clcium clcium occurs occurs with with n n utomted lgorithm which which is is implemented in ech in ech scnner. The The CTCA CTCA llows: llows: 1. 1. identifiction nd nd chrcteriztion of of obstructive nd nd non- nonobstructive lesions lesions 2. 2. ssessment of the of the totl totl coronry plque plque burden; burden; s s composite of extent, of extent, severity, distribution nd nd composition of the of the coronry lesions. lesions. Figure Figure 1. Curved 1. Curved Multi Multi Plnr Plnr Reconstructed (cmpr) (cmpr) CT CT imge, imge, 1, 1, nd nd cross cross section section (inly), (inly), 1b, 1b, showing showing non-disesed Right Right Coronry Artery. Artery. Figure Figure 2. cmpr 2. cmpr CT CT imge, imge, 2, 2, nd nd cross cross section section (inly), (inly), 2b, 2b, CT CT imges imges showing showing the the Left Left Anterior Anterior Descending Artery Artery (LAD) (LAD) with with smll smll clcified clcified plque. plque. Figure Figure 5. 5. Dul-source Computed Tomogrphy Scnner Scnner (DSCT) (DSCT) (Somtom Definition, Siemens Siemens Medicl Medicl Solutions, Forchheim, Germny) in the in the Ersmus Ersmus MC MC Rotterdm Objective The The objective of our of our study study is to is to remodify risk risk in in high-risk individuls (s (s estimted by by trditionl riskfctors), into into low, low, intermedite nd nd high-risk groups, groups, ccording to the to the clcium clcium score score nd nd the the coronry plque plque burden burden obtined by by MSCT. MSCT. Figure Figure 7. Volume 7. Volume rendered CT CT Figure Figure 8. Volume 8. Volume rendered CT CT imge imge of the of the hert, hert, showing showing 3 3 imge imge of the of the coronry coronry rteries, rteries, dimensionl ntomicl overview. showing showing right right dominnt system. system. Ao, Ao, Aortic Aortic Root; Root; PA, PA, pulmonry LAD, LAD, Left Left Anterior Anterior Descending rtery; rtery; LAD, LAD, Left Left Anterior Anterior Coronry Artery; Artery; LCX, LCX, Left Left Descending Coronry Artery; Artery; LCX, LCX, Circumflex Coronry Artery; Artery; RCA, RCA, Left Left Circumflex Coronry Artery; Artery; Right Right Coronry Artery. Artery. RCA, RCA, Right Right Coronry Artery; Artery; LV, LV, Left Left Ventricle; RV, RV, Right Right Ventricle. This This study study is is pproved by by the the institutionl bord bord of the of the Ersmus MC MC nd nd ll ll prticipnts hve hve to give to give informed consent. MSCT protocol - hert - hert rte: rte: if > if 65 > 65 bpm bpm dminister 100 100 mg mg metoprolol orlly. orlly. Re-check hert hert rte rte ± 30 ± 30 45 45 minutes minutes lter. lter. If HR If HR still still >65 >65 bpm bpm metoprolol IV (1 IV mg/ml) (1 mg/ml) cn cn be be used: used: with with mximum of 15 of 15 ml. ml. - IV - needle IV needle (7 Guge) (7 Guge) in ven in ven cubiti cubiti - 80-100 - 80-100 ml ml contrst (Iomeron 400, 400, Brcco, Brcco, or or Ultrvist 370, 370, Schering), flow flow rte rte 5-5,5 5-5,5 ml/s ml/s - - Bolus-trcking technique - - Retrospective cquisition technique (with (with smll smll pulsing pulsing window) Supported by by NHF NHF grnt grnt 2006T102. 55

Reserch Groups - theme 3 Crdic imging (MRI nd CT) Project leders PJ de Feyter, PMT Pttynm Project leder AFW vn der Steen Stff PA Wielopolski, K Niemn, RJM vn Geuns, N Mollet Stff N de Jong, JG Bosch GP Krestin, W Niessen JHC Reiber PhD cndidtes SWM Kirschbum, WB Meijboom, T Springeling, LAE Vermunt-Neefjes, A Weustink PhD cndidtes KYE Leung, M vn Strlen Biomechnics Project leder Stff PhD cndidtes JJ Wentzel FJH Gijsen AFW vn der Steen, A vn der Lugt, PJ de Feyter H Groen, AG vn der Giessen Neurovsculr imging (MRI nd CT) Project leder A vn der Lugt Stff PA Wielopolski, DWJ Dippel GP Krestin, PMT Pttynm PhD cndidtes QJA vn den Bouwhuijsen, HZ Flch, MJ vn Gils, PJ Homburg, C de Monyé, M Ouhlous, S Rozie, TT de Weert Imge processing (Crdiovsculr) Project leder WJ Niessen Stff A vn der Lugt, JJ Wentzel, Th vn Wlsum, R Mnniessing PJ de Feyter, GP Krestin, PW Serruys, AFW vn der Steen PhD cndidtes A Firouzin, C Metz, M Schp, D Vukdinovic Peripherl imging (MRI nd CT) Project leder PMT Pttynm Stff LC vn Dijk, PA Wielopolski GP Krestin PhD cndidtes A Wils Crdic imging (ultrsound) Project leder FJ ten Cte Stff ML Geleijnse PhD cndidtes A Anwr, BM vn Dlen, TW Glem Ultrsound Trnsducers Project leder N de Jong, AFW vn der Steen JRTC, Roelndt, N Bom, C Lncee PhD cndidtes GM Mtte, EJW Merks, P vn Neer, M Psovic C O E U R Annul Report 2008 Intrvsculr imging nd interventionl crdiology Project leder PW Serruys PJ de Feyter, WJ vn der Giessen, AJW vn der Steen PhD cndidte HM Grcí Grcí, S Grg, AL Gster, NGL Gonzlo Lopez, N Kukrej, CAG vn Mieghem Intrvsculr ultrsound techniques Project leder AFW vn der Steen Stff D Goertz, R Bouchrd PW Serruys Postdocs JA Schr, G vn Soest, M Dnilouchkine, M Muller PhD cndidte vcncy, vcncy Ultrsound contrst gents Project leder N de Jong Stff FJ ten Cte J Klein, AFW vn der Steen Postdocs JET vn Wmel PhD cndidtes M Emmer, K Kooimn, S vn der Meer, HJ Vos C O E U R Annul Report 2008 56 57

Them 3 Imge Guided Crdiovsculr Medicine Nme Subject Promotor(s) Copromotor(s) Funding C O E U R Annul Report 2008 A Anwr QJA vn den Bouwhuijsen BM vn Dlen M Emmer A Firouzin HZ Flch TW Glem HM Grcí Grcí SA Grg AL Gster AG vn der Giessen MJ vn Gils NGL Gonzlo Lopez H Groen PJ Homburg SWM Kirschbum K Kooimn N Kukrej KYE Leung GM Mtte S vn der Meer WB Meijboom EJW Merks C Metz 3-D echo in vlvulr disese The predictive vlue of vulnerble plques in the crotid rteries for risk of coronry hert disese nd stroke Speckle trcking echocrdiogrphy Microbubbles for medicl pplictions Imge nlysis of brin neurysms Complictions of crotid intervention ssessed with DW-MRI Aortic vlve bnormlities Crdiovsculr imging of therosclerotic plques The clinicl ppliction of Ner Infr Red light in Interventionle Crdiology Virtul histology of the vulnerble plque Plque vulnerbility ssessed from CT imges nd biomechnicl prmeters Seril CT Anghiogrphy of therosclerotic crotid plque: determinnts nd prognosis of chnge in volume composition nd morphology Intrcoronry dignostic techniques High sher stress nd vulnerble plque rupture Atherosclerotic plque chrcteriztion with CT ngiogrphy Mgnetic resonnce imging in ischemic hert disese Bubbles for therpy nd dignostics Vulnerble Plque Imging Automted nlysis for 3D stress echocrdiogrphy Dul frequency probe conception for superhrmonic imging Ultrsound contrst gents for dignosis nd therpy Noninvsive visuliztion of coronry vessels with multislice CT Instntneous non-invsive ultrsonic mesurement of volume within fluid-filled cvity Imge guided vsculr interventions ML Simoons FJ ten Cte 4 JCM Wittemn, GP Krestin A vn der Lugt 2 ML Simoons ML Geleijnse 1 N de Jong 2 WJ Niessen A vn der Lugt 2 GP Krestin A vn der Lugt 1 ML Simoons 1 PW Serruys 4 PW Serruys PW Serruys, AFW vn der Steen 1 AFW vn der Steen, PJ de Feyter FJH Gijsen 2 WW Btenburg 3 PW Serruys, AFW vn der Steen 4 AFW vn der Steen JJ Wentzel 2 GP Krestin A vn der Lugt 1 PJ de Feyter, GP Krestin RJM vn Geuns 4 N de Jong JET vn Wmel 2 PW Serruys 4 AFW vn der Steen, N de Jong JG Bosch 3 N de Jong 2 N de Jong 2 PJ de Feyter, GP Krestin 2 N Bom, N de Jong 2 WJ Niessen 2 C O E U R Annul Report 2008 58 59

