THE SEVEN COUNTRIES STUDY

A scientificadventure in
cardiovasculardisease epidemiology
T H E SEVEN COUNTRIES STUDY

Ascientific adventure in

cardiovasculardisease epidemiology
 Editors:

Daan Kromhout
Professor, Director Division ofPublic Health Research
National Institute of PublicHealth and Environmental Protection
P.O.Box1,3720BABilthoven,The Netherlands

Alessandro Menotti
Professor, Director
Laboratory of Epidemiology and Biostatistics,
IstitutoSuperiore di Sanita
VialeRegina Elena299,1-00161Rome,Italy

Henry Blackburn
MayoProfessor, Division of Epidemiology
University of Minnesota
Suite300,1300SouthSecond Street, Minneapolis,
MN55454-1015,USA
T H E SEVEN COUNTRIES STUDY

A scientificadventurein
cardiovascular disease epidemiology

Editors:
Daan Kromhout,Alessandro Menotti and Henry Blackburn

Investigators and Contributors:

AncelKeys,ChristosAravanis, Henry Blackburn,FransSPvanBuchem*,
RatkoBuzina,BozidarSDjordjevic", Anastasios SDontas
Frederick H Epstein,FlaminioFidanza,MarttiJKarvonen
Noboru Kimura*,Daan Kromhout,Alessandro Menotti,SreckoI Nedeljkovic
AulikkiNissinen,Maija Pekkarinen ,VittorioPuddu",Sven Punsar
Leena Räsänen,Henry LTaylor*,Hironori Toshima

*deceased
Cover/design: Anne-Claire AltabNO,RIVM,Bilthoven,The Netherlands
Production: Marjan Nijssen-Kramer, StudioRIVM,Bilthoven,The Netherlands
Printing: BrouwerOffset bv,Utrecht,The Netherlands

Thepublication ofthis bookwas madepossiblebygenerousgrantsofthe

Centre for the Fightagainst Infarction, Rome,Italy.

Division of Epidemiology, Universityof Minnesota,

SchoolofPublicHealth,Minneapolis,Minnesota,U.S.A.

Finnish Heart Foundation,Helsinki,Finland.

National Instituteof PublicHealth and Environmental Protection,Bilthoven,TheNetherlands.

Netherlands Heart Foundation,TheHague,The Netherlands.

North Karelia Project Research Foundation,Joensuu, Finland.

Third Department of Medicine,KurumeUniversity Schoolof Medicine,Kurume,Japan.

ISBN90-6960-048-x

Allrightsreserved.No partof thispublication maybereproduced, stored inanautomatic retrieval

system,ortransmitted inanyform orbyany means,electronic,mechanical,photocopying, recording
orotherwise,without thepriorpermission of theeditors.
 7
ToAncel Keys
onhis 90th birthday
 PREFACE

I hefieldwork for theSeven Countries Study began in1958.

During thepast 35yearsa tremendous amount of work hasbeen carried out in that
study, under theleadership ofAncelKeys.Three monographs and a countless
number of papers have been published. Nevertheless,there isnopublication sum-
marizing how thestudy developed in thedifferent countries,nor arethe major
resultsof thestudy and theirpublichealth implications available inoneplace.
Therefore theidea arose inconnection with theinternational symposium, 'Lessons
for Sciencefrom theSevenCountries Study' (held onOctober 30,1993,in Fukuoka,
Japan,organized by Professor H.Toshima),toassemble thishistory.An editorial
committee wasformed, consisting of Daan Kromhout, Alessandro Menotti, and
Henry Blackburn and allprincipal investigators ofthecohortsparticipated in this
undertaking. Professor Frederick Epstein kindly provided achapter on the public
health implications of thestudy.Allthesemade thisdocument possible,from the
personal perspectives of theinvestigators. Thisbook provides anoverview ofa
study that hasgreatly influenced scienceand thepublic health aswell asour own
careers.Itwould not haveseendaylight without theadministrative supportof
Anke Roccuzzo,Karin Bruineman and Nola Fortner.Wegratefully acknowledge
their contribution.

The Editors
December 1993
 ACKNOWLEDGMENTS

I hePrincipal Investigators acknowledge thegracious cooperation

of thestudy communities, participants and field teams over thepast35years as
wellasachievements of thecoordinating centers:

Laboratory of Physiological Hygiene and Division of Epidemiology,

University of Minnesota, Schoolof PublicHealth,Minneapolis,Minnesota, U.S.A..

Laboratory of Epidemiology and Biostatistics,Istituto Superiore diSanitâ,

Rome,Italy.

University of Leiden and theNational Institute of PublicHealth and Environmental

Protection, Bilthoven,The Netherlands.

Alltheseplayed acrucial rolein realizing the study.

Themany sourcesof financial support thatcarried theSevenCountries Study

through theentryexaminations and thefive and 10years' follow-up surveys have
been acknowledged inthe 1967,1970and 1980monographs.The25-year mortality
follow-up was realized mainly through localgrants.Theresearch of the25-and 30-
year follow-up data from Finland, Italy,and TheNetherlands was partly madepos-
siblethrough agrant from theNational Institute of Aging,Bethesda,U.S.A..
CONTENTS

INTRODUCTION //
The Editors

THE INCEPTION AND PILOT SURVEYS 15

Ancel Keys

IMPRESSIONS FROM THE FIELD 27

Henry Blackburn

COORDINATION OF THE SEVEN COUNTRIES STUDY 37

Henry Blackburn and Alessandro Menotti

STUDIES IN THE U.S. RAILROAD 45

Henry Blackburn

THE EAST - WESTSTUDIES OF FINLAND 57

Martti J. Karvonen, Sven Punsar, Aulikki Nissinen,
Maija Pekkarinen and Leena Räsänen

STUDIES IN ZUTPHEN 79
Daan Kromhout

STUDIES IN RURAL ITALY 91

Flaminio Fidanza and Alessandro Menotti

STUDIES ON THE ROME RAILROAD 103

Alessandro Menotti

STUDIES IN THE GREEK ISLANDS 109

Christos Aravanis and Anastasios S. Dontas

STUDIES IN CROATIA //7

Ratko Buzina

STUDIES IN SERBIA 123

Srecko I. Nedeljkovic
STUDIES IN RURAL JAPAN 141
Hironori Toshima

DIETARY SURVEYS IN THE SEVEN COUNTRIES STUDY 151

Flaminio Fidanza and Daan Kromhout

MAJOR RESULTS OF THE SEVEN COUNTRIES STUDY 159

Henry Blackburn and Alessandro Menotti

PUBLIC HEALTH IMPLICATIONS OF THE SEVEN COUNTRIES STUDY 169

Frederick H. Epstein

THE FUTURE OF THE SEVEN COUNTRIES STUDY /75

Daan Kromhout, Alessandro Menotti, Aulikki Nissinen

ABOUT THE INVESTIGATORS AND AUTHORS ƒ78

10
 INTRODUCTION
The Editors

I heSevenCountries Study (SCS)hasbecomeaclassicin science

for itspioneering effort incardiovascular disease (CVD)epidemiology and for its
powerful lesson toscience:that mass phenomena determine thepopulation rates
and thepreventive strategiesofCVD.Theidea of theSCSarose invarious forms in
themindsof imaginative individuals capableof integrating laboratory,clinical,and
population evidence.Thestudy wasgiven substance and direction by itsleader, our
colleague,AncelKeys.
TheSCSdeveloped out of arichsetofobservations madeby anumber of clini-
ciansand investigators.Itemerged inembryonic form in each of theseven coun-
tries.Therewas,in thelate1950s,areadiness for theideas,alongwith preparedness
for effective research among disciplines and acrosscultures.Ancel Keysand the
Minnesota group,who had participated in physiological studies during and after
World War II,had found theimportance of nutrition and lifestyle in human biology
(which they called physiological hygiene),and had recognized early that cardiovas-
cular diseaseswereamajor new publichealth concern.Keysand colleagues were
alsoprepared with quantitative thinking and computational skills,abletolinkide-
as,bridge disciplines,and apply methods appropriate tothescientific question.
Taylor and colleaguesat Minnesota in 1957initiated U.S.efforts for theSCSina
study ofCVDratesinrailway occupations that required different levelsof physical
activity.Atthesame time,researchers inseveral partsof theworld were examining
similar issues:Karvonen and theFinnish group,Fidanza and Puddu of the Italian
group,Buzina and Djordjevic with theCroatian and Serbian groups,Aravanis and
Dontas and theGreek group,Kimura and Toshima and theJapanese group,and
Van Buchemand Dalderup and theDutch group.Eachhad already begun explora-
tionsof population phenomena inCVD,testing hypotheses about thecausal roleof
diet,physical activity,and lifestyle. BackinMinnesota, Keys,Grande,and Ander-
sonalsomadecrucial systematic metabolicexperiments in thepreciseserum choles-
teroleffects of dietchanges.Essential tothewholewere theobservations of Paul
Dudley Whiteand Noboru Kimura,whoput intobold and simpleterms the differ-
encesinCVDfrequency and arterial pathology seen around theworld. Meetings
between allthese remarkable peoplewerestimulated byAncel Keys;theideas for
collaborative research rapidly took hold,and activework began. Pilotstudies with
theFinnsin 1956,and theItaliansand Greeks in 1957,demonstrated feasibility of
theSCSinthefield. Thecentralcoordinating grant toProfessor Keysfrom NIH
allowed thedefinitive cohort surveys tobegin inCroatia in 1958, whiletheU.S.
Railroad Study had proceeded in 1957under aseparate grant toHenry Taylor.
 "Fortunately for theSCS,national Heart Foundations and other groups were
ready tosupport theearly phasesof theseactivities.TheU.S.Railroad Study profit-
ed from thesupport of thenew National Heart Institute (NHI).AncelKeys, of
course,played thecrucial roleof puttingall theideas together inaclear proposal to
theNHI for collaborative research among theseven countries.Hehad the interna-
tional contacts,thevision,and theexperience tomove thismajor project forward.
Finally,thespecial experience and knowledge of each of theSCSprincipal inves-
tigatorsabout their professional fields, and about thegeography and culture of their
lands,along with theirclinical contactsand political clout,enabled thewholeSCS
operation tobeput in motion.Thecentral NIH budget at thetimewasonly about
$25,000peryear percenter, sothefund raisingtalents ofall the Piswere quickly
developed!
Keysand collaborators hypothesized that differences inpopulation ratesof
CVD,and individual risk within populations,wererelated tomodeof life and risk
factors, including composition of thediet.Toexamine thishypothesis, formal cross-
sectional surveys wereconducted, starting in 1958, among samplesof men ages40-
59,in seven countriescontrasting in composition of thediet and inpurported heart
diseaserates:former Yugoslavia, Italy,Greece,TheNetherlands,Finland,Japan and
theU.S.A..Baselinesurvey participants wereentered intocohorts,and both thedis-
eased and disease-free were followed for 30yearsin most areas.Thestudy was
unique for itstime,with 'adequately' sized 'chunk' samples in 16areasas the
cohorts,with standardized risk factor and disease measurements,training of teams,
and central coding and analysisofdata.TheSCSbecametheprototypical popula-
tion comparison study, made acrossawiderangeofdiet and disease experience.
Asremarkable asthesebeginnings was thelater emergenceofleadership in the
SCSfrom variousplaces,where and when itwasneeded.Ancel Keys' leadership
was essential toorganize thestudy, prepare theinitial collaborative proposal and,
over theyears, bring out the threemajor monographs: the 1967Acta Medica
Scandinavica Supplement, the 1970Circulation Supplement, and the 1980Harvard
University PressMonograph. Eachof theseefforts wasa tourdeforcewhich brought
thediverse findings together inaway noother investigator oreditorial board could
havedone ascogently and effectively. Butother leadership appeared when theSCS
cameunder itsgreatest threat;thecentral grant expired inthelate 1960s,and soon
after Dr.Keysretired, hisbaseofoperations wasconstrained. Thiswas paralleled
bythenecessarily intense preoccupation inMinnesota with new activities to assure
thesurvival and growth of theLaboratory of Physiological Hygiene,then and still,
a largely self-supporting academicinstitution.Thus,in thelate1960s,much of the
SCSenergy,data collection,and coordinating responsibilitywas shifted to the
capablehands ofAlessandro Menottiand theRomecenter.Sincethen,an important
new axisof leadershiphasdeveloped between theNetherlands,Rome,and Finland,

12
with arichcollégialsharing of ideas,initiatives and new data collection for new
researches.TheSCSowes much totheenterprise of Daan Kromhout, Alessandro
Menotti,and AulikkiNissinen in this development.
TheSCSwas first tomake systematiccomparisons ofCVDrates and characteris-
ticsof risk incontrasting cultures.Itwas first tocombine cross-sectional surveys
with long-term follow-up among cohorts.Itwasfirst tocompute population (eco-
logie)correlationsbetween lifestyle and riskfactors,and between risk factors and
disease,and their changes over time.Itwas first toapply multivariate regression
coefficients derived inone population tofindings inmen of thesameagein
another. Inaddition totheseachievements,thestudy continues toredefine itsmis-
sion and hypotheses.Forexample,thereisevery evidence ofcontinued successin
long-term follow-up of survival in thecohorts.Dr.Keyscontinues tostudy lon-
gevity related tocharacteristics atentry.And research bytheseveral investigators
movesforward toexplain further thelargedifferences in population CVDrates and
theindividual differences in risk,with respect todifferences and tochangesovertime
indiet,and other risk factors.
Ofcourse,there areproblems.TheSevenCountries Study has arelatively small
number ofunits tocompare,with few degrees offreedom for theecological correla-
tions,and making thesecorrelations atallwas early criticized.Somehavealsocriti-
cized theselection ofthedifferent geographic areas,thevaried occupational compo-
sition of thepopulations compared, and theobvious technical limitations of meas-
urement and classification acrossareasby national teams,often under difficult field
survey conditions.Itistrue that improvements havebeen made inthe configura-
tionofpopulations for such internal and international comparisons by random
selection ofgreater numbers ofunits,etc.ButtheSCSwas notonly 'state-of-the-art'
for itstime,itwasbold and foresighted initsconcepts and thrust. And, as we
increasingly realizetoday,theecologicalassociationsofhabitual diet,other risk fac-
tors,and population ratesof disease,inthemselves weak sourcesof causal infer-
ence,are,nevertheless,with strong congruent evidence from the laboratory and
clinic,valuable indicators of theforces underlying massdiseases.When theevi-
denceisconsistent, thepopulation correlations mayindicatethemajordeterminants
ofdifferent population ratesofdisease.
Thisvolume describes agreat scientific adventure incardiovascular diseaseepi-
demiology. Allprincipal investigators wrote chaptersabout their contributions to
theSCSfrom their personal perspectives.Theresulting unique document describes
thedevelopment ofan international collaborative study which hasgreatly influ-
enced thinking,practice,and policyincardiovascular medicineand public health.

13
 I
THE INCEPTION A N D PILOT SURVEYS
A. Keys

T h e SevenCountries Study istheculmination ofa prospective

study started in Minnesota in 1947,longbefore therewasany idea of an interna-
tional study,and 10yearsbefore international field testsof methods inNicotera in
southern Italy,and then on theisland ofCrete.Theactual startof thestudy wasin
Makarska inCroatia,then apeaceful part of Yugoslavia.
Theend ofWorld War IImeant releasefrom war-related work;time to think
and plan new research.Thenews in theAmerican public presswas nolonger only
about thewar and itspoliticaland economic aftermath. Among reports of new
eventswereincreasing noticesof executives dying from heart attacks.Wecould
speculate about theepidemic ofcoronary heart diseaseand itscause. Middle-aged
men,seemingly healthy,weredropping dead.Therewastalk of thestressof being
an executive.Butwhat was thedifference between thoseattacked and those who
stayed well?

The Basic Idea - The First Prospective Study

Suppose weexamined middle-aged executivemen,measuring and recording char-
acteristics that would identify them inregard toitemsconceivably associated with
susceptibility tocoronary heart disease.Iftheexaminations wererepeated annually
and vitalstatus checked over theyears,eventually someof themen would have
heart attackswhileotherswould staywell.Comparison of theentry characteristics
of thecoronary victimswith thoseof themen who stayed wellwould reveal what
yearslaterwould becalled risk factors.With such knowledge wecould warn men
about their risk and try toaltertherisk factors.
Here was thechallenge tothestaff of theLaboratory of Physiological Hygiene at
theUniversityofMinnesota.Wehad noideaof thenumber ofmen tostudyor the
length of timeneeded todistinguish, statistically,coronary victimsand their fellows
remaining healthy.Inplanning such aprospective study itwasnecessary totake
account offacilities,staff, and costs.Aplan wasdrawn up and, with agreementof
theSchoolof Public Health of theUniversity,arequest for agrant wassubmitted to

15
theU.S.PublicHealth Service.Asitturned out, theplan was toolimited,and the
request for agrant toomodest.Therequest was promptly approved.
Theidea appealed somuch tothePublicHealth Servicethat itquickly followed
suit,organizing and financing thesamekind of prospective study onamuch bigger
scale.Thestudy was tobeoperated by acommittee with Dr.RoyDawber aschair-
man.Thus wasborn theFramingham Study.
Plansfor thestudy in Minneapolis weremade in 1946.Thesubjects, executive
men aged 45to55in Minneapolis and St.Paul,wererecruited, and their entry
examinations,started in 1947,werecompleted inFebruary, 1948. Thestudy was
called theCVDStudy,short for cardiovascular disease.There-examinations in1949
and 1950weresatisfactorily made with theableassistance of Doctors HenryL.
Taylor,Austin Henschel,and ErnstSimonson, allnow deceased, the clinicians
being Doctors Rafael Carmena and Carleton Chapman.They were followed by
Dr.Henry Blackburn whobecame thepermanent member of thestaff inchargeof
clinical work.

A Year at Oxford, Visiting Professor in Magdalen College

In 1951,1 was abletotakesabbatical leave and gotoOxford University for a year
asvisiting professor inMagdalen College.In that year,Iwas called toRometobe
chairman of thefirst committee on food and nutrition of theFood and Agriculture
Organization (FAO)of theUnited Nations.At themeeting allthediscussion was
about undernutrition in theun-developed countries.When Iasked about theprob-
lemofdietand coronary heart diseasenoone was interested. Dr.Gino Bergami,
Professor of Physiology at theUniversity of NaplesMedical School,said coronary
heart diseasewasnoproblem inNaples.
BackinOxford Imade obligatory visitstocolleaguesand medical schoolsin
Aberdeen and Glasgow in early 1952and was free for atime.Itwas cold in Oxford,
weweretired of food rationing and Iremembered Bergami'sclaim.When Iasked
him about ithesaid, 'Come and see.'Itwasawelcome invitation.
Margaret and Iloaded our littleHillmanautomobile with apparatus for measur-
ing serum cholesterol and headed for Naples.InNapleswe found Bergami was
rightabout thegeneral population's freedom from coronary heart disease,but there
werepatients with myocardial infarction inprivate hospitalscatering torich people.
Thediet of thegeneral population wasobviously very lowinmeat and dairy prod-
ucts,and Margaret found very low serum cholesterol levelsinseveral hundred
workmen and clerksbrought infor examination byDr.FlaminioFidanza,an assist-
ant toBergami in thePhysiology Department.
Iwas taken todinewith members of theRotary Club.Thepasta was loaded with
meat sauceand everyone added heapsofparmesan cheese.Roast beef was the main

16
course.Dessert was achoiceof icecream or rich pastry. Ipersuaded a few of the
diners tocomefor examination, and Margaret found their cholesterol levels were
much higher than intheworkmen (Arch Intern Med 1954;94:328).Afew months
later wewent toMadrid asguestsof Professor Jimenez Diaz,theforemost cardiolo-
gistinSpain,and found asimilar picture inapoor area of Madrid (Metabolism
1954;3: 195).Professor Diazwasa genial host but scoffed when Isuggested that
heartattacks might berelated tothediet. Dr.FranciscoGrande Covian organized
all thework in Madrid and madesure weenjoyed our stay in that great city.Paco,
aseveryone called him,was unhappy with hisposition in theMedicalSchool and
before long hejoined thestaff ofthe Laboratory of Physiological Hygiene. He
remained asamajor collaborator for 20yearsbefore returning toSpain.

Telling the Story in Amsterdam and New York

Shortly after thesurvey inSpain Iwas invited tospeak atajoint session in
Amsterdam of twointernational congresses,oneon diabetes,theother on nutrition.
Itold about thesurveys inNaplesand Madrid and suggested that therecould bea
sequence -fatty diet,raised serum cholesterol,atherosclerosis,myocardial infarc-
tion.Almost noonein thebigaudience took meseriously.Thesponsors of the
Amsterdam Congresses gavemylecture toVoeding, thelocaljournal on food and
nutrition, which promptly published it (Voeding 1952;13:539-555).Voeding isa
respectable journal with very littlecirculation outside theNetherlands and even
thereprimarily read bynutritionists.Not surprisingly, thelecture had no interna-
tional attention. Yearslater Imade somephotocopies for colleaguesbecause they
had never heard of it.Afew months after Amsterdam Igave thesame lecture at
Mount Sinai Hospital inNew York.Theaudience wasvery small,but oneof thelis-
tenerswas excited by thethesison therelation of thediet tocoronary heart disease.
That was Dr.Frederick Epstein.When someother reports seemed tobein harmony,
hebecameextraordinarily effective inspreading themessageallover the world.

Different Populations
Thecrude surveys inNaples and Madrid convinced us that surveysofmen indif-
ferent populations would berevealing. In 1954,1 organized ameeting inNaplesof
prominent investigators from severalcountries todiscussthecoronary problem.
Hakvin Malmros from Sweden told about thedisappearance of coronary heart dis-
easeinpopulations whosefood was greatly reduced bytheGerman occupation in
World War II.Hehad reported itin 1950inActa Medica Scandinavica 1950;
Supplement 246:137.Vartiainen and Kanerva inFinland had written about athero-
sclerosis and wartime in 1947(Ann Med Inter Fenn 1947;36:748).The connection

17
between nutrition and mortality from coronary heart diseaseduring and after
World War IIwasreviewed bySchornagel (Docum Med Geogr Trop, Amsterdam
1953;5:173).
Themajor change inthe food supply inwartime had been agreat reduction in
meat and dairy products.Inhindsight, food calorieswere reduced,but more signific-
antly there had been adrasticreduction insaturated fatty acidsin thediet.No one
atthemeeting in Naples cameup with another inference that could be suggested.
Undoubtedly many of theolder members ofthestarving populations had well-
developed atherosclerosisbefore thediet change.Why did someofthem not have
heart attacks? Certainly thediet changemust havecaused agreat decreasein the
cholesterol levelin theblood serum,sothere could havebeen adecreaseorcess-
ation of further enlargement of theatheromata. Butwould that alonehave prevent-
ed heart attacks? Could itbethat atheromas in thecoronaries werereduced by the
drasticchangein thediet?Inrecent years ithasbeen reported that thisispossible
with adrasticchange inthediet,but there iscontroversy about it.
At theNaples meeting allagreed thatcomparable prospective studies in differ-
ent populations could discover common characteristics associated with susceptibil-
ity tocoronary disease.Theproblem was how toorganize,finance, and carry out
such comparable studies indifferent populations.In themeantime surveys would
be useful.

International Surveys
Themost prominent participant at theNaples meeting was Dr.Paul White,
President Eisenhower's physician, who would thereafter bewith us invisitsall over
theworld,discussing and surveying thecoronary problem.Alldoors of medical
schoolsand hospitals wereopen tohim,Margaret and Itrailing along taking meas-
urements, including serum cholesterol,on samples of men in the populations.
Those travels found great differences in thefrequency of hospitalized coronary
heart disease,in themodeof life,including thediet,and inserum cholesterol levels.
Professor JackBrock,head of theDepartment of Medicineat theUniversity of Cape
Town MedicalSchool,invited us tolookat thesituation inCapeTown.On the way
toCapeTown westopped inUganda where Dr.Jack Davies,pathologist in
Kampala for theregion, had made preparations toentertain and instruct us.He had
arranged adisplay of200hearts dissected with thecoronary arteriesopened. Inall
but twoof theheartswere thecoronaries essentially clean,but those twohad exten-
siveatheromata. Heexplained that those were theheartsofbutchers whose pay for
theirwork was theoffal, theentrails,which formed apart of their diets.
InCapeTown theexcellentGrooteSchuur Hospital has twowings,one for
'Europeans',aswhitepeople arecalled there,theother for allother patients-

18
Blacks,EastIndians and mixed groups called 'Capecolored'.Themedicalstaff, all
trained in England,served both wingsequally.There wasdiscrimination in admis-
sion tothehospital but,sofar aswecould see,not in thequality of diagnosis and
treatment. Inthewing for Europeans coronary patients werecommon but perhaps
somewhat fewer than would beseen in Minnesota hospitals.Intheother wingof
thehospital coronary patientsweresaid tobeextremely rare.Someof the findings
inCapeTown werereported inThe Lancet 1955;2:1103.
Wemade nocholesterol measurements ordiet surveysbut in amonth of eating
inprivate homes and restaurants thedietsof the Europeans seemed tobe primarily
English,with localmodifications reflecting themild climate.Incontrast, the mar-
ketsand eatingplaces for the Blacksindicated very littleconsumption of meat and
dairy products.Therewasone curiosity.Wesawlobstersin thecommon markets
but neverwereserved lobsters toeat.Weasked why,and were told only the blacks
eatlobster!Wewerepuzzled, especially when welearned that some lobsters were
shipped toEurope.

Surveys in Italy
Afew days after returning from CapeTown wewereoff toSardinia tomakea sur-
veyinCagliari.Our host,Professor Aresu,arranged everything for our conven-
ience,finding agood placefor Margaret tomeasure cholesterol,getting helpers to
bring men for examination, escorting Dr.Paul Whiteand Dr.Reuben Berman,car-
diologist from Minneapolis,on toursof thehospitals.Paul and Reuben saw some
heart patientsbut very few of them wereof coronary origin.Margaret found the
serum cholesterol levelvery low,and somedoctors remarked that was surprising in
view of thefact that eggswereabundant, and themen were eatingan eggor two
every day.They knew that eggyolksarefull of cholesterol but they did not know
that inman,incontrast torabbits,dietary cholesterol inordinary diets has relatively
littleeffect on theserum cholesterol (Arch Inter Med 1950;86:189).Controlled
experiments on man found littleor noeffect on theserum from adding cholesterol
todietscontaining theusual amountsofcholesterol in ordinary diets (Science1950;
112:79,JNutrition 1056; 59:30).Later studies found asmallrelationbetween serum
cholesterol and cholesterol inthediet (JNutrition 1960; 71:61,JLabClinMed1961;
57:331).Moreevidence on thesubject was reported inJNutrition 1953;87:52and
1965;67:52.Considering thefindings incontrolled experiments,thefindings in
Cagliari werenot exceptional.Itwasgratifying tonote that apopulation survey can
agreewith controlled dietary experiments.
FromCagliariwewent toBologna and found anentirely different picture.In
Italy,Bologna iscalled 'la grassa', meaning itisthefat cityand themost cursory
inspection showed theappellation isjustified. Not only was thediet fatty, people

19
tended tobefat. Weexamined themen intheFireDepartment. Theaverage Body
MassIndex was higher than that of themen wehad been studying in Minnesota.
Wecould not blame itall on thediet;how much exercisedo firemen have inacity
whereeverything isbuilt with stone?Theserum cholesterol levelsin Bologna were
much higher than Margaret had recorded inCagliari.Meanwhile,Paul White found
nolackof coronary patients in thehospitals of Bologna and nearby Modena where
themode oflife was similar.

What about the Japanese?

Thevital statistics forJapan showed extremely few deaths attributed to coronary
heart disease.InCape Town thecomparison wasbetween two different raceswitha
great difference ineconomic level.Morerelevant would beacomparison of menof
a single non-white racediffering in mode of life.Dr.Paul Whitejoined us when we
made surveysofJapanese men in Hawaii and Japan.At theexcellent Kuakini
Japanese hospital in Honolulu thedoctors told Dr.White they occasionally had cor-
onary patients.Theserum cholesterol levelsin samplesof healthyJapanese men
brought in for examination wererather lowbut not extremely so.
Wefound adifferent picture inJapan. Dr.Noboru Kimura,Professor of
Medicineat theKurume MedicalSchool,had farmers in nearby Tanushimaru
brought in for us toexamine.Their serum cholesterol levelswereextremely low.
Wecould not properly survey theirdietsat that time,but,clearly,they were almost
fat-free, nodairy products of any kind,almost no meat;theonly animal foods were
from thesea.InFukuoka, thenearest largecity,thediets and serum cholesterol
levelswerelikethosein Kurume,and thedoctorswereunable tofind a coronary
patient for PaulWhite toexamine.Thepathologist inFukuoka told us about agreat
rarity hehad found in theprevious year.AJapanese doctor who had returned to
Japan after practicing in Hawaii for 20years had dropped dead;hiscoronary arter-
ieswere atheromatous.
InLosAngeles theJapanese men werelargely Americanized intheir way of life,
including thediet.Their serum cholesterol values tended tobeonly alittle lower
than theaverage for whitemen inMinnesota.Atthehospitals wewere told that
Japanese men with myocardial infarction werenot rare.Thefindings on the
Japanese men in these surveyswere reported in theAnnalsof Internal Medicine
1958;.48:83.Adietary experiment onJapanese coalminers in southern Japan found
their serum cholesterol response toachangein thediet was not different from that
expected from diet experiments inMinnesota. (AmJClin Nutr 1957;5:245).Several
miners could not finish theexperiment; more fat in thediet than in their ordinary
diet made them sick.

20
Ilomantsi and Surveys in Finland
Amajor stimulus towork on thecoronary problem inpopulations was avisit to
Ilomantsi,alargevillagein Karelia in themost eastern area of Finland,only a few
kilometers from theRussian border. Martti Karvonen said itwas reputed beset with
coronary heart disease,and hetook methere tosee.Therewasno hospital buta
kind of lazarette with beds for sixmen.Oneman was very illwith emphysema,
another had pneumonia, athird was ayoung man who had been bitten byabear;
three men suffered from myocardial infarction. Wewent toalogging campsoclose
tothe Russian border wecould hear sounds from Russia.Weenjoyed asauna with
theloggersand when wecameout therewererefreshments. Theloggershad slabs
ofcheese thesizeofasliceofbread on which they smeared butter; they washed it
down with beer.Itwas an object lesson for thecoronary problem.
In 1956Martti Karvonen organized surveysonmen ineastand west Finland and
inHelsinki.The24-yearfollow-up found 345men alive,152dead.Thehabitof
smoking cigarettes was themajor risk factor for cardiovascular and all-causes
deaths.Thedata werereported in theInternationalJournal of Epidemiology 1984;
13:428.TheBodyMassIndexatentry was higher in thesurvivors than inthe men
who died.Thelevelof HDL(alpha lipoprotein) cholesterol in theserum atentry did
not distinguish thesurvivors from thedead. Epidemiologists could object that the
men werenot random samples of populations.

Prospective Studies in Different Populations

Allof thestudiesdescribed abovehad faults.Themen weexamined were not ran-
dom samplesof populations,and therewas alackofproper controlsand numbers.
Prospective studiesindifferent populations wereneeded. Itwasdecided that the
men tobestudied prospectively should berelatively stable inlifestyle toreduce the
problem of evaluating effects ofchanges.Inthisrespect men invillages would be
preferred tomen incitieswho toooften change theirways and placeof residence.
Besidesfocusing onvillages,wefelt men longemployed byrailroad companies
would besuitablefor along-time prospective study,becauseboth in the United
Statesand inItaly they seldom seekother employment. When they retire they
receiveagood pension and when they diethe heirshaveadeath benefit certified by
an official death certificate. Thefindings inprospective studieson railroad men in
theUnited Statesand inItalyaresummarized inanother section of thishistoryof
theSevenCountries Study.
Prospective Studies in Villages
Wewanted tomakeprospective studiesonmen invillages,but thefirst require-
ment was toput together international teamsfor working invillages.Methods and
procedures mustbe tested and established. Atrialin avillagewas needed. Forthis,
Dr.Alfonso DelVecchio,an associateof Dr.Fidanza inNaples,suggested his native
village,Nicotera in southern Italy.Therewas nohousing for ateam in Nicotera, but
notfar away in Gioia Tauro therewas anewJolly Hotel and restaurant suitable for
livingquarters for the team.
Thedoctorsand officials inNicotera weredelighted about having an interna-
tional group work in theirvillage.Theydid everything tohelp,providing quarters
for thework and gettingassistants toround up men for us toexamine.Soon we
werebusy with examinations. Forserum cholesterol measurements wetook advan-
tageof afact found by Dr.Joseph Anderson in Minneapolis.Thecholesterol in
blood serum dried on filter paper isstablefor months ifkept away from heat and
light. Blood serum put on filter paper with acalibrated micro-syringe and dried in
room air canbeextracted and thecholesterol measured with amethod adapted for
micro-amounts. (ClinicalChemistry 1956;2:145).Great for working inthe field
without fancy apparatus!
Dr.Anderson reported hischolesterol measurements tousbut said ina few sam-
plestheamount was unbelievably high.Somedetective work found the explana-
tion.Our work room had no window screens and therewere flies.We discovered
that fly speckscontain cholesterol or something that actslikeitin theanalysis!
Putting screenson thewindows was thecure.
Oneday therewasaterrific thunder storm,much lightning and high winds.
Whilewewerecovering inour workplace acardrove up and awoman under an
umbrella came tothedoor.Sheintroduced herself asDr.Louise Dalderup,sent by
Dr.Muntendam, Secretary of Statefor PublicHealth in theNetherlands,to inspect
our work.Theoutcome,severalyears later,was theestablishment of theSeven
Countries'cohort of men inZutphen, atown inthecentral-east part of the
Netherlands.
Iwanted tofind something about themortality inNicotera,and was given
accesstotheofficial death certificates. Inchecking thecertificates for the twoprevi-
ousyears,Icould not understand sixrecordsofmen for whom death was attributed
to 'gelosia',jealousy in English.Iasked thelocaldoctor toexplain. Hethought abit
and said itcould becalled lead poisoning. Iquickly caught on;bulletsaremadeof
lead.Amusing,but enough toconvinceus that thelocaldeath recordsneeded spe-
cialexplanations for epidemiological purposes.

22
 Pilot survey in Nicotera, Italy, 1957.

A Trial of Working Men in Greek Villages - Crete

Theexperience of working inNicotera showed that an international team could
makeagood survey inavillage inItaly.Thenextquestion was toseeif similar
work could bedonereadily invillages in other countries.Dr.Andy Dontasin
Athens was privy toour work and proposed wetry todo thesame kind of survey
on theisland ofCrete.He,and Dr.Christ Aravanis,aleading cardiologist in
Athens,made arrangements for similar work in villagesonCretewith headquarters
inHeraklion, themain port and largest city inCrete.
InOctober 1957weloaded our station wagon in Romefor thework inCrete and
had dinner with Dr.Vittorio Puddu, thefamous cardiologist, in hisapartment ina
quiet area of Rome.Returning tothecarwefound aboxof paper for the electrocar-
diograph machine wehad lashed on topof thecar wasgone.Nothing could be
done about itbecause wehad toleavein themorning ona tight schedule.AtVibo
Valentia westayed overnight before taking theferry toSicily,wherewe would
board theship bound for Athens.
InAthens weleft our daughter, Martha,withJenny Dontas,sent our station
wagon by ship,and took a 'plane' toHeraklion, whereweset up headquarters in
therecently completed Hotel Astir. Wewere truly an international team. Besides
Margaret and I,and theGreeks,including Dr.Constantine Chlouverakis and the
nutritionist Helen Sdrin from Athens,wewerejoined by Dr.Flaminio Fidanza from
Italy, Professor Noboru Kimura from Japan,and Dr.Martti Karvonen from Finland.
Theshortage of paper for theelectrocardiograph machine wasa problem.Jenny
Dontasbrought Martha to Heraklion for avisit.Shehelped her mother cut the
paper lengthwise, doubling thelength.Thesensitivity of themachine was reduced,
sowecould get thewholerecord on thehalf-sized paper.

23
 Thework went wellin thesixdesignated villages inspite of very bad roads and
thelanguage problem.Only theGreekscould speak Greek,but wewere fortunate
in finding alocalwho spoke English.George Arniotakiswas not only a translator,
but he helped every stageof thework, including enlisting other helpers and repair-
ing our automobile,therear springsof which werebroken bydriving on thebad
roads. Nomatching springswere available,soGeorge had thebroken springs
replaced with truck springs.They lifted up therearend of thecarsothe headlights
pointed straight down. Nomatter;wedid not have todrive at night.
ButGeorgecould not rebuild theroads tothe villages.Toget toone of thevil-
lages1 drove thecaratasnail'spacewhileMargaret and Noboru walked ahead
removing boulders on theroad .Ihad toreturn to theStatesfor acouple of weeks,
so Margaret had todrive thecar.The narrow road from Heraklion tosomeof our
mountain villages had been carved out of theside of themountains.Gravel for
eventual road repair wasdeposited on theedge of the road, where there wasa steep
slopedown.Therewereoccasional placesfor passing,but coming down one late
afternoon, Margaret encountered astring of buses going up inastretch of road with
nopassing space.Shehad nochoicebut todrive up onto thegravelpile,where sev-
eral men from thebuses got out and held thecar almost out of theway;only the gas
capwas knocked off.
Wecould not measure serum cholesterol in Heraklion. Thesamplesof blood
serum were frozen and sent by air toAthens,where they were kept frozen until
they could bepacked tostay frozen until carried to Minneapolis for analysis in the

Arrivalof pilot study group in Crete, Greece, 1957

24
laboratory at theUniversity of Minnesota.Thelevelsof cholesterol proved tobe low
but not strikingly so.Helen Sdrin, thenutritionist, reported diets moreorlessin
keeping with thecholesterol levels,but shecould not do acompletejob.Inoneof
thevillages Itold George toask thefarmers about breakfast, wondering if they
werelikemost farmers in southern Italy,whoeatnobreakfast. Mostof theGreek
farmers said theyatenothingbefore going towork inthefields but somesaid they
had aglassof oliveoil.
In theCretevillagescoronary heart diseasewas rare,and themen seemed tobe
long-lived. Wewere told about farmers still workingat 100yearsofage,but could
notcheck thevital statistics with death records which werewritten byhand in
Greek.ThevillagesofCrete werecandidates for aprospective study,and our expe-
riencethereassured us that thereal work of theSevenCountries Study could be
done invillages likethose.When wetold Dr.RatkoBuzinainthe Universityof
Zagreb,inwhat was then Yugoslavia,about theway things went inCrete,he said,
'Fine!' and began making arrangements for thefirst examinations for theSeven
Countries prospective studies inMakarska and Slavonia tostart in 1958.What hap-
pened in 1958,and later inMakarska and Slavonia,isanother part of thestoryof
theSevenCountries Study,which will follow.

