Promoting Cardiovascular Education, Research and Patient Care

Vol 6 No 3AUTUMN 2007

37 AChallenge37 AMost-DeservedHonour38 ExecutiveCommitte40 ReportsfromJapanMeeting41 DoctorReceivesVolvosforLife42 XVIIBrazilForum43 LaskerAwardforDevelopment

ofProstheticHeartValves44 IndianFirst-in-manTrials47 TurkeySymposium48 JohnMadden’s“Coach’sCorner”49 MendelSymposiumII50 Dr.WilliamParmley50 Dr.BohdanLewartowski51 Dr.SergioDalla-Volta52 Dr.GarrettGross53 Dr.AdolfodeBold55 3rdCongressinSerbia56 State-of-the-brain-and-heart:

HomoObesusBulgaricus56 25thBrazilianCongress58 WorldHeartDay59 AmericanJournalof

CardiovascularDrugs60 Jordan–the

Landoftreasureandbeauty62 JordanSymposium

In This Issue A ChallengeOver the past 10 years, theAcademy has built a basefor international connectiv-ity forpromotingcardiovas-cular health. This has beenachieved by establishingseven sections and hold-ing a variety of workshops,symposia and conferencesallover theworldaswellashaving several publicationsanditsownwebsite.

Currently,theAcademyisproposingtopromotelink-ages among cardiovascular institutes and centres intheareaofpopulationhealth,clinicalstudies,scientificinvestigations,preventionandeducationforimprovingcardiovascularhealth.Thiscouldhelpfacilitateexchang-esofhealthprofessionalsandfostercollaborations.Wewishtoencourageallcardiovascularhealthprofession-alstosendussuggestionsforbuildingthisprogram.

Fordiscussions,pleasecontactmeoranymemberofthe Executive Committee. For your convenience, theircontactinformationonpages38-39.

IvanBerkowitz,MBADirectorofDevelopment,IACSc/oSt.BonifaceGeneralHospitalResearchCentre3021-351TacheAvenueWinnipeg,MBR2H2A6CanadaTel:(204)228-3193Fax:(204)233-6723E-mail:ivan@mts.net

A Most- Deserved Honour“HOUSTON -- (October 2, 2007)LegislationauthorizingaCongres-sionalGoldMedalforDr.MichaelE.DeBakey,pioneeringheartsur-geonandchancelloremeritusofBaylorCollegeofMedicine,isonits way to President George W.Bushforhissignature.

The U.S. Congress today ap-proved the bill that now will beforwarded to the president. U.S.SenatorKayBaileyHutchisonandU.S.Reps.AlGreen,MichaelBur-gessandJohnCulbersonledtheeffortsonthelegislation.

‘After learning that I was go-ingtoreceivethisfinehonor,theCongressional Gold Medal, mypride as a citizen of the UnitedStatesofAmericaisoverflowing,’DeBakey said. ‘It is a wonderfulhonorandI’mdeeplygrateful.’

TheCongressionalGoldMedalisconsideredthenation’shighestand most distinguished civilianaward.

Coninued on page 38

37

38

P E o P l E A N D P l A C E S

A Most-Deserved Honour Coninued from page 37

Thefirstwasawardedin1776toGen.GeorgeWashington.Itisawardedbothforsingularactsofexceptionalserviceandforlifetimeachievement.

‘Dr. Michael DeBakey has given so much to medicine and to the world at large,’ said BCMPresident and CEO Dr. Peter G.Traber.‘It is most fitting that this high honor be given to him.Dr.DeBakey’scontributionstomedicalcare,educationandhealthcarepolicyarelegendary.Hehastouchednotonlythepatientswhose liveshedirectlysavedbutthousandsofotherswhobenefitedfromhissurgicalinnovations.TheBaylorCollegeofMedicinefamilylooksforwardtocelebratingthisrecognitionwithhim.’

Hutchison,whohasworkedwithDeBakeyonmanyprojects,spearheadedtheeffortsfortheaward. The Senate legislation passed in March. Green, Culberson and Burgess picked up thechargeintheHouse.FinalapprovalwasgivenintheHousethismorning.

‘WeareverygratefultoSenatorHutchisonandtoCongressmenGreen,CulbersonandBurgessfortheirleadershipinmakingthisawardpossible,’saidRobertH.Allen,chairoftheBCMBoardofTrustees.‘Dr.DeBakeyisatrueheroandverydeservingofthisrecognitionfromtheU.S.Congress.WeareveryproudofthecontributionsDr.DeBakeyhasmade,andcontinuestomake,toBaylorCollegeofMedicine.’From Baylor College of Medicine web site

E X E C U T I V E C o M M I T T E E o F T H E I N T E R N A T I o N A l A C A D E M Y

o F C A R D I o V A S C U l A R S C I E N C E S

A. INTERNATIoNAl 1. Dr. Stephen F. Vatner, MDPresident,IACSDirector,CardiovascularResearchInstituteUMDNJ,NewJerseyMedicalSchool185SouthOrangeAvenue,RoomG609Newark,NJ,07103,USATel:(973)972-8920/4414Fax:(973)972-7489E-mail:vatnersf@umdnj.edu2. Sir Magdi Yacoub, FRS President-Elect,IACSProfessor,ImperialCollegeLondonTheMagdiYacoubInstituteNationalHeart&LungInstituteatH.S.C.Harefield,MiddlesexUB96JH,UKTel:+44-1-895-453-893Fax:+44-1-895-828-902E-mail:m.yacoub@imperial.ac.uk3. Dr. Howard Morgan, MDPastPresident,IACS223FoxRidgeLane,Winfield,PA,17889,USATel/Fax:(570)524-7602E-mail:morgans@ceinetworks.com

4.* Dr. Makoto Nagano, MDChairmanoftheBoard&President,Japa-neseSection,IACSProf.Emeritus,JikeiUniversitySchoolofMedicinec/oMedicalThinkTankEbisu3-31-3,Shibuya-kuTokyo150-0013,JapanTel:+81-3-3444-3567Fax:+81-3-3440-3455E-mail:naganopr@st.catv.ne.jp5. Dr. Naranjan S. Dhalla, FRSCExecutiveDirector,IACSInstituteofCardiovascularSciencesStBonifaceGeneralHospitalResearchCentre351TacheAvenueWinnipeg,MBR2H2A6CanadaTel:(204)235-3417Fax:(204)233-6723E-mail:nsdhalla@sbrc.ca6. Dr. Grant N. Pierce, PhDDirectorofScientificAffairs,IACSExecutiveDirectorofResearchSt.BonifaceGeneralHospital

351TacheAvenueWinnipeg,MB,R2H2A6,CanadaTel:(204)235-3414Fax:(204)231-1151E-mail:gpierce@sbrc.ca7. Dr. Pawan K. Singal, PhDDirectorofEducation,IACSDirector,InstituteofCardiovascularSciencesSt.BonifaceGeneralHospitalResearchCentre351TacheAvenueWinnipeg,MB,R2H2A6,CanadaTel:(204)235-3416Fax:(204)233-6723E-mail:psingal@sbrc.ca

8. Dr. Alan Menkis, MDDirectorofHealthCare,IACSMedicalDirector,CardiacSciencesProgramSt.BonifaceGeneralHospital409TacheAvenueWinnipeg,MB,R2H2A6,CanadaTel:(204)258-1203Fax:(204)233-6065E-mail:amenkis@sbgh.mb.ca

Editor’s note: DrDebakeyisaFellowoftheIACSandwasthefirstrecipientoftheAcademy’smostprestigiousMedalofMeritin2001.Foranextraordinaryarticleabouthislife,pleaselookatourrecentCVNetworkVOL6NO2,page31

Bush signs bill giving Dr. Michael DeBakey top civilian honoron Tuesday, october 16, 2007 Famed Houston heart surgeon Michael DeBakey has been awarded the nation’s top

civilian honor – the Congressional Gold Medal. President Bush finalized the award Tuesday by signing a bill approved recently by the Senate and the House of Representatives.

39

B. JAPANESE SECTIoN*Dr. Makoto Nagano, MDChairmanoftheBoard,IACS&President,JapaneseSection,IACSProf.Emeritus,JikeiUniversitySchoolofMedicinec/oMedicalThinkTankEbisu3-31-3,Shibuya-kuTokyo150-0013,JapanTel:+81-3-3444-3567Fax:+81-3-3440-3455E-mail:naganopr@st.catv.ne.jp9. Dr. Nobuakira Takeda, MDSecretary,JapaneseSection,IACSProfessor&DirectorDepartmentofInternalMedicineAotoHospitalJikeiUniversitySchoolofMedicineAoto6-41-2,Katsushika-kuTokyo,125-8506,JapanTel:+81-3-3603-2111Fax:+81-3-3603-2234E-mail:ntakeda@jikei.ac.jp

C. EURoPEAN SECTIoN10. Prof. Dr. Bohuslav ostadal, MDPresident,EuropeanSection,IACSInstituteofPhysiologyCzechAcademyofSciencesDepartmentofDevelopmentalCardiologyVidenska1083Prague4,14220,CzechRepublicTel:+420-2-4106-2553Cell:420-6033-37161Fax:+420-2-9644-2125E-mail:ostadal@biomed.cas.cz

11. Dr. Keld Kjeldsen, MDSecretary,EuropeanSection,IACSProfessor&HeadofCardiologyMedicalDepartment-B2142TheHeartCentre-RigshospitaletBlegdamsvej9Copenhagen,2100,DenmarkTel:+45-3545-2343/Cell:+45-4025-3789Fax:+45-3538-3186/3545-2648E-mail:keld.kjeldsen@rh.hosp.dkkjeldsen@rh.dk

D. AMERICAN SECTIoN12. Dr. Karl T. Weber, MDPresident,AmericanSection,IACSNeutonSternProf.ofCardiovascularMedicineDirector,DivisionofCardiovascular

DiseasesUniversityofTennesseeCollegeofMedicineDepartmentofMedicine920MadisonAvenue,Suite300Memphis,TN38163,USATel:(901)448-5759/5750Fax:(901)448-8084E-mail:ktweber@utmem.edu

13. Dr. Dennis B. McNamara, PhDSecretary,AmericanSection,IACSProfessor,TulaneUniversity200GeraniumStreetMetairie,LA70005,USATel:(504)835-5995/Cell:(504)782-0678E-mail:dbmcnamara@yahoo.com

E. SoUTH AMERICAN SECTIoN14. Dr. Ricardo J. Gelpi, MDPresident,SouthAmercianSection,IACSDepartamentodePatologiaLaboratoriodeFisiopatologiaCardiovascularFacultaddeMedicinaUniversidadedeBuenosAiresJ.E.Uriburu950-Piso21114BuenosAires,ArgentinaTel/Fax:+54-11-4962-4945Cell:1554-996919E-mail:rgelpi@fmed.uba.arrjgelpi@aol.com

15. Dr. otoni Moreira Gomes, MDSecretary,SouthAmericanSection,IACSRuaJosedoPatrocinio,522SantaMonica–31525-160BeloHorizonte-MG,BrazilTel:+55-31-3444-8807/3441-2254(res.)Fax:+55-31-3452-7143E-mail:gomes@servcor.com

F. INDIAN SECTIoN16. Prof. Nirmal K. Ganguly, MDPresident,IndianSectionDirectorGeneral,IndianCouncilofMedicalResearchV.RamalingaswamiBhawan,PostBox4911AnsariNagar,NewDelhi110029,IndiaTel:+91-11-2658-8204Res:+91-2649-3145Fax:+91-11-2658-8662;2658-9791;265-889258E-mail:icmrhqds@sansad.nic.ingangulynk@icmr.org.indg@icmr.delhi.nic.ingangulynk@icmr.delhi.nic.in

17. Dr. Suresh K. Gupta, PhDSecretary,IndianSection,IACSDean,InstituteofClinicalResearchIndiaDelhiCampusA-201,OkhlaIndustrialAreaPhase1NewDelhi,110019,IndiaTel:+91-11-5140-6945-49Res:+91-11-2955-2732Fax:+91-11-5163-4963E-mail:skgupta@icriindia.com

G. RUSSIAN SECTIoN18.Prof.Dr.VladimirN.Smirnov,PhDPresident,RussianSection,IACSDirector,InstituteofExperimentalCardiologyCardiologyResearchCenter3rdCherepkovskayaStreet,15AMoscow,121552,RussiaTel:+7-095-444-0035Cell:+7-095-967-2060Fax:+7-095-415-2962/414-6699/149-0559E-mail:v.n.smirnov@mtu-net.ru;v.n.smirnov@inbox.ru

19. Dr. leonid V. Rosenshtraukh, PhDSecretary,RussianSection,IACSLaboratoryofHeartElectrophysiologyInstituteofExperimentalCardiologyCardiologyResearchCenter3rdCherepkovskayaStr.15AMoscow121552,RussiaTel:+7-095-149-6739Fax:+7-095-149-0071E-mail:LVRos@cardio.ru

H. CHINESE SECTIoN20. Dr. Rutai Hui, MDPresident,ChineseSection,IACSFuwaiHospital167BeilishiluBeijing100037,P.R.ChinaTel:+86-10-6833-3902Fax:+86-10-6833-1730E-mail:Huirutai@sglab.orghuirutai@hotmail.com

21. Dr. Xian Wang, MDSecretary,ChineseSection,IACSProfessor,DepartmentofPhysiologyPekingUniversityHealthScienceCenter38XueYuanRoadBeijing,100083,P.R.ChinaTel:+86-10-8280-7700Fax:+86-10-8280-1443E-mail:xwang@bmju.edu.cn

E X E C U T I V E C o M M I T T E E o F T H E I N T E R N A T I o N A l A C A D E M Y

o F C A R D I o V A S C U l A R S C I E N C E S

40

P E o P l E A N D P l A C E S

Atthe7thAnnualMeetingofIACSJapanSectioninKyoto,July14-15,2007,theJapanSectionofIACSselectedDr.KentoTateishi,anexcellentyoungresearcher,forthe3rdYoungInvestiga-torAward.Siemens.AsahiMed.TechnoLtd.inJapan,sponsorsthisYoungInvestigatorAward.

Atthismeeting,16candidatesfrom16differentUniversitydepartmentswererecommend-edandDr.K.TateishireceivedtheAward.

He is researching at the department of ExperimentalTherapeutics,Translational ResearchCenter,KyotoUniversityGraduateSchoolofMedicine.HewasborninKyoto,Japan.Aftergradu-atingfromSchoolofMedicine,KyotoPrefecturalUniversityin1998(MD),hewastrainedasanin-ternininternalmedicine.From2000to2006hewasapostgraduatestudentofKyotoPrefecturalUniversitySchoolofMedicineandworkedinthedepartmentofExp.Therapeutics,TranslationalResearchCenter,KyotoUniversityGraduateSchool.HereceivedhisPhDinMarch2007.