Them 3 Imge Guided Crdiovsculr Medicine Nme CAG vn Mieghem C de Monyé P vn Neer M Ouhlous M Psovic S Rozie M Schp T Springeling M vn Strlen LAE Vermunt-Neefjes HJ Vos D Vukdinovic TT de Weert A Weustink A Wils Subject CT coronry ngiogrphy: vlidtion nd clinicl implementtion Role of CTA crotid plque chrcteriztion in TIA nd ischemic stroke crdiology Superhrmonic Imging MRI of crotid therosclerotic plque Imging of the non-linerity of tissue Imging of therosclerotic plque in the crotids Coronry imge nlysis Acute myocrdil infrction nd MRI Model-guided segmenttion of moving left ventricle in 4D imges obtined with fst-rotting ultrsound trnsducer Crdic Computed Tomogrphy A new bio-sensor concept for medicl dignosis: Trgeted Microbubbles nd Remote Ultrsound Trnsduction (TAMIRUT) CTA imge nlysis Chrcteriztion of therosclerotic crotid plque Non invsive imging coronry rteries Defining the clinicl role of e-ptfe covered trnsjugulr intrheptic portosystemic shunts Promotor(s) Copromotor(s) Funding PW Serruys, PJ de Feyter 4 GP Krestin, PJ Koudstl A vn der Lugt, DWJ Dippel 1 N de Jong 2 PMT Pttynm A vn der Lugt 1 AFW vn der Steen, C Cchrd 2 PMT Pttynm A vn der Lugt 1 WJ Niessen 2 GP Krestin RJM vn Geuns 1 AFW vn der Steen, JHC Reiber JG Bosch 2 PJ de Feyter, GP Krestin 3 AFW vn der Steen, N de Jong 2 WJ Niessen 2 PMT Pttynm A vn der Lugt 1 PJ de Feyter, GP Krestin 2 PMT Pttynm 1 C O E U R Annul Report 2008 Theme 4 Surgicl- Interventionl- nd Device therpy of crdiovsculr disese Progrm Code: EMC COEUR 04-43-04 C O E U R Annul Report 2008 60 61

Coronry Drug-Eluting Stents Interfere With Distl Microvsculr Function M. M. vn den Heuvel¹ ², ², O. O. Sorop¹, W.W. Btenburg², A.H.J. Dnser², W.J. vn der Giessen¹ Deprtments of of Experimentl Crdiology¹ nd Vsculr Phrmcology² of of Ersmus Medicl Center, Rotterdm, the the Netherlnds COEUR PURPOSE Drug eluting stents (DES) re re ssocited with coronry endothelil dysfunction six six months fter implnttion in in ptients. The effects of of cliniclly pproved DES on on distl epicrdil microvessels hve not not been studied to to dte. Therefore, in in this this niml study, we we evluted the the effects of of DES sirolimus-eluting nd pclitxel-eluting stent versus bre metl stent (SES, PES vs vs BMS) implnttion, on on vsomotor function of of distl lrge (>2 (>2 mm) nd smll coronry rteries (<0.3 mm). of of distl lrge nd smll coronry rteries. Furthermore, contributions of of NO NO nd endothelium-derived hyperpolrizing fctor (EDHF) to to endothelium-dependent vsodilttion were exmined using the the NO-synthse inhibitor L-NAME. In In vitro ssessment vsomotor function: BMS SES metl strut in in void fibrinoid PES metl strut in in void RESULTS-1 RESULTS-2 Qulittive nlysis showed tht the the vsculr response Vsomotor responses of of lrge coronry rteries were not not fter stenting followed ptterns typicl for for BMS (A) (A) nd DES ffected by by DES. However, PES, but but not not SES, resulted CONCLUSIONS (B, (B, C). C). The neointim in in BMS (thickness: 306 ± ± 84 84 μm) in in impired BK-medited microvsculr diltion (*P=0.08 This study shows for for the the first time tht chronic PES consisted of of smooth muscle like like cells within collgenous vs vs BMS) tht ws principlly due to to loss of of BK s EDHF- implnttion cn led to to endothelil dysfunction of of the the distl mtrix covered by by endothelil cells. The neointim in in DES component (#P<0.01 vs vs BMS). This ws not not due to to non- microcircultion. ws similr including the the presence of of endothelil cells in in specific loss of of coronry microvsculr responsiveness, METHODS ll ll DES. Typiclly, however, the the neointim lso contined s s endothelium-independent vsodilttion by by SNAP ws Cliniclly, microvsculr dysfunction cn thus impir distl SES, PES, nd BMS were implnted for for 55 weeks in in 55 pigs. fibrinoid surrounding the the stent struts (B, (B, C). C). In In ddition, in in not not ffected. PES-induced endothelil dysfunction ws coronry blood flow regultion nd therefore locl crdic Stented segments were prepred for for routine histology. PES (thickness: 241 ± ± 43 43 μm) mitotic figures chrcteristic not not ssocited with enhnced vsoconstriction to to ET-1. perfusion, especilly in in episodes of of incresed myocrdil Vsomotor responses to to different doses of of brdykinin for for pclitxel were observed (C), while SES (thickness: 606 Surprisingly, SES reduced ET-1 induced microvsculr oxygen demnd. (BK), endothelin-1 (ET-1), nd the the NO-donor SNAP were ± ± 252 μm) showed more inflmmtion resulting in in more constriction ($P<0.02 vs vs BMS). ssessed ex ex vivo using orgn chmbers to to study both neointim formtion (thickness without inflmmtion: 428 ± ± 62 63 endothelium-dependent nd independent responses 88 88 μm). CONTACT: m.vndenheuvel.1@ersmusmc.nl