25
IMPRESSIONS FROM THE FIELD
_ ^ ^ _ H. Blackburn

rieldwork in theSeven CountriesStudy was agreat adventure for

all who participated, delightful and satisfying when schedules moved along well,or
frustrating and threatening,requiringemergency correctiveactions indaysof fail-
ures and confusion. Thefollowing areexcerpts from field journals depicting these
extremesofexperience and emotion while 'under fire.' Elsewhere,an extensive
description isgiven about thedetailsand 'color' of thefield survey operations in
eachof theSeven Countries'areas for thebaselineand 5-yearfollow-up surveys,
compiled from vivid memories and journals kept inmany of theareas.Theseanec-
dotesareavailable toany interested reader.1

D a l m a t i a , First Round, 1958

September 28th. 'Weallroseearly thismorning tobid adieu toPaul Dudley White,
after which weformally opened theSevenCountriesStudy inMakarska,on the
Dalmatian coast ofCroatia inYugoslavia.Wearesituated inavirtual desert ofcrys-
tallinelimestone mountains that tower abovetheAdriatic,tinyvineyards scattered
on their slopes.Shepherds arehuddled hereand therein thecold dawn as others
moveintothe terraced olivegroves.Thereiseverywhere thetiresome,focused pre-
occupation of peoples inaland wheresoiland water arescarce.Our central head-
quarters,HotelJadran,ispoised above theshimmering sea with aview of thearchi-
pelago through ahazeon the horizon.
Day 1inour first village,Tucepi,just south of Makarska.Wehad afive minute
power failure at 1:00 p.m.that required acall tocentralpower.Theypromised no
further breaks!Thetechniciansarenew and inexperienced but full ofgood will.The
clinicians arewelltrained, familiar with American nomenclature and diagnosis, and
makethorough examinations whileremaining on schedule.Weexcluded only two
people from theexercisetest today,onedue toemphysema and onefor hip disease.

H.Blackburn, The Seven Countries Study:Adventures inthe Field,Division of Epidemiology, School of Public Health.
1300 2nd St,Suite 300,University of Minnesota, Minneapolis, Minnesota SS454.

27
 Dalmatian coastal road, I 958

Thecoastal road from Split south to Dubrovnik was apparently last redesigned
and repaired under Napoleon! Acoupleof men inevery village along theroute are
delegated full time tomaintain theroad, filling pot holes in theclay,scraping and
smoothing and tamping. Welearned that wecan often transport our team from
coastal village to village moreeffectively and comfortably byboat than bybusor
jeep.Thus,wetrundle generator and ECGmachines and laboratory equipment
aboard ship at the hotel dock, and accompany them tothenext stop.Becauseof
power variations and failures weuseagenerator, sometimes running allday, but
placed as far away from thesiteas possible to reduce noise.Today an unanticipated
hazard wasan invasion by wasps!Our faithful driver, with a longcane poleand
gasoline-soaked flare, saved usby smoking out their nest under theeaves. Another
hazard required particular ingenuity. When theblood sample iscentrifuged and
serum separated, standard aliquotsarepipetted ontospotsof Watzman #2 filter
paper, and these hung outdoors todry. Wehad neither anticipated that fly specks
would bedeposited on thedrying spots,nor that they would contain cholesterol!
Wetherefore hired a localchild to fan thedrying serum to keepaway the flies. The
dried serum strips are then cut,two kept in thelocal laboratory and two placed ina
glassineenvelope,and sent airmail back to Memorial Stadium in Minnesota.
September 30th.Much of our equipment has not yet arrived, from which experi-
encewewilllearn tocarry, in future, all important supplies aspersonal baggage!
Thelovely Indian Summer changed abruptly today toa rareand furious thunder-
storm.Thesound of thecrashing surf isprolonged by tons of water sucking back

28
through a myriad of pebbleson thebeach.In thefield, weagreed today on alldiag-
nosticclassifications with Professor Hahn of Zagreb,and our chief physician, Ivan
Mohacek, theirsbeing perhaps moreobjective than ours for 'chronic non-rheumatic
endocarditis'.Wealsoagreed that all four casesof chest pain werenot angina pec-
toris.Professor Fidanza suggests that comparisons of coronary disease frequency
madebetween samples in Dalmatia,Crete,Italy,and Finland maybe inappropriate
because themake-up of thecommunities issodifferent, alarger proportion of
upper socioeconomic classesbeing found insomeSeven Countries' areas than in
others.Werefer him and hisobservations toAncelKeysfor satisfaction!
October 1st.Sincewehavenot yetreceived our U.S.equipment and the precious
Sanborn Electrode paste,weget terribleelectrocardiographic recordsusing home-
made,brine-soaked pledgets.Our frustration intheexamination room is assuaged
only slightly by themagnificent view from our window inthe Podgora Civic Center
perched high abovethesea.Our routineisinterupted bypeople who constantly
bring us 'moste' todrink ateach day's stageof thenew wine,along with fresh figs,
grapes,and applesby thebasketful. Constipation isno hazard in this land!
October 7th.Tonight the team conducted aseminar on arterial thrombosis and
reviewed thetheory that thrombus formation isa focus for organizing atheromas.
Weconcluded 'that thevery labileand dynamic factor of clotting may be highly
important, aswellastheslower cumulative process of atheroma; they may even be
related, and factors of diet,emotion,and physical activity may influence both.'(Eds.
Not badfor atheory in October, 1958!)
Due toterriblealternating current (AC)interference from defective internal wir-
ing and nearby power lines,weconverted tobattery operation today, rotating
between threedirect current (DC)sourcesusing a 12-voltcapacitor vibrator givinga
constant 60cyclesat maximal output, stepping itdown with a transformer.
Batteriesareconnected in parallel but their effective life isonly half aday.Our ECG
paper drives fail,due apparently tothefact that thepaper rollswere compressed
intooval shapesduring travel and areacting ascams,putting undue stresson the
motors!ButtheECGoperation has improved vastly sincethe final arrivalof
American electrodejelly!
Professor Ferber ofZagreb pointsout that thereisahigh intakeof grains from
breads in thisregion,with arecent shift from corn towheat flour. Thebest local
products with thegreatest nutritional valuearesold immediately through traveling
salesmen tourban markets.Wivessellall theeggsbecause 'egg money' is tradition-
ally theirs.Itturnsout that children on occasion stealeggsfrom under thechickens
for money tobuy sweets.Mostof themilk isskimmed and fed tohogs.Vitamin and
mineral intake isborderline;ricketsiswidespread inDalmatia but much worse
apparently inneighboring Bosnia.Itappears that theMuslim men theremay pay as
much as300,000dinars for awife and they apparently choose nutritional deficiency

29
over wife deficiency! Mostof themeager 10%of fat in thediet herecomes from
lard,never butter. Butclearly,wemust carry out seasonal dietary surveys because
of theremarkable seasonal variations in foods available.
Our backs takea tremendous jarring when wecommute in theU.N.jeepon the
narrow, winding, rocky road.That 'highway' becomes thecentral focus of our lives
when wecommute down thecoast tonew villages.Itis,in fact, quite dangerous.
One wheel off on theshoulder, oran unexpected encounter with a 'Dalmatian jeep'
(donkey) would send our vehiclebounding, rock torock, terracetoterrace,a long
way down to thesea.
Weare300cardiograms behind schedule inmounting due toa defective
Hungarian stapler.Our thumbs arebruised and bleeding from operating this awful
machine.WeuseScotch tape tomount ECGsin anemergency and Dr.Keys has
suggested that wecableMinnesota Mining's Mr.McKnight himself,as follows:
'Stuck for stickystuff.Send 1mileof3/4' Scotch tape.'(Itwas fortunate wedid not
do thisasallrecords tacked down with Scotch cellophane tapequickly became per-
manently blackened beneath the tape.)
October 8th.After 10daysofconstant field operation, several of us took a day's
break for afishing trip with alocalpartisan leader.Themorning was warm witha
soft hazeand theseaaflat calm aswe pulled ontoan island.Thereoneof the fisher-
men cooked our breakfast of sardines and tuna, roasted over coals.After eating
morethan usually of thefish, Idiscovered aliveascarid wrigglingjust under the
skin,abruptly terminating my fish eating!Apparently all thefish areinfested. The
fishermen seemed scornful of mymeagre appetite,aswellasinability todrink sli-
vovica (plum brandy) early inthe morning,and wondered about my elaborate pro-
tection against sunburn. Wesoft Americans have twostrikes against uswhen we
attempt tosocialize with seasoned peasants and powerful partisans!
October 10th.FlaminioFidanza left thefield study today and all parted good
friends. Somehad becomeill-humored at hisincessant preoccupation with thequal-
ity of field operations atevery station,including themedical clinicand ECG room!
That sentiment dissolved lastevening with Fidanza's departing speech,given in
eloquent Italian, inwhich heshowed thegreatest respect for theleadership ofAncel
Keys,for thegeneral spirit of international cooperation of theSeven Countries
Study,and for thescientific and socialsignificance ofour common research effort.
When thepower failed hefinished hisfine oration,dramatically,by candlelight.
Forthedietary survey, Fidanza and Ferber had ground up foods purchased
from thelocalmarket, and aliquotsof mealscollected in random households.They
put allin thedeep freeze for later analysis for total lipids,fatty acids,aminoacids,
nitrogen, and ash inthier labsand Minnesota. Flaminiowas persistent in running
down such itemsasspinach,sheep's milk,and turnips,which others said would be
impossible tobuy onthe market.

30
 Group of examiners at Makarska, Dalmatia, 1958.

October 15th.Finally,our survey routine is'perfected'. Thegasoline generator

functions splendidly asastable power source,and there isnohitch in the examina-
tion schedule,now running at40men aday.Tonight wehad along electrocardio-
graphic mounting session with much pleasant banter (and lesspleasant singing).
Professor From-Hansen and wife from Denmark worked diligently as the professor
sang bassand stapled records,both with great aptitude. Weliveintrepidation each
timethestapling machinejamsthat itwill never work again.One technician writes
names and numbers on therecords.Peter and Margaret Brozek arrange cards for
mounting the resting and post-exercise records.Professor From-Hansen cuts the
strips with great accuracy. Liliana and Iform astrong team,arranging theECG
strips prior tostapling. Itlooksasifwewill get thewholebatch mounted and ready
for shipment to Minnesota by theend of the week.

D a l j , Slavonia, O c t o b e r 20, I 9 5 8 .
Chosen for adiet contrasting with Dalmatia, thisisaregion of drab farming villages
having nocenter, strung out,one-house deep,along a2-3kilometer main streetof
pitted slippery clay.Thesenon-towns aresurrounded by vast plainsreaching far
into themistsofSlavonia and Hungary. Myriads of geesehonk and huge black pigs
snuffle along theroad,grunting indirty belches.Thecattle,too,areimmense. Here
isevery evidence of material richness amidst spiritual poverty. Houses are
unkempt, thewater filthy, hygiene wretched, thepeople obeseand sodden, living
inaconstant downpour of rain externally and slivovica internally. These prosper-
ous 'kulaks' avoided Stalin's genocidebut guard an ingrained prejudice against
orders ofany sort,government of allsorts,and particularly against giving blood
samples.Therumor going about isthat following our dietary survey their local tax-
eswillbeincreased. Thismaybeareason for our poor survey start in Dalj.
Today we 'brokeour backs' with 43participants seen.Remarkably, none was
drunk. Butdisaster lurks every morning asweturn on theECGmachines.The

31
machine Irecently carried allthewaytoParisforrepairsisstillunstable. Careful
calculationsoftheelectrode pasteandpaper rollsavailable suggest thatwewill
makeit—butbarely.
October 24th.Thefogisheavy today.Theruddy farmers andrustic wivesin
patched trousers,themudandfilth, screeching geeseandgrunting pigsand rattling
wagons;allrecallthecoarse peasantry ofBreughel paintings from theMiddle Ages.
On sunny dayswehavenoparticipant response atall;simply nooneshows!The
nearby market fair hasalsoreduced flow toatrickleof27participants,onaverage,
aday.
On thepositiveside,weareblessed with marvelous ECGtechnicians here;
Sabina andVelicaarecompetent, hard-working,uncomplaining and,most impor-
tant, non-singing!AlltheDalmatian cardiograms arenowmounted andweare
plowing through initial codingattherateof40anhour, mostly 'normal' records,as
weapply ournewlydevised Minnesota Code.
October 28th.After allwassaid anddone,wefinished inDaljwith onlyone
missing participant andidentified therebyelectrocardiogram twomyocardial
infarct patients.Wehavehadawonderful timewith Pentti Rautaharju from the
Finnish team.Heworks meticulously ontheelectrocardiograms andwillsoon come
toMinneapolis where wewillcompleteanddocument theMinnesota ECG coding
system.Iamnowleaving mypart ofthefieldwork supervision toPentti,and
departing from Yugoslavia with mixed feelings.Imuch enjoy thecompany ofcol-
leaguesandstaff, need more timetocomplete theclinical classifications, and want
toseethefirst formal round oftheSevenCountries Study surveys wound up 'tight'.
On theother hand,alongperiod ofdysentery hasleft menear collapse.
Accompanied byagood nurseinafirst-class railcar toZagreb,restored byalittle
saltybullion, IamnowenroutebyrailtoTrieste,andfind Ihavethestrength to
makeittoVenice.ThereIcanrest andrecover within reach ofmedical colleagues
and friends inItaly.From 'thepits'ofSlavonia, working inanepidemicofalcohol-
ismandshigellosis,residing inafilthy hotel,andsuffering bone-shattering roads,
mire,andmisty cold,andgruelling hoursofsurvey routine,itisapleasant relief
indeed tohear therailsclicking,leadingtothenorth andwest,andtoimaginethe
lightsofItaly,Austria,andParis.Icaneven dream ofacold glassoffresh orange
juice!

Crevalcore, Survey Round I , March I960

Chosen fordiets contrasting with southern Italyweareintothe'tough stuff' al-
ready inthisprosperous farming country north ofBologna.ACinterference seems
with uspermanently,andthereisnoconvenient other room inwhich tohousethe
ECGoperation.Two typicaloldanterior myocardial infarctions were already

32
observed in thefirst 100participants,plusacaseofmalignant hypertension with
retinal findings and onediabeticwith capillary aneurysms. Buttheroutine iswel)
established and Ican securely depart from thefield, leaving these instructions for
Doctors Mohacek and Tedesco:
• Seekperfect ECGtechnique at alltimes,with aminimum of ACinterference and
baseline wandering;
• Good records arethemost important asset inrendering thereadings and the
measurements reliable and accurate;
• Transport allapparatus by train after secure packing;
• Pleasemakecomments on theSeven Countries clinical criteria before they are
put infinal form;
• Record thefirst blood pressurebefore takingthesecond,asadiscipline for let-
tingthemercury fall tozero;
• Between stations,please takeallElemaelectrodes toMilanoand exchange them
or have them replated;
Suggested pattern for SevenCountries morbidity and mortality surveillance:
1 Mortality. Aphysician should interview theparticipant's physician and/or fami-
lyineachdeath case.Review records madeduring terminal illness;createabrief
narrative account with clinicalor pathological diagnosis ofcauseof death.
2 Morbidity. Usethesameprocedure, including arepeat examination of the survey
ECGand urinalysis on thosewith suspect cardiovascular diseaseevents.Wewill
provide central criteria for classification of new events.
3 Electrocardiograms. Repeat ECGsonallthose found with abnormalities,or techni-
callyunsatisfactory records.
4 Urinalysis. Repeat urinalysis on allthosewith dubious or positive findings.
5 Bloodcholesterol. Consult Dr.Keysfor quality control measures.
6 ECG trouble-shootingchecklistforerraticrecords. Check skinresistance, contact,
grounding, polarity,magneticfields, tremors,transformer, and amplifier defects,
and power failure.

March 22nd.Thefirst Crevalcore survey round hassettled into asmooth routine.

TheItalian team,lessstoicalthan theYugoslav,Dutch, Finnish,orJapanese teams,
works together effectively, isquick toidentify bottlenecks and resolve them, and
responds welltothedaily confusions of allsorts.Thenoonday break,traditional in
Italy,becomes apleasant part of thelongwork day,when wecanvisit Trattoria
Julia,a 'hole inthewall' with tablesfor adozen peopleand atinykitchen with open
gasburners onwhichJulia prepares exquisitedishes,especially spinach lasagna.
Unfortunately, Ihave 'threestrikesagainst me'withJulia;Iam American and non-
communist, Ispeak littleItalian,and am not possessed of agiganticappetite like
myItalian colleagues!

33
G r e e c e , First R o u n d , S e p t e m b e r I 9 6 0
Thespecial knowledge of theProfessors Aravanis and Dontasand their colleagues,
students,families, and friends living on Corfu and Crete,provides the background
for themajor scientific question addressed here:What isthelong-term effect among
rural,activepeasant populations of arelatively high fat diet composed of high
monounsaturated and lowsaturated fatty acids?Any 'mystical,life-giving proper-
tiesof oliveoil'can alsobe tested stringently.TheGreek Islands otherwise sharea
salubrious environment, gentleclimate,and characteristic Mediterranean living pat-
tern,adiet with onlyoccasional meatand chicken, frequent fish and seafood, and
traditional daily staplesof grains,legumes,vegetables,and fruits.
Thefield team ishighly compatible, 'veryGreek',expressing deepaffection for
their homeland.They enjoy working with thedark Cretan pappas,exploring their
salubrious diet and dignified, timeless lifestyles. Wesharewith participants alemo-
nade or an ouzoin thelocaltavern and listen asthey do,with appropriate skepti-
cism,tothepolitical rantings from Athensover theradio in the square.
There isminimal evidence of modern industrial society on thisisland.Themen
walk totheirfields or ridebicycles;television isnot amajor influence. Weseegrain
winnowed instonecircleshigh on theplateaus of Creteby thefeet of men orby
women inblack,pulled on awooden sled bydonkeys.Weexperience the mystery
of thearid, rock-strewn plateaus during thegrain harvest and travel tohigh pas-
tures inwhich men enjoy each other's storiesand company and dance at midnight
under thebright moonlight. Wenow know Zorba's madness.Wetoohave felt the
heart swell inthisstarkbut sereneenvironment. Wearemesmerized by the buzzing
of midday flies.Thecicadas 'saw' away at frequencies that mount during the day
and slackoff in thecoolofdusk.Atdawn weenjoy thedonkey'sbray while the
whippoorwill's and nightingale's callsarewafted tous asfrom afar. Weare
enchanted by thepurple sky that melds into theviolet sea,by thesoftly lapping surf
and thedappled sunlight through thegrapearbors,aswegather at tables during
thelong midday break.Weare fascinated by thepreoccupation everywhere with
obtaining water in thisarid land and by thelushnessof tinyoasesfound here and
thereunder thepanoply ofolivesand grapes,and on thesouthern coast,of bana-
nas.Everything isdesigned according toancient principles tomaximize the water
supply and guard its runoff.

F i n l a n d , Second R o u n d , S e p t e m b e r 1964
TheFinnsmakelongvoyagesbyboat,bus,truck,carand often bybicycletocome
for theirSevenCountries 5-year examinations at theSovietborder guard station in
Ilomantsi.Oneof theremarkable thingsabout Finland isthat the men are sophysic-
allyfit, yet their arteries aresoinvolved with atherosclerosis.Wearehere because

34
of evidencethat they eat theworld's most effective cholesterol-raising diet,high in
butterfat! Thelanguage tooisdistinctive,having astaccatosound, full of vowels
and bell-like from the tongueofour young technicians,clipped and swallowed by
our medical colleagues,and abearish growl from themouths ofour participants.
Allcreatesapleasant background harmony in thefield station.
Culturally-determined motivation and competitiveness differ in theSCSfield
operations.The Finnparticipants,for example,appear generally challenged by an
exercisestress test,'givingit their all'.These examinations are themore technologic-
ally advanced of allsurveys todate.Pentti Rautaharju and Herman Wolf have
developed systemsfor recording simultaneous multi-lead electrocardiograms and
exercisecardiograms,phonocardiograms, chest displacement curves,pulse wave
velocities,and pulmonary function, with thepromise that these willeventually be
integrated intoaquantitative prediction of functional capacity and,itishoped,of
future disease risk.Asan interested collaborator insuch highly technical undertak-
ings,perhaps Imaybepermitted toobservethat theinstrumentation seems perpet-
ually obsolescent, new instruments always takingprecedence over therecent old;
new questions consistently displacing theold ones,and new recording modes used
before old onesarethoroughly exploited orpublished.Theepidemiological need
for consistency, and comparability and stabilityof measurement, isoften supersed-
ed by thedriveof new ideas,new recording systems,and new technology!
Nevertheless,Ifully expect someyears from now tohaveavailable smallblackbox-
estotietopeople in field surveys;instruments that willintegrate respiration and
heartbeats,and electrocardiograms and pulsewaves,and givecontinuous read-
outsand predictions,inreliableand rugged recording systems.Perhaps we can
then moveintoamodern era of physiological data processing applied towhole
populations!(Eds. This1960dream isnotyet realized!)

Japan,SecondRound,March1968.
Wehaveexamined 100%of farmers inthetownship ofTanushimaru!Hereisthe
world's lowest diet insaturated fatty acids!Themajor field problem here isthe
damp cold,and wedo alotofwalking around thestation toensure that kerosene
stoves aredistributed, sothat themen waiting for blood pressure measurements
willnotbeexposed tocold stress.Weneedn't haveworried.Thesemen arewell
adapted toinclemency.Another 'hazard' isour catered lunches,arriving inlac-
quered boxeswith littlebamboo traysof highly colored,sundry unmentionable
squares,rounds and trianglesof fish paste,ricepaste,cold clotsof ricewrapped in
dark paper thin, spinach-like seaweed, allsortsofbriny fruit and vegetable pickles
and semi-cooked mussels and shrimps.Imanage todoaway with therice,using
chopsticksclumsily,much totheamusement ofJapanese colleagues,washing it

35
down with Kirinbeer,sufficient tosurviveuntil dinner with sake,and tasty tempu-
ra or sukiyaki!
Butthereisanother field hazard:the legendaryJapanese earthquake!This morn-
ingwewere hard atwork inthe littleframe school houseofTanushimaru, counting
pulses,taking blood pressures and supervising exercisetestsmadeon the incred-
iblypowerful Japanese men.Theflimsy school partitions,tied together around
largebamboo poles,were set on wooden floorboards, set,in turn,onwood pilings.
Suddenly,Ifelt an attack ofvertigo.Looking out thewindow, Inoticed the stone
memorial tothefounder of theschool,made of threelargestones,undulating each
on theotherand dancinga tango,yetnot falling. Theschool floors and walls,tied
together loosely,creaked wildly.Allmotion of theexaminations poised, the
Westerners lookingat eachother inconsternation, theJapanese calm at their posts.
Theundulations continued for agood 10seconds,subsided,came again slightly
and then weregone.Thelightness of theschool's construction was then explained.
Itwould havecrumbled and fallen upon us ifithad been built ofmasonry. We then
felt a 'rush' from theearthquake experience,on this,theearth's most tremulous
island.
Thereisanother socialhazard inJapan,which Iencountered with thekind local
physician ofTanushimaru. On hisvisitstoour examining stations,welearned of his
sensitivity and intelligence,and understanding of what wewereabout, aswell as
sensing hisdevotion tothecommunity.When heinvited us tohis home,Icom-
mented on itssimplebeauty and tradition. Hemust haveseen myeyesrest momen-
tarily on aparticular lacquer before shifting toother lovely artifacts around his
house.Imagine mychagrin when,on the train north toTokyo,Iopened the package
hehad put inmy armsaswe left theTanushimaru station and found that very same
lacquer,adeep Chinese red with emblazoned giltdragons,even now tobefound in
a 'Japanese Corner' ofmyMinnesota home after 25years.Imagine mygreater cha-
grin when Ilearned later that thelacquer had been handed down tohim from his
great-grandparents. Itisdifficult todeal with such generosity —or with thesocial
debt that itincurs!'
Thisisonly asample of thelaborsand pleasures,and ardors and concerns,of
many months in thefield, and at theSeven Countries coordinating centers,in
efforts toinsure theeffective collection and handling of data,aswell as coordina-
tion and collegiality among thestudy's devoted investigators.

36
C O O R D I N A T I O N OF
THE SEVEN COUNTRIES STUDY
H. Blackburn and A. Menotti

Itwasanticipated that thischapter would beconstructed by the

twoof us entirely from mutual records and memories.However, ashasoften been
thecaseinour longexperience with AncelKeys,hisclearand concise language
would render unprofitable our attempts atduplication.Thus,wequoteKeysexten-
sivelyfrom the 1967SevenCountries Monograph inActa Medica:
The basicplan of theprogram from which data arereported herewas to organ-
izeparallel studies on men aged 40to59inareasdiffering in thediet orin the
reputed incidenceof heart disease,orboth,but with areas sochosen that within
each therewould berelativehomogeneity.Amajor feature of theentire program
was theadoption of therigidly standardized methods and criteria,common proto-
col,and battery of observations and tests,and central coordination.This would
assure,sofar aspossible,completecomparability of thedata collected.Further, to
assuresuch comparability,arrangements weremade for interchange of professional
personnel among theteams working intheseveralareas,and for centralizationof
statistical and someanalytical services.Theextensive explorations prior to 1957led
tomoresystematic programs with aplan tofollow up men examined for five or
moreyears.Itwasagreed that asuitableagerangewould be40to59,and thata
seriesof population samplesshould bestudied inparallel.Accordingly,new pro-
grams from which data areherereported,werestarted in 1957with the railroad
employees intheU.S.,and in 1958in Dalmatia and Slavonia,Yugoslavia. These
werefollowed by theprograms whichbegan intwoareasof Finland in 1959,and in
1960inCrevalcore and atMontegiorgio inItaly,Zutphen intheNetherlands and
again onCrete.In 1961,thesampleinCorfu, Greecewasexamined. In1962another
study was added, thevillageofVelika Krsna,50kilometerssouth of Belgrade,
Yugoslavia.Thesampleof U.S.railroad employees was (re-)examined inthe same
summer.Theprogram inJapan,not strictly comparable inalldetails,began in1958,
at thefarming villageofTanushimaru and in 1960atthefishing villageof
Ushibuka.' In 1962theRomerailroad samplewasexamined asacounterpart of the
U.S.A.railroad. In 1963theSerbian cohort atZrenjanin (Vojvodina) was added, con-

37
sistingof men working inalargeagro-industrial cooperative.Finally,inearly 1964
thesample of Belgradeprofessors became thelast cohort enrolled.
'Members of thecentral organization (Professor Keysand Dr. Blackburn)
worked closely with teamsin each of thecountries.During theperiod of the initial
examination in each area thecentral organization provided help tothe local organ-
izations in theform of supplies,equipment, and professional personnel'.

Establishment of Rosters
'In theareasof work in Europe and Japan,official listsof residents,with birth dates,
arelocally available.However, such listsrequire careful scrutiny. Men who migrate
away from thearea areoften long retained on thelistof residents while newcomers,
particularly from that samegeneral region,may not belisted for yearsand, inevita-
bly,thereareclerical errors innamesand dates,and delays incorrecting for deaths.
Parish church registers,and electoral and taxation listsprovide additional data, but
detailed localinquiry among responsible residents isessential.
Initialofficial resident rollsarecorrected for emigration and additions for the
formation of a trueroster of theeligiblesample.Non-respondents are characterized
asbeing in hospital,disabled, not in thearea but reputed tobehealthy, refused,
apparently healthy,orrefused with possible heart disease.Accordingly, there were
13'chunk' samplesof allmen ofspecified age in thedefined areas.
Among thetotal of9,564eligiblemen,9,170wereexamined infull, the coverage
being95.9%.Itisnotable that thecoveragewasnearly perfect intherural areas,less
satisfactory in thesmall town ofZutphen,and considerably poorer among therail-
road employees'.

Examination Procedure
'Great efforts were made toassure comparability ofmethods and procedure on sev-
eral sites.Thelocally responsible team wasaided inthe field by professional experts
from theteams inother countries.Electrocardiograms wereindependently classi-
fied [centrally in Minnesota]by twoor moreelectrocardiographers, atleast oneof
whom was from another country. After theroster wasestablished, ascheduleof
examinations was adopted and headquarters wereorganized,both for the examin-
ation and for housing theteam of investigators and assistants.Ineacharea local
assistantsmade appointments for thesubjects and then reminded or escorted them
on theappointed day,soastoassureattendance attheexamination centers.
Transportation was provided when needed. Efforts were made toprevent the men
from indulging inheavy exerciseor heavy mealsbeforehand. Whilewaiting, smok-
ingwasnot allowed.'

38
 Thefield survey procedure wasasfollows:aregistration; banthropometry;
cmedical history and physical examination;delectrocardiogram and exerciseelec-
trocardiogram;eurinesample;ƒrespiratory test;gexit interview.

Classifications
Formsand codesdeveloped centrally inMinnesota for common use inthesecollab-
orativestudiescoverdemographics,medical history,physical examination, par-
entalmortality, family status,smoking habits,and anthropometry.
'Serum samples from allareaswere analyzed for cholesterol inthe coordinating
center at theUniversity ofMinnesota. Dr.Joseph T.Anderson directed theanalyti-
callaboratory and Nedra Foster supervised thetechnicians.Allof the electrocardio-
graphic tracingswereindependently read byat least two internists with special
experience inelectrocardiography. Dr.Henry Blackburn supervised thereadings by
thecollaborating physicians and reconciled disagreements in classification.
Dr.Joseph Brozek developed and standardized theanthropometric methods.
Drs.J.K. Kihlberg,R.WillisParlin and NorrisSchultzoftheUniversityof
Minnesota wereresponsible for thestatistical work on thedata from alltheareas.'

Fieldwork
'Selection of theperiod for fieldwork inagiven area required consideration of the
seasonal activity of thesubjects,aswellasthatof theproposed staff and, in general,
thismeansconcentration ofexaminations inaperiod notover one month. Before
thefieldwork proper begins,thefinal roster of subjects must beestablished, local
headquarters arranged,suitablelocalassistantsengaged, and provision made for
localtransportation ofboth subjects and staff.
Ingeneral,itwasfound tobeefficient toorganize scheduleand staff soas to
'process'from 150to200men per week for 6to8weeks;thisrequired making effec-
tivearrangements tohavethesubjects availableonschedule.Itproved tobe suit-
abletoconcentrate theexaminations inthemorning,leaving theafternoons free for
'bookwork',ECGclassification, working upblood samples,etc.,plushandling a
few stragglers that could not beexamined in themornings.Theclinician's schedule
had toallow for thefact that inmany areas itisimpossible toavoid some demands
for medical advice,particularly for localwomen and children.'

Suchaprogram for cardiovascular field surveys requiresastaff as follows:

1director of field operations; 2internistswho takehistories and make
1electrocardiographer; physical examinations;
1anthropometrist; 1 or moreclinical consultants;

39
1 physician or physiologist toconduct 1 biochemist orchemical technologist;
respiratory tests; 1registrar;
2assistants for electrocardiographic 4helpers;
recording; 1catcher tobring insubjects and run
1driver; errands;
1dishwasher; 1 general helper.

'Everyeffort should bemade toassure that therelationship with thesubjects is

developed from thestart on awarm and personally sympatheticbasis.The subject
may seem tobeonlyaserialnumber on theroster and appointment schedule, but
hemust never betreated that way.Ideally,abrief noteabout thefindings on each
man isprovided tothelocalphysician or public health nurse,not tothesubject him-
self.When itisnot feasible, each subject should begiven afew words of reassu-
ranceat theend of theexamination. When medical careisreally needed, efforts
must bemade toprovide thisthrough localsources.
Theexperience of theteams inthefield inEuropeand Japan quickly made con-
vinced internationalists of most staff members.Political arguments were avoided,
and concentration was on theprofessional and purely individual human aspectof
thework and life together; theresult was adevelopment of truefriendships among
staff workers of allnationalities and themost cordial cooperation of the subjects,
their families, and thelocalofficials. Though thesubjects frequently had littlecom-
prehension ofwhat thework wasallabout,thegood willonboth sides was readily
apparent; itwasoften aproblem toescape toomuch localhospitality in thevillages.
Ingeneral,theresponse of the populations totheappeal toparticipate in such sur-
veysseems tobeinversely proportional tothesizeof thecommunity; the response
isbetter invillages than intowns,and better in towns than incities.'

Forms and Procedures

Allforms and procedures weredeveloped centrally in theLaboratoryof
Physiological Hygieneand tested extensively in thefield in 1957,in theU.S.
Railroad Study,and in theNicotera and Crete field trials.Wewere considerably
influenced indevising these forms and proceduresby theprinciples of classification
proposed byMoriyama (JournalofClinical Diseases1960;11:462):
1 Thecategoriesof aclassification should bemutually exclusiveand clearly
defined;
2 the rubricsorcategoriesunder thevarious itemsshould berelated tothe item
and meaningful in termsof theireventual use;
3 thecategoriesmust beselected insuch a way that thedata within each sub-class
arerelatively homogeneous;

40
4 provision should bemade for theclassification of everycase;
5 areasonable frequency distribution should beobtainable from agood classifica-
tion system;
6 thefiner theclassification themorespecific willbethedata; and
7 allclassifications and editingprocedures should beclearlyspecified in writing.
Nothing should betrusted to memory.

Itwasalsoclear tousthat aclassification canonlybeasgood asthequalityof

theobservations onwhich itisbased.Theseshould beasobjective aspossible and
based upon distributions ofvaluesobtained from well-defined normal and abnor-
malgroups.Moreover,clinical disease classification for wide application cannot
require radicaldeparture from common diagnostic methods,and oneaxisofclas-
sification cannot beexpected tobeapplicable toallpurposes.Allclassesmust be
coded inbinary ordecimal form. Finally,there should besomebasisfor optimism
concerning acceptancebyauthoritative medicalbodiesbefore attempting to prom-
ulgateaclassification system throughout thewider medical public.

Coordinating Center, Stadium Gate 27.

41
Training
Inalmost everyinstance thePrincipal Investigator, or coordinators from each over-
seas teamof theSeven Countries Study, visited thecentral Laboratoryof
Physiological Hygiene inMinnesota for a period of orientation tofield procedures.
For thefirst round surveys we,orsomeone wehad trained,supervised theopera-
tion and data collection for allareas.On field sites,in thedaysjust prior to initiation
ofsurveys,regular staff review sessions wereheld on theuseof forms and on pro-
cedures for interviews,anthropometric measurements, historyand physical exam-
inations,electrocardiographic and respiratory function testing,as wellas urine and
blood samplecollection and processing.
Oneof us,oroneof thecentrally trained colleagues,circulated among examina-
tion stations asquality control officers, reporting needed adjustments in procedure
and technique atregularly scheduled field staff gatherings.Quality control in the
field alsoinvolved systematic editing of forms for grosserrors,deficiencies, and
omissions thatcould becorrected on site,aswellasmounting and inspectionof
electrocardiographic and other technical records.
Inmost circumstances,for most items,duplicate forms and recordsand samples
werecollected both for safety and for theindependent useof theregional teams for
their own researches.Theduplicates or aliquots were then forwarded by standard
shipping practices,registered and insured, toStadium Gate27,Universityof
Minnesota. There astatistician,and trained clerksreceived therecords,labelled and
entered them into appropriate files,and systematically edited theforms for errors
and completeness.Thefield supervisor or Principal Investigator was notified in
caseof seriousdeficiencies, which werecorrected byre-examinations inthe field.
Clinical classification of findings at entry examination (prevalence coding) and
for incidencecases wascarried out inadetailed hierarchy,asdescribed inthe1970
SevenCountriesStudy Monograph.Thisinvolves systematic application of criteria
for combined data from themedical history and physical form, alongwith theelec-
trocardiogram.