Hispresentation,forwhichheearnedtheYoungInvestigatorAward,was:“Clonallyampli-fiedcardiacstemcellsareregulatedbystemcellantigen-1signalingforefficientcardiovas-cularregeneration”.Cardiacstemcells(CSCS)fromtheadultheartcandifferentiateintofunc-tional cardiomyocytes; however, the definite surface markers to identify the entity of CSCSandthemolecularmechanismsregulatingtheirgrowthhaveremainedunknown.Dr.Tateishidemonstratedasingle-cellanalysistoisolateCSCSfromtheadultheartsandinvestigatedthe

signalsrequiredfortheirproliferationandsurvival.ClonallyproliferatedCSCSexpressstemcellantigen-1(Sca-1)andareassociatedwithtelomerasereversetranscriptase(TERT).Using

GFP-reportertransgenicmiceunderthecontrolofTERTpromoter,hedemonstratedthatTERTGFP+fractionsfromtheheartwereen-richedforthecellsexpressingSca-1.TargetingSca-1transcriptsinCSCSshowedthatCSCproliferationandsurvivalrequiredAktsignal-ingtoupregulatethesecretedparacrineeffectorstolimitcardiacapoptosisinischemicmyocardium.Thus,Sca-1mightbeanessentialcomponentthatpromotesCSCproliferationandsurvivaltofacilitatecardiovascularregenerationafterCSCtransplantation.

OntheleftisProf.T.TOYO-OKA,chairmanofthesession,ontherightDr.K.TATEISHI

3rd Young Investigator Award of IACS Japan SectionbyMakotoNagano,Tokyo,Japan

P E o P l E A N D P l A C E S

The 6th Annual Meeting of IACS Japan SectionbyAkiraMatsumori,Kyoto,Japan

The6thAnnualMeetingoftheInternationalAcademyofCardiovascularSciences(the30thJapaneseWorkingGroupforCardiacStructureandMetabolism)washeldonJuly14-15th,2007attheParuruPlaza,Kyoto,Japan.Prof.AkiraMatsumori,MD,PhD,FACC,FAHA,FESC,DepartmentofCardiovascularMedicine,KyotoUniversityGraduateSchoolofMedicinechairedthemeeting.

Themeetingwasfruitfulandsuccessful,with110basicscientistsandclinicalresearchersgatheringfromalloverJapantodiscussrecenttopicsinthefieldofcardiovascularmedicine.

Dr.PeterLiu,UniversityofTorontoandCanadianInstitutesofHealthResearch,gaveaspeciallecturetitled“Interplaybetweencardiovascularremodelingandmetabolisminheartfailure.”Fourinvitedlecturesweregivenbyexpertsinbasicsciencefromoutsideofcardiovascularfield.1.Dr. Akihiko Yoshimura,DivisionofCellularandMolecularImmunology,MedicalInstituteofBioregulation,KyushuUniversity.“MolecularmechanismsandfunctionsoftheSPRED/SPROUTYfamilyproteins:NegativeregulatorsfortheRAS/ERKpathway.”2.Dr. Jun-ichi Miyazaki,DivisionofStemCellRegulationResearch,OsakaUniversityGraduateSchoolofMed-

icine.“Regenerationofpancreaticbetacellsinvitroandinvivo.”3.Dr. Hidetoshi Inoko,DivisionofMolecularMedicalScienceandMolecularMedicine,TokaiUniversitySchoolofMedicine.“Genome-widescanofgenesformulti-factorialdiseasessuchascommondiseasesbyassociationanalysisusingmicrosatellites.”4.Dr. Hajme Kubo,DepartmentofSurgery,KyotoUniversityGraduateSchoolofMedicine.“Expandingworldoflymphangiogenesis:Theroleoflymphaticsindiseases.”

Allfourlecturewereexcellent,impressive,andinstructive,andmadeagreatimpactontheaudience.Abstractssessionswereheldonthetopicsofregenerativemedicine,cardiacfunction,signaltransduction,calciumsignaling,ath-

erosclerosis,myocardialischemia,cardiomyopathies,andheartfailure.Eachofthe30presentationswashighinquality.Sixteenab-stractsweresubmittedtotheCompetitionforYoungInvestigatorsAwards.Dr.KentoTateishi(DepartmentofExperimentalTherapeu-tics,TranslationalResearchCenter,KyotoUniversityHospital,andDepartmentofCardiovascularMedicine,KyotoPrefecturalUniversitySchoolofMedicine)wonthefirstprizeofthiscompetition.Hispresentationwas“Clonallyamplifiedcardiacstemcellantigen-1signal-ingforefficientcardiovascularregeneration.”

ThenextmeetingwillbeheldonJuly12-13,2008inTokyounderthechairmanshipofDr.SatoshiKurihara,JikeiUniversitySchoolofMedicine,Tokyo.

AkiraMatsumori,Kyoto,Japan

41

AlocalherofromtheDetroitareatodayisreceivinga“thankyou”tolastalife-time:acomplimentarynewVolvocareverythreeyearsfortherestofhislife.

Earlierthisyear,celebrityjudgesnamedDr.IngidaAsfaw,“America’sGreatestHometownHero”inthefourthannualVolvoforlifeAwards,thenation’slargestsearchforandcelebrationofeverydayheroes,withVolvoproviding$1millionincontributionsinhonoroflocalheroes.Dr.AsfawisanEthiopian-bornheartsurgeonwhokeptahalf-centurypromisetohimselfbycreatinganinternation-alcoalitioncalledtheEthiopianNorthAmericanHealthProfessionalsAssocia-tion(ENAHPA)toaddresshishomeland’smedicalcrises.

Launchedin2002,theVolvofor lifeAwardscallsforpeoplenationwidetonominatealocalherotheyknowdoingtheextraordinaryintheareasofsafety,qualityoflifeorenvironmentatwww.volvoforlifeawards.com.SinceJune2005,Volvohasreceivedmorethan4,341nominations,includingDr.Asfaw’sand49

othersfromMichigan,forthe4thAnnualVolvoforlifeAwards.InFebruary,Volvoselectedthreewinningheroesineachcategory.JudgesHankAaron,Sen.BillBradley,CarolineKennedy,SirRichardBranson,EuniceKennedyShriver,ValKilmer,MayaLin,Paul

Newman,Dr.SallyRideandHopeBevilhymer(3rdAnnualVolvoforlifeAwardswinner)thenselectedtheoverallcategorywinners,whoreceiveda$50,000charitablecontribution.AtagalaceremonyinNewYorkthispastApril,judgesannouncedDr.AsfawasthewinnerinthequalityoflifecategoryandalsounveiledhimastheoverallgrandwinnerandarecipientofaVolvocareverythreeyearsforlife.

Forhisfirstcarchoice,Dr.Asfawselectedthe2007VolvoXC90V8.TodayatalunchtimeceremonyatSuburbanVolvoinTroy,Mich.attendedbyDr.Asfaw’sfriends,familyandassociates,theretailerandexecutivesfromVolvoCarsofNorthAmericapresentedDr.Asfawwiththekeystohisnewcar.

“EveryyearIamtouchedbytheamazingstoriesandthousandsofnominationswereceivethroughtheVolvoforlifeAwards,”saidAnneBelec,presidentofVolvoCarsofNorthAmerica.“Dr.Asfawstandstallasamanwhohasdevotedhisenergyandskillstoaddressingadevastatingcrisisinhishomeland.It’sanhonorforVolvotohelphimadvancehiscause.”

The5thAnnualVolvoforlifeAwardsalreadyisunderway.Volvohasnamed250extraordinaryheroesnationwide--fiveperstate--assemi-finalists.Now,forthefirsttime,individualscanvotefortheirfavoriteheroesatwww.volvoforlifeawards.comthroughFeb.4,2007.InMarch,Dr.Asfawwilljoincelebrityjudgesinselectingnextyear’swinningheroes,tobehonoredAprilinNewYork.

About Dr. AsfawAttheyoungageof16,AsfawdepartedfromhishometowninEthiopiadeterminedtostudymedicineintheUnitedStatesandinreturnputanendtothelackofanationalhealthcareprogram.Now,at68yearsofage,hehaskepthispromiseofsomedayreturn-ingtoEthiopiawithhelpinghands.

In1999Dr.AsfawstartedENAHPAandencouragedotherstojoinhimintreatingthepeopleofEthiopia.Inacountrywheretheratioofphysicianstopopulationis1per100,000,theideaofahealthcaresystemwasnonexistentandDr.Asfaw’sdreamwastochangejustthat.Withsupportfromover500medicalandnon-medicalprofessionalsandvolunteersfromtheUnitedStates,Cana-da,ChinaandSouthAmerica,asenseofhopehasbeenreturnedtothepeopleofEthiopia.ENAHPAhasledthevolunteersthroughmissiontripsandothersocialinitiativestoaddressthehealthcarecrisisbydonatingtheirtimeandservice.

ThisrenownedsurgeonalongwithhisteamofENAHPAvolunteershasperformednearly100surgicalprocedures;conductedadvancedtrainingfor250Ethiopianhealthcareprofessionalsanddonated32,400books;providedlifesavingmedicalequipment;instrumentsandsuppliestoseveralspecializedhospitals,threeuniversitiesandaleprosyresearchtrainingcenter.Nowover500AIDSorphansarebeingcaredforbyanewlycreatedprogrambyDr.Asfaw,whichsupportsagrassrootsEthiopianorganizationtoprovidethepatientswiththemedicalcaretheyneed.

NowresidinginMetroDetroit,workingascardiovascularsurgeonat;Sinai-GraceHospital,St.JosephPOHNorthOaklandMedicalCenter,HuronValleyHospital,HarperHospitalandCrittentonHospitalDr.Asfawhastakenonanotherchallengeworkingasaclini-calprofessorofsurgeryatWayneStateUniversity.Dr.AsfawisalsothechairmanofcardiothoracicsurgeryatTrinityHeath-St.JosephMercyOaklandandchiefexecutiveofficerofCardiothoracicandVascularSurgeonsofMichigan.

About Volvo for life AwardsTheVolvoforlifeAwardswaslaunchedin2002torecognizeandcelebratelocalhero’snationwide.FormoreinformationortovoteforthefifthannualVolvoforliferecipientpleasevisitourwebsiteatwww.volvoforlifeawards.com.WhowouldyougiveaVolvoto?Joinusinthesearchforthe2007Volvoforliferecipientbysimplysubmittinganominationandvotingforyourlocalhero.

For photos and more information on the Volvo for life Awards: www.volvocars-pr.com

Doctor Receives Volvos for Life

Dr.IngidaAsfaw,“America’sGreatestHometownHero”

P E o P l E A N D P l A C E S

Source:VolvoCarsofNorthAmerica

42

43

Lasker Award for Development of Prosthetic Heart Valves

P E o P l E A N D P l A C E S

fromLaskerAwardswebsitebyMichaelS.Brown,MemberoftheLaskerAwardsJury

Ifyou’veeverusedahand-heldpumptoinflateabicycletire,youknowthatpumpsneedtwovalves—onetopermitairtoenteronthe intakestroke,andtheothertopermitairtoexitduringexpulsion.Ourheartsarenodifferent.Eachofthetwopumpingchambershastwovalves—oneforintakeandoneforexpulsion.Heartvalvesareremarkablyresilient.Overahumanlifetimetheyopenandclose3billiontimes,allowing50milliongallonsofbloodtopass.Whentheyclose,theypreventthebackflowofthisdeluge.It’snowonderthatheartvalveswearout.

Theycanwearsimplywithage,ortheycanfailearlyinlifeasaresultofbirthdefects,ordiseaseslike rheumatic feverandbacterial infections.Diseasecanconstrict thevalve,blockingtheflowofblood,or itcanrenderthevalve leaky,permittingdevastatingback-flow.Oftenasinglevalvecansufferbothproblems.

Before1960,diseaseofheartvalvesmeantcertaindeath—eithercatastrophicallyorslowlywhentheheartfailedasittriedtoovercometheinefficiencyinpumpingblood.Allofthatchangedonasingleday—September21,1960—inasurgicalsuiteinPortland,Oregon.There,AlbertStarrimplant-edthefirstsuccessfulartificialheartvalveina52-year-oldmanwhowasliterallyonhisdeathbed.Inchildhood,thismanhadsufferedfromrheumaticfever,whichhadfatallydamagedhismitralvalve,theonethatadmitsbloodintotheleftventricle.Earlier,surgeonshadtriedtorepairthevalve,butthevalvewasbeyondrepair.Withoutanewvalvethismanwouldsurelydie.Starr’sartificialvalvewasaremarkablesuccessandthemanlivednormallyfor10yearsuntilhewaskilledbyfallingoffaladder.

ThestorythatledtothismedicalmiraclebegantwoyearsearlierwhenLowellEdwards,a62-year-oldinventorwithexperienceinfluiddynamics,walkedintoStarr’sofficeandproposedtheinventionofanartificialheartvalve.Starrwasayoungsurgeon,freshoutofresidency,whohadtrainedatColumbiaCollegeofPhysiciansandSurgeonsrighthereinNewYork.AfterfurthertrainingatJohnsHopkins,in1957StarrmovedtoPortlandtostartaclinicalandresearchprograminthebrandnewfieldofopenheartsurgery.HetookEdwardsuponhischallenge,andthetwosetouttoinventaheartvalve.Forthenexttwoyearstheyexperimentedintenselyondogs.Aftertryingotherdesigns,theyeventuallychoseacagedballvalvelikeonethatwasinventedasawinebottlestopperinFranceacenturybefore.Itdidn’tlooklikenature’ssolution,butithadtwopropertiesthatmadeitideal:First,itdidnotdamagethebloodcellsastheypassedthroughit;andsecond,itwaspartiallyresistanttoclotting.

StarrandEdwardsmadecarefulcalculationsofthesizeoftheopeningandthephysicalandchemi-calpropertiesnecessaryfortheballanditscage,andthentheytesteditbyimplantationintodoghearts.Theirbiggestproblemwasbloodclotting.Whenbloodtouchesaforeignsurfaceittriggersacascadeofenzymesthatquicklymakethebloodcongeal.Clottingisessentialtolife.Butitcreatesanenormousproblemwhenoneplacesaforeignobjectinthebloodstream.Fortunately,StarrandEdwardscouldtakeadvantageofinventionsmadeforotherreasons.First,theymadetheballfromsilastic,acombinationofsiliconeandplasticinventedbyDowCorningscientistsinthe1940’sasaseal-ant.Whenexposedtoblood,silasticisrelativelyinert.Second,theycouldblockclottingbyusinganeworalanticoagulant,coumadin,thathadbeeninvented10yearsearlierasaratpoison.

Ofcourse,theveryideaofheartvalvereplacementcouldnothavebeenenvisionedwithoutthepioneeringworkofJohnGibbon,whoin1953performedthefirstopen-heartsurgeryusingaheartlungmachine.GibbonreceivedtheLaskerAwardin1968.TheworldalsoowesadebttoCharlesHufnagel,asurgeonwhohadearlier implantedacagedballvalve in theaortaofapatientwithaorticregurgitation.

Inadditiontotheircreativity,skillandcourage,StarrandEdwardsarenoteworthyfortheirunself-isheffortsatteachingothersurgeonshowtoduplicatetheirsuccess,andtheirdiligenceatkeepingtrackoftheirpatientsandreportingtheirfailuresaswellassuccesses.Bythepresenttime,modifica-

tionsoftheoriginalballvalvehavebeenmade,andnewapproacheshavebeenpioneered,aswewillhearinamoment.Nevertheless,itispropertoconsiderAlbertStarrandLowellEdwardsasthefathers

ofartificialvalves,andmillionsofpatientsliterallyowetheirlivestothem.Unfortunately,LowellEdwardspassedawayin1982.Oth-erwise,hewouldsurelyhavesharedtoday’sAward.