Interventionl rdiology Project leder PMT Pttynm Stff LC vn Dijk PhD cndidte JM Hendriks Lung surgery nd lung trnsplnttion Project leder AJJC Bogers Stff H de Bruin, AP Kppetein B Lchmnn Postdocs O Birim PhD cndidtes APMW Mt, NP vn der Kij Reserch Groups theme 4 Experimentl interventionl crdiology Project leder WJ vn der Giessen Stff HMM vn Beusekom, O Sorop DJGM Duncker PhD cndidte M vn den Heuvel Mieke vn den Heuvel Novel spects of interventionl crdiology Project leder PW Serruys Stff G Sinos PJ de Feyter, JRTC Roelndt PhD cndidte Y Onum Novel strtegies in clinicl electrophysiology Project leder L Jordens Stff JCJ Res, RJM vn Geuns, T Szili-Torok AJJC Bogers, RJM vn Geuns PhD cndidtes Y vn Belle, M Rivero-Ayerz, BKR Schwgten C O E U R Annul Report 2008 Hyperplsi fter surgery Project leder HJM Verhgen Stff JM Hendriks PMT Pttynm PhD cndidtes WB vn Gent Improvement in ptient selection for defibrilltor therpy Project leder L Jordens Stff JCJ Res, DAMJ Theuns BHC Stricker PhD cndidtes P Knops, T Smith, SDA Vlk Short nd long-term spects of interventionl crdiology Project leder PW Serruys Stff RT vn Domburg, PF de Jegere, J Wykrzykowsk PJ de Feyter, WJ vn der Giessen PhD cndidtes CHD Girsis, E Melig, S Tnimoto Surgicl spects of cute nd chronic crdiovsculr disese nd hert filure Project leder AJJC Bogers Stff JJM Tkkenberg, AP Kppetein, E Boersm J Klein, W Weimr PhD cndidtes F Brtolozzi, JA Bekkers, GFM D Ancon, M vn Gmeren, JM Hrtmn, WJ vn Leeuwen, RJM vn Thiel C O E U R Annul Report 2008 64 65

Theme 4 Surgicl Interventionl nd Device Therpy of Nme Subject Promotor(s) Copromotor(s) Funding F Brtolozzi Evlution of coronry rtery bypss results AJJC Bogers AP Kppetein 3 JA Bekkers Y vn Belle GFM D Ancon M vn Gmeren WB vn Gent C Girsis Clinicl tretment of ortic bnormlties Cryo-bltion for tril fibrilltion Flow mesurements in coronry surgery Determinnts of short term complictions fter crdiothorcic interventions The SEPS tril: Conservtive versus scopic surgicl tretment of the ulcus cruris venosum Prognostic Impct of Left Min Coronry Artery Antomy AJJC Bogers JJM Tkkenberg 1 L Jordens 1 AJJC Bogers AP Kppetein 4 AJJC Bogers JJM Tkkenberg, AP Kppetein 1 H vn Urk MRHM vn Smbeek 1 PW Serruys 1 JM Hrtmn JM Hendriks M vn den Heuvel NP vn der Kij Postopertive suprclviculr duplex of the left internl mmmry rtery in coronry rtery bypss surgery Technicl issues in crotid rtery stenting Vsculr repir in dibetes Ischemi reperfusion injury s risk fctor for the development of chronic trnsplnt dysfunction fter lung trnsplnttion AJJC Bogers AP Kppetein 1 H vn Urk, PMT Pttynm MRHM vn Smbeek 1 WJ vn der Giessen AHJ Dnser 4 AJJC Bogers, B Lchmnn RWFde Bruin, J Vn der Kluin 3 C O E U R Annul Report 2008 P Knops WJ vn Leeuwen APMW Mt E Melig Y Onum M Rivero-Ayerz BKR Schwgten T Smith S Tnimoto RJM vn Thiel SDA Vlk Energy sources for ctheter bltion Clinicl results of mitrl vlve surgery Surgicl spects of mesothelomi tretment Cell therpy nd hert mechnics Novel technology in coronry intervention nd coronry stents The role of the electrophysiologist in hert filure Stremlining electrophysiology procedures The genetic bckground of suddent deth New coronry stent technologies: Beyond the conventionl drug-eluting stent Metbolic spects of crdic surgery Approches to ventriculr tchycrdi nd sudden deth L Jordens 1 AJJC Bogers JJM Tkkenberg, AP Kppetein 1 AJJC Bogers AP Kppetein 1 PW Serruys 4 PW Serruys 4 L Jordens 3 L Jordens 3 L Jordens 2 PW Serruys 3 AJJC Bogers 1 L Jordens, BHC Stricker 1 C O E U R Annul Report 2008 66 67

C O E U R Annul Report 2008 Theme 5 - Congenitl Hert Disese Progrm code: EMC 05-43-05. C O E U R Annul Report 2008 68 69

Assessment of pulmonry rtery size nd function with phse contrst mgnetic resonnce imging in ptients fter Fontn opertion t young ge COEUR Dnielle Robbers-Visser (1,2), Frnk Heldermn (3), Jn L.M. Strengers (4), Livi Kpust (5), Michiel Dlinghus (1), Ad J.J.C. Bogers (6), Peter M.T. Pttynm (2), Rob Krms (3), Willem A. Helbing (1,2) 1 Deprtment of peditric crdiology, Ersmus MC - Sophi Children s Hospitl, Rotterdm, 2 Deprtment of rdiology, Ersmus MC, Rotterdm, 3 Deprtment of crdiology, Ersmus MC, Rotterdm, 4 Deprtment of peditric crdiology, University MC Utrecht - Wilhelmin Children s Hospitl, Utrecht, 5 Children s Hert Center, UMC St Rdboud, Nijmegen, 6 Deprtment of crdiothorcic surgery, Ersmus MC, Rotterdm, the Netherlnds. Introduction The Fontn opertion is performed in ptients with functionlly univentriculr hert: in stged procedure, the superior nd inferior cvl veins re directly connected to the right pulmonry rtery (PA). After Fontn opertion, bsence of ventricle supporting the pulmonry circultion results in (substntil) loss of pulstile flow in the PA s. The long-term effects of this bnorml flow pttern on PA growth nd endothelil nd vsculr function re mtter of concern nd limited studies hve been performed with disprte results. The Fontn opertion is performed in ptients with functionlly univentriculr hert: in stged procedure, the superior nd inferior cvl veins re directly connected to the right pulmonry rtery (PA). After Fontn opertion, bsence of ventricle supporting the pulmonry circultion results in (substntil) loss of pulstile flow in the PA s. The long-term effects of this bnorml flow pttern on PA growth nd endothelil nd vsculr function re mtter of concern nd limited studies hve been performed with disprte results. Objective Assessment of PA size, flow vribles nd wll sher stress (WSS) to gin more insight in PA growth, endothelil nd vsculr function in ptients fter Fontn opertion t young ge with crdiovsculr mgnetic resonnce (CMR) imging. Methods 14 ptients, in good clinicl condition fter Fontn opertion, nd 17 helthy controls (tble 1) underwent phse-contrst velocity encoded CMR imging of the brnch PA on 1.5 T GE Sign whole body system. The brnch PA s were loclized on trnsverse set through the thorx nd cut longitudinlly (figure 1). On the subsequent doubleoblique loclizer, the flow mesurement ws plnned hlfwy the origin of the brnch PA nd the first brnching point, perpendiculr to the flow. In ptients flow mesurements were done t rest nd during lowdose dobutmine stress (7.5 microgr/kg/min), in controls flow mesurements were only done t rest. Tble 1: chrcteristics of study popultion ptients controls totl (mle) 14 (9) 17 (9) ge (yers) 13.1 (4.0) 13.3 (2.3) BSA (m2) 1.37 (0.35) 1.54 (0.20) Follow-up fter Fontn completion (yrs) 9.7 (5.4-16.8) Age t Fontn completion (yrs) 3.3 (1.0-6.8) Fontn type: APC 3 TCPC: LT/EC 8/3 Pre-Fontn: BT-shunt 7 PA-bnding 2 Glenn 9 brnch PA ugmenttion 2 Abbrevitions: BSA=body surfce re; APC=triopulmonry connection; TCPC= totl cvopulmonry connection; LT=lterl tunnel; EC=extrcrdic conduit; BT= Bllock Tussig; PA=pulmonry rtery b Figure 1. : trnsverse plne for the loclizer of the brnch PA, b: doubleoblique loclizer for the PA flow mesurement Tble 2: comprison of PA flow vribles between controls nd ptients (rest nd stress) vribles controls ptients ptients p-vlue p-vlue rest stress ptients vs controls rest vs stress hert rte (/min) 72 (12) 69 (12) 93 (17) NS <0.001 stroke index (ml/m2) 31 (7) 19 (7) 19 (7) <0.001 NS totl flow (ml/min/m2) 2189 (463) 1244 (274) 1705 (308) <0.001 <0.001 verge flow (ml/s) 56 (15) 28 (6) 39 (13) <0.001 <0.001 pek flow (ml/s) 187 (48) 55 (31) 71 (44) <0.001 <0.001 pulstility index 3.3 (0.4) 1.6 (1.2) 1.4 (1.1) <0.001 NS verge dimeter (mm) 16.2 (1.7) 15.1 (2.7) 15.2 (2.8) NS NS mximl dimeter (mm) 18.2 (2.1) 16.0 (2.8) 16.0 (3.1) 0.02 NS distensibility 0.41 (0.09) 0.22 (0.06) 0.20 (0.07) <0.001 NS verge WSS (N/m2) 0.84 (0.14) 0.38(0.15) 0.50 (0.18) <0.001 <0.001 Abbrevitions: NS = not significnt; WSS = wll sher stress Clcultions: pulstility index = (mximl re - miniml re) / mximl re, distensibility = (mximl flow rte - miniml flow rte) / men flow rte. Averge dimeter: derived from the verge intrluminl re of the brnch PA throughout the crdic cycle. Mximl dimeter: derived from the mximl intr-luminl re of the brnch PA in the crdic cycle. b Figure 2: WSS determintion ccording to Wentzel et l (JACC 2005). : phse imge of flow mesurement in brnch PA, b: WSS determintion in the 12 closest regions to the vessel wll, c: WSS results of ll 24 crdic phses of the flow mesurement Figure 3. WSS pttern throughout the crdic cycle of helthy control (blue line), ptient with TCPC (red line), nd ptient with n APC (green line), comprble with the PA blood flow pttern in these subjects (dt not shown) Results The study protocol ws well tolerted by ll subjects without side effects. Results re summrized in tble 2 nd figure 3. Conclusions CMR imging combined with low-dose dobutmine stress is sfe, non-invsive, nd esily pplicble method to ssess PA size nd function in selected ptients PA size is norml long-term fter Fontn opertion t young ge. PA blood flow, pulstility nd distensibility re significntly lower in Fontn ptients when compred to helthy controls, nd do not show dequte rections with low-dose dobutmine stress implicting endothelil nd/or vsculr dysfunction. WSS throughout the crdic cycle shows distinct pttern comprble with the blood flow pttern. Averge WSS is significntly lower in Fontn ptients compred to helthy controls, substrte for endothelil dysfunction. 71