Adventures in Death Certification

Amajor central responsibility was standardized coding ofcausesofdeath,based on
death certificates and medical histories,provided tothecoordinating centerby the
responsible investigators.
Inthe25-year follow-up experience,almost6,000deathsoccurred in the16
cohorts;about half theoriginal participants.Becauseof thelargevariations in death
rates,extremely high inSlavonia and East Finland,and low inCreteand the
Belgradeprofessors, thepreferences for one instead of another causeofdeath had
tobeexamined carefully. Diagnoses and medical termswere frequently reported in

42
Latin in material coming from former Yugoslavia, reflecting the tradition of middle-
European medical schools. Some knowledge of Greek helped in interpreting the
Greek material.
The basically routine process of death coding provided personal insights for the
reviewers on death as part of life, and on the destiny of individuals and whole pop-
ulations. Some deaths were bizarre, others particularly tragic. For example,we
recorded one death in an air crash (a Finnish farmer), 4deaths due to lightning, and
4 from tetanus. An apparently late consequence of malnutrition and hardship dur-
ing World War IIwas 119cases of fatal tuberculosis, the majority in Slavonia and
Velika Krsna of former Yugoslavia. Not a single tuberculosis case was recorded in
the railroad cohorts of the U.S.A. and of Rome.
An indicator of the socio-cultural environment is provided by the suicide rate,
highest in Slavonia, an agricultural area of inner Croatia, contrasting with no sui-
cides in the Rome railroad employees, and only one in both Japanese cohorts!
Suicide by firearms was preferred in the U.S.A. and Finland; hanging was used in
the Mediterranean areas, with the exception of Crete where desperate people dove
into a well! We recorded 7homicides, 3in Finland, 3in former Yugoslavia, 1in
Rome and none in the U.S.A.,Japan, Italy, or the Netherlands.

On-going Coordination and Anal/sis

In 1967Alessandro Menotti took over in large part the coordination responsibilities
then held by Henry Blackburn. Meanwhile, Menotti had completed a second period
of formal training in epidemiology at the London School of Hygiene and Tropical
Medicine and had participated in practically all the field activities held in the
European areas from 1963on. He had already started a long-term appointment as
Research Associate at the Laboratory of Physiological Hygiene of the University of
Minnesota. Our joint activities included training and testing field personnel in the

Preparation of the summary diskette by

Bennie ß/oemberg, S/mono Ciampaoli,
Daan Kromhout and Alessandro Menotti,
Rome, June 1990.

43
several measurement and clinical techniques,being present for allsurvey examina-
tions,reviewing all clinical records for thefinal assignment ofclinical diagnoses,
and reviewing and coding all forms and death certificates, and descriptions for the
final allocation of causeof death,following defined criteria.Thiswork continued for
the15thanniversary examination inFinland (1974)and wasextended totheassociat-
ed studyareasinHungary,which wereneverfully incorporated into theSeven
CountriesStudy,although theyfollowed asimilar protocol (starting latein1965).
In 1973Alessandro Menotti started scientific cooperation with the Istituto
Superiore di Sanità in Rome(theNational Public Health Institute of Italy),which
involved accesstothe largest computer then available in Romeand toagroupof
physicists,mathematicians,statisticians,and computer peoplewho,littleby little,
were 'converted' toepidemiological pursuits.Thisallowed relatively sophisticated
analyses tobemadeon theItalian data and tofull collaboration with theSeven
Countries Study Group.Forexample,alarge part of theanalyses for the 10-year
monograph and most subsequent analyseswereperformed in Rome.Thiswas par-
ticularly useful after theUniversity retirement ofAncel Keysin 1972and theendof
central funding for the study.
Theroleof theRomecenter,crucial for coordination,becameeven greater when
mortality data started tobecome availableafter the 10thanniversary surveys and
when Menotti was appointed, in 1979,asresearch director for chronicdiseases at
theLaboratory of Epidemiology and Biostatisticsof theIstitutoSuperiore di Sanità.
Inthat laboratory, those whocontributed tothecentral analyses wereGino Farchi,
Arduino Verdecchia, RiccardoCapocaccia,SergioMariotti and Susanna Conti, from
1973to 1984,and Fulvia Seccareccia and Mariapaola Lanti from 1984on. Several
original analytical approaches originated from thisgroup,such astheconceptof
'saturation effect' in multivariate prediction, theattempt tomeasure the proportion
of theinter-cohort incidenceor mortality differences explained bydifferences in risk
factor distribution,and theuseof risk factor changesover timeinprediction of mor-
bid or fatal events.
In 1979cametheofficial introduction of Daan Kromhout, then of the University
of Leiden (and later of theNational Institute of Public Health, Bilthoven,The
Netherlands) totheSeven Countries Study Group,on occasion of themeetingof
principal investigators held inSeptember of that year in Heraklion,Crete.Soon
after, aclosecooperation started between Kromhout and Menotti,sothat ina few
years they shared allthecoordination of thestudy group,with themajor interestof
Daan Kromhout inthenutritional aspectsand of Alessandro Menotti intherisk fac-
tors.Between 1990and 1991they realized, with thehelpofcollaborators in
Bilthoven and in Rome,thesummary tape,and then thedisk,oftheentireSeven
Countriesdata,covering25yearsof follow-up for allareas.Thishasbecome the
basisfor 25-year data analyses used byall investigators.

44
STUDIES IN THE U.S. RAILROAD
— _ _ H. Blackburn

T h e study of U.S.railroad men (USRRStudy) was the 'baby' of

Henry Longstreet Taylor, professor at the Laboratory of Physiological Hygiene
(LPH) in Minnesota. He had the idea to compare coronary heart disease (CHD)
rates among rail occupations to get at the causal role of habitual physical activity.
Taylor realized that there would likely never be a 'definitive experiment', due to
feasibility and cost, in which physical activity would be modified and the effect on
heart attack rates measured.
Lewis Thomas once defined epidemiology as 'thumbing through death
certificates', an insensitive and uninformed depiction, at best. But such a
'thumbing', done systematically and early on, revealed to Henry Taylor and those
of us who had become his colleagues, that CHD death rate differences among rail-
workers were in the direction of the hypothesis that physical inactivity is associated
with higher rates.Taylor was also the first to criticize his own brainchild, pointing
out, on the one hand, problems of misclassification of physical activity in the
Railroad Retirement Board list of occupations, and, on the other, of selection bias
which might concentrate workers who were ill,or becoming ill,among the less ac-
tive railroad professions. This candid criticism of one's own offspring is perhaps
less often found in science today. Taylor's basic integrity had been nurtured in a
skeptical and dispassionate 'Old School Physiology' which put him in good stead
for epidemiological pursuits.
To reduce these errors and biases the novel idea was proposed to NIH of exam-
ining the active and less active rail workers at their worksites, measuring incidence
in the railway cohort while accounting for measured confounders and co-morbidity.
To Taylor's surprise, and certainly to the surprise of some of his Minnesota col-
leagues, the proposal was approved by peer review in the National Heart Institute.
Thus began the independent U.S.Railroad Study, which only later was coopted into
the Seven Countries Study comparisons.
Ifirst worked with Henry Taylor in 1954,as an LPH fellow, examining some 400
Minneapolis firemen in a tentative that failed for want of numbers or an adequate
range of job activity, but that provided field experience which greatly strengthened

45
thesubsequent proposal tostudy theUSRRcohort.Early intheseplans Iwas
tapped todevelop the 'instruments' and thediagnostic criteria for therail study,
which was tobeput intothe field formally insummer 1957,atabout thetime that
AncelKeyswas tocarry out pretests for overseasSevenCountries field surveys.
Thosesurveys,tobegin formally inthe fall of 1958,needed comparable clinical-
organizational efforts. Whether Iwastobeengaged immediately and directly with
the USRRStudy,orwith the overseasSeven Countries plans,wasamatter of debate
between Keysand Taylor. Ipresume thatTaylor won outbecause therailway activ-
itieswere tobegin ayear earlier,and becauseboth undertakings would profit from
theearliest possibledevelopment and testingof examination methods,forms, and
diseaseclassifications for theUSRR,with which Iwasdeeply engaged after joining
theregular LPHstaff in1956.
TheUSRRStudy operation was 'first class' from thebeginning,and one in which
Iwas happy tobeinvolved. Ihad a few pangs of regret when unable to accompany
Ancel Keysinthe fall of 1957toconduct thepilot surveys in Finland,Nicotera in
southern Italy,and Crete,but my serviceswereurgently required toget theUSRR
show 'on theroad'.Thiswedid, with procedures,forms, and thebeginnings of the
CVDclassifications, which would eventually includeTheMinnesota Code.In those
excitingearly days Ienjoyed particularly working with Taylor in thedesign ofa
unique railcar traveling laboratory. Heproved extremely skillful in face-to-face ne-
gotiations with railmanagement and union brotherhoods,obtaining,among other
things,thelong-term loan ofa Pullman car.With thenew NIH grant,he proceeded
tohave that carrenovated in theGreat Northern maintenance yardsoff Como
Avenue inSt.Paul (thesiteof thepresent-day Bandana Square Mall),where we
spent countlesshours supervising and kibitzing.TheLaboratory car was well laid
out, with areception area,aseriesof examining rooms for anthropometric measure-
ments,themedical history,and physical examinations and blood pressure,as well
asalargework area for theresting and exerciseelectrocardiogram. Down the line
wasabooth for thechest x-ray and then a 'wet lab.'for theblood and urine sample
processing.
After atrial run intheold St.Paul Depot,we moved out with our efficient mo-
bilelaboratory, hooking up tothepower,water and steam ineach railyard across
theline,moving northwest tothecitiesofSpokane,Pasco,Seattle,down to Portland
and San Francisco,and back again totheTwin Citiesin Minnesota.
Taylor had carefully negotiated twoessential elements for successof theUSRR
study:that therailclerkscould beexamined at theirworksite during working hours
without their paybeingdocked, and,at my insistence,that the information wecol-
lected onallemployees would beheld confidential and not provided to railway
physiciansor thecompanies.Theseguaranteesclinched theenlistment of therail
brotherhoods.Off wewent, then,in 1957,on thefirst round survey,tocompare the

46
The US Rail car.

risk factors and themedical findings of railexecutives,sedentary clerks, switchmen,

and right-of-way personnel, among whom Taylor's pilot work had validated differ-
ent habitual activity and oxygen consumption levelson thejob.
Therailmen were ajovialbunch and our crew,too,wascongenial,working to-
gether effectively and examining up to40men aday atstationsand switchyards
across thecountry.Thisteam developed inthisfirst survey round many of the field
strategies thatbecametrademarks of Minnesota population studiesover theyears:
careful planning and pre-negotiations, field testing and pilot studies,clear popula-
tion definition, census,and recruitment, thoughtful scheduling,on-site quality con-
trol,and central data editing, processing and analysis.Taylor wasno trained epi-
demiologist, and may only latehave heard theword 'epidemiology'. Rather,he was
a physiologist with apenchant for clearthinking and careful methods,along witha
lifelong curiosity about the physical activity of humans.Hesoon became oneof the
morecompetent ofchronicdisease epidemiologists, and an acknowledged expert in
recruitment and field operations.
Myearliest experience with Henry Taylor in 1954,having chosen to spend asix
month's research rotation in the LPHaspart of an Internal Medicine fellowship,
taught memuch about hisforthrightness and integrity.On my first visit to the
Laboratory, driving abattered green '41Chevrolet coupe',dressed ina battered

47
Bavarian hat,and old Navy overcoat, Iwasaccosted by HLTintheStadium park-
inglot,asif IwereaUniversity student attempting topark illegally. He challenged
mebrusquely, 'What's your business in theStadium,young fellow?' Wewere both
relieved when 1 wasabletoraisethenameofelectrocardiographer, Ernst Simonson,
as thecontact Isought. Not longafterward, engaged in physiological testsin the
main laboratory ofStadium Gate27,hequestioned aheart rateIhad recorded of
148beats per minute,saying, 'How did you count 148beats per minute -counting
fora whole minute?' 'Icounted 37beats in 15seconds',Ireplied. He was quite
aware that noonecould keepadequate count of a rapid pulsefor a full minute and
simply wanted tobesure Iwasn't 'guessing'.Our mutual ethical 'blue noses'led
much later totheonly explosion between us in almost 30years'association. But
that's another story.
Therailsurvey team was highly competent and compatible and in our working
and traveling together weelaborated,by plan and by trial and error,much of the
general field experience that theLPHutilized insubsequent operations:that six
days running was thelimit of effective staff performance, requiring abreak; that
three weeks running wasabout thelimit ofeffective staff participation withouta
brief homeleave,and that itwas not possible toemploy our converted 1895presi-
dential RockIsland Linesleeping carasadormitory and stillmaintain efficiency,
etc.Thelatter led tostaff being quartered in quiet motels,and tohaving pleasant
team dinners inattractive restaurants in theevenings torelieve theheavy work rou-
tine.Welearned caretoavoid over-booking participant appointments, particularly
thefirst day ofa new location,and other ways toencourage 'happy campers'
among staff and participants.
Itwasa fine field operation, from which we wereabletoapply what we learned,
aswell as theUSRRforms and procedures and classifications of disease,to the
broad overseasoperation of theSeven Countries Study beginning inthe fall of 1958
in Dalmatia.
There weremany adventures 'on therails',both intellectual and social.We usu-
allyhad asix-packof beer inthe fridge, and aswe traversed the land,held long
conversations about thecolorful railmen wemet,and about theburgeoning new
field of CVDepidemiology inwhich wewere involved.On thesecond round ofex-
ams,starting in 1962,1had mysoprano saxophone along and often serenaded the
countryside from therear of theLabcar,which usually served asthecaboose for
thetrain towhich wewereattached.Weacquired many friends along thelineas
Taylor and Imade contacts tohire and train short-term medical examiners.
Numerous American colleaguesparticipated over thecourseofsixyearsof exam-
inations intwo rounds,'57-58and '62-63,and we werejoined by aseriesof overseas
visitorscomefor training at thenew 'epidemiological Mecca' inStadium Gate27.
Thestaffing wasexceptional aswebegan the first round USRRsurvey, with

48
Henry Blackburn, Nedra Foster and two subjects in US Railroad mobile lab, 1957.

such experts asPacoGrande assisting at theinitial dietary interviews and Jaschka

Brozekdoing theanthropometric measurements. I,along with WaltCarlson and
John Vilandre,and later Pentti Rautaharju, carried out theexercise electrocardio-
graphic monitoring;Nedra Foster and Gail Dolliff handled theblood,urine,and
X-ray technical duties,while Ishared theclinical examswith our drop-in col-
leagues.Inall itwasa happy, yetdisciplined and effective operation.

Methods
U.S.railroad employees werechosen because theyarelargely stable in their specific
occupations and in their lifetime employment, and had measured differences in
physical activity at work.Moreover, allrailemployeesarecovered bya pension
plan for which theRailroad Retirement Board maintains detailed records of em-
ployment, disability, retirement, and death. Permission of thecompanies,of the
Retirement Board,and thevarious labor unions involved, was required, including
each local Railroad Brotherhood official. Geographic dispersion of the industry
made itimpossible toconcentrate on afew largecenters,sothat men had tobeex-
amined along therail lines.All20railcompanies operating in the northwestern
quadrant of theUnited States,circumscribed byChicago,St.Louis,SanFrancisco,
and theCanadian border, wereinvolved. Only twocompanies refused full partici-
pation.Companies were asked tosupply thenames ofallmaleclerks,switchmen,

49
dispatchers,and executives,aged 40or more,employed in 1957.Selection from this
roster excluded stations with less than 10employees in thesecategories,and clump
sampling wasused.Selection of30units ensured proportional representation in
each geographical area and each sizeof urban area.
Firstcontact was made with thegeneral chairman ofeachunion who was asked
towritea letterofendorsement. Thiswas reproduced and enclosed in an individual
invitation letter toeachsubject. Lodgemeetings werevisited by members of the
staff beforehand, usually Dr.Taylor orme,and the meeting was advertised
throughout offices of therailroad. Union membership listswerechecked against the
worker listsprovided by therail company. Personal invitations tothesurvey were
then issued and examination datesassigned.TheLabcarvisited eachlocation at
least twiceduring each of two survey rounds,five yearsapart. Chief clerks and
yard mastersand switch tenderswereexcluded because ofunusual pay,or activ-
itiesdifferent from thegeneral membership of that occupation. Clerks were exam-
ined oncompany time.Clerical desk workers,switchmen, and maintenance of way
personnel wererepresentative ofsedentary, moderately active,and active groups,
respectively. Clerks were sub-categorized asnon-sedentary if they had walking and
baggage-handling activities.Executives were mixed in their activity leveland dis-
patchers werecompletely sedentary on thejob.Oxygen requirements for each of the
several main tasksrequired of men in theswitchmen and clerk occupations were
studied insmallsamples,and data linked with timeand task measurements and a
dietary survey.Theswitchmen averaged 600kilocaloriesaday moreenergy expen-
diture than clerks.
Data wereobtained on apopulation of8,053clerks,switchmen and executives
employed bythe20railroad companies in thenorthwest quadrant of the United
States.Asample of 1,163 sedentary clerks,1,414 switchmen and 363executives was
selected for examination and 74%of thesedentary clerks,59%of the switchmen,
and 68%of theexecutives responded and were examined.

Cross-sectional Comparisons
Thesedentary clerkshad been in therailroad industry longer on average than the
switchmen but changed jobsmoreoften. Therewasa homogeneous distribution of
parental nationality. Clerks and switchmen wereonthesameeconomiclevel,and
switchmen wereheavier cigarette smokers.Therewasnoimportant difference in
electrocardiographic itemsbetween occupations except for post-exerciseSTdepres-
sion,which was significantly higher inclerksand switchmen.Theprevalence of hy-
pertension wasnot remarkably different, though theexecutiveshad fewer men
with elevated diastolic pressure.
Prevalence of hypertension increased with relativebody weight and with serum

so
cholesterol concentration. Overweight was greater among theswitchmen, least
among clerks,and increased in allwith increasing blood pressure.Thewest coast
had thehighest reported death rateat theRRRetirement Board,Rocky Mountain
areas thelowest,and theplain statesintermediate.Thegeographic distributionof
measured variables wasdifferent for theswitchmen, in which casetheRocky
Mountain switchmen were thinner and lighter,had lowerblood pressure,and
smoked less.
Blood cholesterol concentration wasnot different between occupations orgeo-
graphical areas.Themost striking differences between switchmen and clerks were
inrelativebody weight and systolicblood pressure.Examination of employment
recordsrevealed therewasnodifference inblood pressure of clerksand switchmen
at their entry torailway employment,but theswitchmen wereheavier, indicating
occupational selection.
Theobserved prevalence of coronary heart diseasewas influenced by agreater
rateofwithdrawal ofyounger switchmen with coronarydiseasecompared toclerks.

Five-year Follow-up
Theconceptbehind joiningtheUSRRStudy tothecomparative spectrum of the
SevenCountiesStudy was described by HenryTaylor and colleaguesas follows:
'Therailroad industry presented an attractive setting tostudy theepidemiologyof
coronary heart diseaseincontrasting populations because thestability of employ-
ment and theextensiverecords maintained by theRailroad Retirement Board made
itpossibletoevaluate therelevanceofparticular samples totheindustry asawhole
and toanalyze theeffect onincidenceratesof withdrawals from theindustry,job
transfers, etc.Proof of death wasrequired for payment ofdeath benefit.' Moreover,
itprovided 'theprevalence and incidenceofCHDin thelargeAmerican cohort for
comparison with men in other populations with different dietsand activities,with
respect totheuniversality of risk factors and whether they had equalweight inall
populations.'
Theage-standardized prevalence ratesofcoronary heart diseasedid not differ
significantly between activeand sedentary men.Evenif theyhad, theproblem with
differential retirement ofswitchmen with coronary disease,theshift tomore seden-
taryoccupations,and thelarger proportion ofswitchmen and clerkswith heart dis-
easethatreported for examinations,would havemade interpretation difficult.
After five years,62men died from CHDdeathsand 124from allcauses.All-
causedeath rateswerehigher for activeswitchmen than for sedentary men,but the
difference wasnot significant. Thecoronary death ratewas loweramong switch-
men and again,thedifference wasnot significant. Nevertheless,with all occupa-
tionspooled, therewas astrong and significant relationship between blood pres-
sureand all-causesdeath,largely confined totheupper 4th and 5thquintilesof
blood pressure level.Therelationship toskinfold measurement ofobesity was not
significant. Thedeath rates from coronary diseaseand allcausesincreased progres-
sively from never-smokers,tostopped smokers,up tomore than 20cigarettesa day,
being 400%higher in thelatter than thefirst category,and threetimeshigher for
non-coronary death causes.
Despite theapparent tendency toward concentration of coronary deaths, angina
pectoris,and CHDincidence insedentary classes the5-yearCHDincidence differ-
enceswerenot significant. Smoking wasan important factor ineach of the occupa-
tions,with therate among non-smokers half that expected, whereas theCHD death
rateratiowas 3.6for heavy smokers after holding blood pressure and cholesterol
constant.
Blood pressure,obesity and cholesterol wererelated tohard CHDcriteria and all
criteria for coronary death.However, theseareunivariate relationships,and there-
lationship with body weight drops out entirely when systolicblood pressure isheld
constant.
Many moreresultsaretobefound in the 10-year and later follow-up data of
deaths among theUSRRcohort.Thesehavecontributed tonew insightson cultural
differences intheforce of riskfactors.Follow-up for25to30years provides under-
standing of thesometimes different predictive power of physical risk characteristics
over thelong-term versus theshort.TheItalian group with Menotti have analyzed
these relations indetail,including thelatepredictive importance of changesin indi-
vidual risk factors early in the follow-up of SevenCountries cohorts.AncelKeysre-
portsevidence that body massand fatness areunrelated with survival toold age,
whilecigarettesmoking consistently predictsearly demise.

Conclusion
Welearned many things from theUSRRStudy initsfirst years,particularly thedif-
ficulty tomakevalid occupational comparisons ofCVDrates;much depends onse-
lection at the timeof entry into theoccupation,and subsequently, when thereisse-
lection against activeoccupations byconcentration ofcoronary eventsamong the
lessactivejobs.Wealsolearned 'thehard way' that thecohort numbers wereinade-
quatefor apowerful comparison of activeand inactivepopulations.Some 10,000to
15,000men would havebeen required ineachactivity class,based on the5-year
CHDincidence weobserved inthe sedentary group,todemonstrate differences.
Detailsaregiven in thechapter on Main Results,but theUSRRStudy was among
thefirst major longitudinal CVDstudies in which an independent relationship was
not found between relativeweight or skinfold obesity and CHDrates.On the other
hand, theUSRRStudy confirmed theuniversality of the main CHDrisk factors,

52
contributing tothestrong inference of their causal role,and itsdata were entered
into theAmerican Heart Association Pooling Project, thefirst formal statistical sum-
mary inCVDepidemiology.
Inparallel with thecohort studies westudied occupational differences in death
ratesusingdeath certificates for theentire railway population, industry-wide.The
relative risk for sedentary versus activeoccupations was 1.18 for infarction orcoro-
narydeath, 1.2 for coronary death,and 1.18overall for men free ofCHDon entry
examination. Biasindeath ratescalculated among men whodid not retire or change
jobswasavoided by including deathsof allmen inthecohort after anyjobchange.
Withdrawals from jobsfor coronary diseasewereidentical between thetwo occupa-
tions.TheRailroad Retirement Board mayaward disability retirement more readily
for men working inswitchyards whereaheartattack might result inacostlyacci-
dent. Thiswould explain why coronary deaths,plusdisability retirement, account-
ed for onethird of coronary casesamong switchmen,but only onesixth among
clerks.
Therelativerisk ratioof 1.18 is,nevertheless,thebest estimateavailableof the
truedifference inCHDincidencebetween sedentary and activerail occupations
having an averagedifference indaily physicalactivityof 600kilocalories.Thiscom-
pares torisk ratiosof 2.2for blood cholesterol level,2.1for systolicblood pressure,
0.95for relativeweight, 1.2 for skinfold thickness,and 1.3for height.TheUSRR
Study led us toconclude,therefore, that within high-risk cultures,skinfolds, height,
relativeweight, and job-related physical activity arerisk factors of 'a second order
of magnitude' for individuals.

S3
Publications
1. TaylorHL.Diet,physicalactivityand the
serum cholesterol concentration.MinMed
1958;41:149-153.
2. TaylorHL.Relationshipofphysical activity
toserumcholesterol concentration. In:Work and
theHeart.Transactions oftheFirst Wisconsin
Conference on Workand the Heart. Rosenbaum
FF,BelknapEL(Eds).NewYork.Paul Hoeber,
Inc.1959:111-116.
3. Taylor HL.Themortality and morbidityof
coronary heart diseaseof men insedentary and
physically activeoperations.In:Exerciseand
Fitness.ACollection of Papers Presented in the
Colloquium on Exerciseand Fitness.Universityof
IllinoisCollegeof Physical Education and The
AthleticInstitute1960:20-39.
4. Taylor HL,Klepetar E,KeysA,ParlinRW,
Blackburn H,PuchnerT.Death rates among
physicallyactiveand sedentary employeesof the
railroad industry.AmJPubl Health1962;52:1697-
1707.
5. Taylor HL.Coronary heartdiseaseinphysi-
callyactiveand sedentary population.JSports
Med Physical Fitness1962;2:73-82.
6. Blackburn H,Taylor HL,ParlinRW,
KihlbergJJ,KeysA.Physicalactivity of occupa-
tion and cigarettesmoking:Relationship toventil-
atory function and respiratory symptoms.Arch
Environ Health 1965;10:312-322.
7. Taylor HL,Parlin RW,Blackburn H,KeysA.
Problems intheanalysisof therelationshipofcor-
onary heart disease tophysical activity oritslack,
withspecialreference tosamplesizeand occupa-
tion withdrawal. In:PhysicalActivity in Health
and Disease.EvangK,Andersen KL(Eds).
1966:242-261.
8. Taylor HL,Blackburn H,BrozekJ,Parlin
RW,Puchner T.Railroad employeesintheUnited
States.KeysA,etal(Eds).Epidemiological stud-
iesrelated tocoronary heartdisease:characteris-
ticsof menaged 40to59inSevenCountries.Acta
Medica Scand 1967;Suppl460:55-115.
9. TaylorHL.Occupational factors inthestudy
ofcoronary heartdiseaseand physical activity.
Can Med AssocJ 1967;96:825-831.
54
10. TaylorHL,HaskellW,FoxS,Blackburn H.
Exercisetests:asummary of proceduresand con-
ceptsofstress testing forcardiovascular diagnosis
and function evaluation. In:Measurement in
ExerciseElectrocardiography.CharlesC.Thomas,
Springfield, IL1968:259-305.
11. Taylor HL,Blackburn H,KeysA,Parlin RW,
Vasquez C,PuchnerT.KeysA(Ed).Coronary
heart disease inSevenCountries:5-Year follow-
upof employeesofselected U.S.railroad compa-
nies.Circulation 1970;41(Suppl D.20-39.
12. Blackburn H,Taylor HL,KeysA.Theelec-
trocardiogram in prediction of5-yearcoronary
heart disease incidenceamong menaged forty
through fifty-nine. Circulation 1970;41(Suppl
1):154-161.
13. Hamrell BB,Blackburn H,Taylor HL.
Disablingcomplications of physicalexercise train-
inginmiddle-age,coronary-prone American
men.In:Exerciseand theHeart. MorseRL (Ed).
CharlesC.Thomas,Springfield, IL1972:188-199.
14. KeysA,Blackburn H,TaylorHL.
Relationshipofblood pressure,serum cholesterol,
smoking habit,relativeweight and ECGabnor-
malitiestoincidenceof major coronary events:fi-
nalreport of thePooling Project.JChronicDis
1978;31:201-306.
15. Taylor HL,JacobsD,Schucker B,KnudsenJ,
Leon AS,DeBackerG.Aquestionnaire for theas-
sessment ofleisure timephysical activities.J
ChronicDis1978;31:741-755.
16. Remington RD,Taylor HL,Buskirk ER. A
method forassessingvolunteerbiasand itsappli-
cation tocardiovascular diseaseprevention pro-
gramme involving physical activity.JEpidemiol
Comm Health1978;32:250-255.
17. Taylor HL.Disabling effects of inactivity.In:
Proceedingsof thefirst International Conference
on Lifestyle and Health.LeonAS,AmundsonG
(Eds).Minneapolis,MN.Universityof Minnesota
Press,1978.
18. LeonAS,JacobsD,DeBackerG,TaylorHL.
Relationshipof physicalcharacteristicsand life
habits totreadmill exercisecapacity.AmJ
Epidemiol 1981;113:653-660.
19. Taylor HL. Physical activity: Is it still a risk
factor? Prev Med 1983;12:20-24.
20. Slattery ML,Jacobs DRJr. Physical fitness
and cardiovascular disease mortality. The US
Railroad Study. Am JEpidemiol 1988,127:571-580.
22. Jacobs DRJr, Hahn LP,Folsom AR, Hannan
PJ,Sprafka JM, Burke GL.Time trends in leisure-
time physical activity in the upper midwest 1957-
1987:University of Minnesota Studies. Epidemiol
1991;2:8-15.

21. Slattery ML,Jacobs DR Jr,Nichaman MZ.

Leisure time physical activity and coronary heart
disease death. The U.S.Railroad Study.
Circulation 1989;79:304-311.

55
THE EAST-WEST STUDIES OF FINLAND
M.J. Karvonen, S. Punsar, A. Nissinen, M. Pekkarinen
and L. Räsänen

I heFinnish participation in theSevenCountries Study had itsori-

gin inan encounter of MarttiJ.Karvonen (MJK)with AncelKeysin Minneapolis,
May 1954.Finland,with itsexceptionally high mortality from cardiovascular dis-
eases(CVD),stood insteepcontrast with theMediterranean nations;moreover,in
eastern Finland both mortality and disability due toCVDweremarkedly higher
than inthesouthwest of thecountry.MJK,then director of the Physiological
Department of theInstitute ofOccupational Health (IOH)inHelsinki,was further
intrigued by thehigh premature mortality among apopulation which earned itsliv-
inglargelyfrom heavy forest and farm work,who might havebeen expected to
enjoy thebenefits of aphysically active,healthyoutdoor life.Thetwo physiologists,
Keysand Karvonen,agreed that aninternational study wasneeded;aprotocol had
tobeworked out and resourcesobtained for thecollaborative effort.
Twoyearslater,inearly autumn 1956apilot study wasorganized in twocon-
trasting regionsof Finland among therural population: in thecommunes ofJuuka
and Ilomantsi in theeast,and Mietoinen,Nousiainen,Vehmaa,Karinainen,Mellilä,
and Pöytyä in thesouthwest.Men and women 20-59yearsofagewho were judged
healthy were invited toasurvey,which included medical examination, smoking
history,anthropometric data,both serum totalcholesterol,and itsalpha (HDL) and
beta (LDL)fractions; and conventional 12lead ECG'sand spatial vector electrocar-
diograms using Frank'sorthogonal system.After therural fieldwork, the Helsinki
FireBrigadeand maleexecutivesvisiting for annual health checkswerealsogiven
thesameclinicaland laboratory examinations.Thetotalnumber ofpersons exam-
ined was967,most of them men.Dietand theriskofCHDwere tobea major
theme.
The 'clinical' team in 1956consisted ofAncel Keys,FlaminioFidanza from Italy
for analysis oflipoproteins,and from thehostcountry,MJK,medical student Pentti
Rautaharju for theECG,and two women staffmembers for thelaboratory and ECG
recording. Professor Paavo Roineof HelsinkiUniversity was theleader of modern
nutrition scienceinFinland;hejoined our teambyorganizing an independent par-

57
allelEast-West project ofdietary surveys,closelycoordinated with our epidemi-
ological studies and applied to the 1956survey.
From the 1956survey welearned how torun a field study. Wealsograsped that
for an unbiased, full pictureof thehealth ofa population, total cohorts,instead of
ostensibly healthy onesonly, must berecruited or randomly sampled. We thus
obtained the first valid data on thedistribution of variablesof interest among these
populations.These Finns had higher serum cholesterol than any other major popu-
lation that had beenstudied;intheeast thevalueswere highest.The Finns thus
belonged tothe family of nationswith high cholesterol and high mortality from cor-
onary heart disease (CUD)and,in fact, appeared tocarry the 'world record' in both.
Men involved inheavy physical work in theeastern forests had equally high choles-
terol level asmen in lighter jobs,although they ate more than double theamountof
fat. Alargeseasonal variation was noted in theserum cholesterol level, particularly
in theeast,with highest values in the winter; timing further surveys tothe same
season thusappeared anecessary condition for comparableresults.The Finnish
men alsosmoked a lot.

Member of the Seven Countries Study

TheSevenCountries approach thusbegan totakeshape.Cardiovascular epidemiol-
ogists wereneeded; they had tobetrained. InSummer 1957,EskoOrma,MD,with
previousexperienceinexperimental atherosclerosisand geriatrics,wassent from
the IOHtotheUniversity of Minnesota;some months later Sven Punsar,MD,a
young clinician from theleading Helsinki unit incardiology, led by Professor Pentti
Halonen, first took part in theNicotera pilot survey in southern Italy,and then con-
tinued on toMinneapolis,whereboth stayed for a year.
TheFinnish Heart Association (FHA) wasfounded in 1955at the initiative ofa
layman,Mr KullervoHeiskanen, alsoa staff member of theIOH.Ancel Keys was
invited togiveapubliclectureinHelsinki in November 1955and then established
contact with theFHAand leaders in thehealth field such asthe DirectorGeneralof
Health Services,Professor NiiloPesonen,the Director of IOH,Dr.LeoNoro,and
the Medical Director of the largest Helsinki City Hospital, Professor PauliSoisalo,
an ardent promoter of the FHA.InAugust 1956theFHAopened itsfirst health
education campaign with alectureby Paul D.White,the famous U.S.cardiologist;
healsovisited theteam starting itswork in Ilomantsi,closetotheSoviet border and
'eastof Leningrad and north ofAnchorage'.Theorganizational home for the East-
WestStudy was provided by the IOH (until 1974)and then by the FHA (until1984),
when theFinnish National Instituteof Health adopted it within the Department of
Epidemiology and Health Promotion,directed by Professor Pekka Puska.As the
first principal investigator, MJKremained until 1980;hewas followed by Sven

58
 Field examination in Finland, 1959.

Punsar until 1984,and sincethen Professor Aulikki Nissinen, presently Chief of the
Department of Public Health and Primary Care,KuopioUniversity has served.
EskoOrma served as full-time epidemiologist from 1962-64,and Sven Punsar fol-
lowed him, 1964-1984,serving asalargely unpaid volunteer, after hisdaily hospital
work. MJKworked abroad for WHO in theyears 1966-67,givingSven Punsar full
responsibility. Theproject was funded from the U.S.Public Health Service (until
1969)aswell as from Finnish sources,among which was first theYrjöJahnsson
Foundation and later theAcademy of Finland;both eventually became long-term
supporters. From 1970to 1989only Finnish sources wererelied upon.

T h e Epidemiological Surveys 1959 - 1984

Among theeight communes visited inthe 1956pilot Study,one in theeast,
Ilomantsi,and twoin thesouthwest, Pöytyä and Mellilä,were selected for the main
prospective study. Prior totheSeptember 1959survey theFHAorganized a work-
ingmeeting in August for experts and investigators of theSevenCountries Study,
with 11foreign participants from the United States,Denmark, England, The
Netherlands, Norway, Sweden,and Yugoslavia,inaddition tothe Finnish group.
TheIOHin Helsinki and theLaboratory of Physiological Hygieneat Minnesota
provided logisticsupport for the 1959-1969surveys;premises in Ilomantsi were
obtained in 1959from theFrontier Guard and in thewest from themunicipal health
services.Thefield work in Ilomantsi wasdoneasaruleduring September and in
Pöytyä and Mellilä inOctober, which timing provided similar seasons for the two
areas.Several of theAugust meeting participants from abroad joined the fieldwork
for various lengthsof time,and got practice instandardization of survey methods,
thebattery for which now included:
• full medical examination,
• 12-lead resting and post exerciseECGs,

59
• lung function tests:vital capacity and itssubdivisions,maximal breathing ca-
pacity,and peak expiratory rate,
• anthropometric measurements,
• blood samplesfor serum total cholesterol and thiocyanate,amarker for smoking
habits,
• questionnaires on personal diet and smoking habits,and respiratory symptoms.
Insub-samples,residual volume and diffusion capacity of thelungs, serum
fibrinogen, and blood fibrinolysis weredetermined. Ian Higgins,of theMRC
Pneumoconiosis Research Unit inCardiff, Wales,tookcareofstandardizing the
lung function testing tocorrespond with that used intheir studies.In 1959 1,675
menwereexamined,about 98%of thetotaleligible population of men born from
1900-1919.During thefirst week ofthe survey an important observation was made:
thenew standard mercury sphygmomanometers had cuffs with hooks and with too
short rubber bags,and thusgaveerroneously high blood pressure values,particu-
larlyfor personswith thick arms.Aworldwide pseudodisease, 'cuff hypertension'
was thus discovered. Itmay haveimproved thesalesofantihypertensive medica-
tions,but may alsohavecontributed totheapparent epidemiological associationof
hypertension with body massand muscularity.Getting specially hand-made,ade-
quately sized cuffs 'cured' theepidemic in Ilomantsi,but many commercial makers
of sphygmomanometers wereslowin learning thislesson.
Serum total cholesterol levelswere now analyzed from refrigerated sera trans-
ported byair toHelsinki,and alsofrom duplicate samplesdried on filter paper and
then sent air mail toMinneapolis.Theagreement of thetwolaboratory series was
good;nevertheless the East-WestStudy preferred touseitsown analyses for inter-
nal consistency,while for theSevenCountries publications thedried samples,cen-
trally analyzed,were thestandard. Aparallel dietary surveywascarried out on60
families chosen at random in each field area.
In 1960theannual follow-up of incidenceand deaths wasdeveloped among the
1959examined cohort,thelocalcontact persons recruited,and monitoring started.
Wehad accesstoallhospital recordsand information from localphysicians.By
1961thesurvey data had been transferred toHollerith cards for analysesin
Helsinki,and alsohad been sent toMinneapolis.Thedata base wascompleted by
enquiring ofthemen theageat death of their parents.
In 1962theoldest men,thoseborn in 1900-1904,wereinvited toa re-examina-
tion;the team consisted of EskoOrma,Henry Blackburn, Pentti Rautaharju, Marja
Keinonen,VeikkoKallio,and laboratory staff.Atotalof347men,92.5%of the sur-
vivors,wereexamined.Thebattery comprised clinical examination, conventional
12-lead ECGat rest and Frank's orthogonal lead vectorECGonmagnetic tape,ana-
lyzed with an analog-digital computer. Special attention was devoted toan exact
description of angina pectoris,and totheunbiased measurement ofblood pressure.