TheStarr-Edwardsvalvebroketheground,butitleftaproblem.Therecipientswerecommittedtotakinganticoagulantsfortherestoftheirlives.Thedosemustbeadjustedcarefully.Ifthedoseistoolow,clotsformonthevalve,triggeringstrokesandothercatastrophes. Ifthedoseistoohigh,bloodwillnotclotandfatalbleedingwilloccur.NowthesceneshiftstoParisandanotheryoungsurgeon,AlainCarpentier.Asasurgeryresidentintheearly1960s,CarpentierobservedayoungmanwhohadreceivedaStarr-Edwardsvalveandhadsufferedastrokecausedbyabloodclot.Carpentierdecidedtodevotehimselftofindingavalvethatwouldnotclot.

AlainCarpentierHopitalEuropeenGeorgesPompidou

AlbertStarrProvidenceHealth

andServices

44

Previousworkhadshownthatanimalvalvescouldbeimplantedintohumanhearts,andtheydidnotclot.Buttherewasaprob-lem.Afterafewmonthstheanimalvalvesdeteriorated.ThroughbrilliantdeductionCarpentierdiscoveredthatthevalveswouldfunctionmuchlongeriftheywerefirsttreatedwithglutaraldehyde,achemicalthatcrosslinkstheproteinsofthevalves,reinforcingthestructuremuchlikebridgesaresupportedbycross-linkedtriangularbeams.Glutaraldehydealsoreducesthetendencyofthevalvetostimulateimmunerejection.Carpentierobtainedvalvesfrompigs,treatedthemwithglutaraldehyde,andattachedthemtoaringthatkeptthemexpandedandallowedthemtobesewnintothehumanheart.Afterthistreatmentthepigvalvewasnolon-gernatural—itwasanewstructurethatCarpentiercalledabioprosthesis.Theresultwasdramatic.Bioprostheticvalvesareefficientandlong-lasting.Moreover,thepatientsdonotrequireanticoagulants.Thevalvesworkespeciallywellinolderpatients.

Today,themajorityofvalvesimplantedintopeopleaboveage60areCarpentiervalves.ButCarpentierdidnotstopwithbiopros-theses.Herealizedthatsometimesthevalvedidnotneedtobereplaced.Hedevelopedingeniousmethodstoreinforceandrepairthepatient’sownvalve.Hisrepairmethodsrevolutionizedcardiacsurgery.

AnotherofAlainCarpentier’scontributionsdeservesrecognition.Hehasusedhisskill,hisinfluenceandhispersonalwealthtobringthebenefitsofcardiacsurgerytothousandsofpoorpeopleindevelopingcountries.In1992,hefoundedahospitalinVietnamthatperforms1000openheartsurgerieseveryyear.AsaDirectoroftheWorldHeartFoundation,CarpentierhasbroughtthebenefitsofcardiacsurgerytomanynationsinAfrica.ButDr.Carpentierdoesn’tonlyhelpthepoor.Hesavessometimefortherich.LastyearheperformedemergencysurgerythatsavedthelifeofaprominentNewYorker,CharlieRose,whosemitralvalvefailedwhileinSyria.

AsIlookbackattheenormouscontributionsofStarrandCarpentier,Iamstruckbytheconfluenceofprioradvancesthattheybroughttogether.Ofcoursetherewastheheart-lungmachine.Butthismachinecouldnothavebeeninventedwithoutsomethingasmundaneassilastictubing.Coumadinwasaratpoison.Glutaraldehydecamefromleathertanningandelectronmicroscopy.Andnosurgicaladvancecouldtakeplacewithoutmedicaldiscoverieslikeantibiotics,methodstomanagefluidandelectrolytes,selec-tionofblooddonorswhoarecompatibleimmunologically,andtreatmentofheartarrhythmias.Technologyexpandsgeometrically.Eachadvancemultipliestheadvancesbeforeit.Weliveontheascendinglimbofthisexpansionwhereunrelatedadvancescanbebroughttobearonasingleproblemlikevalvularheartdisease.AndallofthishappenedbeforeGoogle,thelimitlesslibrarythatallowseveryinventorimmediateaccesstoallpriorknowledge.WhataplaygroundforcreativemindslikethoseofStarr,EdwardsandCarpentier.Letusallacttoinsurethatthehumanbenefitsfromthisageofenlightenmentdonotfallvictimtothosewhowouldreturntheworldtoignorantdarkness.

©LaskerMedicalResearchNetwork

P E o P l E A N D P l A C E SLasker Award for Development of Prosthetic Heart Valves – continued

Emerging trends of Clinical Research in India: Developinganewdrugtodayestimatestoalmost$800milliontonearly$2billion,withthiscostcontinuingtorise.ThetotalglobalpharmaceuticalR&Dexpenditurehasbeenincreasingbymorethan11%everyyearsince2001tosurpassacolossal$60billionthisyear.Pharmaceuticalcompaniesarethereforeactivelysearchingforsolutionstoreducecosts.Clinicaltrialsareofparticularconcern,sincetheycanaccountforalmosttwothirdsofthecostsofdevelopinganewdrug.FDAregulationsrequiremoreandmoreresultstoapprovenewdrugsbutcontractandbudgetdelaysandpatientrecruitmentdifficultiesresultin94%ofallUStrialsbeingdelayedoveramonth,witheachadditionaldayleadingto$1milliondollarslostinrevenue.

RecenttrendshaveseenclinicalresearchsegmentemergingoutsideUSboundariesandgettingestablishedinEuropeandAsia.IndiaandChinasharethemajorchunkofbenefitsfromariseinclinicalresearchactivities inAsia.7Avast,unwieldypopulation,aplethoraofdiseases,andrampantpoverty-wasthepictureIndiapresentedtotheoutsideworldtillawhileago.ButthesedaysthefactthatIndiahasthelargestpoolofpatientssufferingfromcancer,diabetes,cardiovasculardiseasesandothermaladiesisleadingthecountrytobecometheglobalhubofclinicaltrialsoutsourcing.PfizerinitiatedthistrendwithasmallclinicalresearchunitinMumbaiin1995.Adecadelater,allglobalpharmaceuticalcompaniessuchasNovoNordisk,SanofiAventis,Novartis,GlaxoSmithKlineandEliLillystartedconductingclinicaltrialsacrossvariousIndiancities.

Why India:India,beinga“low-costcountries”isbecomingincreasinglyattractiveasclinicaltrialoutsourcingdestination.Ithasthelargestpoolofpatientssufferingfromthedevelopingworld’smostcommondiseases.TheWorldHealthOrganizationestimatesthatin2010sixcar-diovascularpatientsoutoftenwillbeIndian,withdevelopingurbanizationandgrowinglifeexpectancysustainingthisphenomenon.Whilelessthan5%ofthepatientsinUSarewillingtoparticipateinclinicaltrials7,Indianpatientsseetrialsasauniqueopportunitytoreceiveextensivehealthcare,thusallowing5to6timesfasterrecruitment.Mostpatientsaretreatment-naïveandtheirgeneticdi-versityareadditionalassetsoftheIndianpopulation.Moreover,Indiahasanattractivenumbersmallandlarge,generalandspecialtyhospitals,medicalcolleges,along-establishedpharmaceuticalindustryandalargepoolofhighlyskilledEnglishspeakinghealthcareprofessionals;manyofwhomarealsotrainedoverseas.Allthisenablesgenerationofwellaccepted,goodquality,auditabledataat

F U T U R E o F H E A R T H E A l T H

First-in-man Clinical Trials in IndiabyRameshKGoyal,KeyurHParikhandHetalAShah,Ahmedabad,India

45

verylowcosts.A2004RaboBankIndiastudyestimatedthatPhaseIIandIIItrialsinIndiacancost60%lessthanintheUS.The2004A.T.Kearney’sreportratesIndiaatthetopforoffshorelocationattractivenessindex.The2005A.T.Kearney’scountriesattractivenessindexforclinicaltrials,rankedIndiasecond.Theindexwasbasedonpatientpool,costefficiency,regulatoryconditions,relevantexpertiseandinfrastructureandenvironment.

Insufficient regulatory infrastructures, experience to monitor the situation tightly, ethic dilemmas in patient recruitment and ahistoryoflittle-protectingIPlawscautionstheinvestors’interest.Thereareindicationstowardsthegrowingshortageofexperiencedclinical research professionals as well. However, the recent government measures taken boost the promising market. In 2005, anamendmenttotheScheduleYoftheDrug&CosmeticsActdefinedIndianguidelinesforGCPbasedontheInternationalConferenceonHarmonization’sguidelines.InthatsameyearthecontroversialPatentActwasamended,strengtheningintellectualpropertypro-tectiontoapointconsideredasbeyondtheWTO’srequirementsbyafew.InDecember2006,theDrugsControllerGeneralofIndia(DCGI)hassimplifiedtheprocessforgainingregulatoryapproval forglobalclinicaltrials.ProtocolsalreadyapprovedinaselectednumberofcountriesincludingUS,UKandtheEMEAwillbeacceptedwhichwouldshortentheregulatoryapprovaldelays.Recently,inApril2007allservicescarriedoutbytheIndiancontractresearchandclinicaltrialsindustrywereexemptedfromapreviousservicetax,allowingevenmorecompetitivecosts.

AllthesechangesshouldsustaintheexplodingIndianclinicaltrials’market.AconfederationofIndianIndustryStudyevaluatedin2002thatclinicaltrialsinIndiagenerated$70millionthatyearandpredictedthatitwouldgrowto$200millionby2007andtobetween$500millionand$1billionby2010.InJune2007,theUSNationalInstituteofhealthclinicaltrialregistrylisted256trialsrecruitingorduetorecruitinIndia,33ofwhichhadcardiovasculardiseaseasacondition–andtherearecertainlymanymoreunregisteredtrials.

Moreandmoreplayersareappearing, from internationalcompaniessettingup localdivisions in India togrowing Indiancom-panies. Simultaneously, numerous Clinical Research Organizations have appeared, including well-known names such as Quintiles,ClinTec, Covance, Pharm-Olam, Pharmanet, Omnicare, PPD, Icon, Chiltern and Kendle. Indian CROs have also been mushrooming,includingLambdaTherapeutics,ClinWorld,ClinInvent,ClinRx,PharmaIntelandSynchron.

Almostallthetopnamesinthepharmaceuticalworldhavezeroed-inonIndia,settingupclinicaltrailfacilitiesinmajorcities,es-peciallyHyderabadandAhmedabad.

Ahmedabad – A promising metropolitan for cardiovascular diseases:AhmedabadisIndia’ssixthlargestcitywithapopulationof5million.LeadingIndianpharmaceuticalcompaniessuchasZydusCadilaarebasedinthecity,takingadvantageofitssoaringeconomicalgrowthandrenownedentrepreneurialspirit.ThelargestIndianCRO,LambdaTherapeuticsisheadquarteredinAhmedabadbesidesSynchronandAccutest.Thecityisalsoattractivetoforeigninterests;thefirstglobalCROestablishmentinIndiawastheopeningofQuintiles’Ahmedabadoffice.Furthermore,theimportanthealthinfrastructureofthecityisadefiniteasset,withnumeroushospitalsandclinics,3renownedmedicalcollegesandtherecently-openedIndianClinicalResearchInstituteAhmedabadcampus.Inthecardiovasculararena,Ahmedabadproposesmorethan30hospitalcardiologyunitsandmorethan10cath-labs,mostofwhichequippedstateoftheartandtheU.N.MehtaInstituteofCardiologyandResearchCentre.

First-in-man Clinical Trials at Ahmedabad:First-in-mandrugstudiesarecurrentlyrestrictedinIndia,butavenuesareopenformedicaldevices.Asanexampletothis,twofirst-in-manmedicaldevicetrialsweresuccessfullyaccomplishedbytheTeamofCardiologistsofTheHeartCareClinicatAhmedabadledbyDrKeyurHParikh.Thiscenterwasoneofthethreecentersacrosstheworld,participatinginthispilottrial.Themedicaldevicestudiedwasastent-likedevicedesignedtoestablishcoronarysinus(CS)narrowingandtoelevateCS pressure inpatientswithrefractoryangina.

Patientswithrefractoryanginapectorisalsoknownas‘nooption’patients,areoftenhavingseverediffusecoronaryarterydiseaseandarenotcandidatesforfurtherrevascularizationbycoronaryarterybypassgraft(CABG)surgeryorpercutaneouscoronaryinter-vention(PCI).Thesepatientscontinuetobeasymptomaticinspiteofongoingpharmacologicaltherapy.Theestimated1-and3-yearmortality rates for thesepatientsare1%to5%,andupto24%, respectively. Aconsiderablenumberof therapeuticstrategies fortreatingseverechronicanginahavebeeninvestigated,however,theyallhaveonlylimitedfeasibilityandnoneofthemhasbecomeawidelyusedtherapy.

IncreasedCSpressurecanreducemyocardial ischemiabyredistributionofbloodfromnonischemicto ischemicterritories.Thestudyevaluatedsafetyofthisstent(Reducer®;NeovascMedicalLtd,Israel)asapotentialalternatetherapyforpatientswithrefractoryangina.ThedevicewasintendedtoestablishCSnarrowingandelevateCSpressure.Inpreclinicalexperiments,implantationoftheReducerwassafeandwasassociatedwithimprovedischemicparameters. Inthepresentstudy,thesafetyandfeasibilityoftheCSReducerwasevaluatedinfifteenpatientswithrefractoryanginawhowerenotcandidatesforrevascularization.

Tenoutofthefifteenpatientsenrolledacrossotherpartsoftheworld,werestudiedattheAhmedabadcenterbetweenMarch–Sep-tember2005.Ethicscommitteeapprovalwassoughtbeforetheinitiationofthestudy.ThestudywasconductedadheringtoICH-GCPguidelinesandallpatientsgavewritteninformedconsentfortheirparticipation.Thedeviceswerepercutaneouslyimplantedandallthepatientswerefollowedforoveroneyear.Allprocedureswerecompletedsuccessfully.Noprocedure-relatedadverseeventsoccurredduringtheperiproceduralandthefollow-upperiods.Implantationofthisdeviceledtoimprovementintheanginascore,reductioninstress-inducedST-segmentdepressionandextent&severityofmyocardialischemiainthesepatients.12Thus,thisnoveldeviceappearedsafeandfeasiblewithclinicalimprovementsinthesepatients,whowereotherwisewith‘nooptions’.

Thesecondpilotstudyevaluatedanimplantabledevicefornon-invasivemonitoringofpulmonaryarterypressureinheartfailurepatients.ThisstudywasalsoconductedbytheteamofCardiologistsofTheHeartCareClinic,Ahmedabadundertheprincipalsuper-visionofDrParikh.Thiswastheonlycenteracrosstheworldtoconductthisfirst-in-manstudy.Thesystemevaluatedconsistsofa

miniatureimplantandadesktopmonitoringsystem(ImPressure®;RemonTechnologies,Israel)tomonitorpulmonaryarterypressurenon-invasivelyinpatientswithCongestiveheartfailure(CHF).