Reserch Groups Theme 5 Dignosis ssessment nd ctheter intervention for congenitl hert disese Project leder WA Helbing, JW Roos-Hesselink Stff M Dlinghus, JJM Tkkenberg, L vn Osch-Gevers, M Witsenburg, F du Plessis, L Koopmn FJ Meijboom, PMT Pttynm PhD cndidtes LMJW vn Driel, MJ Fber, WB de Koning, SE Luijnenburg, E Moltzer, D Robbers-Visser, HB vn der Zwn Outcome of surgery for congenitl hert disese Project leder AJJC Bogers Stff AP Kppetein, JW Roos-Hesselink, JJM Tkkenberg, L vn Osch-Gevers AC Gittenberger-de Groot, J Klein PhD cndidtes I Erlp, HD Golb-Schwrz, PC vn de Woestijne C O E U R Annul Report 2008 C O E U R Annul Report 2008 72 73

Them 5 Congenitl Hert Disese Nme LMJW vn Driel I Erlp MJ Fber HD Golb-Schwrz WB de Koning SE Luijnenburg E Moltzer D Robbers-Visser PC vn de Woestijne H vn der Zwn Subject Genetic nd environmentl risk fctors for congenitl defects The role of the epicrdium in crdic development Hemodynmic nd proteomic chnges in chronic right Improved ppliction of the hert-lung mchine in congenitl hert disese Qulity of life with congenitl hert disese medicl spects Erly dignosis of right ventriculr dysfunction in ptients operted for tetrlogy of Fllot. A multicenter study with seril follow-up Aortic pthology Hemodynmics vribles nd longterm outcome of fontn circultion Pulmonry rtresi with ventriculr septl defect nd systemic-pulmonry collterl rteries Rel time 3-D echocrdiogrphy Promotor(s) Copromotor(s) Funding WA Helbing 3 AJJC Bogers, AC Gittenberger-de Groot 1 WA Helbing, JMJ Lmers M Dlinghus 1 AJJC Bogers JJM Tkkenberg 1 WA Helbing 1 WA Helbing 2 ML Simoons, AHJ Dnser JW Roos-Hesselink 1 WA Helbing, PMT Pttynm 3 AJJC Bogers ML Simoons, WA Helbing JW Roos-Hesselink Rohit Oemrwsingh C O E U R Annul Report 2008 Theme 6 - Neurovsculr nd Crdiovsculr Clinicl Epidemiology Progrm code: EMC 06-43-06 C O E U R Annul Report 2008 74 75

BIOMrker study to to identify the the Acuteriskof Coronry Syndrome (BIOMArCS) COEUR RM RM Oemrwsingh 1, KM 1, KM Akkerhuis 1, ML 1, ML Simoons 1, RJ 1, RJ de de Winter 2, 2, T T Lenderink 3, 3, VAWM Umns 4, L 4, L Hofstr 5, F 5, F Zijlstr 6, 6, PAFM Doevendns 7, H 7, H Rmnn 8, D 8, D Neumnn9, AJM AJM Oude Ophuis 10-1 10-1 1, 1, WH WH vn vn Gilst Gilst 12, 12 E, E Boersm 1 ; 1 ; BIOMArCS Investigtors Bckground Clinicins currently lck lck the the possibility to to identify incresed vulnerbility for for the the occurrence of of n n (repet) cute cute coronrnry syndrome (ACS) (ACS) within within precise, short short timefrme t t coro- the the individul ptient level. level. Coronry rtery rtery disese (CAD) progresses dynmiclly nd nd incresed coronry tion tion could could led led to ACS to ACS within within short short timefrmes. Hypothesis inflmm- The The BIOMArCS investigtors postulte tht tht biomrkers reflecting vsculr inflmmtion, endothelil dysfunction, decresed endothelil regenertive cpcity, distorted lipipid metbolism nd nd incresed thrombogenicity re re up- up- or or down-regulted severl dys dys to to weeks before n n ACS. ACS. Di- Divergent biomrker ptterns, identified by by seril seril biomrker mesurements, might might indicte vulnerble periods during li- which which CAD CAD ptients re re t t incresed short-term risk risk of of de- developing n n ACS ACS (Figure). Actul identifiction of of vulnerblrble period nd nd subsequent therpeutic djustment could could vulne- led led to to Methods BIOMArCS is is ntionwide, multi-centre, prospective, ob- observtionl study study with with 1-yer follow-up of of 700 700 ptients fter fter ACS, ACS, both both with with nd nd without ST-elevtion. Ptients with with t t lest lest two two crdiovsculr risk risk fctors re re included, so so tht tht the the primry endpoint (crdiovsculr mortlity or repet non-ftl ACS) ACS) is is likely likely to to occur occur in in 10% 10% of of the the cohorthort. Venpuncture is is plnned every every fortnight during the the co- first first hlf-yer nd nd monthly therefter. Biomrker ptterns (of (of pproximtely 15 15 bio-mrkers) prior prior to to the the endpoint will will be be determined t t the the end end of of follow-up in the in the 70 70 cses cses nd nd compred to to 210 210 event-free, mtching controls. ble ble regression will will djust djust for for differences in bseline ch- chrcteristics between cses cses nd nd Multivri- controls. Expected Rresults This This design llows to to sufficiently detect detect odds odds rtios rtios round 2.0-2.5 for for the the upper upper tertile tertile of of biomrker ssocited with with the the endpoint. Strt Strt of of enrolment: Jnury 2008. 2008. tion tion is is expected in 2011. in Comple- 2011. 76 77