60
 In 1963Marja Keinonen made acomplementary East-Westfield survey covering
a wideagerangeof men and women;shemeasured blood pressure blinded and
tookblood samples for serum totalcholesterol.Ilomantsi alsoattracted awidely
travelled otolarygologist, SamuelRosenofNew York,whowas making an audio-
metric survey among adultsand children worldwide;defects in hearing proved
prevalent inIlomantsi already from childhood.
In 1964an International Symposium onPhysicalActivity and the Heart was
organized bythe FHAinHelsinki,August 27-29,justprior tothestart ofthe5-year
SevenCountriesre-survey.Severaloftheparticipants cametoseeorparticipate in
thework in Ilomantsi,among whom onceagain wasPaul D.White,Henri Denolin
from Belgium,Zdenek Fejfar from WHO,Samuel M.Fox,III,Richard D.
Remington,Jeremiah Stamler,and HenryTaylor from theU.S.A..Henry Blackburn
and othersjoined theteam for theregular survey work orfor special projects.
The 1964,5-yearresurvey aimed atidentifying incident casesofCHD,aswell as
charting thedeterminants ofCHDover acontinuum ofage.Moreover, the coverage
ofindividual physiological variablesand life habits wasalsowidened. Blood sam-
plesweretaken for totalcholesterol,thiocyanate,and coagulation time.Allinter-
views werenow taped.Theparticipation ratewasagain high:1,529 meninall were
examined, 740in Ilomantsi and 789inMelliläand Pöytyä,and theteam counted 17
research workers from 9countries.

ECG Coding and Vector-ECG Projects

Oneof theearlyobjectives of theEast-West Finland component of theSeven
Countries study was todevelopastandardized system for classification ofECG
findings for epidemiological investigations inprogressat that timein Finland.This
development was initiated in 1954byPentti Rautaharju, and was first used in the
1956East-WestFinland survey.Another research objective during thisearly period
was tointroduce quantitative methods for analysisof thestandard 12-leadECGs
usingvectorcardiographic principles.Thislatter objectivewas achieved bymeansof
a mechanical vector analyzer invented byErnst Simonson and constructed by Pentti
Rautaharju in1954.
Theseearly efforts atquantification and standardization resulted inthe publica-
tionof several reports on normal ECGstandards inrelation tosexdifferences, age
evolution, occupation and physical fitness level,and hypertensive status.Thecon-
ventional ECGshowed substantial differences intheprevalence of ECGabnormal-
itiesamong variouspopulation samplesof ostensibly healthy men,ranging from
13%among lumberjacks inEastFinland to29%among the Helsinki FireBrigade.
Coronary heartdiseaseprevalence was estimated tovarybetween 4.0%and 8.9%,
with thehighest prevalence inrural EastFinland. Hypertension with ECG evidence

61
of left ventricular hypertrophy was observed in8%of thefiremen and in6%of the
eastern rural men,but in noneof the99lumberjacks. Theelectrocardiogram had
clearly proved its validityasa toolin epidemiological studies!
ECGcoding efforts inFinland aroused theinterest of AncelKeys,who visited
theWest Finland survey with PaulWhite in 1956.In 1958Dr.Keysarranged for Dr.
Rautaharju tojointhe research group ofthe Laboratory of Physiological Hygiene,
where Henry Blackburn had alsobeen involved for severalyears in a concentrated
effort todevelop and validate astandardized ECGclassification system for the
USRRand other Minnesota epidemiological studies.Dr.Rautaharju and Dr.Sven
Punsar, another visiting scientistin Minneapolis from theFinnish team,joined Dr.
Blackburn and Dr.Simonson in thisintenseundertaking, which resulted in the1960
publication of theMinnesota Code in Circulation. Thisarticleby Blackburn etal. was
some timeagoreported by theCitation Index asoneof themore frequently quoted
papers in theentirecardiovascular literature.
Theprospects for computer analysisof theECGemerged during theearly 1960s,
and electronictaperecording technology wasintroduced intothe East-West Finland
Studyby Pentti Rautaharju in 1962. Thecapacity of theseearly tape recorders and
amplifier systemsconstructed in the Biophysics Laboratory ofOttoSchmitt was
limited tothree simultaneous channels.Therecordings weremade using the
orthogonal ECGleadsof theFrank system.Theprimary focus wason computer
analysis of theischemic ECGresponse toexercise from tape recordings performed
by Pentti Rautaharju and Henry Blackburn inseveral surveysof theSeven
CountriesStudy.Dr.Hans Friedrich and Dr.Herman Wolf from the Dalhousie
group wereresponsible for themedical engineering aspectsof thesepioneering pro-
jects.Inretrospect, theSevenCountriesStudy was afertile proving ground in the
development ofconventional and computerized ECGclassification methods.With
gradually enhanced power and capacity of electronic ECGacquisition and comput-
er technology, theDalhousie ECGProgram wasdeveloped by Rautaharju's team in
Halifax. Themost recent version of thisprogram (NOVACODE) hasemerged as the
standard for major national health surveys and clinical trialsintheU.S.A.

Studies Outside the Scope of the Seven Countries Basic Program

TheEast-West project has included the following studies,carried out inaddition to
thebasicSevenCountries program, partly bythecorepersonnel,but largely alsoby
guest investigators from Finland and abroad.
1. Vector electrocardiography project, Rautaharju etal, 1959
2. Random zeroblood pressure measurement, Keinonen (Lappi),1962,1963
3. Psychological variables,Barry,1964
4. Pulse wavevelocity,Dontasand Herron,1964

62
 5. Apex cardiography and carotid pulsewaves,Heikkilä and Luomanmäki,1964
6. Heart sizebyX-rays,Koskela,1964
7. Lungdiffusion capacity,Heinonen,1964
8. Habitual physical activity,Karvonen, Punsar etal, 1964,1969
9. STinterval inECG,Punsar,Pyörälä,and Siltanen,1968,1974
10. Heart diseaseand perceived exertion,Barry,1969
11. Life changesas predictors ofCVD,Raheand Arajärvi, 1969
12. Thyroid antibodies asriskdeterminants ofCHD,Bastenieetai, 1969,1974
13. Subjective, medical,and social lossofwork capacity,Nygârd (Tuomi),1969
14. Prognostic significance ofthe ECG,Punsar and Pyörälä,1969
15. PrognosisofCHDand angina pectoris,Punsar and Karvonen,1969
16. 'Waterfactor' project, Punsar, Erämetsä,and Karvonen, 1974,1979
17. 'Hair study', Punsar, 1974
18. 24-hr sodium and potassium excretion,Karvonen and Punsar,1974
19. Urinary chromium excretion and atherosclerosis,Punsar,Wolf,and Mertz,1977
20. Inverserelation of silicon indrinking water and atherosclerosis,Schwarz,Ricci,
and Punsar, 1977
Asub-study wasmade on systolictimeintervalsin 139healthy men in western
Finland.Thedata were later used asreference infour published papers related to
theuseofsystolic timeintervalsinestimating L-Rshunt inpatent ductus, severity
of aorticvalveincompetence,power failure inacute myocardial infarction, and
prognostic scoreofacute infarction.
Thyroid function hasbeen among thesuspected determinants of atherosclerosis
and CHD;thyroid hormone markedly affects theserum cholesterol level.Thesoil
and water in theeastern lakearea of Finland arepoor iniodine:hypothyroidism as
wellascompensatory thyroid hypertrophy, goiter,wereendemicaslongasthe diet
wasessentially composed of localfood itemswhich prevailed during thefirst half
of the20thcentury.Our men of theEasttherefore had beenexposed intheir young-
eryears toiodinedeficiency. Thyroid disease isnow known alsotobe associated
withautoimmune processes.P.A.Bastenieof Belgium (1971,1972)observed thyroid
antibodies in theblood ofCHDpatients moreoften than inothers.Heproposed to
includealsotheEast-Westmen inhisproject, and in1969blood sampleswere taken
ineastand west for:
• thyroglobulin antibodies,
• microsome antibodies,
• protein-bound iodine,and
• butanol extractable versusnon-butanolextractable iodine.
In1974thyroid function inseveralof thesamemen wasassessed by determining
thyroxine iodine (T4),tri-iodotyronine (T3),and thyreotropine (TSH)in serum.
Antibodies were moreprevalent among thosewith CHDthan among those with-

63
out;over theperiod 1969-74CHDincidenceand mortality werealsohigher among
thosewith antibodies.While theprevalence ofantibodies in theeast was5.9%and
6.8%in thewest,in theDalmatian cohort of theSevenCountries Study itwas only
half that,3.6%.Thyroid autoimmunity thusemerged asan important risk factor
both in eastand west,with risk ratios of 1.5-1.9,somewhat lower than smoking,
serum cholesterol orblood pressurein the 15-year follow-up.
TheEast-WestStudyin 1971joined thesearch and identification for a hypotheti-
cal 'water factor' asadeterminant of geographic differences in theincidenceof
CVD,as wellasof itspossibleassociations with major risk factors ofCHD,by ana-
lyzing water samples from 339individual wellsserving membersof the East-West
cohorts.Thedata were thenrelated tothe 10-year record of health and tothe1969
blood pressure,serum cholesterol,and extrasystoles inthe ECG;for smoking habits
the 1959data wereused.Twenty-two characteristics ofwater were determined,
among them theconcentrations of 13traceelements.Inboth populations the indi-
vidual risk ofCHDdeath and incident CHDwereassociated with low concentra-
tion of water constituents.When comparing thetwo cohorts,CHDwas associated
with lowchromium and with high copper in drinking water.Theeast-west differ-
enceinchromium wasconfirmed alsoin the24-hour excretion rates inurine.At
present, theseobservations add support totheroleofantioxidants in atherogenesis.
Infurther studies theessential elements:selenium, silicon,and iodine were also
examined. Siliconconcentration inwell waters was lowinboth areas, particularly
in theeast.Samplesofhead hair werealsocollected from themen ofthe two
cohorts and shipped to thelaboratory ofour co-worker, Professor KlausSchwarzof
theUniversity ofCalifornia at LosAngeles.Heunfortunately died,and the new
directors of thelaboratory threw away thehair samples (without making contact
with us).Thisexampleof insecurity inresearch data (and blindness totherightsof
faraway partners of thelateeminent scientist)shocked us,making thepursuitof
further studieson traceelements unattractive!
Simultaneously, theexterior characteristics ofhead hair had attracted interest,
together with their possibleassociations with other body characteristics or diseases.
Threecharacteristics of hairwereexamined:thedegrees ofbaldness and grayness,
and thesizeof hairs.Menwho had anadvanced degree ofbaldness had a slightly
higher blood pressure and serum cholesterol concentration than other men ofsimi-
lar age.Baldness,however, was unrelated toincreased deaths from allcauses,CHD,
or cancer.Hair graynesswas positively related toblood hemoglobin concentration
and toabsolute and relativebody weight. Hair sizewasgreater inwestern Finns
than eastern.Themedian hair sizeinindividuals was positively associated with
body height and blood hemoglobin concentration, and inversely with cigarette
smoking.

64
 Dietary salt intakehad been proposed asadeterminant of blood pressure in the
1960sand 1970s.Previous reports inFinland had suggested a 'moderate' daily
intake,8.3gramssodium chlorideper day.Inthe 1974survey 24-hour urine was
collected inarepresentative sampleof theEast-Westmen for sodium and potas-
sium analyses.Thesodium excretion turned out tobemuch higher than anticipat-
ed, 16.0gNaCl/24h inboth areas.Theintakeof sodium thus exceeded the known
valuesfor other populations examined up tothat time,except for thehighest ones
reported for regional populations inJapan. Attheindividual level,however, thecor-
relationsbetween sodium intakeand blood pressure werelow,asmightbe expected
from aone-day sampleofanycomponent ofdiet inahomogeneous population.
The ECGisademonstrated useful toolofresearch inepidemiologic studiesof
CHD.STsegment depressions inresting and post exercise ECGarecommon signs
ofCHD.Anew classification ofSTsegment depressions,modified from that of the
Minnesota Codeand largelybased onexperience obtained in theEast-West Study,
was presented in 1968.Intheclassification theSTsegment depressions were divid-
ed in threecategories:horizontal ordownward sloping ('ischemic') (I),slowly
ascending (S),and rapidly ascending (R)STsegment. Infollow-up of themen, the
categories werefound tohavedifferent prognosticsignificances, theR-type post-
exerciseSTdepression being abenign phenomenon.

T h e E p i d e m i o l o g i c a l Surveys in 1984 and 1989

Theplanning of the25-year follow-up surveyof theSevenCountries cohorts started
in 1982. Theaimwas tostudy thetrendsin serum cholesterol,blood pressure,
smoking,body mass index,and pulmonary function in thecohortsbetween 1959
and 1984.Theidea was toprovide someinsight into thereasonswhy a rapid
decrease incoronary heart diseasemortality had taken place inFinland during the
1970sand 1980s.Another aim wastoassess thefunctional, mental,and socialca-
pacitiesof the men growing older and toexamine lifestyle-related factors predicting
independence at older ages.Altogether,321men from theEast (94%)and 395men
from theWest (93%)participated in thesurvey,which wascarried out in September
-November, first in Ilomantsi and thereafter inPöytyä-Mellilä. Theprotocol adopt-
ed in theprevious surveys was strictly followed. Inaddition, thefunctional, mental
and socialcapacities,blood sugar level,and drug useweremeasured. The study
team now included expertsfrom different disciplines.Martti Karvonen and Sven
Punsar represented continuity inthe study.
Theanalysesofthedata started immediately after thesurvey,and Juha
Pekkanen, MD,did hisPhDthesison coronary heart diseaseduring a25-year fol-
low-up and Ulla-Kaija Lammi,MD,on functional and mental capacity,and predic-
tivefactors.Theanalysesalsofocused alsoon assessment of diabetesmellitus and

65
impaired glucose intolerance aswellasvitamin A.
Soon after the25-year follow-up survey theplanning for the30-year follow-up
started. Themain aim was toanalyze thechangeofcoronary heart disease, diabetes
mellitus,pulmonary function, and personal autonomy or independence atold age.
Examining the lifestyle-related factors predicting general well-being at old age was
alsoapurpose.Thesurvey wascarried out again inSeptember -November 1989in
both cohort areas.Altogether,470men were studied (91%),and thesurvey was
morecomprehensive than previously. Inaddition tomental and functional ca-
pacitiesand useofdrugs,other parametersrelated tohealth statuswere measured,
such asquality oflife during thelast year of life and reliability and validity of meas-
urement of functional and mental capacities.The30-year follow-up study was
planned jointly with theresearch group responsible for Dutch and Italian cohortsof
theSeven Countries Study.
Theresults showed that in30-yearfollow-up thedifference inlifestyle related to
coronary heart diseaserisk factors between East-and West-Finland have largely
disappeared or even partially reversed.Thepredictive valueof thebaselinecoro-
nary risk factors showed largedifferences during 30years of follow-up. For
instance,smokingand serum cholesterol werestrong predictors of risk for coronary
heart diseasedeath occurring early and lateduring the30-year follow-up period.
After 20yearsof thefollow-up, systolicblood pressure was nolonger associated
with coronary heart disease risk.Incontrast, the highest tertileof BodyMass Index
(over24.7kg/m 2 ) wasassociated with increased coronary heart disease risk only
during thelater part of thefollow-up period.
Glucose tolerancewasexamined during 25-and 30-year follow-up surveys to
test thehypothesis that thegeneticsusceptibility tonon-insulin-dependent diabetes
mellitusisthesame asthat toinsulin dependent disease.Alsothe association
between glucose intolerance and specific HLAhaplotypes was investigated. HLA
haplotype data from apopulation-based FinnishStudy ofchildhood diabetes were
used for predicting non-insulin dependent diabetes and impaired glucose tolerance.
Results showed that diabetes-associated HLAhaplotypes were present in94%
(85/90) ofdiabetes subjects, 79%(27/34) of subjects with impaired glucose toler-
anceand only 13%(3/23) of non-diabetic subjects.These findings support the
hypothesis that specific HLAhaplotypes exhibit acommon geneticdeterminant for
insulin dependent and non-insulin dependent diabetes.Furthermore,HLA isa
major geneticdeterminant ofglucoseintolerance inelderly Finnish men.

Dietary Surveys 1956-1989

Severaldietary surveyshavebeen carried out in Finland since 1956in connection
with theepidemiological studiesoncardiovascular diseases.Thedietary surveys

66
 wereplanned and put into practice through theDepartment of Nutrition
Chemistry, later theDepartment of Nutrition, University of Helsinki,by Professor
PaavoRoine,Head of theDepartment, asprincipal investigator between 1956and
1969,assisted by Dr.Maija Pekkarinen, who wasresponsible for thefield surveys,
statistical helpin theselection of themen and participating families,and in data
analysis,wasreceived from theInstituteofOccupational Health (M.Pol.Sc.Jaakko
Kihlberg)and later from theComputing Center,University of Helsinki.Dietary sur-
veys werecarried out in Eastand West Finland altogether sixtimesin 1956,1957,
1959,1964,1969,and 1989. The 1989survey wascarried out by Dr.Leena Räsänen
and Dr.Marja Mutanen.Themethods used wereeither precise weighingor dietary
history interview. University students majoring innutrition collected food con-
sumption data and calculations onenergyand nutrient intakes werebased mainly
on Finnish food composition tables.
Dietary surveys in 1956and 1957werecarried out in thesameareas in East and
West Finland as themedical studies.In 1956,42families from each area were stud-
ied with theweighing method inJune,when thediet wasmonotonousbecauseof
thescarcity of fresh vegetables and fruits. Forseasonal variation,40families were
studied again inJanuary 1957. During sevenconsecutive daysallitemsused in food
preparation, during and between meals,aswellastablewaste,wereweighed, with
theassumption that thequalitative character of thediet of thefamily wasalsoasat-
isfactory indicator for that of the men.
Bread,milk,butter,and fish consumption was higher intheEast,and thatof
vegetables,margarine,and eggswas higher in theWest.Thetotal intakeof energy
and nutrients wassimilar between seasonsand areas.Dietary fat was more saturat-
ed in the East than in theWest,and theintakeofiodine,ascorbicacid,and vitamin
Ewas higher inthe West.
Thediet and serum cholesterol levelsof 110forestry workers were studied in
1959,separately from theSevenCountriesStudycohort,in 15-to66-year-old lum-
berjacks, who had theirmeals inbarracks,and thetotal amount of food consumed
ineachcamp wasestimated from thebook-keeping recordsof thecooperative.The
largeconsumption ofcereal products,butter,and meat products was noteworthy,
with ameandaily energy intakeof4,763kcal,almost half of which (45%)was
derived from fat. Theaverage total fat intakewas237gramsperday,of which milk
and butter covered 60%and meat 30% ofthetotal.Though thedietary fat was thus
highlysaturated, theserum cholesterol levelsof thelumberjacks (246-274mg/100
ml)weresimilar tothoseofother men in thelocal population.
Thedietary survey in thefall of 1959explored thepossibleroleofdietary fat in
theetiology ofcardiovascular diseasesusing population (ecologie)correlations in
all theSevenCountries cohorts.Altogether 30families from Westand 30from East
Finland participated inthissurvey,randomly selected from thosefamilies of men

67
who participated inthecardiovascular diseasestudy at thesame time.The food
consumption ofthemen,in addition tothat ofthe families,was studied separately,
byprecise weighing for one week.Thediet was typically Finnish,themain energy
sourcesbeingcereals,milk and milkproducts,sugar, meat and potatoes,and aver-
ageenergy intakewas 3,760and 3,805kcalfor men inthe Westand inthe East,
respectively, ofwhich fat contributed 35.4%and 39.2%ofthetotalenergy intake.In
the eastern area the fats used weresignificantly moresaturated than thoseused in
thewestern part ofthecountry.With theexceptionofvitamin A,other nutrients
did not present any regional differences.
Inaddition tothepreciseweighing study conducted among 60families, dietary
interviews werecarried out among the1,676 men participating in theSeven
Countries cohort in 1959(817men in theEastand 859men in theWest),toobtain a
general view about the food habits of alarger group of men than was possible in the
restricted weighing surveys.Intheinterview theconsumption of only main foods
wasasked.Then,30yearsago,thefamilies had two main mealsand three to five
snacks aday;energy intake from themealswashigher intheafternoon. The energy
valueof food lostin food wastewasabout 11% of totalenergy.The differences
between weekdays wererather small,though mealson theweekend differed clearly
from thoseon weekdays.
A5-year follow-up study wascarried out inJanuary 1965with 48subjects who
had participated in thestudy in 1959. Theconsumption of cereals,potatoes,milk,
and butter was lower than five years earlier,whileconsumption of meat and fruits
had increased and that ofvegetables decreased,both in theEastand theWest.A
smalldecrease intotal fat intakewas found intheeastern area,but not in thewest,
where thecontribution of fats tothetotal energy wasactually higher than in1959.
During thepreceding five years'period themen had gained weight,but itwas not
reflected in skinfold thickness.Blood cholesterol levelsof men were somewhat
higher than earlier inboth areas.
Adietary history interview survey wascarried out inconnection with thesec-
ond round medical study in thefall, 1964,with 319men inthe Eastand 764in the
West,focusing ontheuseof tablefats,other foods rich infats,and carbohydrate-
rich foods.Therewas higher consumption of sugar,butter,and meat intheEast
than intheWest,whereas theuseofcereals,potatoes,and eggswashigher in the
West.Contribution tothetotalenergy intakeby fats was43%in the East and 40%in
theWest.Thedaily intakeof dietary cholesterol washigh inboth areas,666mgin
theWestand 616mg in theEast.Themen intheWestweresomewhat taller and
heavier than inthe East,and alsotheir skinfolds werethicker. Blood cholesterol lev-
elsofmenwerehigher intheEast (290mg/100ml)than intheWest (266mg/100ml).
Inthefallof 1969thedietsof612menintheEastand 694men intheWest were
re-examined by applying amoredetailed dietary history method than that used in

68
1964.Theconsumption of potatoes,sugar,and butter waslower,and that of cereals
higher,than in 1964. Themen in theEastused more fish, vegetables,fruit, and ber-
riesthan men in theWest.Theamounts of sugar,butter, and meat in thediet were
quitesimilar inboth areas.
During the 1964-69period thedietary fat intakeof themen in theEast had
decreased from 43to39%of total energy.Milkand meat together provided about
90%of thetotal fat intakeinboth areas.Fatwasstillhighly saturated,morein the
Eastthan in theWest.Thediet ofmen in theEastcontained more carbohydrates
than five yearsearlierbut remained almost unchanged in theWest.Thecholesterol
content of thedietshowed an increase inboth areas.Inspiteof thelower energy
intake themen had gained weight,and skinfolds were thicker than in 1964.Blood
cholesterol valuesinthe East,however,werelower than earlier (East276mg/100
ml,West262mg/100ml).
Indietary studies,nutrient intakedata areusuallybased onfood composition
tables.Thecalculated valuesofnutrients from thestudiesof 1959and 1965werein
part checked by chemicalanalyses.In 1959thechecking study included thedietsof
10men inthe Eastand 10in theWest;in 1965,24men from both areas.Samples cor-
responding tothemean daily amount of foods consumed byeachman during the
survey period werecollected at theirhomes.Food sampleswereanalyzed for
water,ash,protein, total fat, and fatty acids.In 1959thefatty acid determinations
werecarried out inthe Laboratory of Physiological Hygiene,Universityof
Minnesota, U.S.A,by Dr.Joseph T.Anderson. Other analyseswereperformed in
theDepartment ofNutritional Chemistry at theUniversity of Helsinki.The results
oftheseanalyseswerecompared tothecalculated nutrient intakes of themen.The
comparison showed such great agreement,particularly in themean values ofpro-
tein and fats,but alsoin thoseofcarbohydrates and totalenergy, that further chemi-
calanalyseswerenot considered necessary.Italsoshowed the reliability of Finnish
food composition tablesused inthecalculations.
All48food samplesofthe 1965study wereused for analyzing the following
mineralelements:Fe,Cu,Mn,Na,K,Ca,P,and ash.Analysesweredone in the
Instituteof Food Chemistry and Technology at theUniversity of Helsinki under the
leadership ofProfessor Pekka Koivistoinen.Theresults showed alinear correlation
between themineral intakeand energyintake.Lowcontentsofironand copper
seemed tobetypical for the Finnish diet.Thequestion hasrisen whether the intake
oftheseelementswas adequate,especially insubjects having lowenergy expendi-
tureand intake.
Thecontent ofchromium and selenium in thedietofmen wasbased on average
food consumption data obtained from thedietary surveysof 1959,1965and 1969,
using food composition data from chemicalanalysisof themineral contentof
Finnish food. Thedaily intakeofchromium was41to45ugand that of selenium 21

69
to34ug in theeastern area.Thecorresponding figures in thewestern area were37
to40ug for chromium and 19to22jagfor selenium.
Asapart of the30-year follow-up survey of the Finnish cohorts,thefood con-
sumption and nutrient intake of themen wasinvestigated again in September-
October 1989.Of theoriginal participants,524,70-to89-year-old men werestill liv-
ing.Arandom sample of298men was chosen for the dietary interview. Complete
dietary history interviews were obtained from 227(43.3%)men.Thedietary history
method which had been used in thestudies in 1964and 1969was modified in 1989
becauseof theadvanced ageof thesubjects and thegreat increasein thenumberof
foods available.The period covered by theinterview was the previous month
instead of theprevious year,asbefore, and interview sheets were much more
detailed toinclude 190precoded food items.Anillustrated booklet with 126color
photographs of variousportion sizesof foods wasused for estimation of portion
sizes. Interviews were conducted in the local health centers (54.4%),at the subject's
home (44.3%),or inahospital (1.3%).Thesubject's wife or someother person assist-
ed with theinterview inone-third of thecases.
Men ineastern Finland consumed considerably more ryeproducts, vegetables,
and berries and alsosour milk, fish and fish products, than men inwestern Finland,
whoconsumed morefruits, cheese,eggs,and alcoholicbeverages.Inboth areas the
diet in 1989contained about one-third lesspotatoes than in the 1960s,while the

Dietary survey in Finland, 1989.

70
energy-adjusted amounts of vegetables,fruits, and berries had doubled compared
tothesituation in 1969.Fifty per cent of thebutter had been replaced by other diet-
ary fats such assoft margarines. Inthewestern area theamount of fish was three
timeshigher in 1989than in1969.
Thequality of thediet in theEastappeared tobesomewhat 'better' than in the
West;for example,theintakeof dietary fiber, and several mineralsand vitamins,
wasclearly higher due to thegreater consumption of rye,vegetables,and fruits, and
alsothelower energy intakefrom fat and alcohol.Thenutrient density of the diet
overall was higher in this most recent survey than in theearlierones.The dietary
history data collected from the227elderly men in 1989showed that diet inold age
cancomply with general recommendations,and isquitecomparable tothatof
younger agegroups.
Alongitudinal analysis hasrecently been completed on thechanges indietof
men who participated in thedetailed dietary survey both in 1969and in1989.

The General Importance of the Dietary Surveys

Themain purpose ofthedietary studieswasanattempt toidentify thedietary fac-
torsassociated with thehigh incidenceof cardiovascular diseases in Finland.
Besidesthis,thesesurveys haveprovided information concerning thecharacteris-
ticsand thedevelopment of theFinnish diet ingeneral.Thecollected data reflect
changes which havetaken place in thediet of therural population since 1956.They
alsoshow thechanged importance ofseasonal and regional variation.Thedevelop-
mentof thedietary survey methodology, which hasbeen an integral part of these
studies,hasbeen valuable for other dietary surveys inFinland.Sincethe 1950sdoz-
ensof nutrition students havehad anopportunity toparticipateinthe fieldwork.
Furthermore,morethan 10of them havewritten Master'sTheseson theresultsof
thesestudies.Inconclusion, thisseriesofdietary studiesappears tohavebeenof
great value for thedevelopment of nutrition research in Finland.

Continuation of the Follow-up after 30 Years

Becauseofconcern about thehealth status of theelderly,itwasof great interest to
haveafurther follow-up of theoriginal SevenCountries cohort.Therefore apostal
survey wasconducted among men stillalivein 1992. Information was collected
about lifestyle factors, functional and mental capacity,and self-perceived health.
Recently thedecision was made that similar information willbecollected ina
3
5-year follow-up survey in1994.

71
Publications
1. KeysA,Karvonen MJ,Fidanza F.Serum
cholesterol studies inFinland. Lancet1958;2:175-
178.
2. Orma E,Karvonen MJ,KeysA,BrozekJ.
Cigarettesmoking,serum cholesterol and blood
pressure.Fed Proc1958,17:120.
3. RoineP,Pekkarinen M,Karvonen MJ,
KihlbergJ.Dietand cardiovascular diseasein
Finland. Lancet1958;2:173-175.
4. Karvonen MJ,Orma E,KeysA,Fidanza F,
BrozekJ.Cigarettesmoking,serum cholesterol,
blood pressure.Observations inFinland. Lancet
1959;1:492-494.
5. Orma E,Karvonen MJ,KeysA. "Cuff
hypertension. Lancet1960;2:51.
6. Rautaharju PM,Karvonen MJ,KeysA.The
mean spatialQRSand Tvectors in468healthy
Finnish men,aged 20to59years.Normal stan-
dards.Theeffect ofage.Acta Med Scand
1960;167:153-157.
7. Karvonen MJ,Pekkarinen M,Metsälä P,
Rautanen Y. Dietand serum cholesterol of lum-
berjacks. BritJNutr1961;15:157-163.
8. Karvonen MJ,Rautaharju PM,OrmaE,
PunsarS,TakkunenJ. Cardiovascular studieson
lumberjacks.JOccupMed1961;3:49-53.
9. Rautaharju PM,Karvonen MJ,KeysA.The
frequency of arteriosclerotic and hypertensive
heart diseaseamong ostensibly healthy working
populations inFinland.An electrocardiographic
and clinicalstudy.JChron Dis1961;13(5):426-438.
10. Rautaharju PM,Karvonen MJ,Leuthold E.
Sexdifferences in theorientation and magnitude
of themeanspatialQRSand Tvectors.Acta Med
Scand 1961;169:405-410.
11. Karvonen MJ.Arteriosclerosis:Clinical sur-
veysinFinland. ProcRoySocMed1962;55:271-
274.
12. Karvonen MJ.Effect of sphygmomanometer
cuff sizeonblood pressure measurement.Bull
WHO1962;27:805-808.
72
13. Karvonen MJ.Arterial pressure inthe East
and West Finland. PembertonJ (Ed).
Epidemiology. Reportson Research and
Teaching.London 1962,Oxford University Press
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STUDIES IN ZUTPHEN
D. Kromhout

The Netherlands joined theSeven Countries Study due to personal

contactsbetween Professor Ancel Keysand Professor M.J.L.Dols,Chairman of the
Netherlands Nutrition Council,which developed during joint work on United
Nationscommittees. Professor Dolscontacted Professor Muntendam, Secretaryof
State for Public Health, about thepossibility tojoinan international study on risk
factors for atherosclerotic complications. Afellowship of theCouncil of Europe en-
abled Dr.Louise M.Dalderup tojoin thepilot study in Nicotera,asmall villagein
southern Italy, inOctober 1957.
Vital to theorganization of asimilar study in the Netherlands was this contact
with Professor Keysand hisco-workers during thepilot study, meeting the enthu-
siastic investigators of different interested countries (e.g.England, Finland, France,

Townof Zutphen.

79
Greece,Italy,Japan and the United States),observations of equipment and meth-
ods,and discussions about pro'sand con'sof thestudy. Dr.Dalderup's presence
from theunloading of theequipment, itsarrangement and thestartof theactual
fieldwork, gave her anexcellent opportunity tostudy thelogistics,see the inter-
actions between members and thecomposition of the team,and observe the
schedule toexamine participants.
Thereafter itwasdecided that the Netherlands should join this international
study. Acommittee on 'Nutrition and Atherosclerosis' wasestablished by the
Netherlands Nutrition Council under chairmanship of Professor F.S.P.van Buchem.
Other members of thecommittee wereDr.E.H.Groot,Professor C.den Hartog,
Professor G.A.Lindeboom, Professor H.Mulder,Professor P.Muntendam and
Professor A.Polman. In 1959Professor Van Buchem was appointed principal medi-
cal investigator and Professor Den Hartog asprincipal investigator for the dietary
studies.Professor Muntendam becamechairman of thecommittee on 'Nutrition
and Atherosclerosis'. Additional money was raised tosupplement the grants
obtained by Professor Keysfrom the U.S.Public Health Service.
Thetown ofZutphen, located in theeastern part of theNetherlands, was select-
ed for the Dutch contribution totheSevenCountries Study because there was little
mobility of thepopulation, and an earlier investigation for theWHOby Dr. C.A.A.
Bramlage,Institute ofSocial Medicine,University of Leiden (Director: Professor P.
Muntendam),had shown thewillingness of thecitizens toparticipate inan epidem-
iologicalstudy. In1960thenumber of inhabitantsofZutphen wasabout 25,000.For
thisinvestigation,allmen born between 1900-1919who had lived inZutphen for at
least five years were selected.Of these2,450men,arandom sample of4out of9
wasdrawn. Due tofinancial limitations,onlyabout 1,000 mencould be examined.
Finally, 1,088 men were invited for the study.

The Period I 9 6 0 - 1975

FromJanuary 1960until thestart of fieldwork in May,Dr.Dalderup, Dr.E.E.J.
Marlerand Mrs.W.B.Buchel,public health nurse who had participated in the study
by Dr.Bramlage,made allthe necessary preparations inZutphen. Medical examina-
tionswerecarried out by Professor VanBuchem and a team including seven physi-
cians.Dietary surveys werecarried out by sixdietitians supervised by Professor
Den Hartog and Dr.Th.F.S.M.van Schaik.Of allmen invited,908were medically
examined, 1,049 participated in thedietary survey and 872men (aged 40-59)par-
ticipated inboth themedical and dietary survey. Much helpwasgiven by local
people,including Dr.J.W.Eerkens,director ofoneof thelocalhospitals,E.B.
Bosschieter, internist, Mrs.A.H.Thomassen-Gijsbers, nurse,Mrs.J.Brands-
Thomassen, Mr.and Mrs.H.Bogers,and manyothersof thelocal Red Cross

80
Frons van Buchem reading ECC's, Zutphen, I960 ECG taken by Ans Thomassen, Zutphen, 1965

Organization. Without theirenthusiasticand practical help thestudy would not

havebeen realized.
In the period 1960-1973thecoremedical examination was repeated annually by
Professor Van Buchemand collaborators. E.B.Bosschieter, internist, who was
involved in thestudy from thebeginning,becameco-investigator in 1966.The diet-
ary surveys were repeated in 1965and 1970by Professor Den Hartog and Dr.Van
Schaik. During this period several additional investigations werecarried out.
Between I960and 1963comparative dietary studies werecarried out in small sub-
samplesand in 1960and 1963an examination of theocular fundus wasdone.In
1965an extensive study on energy expenditure and lung function was carried out
by investigators of theNetherlands Instituteof Preventive MedicineTNO, Leiden.
In 1967blood groupings and uricacid determinations werecarried out. Fasting
blood glucose determinations were made in 1968, and acomplete glucose tolerance
testcarried out in 1970aswas Protein Bound Iodine (PBI).Between 1964and 1971
blood lipid and lipoprotein levelsweredetermined by theGaubius InstituteTNO,
Leiden,and thedata used in severalcase-control studies.
Indata analyses and publications of theZutphen Study most emphasis during
thefirst 15years wason hypertension and electrocardiography due tothe personal
interestsof Professor Van Buchem. Healsopublished acasereport of congenital
beta-lipoprotein deficiency ina participant in theZutphen Study with avery low
total serum cholesterol level,showing hisprimary clinical interest. Professor Den
Hartog and Dr.van Schaik published descriptive studies ofdietary data.