CHFisamajorcauseofmortality,morbidity,andhospitalizationworldwide.TheLeftVentricularEndDiastolicPressure(LVEDP)isacriticalhemodynamicparameter,whichisthebasisformostdecompensationevents.TheLVEDPisobtainedclinicallyfromthePul-monaryCapillaryWedgePressure,whichcorrelateswiththePulmonaryArteryDiastolicPressure(PADP).Thus,frequent,readilyavail-able,monitoringofPulmonaryArteryPressure(PAP)andPADPshouldsupplythenecessaryfeedbackloopforappropriatetherapy.Whilecardiaccatheterizationisthemostaccuratewaytodefinethehemodynamics,theinvasivenatureofthisprocedurelimitsitsuse.Clinicaldeteriorationsareoftenprecededbyelevationofleftventricularfillingpressuresandincreasedfluidvolumesinthelungandnoninvasivedetectionofthesechangesmightbehelpfulforpatientcare.Thenoninvasivedetectionofhemodynamicabnormali-tiesbeforeclinicaldeteriorationoccursmightbehelpfultoimprovecareandhenceiscurrentlythenewtargetresearch.Hence,thepurposeofthisfirst-in-manstudywastoexaminethefeasibilityofrepeatedPAPdeterminationsusinganewlydevelopedacousticwirelessimplantedcommunicationsystem.Pre-clinicalstudywiththisdevicein10pigswasconductedtoestablishabilityofPAPde-terminationfromtheImplantusingwirelessacousticcommunication.

The clinical study enrolled ten NYHA class III/IV heart failure patients in July 2005 after the approval of the Institutional Ethicscommittee.ICH-GCPprincipleswereadheredthroughouttheconductofthestudyandallpatientsgavewritteninformedconsentforparticipation.ThedevicewasimplantedusingrightheartcatheterizationandaccuracyofPAPmeasurementwasdeterminedbycomparisonwithsimultaneouspressuremonitoringformaControlMillarcatheter.ThedevicewassuccessfullyimplantedinthePAus-ingrightheartcatheterizationinallthepatients.Therewerenoimplantationsorlaterdevice-relatedcomplications.Pulmonaryarterypressuretracingswererepeatedlyobtainedfromallimplants.Allthepatientsweresystematicallyfollowedforoveroneyear.Thispilotstudysuccessfullydemonstratedthefeasibilityofacousticwirelesscommunicationwithaminiatureimplantedsensorforrepeatedpulmonaryarterypressuremonitoring.

CHFpatientsshowdiurnalvariationinhemodynamicswithnocturnalworseningofsymptoms.ThereductionofexercisecapacitywithearlyoccurrenceoffatigueanddyspnoeaisahallmarkofHFsyndrome.Further,managementoftheCHFpatientisacomplextaskthatinvolvestitrationofseveraldrugs,whichmayinteractwitheachother,andtriggerundesiredresults.Therefore,followingthissuccessfulimplantationandfunctioningofthedevice,weevaluatedthediurnalvariation,exerciseinducedvariationinPAPandeffectofmetoprololonthePAPusingnon-invasivemonitoringbythisdevice.Followingtheimplantation,allpatientswereloadedwithmetoprolol25mg/dayandthenuptitratedtill200mg/dayasperMERIT-HFcriteria.DiurnalvariationwasdonebymeasuringPAPeverytwohoursduringdayandeverythreehoursduringnightatbaseline,andafter100mg/dayand200mg/daymetoprolol.TMTwasdonebeforeeachuptitration.MetoprololuptitrationcausedaslightriseinPAP.WedidobserveanocturnalriseinPAPinthesepatients,butthisrisewasbluntedeventuallybyuptitrationofmetoprololtothetargetdose.PAProsesignificantlyafterTMTinallpatients.MetoprololuptitrationimprovedtheexercisetimeandexercisecapacitywithoutanysignificantriseinPAP.Thus,thenon-invasivemeasurementofPAPwiththisnoveldevice,indeedassisteddailymonitoringofhemodynamicchangesandmaythereforeguidetheadjustmentoftherapyinthesepatients.

Clinical development is complex and highly sensitive to globally-accepted quality, compliance, GCP and ethics standards. Although clinical development in India still relies heavily upon its cost-effectiveness to attract outside firms, there is increased awareness of qual-ity requirements. Both these first-in-man studies demonstrated new therapeutic and diagnostic applications for the patients with end stage diseases. The feat of such continuing trials in India, further assures the quality along with low cost benefits for the extra-ordinary proliferation of companies and research units in coming years. Moreover, India’s IT strength provides opportunities to capitalize on clini-cal data management much more quickly than clinical trials, where quality, compliance, drug safety, risk management and regulatory aspects dominate. While offering promising new clinical trial outsourcing opportunities, India still needs to address many challenges to meet global standards.

References1.Dr.NealMasia,directorofeconomicpolicyatPfizer,Inc.,writesinhttp://usinfo.state.gov/2.ACRO,January20063.Pfizer,April20064.A.T.Kearny,20055.http://www.outsourcing-pharma.com/news6.http://www.hcs.harvard.edu/~cyberlaw/wiki/index.php/Candice_Player:_Outsourcing_Clinical_Trials_to_India7.GeorgeIype.ClinicalTrials:WhyIndiaisirresistible.December22,2004;http://www.rediff.com8.MannheimerC,CamiciP,ChesterMR,etal.Theproblemofchronicrefractoryangina.EurHeartJ2002;23:355–70.9.McNabD,KhanSN,SharplesLD,etal.Anopenlabel,singlecenter,randomizedtrialofspinalcordstimulationvs.percutaneousmyocardiallaserrevascularization

inpatientswithrefractoryanginapectoris:theSPiRiTtrial.EurHeartJ2006:27:1048–53.10.NordrehaugJE,SalemM.Treatmentofchronicrefractoryanginapectoris—lightattheendofthetunnel?EurHeartJ2006;27:1007–9.11.BanaiS,BenMuhvarS,ParikhKH,AharonMedina,HorstSievert,SethA,TsehoriJ,PazY,SheinfeldA,KerenG.CoronarySinusreducerstentforthetreatmentof

chronicrefractoryanginapectoris.JAmCollCardiol2007;49:1783-9.12.BinanayC,CaliffRM,HasselbladV,O’ConnorCM,ShahMR,SopkoG,StevensonLW,FrancisGS,LeierCV,MillerLW;ESCAPEInvestigatorsandESCAPEStudyCoor-

dinators.Evaluationstudyofcongestiveheartfailureandpulmonaryarterycatheterizationeffectiveness:theESCAPEtrial.JAMA2005;294:1625-33.13.YuCM,WangL,ChauE,Hon-WahChanR,KongSL,TangMO,ChristensenJ,StadlerRWLau,MDCP.Intrathoracicimpedancemonitoringinpatientswithheart

failure.Correlationwithfluidstatusandfeasibilityofearlywarningprecedinghospitalization.Circulation.2005;112:841-8.14.AdamsonPB,MagalskiA,BraunschweigF,etal.Ongoingrightventricularhemodynamicsinheartfailure:clinicalvalueofmeasurementsderivedfromanim-

plantablemonitoringsystem.JAmCollCardiol2003;41:565–71.15.RozenmanY,SchwartzRS,ShahH,ParikhKH.WirelessacousticcommunicationwithaminiaturepressuresensorinthePulmonaryarteryfordiseasesurveillance

andtherapyofpatientswithcongestiveheartfailure.JAmCollCardiol2007;49:784-9.16.HjalmarsonA,GoldsteinS,etal.EffectsofControlledReleaseMetoprololontotalmortality,hospitalizations,andwellbeinginpatientswithheartfailure.The

MetoprololCR/XLrandomizedinterventiontrialincongestiveheartfailure(MERIT-HF).JAMA2000;283:1295-1302.

46

47SPONSORED by INTERNATIONAL ACADEMY of CARDIOVASCULAR SCIENCES

48

F U T U R E o F H E A R T H E A l T H

”Coach’s Corner”reprintedfromwebsiteofPacificVascularResearchFoundationwithpermissionoftheauthor

ManypeoplesaythatJohnMaddenwasborntocoach,andthatmaybetrue. In fact, John has enjoyed several successful careers, all centeringaroundtheworldofsports.Heisthewell-knownformerNFLfootballheadcoachwholedtheOaklandRaiderstovictoryinSuperBowlXI.Hehasau-thoredseveralbest-sellingbooks.Andhehasreceived13EmmyAwardsover20seasonsasapopularTVsportsbroadcaster.Currently,JohnMad-den isseenandheardweeklyonthe“SundayNightFootball” televisionprogram.Whenheisn’ttravelingthecountryfromassignmenttoassign-mentinhisMaddenCruiserbus(Johnrefusestofly),Johnresideswithhiswife,Virginia,intheSanFranciscoBayArea.Thecouplehastwosonsandseveralgrandchildren.

John Madden Speaks of the Madden Family’s Experience With Vascular Diseases“Whileinhermid-40s,mywife,Virginia,developedahealthconditionthat,frankly,atthetimewedidn’tknowanythingabout.Atfirstitwasmisdiag-nosed.Fortunately,weendedupgoingtotherightdoctorwhocorrectlyidentifiedtheproblem-ablockedcarotidartery, themainbloodvesselthatleadsthroughthenecktothebrain-adeadlyconditionifnottreated.Today,Virginia is fine and our family is better informed.We learned herconditionwasavasculardisease.Andwelearnedthatvasculardiseaseisasilentkiller.

Virginia’sconditionopenedoureyestovasculardiseases,aworldofseri-ousmedicalconditions affectingarteries andveins that, likeus,very fewpeople are familiar with. It’s true people have heard about heart attacks,

buttheymaynotknowwhatcausesthem,eventhoughaheartattackisusuallytheresultofaproblemwithanartery.Andpeoplehaveheardaboutstrokeswhichareoftencalled“brainattacks”becausetheyaffectthebrainthewayheartattacksaffecttheheart,throughaproblemorblockageinanartery.Thereagain,peoplemaynotconnecttheterm‘stroke”tovasculardisease,butthey’reoneandthesame.

Doyouknowthatalmostoneintwowomenoverage55diesfromvascularillness?Doyouknow,forexample,thateverythirtyseconds,someoneintheU.S.diesfromavasculardisease?And,perhapsmostimportantly,doyouknowthatvasculardiseaseisnotjustaconditionaffectingwomenorolderfolks,butisonethatcanaffectpeopleacrossallethnicgroupsandages?Yousee,notonlydidVirginiahaveherproblem,butourgrandson,Sam,hasavasculardisorder,similartotheconditionthatafflictsCaseyMartin,thetalentedgolferwhocan’twalkthecourseandneedsagolfcarttogetaround.Thanksagaintoexcellentcarefromoutstandingvascularspecialists,Sam’sprognosisisexcellent.

Thefactisvasculardiseasesarelife-threatening,potentialkillersthatcanstrikeanyoneatanyageatanytime.Cardio-vascular(heartandbloodvessel)diseaseistheleadingcauseofdeathintheUnitedStates-onemillionpeoplediefromitannually.Othervasculardiseases,excludingtheheart,accountforathirdofamilliondeathsandcripplehalfofthesurvivors.Thesediseasesincludestroke,abdominalaorticaneurysm,highbloodpressureandkidneyfailure,peripheralvascular(arterial)diseaseandvein(venous)disease.

But there are dedicated scientists and doctors who are trying to get to the bottom of these diseases.The non-profit PacificVascularResearchFoundation(PVRF)supports innovativeresearchintothecausesandtreatmentofvasculardiseases,educatesphysiciansandpatients,andconductsongoingpublicoutreachprogramstoalertthepublicaboutthisserioushealththreat.Infact,PVRF’sPresident,Dr.RonStoney,isthevascularsurgeonwhooperatedonmywife,Virginia,andmaywellhavesavedherlife.

PVRFsupportsascientificresearchfacility,thePacificVascularResearchLaboratory,locatedattheUniversityofCalifornia,SanFrancisco(UCSF),andawardgrantstomedicalacademicscientistsengagedinindependent,breakthroughresearchintolife-savingtreatmentsforvasculardisease.

TheMaddensaredoingwhatwecantohelppeoplelearnmoreaboutvasculardisorders.Ithinkit’slikepreparingateamforanyupcominggameorchallenge-themoreyouknowaboutyourpotentialopponent,thebetterpreparedyouareandthegreaterthelikelihoodyou’llbesuccessful.

JohnMaddenSpeaksoftheMaddenFamily’sExperienceWithVascularDiseases

Scientificprogram:GeneandcelltherapyGeneticaspectsof Cardiacdevelopment Experimentalmodels Cardiovasculardiseases Hypertension Atherosclerosis Coronaryarterydisease Arrhythmias Heartfailure

MENDEL SYMPOSIUM II

GENES AND THE HEARTfrOM bENch tO bEDSIDECastle Liblice, Czech Republic

September 24 – 27, 2008

SponsoredbytheJapanSectionoftheInternationalAcademyofCardiovascularSciencesJapanHeartFoundation

CANONInc.SIEMENS-AsahiMed.Tech.Ltd

SymposiumSecretariat: CongressBusinessTravelLtd. ZinaPecková Lidická43/66 CZ–15000Praha5 tel:+420224224646 fax:+420224942550 e-mail.peckova@cbttravel.cz

JointmeetingoftheJapanandEuropeanSectionsoftheInternationalAcademyofCardiovascularSciencesorganizedbytheCentreofCardiovascularResearch,InstituteofPhysiology,

AcademyofSciencesoftheCzechRepublic,Prague

LocalOrganizingCommittee:B.Ostadal(chairman),F.Kolar(scientificsecretary),P.Braveny,

J.Herget,J.Kunes,M.Novakova,J.Neckar,F.Papousek,I.Ostadalova

49

50

P E o P l E A N D P l A C E S

Dr. William Parmley

Editor’s note: As a continuing feature of CV NETWORK ONLINE, to follow are articles about Fellows of the Academy: Dr. William Parmley, Dr. Garrett Gross, Dr. Sergio Dalla-Volta, Dr. Bohdan Lewartowski and Dr. Adolfo J. deBold. We invite all Fellows to submit such information.

Dr.ParmleywasborninSaltLakeCity,Utahin1936.HiseducationincludedanABfromHarvardCollegein1957(summacumlaudeinphysics),andanMDdegreefromJohnsHopkinsUniversitySchoolofMedicine in1963. HeobtainedhisinternalmedicinetrainingontheOslerMedicalServiceatHop-kinsandthenspenttwoyearsattheNationalInstitutesofHealthinBethesda,Maryland,underthetutelageofEugeneBraunwaldandEdSonnenblick.Hiscardiologytrainingwascompletedat thePeterBentBrighamHospitalandHarvardunderthetutelageofRichardGorlinandEdSonnenblick.

Hethenservedfor4yearsasAssociateChiefofCardiologyatCedarsSinaiMedicalCenterinLosAngeles,California,underJeremySwan.In1974hebe-cameChiefofCardiologyattheUniversityofCaliforniaSanFranciscoSchoolofMedicine,apositionheheldfor23years.

HismanyeditorialpositionsincludedsectioneditorofCirculation;Ameri-canJournalofPhysiologyfrom1974-1976;SectionEditor,JournalofApplied

Physiology1974-1976;AssociateEditor,AmericanJournalofPhysiology1976-1978;AssociateEditorofCirculation1976-1983;Edi-torinChief,JournaloftheAmericanCollegeofCardiologyfrom1992to2002.

HishonorsincludePhiBetaKappafromHarvard;AlphaOmegaAlphafromJohnsHopkins;DistinguishedFellowandMaster,Ameri-canCollegeofCardiology;DistinguishedServiceAward,CollegiumAescullapium;BrighamYoungUniversity,AcademyofMedicine.