The The effect of of fluvsttin extended relese on on periopertive crdic complictions in in ptients undergoing vsculr surgery O. O. Schouten 1, E. 1, E. Boersm 2, S.E. 2, S.E. Hoeks Hoeks 2, R. 2, R. Benner Benner 3, H. 3, vn H. vn Urk Urk 1, 1, M.R.H.M. vn vn Smbeek 1, 1, H.J.M. H.J.M. Verhgen 1, N.A. 1, N.A. Khn Khn 3, M. 3, M. Dunkelgrun1, J.J. J.J. Bx Bx 4, D. 4, D. Poldermns 5 5 Deprtments of of Vsculr Surgery 1, 1, Crdiology 2, 2, Immunology3, Anesthesiology 5, 5, Ersmus MC MC Rotterdm, the Netherlnds nd Deprtment of of Crdiology 4, LUMC, 4, LUMC, Leiden, Leiden, the Netherlnds COEUR Bckground Crdic Crdic events events re re the the mjor mjor cuse cuse of dverse of dverse outcome fter fter vsculr surgery. surgery. The The stress stress of surgery, of surgery, inducing coronry plque plque instbility, rupture rupture nd nd thrombosis plys plys mjor mjor role. role. We We hypothesized tht tht lipid-lowering therpy therpy with with nti-inflmmtory effects effects would would stbilize stbilize coronry plques plques nd nd improve improve postopertive outcome. Methods In this In this double-blind, plcebo-controlled tril, tril, sttin sttin nïve nïve ptients ptients were were rndomly ssigned to to receive receive either either 80 80 mg mg fluvsttin extended relese relese once once dily dily or or mtched plcebo plcebo on on top top of of bet-blockers, strting strting 37 37 dys dys prior prior to to surgery. surgery. Interleukin-6 nd nd C-rective protein protein were were mesured t t rndomiztion nd nd prior prior to to surgery. surgery. The The primry primry endpoint ws ws the the occurrence of of myocrdil ischemi ssessed by by continuous ECG ECG registrtion during during the the first first 48-hours postopertively, ECG ECG recordings on dys on dys 3, 73, nd 7 nd 30, 30, nd nd troponin troponin T T mesurements on on dys dys 1, 3, 1, 3, 7, nd 7, nd 30. 30. The The secondry endpoint ws ws the the composite of of crdic crdic deth deth nd nd myocrdil infrction. Results Primry Outcome Myocrdil ischemi ws ws detected in 74 in 74 (14.9%) (14.9%) ptients ptients within within 30 30 dys dys of the of the initil initil vsculr surgicl surgicl procedure. A totl A totl of 27/250 of 27/250 (10.8%) (10.8%) ptients ptients llocted to to fluvsttin reched reched the the primry primry endpoint compred to 47/247 to 47/247 (19.0%) (19.0%) ptients ptients llocted to plcebo to plcebo tretment (HR (HR 0.55; 0.55; 95% 95% CI CI 0.34-0.88). Hence, Hence, the the number number needed needed to tret to tret (NNT) (NNT) to to prevent prevent one one ptient ptient experiencing myocrdil ischemi ws ws 12 12 ptients. Plcebo Fluvsttin Plcebo Fluvsttin Secondry Outcome Tble Tble 1. Levels 1. Levels of Lipids of Lipids nd nd Inflmmtory Mrkers Mrkers t Bseline t Bseline nd nd t dy t dy A totl A totl of 18 of 18 (3.6%) (3.6%) ptients ptients died died within within 30 30 dys dys fter fter surgergery sur-of Hospitl of Hospitl Admission Admission fter fter medin medin tretment tretment of 37 of dys 37 dys of which of which 12 12 (67%) (67%) were were ttributble to to crdiovscu- Plcebo Plcebo Fluvsttin Fluvsttin P-vlue P-vlue lr lr cuses. cuses. Additionlly, 25 25 (5.0%) (5.0%) ptients ptients experienced N=247 N=247 N=250 N=250 Level Level t bseline t bseline nonftl nonftl MI. MI. The The combined endpoint of of crdiovsculr Cholesterol Cholesterol (mmol/liter) (mmol/liter) deth deth nd nd nonftl nonftl MI MI ws ws reched reched in 37 in 37 (7.4%) (7.4%) ptients. Totl Totl 5.30 ± 5.30 1.20± 1.20 5.40 ± 5.40 1.14± 1.14 0.34 0.34 A totl A totl of 12/250 of 12/250 (4.8%) (4.8%) ptients ptients llocted to to fluvsttin LDL LDL 3.26 ± 3.26 0.93± 0.93 3.36 ± 3.36 1.06± 1.06 0.27 0.27 therpy therpy reched reched the the combined endpoint, compred to to HDL HDL 1.53 ± 1.53 0.70± 0.70 1.61 ± 1.61 0.81± 0.81 0.27 0.27 High-sensitivity C-rective C-rective protein protein (mg/l) (mg/l) 0.32 0.32 25/247 25/247 (10.1%) (10.1%) llocted to to plcebo. Hence, Hence, fluvsttin Medin Medin 5.80 5.80 5.93 5.93 therpy therpy ws ws ssocited with with 53% 53% reltive reltive reduction in in Interqurtile Interqurtile rnge rnge 3.00 to 3.00 10.40 to 10.40 2.42 to 2.42 10.89 to 10.89 the the incidence of of crdiovsculr deth deth or nonftl or nonftl MI MI (HR (HR Interleukin-6 Interleukin-6 (pg/ml) (pg/ml) 0.80 0.80 0.47; 0.47; 95% 95% CI: CI: 0.24-0.94). The The NNT NNT for for the the composite endpoinpoint end- Medin Medin 8.76 8.76 8.55 8.55 of of crdiovsculr deth deth or nonftl or nonftl MI ws MI ws 19. 19. Interqurtile Interqurtile rnge rnge 2.54 to 2.54 15.66 to 15.66 1.26 to 1.26 16.59 to 16.59 Percent Percent chnge chnge from from bseline bseline The The medin medin bseline high-sensitivity C-rective protein protein levevel ws ws 5.93 5.93 mg/l; mg/l; levels levels were were similr similr in ptients in ptients llocted Totl Totl le-cholesterol Cholesterol - 3.9 ± - 3.9 4.6± 4.6-19.0 - ± 19.0 9.6 ± 9.6 <0.001 <0.001 LDL LDL - 3.1 ± - 3.1 6.4± 6.4-23.2 - ± 23.2 11.4 ± 11.4 <0.001 <0.001 to to fluvsttin (5.93 (5.93 mg/l) mg/l) or plcebo or plcebo (5.80 (5.80 mg/l). mg/l). At hospitl At hospitl HDL HDL + 4.3 + ± 4.3 14.8 ± 14.8 + 2.5 + ± 2.5 16.1± 16.1 0.20 0.20 dmission, medin medin 37 37 dys dys fter fter rndomiztion, tin treted tin treted ptients ptients hd hd medin medin decrese in in Medin Medin +3.3 +3.3-20.5-20.5 fluvst-high sensitivity High sensitivity C-rective C-rective protein protein <0.001 <0.001 high-sensitivity C-rective protein protein levels levels of 21% of 21% s oppo- s oppo- Interqurtile Interqurtile rnge rnge -20.5-20.5 to 30.3 to 30.3-26.8-26.8 to -12.0 to -12.0 Interleukin-6 Interleukin-6 <0.001 <0.001 sed sed to n to n increse of 3% of 3% in the in the plcebo plcebo group group (p<0.001). Medin Medin -4.2-4.2-32.7-32.7 The The medin medin Interleukin-6 levels levels t t bseline were were similr similr Interqurtile Interqurtile rnge rnge -16.7-16.7 to 10.2 to 10.2-42.3-42.3 to -21.6 to -21.6 in ptients in ptients llocted to to fluvsttin (8.55 (8.55 pg/ml) pg/ml) or plcebo or plcebo (8.76 (8.76 pg/ml) pg/ml) nd nd significntly decresed t the t the time time of surgergery in ptients in ptients on on fluvsttin (-33% (-33% vs -4%, vs -4%, p=<0.001). of sur- Tble Tble 2. Sfety 2. Sfety Mesures Mesures of Sttin of Sttin Use Use Plcebo Plcebo Fluvsttin Fluvsttin P-vlue P-vlue N=247 N=247 N=250 N=250 Conclusions Discontinution of tretment of tretment In ptients In ptients undergoing vsculr surgery surgery fluvsttin Temporrily Temporrily no. (%) no. (%) 54 (22) 54 (22) 61 (24) 61 (24) 0.53 0.53 therpy therpy is is ssocited with with n n improved postopertive Permnently Permnently no (%) no (%) 18 (7.3) 18 (7.3) 16 (6.4) 16 (6.4) 0.73 0.73 crdic crdic outcome nd nd reduction of of inflmmtion ctivity. ctivity. CK > CK 10x > ULN 10x ULN no. (%) no. (%) 8 (3.2) 8 (3.2) 10 (4.0) 10 (4.0) 0.81 0.81 CK (U/L) CK (U/L) 0.24 0.24 Medin Medin 113 113 141 141 Interqurtile Interqurtile rnge rnge 66 to 66 369to 369 77 to 77 380to 380 78 ALAT ALAT > 3x ULN > 3x ULN no. (%) no. (%) 13 (5.3) 13 (5.3) 8 (3.2) 8 (3.2) 0.27 0.27 ALAT ALAT (U/L) (U/L) 0.43 0.43 Medin Medin 23 23 24 24 Interqurtile Interqurtile rnge rnge 15 to 15 37to 37 17 to 17 50to 50 Myopthy Myopthy no. (%) no. (%) - - - - Rhbdomyolysis no. (%) no. (%) - - - -