T
h e Period after 1975
Professor Van Buchem resigned asprincipal investigator of theZutphen Study in
19
74,and Dr.Dalderup looked after thestudy in 1976and 1977.In 1977the commit-
teeon 'Nutrition and Atherosclerosis' of theNutrition Council asked Professor

81
Kromhout towriteaplan for analysis of thedata collected in theZutphen Study.
That plan was accepted and Kromhout becametheprincipal investigator of the
Zutphen Study in1978.
Dr.Dalderup started preparations for anew survey round in 1976.In 1977,500
men wereexamined and in 1978,111men,with aresponse rateof 91%. Kromhout
submitted agrant application for a20-yearfollow-up study in 1980,but the grant
application wasnot funded, with theargument that analyses ofcollected data were
moreimportant than new examinations.
In 1978Kromhout, incollaboration with the medicaladministration department
of theNieuwe Spittaal Hospital inZutphen,started amortality register for partici-
pants in theZutphen Study.Themorbidity history of men who died was summar-
ized by Dr.E.B.Bosschieter,based on information present in hospital records.The
morbidity histories of allparticipants in theZutphen Study covering the period
1960-1985werecoded inastandardized way in 1986byonephysician,Dr.M.
Drijver. Information oncauseof death according totheInternational Classification
of Diseasesof men whodied between 1960and 1985was obtained from the Central
Bureau ofStatistics (CBS). Thecollaboration with Dr.L.M.Friden-Killof theCBSis
recognized with gratitude.
Before 1978information on themajor risk factors wascomputerized byIWIS-
TNO,Rijswijk. However,information on occasionally determined risk factors was
notcomputerized. Thus,alldietary data had tobecoded and entered intothecom-
puter file,which wascarried out bygrants from theNutrition Council.Drs.C. de
LezenneCoulander played acentral roleinpreparing thedata setsbefore statistical
analysiscould start.
In 1980Kromhout obtained afellowship from theNetherlands Organizationof
Scientific Research (NWO) towork and study for oneyear attheLaboratoryof
Physiological Hygiene,Schoolof PublicHealth,University of Minnesota,
Minneapolis,Minnesota (Head: Professor Henry Blackburn).During thisyear he
took aMastersof PublicHealth degree inEpidemiology.Kromhout prepared incol-
laboration with Professor Blackburn and Professor Keysagrant application for
extensiveanalysesondiet and chronic diseasesin theSevenCountries Study.
Finally,hestarted analysesof theZutphen dietary data and wrote four papers on
thedietary pattern ofZutphen men in theperiod 1960-1970,dietary determinantsof
body fatness and serum cholesterol,and therelation between diet and 10-year mor-
tality from coronary heartdisease.After hisreturn totheNetherlands in 1981,he
started extensiveanalysesin collaboration with Cor de Lezenne Coulander.
In 1984agrant application wassubmitted for anew round of fieldwork to study
lifestyle factors and chronicdiseases in 1,000 men,aged 65-84,inZutphen. This
grant application was funded in 1985bytheNetherlands Prevention Foundation.
Of the 1,088 men selected in 1960,555werestillaliveonJanuary 1,1985.Of the

82
remaining 1,075 men,aged 65-84,inZutphen, a two-thirds random sample was
drawn. In total, 1,266 men wereinvited for thestudy and 939(74%) participated.
The721survivors were invited for are-examination in 1990and 560(78%) persons
were examined.
In 1985and 1990extensivesurvey examinations werecarried out. Physicians
asked for information on the prevalence of major chronicdiseases and smoking
habitsof the participants using astandardized medicalquestionnaire. Aphysical
examination wascarried out,including blood pressure and anthropometric meas-
urements.Anelectrocardiogram was taken, and blood collected for determination
oftotal and HDLcholesterol, hematologic, hemostatic,and clinical chemical vari-
ables.Adietary survey wasconducted athomeby dietitians using the cross-check
dietary history method. Finally,participants filled out a lifestyle questionnaire pro-
viding information on demographic variables,occupational history,daily activities,
subjective health, lifeevents,loneliness,coping,and future orientation. Aglucose
tolerance test wascarried out in 1990,and blood glucose and serum insulin were
measured fasting, and one and two hoursafter a 75-gram glucose load. Inthe1990
survey information was alsocollected on functional and mental capacities of the
participants.In 1993theinformation on lifestyle, functional, and mental capacities
wascollected again in 389of theremaining 553(70.3%)men.Also,four tubesof
blood werecollected for analyses of total and HDLcholesterol, glycosylated hemo-
globin,HLA-typing,and storageof leucocytes.
Since 1985more possibilities havebecomeavailable for automation of the mor-
bidity and mortality data. Hospital discharge data since 1985of participants in the
Zutphen Study were provided by the 'Nieuwe Spittaal' hospital, and coded cancer
data of thecancer registry have been obtained sincethat time.All thisgreatly facili-
tated thecomplete morbidity and mortality follow-up of theZutphen men, and
made much broader analyses possible. Besidestraditional analyses on the relation
between lifestyle factors and theincidenceofand mortality from chronicdiseases,
other aspects of health can beanalyzed inrelation tocharacteristics of themen.The

Edward Bosschieter taking bloodpressure,

Zutphen, 1985

83
physical,mental,and social aspectsof health havethereby been integrated, physical
health measured by physical examination, medical history,physical performance
and functional capacities,mental health by different questionnaires, (e.g.Mini-men-
talState Examination and Zung depression scale)and socialhealth by question-
nairesabout social contacts,marital status,and loneliness.

Results since 1980

Inanalyses of Zutphen data collected up to 1985,emphasis wasplaced on dietary
data.Theyhavebeen analyzed descriptively, and inrelation tobiological risk fac-
tors and incidenceand mortality from chronic diseases.Theresultsof these analy-
sesaresummarized here.
Changes indietary and nutrient patterns during 10and 25years follow-up have
been described intwopapers (Kromhout 1983a,Kromhout etal, 1990). These analy-
sesshowed that energy intakeinthisaging cohort decreased by800kcal/day
between 1960and 1985due toadecrease in theconsumption of bread, potatoes,
legumes,vegetables,eggs,milk,ediblefats,and sugar.Ontheother hand, an
increasewas observed inconsumption of fruits, alcoholicbeverages,nuts,and pas-
tries.Resultsof studies onvalidity of retrospectively assessed dietary intake data,
and on reproducibility of dietary intakedata,have alsobeen reported (Bloemberget
al, 1989a,b).
Dietary variableswere alsoanalyzed in relation tobiological risk factors. Energy
intakewasinversely related toindicators for body fatness (Kromhout, 1983b).Body
weight,an indicator ofenergy balance,waspositively associated with serum cho-
lesterol level (Kromhout, 1983c).Alcoholwas positively associated with blood pres-
sure,and calcium and potassium intakewasinversely related toblood pressure
(Kromhout etal, 1985a).Saturated fat and dietary cholesterol wererelated to
decreased glucosetolerance,incontrast tothepositiveeffect ofdietary fiber and
sugar (Feskensand Kromhout,1990).
Severalanalyseswerecarried out on theassociationsbetween different dietary
variables and mortality from chronicdiseases.Dietary fiber was inversely related to
10-year mortality from totalcancer and,in univariate but not in multivariate analy-
ses,tomortality from coronary heart disease.(Kromhout etal, 1982).Energy intake,
a 'proxy variable' for physical activity,was inversely related to 10-year mortality
from coronary heart disease (Kromhout and DeLezenneCoulander,1984).An
inverserelation wasobserved between fish consumption and 20-year mortality
from coronary heart disease (Kromhout etal, 1985b).Thispaper wasrecently select-
ed asaCitation ClassicbyCurrent Contents.Dietary cholesterol was positively
associated with 20-yearmortality from coronary heartdisease (Kromhoutet al,
1985b).Vitamin Cintake wasinversely related to25-yearmortality from lung can-

84
eer(Kromhout, 1987).Sugar consumption waspositively,and calcium intake was
inversely,associated with 25-year incidenceofgallstones (Moerman etal, 1993).
Inrecent yearsinterestsof theinvestigators of theZutphen Study has broad-
ened.Thepredictivevalueof classical riskfactors was studied, including repeated
measures.Physical activity wasstudied inrelation toother coronary heart disease
riskfactors. Occupational exposurewasstudied inrelation totheincidenceof
chronicnon-specific lung disease.Subjective health wasevaluated asapredictorof
mortality.
Acasual serum cholesterol value was found tobea long-term predictor ofcoro-
nary heartdisease incidence inZutphen men (Kromhout etal, 1988).Itwas also
shown that thepredictive power ofacasual serum cholesterol determination
decreased with increasing age (DeVriesetal, 1993).Thiswas partly due toselective
mortality of relatively young men with relatively high serum cholesterol values.
Blood pressure was an independent risk factor for coronary heart disease and
stroke.Thestrength of theassociations improved much byaveraged data from
repeat measures (Kelietal, 1992,DeVriesetai, 1993).
Subscapular skinfold thicknessand cigarettesmoking wereindependent predic-
torsofdiabetes incidence (Feskensand Kromhout, 1989).Glucose tolerance was an
independent predictor ofcoronary heart disease incidence (Feskensand Kromhout,
1993).Diabetics,compared with non-diabetics,had increased risk of fatal coronary
heart diseaseand incidenceofperipheral arterial disease.(Feskensand Kromhout,
1993).
Physical activity of retired men was measured with aquestionnaire on daily
activitiesdeveloped by Professor Morris,London Schoolof Hygiene and Tropical
Medicine.Thisquestionnaire hasbeen validated against thedoubly-labelled water
m
ethod (Sarisetai, 1993).Descriptive data from the 1985survey showed that the
elderly Zutphen men wereactivecompared with their American counterparts
(Caspersen etal, 1991). Asignificant inverse relation wasobserved between physi-
calactivity and HDLcholesterol.When individual activitieswererelated toother
coronary heart disease risk factors,an independent association was observed
between gardening and HDLcholesterol level.
Prevalence and incidenceof chronicnon-specific lung disease (CNSLD) was
higher among workers inagriculture,and in thepaper and construction industries,
compared with whitecollarworkers (Heederik etal, 1989). Theincidenceof
<-NSLDwas alsopositively associated with intakeof linoleicacid. However, the
consumption of applesand alcoholwasinversely related toCNSLD incidence
(Miedemaeffl/,,1993).
Totalmortality was twiceashigh among smallbusinessowners and blue collar
Workersthan inprofessionals (Duykersetal, 1989). Subjective healthwasalsoan
independent predictor of total mortality.Men whorated themselves asnot feeling

85
healthy in 1985had a5.4timeshigher mortality from allcausesduring5-yearsof
follow-up compared with men whofelt healthy (Pijlsetal, 1993).This association
wasindependent of theprevalence of chronicdiseasesand levelsof major risk fac-
torsatbaseline.

Acknowledgments
TheZutphen Study wasinitiated by Professor F.S.P.van Buchemin 1960. E.B.
Bosschieter M.D.becameco-investigator in 1966.Professor van Buchem withdrew
asprincipal investigator in 1974.Dr.LouiseM.Dalderup guided theStudy in1976
and 1977. Professor Daan Kromhout becameprincipal investigator ofthe Zutphen
Study in1978.
The 1985survey wasorganized by Daan Kromhout inclosecollaboration with
Gatske L.Obermann-de BoerM.D.and Mathilde van Kampen-DonkerPh.D.The
medical team wasledby Professor A.C.Arntzenius,cardiologist, physiciansE.B.
Bosschieter M.D.,A.H.A.M.BolsiusM.D.,A.B,van Haaften M.D.and A.F.in't Veld
M.D.AnsH.Thomassen-Gijsbers played acentralrolein thelocalorganization and
was responsible for thesurvey ofnon-respondents.Marianne R.T.van Haaren-
Bouterse M.Sc.coordinated thedietary survey that was carried out with the helpof
25dietitians.Cor de LezenneCoulander M.Sc.and BennieP.M.Bloemberg PhD.
coordinated qualitycontrol of thecollected data and organized thedata sets.
Essentially thesamepersonscarried out the 1990survey,with afew changes.
BennieP.M.Bloemberg Ph.D.replaced Mrs.Van Kampen-Donker in the coordinat-
ing team and thedietary survey wascoordinated bythedietitians Ester Goddijn
and AnnemarieJansen.EdithJ.M.FeskensPh.D.coordinated thebiochemical deter-
minations,including theglucose tolerancetest and alsocoordinated fieldwork
activities in1993.

86
Publications
1. Van Buchem FSP.Atherosclerosis and nutri-
tion. Nutr Diet 1962;4:122-147.
2. Van Buchem FSP. Hypertension, etiology
and diagnosis. Indian Heart J 1963;15:244.
3. Van Buchem FSP,Van de Heuvel-Aghina
JWMT, Van de Heuvel JEA. Hypertension and
changes of the fundus oculi. Acta Med Scand
1964;176:539-548.
4. Van Buchem FSP,Drion EF. Cardiovascular
disease and serum cholesterol. Angiology
1964;15:424-429.
5- Den Hartog C etal.Dietary surveys in con-
nection with epidemiology of heart disease.
Results with 900 men at Zutphen (Netherlands)
Comparison of methods. Proceedings 6th
International Congress on Nutrition, Edinburgh,
9-15 August 1963.E&SLivingstone Ltd.,
Edinburgh and London, 1964:620.
*• Den Hartog C Van Schaik TFSM, Dalderup
LM, Drion E.Methodology of dietary surveys
associated with epidemiological research on the
relationship between serum cholesterol and diet-
ary fat. Nutr Diet 1964;6:52-62.
7 sis. Am Heart J 1970;80:831-837.
- Den Hartog C, Van Schaik TFSM, Dalderup
LM, Drion EF,Mulder T.The diet of volunteers
Participating in a long-term epidemiological field
survey of coronary heart disease in Zutphen, The
Netherlands. Voeding 1965;26:184-201.
8
- Bink B,Bonjer FH, Van der Sluijs H.
Assessment of the energy expenditure by indirect
time and motion study. In: Physical activity in
health and disease. Evang K,Andersen KL(Eds).
Universitetsforlaget, Oslo, 1966:207-214.
'• Van Buchem FSP,Pol G, De GierJ, Böttcher
Q F , Pries C. Congenital b-lipoprotein deficiency.
Am JMed 1966;40:794-804.
1
0. Van Buchem FSPetal.Congenital bèta-lipo-
protein deficiency. Kon Nederl Acad Wetensch,
p
roc Ser C 1966;69 No. 2.
1
1• Van Buchem FSP,Dalderup LM.The town
°f Zutphen, The Netherlands. In: Epidemiological
studies related to coronary heart disease: charac-
teristics of men aged 40-59 in seven countries.
Keys A,etal(Eds).Acta Med Scand 1967;Suppl
460:191-208.
12. Van Buchem FSP.Serum lipids, nutrition
and atherosclerotic complications in man. Acta
Med Scand 1967;181:403-416.
13. Van Buchem FSP.The pathogenesis of athe-
rosclerotic complications in man. Arch Kreislauff
1967;54:140-160.
M. Van Buchem FSPetal. Electrocardiographic
disturbances in asymptomatic men in the course
of seven years. Kon Nederl Acad Wetensch, Proc
Ser C 72,1969 No. 1.
15. Van Buchem FSP,Drion EF,Wigbout M,
Bosschieter E.The clinical significance of an ST-
segment depression in the electrocardiogram.
Arch Kreislauff 1969;60:1-16.
16. Van Buchem FSP,Bosschieter EB.The influ-
ence of sympathicolytics on the electrocardio-
gram. Kon Nederl Acad Wetensch, Proc C 73,
1970No. 1.
17. Van Buchem FSP.The pathogenesis of ath-
erosclerosis and atherosclerotic complications in
man. Indian Heart J 1970;22:269-287.
18. Van Buchem FSP,Schermers TG, Van den
BergJW.The clinical significance of aortic sclero-
19. Van Buchem FSP.Zutphen, a town in The
Netherlands. In:Coronary heart disease in seven
countries. Keys A (Ed).Circulation 1970;40(Suppl
l):76-87.
20. Kromhout D, Bosschieter EB,De Lezenne
Coulander C. Dietary fibre and 10-year mortality
from coronary heart disease, cancer and all caus-
es. The Zutphen Study. Lancet 1982;11:518-522
21. Kromhout D. Changes in energy and macro-
nutrients in 871 middle-aged men during 10 years
of follow-up (The Zutphen Study). Am J Clin
Nutr 1983;37:287-294
22. Kromhout D. Energy and macronutrient
intake in lean and obese middle-aged men (The
Zutphen Study). Am JClin Nutr 1983;37:295-299
23. Kromhout D. Body weight, diet and serum
cholesterol in 871 middle-aged men during 10
years of follow-up (The Zutphen Study). Am J
Clin Nutr 1983;38:591-598
87
24. Kromhout D, De Lezenne Coulander C.
Diet, prevalence and 10year mortality from coro-
nary heart disease in 871 middle-aged men (The
Zutphen Study). Am JEpidemiol 1984;119:733-
741.
25. Kromhout D, Bosschieter EB,De Lezenne
Coulander C. Potassium, calcium, alcohol intake
and blood pressure. The Zutphen Study. Am J
Clin Nutr 1985;41:1299-1304.
26. Kromhout D, Bosschieter EB,De Lezenne
Coulander C.The inverse relation between fish
consumption and 20-year mortality from coro-
nary heart disease. N Engl JMed 1985;312:1205-
1209.
27. Kromhout D,Wibowo AAE, Herber RFM,
Dalderup LM, Heerdink H, De Lezenne
Coulander C, Zielhuis RL.Trace metals and coro-
nary heart disease risk indicators in 152 elderly
men (The Zutphen Study). Am J Epidemiol
1985;122:378-385
28. Kromhout D. Essential micronutrients in
relation to carcinogenesis. Am JClin Nutr
1987;45:1361-1367.
29. Kromhout D, Saris WHM, Horst CH.
Energy intake, energy expenditure, and smoking
in relation to body fatness: the Zutphen Study.
Am JClin Nutr 1988;47:668-74
30. Kromhout, D. Bosschieter EB,Drijver M, De
Lezenne Coulander C. Serum cholesterol and 25-
year incidence of and mortality from myocardial
infarction and cancer. The Zutphen Study. Arch
Intern Med 1988;148:1051-1055.
31. Van Houwelingen AC, Hornstra G,
Kromhout D, De Lezenne Coulander C. Habitual
fish consumption, fatty acids of serum phospho-
lipids and platelet function. Atherosclerosis 1989;
75:157-165.
32. Van Houwelingen AC, Kester ADM,
Kromhout D, Hornstra G. Comparison between
habitual intake of polyunsaturated fatty acids and
their concentrations in serum lipid fractions. Eur J
Clin Nutr 1989;43:11-20
33. Heederik D, Pouwels H, Kromhout H,
Kromhout D.Chronic non-specific lung disease
and occupational exposures estimated by means
of a job exposure matrix: the Zutphen Study. IntJ
Epidemiol 1989;18:382-389.
88
34. Feskens EJM, Kromhout D. Effects of body
fatness and its development over a 10-year period
on glucose tolerance in euglycemic men: The
Zutphen Study.IntJEpidemiol 1989;18:368-373.
35. Duijkers TJ, Kromhout D,Spruit IP,
Doornbos G. The role of some major risk factors
in the relation between socio-economic status and
25-year mortality (TheZutphen Study).Int J
Epidemiol 1989;18:658-662.
36. Bloemberg BPM, Kromhout D, Obermann-
de Boer GL,Van Kampen-Donker M.The repro-
ducibility of dietary intake data assessed with the
cross-check dietary history method. (The Zutphen
Study). Am JEpidemiol 1989;130:1047-52.
37. Bloemberg BPM, Kromhout D, Obermann-
de Boer GL.The relative validity of retrospective-
ly assessed energy intake data in cases with myo-
cardial infarction and controls (The Zutphen
Study).JClin Epidemiol. 1989;42:1075-1082.
38. Feskens EJM, Kromhout D. Cardiovascular
risk factors and the 25-year incidence of diabetes
mellitus in middle-aged men. Am J Epidemiol.
1989;130:1101-1108.
39. Kromhout D, De Lezenne Coulander C,
Obermann-de Boer GL, Van Kampen-Donker M,
Goddijn E, Bloemberg BPM. Changes in food and
nutrient intake in middle-aged men during the
period 1960-1985 (The Zutphen Study). Am JClin
Nutr 1990;51:123-129.
40. Kromhout D,Nissinen A, Menotti A,
Bloemberg B,Pekkanen J,Giampaoli S.Total and
HDL cholesterol and their correlates in elderly
men in Finland, Italy and the Netherlands. Am J
Epidemiol 1990;131:855-863.
41. Feskens EJM, Kromhout D.Habitual dietary
intake and glucose tolerance in euglycemic men:
the Zutphen Study. Int J Epidemiol 1990;19:953-
959.
42. Heederik D, Kromhout H, Burema J,
Biersteker K, Kromhout D.Occupational exposure
and 25year incidence rate of chronic non-specific
lung disease. The Zutphen Study. Int J Epidemiol
1990;19:945-952.
43. Caspersen CJ,Bloemberg BPM,Saris WHM,
Merritt RK,Kromhout D.The prevalence of
selected physical activities and their relationship
with coronary heart disease risk factors in elderly
men: The Zutphen Study, 1985.Am J Epidemiol
1991;133:1078-1092.
44. KeliSO, Bloemberg BPM, Kromhout D. The
predictive value of repeated systolic blood pres-
sure measurements for stroke risk -The Zutphen
Study. Stroke 1992;23:347-351.
45. Heederik D, Kromhout H, Kromhout D,
Burema J, Biersteker K. Relations between occu-
pation, smoking, lung function, and incidence
and mortality of chronic non-specific lung dis-
ease. The Zutphen Study. Brit JInd Med
1992;49:299-308.
46. Kromhout H, Heederik D, Dalderup LM,
Kromhout D. Performance of two general job-
exposure matrices in a study of lung cancer mor-
tality in the Zutphen cohort. Am J Epidemiol
1992:136:698-711.
47. Feskens EJM, Kromhout D.Glucose toler-
ance and risk of cardiovascular diseases: the
Zutphen Study. JClin Epidemiol 1992;45:1327-
1334.
48. Feskens EJM, Bloemberg BPM, Pijls LTJ,
Kromhout D. A longitudinal study on elderly
men: the Zutphen Study. In:Aging, health and
competence: the next generation of longitudinal
research. Schroots JJF(Ed).Amsterdam, Elsevier
1993:327-333.
49. Sandker GW, Kromhout D, Aravanis C,
Bloemberg BPM,Mensink RP, Karalias N, Katan
MB.Serum cholesterol ester fatty acids and their
relation with serum lipids in elderly men in Crete
and The Netherlands. Eur JClin Nutr 1993;47:201-
208.
50. De Vries CL, Feskens EJM, De Lezenne
Coulander C, Kromhout D. Repeated measure-
ments of serum cholesterol and blood pressure in
relation to the longterm incidence of myocardial
infarction. Cardiology 1993;82:89-99.
51. Miedema I, Feskens EJM, Heederik D,
Kromhout D. Diet and the risk of chronic non-
specific lung diseases in middle-aged men: The
Zutphen Study. Am JEpidemiol. 1993;138:37-45.
52. Hertog MGL, Feskens EJM,Hollman PCH,
Katan MB,Kromhout D. Dietary antioxidant fla-
vonoids and risk of coronary heart disease. The
Zutphen Elderly Study. Lancet 1993;342:1007-
1011.
53. Pijls LTJ,Feskens EJM, Kromhout D.Self-
rated health, mortality and chronic diseases in
elderly men. The Zutphen Study 1985-1990.Am J
Epidemiol 1993;138:840-848.
54. KeliSO, Feskens EJM, Kromhout D. Is fish
consumption inversely associated with stroke
incidence? The Zutphen Study. Stroke
1994;25:328-332.
55. Moerman CJ, Berns MPH, Smeets FWM,
Kromhout D.Obesity as a risk factor for clinically
diagnosed gallstones in middle-aged men: a25-
year follow-up study (TheZutphen Study). IntJ
Obesity. Accepted.
56. Moerman CJ, Smeets FWM, Kromhout D.
Dietary risk factors for clinically diagnosed gall-
stones in middle-aged men: a 25-year follow-up
study (The Zutphen Study). Ann Epidemiol.
Accepted.
57. Hertog MGL, Feskens EJM,Hollman PCH,
Katan MB,Kromhout D. Dietary flavonoids and
cancer risk in theZutphen Elderly Study.
Submitted.
58. Dekker JM, Schouten EG, Kromhout D, Pool
J.The cardiac infarction injury score as predictor
of coronary heart disease. The Zutphen Study.
Submitted.
59. Bloemberg BPM, Kromhout D, Räsänen L,
Pekkarinen M, Fidanza F,Menotti A. Influence of
measurement error on the observed relation
between the intake of fatty acids and serum cho-
lesterol on the group level and the individual lev-
el. Submitted.
60. Bloemberg BPM, Kromhout D. Relation
between changes in fatty acids intake and changes
in serum cholesterol (TheZutphen Study).
Submitted.
6 1 . Saris WHM, Bloemberg BPM, Westerterp
KR, Kempen K,Caspersen C, Kromhout D.
Validation of the Zutphen physical activity ques-
tionnaire among elderly men by the double
labelled water technique. Submitted.
89
STUDIES I N RURAL ITALY
F. Fidanza and A. Menotti

Beginning in 1952cross-sectional surveys ofdifferent populations

werecarried out inNaplesand elsewhere by Flaminio Fidanza incollaboration with
AncelKeys.Theyshowed that serum cholesterol was related tofat intake (and par-
ticularly saturated fatty acids)and thatareas with lowcholesterol values were char-
acterized by low prevalence ofcoronary heartdisease (CHD).Itwasdifficult to
identify appropriate population samples having internally contrasting subgroups
becauseconfounding variablescould beintroduced incomparisons made between
socio-economic classes.Therefore itwasdeemed necessary tosetup,in parallel,
longitudinal studieson men in areasdiffering indiet orin thealleged incidenceof
CHD,orboth.Finally,rural areascharacterized bysimpleagricultural pursuits
wereselected for drawing 'chunk' samplesof men aged40-59.
Apilot survey,led byAlfonso DelVecchioand Flaminio Fidanza,was carried
out inSeptember-October 1957inNicotera,Calabria,near thetoeofItaly.That rural
villagewas selected because DelVecchio,first medical student and then intern at
theInstitute of Human Physiology of theUniversity ofNaples,was anative and
provided introduction tothecommunity.Vittorio Puddu, then Director of the
Center for Cardiovascular Diseases of theSt.CamilloHospitalinRome,was
responsible for allclinical aspects.Headquarters of thesurvey was ina rented
housein thecenterofNicotera.Thefield staff included Domenico Cotrone,cardi-
ologist of Rome,LouiseDalderup,internist ofAmsterdam, MarioMancini, internist
ofNaples,and othersfor anthropometric measurements and ECGrecording. Major
international participants inthispilot survey wereAnceland Margaret Keys from
Minneapolis,RatkoBuzina from Zagreb,Martti Karvonen from Helsinki, Noboru
Kimura from Fukuoka and Paul Dudley Whitefrom Boston.
Thesurvey wasnoeasymatter. BecauseaSwedish ElemaECGmachine was
used,and itwas verydifficult toobtain theproper paper,someofusspent partof
theafternoons and sometimes eveningscutting down larger-sized paper which was
moreavailable.Moreover, therewere nohotelsinNicotera,theclosestbeing the
HotelJollyinGioia Tauro,about 30kmsouth.Thecobblestone road was terrible,
and bycarwewerejolted for anhour eachway.On theother hand, the 'invasion'of

91
an American TVteam for adocumentary of thestudy was very rewarding for us
and for the localpeople.PaulWhitewascaptured on film auscultating patients
with hisfamous gold stethoscope.
InAugust 1958Flaminio Fidanza carried out,in cooperation with theCenter for
Cardiovascular Diseasesof Ancona,apilot epidemiological survey on agroupof
peoplein Montegiorgio,in Marche,achieving avery high response rate.In the same
year,theformal research program and Seven Countries surveys,launched byAncel
Keysand hisstaff,becameoperative.Accordingly, in 1959wecreated inItalya
Supervisory Committee made up of FlaminioFidanza from Naples,Arrigo Poppi
from Bologna,and VittorioPuddu from Rome.Wemet inJanuary 1959toselect
threerural areasinItalycontrasting indietand geography, and topreparea finan-
cialplan of thestudy tobeconducted during thenext sixyears.Foran exampleof
southern Italy,itwas decided tore-examine thesubjects ofNicotera using the new
standard methodology adopted by theinternational SevenCountries Study. For
central Italy,thevillageof Montegiorgio was selected because Flaminio Fidanza
grew up in that area and becauseof thesuccessof thepilot study therein 1958.For
northern Italy,ArrigoPoppi proposed thevillageof Crevalcore because Augusto
Pezzoli,theDirector of thelocalhospital,wasagood friend. Due toshortageof
funds, and similarity with thepreliminary results obtained inCrete,the survey
planned for Nicotera was canceled.
After approval of USPHSGrant H-4672,the first Italian field survey started in
February 1960in thevillageof Crevalcore,located about 30km north of Bologna in
theflat and fertile PoValley.Examinations wereconducted in thelocal Barberini
Hospital.MrLorisManfredi, mayor ofCrevalcore and authoritative member of the
localItalian Communist Party,wasvery cooperative.Themunicipal guard, Ivo
Donini,and hisyounger colleague,Alfonso Barbieri,wereof great help in finding
and inviting the 1019men aged 40-59,resident of thevillageproper for at least five
years.Subjects resident inperipheral hamletswereexcluded.Thanks totheir help,
and that ofGinoCavicchi,aphysician in thelocalhospital,weachieved an excellent
response rate (98.5%). Thebasicfield staff included Flaminio Fidanza from Naples,
general coordinator; Marisa Todesco,cardiologist from Bologna;Bruno Imbimbo,
internist from Naples;GiancarloGhironzi and Giorgio Baldacci,both internists
from the RepublicofSt.Marino,Angelo Pezzella,cardiologist from Rome,Ivan
Mohacek, internist and cardiologist from Zagreb,and other peoplededicated to the
anthropometric measurements and theECGrecording.Major international partici-
pants and consultantswereAncelKeys,Henry Blackburn,and Ernst Klepetar from
Minnesota.InCrevalcore,weexperienced good butrichmeals.Thelackof areason-
ablehotelcompelled ustotraveleverydaybackand forth toBolognaby train orcar.
InAprilof thesameyearwe moved toMontegiorgio,ahillvillagelocated in the
Marche,about 30km inland from theAdriaticSea.Headquarters therewas set up

92
in the new town hall.Therewe received excellent cooperation from themayorof
Montegiorgio, Mr.OrtelioOrtenzi,and themunicipal guard, Guerrino
Alessandrini,wasofgreat help finding and inviting the726subjects aged 40-59
who participated enthusiastically, achieving atopparticipation rateof99.2%.The
field staff was thesame asinCrevalcore while added international consultants were
Edvin Ferber and Branka Tiefenbach, both from Zagreb, Paavo Roineand Maija
Pekkarinen, both from Helsinki,Christ Aravanis and Demetrios Lekosfrom Athens
and again, Paul Dudley White from Boston. Picnicsand homemealswith thelocal
farmers wereparticularly rewarding. Whileour hotel was20km away in Fermo,
theroad wasgood, and weenjoyed excellent fish dinners in PortoS.Giorgioon the
Adriatic coast.
Dietary surveys of subjects inall three Italian areas werecarried out byastaff of
four nurses of the Italian Ministry of Health,coordinated by Adalberta Alberti
Fidanza,and in collaboration with Giovanni FerroLuzziand Marcello Proja. The
nurses received specific training indiet assessment before thestart of thestudy and
surveyed subsamples of men in threedifferent seasons between November 1959
and January 1961.These nurses did a wonderful jobcollecting information from all
members of the families to which thesampled men belonged. Inthechapter on
Dietary Surveys,moredetails will begiven about this aspect.
In thespring of 1962Flaminio Fidanza and BrunoImbimbo, re-examined 888
subjects inCrevalcore and 573in Montegiorgio. With the helpof Pier Luigi Mattioli
of Naples werecorded, on a random sampleof 155men of Montegiorgio,a blood
glucose tolerance test,serum cholesterol,and haemoglobin. Inspring 1963and in
1964,Bruno Imbimbo started collection ofdata on mortality and causes of death
and morbidity, recording at thesametime ECGtracingsonsubjects suspected of
having cardiovascular conditions.

Srecko Nedeljkovic (left) and Alessandro Menotti

(third left) during fietdwork, Montegiorgio, I 965

93
 In thespring of 1965wecarried out the5-yearre-examination on allsurvivorsof
the cohortsinCrevalcoreand then in Montegiorgio.Altogether 874men were
examined inCrevalcore and 662inMontegiorgio, then aged 45to64.During the
samesurvey,data on food intakewerecollected inallmen,using thedietary histo-
rymethod. Menbelonging totheoriginal subsample surveyed in 1960underwent
another dietary survey conducted by theweighingmethod,based on three days
intake.In Crevalcore,headquarters for thesecond survey was located inthe foyer
of thelocal theatre.Meanwhile,themunicipal guard, IvoDonini,had died, and
Alfonso Barbieri invited allsubjects tobere-examined. InMontegiorgio examina-
tions wereagain held inthe town hall and EgidioMarziali,municipal clerk,joined
Guerrino Allessandrini for recruitment of subjects.
Thebasicfield staff included Flaminio Fidanza from Naples as coordinator,
Alessandro Menotti,cardiologist from Rome,Bruno Imbimbo,internist from
Naples,IgnazioMazzuca,cardiologist from Rome,George Lamm,cardiologist from
Budapest,SreckoNedeljkovic, cardiologist from Belgrade,Josef Pokorny, cardiolo-
gist from Prague,and Robin Herron from Northern Ireland who recorded apex car-
diograms. Inaddition, Hans Friedrich and Herman Wolf,both engineers from
Munich,guided byPentti Rautaharju from Helsinki,recorded ECGson magnetic
tapefor further computer analysis.Anthropometry and other measurements were
assured byagroup of clerksand technicians.Major international participants were
Ancel Keysand Henry Blackburn from Minnesota.
At theend of 1965Flaminio Fidanza moved from Naples totheUniversityof
Perugia asfull Professor ofNutrition and Food Science,whileinearly 1967Bruno
Imbimbowasappointed inalarge pharmaceutical industry. Asaconsequence,a
largepart of thecoordination of thestudy was taken overbyAlessandro Menottiof
theCenter for Cardiovascular Diseasesof theSt.CamilloHospital in Rome.He also
becameresponsible for collection of morbidity and mortality follow-up data.This
proved an excellent choice,sinceAlessandro Menotti had been trained in epidemi-
ology and medical statisticsat theLondon School of Hygiene and Tropical
Medicinein 1964,and again in 1967,and had participated inthefieldwork of the
RomeRailroad cohort in 1962and inothers inDalmatia,Crevalcore,Montegiorgio,
Creteand Corfu between 1963and 1966.
In 1970the 10-year follow-up survey wascharacterized by thepresence ofa
largeteam of about 20persons.Thegroup of clinicians and cardiologists from
Romewas helped byalargestaff of nutritionists sent from Perugia and byan inter-
national group again led byPenttiRautaharju, then from Halifax, Canada, for the
magnetic taperecording of resting and exercise ECGs,apex-cardiograms, and caro-
tidograms.Again,George Lamm from Budapest provided great help,thanks tohis
skillinItalian.Theother cardiologists onduty in thefield were PaoloDini,
Giuseppe Messina, PaoloSignoretti,allfrom Rome,and Josef Pokorny of Charles

94
University inPrague.On that occasion,examinations wereagain held inthe usual
season, inapartially empty shirt factory inCrevalcore (guarded byastatue ofa
crocodile watch dog),and inthemunicipal offices inMontegiorgio,where there
wasahigh participation rate(93.3%).
Alltheserum cholesterol measurements and food compositeswere analyzed in
Naples at thebeginning of thestudy,and later in Perugia, taking careofall the
Italian and Yugoslavian cohorts,and part oftheGreekones.Thecollection and cod-
ingofmortality data shifted in 1970at theend of central U.S.funding and in the
study's economic crisis. Coordination continued due totheposition of Alessandro
Menotti asResearch Associateat theLaboratory of Physiological Hygiene,
University of Minnesota and hisnew appointment in Italy.
Agap incontinuation of thestudy wascreated bytheretirement of Vittorio
Puddu from hishospital position in 1976and by changesin theinstitutional duties
oftheCenter for Cardiovascular Diseasesof theSt.CamilloHospital of Rome.The
appointment in 1979of Alessandro Menottiaschief for chronicdiseasesat the
Laboratory of Epidemiology and Biostatisticsof theIstitutoSuperiore diSanità in
Rome (theNational Instituteof PublicHealth),re-opened thepossibility to proceed,
with thewhole project incorporated intotheofficial programs of theInstitute,and
with Alessandro Menotti asprincipal investigator. Partial funding from the Istituto
Superiore diSanità and grants from theEuropean Community (mainly for the
study of water characteristics inrelation toheart diseases),and from the Italian
National Research Council,allowed us toresumeand complete themortality fol-
low-up and toorganize re-examinations of theoriginal cohortsin 1980(20yearsof
follow-up), in 1985(25years),and in 1991(31years).
Important rolesinthismorerecent phase were played by BrunoGiuli, mainly
for thefield organization in 1980and 1985;bySimonaGiampaoli,who littleby little
tookover responsibility for training personnel for quality control of the procedures,
and finally alsofor organization ofthe field work,and byGinoMorisi,for thebio-
chemicalmeasurements made from 1980onwards at theIstitutoSuperiore di Sanità.
FlaminioFidanza and Adalberta Alberti Fidanza continued tohandle the dietary
aspectsof thestudy.Among thecardiologists whohelped with the fieldwork were
Salvatore Panicofrom Naples,assistant toMarioMancini and alsoformer fellow at
theLaboratory of Physiological Hygiene,and PaoloEmilioPuddu, nephewof
Vittorio Puddu.
Survey examinations wereheld in 1980inthepremisesoflocalschools,both in
Crevalcore and Montegiorgio;in 1985in theLocalHealth Unit inCrevalcore and in
a school in Montegiorgio;and in 1991inlocalhospitals inboth places.Again, par-
ticipation rateswerehigh (79%in 1980;76%in 1985, and 67%in 1991)in spiteof the
Wcreasingageof thesubjects and thefact that many of them had changed residence.
In 1980,1985,and 1991,itwas necessary tostart,each time,new negotiations

95
with thelocalAdministrative and Health Authorities,due tothetimegap between
1970and 1980and tothefrequent changesin responsible people (and political par-
ties)inthelocal administrations.Theacceptance of theproposed examination was
alwaysgood.Locally weexploited the fine cooperation from themunicipal guards
and population register officers. In 1991an important organizational contribution
was made inCrevalcoreby Giorgio Luppi,medical officer ofthe Regional Health
Serviceof Bologna.
In 1985, for thefirst time,substantial additions weremade totheoriginal exam-
ination protocol (which had alwaysbeen preserved) by including questionnaires on
mental depression and self-sufficiency which werefelt tobeappropriate in dealing
with an elderly population (then aged 65-84).Thisrepresented apilot experiencein
expansion of theobjectives of thestudy, moving from theclassical cardiovascular
risk factors, prevalence, incidence,and mortality, tointerest in thephysical and
functional statusof theelderly and their prediction.Thisoperation waslater con-
ducted jointly with theDutch group,led by Daan Kromhout, for thecohortof
Zutphen,and with theFinnish group,led byAulikki Nissinen,for the East and
West Finnish areas.
Thewholeplan wasdeveloped through cooperation among thethree national
groups;alarge number of testsand questionnaires targeted at thedescriptionof
depression, self-sufficiency, mental state,and physical functions was developed,
tested,and standardized and then applied toallmen in the30th-anniversary re-
examination in Finland (1989),in theNetherlands (1990),and on the31st anniver-
sary inItaly(1991).
Inthe 1991field examination inrural Italy,assistance wasalsoobtained from
Edith Feskensof theDutch team,who took careofblood glucose,hemostatic,and
otherbiochemical measurements,and of Paula Kivinen of theFinnish group, who
supervised functional tests.Simona Giampaoli was fully responsible for the field
operations in 1991and wasco-principal investigator in the 'elderlypart' of the
study.Other physicians participating inthe fieldwork in 1980,1985,and 1991were
Giuseppe LaPera,Gisella Faggioli,Antonio Parma,MichèleMatano, Giuseppe
Cigna,and Roberto Amici.
Twoother important operations werecarried out in the 1980s.Between 1985and
1988acomplex and extensivedata gathering system wasestablished by Alessandro
Menotti in thetwosurvey communities.Itprovided thedateof eachmajor coronary
and cerebrovascular incident event that had occurred during thefirst 25yearsof
follow-up. Inthisway alargenumber ofeventswereidentified which,for several
reasons,werenotcompletely ascertained from procedures of thequinquennial sur-
veysand routine collection ofmortality data.Forthemajor coronary events,in par-
ticular,about 50morecasesofdefinite non-fatal myocardial infarction were added
totheabout 250found through theoriginal system.Thegreater completeness in

96
Fieldwork team and some participants in Crevalcore, 1991.

incidencedata improved current analyses.