HeservedontheABIMsubspecialtyBoardonCardiovascularDiseasefrom1981to1987andasitschairmanfrom1985to1987.HeservedonseveralreviewboardsincludingtheVA,NIH,andFDA.HehasservedonmanyCommitteesoftheAmericanCollegeofCardiology,includingbeingitsPresidentfrom1985-1986.HewasaVisitingProfessorover40timesatvariousinstitutions.Heisanauthororcoauthorofabout350scientificpublications,twotextbooks,and125editorials.

“AsIreflectbackonmycareerincardiology,IamgratefulforthementorshipIreceivedfrommoreseniorcolleagueswhohelpedmeinmycareer.Ihavealsotriedtostimulateyoungercolleaguestohaveasuccessfulcareerinacademicmedicine.Thatperhapsisoneofthebestwaysforustopaybackourthanksforallwehavereceivedinourowncareers.Passingthetorchtothenextgenera-tionisclearlyourobligationandouropportunity.

Afterretirementin2003,Ihavecontinuedtohavetheopportunitytoteachandhelpothers,inthiscaseinAfrica.IhavetheadministrativeresponsibilityfortheaffairsofourChurch(ChurchofJesusChristofLatter-daySaints)in30countriesinsoutheastAfrica.Wehaveextensivemissionary,humanitarian,educational,literacy,employment,andwelfareprogramsinthesecountries.AIDSandMalariaaretwoofthemajormedicalproblemsweface,andweareengagedinpreventiveeducationalefforts.Wehavedugscoresofboreholestoprovidecleanwater,especiallyoutinthevillages.Althoughtheseactivitiesarequitedifferentfrommycareerincardiology;inmanywaystheyaremoresatisfying.Theneedhereissogreatthatthepersonalsatisfactionlevelisalsogreat.Weanticipateatotalof5yearsinthisassignmentinAfrica,whichhasnowbecomeoursecondhome.MywifeandIhavecertainlylearnedthatservicetoothersisthekeytopersonalhappiness.”

Dr. Bohdan Lewartowski DrBohdanLewartowski,MD.,PhDwasborninWarsaw(Poland)in1929.DuringtheSecondWorldWarheservedinPolishUndergroundResistanceForces(HomeArmy)andfromthe10thofAugust1944,tillthe3rdofMay1945,hewasaprisonerintheNaziGermanConcentrationCampSachsen-hausen.Afterthewar,hecamebacktoWarsawwhereheobtainedhisscientificdegrees(MD,PhD)andspecializationininternaldiseasesattheUniversityMedicalSchoolofWarsaw.Hereceivedhispostdoctoral training intheDepartmentofHumanPhysiologyoftheMedicalSchool inWarsawandintheDepartmentofExperimentalCardiology(headedbyProf.DirkDurrer)oftheUniversityofAmsterdam.In1967,heobtainedadegreeofthehabilitateddoctor(docent)andmovedtotheMedicalCenterofPostgraduateEducation(MCPE)inWarsawwhereheorganisedtheDepartmentofClinicalPhysiology(headedbyhimuntilhisretirementin1999).From1972until1982hewasaDeputyDirectorandDirectorofMCPE,whichisanacademicinstitutionheadingthenation-widesystemandprovidingfacilitiesforspecializationandcontinuingpostgraduateeducationofPolishmedicaldoctors.In1978,heobtainedthetitleofProfessorinMedicalSciences.During1988/89,DrLewartowskiwastheVisitingScientistintheLaboratoryofCardiovascularSciences(headedby

51

P E o P l E A N D P l A C E S

Sergio Dalla-Volta

DrEdwardG.Lakatta)oftheInstituteofAgeingoftheNationalInstitutesofHealthandintheLaboratoriesofCardiovascularSci-ences(headedbyDrGlennA.Langer)oftheUniversityofCalifornia,LosAngeles.Since1993,Dr.LewartowskiisacorrepondingmemberofthePolishAcademyofSciences.During1998/2001,hehasbeenachairmanoftheScientificBoardoftheInstituteofExperimentalandClinicalMedicineofthePolishAcademyofScinces.AtpresentheisamemberofthisBoardandamemberandachairmanofaworkinggroupforprogrammingofresearchoftheScientificBoardoftheNationalInstituteofCardiologyinWarsaw.HeisamemberofthePolishCardiologicalSociety,EuropeanCardiologicalSociety,InternationalSocietyforHeartResearchandahonorarymemberofthePolishPhysiologicalSociety.

DrLewartowskiisanauthororco-authorof90originalresearchpapers,11reviewsand12chaptersinhandbooksandmonogra-phies.Hisearlyinterestconcernederythropoietin(EPO)(directproofthatEPOismainlyproducedbythekidneyandinitialdescrip-tionofitschemicalstructurepublishedinBloodandinJournalofLaboratoryandClinicalMedicinein1963/4).Later(andatpresent)hewasmainlyinterestedinthemechanismofexcitation-contractioncoupling(ECC)andcalciumhandlingincardiacmyocytesun-derphysiologicalandpathologicalconditions(infarction,heartfailure).Themainresultsconcerntheroleofsarcoplasmicreticulum(SR)inECCandanalysisoffunctionofmyocyteswithcompromisedfunctionoftheSR.

WhathasbeendescribedabovelookslikeastandardscientificcarreerintheWesternWorld.However,organizingmedicaleduca-tionandresearchinruined,extremelypoorandgovernedbycommunists,post-warPolandwasnotaneasytaskandanysignificantcontributionbythePolishresearcherstotheinternationalsciencerequiredovercomingofincredibledifficultieswhichconsumedmuchoftimeandeffort.Nevertheless,thiseffortwassuccessfuland,besideshardworkandbrains,successdependedverymuchonthesupportbywesterncolleguesandsocietiesliketheEuropeanSectionofISHR.

DrLewartowskisharestheopinionofDrVanhouttethat“thefutureinbiologicalandmedicalresearchlieswiththeintegrationoftheexplosionofknowledgeatthemolecularandcellularlevelwiththeconventionaldisciplineslikephysiologyandpharmacol-ogy”aswellaswiththeclinicalresearch.Inordertoputitinpractice,everyyearDrLewartowskiisaninitiatorandco-organizerofthepermanentsymposiasponsoredbyPolishAcademyofSciencesandPolishCardiologicalSocietyintegratingbasicandclinicalresearch.

SergioDalla-VoltawasbornDecember30th1928.Hepursuedclassicalstudiesinhighschool;graduatedinMedicine,UniversityofPadova(Padua),Italy1952;Fellow in Cardiology, University of Padova 1954; Assistant Etranger, HopitalBoucicaultParis,France1954-55;ResearchFellow,KarolinskaInstitutet(MedicalSchool),Stockholm,Sweden1955-56;Investigador(ResearchFellow)InstitutodeCardiologiadeMexico1956-58;AssistantProfessorofMedicine(Cardiology)UniversityofPadova1959-62;ResearchFellow,DptofPhysiology,UniversityofMississippiinJackson,USA,1962;AssociateProfessorCardiology,UniversityofPadova1962-64;AssociateProfessorofCardiology,ColumbiaUniversity,NewYork,NY,USA,1965-68;ProfessorofCardiology,UniversityofPadova,1969-75;Associate Professor of Pediatric Cardiology, Harvard University, Boston, MA,USA,1975-78;ProfessorofCardiologyandHeadofDptofCardiology,UniversityofPadova1979-2003;ProfessorofCardiology,UniversityofSpalato/Split,Croatia1998-2006;andDistinguishedProfessorofCardiology,UniversityofPadova,since2003.

HehasbeenHoward-GilmanVisitingScientist,CornellUniversity,NewYork,NY,USA,November2001;Memberoftwelveinter-nationalSocietiesofCardiology,amongthemthefellowshipoftheAHAandSilverMedalofAHA,2004;RecipientoftheHans-PeterKrayenbuhlAwardoftheInternationalAcademyofCardiology,LosAngeles,CA,USA,2003;FellowoftheInternationalAcademyofCardiovascularSciences,Winnipeg,MA,Canada2003;Member-electoftheEmaxandPVAClub,Osaka,Japan,2006.

AuthororCo-Authorof500scientificpapers,withimpactfactorofmorethan550(manypaperspublishedinNewEnglandJour-nalofMedicine,Circulation,Cardiology,ArchivesdesMaladiesduCoeur,etc,);AuthorandEditorofsixbooksofCardiologyandEditorinChiefoftheinternational“HotTopicsinCardiology”;MemberoftheScientificBoardofinternationaljournals“Cardiology”,BaselSwitzerland,from2204and“ArchivosdelInstitutodeCardiologiadeMexico”,Mexico,(1998-2004).

Participationofseveral internationalcongressofCardiology,amongthemtheAHA,ESCandother EuropeanandAmericanmeetings.Hisfieldsofinvestigationshavebeenduringtheyears:electrocardiographyofcongenitalheartdisease;physiologyofvallarheartdiseaseandheartfailure;ventricularfunction;spiralCTscanandMRI,inthelastfiveyears,incongenitalandischemicdiseaseandheartfailure.ClinicalCardiologyhasbeenhischieffieldofinterest

MarriedtoSavinasince1959,twodaughters(AlessandraandMaurizia)professionalmusicperformersinParis.Non-medicalin-terests:music(pianoplayer),foreignlanguage(speakstenforeignlanguages),historyandphilosophy.

AftermanyyearsteachingCardiology,doingresearchandcaringpatients,Dr.DallaVoltawantstoassureyoungColleaguesthatMedicinecanbethemostnobleprofessionactivity,providedthatyouneverforgettoshow(andfeel)sympathyforthepatientsandtrytopreparedoctorslovingthismission.

52

P E o P l E A N D P l A C E S

Dr. Garrett GrossDr.GrossgraduatedwithhisB.S. inPharmacy in1965andhisPh.D. inPharmacologyfromtheUniversityofUtahin1971.Hesubsequentlyperformedtwopostdoctoralfel-lowships,oneattheWarner-LambertResearchInstituteunderthedirectionofDr.Mar-tinWinburyandthesecondattheUniversityofWashingtonwithDr.EricO.Feigl.BothoftheseimminentscholarsstimulatedDr.Gross’sinterstinthecontrolofcoronarybloodflowandinpharmacologicalmechanismsforreducinginjurytotheischemicmyocar-dium,anarea inwhichhehasbeenactiveforthepast33years.Dr.Gross joinedthefaculty in Pharmacology andToxicology at the Medical College ofWisconsin in 1973androsetotherankofProfessorin1980.HehasbeenanactiveandcontinuoslyNIH-fundedinvestigatorattheMedicalCollegeofWisconsinforthepast33years.Hismajorareaofresearchconcernsmechanismsbywhichendogenoussubstancesreleasedbytheheartcaneitherinjureorprotecttheheartduringischemiaand/orreperfusionandhehasbeenaleaderinunderstandingmechanismsbywhichtheheartadaptsitselftoan ischemic insult, a phenomenon termed ischemic preconditioning (IPC). In this re-gard,Dr.Gross’slaboratorywasthefirsttodemonstratethatanATP-sensitivepotassiumchannel(KATPchannel)wasacriticaltriggerandeffectorofIPC.Thisbreakthroughhasbeenrepeatedbyanumberofinvestigatorsandhasstoodthetestoftimeasoneofthekeycomponentsofthisremarkablecardioprotectivephenomenon.Thiscontinuestobeanactiveareaofinvestigationinhislaboratoryanditishopedthatapharmacological

activatorofthischannelwillbedevelopedthatissafeandefficaciousandwillbeabletomimicthepotentcardioprotectiveproper-tiesofIPC.Insupportofthisconcept,apotentopenerofthischannel,nicorandil,hasbeenonthemarketinJapanandEuropeforthetreatmentofstableanginasincethe1990sandDr.Gross’slaboratorydidmuchofthepioneeringworkonthedevelopmentofthiscompoundintheearly1980’s.Morerecently,thiswasthefirstdrug(IONATrial)todemonstratealong-lastingcardioprotectiveeffectinpatientswithanginainawell-controledclinicaltrial.

Alongthesesamelines,Dr.Gross’swasalsothefirstlaboratorytoidentifyaroleforendogenousopioidsinmediatingthecar-dioprotectiveeffectsofIPCinseveralanimalmodelsandthatexogenousopioidssuchasmorphinealsopossessedpotentcardio-protectivepropertiesandthattheseeffectsweremediatedviatheactionofopioidsonbothsarcolemmalandmitochondrialKATPchannels..Thisfindinghasalsoledinvestigatorsinmanyotherlaboratoriestostudytheroleandmechanismsresponsibleforthesepotentcardioprotectivepropertiesofopioids.

ThesedatasuggestthatitmaybepossibletousenovelopioidcompoundswhichlackCNSeffectsascardioprotectiveagentsinthefuture.Dr.Gross’slaboratoryalsowasthefirsttodemonstratethatthecardioprotectiveeffectofchronicmorphinetreatmentpersistedfor120hourswhichsuggeststhatthistypeofdrugmightbeusedprophylacticallypriortocardiacsurgerytoputtheheartinaprotectedstateadayortwopriortoandevenafteropenheartsurgery.

InhismostrecentworkinwhichhewasawardedtheprestigiousNIHMERITAward,Dr.GrosshasuncoveredanewendogenouscardioprotectivepathwaywhichappearstomediatedbyCYP450isoformsintheheartandthataproductproducedbyCYP-hydroxy-lases,20-HETE,producesmyocardialinjuryandthatblockingthesynthesisoforthereceptorforthiscompoundproducesamarkedreductionininfarctsizeindoghearts.Thesedatamayleadtoanewtherapeutictargetfordrugdevelopment.Overthepast34yearsGr.Gross’sworkhasresultedinapproximately380full-lengthpeerreviewedjournalarticlesandreviewsand28bookchapters.DrGrosshasbeenaninvitedspeakeratmorethan70universitiesandpharmaceuticalandbiotechnologycompanies.Hehasbeenaconsultantatover20pharmaceuticalcompaniesandhasmentored15Ph.D.studentsand10postdoctoralfellowsallofwhomwerefundedbyfellowshipsfromtheAmericanHeartAssociationandthePharmaceuticalManufacturersAssociationFoundationofAmerica.Dr.Grossisaveryactivereviewerforallthetop-notchcardiovascularjournalsincludingCirculationResearch,CardiovascularResearchandJMCCandcurrentlyservesontheeditorialboardof8journalsandhasbeenanAssociateEditoroftheAmericanJournalofPhysiology(HeartandCirculatory)forthepast7years.DrGrossisaFellowoftheAmericanHeartAssociation,aFoundingFellowoftheInternationalSo-cietyofHeartResearchandisamemberoftheAmericanSocietyofPharmacologyandExperimentalTherapeuticsandtheAmericanPhysiologicalSociety.HeservedasmemberoftheNIHPharmacologyStudySectionfor4yearsandcontinuestobeanactiveadhocre-viewerfortheNIHonPPGsandRO1srelatedtothemyocardialischemiafield.Recently,Dr.GrosshasreceivedanumberofhonorsfromvarioussocietieswhichincludetheJohnFoersterDistinguishedLecture(2005)awardedbytheInstituteofCardiovascularSciencesinWinnipeg,theKeithReimerDistinguishedLecture(2006)awardedbytheInternationalSocietyofHeartResearch,TheDistinguishedScientistAward(2006)awardedbytheAmericanHeartAssociationandthefirstBenedictLucchesiDistinguishedLectureAward(2007)sponsoredbytheAmericanSocietyofPharmacologyandExperimentalTherapeutics.