Reserch Groups theme 6 Crdic risk evlution nd modifiction in ptients with peripherl rtery disese Project leder D Poldermns Stff H Boersm, RT vn Domburg J Klein, H Verhgen, JJ Bx PhD cndidtes JW Flu, W Gel, D Goei, JP vn Kuijk, R Kuyper, O Schouten, R Vidkovic, TA Winkel Clinicl decision mking in crdic surgery Project leder AJJC Bogers, JJM Tkkenberg Stff AP Kppetein PhD cndidtes MWA vn Geldorp, AC Venem, H Heuvelmn Periopertive risk evlution nd mngement using computerized risk modelling Project leders E Boersm, D Poldermns Stff RT vn Domburg J Klein, H Verhgen PhD cndidtes M Dunkelgrun, YRBM vn Gestel, SE Hoeks, I de Liefde, F vn Lier, F Schneider Prognosis dignosis nd decision mking in stroke Project leder DWJ Dippel Stff F vn Kooten, PJ Koudstl, EG Visch-Brink JDF Hbbem, E Steyerberg PhD cndidtes M Dirks, H El Hchioui, E Mslnd, AD Wijnhoud C O E U R Annul Report 2008 Prognostic vlue of biomrkers in ptients with crdic disese Project leder E Boersm Stff KM Akkerhuis ML Simoons PhD cndidtes S de Boer, M de Mulder, R Oemrwsingh Development, vlidtion nd implementtion of clinicl decision models in crdiology prctice Project leder E Boersm, N vn der Putten Stff KM Akkerhuis ML Simoons, EW Steyerberg, J vn der Lei PhD cndidtes vcncy C O E U R Annul Report 2008 80 81

Them 6 Cerebro-Crdiovsculr Epidemiology nd Helth Cre Nme S de Boer M Dirks M Dunkelgrun H El Hchioui WJ Flu Subject determinnts of prognosis in ptients undergoing percutneous coronry intervention Implementtion of thrombolysis for ischemic stroke (cluster rndomised tril) Bet-blockde nd sttin tretment of ptients undergoing noncrdic, non-vsculr surgery Prognosis nd qulity of life in phsi Polyvsculr disese Promotor(s) Copromotor(s) Funding E Boersm? PJ Koudstl DWJ Dippel 2 D Poldermns E Boersm 3 PJ Koudstl EG Visch-Brink 3 D Poldermns 1 C O E U R Annul Report 2008 W Gel MWA vn Geldorp YRBM vn Gestel D Goei SJWM Heuvelmn SE Hoeks JP vn Kuijk R Kuyper I de Liefde F vn Lier E Mslnd M de Mulder RM Oemrwsingh O Schouten Correltion of pre- nd periopertive ischemi in vsculr surgery Severe Aortic Stenosis: incidence, tretment nd prognosis Pulmonry function nd crdic outcome in vsculr surgery ptients The prognostic vlue of NT-proBNP in ptients undergoing mjor vsculr surgery Chrcteristics, tretment options nd prognosis of ptients with ortic stenosis Appliction of guidelines in ptients with rteril peripherl disese Clopidogrel for the prevention of lte crdic events in ptients with symptomtic periopertive cute coronry syndrome Use of hndheld echo device in periopertive cre Blood pressure response during exercise in vsculr surgery ptients Risk ssessment of peripertive stroke Computerized risk fctor eduction nd monitoring fter TIA or minor stroke Intensive glucose regultion in myocrdil infrction Prognostic vlue of biomrkers in ptients with chronic CAD Periopertive myocrdil ischemi nd cytokine response in ptients undergoing high-risk surgery: the influence of sttins D Poldermns 1 AJJC Bogers JJM Tkkenberg, AP Kppetein D Poldermns RT vn Domburg 3 D Poldermns E Boersm 3 AJJC Bogers JJM Tkkenberg, JW Roos-Hesselink 1 D Poldermns E Boersm 3 D Poldermns 1 D Poldermns E Boersm 3 D Poldermns RT vn Domburg 1 D Poldermns 1 PJ Koudstl DWJ Dippel 1 ML Simoons E Boersm, VAWM Umns 2 ML Simoons E Boersm 2 D Poldermns, H vn Urk E Boersm 1 3 C O E U R Annul Report 2008 82 83

Them 6 Cerebro-Crdiovsculr Epidemiology nd Helth Cre Nme Subject F Schneider Mngement of blood glucose levels during nd fter surgery AC Venem Dtbse structures in clinicl reserch R Vidkovic Screening for therosclerosis in peripherl rtery disese AD Wijnhoud Trnscrnil Doppler ultrsonogrphy nd stroke TA Winkel Holter registrtion in non-crdic vsculr ptients Promotor(s) Copromotor(s) Funding D Poldermns 1 AJJC Bogers, J vn der Lei JJM Tkkenberg 1 D Poldermns 1 PJ Koudstl DWJ Dippel 3 D Poldermns 1 C O E U R Annul Report 2008 C O E U R Annul Report 2008 84 85

Doctorl degrees Februry 13, 2008 Hrm HH Fering Crdic risk ssessment nd mngement of ptients undergoing vsculr surgery Promotor: prof dr Don Poldermns (Vsculr Surgery) Copromotor: dr ir Eric H Boersm (Crdiology) Mrch 19, 2008 Michiel J Bos Cuses nd risk of stroke Promotores: prof dr Monique MB Breteler (Epidemiology & Biosttistics) & prof dr Peter J Koudstl (Neurology) My 28, 2008 Ingrid RAM Mertens zur Borg Anesthesi nd peri-opertive Cre for Lproscopic Donor Nephrectomy Promotores: prof dr Jn Klein (Anesthesiology) & prof dr Jn NM IJzermns (Surgery) Copromotores: dr Diederik AMPJ Gommers (Anesthesiology) C O E U R Annul Report 2008 June 4, 2008 Joep HM vn Esch Unrveling the Complexities of the Renin-Angiotensin System: from ACE to renin inhibition Promotor: prof dr Jn AHJ Dnser (Internl Medicine) C O E U R Annul Report 2008 86 87