In 1987the Italian group participated, under theguidance of the Dutch group
led by Daan Kromhout, in thecollection of food composites from local markets,
attempting torepresent theaverage food intake ofeach cohort inthe Seven
Countries Study at thetimeof theentry examination. Thiswasdoneboth in
Crevalcore and in Montegiorgio, and then extended to Rome for evaluation of the
diet of the Railroad cohort.Themajor role in thisfield activity was played, on the
Italian side,bySimonaGiampaoli, with thehelpof AnnemarieJansen of the Dutch
group.

Conclusions
Therural Italy section of theSevenCountries Study represented amilestone in car-
diovascular epidemiology in Italy and set anumber of precedents. Itwas the first
trueepidemiological enterprise on population samples in thecountry, providing
prevalence, incidence,and mortality figures on CHDat short and long term follow-
up. Foryears thesewerequoted astheonly such data available in Italy.Thestudy is
presently still underway, and istheoldest and thelongest in Italy in terms of fol-
low-up.Itwas thefirst studv in Italy toshow therelationship there of theclassical
risk factors toCHDevents and thefirst toprovide multivariate analyseson CHD
and other end-points such ascerebrovascular disease,other causes of death, and all-

97
cause mortality.Analyses identified risk factors for singlediseases specifically in
contrast to thosepredicting several causes ofdeath and all-cause mortality. Again,
thedata setof theItalian cohorts hasbeen thebasisfor new procedures evaluating
risk factor changes over timeaspredictors ofcardiovascular events,which were
then applied toother cohortsof theSeven Countries Study.
Data collected bydietary history contributed largely todefinition of the so-called
'Mediterraneandiet', and more recently have been the first employed for definition
ofdietary patterns,incontrast toanalysisofsingle foods or nutrients,and for study
of their relationship todifferent causes ofdeath and total mortality.

98
Publications
1. Fidanza F,Fidanza-Alberti A, Ferro-Luzzi
G, Proja M. Dietary surveys in connection with
the epidemiology of heart disease: results in Italy.
Voeding 1964;25:502-509.
2. Fidanza F, Imbimbo B,Fidanza-Alberti A.
Five year follow-up on foods and nutrients con-
sumed in two rural areas of Italy. In: Problems of
world nutrition. Kuhnau J(Ed), Pergamon Press,
Oxford, 1966:50-53.
3. Fidanza F,Fidanza-Alberti A. Dietary sur-
veys in connection with the epidemiology of heart
disease: reliability, sources of variation and other
data from nine surveys in Italy. Voeding
1967;28:243-252.
4- Fidanza F,Puddu V,Del Vecchio A, Keys A.
Men in rural Italy. In: Epidemiological Studies
related to coronary heart disease: characteristics
of men aged 40-59 in Seven Countries. Keys A,et
«1 (Eds). Acta Med Scand 1967;460(Suppl 180):116-
146.
*• Fidanza F.Nutrition and atherosclerosis:
controversial views. Proc Eighth Int Congress
Nutrition, Excerpta Medica, Prague 1969;51-57.
'• Puddu V, Menotti A. An Italian study on
epidemiology of ischemic heart disease. Acta
Cardiol 1969;24:558-578.
' • Menotti A, Puddu V.Prevention of strokes:
an epidemiological approach. Int Cardiol
1970;2:248-273.
8
- Fidanza F,Puddu V, Imbimbo B,Menotti A,
Keys A. Five year experience in rural Italy. In:
Coronary heart disease in Seven Countries. Keys
A
(Ed).Circulation 1970;4KSuppl l):63-75.
Fidanza F,Senin-Zanetti P.Comparison of
chemical analysis and calculated values of vitamin
C consumed by population groups of two rural
areas of Italy. Int JVit Nutr Res 1971;41:307-312.
Fidanza F,Senin Zanetti P,Maffioli E.
Com parison of chemical analysis and calculation
° ' vitamin A consumed by population groups of
^ o rural areas of Italy. Int JVit Nutr Res
1
97l;4l313-315.
• Menotti A. Epidemiology of coronary heart
disease in Italy. Scand JClin Lab Invest
1
972;29(Suppl 122):12.
12. Fidanza F.Diet and incidence of coronary
heart disease. Bibl Nutr Diet 1973;19:93-107.
13. Menotti A, Puddu V. Epidemiology of coro-
nary heart disease. A 10year study in two Italian
rural population groups. Acta Cardiol 1973;28:66-
88.
14. Menotti A.Obesity: a risk factor of coronary
heart disease. Arch Mal Coeur Vaiss 1974;68:45-
49.
15. Fidanza F,Fidanza-Alberti A. Dietary vita-
min intake and thiamine and riboflavin nutrition-
al status in two rural population groups of Italy.
Int JVit Nutr Res 1974;44:59-63.
16. Fidanza F.Sources of error in dietary sur-
veys. Bibl Nutr Diet 1974;20:105-113.
17. Fidanza F,Fidanza-Alberti A. Food and
nutrient consumption of two rural population
groups of Italy followed for 10years. Nutr
Metabol 1975;18:176-189.
18. Puddu V, Menotti A,Signoretti P. Drinking
water and cardiovascular disease. Am HeartJ
1980;99:539-540.
19. Menotti A, Farchi G. Epidemiology of coro-
nary heart disease in Italy: a review.
Atherosclerosis Rev, Raven Press, New York
1980;7:97-122.
20. Menotti A,Conti S,Giampaoli S,Mariotti S,
Signoretti P.Coronary risk factors predicting cor-
onary and other causes of death in 15years. Acta
Cardiol 1980;35:107-120.
21. Menotti A,Conti S,Giampaoli S, Mariotti S,
Rumi A,Signoretti P. Prediction of coronary and
other causes of death by some coronary risk fac-
tors in fifteen years. Rapporti ISTISAN 1980/14,
ISSN-0391-1675, Istituto Superiore di Sanitâ.
Roma 1980:1-19.
22. Menotti A, Capocaccia R, Farchi G, Mariotti
S.The estimation of coronary heart disease inci-
dence in a population from the risk function of
another. Przeglad Lekarski 1981;38:761-765.
99
23. The Italian Research Group of the Seven
Countries Study. Incidence and prediction of cor-
onary heart disease in two Italian rural popula-
tions samples followed up for 20years. Acta
Cardiol 1982;37:129-145.
24. Menotti A.Coronary risk factors and mor-
tality for coronary and non-coronary events. In:
Atherosclerosis, Clinical Evaluation and Therapy.
Lenzi S,Descovich G (Eds).MTP Press Ltd.
Lancaster, Boston 1982:343-351.
25. Fidanza F,Fidanza-AIberti A,Coli R,
Mencarini Contini A. Food and nutrient con-
sumption of two rural Italian population groups
followed for twenty years. Int JVit Nutr Res
1983;53:91-97.
26. Menotti A,Conti S,Dima F,Giampaoli S,
Giuli B,Rumi A,Seccareccia F,Signoretti P.
Prediction of all causes of death as a function of
some factors commonly measured in cardiovascu-
lar population surveys. Prev Med 1983;12:318-325.
27. Fidanza F.Diets in communities with high
and low incidence of coronary heart disease:
intercommunity studies. Proceedings XIII
International Congress of Nutrition. Libbey,
London 1985;544-546.
28. Menotti A,Conti S,Dima F,Giampaoli S,
Giuli B,Matano M,Seccareccia F.Incidence of
coronary heart disease in two generations of men
exposed to different levels of risk factors. Acta
Cardiol 1985;40:307-314.
29. Menotti A,Conti S, Farchi G, Giampaoli S,
Dima F,Seccareccia F,Giuli B,Torsello S, Morisi
G, Buongiorno A. The prediction of future health
in healthy middle-aged men. Eur J Epidemiol
1986;2:233-239.
30. Italian Research Group of the Seven
Countries Study. Twenty-five year incidence and
prediction of coronary heart disease in two Italian
rural samples. Acta Cardiol 1986;41:283-299.
31. Conti S,Szklo M, Menotti A, Pasquini P.
Risk factors for definite hypertension: cross sec-
tional and prospective analyses of two Italian
rural cohorts. Prev Med 1986;15:403-410.
32. Menotti A, Mariotti S,Seccareccia F, Torsello
S, Dima F.Determinants of all causes of death in
Italian middle-aged men followed-up for 25
years.JEpidemiol Comm Health 1987;41:243-250.
100
33. Menotti A, Seccareccia F, Pasquali M. Blood
pressure, serum cholesterol and smoking habits
predicting different manifestations of arterioscle-
rotic cardiovascular disease. Acta Cardiol
1987;42:91-102.
34. Menotti A, Mariotti S,Seccareccia F,
Giampaoli S.The 25year estimated probability of
death from some specific causes as a function of
twelve risk factors in middle-aged men. EurJ
Epidemiol 1988;4:60-67.
35. Fidanza-AIberti A,Seccareccia F,Torsello S,
Fidanza F.Diet of two rural population groups of
middle-aged men in Italy. Int JVit Nutr Res
1988;58:442-451.
36. Menotti A,Giampaoli S, Pasquali M,
Seccareccia F,Stuart K.Prognosis of lean and fat
hypertensives. Cardiology 1988;75:448-457.
37. Fidanza F.The Mediterranean diet in the
prevention of coronary heart disease. Diab Nutr
Metabol 1988;3:169-173.
38. Seccareccia F,Lanti MP, Puddu PE, Menotti
A. Normotensive middle-aged men after 5-10
years: normal blood pressure or hypertension?
J Hypertension 1988;6(Suppl 4:S602-S604.
39. Farchi G, Mariotti S,Menotti A, Seccareccia
F,Torsello S, Fidanza F.Diet and 20-year mortal-
ity in two rural population groups of middle-aged
men in Italy. Am JClin Nutr 1989;50:1095-1103.
40. Menotti A,Seccareccia F,Giampaoli S, Giuli
B.The predictive role of systolic, diastolic and
mean blood pressure on cardiovascular and all
causes of death. JHypertension 1989;7:595-599.
41. Menotti A, Verdecchia A, Dima F.The esti-
mate of coronary incidence following different
case finding procedures. Eur Heart J 1989;10:562-
572.
42. Menotti A,Seccareccia Fand the Italian
Research Group of the Seven Countries Study.
Spontaneous changes of systolic blood pressure as
predictors future fatal events. Am J Hypertension
1990;3:549-554.
43. Fidanza-AIberti A. Mediterranean meal pat-
terns. Bibl Nutr Dieta 1990;45:59-71.
44. Menotti A,LantiM,SeccarecciaF,
GiampaoliS,MorisiG.Serum cholesterol and
cancer: theItalian epidemiological experience.
Nutr MetabCardiov Dis1991;1:189-194.
45. Fidanza F.TheMediterranean Italian diet:
Keystocontemporary thinking.ProcNutrSoc
1991;50:519-526.
46. Menotti A.Therelationshipof total serum
cholesterol tocoronary heart diseaseinolder
men.TheItalian ruralareasof theSeven
CountriesStudy.Ann Epidemiol 1992;2:107-111.
47. FarchiG,Fidanza F,Mariotti S,MenottiA.
Alcohol and mortality intheItalian rural cohorts
of theSeven CountriesStudy.IntJEpidemiol
1992;21:74-82.
48. Menotti A,SpagnoloA,Dima F,MeliP,
Scanga M.Theprediction ofcoronary heartdis-
easeindifferent population samples.EurJ
Epidemiol 1992;8:521-526.
49. Seccareccia F,Menotti A.Physical activity,
physical fitness and mortality inasampleof mid-
dleaged menfollowed-up for25years.JSports
Med PhysFitness1992,28:335-341.
101
 8
STUDIES O N THE ROME RAILROAD

A. Menotti

I heSeven Countries cohort known astheRomeRailroad was

enrolled in 1962torepresent thecounterpart of theU.S.Railroad cohort already
studied in thelate 1950s.Myparticipation in theItalian group provided a person
fully dedicated totheSevenCountries project and tocardiovascular epidemiology.
Myprevious experience was working asan internist and cardiologist at the Govern-
ment Hospital ofTripoli,Libya.ThereI'discovered' epidemiology for myself,
observing thedifferent mixof morbid conditions,mainly cardiovascular, on hospi-
talwards inTripoli compared toRome.Imeasured theblood pressure of allin-
patients,out-patients,accompanying relativesof patients,and household dwellers
becauseofan impression that blood pressure was lowerin Libyans than in Italians.
From 1962Ireceived, asunpaid assistant at theCenter for Cardiovascular
Diseases and Division ofCardiology of theSt.CamilloHospital in Rome,the label
°f 'epidemiologist' from Vittorio Puddu,despite lackofformal training in thedisci-
pline.After early experience with theRomeRailroad cohort,Itookover responsibi-
lity for the Italian section of thestudy. Inafew years Ibecametheresponsible per-
son for allthreeItalian areasof theSevenCountriesStudy,establishing an
Epidemiological Unitwithin theCenter for Cardiovascular Diseasesof Rome.
Negotiations for theactivation of theRomerailroad cohort had been started in
1961 byVittorioPuddu, with thecooperation ofrepresentatives of the Italian
InstituteofSocialMedicine,by involving theDirectorate of theMedicalServiceof
theItalian StateRailroad attached totheMinistry ofTransportation. Both the
management and thetrade unionswerewell informed and motivated toward the
study and eventually allowed enrollment of asample of menworking inRome and
surroundings.Akeyrolewas played byMarioMonti,then Deputy Director and
later Director of theRailroad MedicalService,sincehefully understood thescienti-
fic potential of theoperation, together with thepossible 'fall-out' for the Medical
Serviceitself in termsofthepossibleestablishment ofroutine screening for cardio-
vascular risk factors and diseases.TheRailroad Study in Romewassupervised by
HenryTaylorof theMinnesota team whowas,atthesame time,principal investiga-
torforthe U.S.Railroad cohort.

103
 Thesamplein Romewasbased onidentification ofrailroad employees in speci-
fied occupations (station masters,switchmen,electricians,and maintenance-of-way
men) working inthe Department of Romeofthe ItalianStateRailroad system.
Actually thisdepartment included not only thecityof Romebut almost all the
region around Rome(Lazio),the southern part ofTuscany (north-west),and partof
Abruzzi (south-east of Rome).About half of theidentified men wereliving in the
metropolitan area of thecapital and the other half in small centers up to150km
from Rome.Fortunately, thesubgroup living out of Romenevershowed any diffe-
rencesfrom theothersexcept for thegreater difficulties inorganizing their follow-
up for vitalstatus,mortality, and causes ofdeath.Thework inRomewas greatly
helped byother persons whoseroleisacknowledged here:Vittorio Puddu acted as
principal investigator, together with MarioMontiof theRailroad.Aldo Bellini,a
psychologist working in theMedical Department of theRailroad,was thekey per-
soninthegeneralorganization.MarioManciniofNaples,oneof theearlyfellowsof
the Laboratory of Physiological Hygiene,had theresponsibility totrain the medical
staff, including Alessandro Menotti,BrunoFloris,PieroMarroni,Luigi Struglia,
plus somenursesof therailroad. FlaminioFidanza,from Naples,took responsibili-
tyof treating theblood samplesbefore mailing them dried to Minneapolis.
Thesurvey operations,organized in theFirst-Aid Roomsof theStazione
Termini,themain railstation inRome,wereheld inMay,June,and part ofJuly
1962,and completed inOctober ofthesameyear.Inspiteoftheorganizational diffi-
cultiesin working schedules of railroad employees and appointments for examina-
tion,theparticipation ratewasacceptable,finishing with more than 80%and a total
of 768men.
Allsubsequent operations,consisting of follow-up for vitalstatus,mortality and
causesof death,becamethe full responsibility ofAlessandro Menottiwith the
patronage ofVittorio Puddu, theorganizational helpofMarioMonti,and theassi-
stanceof Flaminio Fidanza for thenutritional aspects,inwhich asubsample of men
was studied in 1969,using theseven-day diary technique.
The5-and 10-year survey re-examinations of therailcohortwereheld in the
out-patient section oftheCenter for Cardiovascular Diseasesof the St.Camillo
Hospital in Romeand in theMedicalServiceof theRailroad,with teams enrolled
among themedical and nursing staff of theHospital and theMedicalServiceof the
Railroad.Thephysicianscooperating on thesetwooccasionswereBrunoFloris,
IgnazioMazzuca,Alessandro Nardelli,FrancescoCeccherini,Giuseppe Lobefaro,
and PaoloSignoretti.Thetwoexaminations took placeinthelatespring of 1967and
in thefall of 1972,respectively.Thelatter survey,inparticular,gaveanumberof
difficulties inobtaining areasonable participation rateinrelation tothedistanceof
men'sresidences (mainly for thoselivingoutside Rome),theconflict between the
working schedule,theappointments,and thefact that many subjects had retired in

104
 Henry Taylor and Vittorio Puddu during fieldwork,
Rome Railroad, I 962

themeanwhile becauseof special benefits offered for early retirement. In 1967the

Rometeam wasagain bolstered by thedirect supervision of Henry Taylor of the
University of Minnesota.
Theperiod between 1973 and 1979wascharacterized by theend ofcentral fun-
ding from NIH for field operations beyond the lOth-anniversary survey and byeco-
nomicdifficulties bound to theinternational oilcrisis.Itwasimpossible for the
Romegroup toget funds for a 15-yearre-examination which would inany case
havebeen unrealistic in view ofachieving ahigh participation rate.Infact, more
and more subjects had retired and moved out of Rometotheir original birthplaces.
Mortality follow-up activities were thus interrupted until 1980,wellbeyond the
15thanniversary (1977).
In 1979Alessandro Menotti moved to theLaboratory of Epidemiology and
Biostatisticsof the Istituto Superiore di Sanità inRome (theNational Instituteof
Public Health of Italy).Thanks tofunding and facilities obtained from the Institute,
and agrant from theItalian National Research Council,itbecame possible in 1980
toresume therailcohort follow-up for vital status and causes of death.The task
wasparticularly difficult despite continued help from theMedical Departmentof
theRailroad. Inany case,thecollection of data covered 15years follow-up (corre-
sponding to 1977),and then the20-and 25-year deadlines corresponding to1982
and 1987.Thejobwas finished in 1989and due tomany difficulties was never con-
sidered likely toreach the30-year follow-up, asfor thetwo Italian rural cohorts.
Thestudy in Romecould, nevertheless,becompared usefully with the U.S.stu-

105
dy of railroad employees.Clear-cut differences wereshown between the two
groups:thegroup with higher levelsofblood cholesterol and cigarettesmoking in
theU.S.,and slightly higher levels inBody MassIndex and blood pressure in Rome.
The5-and 10-year follow-up showed adefinitely higher (about two-fold) CHDinci-
denceand mortality in theU.S.group compared to the Italian,partly explained by
differences incholesterol leveland smoking habits.
Within theRomecohort,different incidence and mortality from CHD were
found amongsubgroups characterized bydifferent amounts ofphysical activity at
work,with higher ratesamong thosewith moresedentary jobs.Inarecent analysis
itwasshown that the25-year all-causesmortality in theItalian Railroad cohort was
definitely lower than that in therural Italian areascombined (about 20%less).This
was not thecase,however, for CHDand lung cancer,which had similar rates in the
railroad totherural men. Finally,all-causesdeath rates,adjusted for risk factors
unrelated tooccupational exposure,made thedifference drop toa non-significant
12%,removing any possible 'healthy worker effect'.
Thereweretwo important 'fall-outs' from theRomerailcohort study.The
Directorate of theMedicalDepartment of therailroad took theopportunity, from
thesuccessof theoperation, tooffer avoluntary screening program tothe employ-
ees,which went on successfully for several yearsuntil themid-eighties when the
wholeorganization of theItalian railroad wascompletely changed, including the
roleof theMedical Department. On theother hand,VittorioPuddu and Alessandro
Menotti,thanks totheexcellent relationships developed with the Medical
Department, could,in 1973,draw anew sample ofmen aged 40-59from the Rome
Railroad (and from theMinistry ofTransportation).Thiswas then studied for many
years within theItalian Sectionof theWHOEuropean Multifactor Preventive Trial
ofCHDin industry.

106
Publications
1. Puddu V,Menotti A, Blackburn HW.
Observations on T wave after effort in active and
sedentary working men. Acta Cardiol 1965;20:210-
217.
2. Taylor HL, Monti M, Puddu V, Menotti A,
Keys A. Rail road employees in Rome. In:
Epidemiological studies related to coronary heart
disease: characteristics of men aged 40-59 in seven
countries. Keys A,etal(Eds).Acta Med Scand
l%7;460(Suppl 180):250-266.
'• Menotti A. Epidemiological study on ische-
mic heart disease in the rail-road employees of
Rome.Cor Vasa 1967;9:28-33.
4- Menotti A, Puddu V,Monti M, Fidanza F.
Habitual physical activity and myocardial infarc-
tion.Cardiologia 1969;54:119-128.
s
- Taylor HL, Menotti A, Puddu V,Monti M,
Keys A. Five years of follow-up of railroad men in
»aly. In:Coronary heart disease in Seven
Countries. Keys A (Ed).Circulation 1970;41(SuppI
D;113-122.
6. Puddu PE,Jouve R,Mariotti S,Giampaoli S,
Lanti MP, Reale A,Menotti A. Evaluation of 10
QT prediction formulas in 881 middle-aged men
from theSeven Countries Study: emphasis of the
cubic root Fridericias equation. J Electrocardiol
1988;21:219-229.
7. Menotti A,Seccareccia F. Cardiovascular
risk factors predicting all causes of death in an
occupational population sample. Int J Epidemiol
1988;17:773-778.
8. Lanti M, Puddu PE,Menotti A. Voltage cri-
teria of left ventricular hypertrophy in sudden
and non-sudden coronary artery disease mortali-
ty: the Italian Section of the Seven Countries
Study. Am JCardiol 1990;15:1181-1185.
107
STUDIES I N THE GREEK ISLANDS
-~KK^_ C. Aravanis and A.S. Dontas

Itwas in thefall of 1954when oneofus (CA)metAncelKeys and

PaulWhiteduring thesecond World CongressofCardiology. Thediscussion cen-
tered around thedifferences in frequency ofcoronary and other heart diseases in
variouspartsoftheworld.Oneofthetopicsdiscussed wasthereputedly low prev-
alenceof coronary and other heart diseases inCretecompared tomostother parts
of thecontinent, and theway of life and diet ofCretans,which differed in many
respects from thoseofurban Athenians ornorthern Europeans.Thisdiscussion was
continued byboth of us during ameeting of theResearch Committeeof the
American Heart Association inChicago,oneyear later.
At that timeevidence had started toaccumulate on thelargedifferences incoro-
nary heart diseaseexistingbetween populations livingin widely separated partsof
theworld.Thesedifferences, on theorder of5to 1,had been known toexist
between Europeans and nativeAfricans, but itwasarelatively unexpected finding
that within Europe,Finnsand southern Europeans could havedifferences almost as
large.Thedifficulty inestimating moreaccurately themagnitude of these differenc-
esled tothedecision tostudy specific population groups in southern Europe to
determine theseprevalences with some precision inwell-defined and demographi-
callystable areas.
Cretehad alreadybeen studied in 1947-1949byagroup ofscientistsfrom the
Rockefeller Foundation asa 'casestudyofanunderdeveloped area' inEurope.Ithad
suffered asavagewarduring the1941 German attack tooccupy it,and subsequently
during an activeguerilla war intheeffort toestablish afree area.Thisculminated in
thecapture (and subsequent evacuation toEgypt)of thecommanding officer of the
German forceson theisland,General Kreipe,byateamof British-Greek commandos.
Inalargeflat, wooded area 30kmsoutheast of Herakleion (Ancient Kandia) the
German forces had created amidst theolivetreesalargeairstripfor ammunition
storageand asafueling station for their activitiesin theMiddle East.Thisarea and
allvillagesnearby had very littlecontact (onewinding country road) with
Herakleion and theother largecitieson thecoast.Theinhabitants for generations
led afrugal life which had barely differed from that of theirancestors.Itwas decid-

109
ed,therefore, tostudy the 13villages surrounding theplain.Preparations for a field
study started early in 1957and thelocalauthorities,inparticular Dr.G.E. Hadjakis,
health commissioner and Dr.E.Staphylakis helped by lending theambulance of the
commission tocarry equipment and personnel.Mr.G.Arnaoutakis,driver and liai-
sonperson,was alwaysofgreat help.
Meanwhile,between October 6and November 1,1957thefirst pilot surveyof
theSevenCountriesStudy,of598men, took placeinNicotera,avillage some miles
north of ReggiodiCalabria in south Italy.Theplacestillbore marksoftheSecond
World War,with manyhousesand roads inneed of repair and children bearing
clinical signsof malnutrition, i.e.,underweight, ricketsetc.
Anumber of interested scientists from variousparts of theworld, aswellas the
twoco-authors of thissection,were invited for a2-day conference inGioia diTauro,
Calabria,at thestart of thesurvey.Theexperience obtained in thisexploratory sur-
veywas quitesatisfying, and theGreek counterpart of thepilot study was carried
out in thecounty of Kastelli Pediada inCretebetween October 22and November24
thesameyear on657men,aged 45-64.Dietary recordsand samples were collected
under theguidance of theveteran dietary scientist,Helen Sdrin,between October
and theend of December1957.
Forthiswork, thesum ofU.S.$2,000 was provided by Dr.Keys,and some addi-
tional funds were contributed by theELAISolive-processing industry in Athens.
Thiscovered travel expenses from Athens and back for thegroup (Ancel and
Margaret Keys,Dr.P.D.White,Dr.Noburu Kimura,Dr.J.Carlotti,Dr.F.Fidanza,
Dr.M.Karvonen, Drs.Aravanis,Costisand CybeleChlouverakis,Dontas,and
Helen Sdrin),theHerakleion Astir hotelcosts,and thedaily travel costs from
Herakleion tothevillagesof Pediada and totheVenizeleion Hospital,where the
food samples werehomogenized and stored.
Transportation of thegroup wassecured in thePlymouth station wagon of the
Keys'family and theAustin ambulance of thehealth commission in Herakleion.
Thesewereloaded very early each morning and driven over primitive roads to the
villages.There wasnohotel in Kastellinor in any of thevillagesin the area.
Running water wasscarceand electricpower was practically absent; thus,a genera-
tor had tobeused for operating allscientific equipment.
Thefield difficulties were astounding: on daysfollowing a rain,roads tothevil-
lageswere impossible,and thePlymouth from Minnesota had tobehelped by
avant-marchers who removed largestonesfrom itspath.Due todelay in transport
of Sanborn Visettepaper from theU.S.A.,ECGpaper wasin such shortsupply that
Margaret Keysand Noburu Kimura spent theevening hourscutting ECG paper
lengthwise and rewinding eachhalf onused axles.Mostof thegroup collected fleas
and other insectsduring thephysical examinations and spent some timeeacheve-
ning in de-infestation.

no
 Theresultsof these two pilot surveys were,nevertheless,amazing:only four cas-
esof myocardial infarction were found inNicotera and two in Kastelli:in similar
total population samplesin the U.S.at least fivefold greater frequency would have
beenexpected.Thediet wasalsoquitepeculiar;morethan 40%of total calories
werederived from fats,29%ofcaloriesweremonoenes of oleicacid,7%were satu-
rated fatty acidsand 3% polyenes.Itwasnot uncommon toseefarmers start their
working day by drinking acupful of oliveoil,topping itoff on cold days with
'tsikoudia',astrong spirit made from grapes.
Unfortunately, thedata from thisstudy,despite theabovefindings, could notbe
used asabasisfor international comparisons and long-term follow-up. Theclinical
records were toosketchy;onlyoneout ofevery five men had serum tested for cho-
lesterol,and thelackof ECGrecording paper madeexercisetesting rare. Further,
respirograms,carotid pulse tracings,and urine testswerenot obtained. Finally, the
consensusof theother groups wasthat thepopulations studied should becom-
posed of40-59year-old men rather then of45-64year-olds.Thus,after long deliber-
ations itwasdecided torepeat thestudy laterin thesamearea and add another
Greek population with similar dietbut a more 'western' way of life.
Application for agrant-in-aid was sent totheNational Heart Institute inJune
1959,some months following asimilar 'group' application from the collaborating
centers from Finland,Italy,Dalmatia,Slavonia,and Serbia.TheGreek application
(H-5037,Nutr.) included arequest for funds tocover asimilar population in Corfu,
where thelevel ofdevelopment and economy was much higher than inCrete;the
application alsoincluded arequest for afull dietary survey onthetwo islands.
Unexpectedly, thisapplication was not approved bytheNational Heart
Institute,for reasons not clear,even today,but presumably from the reviewers'
impression that aprevalence study had already been done,and that asecond onein
thesamearea would not add much moreinformation. TheItalian application, fol-
lowing similar unsatisfactory field experiences inNicotera,wasmodified soas to
study twovillages,Crevalcore innorthern Italyand Montegiorgio incentral Italy,
grossly differing in their diet;itwas approved.
Inthe fall of 1959and thespring of I960,after thenegative outcome ofour first
try,another application wassent totheU.S.P.H.S.for astudy of thesame areaof
Creteand asimilar oneinCorfu; thelatterincluded seven villages around
Corakiana,some 15milesnorth of thecapital,Kerkyra.Although thearea was
chiefly rural,almost one-third of themen weresedentary or engaged in the tourist
industry.Theapplication,submitted by theHellenicSocietyfor theStudyof
Atherosclerosis,included plans tostudy, inaddition tothemain cohort of40-59
year-olds,smaller cohortsof 80-100men aged 25-28,and 70-74years,ineach area.
Thisapplication (HE-06090)wasapproved byN.I.H.Intheinterim, thethen Royal
Hellenic Research Foundation had approved grants-in-aid tothetwo co-authors
here which could be used for epidemiological study in the two areas; a number of
individual donors and the ElaisOil Company in Greece (the late V.and L. Melas)
also contributed various sums for this study. Doctors A. Keys and P.White helped
significantly in realizing these funds. Later grants were obtained from the
International Olive Council, the E.E.C. and the Greek Association of Industries and
Processors of Olive Oil (SEVITAL).
Thus, in the fall of 1960 the 3-year re-survey of the Cretan population, aged 40-
59,became the entry survey of the modified Cretan cohort (686 subjects) and the fol-
lowing year the same age groups of the Corfu cohort (529subjects) were similarly
studied.
These two cohorts had some peculiarities compared to the Italian, Croatian, or
Serbian cohorts: the populations were scattered in small villages; thus, to obtain the
maximum response rate the entire team and equipment had to be transferred from
village to village every few days during the survey. The very poor and hard-work-
ing Greek farmers would not consent to be examined away from their villages. The
help of the local doctors and various local authorities was of immense importance
in securing, finally, a very high rate of participation; in addition, a member of the
Greek team was functioning as a goodwill person to convince doubters of the need
tobe examined and, once examined, have the rest of their families examined as well!

Paul Dudley White, Christ Aravanis, Ivan Mohacek reading ECC's, Crete, I 960

112
 Transportation of thegroup between Herakleion and thevillages was secured
thistimewith apick-up truck,generously loaned by the U.S.AirForcebasein
Herakleion (Col.John Sheen)whoalsoplaced adriver atour disposal (the largest
unexpected grant-in-aid our group received during the 1960survey).
The 1960group included asnew members Doctors.D.Lekos,A.Corcondilas,
D.Galanos,C.Vasilikos,G.Stamatoyanopoulos, M.Tzelisi,M.Papadatou, and
others from theGreek side,Dr.Alessandro Menottiwith hisbride Maria-Luisa,
Dr.B.Imbimbo from theItalian side,and Dr.Henry Blackburn from theU.S.A.
Thedifficulties encountered in thefield study inCorfu wereeven worse than in
Crete:therewerenolaboratory orhospital facilities remotely comparable to those
of theVenizeleion hospital inHerakleion,and alllaboratory work had tobedone in
thevillagecenters,with small rooms and norunning water orelectricpower. The
number of subjects working intheCorfu tourist industry had increased in previous
yearsand maderecruitment ofthelast 10to 15%of thesubjectsanenterprise as
frustrating aschasingbutterflies. Thecostsofprolonging thestayof thestaff soas
toinclude thelast doubters inthesurvey werevery high for theCorfu surveys,and
thecoverageobtained at each resurvey was lower than inCrete.Weare, however,
very grateful tothemen and tothelocalauthorities ofCreteand Corfu, whose early
and continued cooperation made thisgreatstudy feasible and successful.
Thefive, 10,15,20,25and 30-year follow-up surveys on thetwo islands became
progressively easier intechnical details (transportation, recordings,local analyses)
but moredifficult inrecruitment of thehesitant subjects,especiallyfor Corfu.
Intheinterim years,thecollection,reviewing,coding,and processing of mortal-
itydata and causes ofdeath wascarried outby thesameprincipal investigators,
assisted byphysicians mostly from Professor Aravanis' Department of Cardiology.
Doctors Paul Ioanidesand Adrian Corcondilas, twoU.S.-trained cardiologists, were
of immense help;ofgreat assistance alsowereDoctors.J.Steriotis,E.Papasteriades,
J.Ktenas,and N.Karalias.Theteam included cardiologists,dietitians,labpeople,
and helperswhovisited thetwoislandsat regular intervals.With the cooperation
and helpoflocalphysicians,community authorities and others,rosters were
reviewed, and thecauseofdeath wasdiscussed,evaluated, and verified. Avisit or
direct communication with thehospital authorities took placefor alldeaths.
In 1979aJoint Meeting with theinvestigators of theSevenCountries Study was
held in Heraklion,Crete.Paperswere presented by theSevenCountries investiga-
tors:C.Aravanis,A.S.Dontas,A.Keys,H.Blackburn, D.Kromhout,A.Menotti,
H.Toshima, B.S.Djordjevic, and S.Nedeljkovic. Data from related studies were
shown byJ.Stamler,Z.Pisa (WHO) P.From-Hansen,G.Tibblin,L.Wilhelmsen,
I.Balaguer-Vintro,J.Pobee,and D.Kozarevic.During themeeting many new ideas
weredeveloped for future follow-up studiesand data analyses.

113
 Publication ofGreekdata hasbeen slowbecause of thelackotcentral analytical
facilities and scarcityof funds. Nevertheless,interesting reports haveappeared over
theyears,including findings notdirectly connected with coronary heart disease;
numerous follow-up reportsare in preparation.