Dr.Grossfeelsveryfortunatetohavebeenabletohavebeenanactiveparticipantinagoldenareaofresearchinwhichmanyadvanceshavemadeindiscoveringwaysinwhichtheheartcanprotectitselfbyreleasingendogenoussubstances,theprecondi-tioningphenomenon,andthemorerecentadvanceswithgenetherapyandcardiacregeneration,severalareasthatarestillintheirinfancybutshowgreatpromiseforfuturetherapeuticadvances.Heisconvincedthatthebestisyettocome.

53

P E o P l E A N D P l A C E S

Thediscoveryofanendocrinelinkbetweentheheartandthekidneyshasitsbasisontheelectronmicroscopicfindingthatthestri-atedmusclecellsofthecardiacatriainmammalsaredifferentiatedasbothcontractileandasendocrinecells.Thedemonstrationofthefacttheatriaproducepolypeptideshormones,wasestablishedwiththediscoveryofAtrialNatriureticFacto(ANF).ANFisthefoundermemberoftheANFfamilyofnatriureticpeptidesthathaveveryimportantfunctionsinthemodulationofvolumeregula-tionandcardiovasculargrowth.Theunfoldingofthisdiscovery,asmanyothers,hasagreatdealofhumancontentthatoftenislostinourtechnicalwritings.Hopefully,studentsandinvestigatorsjuststartingoutwillfindinspiration(andconsolation)intheinformalaccountoftheANFdiscoverythatfollows.

WhenIarrivedtothePathologyDepartmentatQueen’sUniversityin1968,freshfromobtainingaClinicalBiochemistrydegreefromtheFacultyofChemicalSciences inCordoba,Argentina,mysupervisor,SergioBencosme,was interested inthefunctionalmorphologyoftheendocrinepancreas.Asanaside,Bencosmehadtakenupthequestionofsecretory-likedifferentiationsfoundinatrialcardiocytes,afactknownsincetheearlydaysofelectronmicroscopyandmanifestingitselfmostnotablybythepresenceofstoragegranulesknownas“specificatrialgranules”whosefunctionwasamystery.He,andmanyothernotablesincludingGeorgePaladethenattheRockefellerInstituteinNewYork,couldnotadvancepasttheirmorphologicaldescription.Othersconsideredtheatrialgranulesasanevolutionaryremnant.Ifoundmyselfunabletoignoreasecretoryphenotypemakingitapersonalchallengetodemonstratethatacombinationofmorphologicalandbiochemicaltechniqueswouldunravelthefunctionalnatureoftheatrialgranules.PerhapsIwasinfluencedbythegreatendocrineworkofArgentineanNobelPrizelaureateB.Houssay,whoisaniconofacademicexcellenceforanyoneborninArgentina.AndsotheANFsagabegan.Itwouldtake12yearsofinvestigations(withonlyonemonthofholidays)beforethenatureandfunctionofthedualsecretory-contractilenatureofatrialcardiocyteswouldbecomeapparent(Forareviewsee(8)).

Ibeganmystudiesonthepossiblesecretoryfunctionoftheheartbytryingtoisolatetheatrialgranulesarmedwiththepaperspro-ducedbyChristianDeDuveonisolationofsubcellularorganellesandthepaperbyBlaschoonisolationofadrenalchromaffingranules.Therewasliteraturedatathathintedthattheatrialgranuleswereastoragesiteforcatecholaminesbutacarefulreadoftheliteraturewasnotveryconvincinginthatsense.Atanyrate,thiswasahypothesistotestandthisturnedintomyM.Sc.project.Theisolationofthegranuleswasparticularlydifficultbecausetheywereimmersedinthegreattangleofmyofibrilsandconnectivetissuethatandho-mogenateoftheheartmuscle.Therefore,ittookmetwoyearsandquiteafew20-60-ratultracentrifugationrunstoobtainthepurifiedgranules.Biggeranimals(cowheartsweresuggestedmanytimes)wereofnousebecausethereisaninverserelationshipbetweenthenumberofatrialgranulesfoundinatrialcardiocytesandthesizeoftheanimal.SinceIhadnobiochemicalmarkerforthegranules,themosttediousjobthatIfoundwastolookateveryfractionbyelectronmicroscopytoseewherethegranuleswentwiththemanyvaria-tionstotheisolationtechnique(4).TothispurposeIdevelopedanelectronmicroscopyembeddingtechniquetodealwithsubcellularfractions.Aftermanytrials,Iwasabletoisolateandpurifythegranulesandprovedbybiochemicalmeansthatthegranulesdidnotcontaincatecholamines(3).ThiswassuccessinonesensebutitalsomeantthatIhadnohypothesislefttotest.

Isetouttodeveloptechniquestospecificallyvisualizetheatrialgranulesatthelightmicroscopiclevel.Ireasonedthatwithsuchtechnique,onecouldcorrelatethedistributionofthegranuleswithhistochemicalreactionproducts.Ithelpedmeenormouslythefactthat,byinterventionofDivineProvidenceIamsure,IhadmanagedtotwiceendupworkingasaresearchassistantinPathologyDepartmentsduringmyundergraduateyearswhereIlearnedmanyhistologicaltechniques.

Idevelopedthefirstmethodtospecificallystainthegranulesatthemicroscopiclevelusinglead-haematoxylinfollowingapaperthatmywifehadfoundtostaincellsinthepituitarygland(6).Thestainaldehyde-fuchsinalsoprovidedavisualizationofthegran-ules.WiththesetechniquesathandIcarriedoutawholebatteryofhistochemicalinvestigations(10).Anumberofcytochemicalpropertiesoftheatrialgranuleswerethusuncovered.TheseinvestigationswouldlaterhelpmeisolateandpurifyANF.Forexample,thepoorstainabilityoftheatrialgranulesfollowingBouin’sfixative(afixativethatcontainsaceticacid)suggestedthatthegranules’contentwassolubleinaceticacid.Indeed,ANFandBNParehighlysolubleinaceticacidanditisthebasisforextractantsofthesehormones.Altogether,thesecytochemicalstudiesplustheonesthatIcarriedoutlateronasanindependentinvestigator,providedevidencethattheatrialgranulesstoredarandomcoiled,basicpolypeptidecontainingcystineandtryptophan.Autoradiographicstudieswithradiolabelledleucineshowedthatthegranulescontenthadhighturnoverinamannersimilartosecretorycells(5).AllofthesepropertieswerelaterconfirmedbybiochemicalmeansfollowingtheisolationofANF.

Bythistime(1973)IhadfinishedmyPh.D.thesis,myfirstofourfivechildrenwasbornandwepurchasedourfirsthome.IwasthenofferedapositiontocontinueatQueen’s,movingtothePathologyLaboratoryatHotelDieuHospital,anteachinghospitalassociatedwithQueen’sUniversity,asanAssistantProfessorofPathology.IwastohelpdevelopresearchatthishospitalanditwasaleapoffaithoftheChairmanofPathology,NathanKaufman,toputmethereandforwhichIamverygrateful.Yearslater,afterthediscoveryofANF,NateremindedmethatduringmythesisdefenseIhadguessedthattheatrialgranules,becauseoftheirlocation,mightbeinvolvedinsensingchangesinvolumeload.Ihadforgottenthat.

A Historical Account of the Discovery of ANF and of the Endocrine Function of the Heart

InvitedContributionbyAdolfoJ.deBold,Ottawa,Canadain“MilestonesinNephrology”,JournaloftheAmericanSocietyofNephrology2001Feb;12(2):403-9.(Reprintedwothpermissionofthepublisherandauthor)

54

Aservice-orientedhospital,HotelDieuwasnotthemostpropitiousplaceforayoungscientist.Iwasgivenanoffice,halfalabbench,anoldincubatorandamicroscopetostart.Minewasawindowlessofficeinthebasement,acrossfromtheautopsyroom.Thesmellofformalinwasaconstantcompanion.Lookingback,thisisolationhelpedmeincontinuingwiththegoalofestablishingtheendocrinefunctionoftheheart.

MyfirstgrantapplicationasanindependentresearchertotheMedicalResearchCouncilwasonthestatusofthecardiacadren-ergicinnervationinheartfailure.ThisisthereasonwhyIhaveapublicationonanewmodelforinducingheartfailureintheguineapig.Thisthemewasreallyasafetyvalveincasetheatrialgranulebusinessdidnotworkout.Asitturnedout,thereverseoccurred.

IsecuredfundingfromHeartandStrokeFoundationforcontinuationofmygraduatestudiesonatrialgranulesbutIknewthattheirpatiencewaswearingthinonthistheme.IalsocollaboratedwithJackKraicerofthePhysiologyDepartmentatQueen’sonthemorphologyoftheparsintermediaofthepituitarygland.Mywife,whohadstartedworkingwithme,andIwereabletodefineasystemofcanaliculiinthisavascularglandusingextracellularspacemarkers.Intheprocess,wediscoveredanewcelltypeforwhichmywifedevelopedasilverimpregnationtechniquetodemonstrateitatthelightmicroscopiclevel(11).

Whilethenatureofthegranule’scontentappearedreasonablywelldefinedbythehistochemicalstudies,therewasstillnohintastotheirfunction.However,wehadnowsomethingthatwasnotpreviouslyavailable.Namely,astainthatcoulddemonstratethegranulesatthelightmicroscopiclevelandtherefore,wecoulddevelopaquantitationproceduretoassesschangesinthenumberofgranulesafterdifferentexperimentalproceduresusingthelightmicroscope.Thedifferencebetweenamorphometricprocedureatthelightmicroscopiclevelandproceduresattheelectronmicroscopiclevelisthatthesamplesizeismademuchlargeratthelightmicroscopiclevel.Thiswasparticularlyimportantforquantitationofatrialgranulesbecauseoftheirirregulardistributionintheatriaandevenwithinthesamecell.Wedevelopedamorphometricprocedureusingthelightmicroscopicstainingdevelopedduringthehistochemicalstudiesusingembeddinginplastictoobtainuniformlythinsectionsofatrialtissue.Suchprocedurewasthentesteditstatistically(1)andwaslaterusedtotestclaimsthatpreviousresearchershadmaderegardingtheabilityofcertainexperimentalmanoeuvrestochangethenumberofgranules.Thereweremanysuchclaims,andcounterclaimsandItestedmost.Ifoundun-equivocal,statisticallysignificantchangesinthenumberofgranulesaftersomeproceduresknowntoalterwaterandelectrolytebalanceaspreviouslysuggestedinelectronmicroscopicstudiesbyBencosmeandbyP-YHatt(2).Thedifferenceaffordedbythelightmicroscopicquantitationofgranuleswasthatonecouldbeconfidentthatthechangeswerenottheresultofbiasedsamplingandtherefore,onecouldreallycommitone’stimetofurtherthestudywithoutthefeelingofbeingwasteful.

Thehypothesisthusdevelopedwasthattheatriaproducedandstoredapolypeptidethathelpedregulatewaterandelectrolytebalancegiventhenatureofthecontentsrevealedbyhistochemistryandthechangesinthenumberofgranulesrevealedbythemor-phometrictechniqueafterproceduresknowntoalterwaterandelectrolytebalance.Ithoughtthattheeasiestwayforacardiachor-monetomodifywaterandelectrolytebalancewasbytargetingtheprominentroleofthekidneysinmaintainingwaterandelectrolytehomeostasis.Besides,theatriawereinanidealspottosensechangesinvenousreturn.Lookingforabioassayfordiureticsubstances,IfoundthatHaraldSonnenbergoftheDepartmentofPhysiologyattheUniversityofToronto,whomIdidnotknow,wassearchingforanatriuretichormoneandhadaratbioassayforthatpurpose.Iphonedhimandrelatedtohimmyquestandhypothesis.

Sincetheexistenceofatrialgranuleswasnotwidelyknown,evenbymorphologists,itwasspeciallygenerousofHaraldtoacceptmyinvitation“totakeashotinthedark”.HeinvitedmetogiveaseminarinTorontoandweagreedthatIwouldsendhimatrialextracts.Thefirstextractswere,infact,atrialgranuleextractsthatcontainedahighconcentrationofpotassiumchlorideduetothecompositionofthesolutionsusedforisolation.Thispromptlykilledthebioassayratsuponinjection.IthenmoreorlesssupplicatedHaraldtobepatientandtopleasetryjustcrudeextractsofatria,andofventriclesasacontrol,preparedinsimplephosphate-bufferedsaline.

Someweekswentbyandthen,tomyunbelievingears,Haraldphonedmesayingthattheinjectionofatrialextractsproducedadiuresisandnatriuresisthatwasimmediateandincrediblystrong,justlikefurosemide.Alwaysaworrier,Istartedtowonderaboutwhatcontaminationwouldproducesucheffects.Werepeatedtheexperimentsmanytimesinmylabandtheresultswereequallyimpressive.Also,proteinasedestroyedtheactivity,whichwentrightalongwiththehypothesisthattheatrialgranulescontainedapolypeptidehormone.

ThepotentialimportanceofthefindingpromptedustosendourfindingstotheprestigiousJournalofClinicalInvestigation.ItwasterselyrejectedinaletterdatedMay28,1980,giventhatthefinding“wasnotthoughttobesuitableforpublication…”BecauseIhaddisclosedthefindingspreviouslyatameetingoftheCanadianSocietyforClinicalInvestigationmeeting,wede-cidedtopublishthefindingsasquicklyaspossible.ForthatreasonitwassenttoLifeScienceswhereitwasquicklyacceptedandpublishedin1981(7).By1983thefirstpublicationsonANFfromothercentersstartedtoappear.Notasinglelabfailedtoconfirmourfindingsgiventhatthenatriureticanddiureticactivitiesofatrialextractsweresopowerfulthatnothingshortofadeadbioassayratcouldstopsuchaction.

ThearticleinLifeSciencesspurredaflurryofactivityandwentontobecomeaCitationClassicasqualifiedbytheInstituteofScientificInformation.Needlesstosaythattheresearchersinthehypertensionfieldwerereadytoexploitthefindingofahormonethatwasdiuretic,natriureticandhypotensive.Itisofinteresttonotethedifferentreactionsbydifferentgroupsofinvestigators.Someinvitedmetopresentmyworkandrecognizedthediscoveryinonewayoranother.OthersembarkedinafuriousresearchpaceonANFandinapublicrelationscampaign;someincludingtelevisedspeeches,toconvincetheworldthattheyhaddiscoveredANF.Itwasnevercleartomehowtheyplanedtoclaimadiscoveryforwhichwehadanindisputablethree-yearprecedenceinpub-lishing.Iguessthatadiscoverythatcamefromabasementofanobscurehospitalwasdeemedeasypray.Atanyrate,itlooksthatalldiscoveriesfollowthesamelibretto.TheJapaneseauthors,althoughtheyalsoinventedanewname(ANP)andthusdisregardedaninternationalnomenclatureagreementreachedinNewYorkandstillexisting,didtrulycontributetothenatriureticpeptidefieldbydemonstratingtheoccurrenceofBNPandCNPbasedontheANFdiscovery.