June 25, 2008 Andrew S Thornton Mgnetic nvigtion for ctheter bltion Promotor: prof dr Luc JLM Jordens (Crdiology) October 29, 2008 Frncesc Pugliese Multi-slice computed tomogrphy of coronry rteries Promotores: prof dr Gbriel P Krestin (Rdiology) en prof dr Pim J de Feijter (Crdiology/Rdiology) Copromotor: dr Nico RA Mollet (Crdiology/Rdiology) September 10, 2008 Monique C de Wrd Crdioprotective Effects of Exercise Trining. The importnce of nitric oxide. Promotor: prof dr Dirk JGM Duncker (Crdiology) Copromotores: dr Rini MPG de Crom (Cel Biology) & dr Jolnd vn der Velden (VU Amsterdm) October 29, 2008 Steve Rmchritr Mgnetic Nvigtion in Percutneous Coronry nd Non-Coronry Interventions Promotor: prof dr Ptrick WJC Serruys (Crdiology) Copromotor: dr Robert J vn Geuns (Crdiology) September 10, 2008 Murits Dirksen Primry PCI nd Tretment of Reperfusion Injury in Acute Myocrdil Infrction Promotores: prof dr Mrten L Simoons (Crdiology) & prof dr Dirk JGM Duncker (Crdiology) Copromotor: dr GertJn Lrmn (OLVG) November 14, 2008 Joost Demen The Cvets of Drug-eluting Stents A Criticl Apprisl of the Sfety Concerns Promotor: prof dr Ptrick WJC.Serruys (Crdiology) Copromotor: dr Ron T vn Domburg (Crdiology) C O E U R Annul Report 2008 October 8, 2008 Olivier Mnintveld Protection Aginst Myocrdil Ischemi nd Reperfusion:Preconditioning, postconditioning nd hiberntion Promotores: prof dr Dirk JGM Duncker (Crdiology) & prof dr Jos MJ Lmers (Biochemistry) November 26, 2008 Gijs Welten Prognosis of Ptients with Peripherl Arteril Disese Promotor: prof dr Don Poldermns (Vsculr Surgery) Copromotor: dr Ron T vn Domburg (Crdiology) C O E U R Annul Report 2008 88 89

December 18, 2008 Johnnes JA Auwerd Acquired cogultion bnormlities nd thrombosis in Multi[le Myelom Promotor: prof. dr. Pieter Sonneveld (Hemtology) Copromotor: dr. Frnk WG Leebeek (Hemtolofy) Publictions Cittion Clssics C O E U R Annul Report 2008 1. Serruys PW, de Jegere P, et l. A comprison of blloon-expndble-stent implnttion with blloon ngioplsty in ptients with coronry-rtery disese. New Eng J Med. 1994;331:489-495 [cited 2805x]. 2. Altmn R, et l [incl. Koudstl PJ, Serruys PW]. Collbortive overview of rndomized trils of ntipltelet Therpy. 1. prevention of deth, myocrdil-infrction, nd stroke by prolonged ntipltelet therpy in vrious ctegories of ptients. British Medicl Journl. 1994;308:81-100 [cited 2062x]. 3. Lecht P, et l [incl. Jordens L]. The Crdic Insufficiency Bisoprolol Study II (CIBIS-II): rndomised tril. Lncet. 1999;353:9-13 [cited 1730x]. 4. Morice MC et l [incl Serruys PW]. A rndomized comprison of sirolimus-eluting stent with stndrd stent for coronry revsculriztion. N Engl J Med. 2002;346(23):1773-80 [cited 1390x] 5. Alpert JS, et l [incl Simoons ML]. Myocrdil infrction redefined - consensus document of The Joint Europen Society of Crdiology/Americn College of Crdiology Committee for the redefinition of myocrdil infrction. J Am Coll Crdiol. 2000;36(3):959-69 [cited 1354x]. 6. Appleby P, et l [incl. Simoons ML]. Indictions for fibrinolytic therpy in suspected cute myocrdil infrction - Collbortive overview of erly mortlity nd mjor morbidity results from ll rndomized trils of more thn 1000 ptients. Lncet 1994;343:311-322 [cited 1343x]. 7. Topol E, et l [incl Simoons ML]. An interntionl rndomized tril compring 4 thrombolytic strtegies for cute myocrdil infrction. N Engl J Med.1993; 329: 673-682 [cited 1185x]. 8. Topol E, et l [incl Simoons ML, Deckers JW]. Inhibition of pltelet glycoprotein IIb/III with eptifibtide in ptients with cute coronry syndromes. N Engl J Med.1998; 339: 436-443 [cited 1001x]. C O E U R Annul Report 2008 90 91