114
Publications
I• KeysA,AravanisC,Sdrin H.Thedietsof
middleaged menintworural areasofGreece.
Voeding1966;27:575-86.
!• AravanisC,DontasAS,LekosD,KeysA.
Rural populations inCreteand Corfu, Greece.In:
Epidemiological studiesrelated tocoronary heart
disease:characteristics ofmenaged 40-59in
SevenCountries.KeysA,etal (Eds).ActaMed
Scand 1967;460Suppl:209-230.
3. AravanisC,Corcondilas A,DontasAS,
LekosD,KeysA.TheGreek islandsofCreteand
Corfu. In:Coronary heartdiseaseinseven coun-
tries.KeysA(Ed).Circulation 1970;41(Suppl
D:88-100.
*• DontasAS,KeysA,Anthopoulos L,Schulz
N.Effects ofageon thecarotid pulseintwoGreek
populations.Circulation 1970;42:529-539.
5. AravanisC.TheGreek islandsheart study,
•rocInterCongresson theBiologicalValueof
OliveOil.1976;1:315-319.
"• AravanisC.Nutritional factors and cardio-
vasculardiseases intheGreek Islands Heart
Study.In:Nutritional prevention of cardiovascu-
lardisease.Lovenberg W,YamoriY (Eds).New
YorkAcademic Press1984:125-135.
7. AravanisC.Theclassicriskfactors forcoro-
nary heart disease.ExperienceinEurope.Prev
Med 1984;2:125-135.
8. DontasAS,JacobsD,CorcondilasA,Keys
A,Hannan P.Longitudinal versus cross-sectional
vital capacity changesand effecting factors.J
Gerontology 1984;39:430-438.
9. AravanisC,loanidesP.Evolution ofcardio-
vascular diseasesinruralGreece.BiblNutr Diieta
1986;37:92-96.
10. SandkerGW,Kromhout D,AravanisC,
Bloemberg BPM,Mensink RP,KaraliasN,Katan
MB.Serum cholesterol ester fatty acidsand their
relationwithserum lipidsinelderlymeninCrete
and TheNetherlands.EurJClin Nutr1993;47:201-
208.
11. DontasAS,Menotti A,AravanisC,
Corcondilas A,LekosD,Seccareccia F.Long-term
predicton ofcoronary heart diseasemortality in
tworuralGreek populations.EurHeartJ
1993;14:1153-1157.
115
 10
STUDIES I N CROATIA
R. Buzina

M y introduction tocardiovascular research was inthe fall of1950

when Ijoined theInstitute of Biochemistry of theUniversity of Baselasa postgrad-
uatefellow inbiochemistry and vitaminology. Professor KarlBernhard, then the
Directorof theInstitute,proposed acoupleofthemes for my research activities.The
one Ifound most interesting was tostudy theeffects of deuterium-labelled dietary
cholesterol on thedevelopment of coronary atherosclerosis inrabbits.
Unfortunately, itturned out that theconcentration of thelabel wasinsufficient for
quantitative analysis,and theresults werenever published.On theother hand,I
became interested in theproblem ofdiet and atherosclerosis,and became quite
familiar with thecurrent research on that subject.
At that timeitwasalready recognized that though thelevelofserum cholesterol
could not serveasareliablecriterion ofblood vesselintegrity inindividuals,it was
found useful asan indexof theso-called atherogenic potential inpopulation stud-
ies.Theobserved differences inblood cholesterol intheearly studieswere related
primarily totheamount of fat inthediet.However, in 1952Kinsell and co-workers,
and shortly afterwards, Keysand co-workersfound significantly lower levelsof ser-
um cholesterol when vegetable fats werefed isocalorically than with the fats ofani-
malorigin inthe diet.
Thesedata wereofgreat interest tous,and wedecided toinvestigate how these
resultsof relatively shortexperimental studies would compare with the mean cho-
lesterollevel inpopulations livingon different amounts and typesof fats practically
forgenerations.Opportunities for such anepidemiological study presented them-
selvesin 1953when Dr.Josef Brozek from AncelKeysLaboratory cameto Zagreb
°n sabbatical leave,alsoprovidingasmallgrant which enabled ustoplan the study.
ThreeregionsofCroatia wereselected for thisstudy.Onewas theregionof
°sijek in eastern Slavonia,characterized byahigh animal fat intake (98 g/capita/
day).Thesecond region wasin theDalmatian hinterland and characterized bya
lowfat intake,mainly ofanimal origin (44g/capita/day).The third region was an
Adriaticisland whereoliveoilrepresented 90-95%ofallfat used in the household.
Theaverage fat intakewas 118g/capita/day of which 85gwasoliveoil.

117
Themean serum cholesterol level differed markedlybetween theregions.In the
area where over90%offat intakewasof animal origin, thelevel ofserum choleste-
rol,standardized for age,was239mg/100ml (Bloormethod),but only211mg/100
ml in the 'low fat' region where fat intake,mainly ofanimal origin, wasless than
half that of theother region.Thelowest serum cholesterol level,however, was
found in the 'oliveoil'region. Despite thefact that total fat intake was the highest,
theserum cholesterol level was201mg/100 ml,thelowestofallthree regions(1).
Ihad thechance todiscuss thesedata with Dr.Keysduring astudy he organized
in 1954inNaples,and we agreed that itwould beinteresting toexpand this study
and toinvestigate theprevalence ofCHDin theexamined regionsof Croatia.
Though no final plansweredeveloped atthat stage,during mystay inNaples Ihad
theprivilege tomeet and work with Italian counterparts,Professors Fidanza,
Bergami,and Manciniand alsowith members of Dr.Keys'team,including Mrs.
Margaret Keys,Dr.Henry Blackburn, Dr.J.T.Doylefrom Albany,N.Y.,and Mr.
Ernst Klepetar from Minneapolis.During our work inNaples wehad achance to
meet the 'elite'of world cardiologists headed by Dr.Paul White, including
Professor VittorioPuddu from Rome,Professor Oliver from Edinburgh, Dr.Jacques
Carlottifrom Paris,Professor Gunnar Björk from Gothenburg,and distinguished
researchers from Finland,Professors Paavo Roine,and Martti Karvonen.
Thestayin Napleswasan excellent introduction totheepidemiology ofCHD.A
year later Iwasinvited by Dr.Keystospend oneyearasaresearch fellow in his
laboratory in Minneapolis where,besides other things,Ialsotook part inhis follow-
up study of CHDinMinnesota business and professional men.
During thistimeDr.Keysbecameinterested in theeffects of fats on theblood
coagulation system.SoIintroduced and modified techniques for measuring compo-
nentsoftheblood clotting mechanism, theresultsofwhich werequite interesting;
thesameamount but different types of fats affected thewholeblood clotting time
tovarious degrees,aswell astheconversion of prothrombin tothrombin (2,3).
After Ireturned toZagrebin late 1956,contactswereestablished with a number
of peopleinterested inresearch onCHDintheU.S.A.,Italy,Finland,Greece,and
Japan.In 1957Dr.Keyswas abletosecurecentralfunds for acollaborative study on
theepidemiology of CHD,and was instrumental inenabling Professor Fidanza and
myself toobtainNIH grants for studies in Italyand Croatia.(Duetothevery short
timeleft tomeet theNIH deadline,Dr.Keyssent forboth ofus tocometoRome,
where weprepared theprotocol for thestudy practically inoneday,sittingona
bench amidst thecolorful spring flowers and thesingingbirds ofabeautiful Roman
park.)
Inthefall of 1957afield trialtotest theprotocol,methods,and organization pro-
posed for theSevenCountriesStudy wascarried out inthevillageofNicotera near
ReggioCalabria in southern Italy.Mostof thekeypersons inthelong-term study

118
 Ratko Buzina and a subject,
fieldwork Dalmatia, 1958

from England, Finland,Japan,TheNetherlands,Greece,and theU.S.A.took part in

thispilot study.
Theexperience from theNicotera study enabled us torefine the protocol and
methods,and develop logistics for thefollow-up study. Inearly 1958we started
selecting populations in predominantly 'animal fat' or 'vegetable fat' areas.Tokeep
responsiveness of the population ashigh aspossible and tostrivefor near-zero loss
during follow-up, itwasdecided toselect men of rural areas,who were lesslikely
than urban men tochange occupation, habits,and/or residence.Thetarget was to
include about 700-800subjects aged 40-59,ineach cohort.
Inthe 'animal fat' area for Croatia weselected four villages intheregionof
Osijek in eastern Slavonia,including thevillage where the 1953pilot study was car-
ried out. Thevillages werequite homogenous in regard todiet and occupational
activities,and what was very important, thepopulation, aswell aslocalauthorities,
werevery cooperative and interested in the study.
In the 'vegetable fat' area, however, therewerenot enough subjects of the
required ageon theisland of the 1953study,and we had toorganize arapid screen-
ingof the food intake pattern of much larger populations along the Dalmatian
coast.Eventually about 12villages and hamlets strung along60km of the coastal
area in theregion of Makarska were selected.

119
 Theformal study wasinitiated in Dalmatia inSeptember 1958and inSlavonia at
theend ofOctober.Theresponse ratewas quitehigh.Of 684subjects included in
theroster of Dalmatia,671(98.0%)attended thefield clinics.There anthropometric,
clinical,biochemical,and electrocardiographic examinations werecarried out. The
vital capacity (FEV),aswellasballistocardiography, wereincluded in the examina-
tion.
InSlavonia,from 732included in theroster,696or 95.0%of subjects were exam-
ined.Thereason for arelatively lower response inSlavonia was the temporary
absencefrom thearea ofa number ofsubjects,not uncommon atthat timeof the
year when agricultural activities were lessintensive.However,health certificates
wereobtained from localphysicians for allabsent persons.
During the 1958field study, parallel dietary surveys were initiated. Twenty-four
families in Dalmatia and 25families inSlavonia wereselected inarandom process
from thelistofheadsoffamilies included intheclinicalexaminations.Food con-
sumption wasrecorded for seven consecutive days.Allfoods eaten by the families
and byindividual headsof thehousehold were weighed, and thevolume of bever-
agesexcept water measured.Quantitative duplicates of allfoods except alcoholic
beverages and water werecollected,asconsumed, tomakeaseven-day food com-
positefor chemicalanalysis.Detailed menus and recipeswere alsorecorded, and at
theend of theweek the totalsofeach foodstuff werecomputed for each participant.
Corresponding portions of thosefoods were purchased locallytomakeup equiva-
lent composite aliquots.Theseequivalent composites werehomogenized, lyophi-
lized,sealed under nitrogen, and sent for analysis tothelaboratories in Minneapolis
and Naples.Thedietary studieswererepeated in 1960and 1961,and results pub-
lished together with similar data from Finland,TheNetherlands, Italy,and Greece
(4-6).
Theclinical,anthropometric, and biochemical examinations wererepeated in
1963and 1968,and theresults of thesefindings were published inanumber of jour-
nalsand inthe threemajor SevenCountries monographs.Theyarewellknown and
willnotberepeated here.
Thebaselinestudy, aswell asthefollow-up studies inDalmatia and Slavonia,
werecarried out byinternational teamswith theparticipation ofexperts from other
countriesincluded intheSevenCountriesStudy.Thisopportunity wasutilized to
organize international seminarson theepidemiology ofcoronary heart disease,in
which other prominent scientists,including representatives ofWHO, participated.
Intheviewof Dr.PaulWhitethesegatherings played an important roleinbreaking
downbarriers tointernational scientific cooperation inEurope,then stilldivided by
theCold War.
After 1968the 10-yearfollow-up survey in thestudy inCroatia was concentrated
on thecollection ofmorbidity and mortality data.Thefinancial situation did not

120
permit theclinical and biochemical re-examination ofallsubjects included in the
original roster,but subjects with elevated risk factors wereexamined subsequently
onseveral occasions.After 1980,however,only data on mortality were collected.
The25-year mortality follow-up was made possiblethrough agrant of the
Netherlands Nutrition Foundation toProfessor Kromhout. Thecollection of mortal-
itydata wascarried out under thesupervision of Professor Mohacekby special
teamsofsenior medical students.On thebasisofhouse-to-house visits,they collect-
ed information on deceased subjects originally enrolled in thestudy,including doc-
uments relevant tothecauseof death. Death certificates werecollected and addi-
tional information was sought from localphysicians and/or thehospital,in thecase
ofhospital treatment.
During thecollection of mortality data invaluable assistance was given by the
localhealth services.Information on thehealth status,and incaseofdeath, death
certificates, wereobtained for subjects whoemigrated tofaraway countriessuch as
Australia,Chile,and Canada.After 25yearsof follow-up, mortality data were
obtained from 98%of theoriginally selected roster.Thiswas most rewarding for all
colleagues and members of thelocalhealth services involved inthe study.
After the25-year follow-up theSlavonian cohort had avery high mortality rate.
Thedifference inmortality was primarily theresult of difference inCHD deaths
(ratiotoother area 1.8) but alsointheratiosofall-causesdeath (1.5)and cancer
death(1.2).
During the25-year span of thestudy, membersof thecorefield team were prac-
tically thesame.Among those,Professor Mohacek wasresponsible for electrocar-
diographic and clinical examinations and Professor Marinkovic,with the assistance
of Dr.Smetisko,wasresponsible for clinicalwork. Withregard todietary examina-
tion,most of thework wasplanned and supervised by Professor Ferberand Dr.
BrankaTiefenbach-Agneletto, and laterbyDr.Anna Brodarec.Dr.Agnes Horvat
prepared food composite samples.Butequally important wasthecontribution ofa
number of people instrumental insetting up ahighlycompetent field team and
directly supporting thelogisticsof thefield operations.Among them were Professor
Arpad Hahn, then director of themedicalclinicof theUniversity ofZagreband his
successor Professor Radosevic.Professor Vugrincic,former chief of the medical
department of theOsijek general hospital and Dr.Marinovic,director of the pri-
maryhealth carecenterinMakarska.Theysecured thebest possible cooperation
between field teamsand thelocalprimary carepersonnel inSlavonia and Dalmatia,
respectively.Without the assistance of theseand localauthorities itwould not have
beenpossible tocomplete thestudy so successfully.

121
Publications
1. BrozekJ,Buzina R,MikicF.Population
studieson serum cholesterol and dietaryfat in
Yugoslavia.AmJClinNutr1957;5:279-285.
2. Buzina R,KeysA.Bloodcoagulation after a
fat meal.Circulation 1956;14:854-858.
3. KeysA,Buzina R,Grande F,AndersonJT.
Theeffects ofmealsofdifferent fatson blood
coagulation.Circulation 1957;15:214-219.
4. Buzina R/Ferber E,KeysA,BrodarecA,
Agneletto B,Horvat A.Dietsof rural families and
headsof families in tworegionsof Yugoslavia.
Voeding 1964;25:629-639.
5. Buzina R,KeysA,BrodarecA,AndersonJT,
Fidanza F.Dietarysurveysinrural Yugoslavia.II
Chemical analysisofdiets inDalmatia and
Slavonia.Voeding1966;27:31-36.
6. Buzina R,KeysA,BrodarecA,AndersonJT,
Fidanza F.Dietary surveys inrural Yugoslavia.Ill
Comparison of three methods.Voeding
1966;27:99-105.
122
7. Buzina R,KeysA,Mohacek I,Hahn A,
BrozekJ,Blackburn H.Rural men in Dalmatia
and Slavonia,Yugoslavia. In:Epidemiological
studiesrelated tocoronary heartdisease:
Characteristicsof men aged 40-59inSeven
Countries.KeysA etal. (Ed).Acta MedScnnd
1967;460:147-168.
8. Buzina R,KeysA,Mohacek I,Marinkovic
M,Hahn A,Blackburn H.In:Coronary heartdis-
easeinSevenCountries.Five-year follow-up in
Dalmatia and Slavonia.KeysA(Ed).Circulation
1970;41(Suppl 1):40-51.
9. Buzina R,Suboticanec K,SaricM.Diet pat-
ternsand health problems:Diet in Southern
Europe.Ann Nutr Metab 1991;(Suppl l):32-40.
10. Buzina R.Recentevaluation of food habits
inMediterrarean populations.In:Forabetter
nutrition inthe21thcentury.Leathwood P,
Horrisberger M,JamesWPT(Eds)Nestle Nutr
WorkshopSeries,Raven Press1993;27:67-74.
 Il
STUDIES I N SERBIA
S.I. Nedeljkovic

Early inthe 1950stherewassome 'talk' inBelgradeabout theepi-

demiology ofchronic massdiseases,including cardiovascular diseases(CVD).
Epidemiology at that time,in health servicesand academicinstitutions,dealt pri-
marily with communicable diseases.After theSecond World War,in 1945, the most
prevalent diseasewaspulmonary tuberculosis (TBC),aconsequence of deficient
housing,extensivemigration, food shortages,underdeveloped health services (with
shortagesinessential medicines),primitive communication systems,etc.Aspecial
TBInstitute was founded and a widespread net ofdispensaries organized through-
out thecountry.Other infectious diseaseswereepidemic,too:typhus (typhus exan-
tematicus),typhoid and paratyphoid (Salmonellosis),hepatitis,dysenteries,tetanus,
diphtheria, poliomyelitis,plusendemic malaria and syphilis.Ahuge hospital for
infectious diseaseshad been inoperation for yearsin Belgrade.InInternal ClinicsA
and B therewere many casesof rheumatic fever and valvular heartdisease,as well
asinfectious endocarditis.Inrural areaschronicbronchitis wasprevalent, in most
casesasequelof pulmonary tuberculosis,orother non-specific, repeated bronchial
orpulmonary infections.
Bythelate 1950s,however, therewere moreand morecasesofangina pectoris
and myocardial infarction crowding thehospitals and clinics.At theThird World
CongressofCardiology in 1958in Brussels,Cedomil Plavsicpresented a report
(with myself aco-author) oncoronary heartdiseaseinYugoslavia (YU),which was
later published inActa Cardiologica, showing theupward trend incoronary heart
disease (CHD)inmany parts of theformer YU.Professor Plavsic,awell-knownYU
cardiologist,soon moved toAbazia (Opatija) ontheAdriaticcoast toorganizea
CVDRehabilitation Center - Talasoterapija.
ThelateProfessor BozidarS.Djordjevic (1910-1986),ascholarof theFrenchcar-
diological schooland student of thewell-known cardiologist,Camille Lian, institut-
ed inthe InternalClinicB twowards for cardiovascular patients and formed apro-
fessional cardiological team. In 1965hefounded postgraduate cardiology training
at theMedical Faculty in Belgrade.Hethen sentyounger associates abroad for
additional training.VladanJosipovic'was among thefirst tospend time in London,

123
SanFrancisco,and theTwinCitiesof Minnesota during 1958and 1959,and he was
in touch with teamsalready working inCVDepidemiology.Igot acertificate in
biostatistics during sixmonths training atColumbia University,New York,in1961
and, bycoincidence,was assigned athesison theepidemiology ofCHD!

Seven Countries Study Connections

Earlyin 1961ameeting was held inZagreb (Croatia) with participation ofAncel
Keys,RatkoBuzina,IvanMohacek, Radovan Ivancic',BozidarDjordjevic, and
VladanJosipovic',where plansfor aSerbian Seven Countries Study (SCS)werecon-
sidered. InJune1961 AncelKeysparticipated inthethird YUCongressof
Cardiology inOpatija, lecturing on the 'Riskof CHD',and summarizing the first
resultsobtained in theInternational Cooperative Study hehad already started in
Croatia,Italy,Finland,Japan, theU.S.A.,and Greece (Crete).Invitations had been
sent toBozidar Djordjevic and VladanJosipovic tojoin theSCS,and tocome in
September toCorfu and takepart infield surveysconducted byChrist Aravanis
and Anastasios Dontasfrom AthensUniversity. InCorfu theMinnesota standards,
methodology, and protocols wereagreed upon with Ancel Keys,and the decision
made toconduct theSerbianSCS.

Serbian SCS Beginning Organization

Professor Djordjevic wasthen quiteinfluential asChief ofCardiology in Internal
Clinic B,and alsoasPro-rector and soon-to-be Rector of Belgrade (BG)University,
aswellasDirector of theSerbian Institute for Medical Research.He enthusiastically
organized theSerbian SCS,getting abroad rangeof support. Clinical examinations
of subjects in theSerbianSCSwerecovered indifferent phasesof study,by Vladan
Josipovic,Chief of Cardiology after Djordjevic's retirement, Ivan Lambic',laterChief
ofCardiology inanother hospital,Gradomir Stojanovic',Chief ofCardiology after
myretirement,Ljubica Bozinovic,Chief of theCoronary CareUnit for more than20
yearsbefore retirement,Miodrag Ostojic,nowChief ofCardiovascular Diagnostics
and Interventional Cardiology,Miodrag Grujic, Chief ofArrhythmology in the
Institute ofCardiovascular Diseases (ICVD),and Dejan Boskovic,Chief of
Cardiology inICVD.
ThomasStrasser wasgiven thedelicatelaboratory work of preparation of sera
onfilter papers tobesenttoMinneapolisfor centraldetermination ofserum choles-
terol,avariableconsidered of primary importance in theSCS.Dr.Strasser was with
theSerbian Studyuntil 1969,when hemoved toGeneva tobecome medical officer
in theCardiovascular DiseaseBranchofWHO.Healsospent 1965in Minneapolis
in theLaboratory of Physiological Hygiene (LPH),helping tocodeand sort dataof
the threeSerbian cohorts.Hewas thefirst topublish data on diabetes mellitusin

124
theSerbian cohorts,encouraging endocrinologists from Internal ClinicB to continue
that optional study over25years.In 1962hespent three weeksin Rome participat-
ing in theRomeRailroad study group,and hiscontribution to theSerbian Study
wasessential to theentryand fifth-year field surveys.
BozidarSimic,ahighly reputed nutritionist with experience in the relations
between dietand CVD,had previously published apaperon that topic concerning
Serbia before hejoined thecardiological team.With hisassociate,Arsenije Simic',he
trained students torecord the food intakeof41men in Velika Krsna (VK)in
October 1962and May 1963,of44men inZrenjanin (ZR)inSeptember 1963and
November 1963,and of41Belgrade University professors inFebruary 1964.With
thehelp of nutritional chemist,Sibalic'(Belgrade),and of thelaboratories in Naples
(FlaminioFidanza) and Minnesota (AncelKeys),data on energy intake,protein, car-
bohydrates,and fats (including fatty acid profile) wereobtained in seven-day food
duplicates.Werealized,of course,that diet had priority inAncel Keys'approach to
theepidemiology ofCHD.Inthebeginning,however, mostof theBelgradeclinical
staff wascurious about thenameoftheinstitution which AncelKeysand his staff
represented, the 'Laboratory of Physiological Hygiene' (LPH).Theguiding idea
soonbecameobvious:a laboratory with an interest in research intothe physiologi-
calaspectsof lifestyle,with diet asthecentral point.Thenamehassincebeen
changed totheDivision of Epidemiology (1984).ButIstill feel nostalgia for theold
name,LPH(a nostalgia sharedbytheeditors).
From theverybeginning Iwas,in myroleof fieldwork organizer, personally
responsible for ECGrecordings and codings,and mortality follow up.After 1975,
when professor Djordjevic retired,Ireceived full responsibility for theSerbian CVD
Study.Ihad severalniceopportunities, becauseofAncel Keys'help,tojoin field
surveys with MarttiJ.Karvonen's team inWest Finland in 1964and Alessandro
Menotti's team in Montegiorgio,Italy in1965.
TheSerbian CVDStudy gotoverwhelming acceptance from all professionals
involved inthestudy:clinicians,cardiologists,nutritionists,technical staff, adminis-
trativepersonnel,thesubjects,aswellascommunity support from all levels.The
examinees werenot treated asobjects ofexperimentation, but given afull report
and counsel on their health,with freedom toreturn for medicalcheck-ups ifneces-
sary.They used thisopportunity often, especially inBelgrade.Thereputation of the
SCSwassuch that itwaspossible togetgrants from variousresearch agencies; from
1970-1973NIH Special ForeignCurrency PL-480,02-033-1support wasvital tocar-
rying out the 10-year follow-up surveysand tracingvital statusof allmen entering
theSerbian cohortsin1962-1964.

125
SCS Continued
After thethird round of fieldwork tocollect 10-year data,therewasalull in Serbian
andSCSactivitiesbetween 1974and 1982.Field surveysbeyond 15years were
omitted (1977-1979),except for mortality follow-up. In 1980AncelKeys published
hiscapitalbook 'Seven Countries.AMultivariateAnalysis of Death and CHD',
indicating theneed for further follow-ups, for getting more information on the
power ofclassicCHDrisk factors and theirchangeover time,and factors related to
life expectancy. Criticaldecisions weremade during themeeting of theSCS
Steering Committee at Heraklion inCrete,September 1979,organized by Christ
Aravanis with Ancel Keysand Henry Blackburn,and allprincipal investigators
present. Itwas decided toraisepersonal funds for further continuation of individu-
alcomponents of theSCS.Thenew principal investigator of theDutch study, Daan
Kromhout, who took over theZutphen Study after thedeath of F.S.P.van Buchem,
gaveimpetus totheinternational cooperation. Hewaslaterofgreathelpfor the
Serbian part of theSCS,directly participating infield surveys in 1987(VK),1988
(ZR),and 1989(BG),with hisassistant BennieBloemberg. Hecontinued research on
thebaselinedietary data byanalyzing fresh food composites for nutrients, fatty
acids,and dietary cholesterol,with thehelpofProfessor Martijn Katan from
Wageningen, TheNetherlands.Healsotook sera of participating survivors in three
Serbian cohorts for measurement of thelipid profile.

Velika Krsna (VK), 1962

VKisatypicalSerbian village spread over hillsand streams intheregion called
v

Forestland (Sumadija), with asurface area of 15x15km,250-300mabovesealevel,

inland about 30km south of theDanube river,and about 70km from Belgrade.
Farmland isinterspersed with forested hills,grasslands,fruit orchards, (plums,
apples,pears,peaches),and vineyards.In 1962,when theVKstudy started, thevil-
lagewasinterconnected by smallmacadam roads,with oneroad leading to the
nearby town ofMladenovac, 15kmaway,and toHighway Belgrade-Nis.In1967,
during thesecond survey,therewasapaved road connecting Mladenovac and the
main Highway, through VK.VKhasasmall center with alargecommunity build-
ing,inwhich theexaminations took place,aswellasachurch (Greek Orthodox),an
elementary school,ahealth station (opened in 1966),aveterinary station,afew tav-
erns,and small shops.Thevillagehas about 5,000inhabitants,90%farmers with
smallfarms and limited cultivatingmachinery.Someyoungstersareemployed in
nearby Mladenovac,connected by aregular bus.
Theclimateiscontinental with four typicalseasons,sometimes with heavy snow
and rain,but alsowith very dry weather inJulyand August.Nearby attractions are
a renovated 'SpaSeltersMladenovac',and Topola-Oplenac,aplacewith ahotel and

126
monastery (GreekOrthodox) known asa 'mausoleum' of Karadjordjevic's monar-
chy,and thetombof thelastYugoslav King,Alexander, killed inMarseille in1934.
Thisplacewas visited by most of theforeign guests participating intheSCS.
Thecohort in VKconsisted originally of 706men,but for laterSCSanalyses only
511were included because those aged 35-39and 60ormorewere considered 'outof
age'.Thepopulation ofVKwasstable and only afew men migrated tothe nearby
towns Mladenovac orSmederevo,sincethemajority of examineesowned private
land,houses,cattleand poultry farms, orsmall farming machinery.Most of the
foods, even alcoholicbeverages,werehomemade,and diets wererich in bread,
milk,cheese,eggs,pork,lamb,and chicken.Fish wasonly occasionally used, mostly
during thereligious fasting periodsbefore Christmas and Easter,holidays more
observed in thevillages than in thetowns.Inlocalshopssalt,oils,sugar,beer,can-
dies,textiles,and technicalgoodswereon sale.Theexamining study staff enjoyed
excellent localhospitality and luncheons with homemade food and drink.
Atthebaselineexamination 96.7%of themen aged 40-59participated in the
study.Theentry examinations atVKweresupervised by Anceland MargaretKeys,
and Henry Blackburn, who introduced ECGrecordings and an 'Outline of suggest-
ed criteria for clinical diagnosisinpopulation studies'.Alldata obtained inVKwere
put intospecial Minnesota forms and soon shipped toMinneapolis for analysis.
Among thestandard examinations,anoptional radio-iodine thyroid uptake was
carried out inasubsample by theteam of Professor Peter Milutinovic. Significantly
higher uptakerateswereobserved for theVKcohortcompared with theZRandBG
University cohorts examined in 1963and 1964.Apossibleexplanation for thesub-
jectsinVKcould behigher physical activity,lowerbody weight, lower sum oftri-
cepsand subscapular skinfolds, and thelowest entry serum cholesterol levelof all
SCScohorts (mean 160mg/dl).
Theother 'optional' study was carried out byagroup of pulmonologists who
recorded Spirometriefindings during 25years offollow-up. About 20%of thesub-
jectsinVKhad impaired lung function, asignificant predictor of subsequent mor-
tality from bronchitis (mostly asasequel of previous lung tuberculosis),and cor
pulmonale.
Itwasrelatively easy totrack vital statusand causesof death of men inVKwho
entered theSCSin 1962. Thiswas due totheavailability ofalocaldeath certificate
service,Health Station documentation, nearby hospital records (Mladenovac,
Smederevska Palanka,Belgrade),and theexcellent helpof thelocal physician,
Slobodan Imsiragic'and cardiologist MilanAndjelkovic, whodid histhesison the
causesofdeath inVK.Wehad inVKavery good contact person,PetarVulicevic',
whowas for many yearsofficial clerkof thelocalcommunity and knew every man
there;hewas himself a participant in theVKstudy. Hedied recently from hyper-
tensivevascular disease,Parkinsonism, and stroke.

127
 During thewholeSCSwehad wonderful cooperation with ophthalmologists
looking for changesin theoculifundi: Professors Dobrica Cvetkovic, Dusan
Stojanovic'(died in 1978),and Sinisa Djakovic'.They published afew papers on oph-
thalmologicfindings in thejournal 'Serbian Archive'.
Anotherancillary study done repeatedly on subjects of theSerbian SCSwas test-
ing thevalueof Dock'sdirectbodyballistocardiography inepidemiological sur-
veys.Abnormalitiesof ballistocardiography weresignificantly moreprevalent in
older ageand inmen with hypertension,obesity,and impaired lung function. The
resultswerepresented in an International meeting onballistocardiography and
havebeen published.

Zrenjanin (ZR), 1963

Asacontrasting population with adifferent environment and lifestyle, an
Agroindustrial Combine (AIC)'ServoMihalj'in thetown ofZrenjanin was selected
asthesecond Serbian cohort intheSCS.Zrenjanin issituated 70km north-westof
Belgrade,across theDanuberiver. Itistypical of theprovince ofVojvodina (area
Banat)and thecohort probably deserves themore appropriate name 'Vojvodina'.
ZRsurroundings has22villages,with 81,316inhabitants livingin thetown in
1991,136,778in theregion inall,with many ethnicgroups (25),but mostly Serbs
and Hungarians,and some Romanians and Slovaks.Theterritory isflat, with rich
farming land,bordered by thegreat rivers,Danubeand Tisa,asmaller one,Tarnish,
and the BegejRiver,running directly through thecenter of Zrenjanin. Therearea
few lakesand places for fish breeding (Echka carp stews).There isalsoawater irri-
gation system, theDanube-Tisa-Tamish-Danubecanal.Anabundance of vegetation
and forestry createsopportunities for hunting ducks,pheasants,and rabbits; fishing
intherivers isexcellent.
Out of5,000workersemployed inAIC 'ServoMihalj',aroster ofmen above age
35was established, and a total of 720men examined atentry inSeptember 1963.A
response rateof98%wasachieved.After elimination ofyounger and older men,
516men,aged 40-59,remained for follow-up intheSCS.TheZRcohort is composed
of 253Hungarians,239Serbs,17Romanians,and 7Slovaks.
After 25yearsof follow-up, ZR'scohort reached nearly the topofSCSage-
adjusted CHDand strokedeath rates,181/1000 and 119/1000,respectively. There
werenoethnicdifferences, except for thesmallgroup ofSlovaks,with 6deaths out
of 7examined atentry.IntheZRcohort themean levelsofserum cholesterol
(mg/dl) increased from 169in 1963to207in 1968,and 230in 1973.From ZR's
cohort welearned theepidemiological lesson that people inVojvodina areat very
high risk for CVD,partly through anunhealthy lifestyle and adiet rich in animal
fats asmain risk factors,although causal explanations are far from beingclear cut.

128
 TheSCSteam enjoyed an enthusiastic welcome at 'Servo Mihalj' during 25years
ofcooperation, although the industrial cohort was theone most difficult of the three
Serbian cohorts to tracein the long run. Retirement of workers,and migration all
over former YUand abroad, caused large problems,with at least 15men lost to fol-
low-up. Bygood luck we had a friendly and helpful contact man, social-welfare
worker Danilo Babic,employed with 'Servo Mihalj' for more than 30years and
always at hand. Hedid all mailing and inquires on thewhereabouts of men entered
intotheSCScohort in 1963.Therewas alsoarenovated hospital inZR,city central
office for vital statistics,and ahelpful physician employed at 'Servo Mihalj' Health
Station. Having AICautomobiles at our disposal, we made many visitsto the exam-
ineesand thedisabled in town,aswellasin thevillages.

Belgrade U n i v e r s i t y Professors ( B G ) , 1964

Belgrade University professors werechosen on theinsistenceof theSerbian mem-
bersof theSCS,pointing out differences between intellectual and physical occupa-
tions.Thedifference wasespecially largebetween University persons,with a seden-
tary lifestyle and peasants in VK,engaged in heavy physical activity. Except fora
few administrators at the University,allexaminees were professors or lecturers in
16faculties. Allprofessors engaged in theSerbian SCSalsoentered intotheBG
cohort, and allarealivetoday except Professor Djordjevic, whodied from stroke in
1986,having suffered from CHD.

Srecko Nedeljkovic (second right) supervising the

11
exercise step test, belgrade, I 964
II
I 1}
1 1
1
:

Jm'-

129
 The BGresponse rate for entry examinations was 85%of allprofessors at the
University,aged 40-59inJanuary 1964.However,theoverwhelming responseof
239subjects,aged 40-44,brought themean ageofthecohort of 538men down to
47.8years,the lowestmean ageof allcohortsintheSCS.Theinitialnumber ofBG
subjectswas654,but after elimination ofyounger and older persons,538were
included in theSCScohort.Though theselection of theBGcohort hasbeen criti-
cized,and thecohortleft out ofmany analyses,lookingback after 30years,we were
fortunate with theBGgroup.On subsequent 5-yearexaminations response rates
werebetween 80-85%,and there was no troublefollowing vital status ofall entry
men.Each yearabook of University staff affiliation wasedited with addresses and
phone numbers.Itwas alsopossible toobtain thenecessary information from the
administration, especially for retired professors. Most professors usehealth services
at theUniversity Clinical Center and Instituteof Cardiovascular Diseases(ICVD).
Many whosurvived ordied from CHDweretreated at theCoronaryCareUnitof
the ICVD.Thedaily newspaper Tolitika' regularly publishes obituaries and photo-
graphs of deceased persons,which alsohelps track BG professors.
Atentry BGprofessors had higher levelsof BMI,sum of skinfolds, serum choles-
terol,and CHDprevalence than men inVKand ZR.During thefirst 10years of fol-
low-up,they wereat higher CHDrisk. However, after 25-yearsof follow-up, theZR
cohort reached thehighest total for CHDand strokemortality.The25-year all-cause
mortality rateof BGprofessors was347/1000,lowestamong all 16cohortsof the
SCS.Protective factors might havebeen thehigher educational level of theselect
population,better socio-economic status,and health behavior resulting,for exam-
ple,inalowpercentage of cigarettesmokersafter 25yearsof follow-up. Also,there
was easier accessibility tohealth services,afactor which hasnotbeen specifically
measured inSCSand could haveplayed aroleinreducing mortality risk.
Finally,Iwould liketoclosewith someremarkson Belgradetoday.Belgradeisa
metropolitan,international cityofabout 1.5 million inhabitants,thecapital and
administrative center of theformer and newYU,and hasbeen developed and
enlarged during thelast threedecades.Except for theoutskirts and the industrial
region of Rakovica, 'dirty' industries havebeen kept far outside thecity.Beingan
important political and military strategic point,Belgradewasheavily destroyed
severaltimesduring World War IIand in past warsbetween the Austro-Hungarian
and Ottoman Empires.After World War II,many peopleentered thecity,produc-
inganimmense population growth. Untilrecently,housing hasbeen amajor prob-
lem,but inthelast decade intensive construction and stimulation of private proper-
tyhascoped with the shortage.
Belgrade and suburbs aresituated ontherightbank of theDanube and on both
banksof theSava riverjunction with theDanube.Bothrivers arepolluted by
upstream industries,with chemicalsendangering thequality of thewater supply.

130
Smogsareoccasional,usually shortlasting and cleared by 'koshawa', a north-east
wind coming along theDanube from theKarapati mountains in Romania.
Belgradeissupplied byanextensivecommercial network offood chains,as well
asby many farmers 'green' markets offering fresh produce.Thereare many parks
suitablefor recreational physical activitiesas wellasfor gardening,which is popu-
laramong intellectuals.Therearealsobeacheson theDanubeand Sava,with one
very popular beach, 'Ada Ciganlija', having acrowd of more than 100,000people
dailyduring thesummer months.

Collaboration with Alessandro Menotti

Oneof those who proved most helpful intheSerbian CVDStudy,and who partici-
pated inallfield surveys from thebeginning,wasAlessandro Menotti,whom Ancel
Keysplaced ascoordinator of theEuropean part ofSCS.Following European
cohorts of theSCS,hewas stubbornly insistent oncompleteSCSdata and built in
Rome,incollaboration withAncel Keysand RoseHilkin Minneapolis,a Master
Tapeof SCSdata. In 1979hemoved from theCardiology Department at theSt.
Camilloin Rometohisplacein theLaboratory of Epidemiology and Biostatistics,
IstitutoSuperiore diSanità,dedicating much timetoSCSand analysisofSCSdata,
including theSerbian part.Hisappointment asDirector of theLaboratoryof
Epidemiology and Biostatisticsin 1990did not changehisattention totheSCSand
hecontinued the25-year follow-up analyses,aswellashaving responsibility for
nineorganizational unitsand astaff of 150people.Thelast timehevisited Belgrade
w
as in 1989,during the25-year follow-up examinations of theUniversity profes-
sors.Later,in 1989,1 took theopportunity tovisithisLaboratory in Rome,where he
provided methe tapewith data of theSerbian cohorts.