55

H T T P : / / W W W . I A C S C o N G R E S S 2 0 0 9 . o R G

PROGRESS IN CARDIOVASCULAR HEALTH AND DISEASE

Ourlaboratoryalsowasthefirsttoisolate,purifyandsequenceANF(9,12,13).Thewaythatthiswasaccomplishedwasnotlessheroicthanthe12yearsofworkprecedingtheANFdiscovery.ItwasveryopportuneformetofindintheUSacompanythatpro-videduswithratatria.Intotal,around200,000ratatriawereused.ItwasalsofortunatethatthetechniquesforisolationofpeptidesbyHPLCwerecomingintouse.TheonlyproblemwasthatIdidnothaveanHPLC.TheClinicalLaboratoryinourhospital,however,hadjustpurchasedonetodopatient’stheophyllineinserum.Luckily,Iwasputinchargeofthattechniquesoitwasnotverynotice-ablethatIcameduringthenighttore-configurethemachineandfitteditwithachromatographiccolumntopurifypeptides.

ThreepeopleessentiallydidtheisolationandpurificationofANFinmylaboratory:mywifewouldextracttheatria,Iwouldpurifytheextractsandatechnicianwouldtestthedifferentfractionsobtainedduringpurificationinthebioassayrat.Nootherresourceorpersonwasinvolvedinthiseffort.

Oncethepeptidewaspurifiedtochemicalhomogeneity,mynextproblemwastosequenceit.TheonlypersonatQueen’sin-volvedinaminoacidanalysisandproteinsequencingwasGeoffFlynntowhomIofferedcollaboration.Wehadvariousfalsestarsduetoantiquatedequipment,bothintheaminoacidanalysisandinthesequenceresults.TheproblemswereresolvedwhenweobtainedfundingfromthegovernmentofOntariotopurchaseagasphasesequencerandthuswewerethefirstlaboratorytopro-duceasequencein1983(13).TheJapaneseworkersproducedthehumansequencethefollowingyear.

Studentsoftenaskforadvicetosucceedinresearchandmystandardansweris:“Haveadream,don’tthinksmall,workhardandbelieveinyourself”Ifinishthisinmymindwith:“..andpraythatyouareright”

Reference list1. de Bold, A.J. Morphometric assessment of granulation in rat atrial cardio-

cytes:effectofage.J.Mol.Cell.Cardiol.10:717-724,1978.2. deBold,A.J.Heartatriagranularityeffectsofchanges inwater-electrolyte

balance.Proc.Soc.Exp.Biol.Med.161:508-511,1979.3. deBold,A.J.andS.A.Bencosme.Studieson the relationshipbetweenthe

catecholaminedistributionintheatriumandthespecificgranulespresentinatrialmusclecells:2.Studiesonthesedimentationpatternofatrialnor-adrenalineandadrenaline.Cardiovasc.Res.7:364-369,1973b.

4. deBold,A.J.andS.A.Bencosme.Studieson the relationshipbetweenthecatecholaminedistributionintheatriumandthespecificgranulespresentinatrialmusclecells:1.Isolationofapurifiedspecificgranulesubfraction.Cardiovasc.Res.7:351-363,1973a.

5. de Bold, A.J. and S.A. Bencosme. Autoradiographic analysis of label distri-bution in mammalian atrial and ventricular cardiocytes after exposure totritiated leucine. In: Recent Advances in Studies on Cardiac Structure andMetabolism.TheCardiacSarcoplasm,editedbyP.-E.RoyandP.Harris.Balti-more:UniversityParkPress,1975,p.129-138.

6. deBold,A.J.andS.A.Bencosme.Selectivelightmicroscopicdemonstrationofthespecificgranulationoftheratatrialmyocardiumbylead-hematoxylin-tartrazine.StainTechnol.50:203-205,1975.

7. deBold,A.J.,H.B.Borenstein,A.T.Veress,andH.Sonnenberg.A rapidandpotentnatriureticresponsetointravenousinjectionofatrialmyocardialex-tractsinrats.LifeSci.28:89-94,1981.

8. deBold,A.J.andB.G.Bruneau.NatriureticPeptides.In:HandbookofPhysiol-ogy,Section7:TheEndocrineSystem,VolumeIII:EndocrineRegulationofWa-terandElectrolyteBalance,editedbyJ.C.S.FrayandM.H.Goodman.AmericanPhysiologicalSocietybyOxfordUniversityPress,2000,2000,p.377-409.

9. deBold,A.J.andT.G.Flynn.CardionatrinI-anovelheartpeptidewithpotentdiureticandnatriureticproperties.LifeSci.33:297-302,1983.

10.deBold,A.J.,J.J.Raymond,andS.A.Bencosme.Atrialspecificgranulesoftheratheart:lightmicroscopicstainingandhistochemicalreactions.JournalofHistochemistry&Cytochemistry26:1094-1102,1978.

11.deBold,M.L.,A.J.deBold,andJ.Kraicer.DemonstrationofStellateCellsoftheParsIntermediaofthePituitaryGlandUsingaNewSilverImpregnationTechnique.StainTechnology59:49-52,1984.

12.Flynn,T.G.,P.L.Davies,B.P.Kennedy,M.L.deBold,andA.J.deBold.Alignmentof rat cardionatrin sequences with the preprocardionatrin sequence fromcomplementaryDNA.Science228:323-325,1985.

13.Flynn,T.G.,M.L.deBold,andA.J.deBold.Theaminoacidsequenceofanatrialpeptidewithpotentdiureticandnatriureticproperties.Biochem.Bio-phys.Res.Commun.117:859-865,1983.

56

State-of-the-brain-and-heart: Homo Obesus BulgaricusBulgaria, a country in the epicenter of global healthquake

P E o P l E A N D P l A C E S

GeorgeN.Chaldakov,RouzhaPancheva,AntonB.Tonchev,VesselkaNikolova,StoyanV.Stoev,GoranaRanĉiĉ,AlexandarPetrovic,VesselaZlateva,DimitarKostov,ZhanetaGeorgieva,andPeterI.Ghenev–Varna,Bulbaria

When someone declared that life is an evil, Diogenes said: Not life itself, but living ill.

Today,itisincreasinglyknownthatadipose(fat)tissueisaveryactiveendocrineorganproducingmorethan100typesofbiologicallyactiveproteins,collectivelydesignatedadipokines(1-3).Adipotopography(fatmapping)isanemergingsub-fieldofadipobiology,investigatingthelocalizationandamountofadiposetissueinthehuman’sbody(4,alsoDrJimmyBell-personalcommunication,seebelow).

The present state-of-the-brain-and-heart view deals with feeding behavior, food culture, and obesity-related cardio-metabolicdiseases,themajorrecentenemiesofhumanbrainandhearthealth,especiallytargetingBulgarians.

WerecentlyhaveintroducedthetermHomo obesus(Mantheobese/fat)(3,5)asanovelfeatureofH. sapiens, H. informati-cus,H. globalus.

H. obesusderivesfromadysbalancebetweengenes,lifestyle/qualityoflife(QOL),andenvironment.Mutationsingenesand their on-off switching are now well-accepted as a basic concept of the evolutionary theory of Charles Darwin, also

57

neo-Darvinismofmodernsyhthesis.Suchagameofmutationsensuressurvivalandreproductionofspeciesthroughoutextremely difficult periods of time, including famine.To be ready to cope the next shortage of food, our progenitors ofhunter-gatherer’seraofH.ergasterandH.erectus,inrelaxingperiodsoftheirlife,havehedonisticallyeatenadlibitum,asanadaptationreaction,thatis,accumulatingcalories,whichwillbeusedduringthenextfamine.Inthisera,tobecomefattermenttobettercopesuchahungriness.However,thegenesthatgovereneda“thrifty’feedingbehaviorduringfamine-feastcycling,inthelast20-30years,whenfoodavailabiltyisflourished,predisposetooverweightandobesity.Briefly,thesesamethriftygenesbecameobesigenicintheyearsofmacdonalizationofourfoodculture.Todays’smantakesasurplusamountoffood,believinginhisevolutonarylessonsof“thefatter,thebetter”.Sincetheanticipatedfaminedoesnotoccurandbecauseoflessphysicalactivity,thestoredcaloriesarenotexpended,andthusaccumulatedinfattissue,henceH. obesus.Ineffect,ac-cumulationoffatisanac-cultural(transcultural)phenomenon,includingafast-food/macdonalizedglobalisationofourfoodculture(see6-8forYukioYamori’sdataofJapaneseemigratedtoBrazil-theylive10yearlessthanthoseremaininginJapan).Atabasicresearchlevel,onemaywonderaboutmolecular,particularlyadipokineprofileofbothIsraelifatsandrats(Psammomysobesus)andAtlanticbigeyetuna(Tunnusobesus).

“I am a citizen of the world”–thisstatementofH. obesusisacopyofwordsofDiogenes(412-323BC).Obviously,obe-sityisapandemicevent,andH. obesusisnotlivinginBulgariaonly.AtheroscleroticandhypertensiveBHdiseasesaretheworld’sgreatestkillersofannuallymorethan19millionlives.Additionally,rheumaticheartdiseasekills15.6millionpeopleworldwide,including2.4millionchildren,mainlyinAfrica.

AccordingtotheWorldHealthOrganization’sreports,1billionpeopleworldwideareoverweight,at least300millionofwhomareobese.InEurope(populationofabout700million)thereare130millionobeseand400millionoverweightpeople,thatis,atotalof530millionfatEuropeans,whoremainamajorhealthtargetfortheEeuropeanUnion,includingBulgaria,beingamembersince1January2007.

Of note, about 80% of the world’s brain-and-heart (BH)disease burden occurs in low- and middle-income countries.Because people at low socioeconomical scale are experienc-ingunhealthy lifestyle,duetoashortageofbothmoneyandhealtheducation(manyBulgariansbelongingtothatcategoryof people). However, the poverty itself is not a sin, it is a bigmistakeof thestateallowingpoverty toexistandnotpayingattentiontoQOLthatshouldalsobeembodiedintothelistofhumanrights.

Japanese experienceinBHdisease,particularlystroke,mayindeedservearolemodelforpredictiveandpreventivemedi-cine.Inthe1960’s,JapanesediedfromstrokeevenmoreoftenthanBulgarians.However,duetotheprogressinJapaneseba-sic research in hypertension and stroke and its implication intheprevention,strokemortalitywassignificantlyreducedinJa-pan(6-8).Moreover,Japanesewomenareenjoyinganaveragelifespanof85years,andmen-78years,thusbeingamongthelongestlifespanworldwide.

Since1986,oneofus(GNC)hasalsobeenparticipatinginthisJapanesemedicalprogress,usedtoworkfortheJapanStrokePrevention Center in Izumo, Shimane Medical Universty andnow,anotherofus(DK),isworkingfortheInternationalCenterforResearchonPrimaryPreventionofCardiovascularDiseaseschairedbythefamousYukioYamorisenn-sei,inKyoto.

Bulgaria isamongtheleadingcountryworldwideinmor-talityfromBHdiseasesinthelast3-4decades.Fromlessthan8million,about75,000Bulgariansdieeachyearfromeitherstrokeor myocradial infarction; each third Bulgarian is hypetnesive;about25percentofchildrenareoverweightorobeseandmorethan10percentarehypertensiveand/ordiabetic.Whatesoevercommunism (1944-1989) or democracy (1990- ), Bulgaria is acountryintheepicenterofglobalBHhealthquake.

Acombinationofahightmortalityandalowbirthrate,ac-companied by a low QOL, primitive health culture and an in-creasing emigration, places Bulgaria in a severe demographiccrisis(9).Hence,mostofBulgarianstodayshouldbeconsidered

Editor: Ivan Berkowitz MBA

Assistant Editors:

Arun Chockalingam PhD

Ian Dixon PhD

Lorrie Kirshenbaum PhD

Editorial Board: David Brasil MD

Mike Czubryt PhD

Lois DeBakey PhD

Otoni Gomes MD

Ramesh Goyal PhD

Suresh Gupta PhD

Gania Kessler-Icekson PhD

Keld Kjeldsen MD

Tom Kottke MD

Naoki Makino MD

Ricky Man PhD

Dennis McNamara PhD

Bohuslav Ostadal MUDr

Damaris Osunkwo MD

Pawan Singal PhD

Nobuakira Takeda MD

Guy Vassort PhD

Ursula Muller-Werdan MD

Youyi Zhang MD

Editorial Support: Melissa Dent MSc

CV Network Editorial Team

President Stephen Vatner, Newark, USAPresident-Elect Sir Magdi Yacoub, Hare�eld, EnglandPast President Howard Morgan, Win�eld, USAChairman, Board of Directors Makoto Nagano, Tokyo, JapanExecutive Director Naranjan S. Dhalla, Winnipeg, CanadaDirector of Development Ivan Berkowitz, Winnipeg, CanadaAdministrative Assistant Eva Little, Winnipeg, Canada

Director of Finance Nobuakira Takeda, Tokyo, JapanDirector of Education Pawan K. Singal, Winnipeg, CanadaDirector of Scienti�c A�airs Grant N. Pierce, Winnipeg, CanadaDirector of Corporate A�airs Ian M. C. Dixon, Winnipeg, CanadaDirector of Public A�airs Lorrie A. Kirshenbaum, Winnipeg, CanadaDirector of Health Care Alan Menkis, Winnipeg, Canada

Administrative Structure of the International Academy of Cardiovascular Sciences

58

“malcitizens”,i.e.,patientshavingatleastoneofQOL-relateddiseases.Specifically,H.sanus(Manthehealthy)mustnolon-gerbeignoredinBulgaria.Physicians,scientistsandpatientsmustalltogetherincreasinglypressthepoliticianstoinvestmorefinancialsupporttopredictiveandpreventivemedicine,alsobasicbiomedicalresearch.TowaitdonationfromtheFoundationsofBillandMelindaGatesandBillClintonisnotarealisticstrategy.ThismayindeedarrivefromtheEuropeanUnionbut,atgovernmentlevels,mustbeproperly(andhonestly)utilized.

Recentexperimentalandepidemiologicalstudiesindicatethatcalorierestrictionandmoderatedrinkingofred,resvera-trol-rich,wine(5,10,11),andphysicalactivitymaypromotehealthylongevity,themajorgoalofbothmedicineandsociety.ButnotofBulgarianpoliticians!Inthesametime,inadvancedcountries,bothmedicsandpoliticiansarethinkingofhowtomaketheircitizens“longivitarians”,atermrecentlyemerged.

Further,everyoneshouldalsobeinformedaboutaH. obesus’relative,TOFI(ThinOutside,FatInside),recentlydescribedviaMRIscanningbyDrJimmyBell,headoftheMolecularImagingGroupatHammersmithHospital,ImperialCollege,Lon-don,UK.Note,TOFIisaspecific,“invisible”phenotypeofH. obesus(seeTable,alsoreference4).

Teleologically, our common goal must be (re)creation of H. sanus.“Thinking globally, acting locally” (quoting ReneDubot), we may indeed achieve this goal.Today, the Euro-peanUnionproclaimsbuildingsocietyandeconomicsbasedonthetribologyofeducation,scienceandinnovations.Thismayhelpeachofusto,atlonglast,staysane,andnotlongerbeingobese.

Becauselivinghealthyandwell-educatedmayindeeden-sureEudemonia,thatis,“highestgoodlife”insenseofAristo-telianethicsandlogic.ApplyingCR(calorierestriction)andboosting our CR (creative resources) in our lifestyle couldhopefullycontributetotheeffortsinachievingthatgoal.