C O E U R Annul Report 2008 Pub Med Publictions 2008 Theme 1 Crdiovsculr Biology nd Phrmcology 1. Agnetti G, Bezstrosti K, Dekkers DH, Verhoeven AJ, Giordno E, Gurnieri C, Cldrer CM, Vn Eyk JE, Lmers JM. Proteomic profiling of endothelin- 1-stimulted hypertrophic crdiomyocytes revels the increse of four different desmin species nd lph-b-crystllin. Biochim Biophys Act. Jul-Aug 2008;1784(7-8):1068-1076. 8. 2. Bjpe PK, vn der Knp JA, Demmers JA, Bezstrosti K, Bssett A, vn Beusekom HM, Trvers AA, Verrijzer CP. Deubiquitylting enzyme UBP64 controls cell fte through stbiliztion of the trnscriptionl repressor trmtrck. Mol Cell Biol. Mr 2008;28(5):1606-1615. 9. 3. Bkker J, Jnsen TC, Lim A, Kompnje EJ. Why 4. 5. 6. 7. opioids nd sedtives my prolong life rther thn hsten deth fter ventiltor withdrwl in criticlly ill ptients. Am J Hosp Pllit Cre. Apr- My 2008;25(2):152-154. Btenburg WW, Dnser AJ. Prorenin nd the (pro)renin receptor: binding kinetics, signlling nd interction with liskiren. J Renin Angiotensin Aldosterone Syst. Sep 2008;9(3):181-184. Btenburg WW, de Bruin RJ, vn Gool JM, Muller DN, Bder M, Nguyen G, Dnser AH. Aliskirenbinding increses the hlf life of renin nd prorenin in rt ortic vsculr smooth muscle cells. Arterioscler Thromb Vsc Biol. Jun 2008;28(6):1151-1157. Btenburg WW, Jn Dnser AH. The (pro)renin receptor: new ddition to the renin-ngiotensin system? Eur J Phrmcol. My 13 2008;585(2-3):320-324. Bikker IG, vn Bommel J, Mirnd DR, Bkker J, 10. 11. 12. 13. Gommers D. End-expirtory lung volume during mechnicl ventiltion: comprison with reference vlues nd the effect of positive endexpirtory pressure in intensive cre unit ptients with different lung conditions. Crit Cre. Nov 20 2008;12(6):R145. Boerm EC, Kuiper MA, Kingm WP, Egbers PH, Gerritsen RT, Ince C. Disprity between skin perfusion nd sublingul microcircultory ltertions in severe sepsis nd septic shock: prospective observtionl study. Intensive Cre Med. Jul 2008;34(7):1294-1298. Breeuwer M, de Putter S, Kose U, Speelmn L, Visser K, Gerritsen F, Hoogeveen R, Krms R, vn den Bosch H, Buth J, Gunther T, Wolters B, vn Dm E, vn de Vosse F. Towrds ptient-specific risk ssessment of bdominl ortic neurysm. Med Biol Eng Comput. Nov 2008;46(11):1085-1095. Cheng C, Tempel D, Oostlnder A, Heldermn F, Gijsen F, Wentzel J, vn Hperen R, Hitsm DB, Serruys PW, vn der Steen AF, de Crom R, Krms R. Rpmycin modultes the enos vs. sher stress reltionship. Crdiovsc Res. Apr 1 2008;78(1):123-129. D Ancon G, Hrtmn JM, Brtolozzi F, vn Deel E, Duncker DJ, Bogers AJ, Pilto M, Kppetein AP. Epicrdil coronry rtery Doppler: vlidtion in the niml model. Interct Crdiovsc Thorc Surg. Aug 2008;7(4):634-637. Dnser AH, Btenburg WW, vn Esch JH, Krop M. Prorenin nno 2008. J Mol Med. Jun 2008;86(6):655-658. Dnser AH, Chrney A, Feldmn DL, Nussberger 14. 15. 16. 17. 18. 19. J, Fisher N, Hollenberg N. The renin rise with liskiren: it s simply stoichiometry. Hypertension. Apr 2008;51(4):e27-28; uthor reply e29. Dnser AJ, Nguyen G. The Renin Acdemy Summit: dvncing the understnding of renin science. J Renin Angiotensin Aldosterone Syst. Jun 2008;9(2):119-123. de Beer VJ, Sorop O, Pijnppels DA, Dekkers DH, Boomsm F, Lmers JM, Duncker DJ, Merkus D. Integrtive control of coronry resistnce vessel tone by endothelin nd ngiotensin II is ltered in swine with recent myocrdil infrction. Am J Physiol Hert Circ Physiol. My 2008;294(5):H2069-2077. Dekkers DH, Bezstrosti K, Gurusmy N, Luijk K, Verhoeven AJ, Rijkers EJ, Demmers JA, Lmers JM, Mulik N, Ds DK. Identifiction by differentil proteomic pproch of the induced stress nd redox proteins by resvertrol in the norml nd dibetic rt hert. J Cell Mol Med. Sep-Oct 2008;12(5A):1677-1689. Dobbe JG, Streekstr GJ, Atsever B, vn Zijderveld R, Ince C. Mesurement of functionl microcircultory geometry nd velocity distributions using utomted imge nlysis. Med Biol Eng Comput. Jul 2008;46(7):659-670. Dondorp AM, Ince C, Chrunwtthn P, Hnson J, vn Kuijen A, Fiz MA, Rhmn MR, Hsn M, Bin Yunus E, Ghose A, Rungveeryut R, Limmthurotskul D, Mthur K, White NJ, Dy NP. Direct in vivo ssessment of microcircultory dysfunction in severe flciprum mlri. J Infect Dis. Jn 1 2008;197(1):79-84. Dubin A, Edul VS, Pozo MO, Muris G, Cnulln CM, Mrtins EF, Ferrr G, Cnles HS, Lporte M, Estenssoro E, Ince C. Persistent villi hypoperfusion 20. 21. 22. 23. 24. 25. explins intrmucosl cidosis in sheep endotoxemi. Crit Cre Med. Feb 2008;36(2):535-542. Dullrt RP, Perton F, Sluiter WJ, de Vries R, vn Tol A. Plsm lecithin: cholesterol cyltrnsferse ctivity is elevted in metbolic syndrome nd is n independent mrker of incresed crotid rtery intim medi thickness. J Clin Endocrinol Metb. Dec 2008;93(12):4860-4866. Dullrt RP, Sluiter WJ. Common vrition in the CETP gene nd the implictions for crdiovsculr disese nd its tretment: n updted nlysis. Phrmcogenomics. Jun 2008;9(6):747-763. Duncker DJ, Bche RJ. Regultion of coronry blood flow during exercise. Physiol Rev. Jul 2008;88(3):1009-1086. Duncker DJ, de Beer VJ, Merkus D. Altertions in vsomotor control of coronry resistnce vessels in remodelled myocrdium of swine with recent myocrdil infrction. Med Biol Eng Comput. My 2008;46(5):485-497. Feldmn DL, Jin L, Xun H, Contreps A, Zhou Y, Webb RL, Mueller DN, Feldt S, Cumin F, Mnir W, Persohn E, Schuetz H, Jn Dnser AH, Nguyen G. Effects of liskiren on blood pressure, lbuminuri, nd (pro)renin receptor expression in dibetic TG(mRen-2)27 rts. Hypertension. Jul 2008;52(1):130-136. Feldt S, Btenburg WW, Mzk I, Mschke U, Wellner M, Kvkn H, Dechend R, Fiebeler A, Burckle C, Contreps A, Jn Dnser AH, Bder M, Nguyen G, Luft FC, Muller DN. Prorenin nd renininduced extrcellulr signl-regulted kinse 1/2 ctivtion in monocytes is not blocked by liskiren or the hndle-region peptide. Hypertension. Mr 2008;51(3):682-688. C O E U R Annul Report 2008 92 93

C O E U R Annul Report 2008 26. 27. 28. 29. 30. 31. 32. 33. Fisher ND, Jn Dnser AH, Nussberger J, Dole WP, Hollenberg NK. Renl nd hormonl responses to direct renin inhibition with liskiren in helthy humns. Circultion. Jun 24 2008;117(25):3199-3205. Foin N, Evns P, Krms R. Atherosclerosis: cell biology nd lipoproteins - new developments in imging of inflmmtion of the vulnerble plque. Curr Opin Lipidol. Feb 2008;19(1):98-100. Fries M, Ince C, Rossint R, Bleilevens C, Bickenbch J, Rex S, Mik EG. Levosimendn but not norepinephrine improves microvsculr oxygention during experimentl septic shock. Crit Cre Med. Jun 2008;36(6):1886-1891. Gembrdt F, Heringer-Wlther S, vn Esch JH, Sterner-Kock A, vn Veghel R, Le TH, Grrelds IM, Coffmn TM, Dnser AH, Schultheiss HP, Wlther T. Crdiovsculr phenotype of mice lcking ll three subtypes of ngiotensin II receptors. Fseb J. Aug 2008;22(8):3068-3077. Gommers D, Bkker J. Medictions for nlgesi nd sedtion in the intensive cre unit: n overview. Crit Cre. 2008;12 Suppl 3:S4. Groenewegen HC, Onut G, Goris M, Zndvoort A, Zijlstr F, vn Gilst WH, Rozing J, de Smet BJ, Roks AJ, Hillebrnds JL. Non-bone mrrow origin of neointiml smooth muscle cells in experimentl instent restenosis in rts. J Vsc Res. 2008;45(6):493-502. Groenewegen HC, vn der Hrst P, Roks AJ, Buikem H, Zijlstr F, vn Gilst WH, de Smet BJ. Effects of ngiotensin II nd ngiotensin II type 1 receptor blockde on neointiml formtion fter stent implnttion. Int J Crdiol. My 23 2008;126(2):209-215. Hmdni N, Kooij V, vn Dijk S, Merkus D, Pulus 34. 35. 36. 37. 38. 39. WJ, Remedios CD, Duncker DJ, Stienen GJ, vn der Velden J. Srcomeric dysfunction in hert filure. Crdiovsc Res. Mr 1 2008;77(4):649-658. Heldermn F, Mnoch IJ, Breeuwer M, Kose U, Schouten O, vn Smbeek MR, Poldermns D, Pttynm PT, Wisselink W, vn der Steen AF, Krms R. A numericl model to predict bdominl ortic neurysm expnsion bsed on locl wll stress nd stiffness. Med Biol Eng Comput. Nov 2008;46(11):1121-1127. 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Colophon Edited by: Jp Deckers nd Ern Egelie Photogrphy: Pul Delfos Ly out: Mud vn Nierop Production nd publiction: COEUR Secretrit Ersmus MC Printing: Medijoenit BV Rotterdm Contct: Thorxcenter Room B 573 Ersmus MC P.O. Box 2040 3000 CA Rotterdm The Netherlnds Phone: +31-10-7035312 E-mil: e.egelie@ersmusmc.nl Website: www.coeur.nl C O E U R Annul Report 2008 136