References1. ChaldakovGN,StankulovIS,HristovaM,GhenevPI.Adipobiologyofdisease:adipokinesandadipokine-targetedpharmacology.CurrPharmDes2003;9:

1023-1031.2. ChaldakovGN,FioreM,TonchevAB,AloeL.Adipopharmacology,anoveldrugdiscoveryapproach:ametabotrophicperspective.LettDrugDes2006;3:503-505.3. FantuzziG,ChaldakovGN,editors.AdipopharmacologyofDisease.BiomedRev2006;17:1-122.4. RanĉiĉG,AloeL,TonchevAB,FioreM,KostovD,BojanicV,PetrovicA,GeorgievaZ,GhenevPI,ChaldakovGN.Adipotopography:TOFIversusTOTI.FactaUniver-

sitata(Niš,Serbia)2007;inpress.5. ChaldakovGN,FioreM,TonchevAB,DimitrovD,PanchevaR,RancicG,AloeL.Homoobesus:ametabotrophin-deficientspecies.Pharmacologyandnutrition

insight.CurrPharmDes2007;13:2176-2179.6.YamoriY.Worldwideepidemicobesity:hopeforJapanesediets.ClinExpPharmacolPhysiol2004;31(Suppl.2):S2-4.7. YamoriY,MurakamiS,IkedaK,NaraY.Fishandlifestyle-relateddiseaseprevention:experimentalandepidemiologicalevidenceforanti-atherogenicpotentialof

taurine.ClinExpPharmacolPhysiol2004;31(Suppl.2):S20-23.8. YamoriY.Nutritionandlifestyle-relateddiseasepreventioninthefuture.ClinExpPharmacolPhysiol2004;31(Suppl.2):S65.9. ZlatevaV,GeorgievaZ,ChaldakovG.FoodcultureforhealthylongevityinBulgaria:crisisrevealed.CARIACStudyProceedings.UNESCOReport2007;inpress.

10. LammingDW,WoodJG,SinclairDA.Smallmoleculesthatregulatelifespan:evidenceforxenohormesis.MolMicrobiol2004;53:1003-1009.11. GuarenteL,PicardF.Calorierestriction–theSIR2connection.Cell2005;120:473-482.

Table. Adipotopography (fat mapping) – variations+TOFI**thinoutside,fatinsideTOTI*****thinoutside,thininsideFOFI*fatoutside,fatinsideFOTI***fatoutside,thininside

+ The number of asterisks, as for hotels, indicates quality, here – the QOL in BH health. Hence, stay TOTI!

W o R l D H E A R T D A YCardio-vascular diseases - includingheart attacks and strokes - are theworld’s largest killer, claiming 17.5

millionlivesayear.WorldHeartDaywasestablishedtocreatepublicawarenessof risk factors forheart diseasesand strokeand to pro-moteprevention.

There are 155 million overweight and obese children globally.Parentscaninfluenceandhelpchildreninreducingmajorriskfac-tors for heart diseases and stroke - such as controlling weight byhealthyeatinganddoingregularphysicalactivity.That iswhythisyear’sWorldHeartDay(September30,2007)focusesonthetheme“TeamUpforHealthyHearts”.

InpartnershipwithWHO,theWorldHeartFederationorganizedactivitiesinmorethan100countries.Theactivitiesincludedhealthchecks,organizedwalks,runsandfitnesssessions,publictalks,stageshows,scientificforums,exhibitions,concerts,carnivals,andsportstournaments.”Formoreinformation,visit:http://www.world-heart-federation.org/what-we-do/world-heart-day/about-world-heart-day

2007, Vol. 7, No. 5 (pp. 303-389)ISSN: 1175-3277

Adis

Am

erican Journal of Cardiovascular D

rugs • 2007, Vol. 7, N

o. 5, pp. 303-389

Cardiogenic ShockTherapeutic Potential of Nitric Oxide Inhibitors

Diabetes MellitusDefining the Role of Repaglinide

HypertensionReview of the Efficacy and Safety of PerindoprilDose-Response Characteristics of ARBsFinding the Optimal Dose of Antihypertensive Drugs

Original ResearchOlmesartan/Hydrochlorothiazide versus Benazepril/Amlodipine for HypertensionSubgroup Analysis of ACE Inhibitors and β-Blockers in A-HeFTAntihypertensive and Lipid-Lowering Medications in the Prevention of CVD

9

ISSN 1175-327705

771175 327001

Drugs & Therapy Perspectives

Drugs in R&D

High Blood Pressure & Cardiovascular Prevention

Inpharma® Weekly

International Journal of Pharmaceutical Medicine

Molecular Diagnosis & Therapy

Paediatrics Today

Pediatric Drugs

PharmacoEconomics

PharmacoEconomics & Outcomes News

PharmaNewsFeed.com

R&D Insight

Reactions Weekly

Sports Medicine

American Journal of Cardiovascular Drugs

American Journal of Clinical Dermatology

Anti-infectives Today

BioDrugs

Cancer Today

Clinical Drug Investigation

Clinical Pharmacokinetics

Clinical Trials Insight

CNS Disorders Today

CNS Drugs

Disease Management & Health Outcomes

Drug Safety

Drugs

Drugs & Aging

Official Journal of theInternational Academy of Cardiovascular Sciences

60

”When I first told my friends I was traveling to Jordan, they thought I was crazy. When I then told them I was bringing them along, they tried everything they could to come up with an excuse not to go. I dragged them there, and then a funny thing happened. Five days later, they tried everything they could…to stay. They discovered what I already knew-- that Jordan is one of the safest, most hospi-table places I know. I may live in America, but in Jordan, I am always welcomed home.”

These words were written by PeterGreenberg,TravelEditor,Today’sShow,NBCNews

YesJordanisthesafestplaceinthemid-dleandforeignpeoplecanwalkfreelyalloverJordan.Wereceivelargenumberoftouristsfromallovertheglobe.Theyspendmemorabledaysforalltheirlife.

GodrepeatedlydesignatedJordanasalandofpeaceandrefuge,whereRuth,Elijah,David,Je-sus,JohntheBaptistandthefirstChristiancommunities,amongothers,foundsafetyandpeace.MostofthegreatbiblicalprophetsjourneyedfromtheeastbankoftheJordanRivertothewest,symbolicallymovingfromthe“wilderness”wheremenandwomenaretested,totheHolyLand,the

KingdomofGod.AmongtheseleadingfigureswhosejourneystookthemfromtheeasttothewestbanksoftheJordanRiverwereAbraham,Jacob,Moses,Joshua,Elijah,JohntheBaptistandJesus.

MostoftheholysitesinJordanwherethebiblicalprophetsperformedmiraclesorreachedouttoordinarypeopleareiden-tified,excavatedandeasilyaccessibletovisitorstoday.Newsitesarediscoveredeveryyear.ReligiouspilgrimsandvisitorstoJordanoftencanvisitarchaeologicalexcavationsandshareintheexcitementofidentifyingancientremainsofplaces.For10,000years travelershavemarveledthemajesticarchaeologicalsitesandnaturalwondersofhospitableJordan.TheabundanceofuniquesightsacrossthelandisonlybutareflectionoftherichcultureheritageoftheKingdom.Visitorsareenchanted,mystifiedandcaptivatedbythefamousrose-redNabateancityofPetra;Greco-Romantemplesandcities;CrusaderandUmayyadcastles;thespectaculardesertsmadefamousbyLawrenceofArabia;innumerablebiblicalsitesidentifiedwithJacob,Moses,Elijah,JohntheBaptistandJesusChrist;theRedSeaandtheDeadSea;andthecapitalcityofAmman-afascinatingmixtureofancientandmoderncontrasts.

SoJordanoffersvenuesthatcannotbeduplicatedanywhereintheworldforspecialeventsandthemeparties.We invite you to browse through (Jordan Tourism Board of North America: www.seejordan.org ) and learn all about

the astounding sites in the country, including the capital Amman, the magnificent Nabatean city of Petra, the spectacular Greco-Roman ruins of Jarash, the desert castles, lawrence’s famous Wadi Rum, and many other historical and impressive sites throughout the Kingdom.

Experience the biblical Jordan visiting Bethany - Beyond - Jordan where John the Baptist baptized Jesus, Mount Nebo where Moses stood one day, Madaba the City of Mosaics and various other sites of this eastern Holy land.

We highly encourage you to come and see the beauty of the Kingdom’s treasures and experi-ence the splendor that has dazzled visitors for centuries.

TheancientcityofPetraisoneofJordan’snationaltreasuresandbyfaritsbestknowntouristat-traction.LocatedapproximatelythreehourssouthofAmman,PetraisthelegacyoftheNabataens,anindustriousArabpeoplewhosettledinsouthernJordanmorethan2000yearsago.Admiredthenforitsrefinedculture,massivearchitectureandingeniouscomplexofdamsandwaterchannels,PetraisnowaUNESCOworldheritagesitethatenchantsvisitorsfromallcornersoftheglobe.MuchofPetra’sappealcomesfromitsspectacularsettingdeepinsideanarrowdesertgorge.Thesiteisaccessedbywalkingthroughakilometrelongchasm(orSEEQ),thewallsofwhichsoar200metresupwards.Petra’smostfamousmonument,theTreasury,appearsdramaticallyattheendoftheseeq.Usedinthefinalsequenceofthefilm“IndianaJonesandtheLastCrusade”,thetoweringfacadeoftheTreasuryisonlyoneofmyriadarchaeologicalwonderstobeexploredatPetra.Variouswalksandclimbsrevealliterally

P E o P l E A N D P l A C E S

Jordan – the Holly Biblical Land and the Land of treasure and beauty

TheAmphiTheatreinAmman

“Tyche”–thefirstmanmadestatueonearth

TheTreasuryatPetra

bySaidKhatib,Irbid,Jordan

61

hundredsofbuildings,tombs,baths,funeraryhalls,temples,archedgateways,colonnadedstreetsandhauntingrockdrawings-aswellasa3000seatopenairtheatre,agiganticfirstcenturyMonasteryandamodernarcheologicalmuseum,allofwhichcanbeexploredatleisure.Amodestshrinecommemo-ratingthedeathofAaron,brotherofMoses,wasbuiltinthe13thcenturybytheMamlukeSultan,highatopmountAaronintheSharahrange.

AlsowithintheareaisMountNebo,oneofthemostreveredholysitesofJordanandtheplacewhereMoseswasburied.AsmallByzantinechurchwasbuilttherebyearlyChristians,whichhasbeenexpand-edintoavastcomplex.DuringhisvisittoJordanin2001,theLatePopeJohnPaulIIheldasermonherethatwasattendedbysome20,000faithful.Standontheplatforminfrontofthechurchandadmiretheview.ItoverlookstheJordanValleyandtheDeadSea,acrosstotherooftopsofJerusalemandBethlehemandisabsolutelybreathtaking.Just30kmfromAmman,alongthe5,000-year-oldKings´Highway,isoneofthemostmemorableplacesintheHolyLand.Afterpassingthroughastringofancientsites,thefirstcityyoureachisMadaba,knownasthe“CityofMosaics”.

Best known for its spectacular Byzantine andUmayyad mosaics, Madaba is home to the famous

6thcenturyMosaicMapofJerusalemandtheHolyLand.Withtwomillionpiec-esofvividlycoloredlocalstone,itdepictshillsandvalleys,villagesandtownsasfarastheNileDelta.

TheMadabaMosaicMapcoverstheflooroftheGreekOrthodoxChurchofSt.George,whichislocatednorthwestofthecitycentre.Thechurchwasbuiltin1896AD,overtheremainsofamuchearlier6thcen-turyByzantinechurch.ThemosaicpanelenclosingtheMapwasoriginallyaround15.6X6m,94squaremeters,onlyaboutaquarterofwhichispreserve.

OthermosaicmasterpiecesfoundinthechurchoftheVirginandtheApostlesandintheArchaeologicalMuseum,depictaram-pantprofusionofflowersandplants,birdsandfish,animalsandexoticbeasts,aswellasscenesfrommythologyandtheeveryday

pursuitsofhunting,fishingandfarming.Literally,hundredsofothermosaicsfromthe5ththroughthe7thcenturiesarescatteredthroughoutMadaba’schurchesandhomes

AclosesecondtoPetraonthelistoffavoritedestinationsinJordan,theancientcityofJarashboastsanunbrokenchainofhumanoccupationdatingbackmorethan6,500years.ConqueredbyGeneralPompeyin63BC,itcameunderRomanruleandwasoneofthetengreatRomancities,theDecapolisLeague.

Thecity’sgoldenagecameunderRomanrule,duringwhichtimeitwasknownasGerasa,andthesiteisnowgenerallyacknowledgedtobeoneofthebestpreservedRomanprovincialtownsintheworld.Hiddenforcenturiesinsandbeforebeingexcavatedandrestoredoverthepast70years,Jarashrevealsafineexampleofthegrand,formalprovincialRomanurban-ism that is found throughout the Middle East, comprising paved and colonnaded streets,soaringhilltoptemples,handsometheatres,spaciouspublicsquaresandplazas,baths,foun-

tainsandcitywallspiercedbytowersandgates.Thisisastupendous,timelessplace,virtuallyuntouchedbyhumanityanditsdestructiveforces.Here,itistheweatherandwinds

thathavecarvedthe imposing, toweringskyscrapers, soelegantlydescribedbyT.E.Lawrenceas“vast,echoingandgod-like”..Amazeofmonolithicrock-scapesriseupfromthedesertfloortoheightsof1,750metrescreatinganaturalchallengeforseriousmountaineers.Hikerscanenjoythetranquilityoftheboundlessemptyspaces,explorethecanyonsandwaterholestodiscover4000yearoldrockdrawingsandthemanyotherspectaculartreasuresthisvastwildernessholdsinstore.

Dead SeaWithoutdoubt,theworld’smostamazingplace,theJordanRiftValleyisadramatic,beautifullandscape,whichattheDeadSea,isover400metres(1,312ft.)belowsealevel.Thelowestpointonthefaceoftheearth,thisvast,stretchofwaterreceivesanumber of incoming rivers, including the River Jordan. OncethewatersreachtheDeadSeatheyareland-lockedandhavenowheretogo,sotheyevaporate,leavingbehindadense,rich,cocktailofsaltsandmineralsthatsupplyindustry,agricultureandmedicinewithsomeofitsfinestproducts.

TheleadingattractionattheDeadSeaisthewarm,sooth-ing,supersaltywater itself–sometentimessaltier thanseawater,andrich inchloridesaltsofmagnesium,sodium,potassium,bromineandseveralothers.Theunusuallywarm, incrediblybuoyantandmineral-richwatershaveattractedvisitorssinceancienttimes,includingKingHerodtheGreatandthebeautifulEgyp-tianQueen,Cleopatra.AllofwhomhaveluxuriatedintheDeadSea’srich,black,stimulatingmudandfloatedeffortlesslyontheirbackswhilesoakingupthewater’shealthymineralsalongwiththegentlydiffusedraysoftheJordaniansun.

”ThecrimsonsunsetonitsstupendouscliffsandslantedLaddersofhazyfiredown

itswalledavenue”

MosaicMapoftheHolyLandinSt.George’sChurch

Theimpressivecolumnsatthe‘OvalPlaza’

DeadSea

PrintedinCanada-ISSN1683-0784PublicationsAgreement#40804514

62