Collaboration with George Lamm

TheSerbian Study wasconnected with theHungarian Study started in 1965by
George Lamm and IvanGyarfas.After both of them moved toWHO,the
Hungarian study did not achievelong-term follow-up. George Lamm participated
inthefield examinations inVelika Krsna in 1972and Zrenjanin in 1973; Ihad met
George Lamm earlier during thefieldwork of theItalian cohort inMontegiorgio in
1965.
InFebruary 19711had thepleasure todrive Margaret and Ancel Keys from
BelgradetoSzeged and back toBelgrade for avisit totheHungarian field survey,
including the nearby villages,Szekkutas and Martely.AncelKeysintended to
extend theSevenCountries Study totheEightCountries Study!Itwasapity that
thosedata could notbeincluded in theSCS.Onewould expectsimilar findings and

131
CVDtrendsasintheSerbian Zrenjanin cohort sincenutrition, geography, geology,
climate,and socio-economic conditionsareapproximately thesameinthetwoareas.

Collaboration with Henry Blackburn

Henry Blackburn waspassionately involved intheSerbianSCSfrom the very
beginning until 1972,when hebecameDirector of theLPH after AncelKeys'retire-
ment. Hisresponsibilities wereextended later,when theLPHwas transformed into
theDivision of Epidemiology of theSchoolof PublicHealth of Minnesota, torun-
ningafaculty of40and astaff of more than600employees.Hissupport of theSCS
was encouraging during the meeting ofSCSprincipal investigators inCrete1979,
when hehad toleave themeeting abruptly becauseof theurgent brain operation on
hisson intheU.S.A.
Henry Blackburn made hisappearance inVelikaKrsna in 1962,helping with
ECGrecording and Minnesota coding.Heistheauthor ofthewidely accepted
Minnesota Code,an ECGclassification system soneeded inepidemiological studies
ofCVD.TheMinnesota Codeisanindirect characterization of the cardiovascular
health of populations,and predictsfuture morbidity and mortality events.Later he
formed acentralSCScoding office at theLPH.TheMinnesota Codeprocedure was
technically developed tothepoint that even technicianscould makereliablemeas-
urements and coding of allECGitems.In 1963-1965hemadeanappeal toallcol-
leaguesengaged in ECGrecordings and codingsin field surveystocriticize the
Minnesota Codetoimprove itand avoid ambiguities,and reduce intra-and inter-
observer variability.Toovercome theseproblems,all ECGtracings from theSerbian
SCSwereshipped toMinneapolis for central reading and coding,and for clinical
classification of 'hard' and 'soft' CHD.Thecodewasthen modified inthe WHO
Manual on Cardiovascular Survey Methods in1968.
Wewerethen stimulated tobuy ink-writing ECGmachines (Elema-Schönander,
Sweden) with higher frequency response,instead ofcheaper direct ECGwriters.An
exercise test was adopted for field examinations withastep30cm high tobe
climbed and descended 60timesper 3minutesunder metronome pacing.
In 1967(VK),1968(ZR),and 1969(BG)anew project was introduced in the
Serbian SCSby DoctorsBlackburn and Rautaharju: magnetic taperecording of the
conventional ECG,orthogonal XZYleads,and bilateral carotid and femoral pulses
(atrest,during exercise,and in recovery).Everything sounded very attractive to me
asacardiologist.AncelKeyswroteabout theidea,mentioning 'largecostsmight be
involved,but ifyou could arrange and helpwewillbeinfavour'. Theidea was
costly:new equipment, engineers,customs problems,adjustment ofelectricity in
villages,transportation, personnel,etc.FortheZrenjanin field survey in 1968we
waited, together with Henry Blackburn,at Belgradeairport severaldaysbefore all

132
theequipment came,prolonging work afew days inorder toget anadequate sub-
sampleof examinees.
Nevertheless,everything went off inorderly fashion, according to Henry
Blackburn's suggestions (letter on August 21,1967):'Iwould suggest that thetestbe
aprogressive onesothat theolder or moredisabled subject would notbe over-
stressed at theonsetand provide warm up ...ashortinstruction session of pedaling
againstnoresistanceand optimaladjustment of theheight of thebicycleseat
(Monarch staticbicycle)...Thiswould befollowed bya two-minute warm-up at50
watts,two minutes at 100watts and two minutesat 150watts,with anend heart
rateof 130-140bpm,and threeminutes for therecovery period'.
Thisidea was realized with excellent engineers from theDalhousie University
Department of Physiology and Biophysics,Nova Scotia,Canada, under the logistic
guidance of my acquaintance from the Finnish field survey in 1964,Professor Pentti
M.Rautaharju. Hisassociate,now professor, Herman K.Wolf,was 15dayswith us
inVelika Krsna in 1967,and JohnScherwood for threeweeks (for thecohorts in
Zrenjanin) in 1968, and for theBelgradeUniversity professors in 1969.The other
person activein thisfield, doing thesamework inFinland,Italy,and Croatia, was
frig. Hans Friedrich from Munich,whose visitsIrecallwith gratitude.
Igotapleasant letter from Herman Wolf in 1990:'Wehave pulsewaves from
Yugoslavia and Japan,and acombination of one pulsewaveand heart sounds from
Italy ...Itisour intention toexplorethepulsewavevelocity asapredictor for long-
termblood pressure evolution and event rateprediction.' Ofcourse,Iapproved.
Another sparkling idea wasproposed by Henry Blackburn inaletter tome (July,
1972)recommending studiesof 'hygienic treatment ofpremature ventricular beats
usingphysical activity,stopping smoking,reducing alcoholand coffee, improving
sleeping habits,versusdrugs'.Asaclinically minded cardiologist, hetended to do
bothintervention and observational epidemiological studies(Eds.-butthat 'sparkling'
experiment yielded noclear results!).

Collaboration with the Group of George Kozarevic

Inthe 1980sjoint efforts were made toobtain funds for thecontinuation of the
Serbian SCSaswellasthe"YugoslavCardiovascular Study",ledby George
Kozarevic'with associatesNikola Vojvodic,Jasenka Demirovic',and Zivorad Racic'.
TheYugoslav Cardiovascular Study,inprogress from 1964-1965until 1988,wascar-
ried out with Framingham Studyprotocols inconsultation with Doctors Dawber,
Gordon,Zukel,McGee,Schenker,and Kaelber.Field surveysin thethree Serbian
cohorts wereconducted jointly with Kozarevic'sgroup intheperiod 1982-1989,en-
abling20and 25-yearfollow-up studiesof thesurvivors and collecting information
°n causesof death.

133
International Meetings and Seminars
Important for theSerbian SCSwerethemeetings of theResearch Committee of the
International Societyof Cardiology inMakarska,Dalmatia inSeptember 1963and
inVenice,ItalyinApril 1965under thechairmanship of AncelKeys.Topics covered
issuesof methodology and feasibility ofepidemiological studiesofCVDin free-liv-
ing populations.At that timePaul Dudley White was actively promoting research
in preventive cardiology and organizing international cardiological foundations. In
the Fifth World CongressofCardiology in New Delhiin 1966,hebecamethe first
President of anew cooperative International SocietyofCardiology, stillin existence
under thenameInternational Society and Foundation ofCardiology (ISFC).Ancel
Keysbecamethefirst Chairman (1966-1970)of theSection on Epidemiology and
Prevention of theISFC.That Section with itsCouncil,isstillvery active in World
Congresses ofCardiology and theInternational 10-DayTeachingSeminars.
Themethodology ofCVDepidemiology wasdiscussed inextensoduring a
WHOmeeting held inMoscow in 1965, with participation of D.Ried from London,
Z.Pisa from WHO,G.Lamm from Budapest,A.Mjasnikov, E.Chazov,I.Glazunov
and A.Ahmeteli from Moscow,and myself.Mostof theideasdeveloped in theSCS
weresupported with calls for more intensive research and cooperation.
In 1968,an annual 10-DayInternational TeachingSeminar wasfirst given in
Makarska and continues until today,held in many placesallover theworld, offer-
ingyounger students systematic training in theepidemiology and preventionof
CVD.Iattended thesecond inPioppi in 1969,using theoccasion toparticipate ina
meeting of theSteeringCommittee of theSCSheld atKeys'home,"Minnelea",in
Pioppi.Twoassociates of theSerbian SCSattended 10-DayInternational Teaching
Seminars:Dejan Boskovic'inHungary, (Estergon) in 1972and Miodrag Ostojic'in
Ghana (Accra) in 1977. Ostojic alsoparticipated intheAdvanced 10-Day Teaching
Seminar inSingapore in1993.

Meetings of SCS Members at Zrenjanin and Belgrade in 1985

Animportant stimulus totheSerbian study wasaget-together ofSCSinvestigators,
headed byAnceland Margaret Keys,and the BelgradeSerbian Academy of Science
and ArtsinZrenjanin inNovember 1985.Thefirst symposium inthe Agroindustrial
Combine (AIC)'ServoMihalj'wason 'CVDand nutrition'. Round table discussions
wereparticipated inbyAncel and Margaret Keys,Daan Kromhout, Alessandro
Menotti,AnnemarieJansen,Frederick Epstein (Zurich),RatkoBuzina, Bozidar
Simic',SreckoNedeljkovic',George Kozarevic',AICtechnologists ErneSchvan,
Dusan Radakovic',Miodrag Zotovic,and SavoIvancevic.Thesediscussions includ-
ed resultsofnutritional studies related toCVDintheSCS,aswellas considerations
of nutritional products ofAIC'ServoMihalj' inZrenjanin. Abooklet ofAIC prod-

134
•>reckoNedeljkovic, Alessandro Menotti and Daan Kromhout at meeting of the Serbian Academy of Science
and Arts, Belgrade, 1985

uctswasenclosed for thediscussion, with detailed composition of nutritional items.

Technology of their production was presented tothe participants.
AIC 'ServoMihalj' wasenlarged and intensively developed following World
WarIIfrom a plant originating more than two centuries agoinformer Austro-
Hungaria.Thefirm controls a large food market inYugoslavia and abroad, espe-
cially meat, sugar,beer, fruit products,pharmaceuticals,and cosmetics.AICalso
producescerealsand starch products, many sortsof bread,doughs,desserts,dishes,
Pastries,ready-made pies,biscuits,marmalade,and margarines. Four different
edibleoilsare produced: sunflower seed oil 'Dijamant', soybean oil,rapeseed, and
corn germ oil 'Evit'. Rapeseed oil isrich inoleicacid,50-74%.Sunflower seed oil,
soybean oil,and corn germ (maize)oilsarerich inlinoleicacid,up to60%of all fats,
Wl
th 0%peroxides.Among diary products they produce 3.2%pasteurized cow's
mi
lk, sheep's sour milk,different sortsof yoghurt, butter, and avariety of cheeses.
Allthese products havebeen shown and tasted on several occasionsby our epi-
crniologicresearch team,and werebroadly discussed during theZrenjanin meet-
ln
g in 1985with an international faculty. Itwasconcluded that there ismore work

135
tobeachieved by thefood industry in thesearch for ahealthy diet.On thatocca-
sion,twobooks werebrought totheattention of theaudience and presented to the
'ServoMihalj' library: 'EatWelland StayWell' (edited in 1959and 1963)and 'The
Benevolent Bean' (edited in 1967and 1972),written byMargaret and AncelKeys.In
thelibrary of 'ServoMihalj' therearealsoallmonographs,and many reprints,edit-
ed byAncel Keysand otherSCSauthors.
Thesecond symposium washeld on November 8,1985at theSerbian Academy
ofScienceand Arts (SANU)with thehelpoftheSecretary oftheMedical Unitof
SANU,Academician Vladimir Kanjuh, Professor ofpathology,who,after the death
ofAcademician Djordjevic, provided further grants for theSerbian part of theSCS.
Thetitleof thesymposium was 'Twentyyearsof epidemiological investigationsof
CHDinSerbia.TheSeven Countries Study'. Ancel Keyspresented apaper on 'Diet
and 15-year death rate intheSCS',which waslater (1986)published in the
AmericanJournal of Epidemiology. Alessandro Menotti presented 'CHD risk fac-
torsevaluation in theItalian part of theSCS',Daan Kromhout, 'Fish consumption
and CHD in20yearfollow-up of theZutphen Study',and SreckoI.Nedeljkovic',
VladanJosipovic,BozidarSimic,Vladimir Slavkovic,Gradomir Stojanovic, and co-
workers, different aspectsof theSerbian study of theSCS.RatkoBuzina and Ivan
Mohacek showed resultsof research on 'Risk factors inadolescents in Croatia'.
George Kozarevicand associatespresented different aspects of the 'Yugoslav
Cardiovascular Study'.Frederick Epstein from Zurich reviewed the topic
'Prevention ofCHD:status and perspectives'.President ofSANU,Dusan Kanazir,
reported hisresearch on 'Psychosocial factors inCVDand cancer7,pointing out the
importance of the 'Rationality/emotionality index' asarisk factor. Sorelymissed at
themeeting ofSANUwasAcademician Bozidar Djordjevic', founder of the Serbian
SCS,due tosevereillnessfrom which hedied soon after, in1986.

Summary
ThethreeSerbian cohorts,first examined between 1962and 1964,were thelast to
enter theSCS,already inprogress since 1958, not counting numerous pilot studies
before that year.Thecardiological team of Belgrade Medical Faculty,led at that
timebythelateProfessor DrBozidar S.Djordjevic, founder of theSerbianSCS,
enthusiastically accepted theidea tojoinan International Cooperative Study on
Epidemiology of CVD.After afew meetingswithAncel Keys,founder and coordi-
nator of theSCS,professor Djordjevic and VladanJosipovicwereinvited to attend
field surveysconducted byChrist AravanisinCorfu 1961,and toadopt the same
methodology and protocols for forthcoming studiesinSerbia.Someofthecardiolo-
gistswerealready trained abroad, mostly in theU.S.A.(VladanJosipovic,SreckoI.
Nedeljkovic, TomaStrasser,George Kozarevic,etai), and werebecoming familiar

136
with cardiovascular epidemiology and prevention. BozidarSimicwas engaged for
thenutritional part oftheSerbian study .Hewas already known through research
ondiet and CVDinsome areasof Serbia.
Inasearch for contrasting populations threeYugoslav cohorts wereselected:a
village,Velika Krsna,70km south-east of Belgrade,afood processing plant in the
town Zrenjanin (Vojvodina) 70kmnorth-west of Belgradeand acrossthe river
Danube,and Belgrade University intellectuals.Thus,threesocialclasseswere repre-
sented:farmers, workers,and academics.
Over many yearsnumerous international exchangesof colleagues were realized
toensure rigorousstandards necessaryfor an international cooperativestudy:cen-
tralplanning,reliablemeasurements,data-base construction, sophisticated analy-
ses,and publications.Valuable international help totheSerbian SCSwas afforded
byAnceland Margaret Keys,Alessandro Menotti,Henry Blackburn, Daan
Kromhout, and others.Before writing thisreport, Iarranged twoentirebooksof
correspondence taking placeover the30yearsofour joint endeavour!
Of2,080men examined at entry in threeSerbian cohortsof theSCS,1,563 have
been followed; thecohorts werelimited totheageclasses40-59at entry:511men
from VK,516from ZR-Vojvodina,and 536from BGUniversity.Overall age-adjust-
ed mortality in25yearswas highest inVojvodina (577/1,000),intermediate atVK
(497/1,000),and lowest inBGUniversity (347/1,000),probably explained by higher
socio-economic statusand better healthbehavior in professors versus farmers and
workers.CHDrisk factor increasesover timeweregreatest atZR,especially blood
pressure and serum cholesterol,leading tothehighest 25-yearCHDdeath rateof
177/1000 inZRvs. 122/1,000 inVK,and 118/1,000 inBGUniversity.
Themortality follow-up of theSerbian cohortsoftheSCSwillbe continued.
However, turmoil in theformer Yugoslavian territories iscreating morenew health
problems and human disasters,requiring different types ofepidemiological and
preventive research,and publichealth action.

137
Acknowledgments
The following persons played a central role in realizing the Serbian part of the Seven Countries Study:
Boftdar S.Djordjevic", (1910-1986),internist, cardi-
ologist. Chief Investigator SCSSerbia until 1986,
Director of Institute for Medical Research, Chief
of Cardiology in Internal Clinic B, Pro-rector
and Rector of University Belgrade. Professor of
Internal Medicine and Cardiology of Medical
Faculty Belgrade (MFB).
Vladan Josipovic', (1920-),retired 1985, internist,
cardiologist. Chief of Department of Internal
Medicine, Professor of Internal Medicine and
Cardiology of MFB.
Toma Strasser (1922-),cardiologist, Professor of
Balneoclimatology of MFB.Since 1969 Medical
Officer Cardiovascular Diseases WHO, Geneva.
Srecko I. Nedeljkovic'(1923- ), internist, cardiolo-
gist. Director of Institute of CVD Belgrade,
Director of Cardiology in Internal Clinic B.
Professor of Internal Medicine and Cardiology
of MFB.Since 1986Chief Investigator of the
Serbian part of the SCS.Chief of Postgraduate
Cardiology 1980-1989.
Bo&dar Simic'(1920- ),medical doctor, nutrition-
ist. Head of Nutrition Department, Serbian
Institute of Hygiene of MFB.
138
Ljubica Bozinovic'(1924-),internist, cardiologist.
Chief of Coronary Care Unit 1970-1989 in
Internal Clinic B.Professor of Internal Medicine
and Cardiology of MFB.
Gradomir Stojanovic'(1929- ),internist, cardiolo-
gist. Chief of Third Cardiology Department and
Coronary Care Unit. Professor of Internal
Medicine and Cardiology of MFB.Chief of
Postgraduate Cardiology since 1989.
Vladimir Slavkovic'(1922- ), Professor of Internal
Medicine and Pulmology of MFB,Chief Editor
of Serbian Archive of Medicine.
V
Miodrag C.Ostojic' (1946-),internist, cardiologist.
Chief of Diagnostics Department on ICVD,
Belgrade. Associate Professor of Internal
Medicine and Cardiology of MFB.
Miodrag Z.Grujic'(1944- ),internist, cardiologist.
Chief of Arrhythmology Department on ICVD,
Belgrade. Associate Professor of Internal
Medicine and Cardiology of MFB.
Nikola M. Vojvodic"(1934-), Professor of Internal
Medicine of MFB.Director of Institute of
Gerontology and Home Care, Belgrade.
Publications
1. PlavsicC, Ilic'M, Nedeljkovic'S. Les mala-
dies des artères coronaires en Yougoslavie, Acta
Cardiologica, 1959;14(Suppl 8):79-86.
2. Djordjevic'BS, Nedeljkovic' S. Variabilité des
données electrocardiographiques dans trois
groupes epidemiologiques différants (Recherches
sur ['epidemiologie de la maladie coronaire).
Actualités Cardiologiques et Angeiologiques
Internationales 1965;14(4):281-286.
3. Djordjevic BS,Simic' B,Simic?A,Strasser T,
Josipovic'V,Macarol V, Klinc I,Nedeljkovic S,
Todorovic'P. Dietary studies in connection with
epidemiology of heart diseases: results in Serbia.
Voeding 1965;26:117-127.
4. Djordjevic' BS,Josipovic'V,Strasser T,
Nedeljkovic'S, Lambic'I,Balog B,Stojanovic G,
Macorol V,Simic'B,Simic A, Slavkovic'V,
Milutinovic"P, Klinc I,Jovanovic"M: Les premiers
résultats des recherches sur l'epidemiologie de la
maladies coronaire dans trois groupes différants
de population en Serbie. Actualités
Cardiologiques et Angeiologiques Internationales
1966;15(1):15-21.
5- Djordjevic' BS,Josipovic'V,Nedeljkovic' S,
Strasser T,Slavkovic?V,Simic"B,Keys A,
Blackburn H. Men irrVelika Krsna, A Serbian
Village. In: Epidemiological studies related to cor-
onary heart disease.Characteristics of men aged
40-59 in Seven Countries. Keys A,etal(Eds). Acta
Med Scand 1967;460(Suppl 180):267-277.
'• Nedeljkovic S, Djordjevic" BS,Stojanovic? G.
Ballistocardiographic findings in an epidemi-
ological study of cardiovascular diseases in
Yugoslavia. Ballistocardiography. Bibl Cardiol.
Krager, Basel 1968;21:16-20.
7 14. Kromhout D, Nedeljkovic? S,Grujic? MZ,
- Djordjevic"BS,Balog B,Bozmovic?Lj,
Josipovic'V, Nedeljkovic S,Lambic I,Sekulic'S,
Slavkovic V,Stojanovic'G, Simic'A,Simic'B,
Strasser T, Blackburn H, Keys A.Three cohorts of
men followed five years in Serbia. In: Coronary
heart disease in Seven Countries. Keys A (Ed).
Circulation 1970;41(Suppl 1):123-137.
'• Nedeljkovic'S, Djordjevic' BS,Stojanovic'G.
Follow u p ballistocardiographic findings in an
epidemiological study of cardiovascular diseases
ln
Yugoslavia. Ballistocardiography. Bibl Cardiol.
Krager, Basel 1973;31:237-244.
9. Vojvodic N, Nedeljkovic S, Demirovic'J,
Djordjevic BS,Josipovic V,Kozarevic'Dj,
Bozinovic'Lj,Stojanovic'G, Grujic M, Racic Z,
Ostojic M, Bo^njak N, Milosevic M. Leading caus-
es of mortality in middle-aged men: 15years fol-
low up of three population groups in Serbia. A
part of Seven Countries Study. CVD
Epidemiological Newsletter 1985;38:120-121.
10. Nedeljkovic S,Djordjevic BS,Josipovic V,
Bozinovic"Lj, Kozarevic"Dj, Demirovic"J, Vojvodic'
N, Simin N, Ostojic?M, Grujic? M, Milosevic'M.
Twenty year follow up of three population
groups in Serbia: re-examination of University
professors in Belgrade. A part of Seven Countries
Study. CVD Epidemiological Newsletter
1985;38:119-120.
11. Demirovic'J, Epstein F,Boduza B,Bothig S,
Eaker E,Gallacher J, Henry J,Johnston D, Kline P,
Kornitzer M, Marmot M, Mulcahy R, Nedeljkovic'
S,Orth Comer K, Patel C, Pyorälä K, Rywick S,
Sartorius N, Shkvatsabya I,Siegerst J,Theorell T,
Tiblin G, Weis M. Summary of the workshop on
psychosocial factors in coronary heart disease:
measurement, evaluation and intervention. Eur
Heart J 1988;9:687-689.
12. Nedeljkovic'S, Menotti A, Keys A, Ostojic
M,Grujic?M, Kromhout D,Stojanovic? G.
Coronary heart disease in three cohorts of men in
Serbia followed up for 25years as a part of Seven
Countries Study. Kardiologija 1992;13(l-2):35-44.
13. Nedeljkovic"S,Ostojic?M, Grujic? M,
Josipovic'V, Keys A, Menotti A,Seccareccia F,
Lanti M, Kromhout D.Coronary heart disease
deaths in 25years. The experience in three
Serbian cohorts of theSeven Countries Study.
Acta Cardiologica 1993;48(l):ll-24.
Ostojic MC, Keys A, Menotti A, Katan MB, Van
Oostrom MA, Bloemberg BPM.Changes in major
risk factors for cardiovascular diseases during 25
years in the Serbian cohorts of the Seven
Countries Study. Int JEpidemiol. Accepted.
139
 12
STUDIES IN RURAL JAPAN
H. Toshima

T h e story of theSevenCountries Study inJapan begins with the

lateProfessor Noburu Kimura,whodied of acuteleukemia in 1983.Only he could
provide details of thebeginning of theJapanese study cohorts.Therefore we will
citeashort essay that Professor Kimura wrotein 1971,describinghisclose friend-
ship with Dr.Keys.

My Friendship w i t h D r . Keys
'Itwas inthefall of 1954,or 18yearsagofrom now,when Ifirst met Professor
AncelKeys,who laterbecamealeading researcher of thewell-known epidemi-
ologicsurvey called 'SevenCountries Study'. Iwasinvited toasymposium of the
Second World CongressofCardiology,entitled Epidemiology of Atherosclerotic
Heart Disease.Inthe symposium, Iplanned topresent thepathological data of cor-
onary atherosclerosis of theJapanese,based onexamining 2000autopsied hearts
that had been stored in Kyushu University.Thedata were completed through the
efforts of themembers of thecardiology laboratory in theFirstDepartmentof
Internal Medicine,Kyushu University.
On theway toattend thecongress,Ivisited theUniversity of Minnesota,whereI
had stayed for 6months,2.5years earlier,toask myfriends therefor stylistic cor-
rection ofmy English presentation.They wereallelectrocardiologists, sotheyre-
commended that Iconsult with Professor Ancel Keyswhowasalsoan invited
speaker at thesamesymposium.Although hewasverybusy preparing for his own
presentation, hewas kind enough not only tocorrect my English but alsoto renew
myslides.Hiskindness greatly contributed tomyvery successful presentation in
theCongress.
In 1955, the following year, Ienjoyed thesecond meeting with Professor Keys,
when Iattended thefirst assembly of theExpertCommittee ofWHOin Geneva,
representingJapan.Thisreunion brought us theopportunity todiscussaplan for
°ur future collaborative study.Our idea camefrom theconsensus inthe previous
symposium that revealed much lessfrequency ofcoronary arteriosclerosis in

141
Japanese ascompared with U.S.Caucasians.Thedifference could offer akey to
understand underlying mechanisms for thedevelopment of atherosclerosis. Four
months later in March 1956,Professor Keysvisited Fukuoka, together with
Professor Paul D.Whiteand Professor Bronte-Stewart.Weextended our idea and
reached an agreement toconduct acollaborative study onJapanese men intheir for-
ties,including employees working in aShimecoalmine,farmers residing in village
of Koga,and medical doctors practicing inprivate clinicsin Fukuoka.
In thefollowing year, 1957,weparticipated in theinternational collaborative
surveysconducted insouthern Italyand Crete,Greece.Professor Keysand Iwere
assigned tocarry instruments for thesurvey,driving astation wagon from Rometo
Nicotera,which islocated inthe tipof theboot-shaped Italian Peninsula.On the
way,westayed one night inamotel,where wehad theunforgettable experienceof
beingthevictims ofarobbery.Wewerevery upset toseeall therecording papers
for theelectrocardiograms were stolen.
Weboth participated invarioussubsequent surveysin Italy,Yugoslavia,and so
on.Istillremember that wetook apleasant stroll inseveral townsconnected with
Baroque music,our common pastime,inVienneseand Cremona innorthern Italy
for afew days.Shortly afterwards Iwas hospitalized, and had asurprising visit
from Professor KeysinFukuoka toinquireabout my health after hearing a rumor
that Iwassuffering from lungcancer (which wasfortunately incorrect and proved to
belungabscess).And stilltoday wearepersonal friends and professional associates.'

The Period 1958-1976

Tanushimaru and Ushibuka men wereselected for theJapanesecohorts in the
SevenCountries Study for the following reasons:1thefirst criterion wasstabilityof
thepopulation that seemed important toassuresuccessof thelong-term follow-up;
2thesecond criterion was theavailability of localphysicians whounderstood the
importance of thestudy and werewilling tosupport it.Professor Kimura had aspe-
cialinterest at that timeinwhether dietary protein intakecorrelated with theinci-
denceof cerebrovascular attacks,particularly cerebral hemorrhage,and therefore
selected possiblecontrasting cohorts,Tanushimaru and Ushibuka. Tanushimaru
was afarming town,located in thesuburbs of Kurume,where the traditional
Japanese diet was maintained, with calorieintake largely depending on rice.Incon-
trast,Ushibuka wasafishing area,where fish protein intakewasvery high.Both
cohorts had localphysicians whowerehighly collaborative inthe study:Dr.Toshio
Onitsuka and Dr.Rokuroh Harada inTanushimaru, and Dr.Akinori Fukumoto in
Ushibuka.Thefirst fieldwork inTanushimaru wascarried out from March 18to
June 19,1958.Thisbegan shortly after Professor Kimura moved to Kurume
University SchoolofMedicineand established anew Third Departmentof

142
Mediane inJanuary, 1958.All 10staff members of thenew department (listed
below) madeextraordinary efforts inundertaking simultaneously duties in outpa-
tient clinics,in hospital wards and instudent education aswellas in the survey
fieldwork. They were Professor Noboru Kimura,Drs.Ichiro Furukawa, Hironori
Toshima,Shoji Nishimoto,YoshioNawata, Shigeru Soejima, Fuminobu Mori,
Shigeo Nakakura, Izumi Mori,and Syunichi Kodama.This fieldwork was support-
ed by great contributions of themembers of thecardiology laboratory (former chief,
Professor Kimura),theFirst Department of Medicine,Faculty ofMedicine, Kyushu
University; Drs.IkuroGoto,Hiroyuki Kimura,Tadashi Irie,AkiraSeki,Tsuyoshi
Murakami, EizaburoYamagata,YasuhikoOkamura, Hiroto Mashiba, Mikitoshi
Hiramatsu, and Toshiro Ohta.

For thefirst survey,682men,aged 40to64years,who were born and had lived

in theChikuyo area ofTanushimaru, wereinitially registered, while43men who
had been in foreign countries or inother placesofJapan for 10yearsor more were
excluded becauseof possible differences inlifestyle. Theinvitation was therefore
sent to639men,consistingof508men,aged 40-59,and 131men,aged 60-64.The
Japanese cohort thus included men over 60yearsinaddition tothestandard cohorts
of theSevenCountries Study, aged 40-59years.Theentry measurements made

Fieldwork in Tanushimaru, 1958

143
were:1 age,2occupation,3eating pattern (24-hour dietary recall) and salt intake
estimation (bytheamount of soupconsumed),4area of arable land and amount of
physical work,5family history,6previous illness,7drinking and smoking pattern,
8body size,9physical examination, 10 blood pressure, 11 electrocardiogram and
exercise stresstest by the Master's method' 12 serum cholesterol (Keys' method)
and serum lipoprotein (Swahn'smethod),and 13 chest X-ray (indirectly photo-
graphed on 35mm film).
Thefull survey clinicwassetup in roomsof the localelementary school.
Examinations were carried out indaytime for 441farmers (69.2%),and intheeve-
ning orweekend for office workers and industry employees.Participants who were
sick inbed orinhospital received visiting interviewers and examinations.The field-
work wascompleted with great collaboration of localdoctors.There was, however,
oneepisode in which homevisiting staff members wereattacked with a shower
from awater hosebyaparticipant with apsychiatric problem.The enthusiastic
efforts of allstaff and paramedical personnel,inaddition tothepowerful leadership
of Professor Kimura,finally enabled theunbelievable response rate in Tanushimaru
of100%!
Thefieldwork in Ushibuka started on May6,1960,inviting 614men,aged 40-64
years.Ushibuka islocated on theisland sideof Minamata Bay(later famous for
organic mercury poisoning,known asMinamata disease),and themajority of par-
ticipantswere fishermen. Sincethere was afive-hour drive from Kurume to
Ushibuka, fieldwork required two rounds of examination periods;thefirst round
was from May6to 14,and thesecond from June4to 12,1960,with 6medical and
3-4paramedical staff residing inatraditionalJapanese inn.Thevery high response
rate (99.6%)again largely depended on thegreat efforts of thestaff and devotionof
thelocaldoctor, thelateDr.Terunori Fukumoto.Theexpense of thefieldwork was
made possiblebyrelatively lowpricesand cheap labor in theJapan of that time.
Theinitial survey wassucceeded bysystematic follow-up surveys of the cohorts
on incidenceand death rate for cardiovascular diseases in 1961(third year),in1965
(seventh year)and in 1968(10thyear) inTanushimaru; and in 1963(third year),in
1965(fifth year) and 1970(10th year) inUshibuka. Inthe 10-year follow-up exam-
ination (1968)thefieldwork was repeated with a larger number of measurements,
including:the Rosequestionnaire,a pulmonary function test,opticfundi examina-
tion,vectorcardiography, serum proteins and fractions, and triglycerides. Among
these,opticfundi and serum protein wereincluded toinvestigate thesignificance of

The step stress test with double Master's method was included by Professor Kimura.W e fortunately experi-
enced no accident with the exercise test inthe fieldwork, andthis wasattributed to avery low frequency of
coronary artery disease amongJapaneseinthe 1950s.The exercise step test, single stage,with an intensity
approximately 6-7 Mets,may today carry increasedrisk ofaccident ifperformed ina population survey in Japan,
due to agrowingfrequency of coronary artery disease.

144
 HenryBlackburn andJapanese doctorsontheboat
to Ushibuka, fieldwork 1970.

theseasrisk factors for cerebrovascular diseases,cerebral hemorrhage,in particular,

which was frequent amongJapanese inthe 1960s.Vectorcardiography wasintro-
duced for clinicalinvestigation.Thischaracterized our approach,conducted mainly
by clinical cardiologists,in contrast tocohortsdirected bypublichealth scientists.
Theadditional measurements later provided theinteresting finding ofan inverse
correlation between stroke incidence and entry serum albumin concentration.
Bicycleergometer stress testswereperformed insubgroups ofTanushimaru men in
the 1968examination by Dr.Herman Wolf,with thekind collaboration of Professor
Pentti Rautaharju from Canada.

The Period 1977-1992

InMarch 1977,when Professor Noboru Kimura resigned from Kurume University
School of Medicine,heestablished the Kimura Memorial Heart Foundation, donat-
ing toithisretirement fund, and calling for support from medical and pharmaceuti-
calindustries.Thepurpose ofthefoundation reflected hisviews,achieved through
life-long research and clinicalcareer,that: 'Medical scientistshavecontributed to
progressive advances in therapeutic medicine,although stillincomplete. However,
the real taskof medical scientists must bedirected not only tofactors acting nega-
tively against health but alsotofactors positively promoting health asa gatekeeper
of healthy life.' Inorder toachievethisgoal,thefoundation aims tosupport preven-
tivemedicine for cardio-cerebrovascular diseases and broad educational activities
tospread knowledge of primary prevention tothegeneral public.
Dr.Hironori Toshima M.D.succeeded Professor Kimura asprincipal investiga-
torof theJapanese cohortsinApril 1977.Celebrating thefounding of the Kimura
Memorial Heart Foundation, Professor Toshima started anew survey in
Tanushimaru inthespring of 1977.Thestudy wasdesigned toexaminetime trends
incardiovascular diseasesand in their risk factors, sinceJapanese traditional life-
stylehad made remarkable evolutionary changesduring the20yearssincethe first

145
survey in 1958.Thenewly selected cohort consisted of590malefarmers, aged 40to
64years,across-sectional sample,including somewho participated in thefirst sur-
vey in 1958.Of these,573participants completed theexamination with a response
rate of90.1%.In 1982,fiveyearslater,when asystematic follow-up was conducted,
thecohort was extended towomen and widened inagerange,inviting men and
women aged 20to69years.Thenumber of measurements alsoincreased, including
HDL-cholesterol,hematocrit, creatinine,GOT,GPT,r-GTPetc.On theother hand,
nosystematic population survey hasbeen carried out inUshibuka since 1970,
becauseincidenceand death rate thereshowed nodifference from those in
Tanushimaru orfrom statisticsderived from other population studiesinJapan.
Also,thelongdistance from Kurumerequired much higher costs.However, yearly
follow-up onmorbidity and mortality intheinitialUshibuka cohort hasbeen regu-
larlycontinued by physicians sent from Kurume University Hospital to the
Fukumoto Hospital in Ushibuka.
In 1989,30years after thefirst survey,when further changes inJapanese lifestyle
and environmental factors had occurred,an additional population survey was
designed, invitingall inhabitants aged 40yearsor morelivingin thesame region in
Tanushimaru asthe first cohort in 1958.Tosurvey 752maleand 707female partici-
pants,thefieldwork wascarried out from June 19toJuly 12,1989,with a response
rateof 89%in men and 70%inwomen.The 1989survey added measurements of:
1HbAle,toassessthefrequency ofdiabetes,2serum apoproteins,and 324-hours
physical activity recording for estimation ofaveragedaily energy expenditure,
among asample of 272men farmers aged 40to69.
Dietary surveys wereperformed by the24-hour recallmethod sincethe first
study in 1958.Chemical analyseswerecarried out of duplicates of meals,ascon-
sumed byrandomly selected individual men during aseven-day period in 1964and
athree-day period in1984.
Sincethestart of thefieldwork in 1958morethan 100physicians from theThird
Department of Medicine,Kurume University SchoolofMedicinecontributed to the
surveys,but alltheirnames,unfortunately, cannot belisted.Major staff who con-
ducted theseinvestigationsunder theleadership of Professors Kimura and Toshima
were:Drs.YuhkiNakayama (1965-1970),HiromiTashiro (1970-1985),and Ryuichi
Hashimoto (1985tothepresent).

Results of the Analyses carried out since 1977

Changes incardiovascularriskfactors in Tanushimaru.

Thefrequency ofobesepersonswith aBodyMassIndexexceeding26was8%in
1958,and gradually increased to 11% in 1977,and to 18%in 1982. Thisincrease con-

146
tinues inthelatest survey and ishighest inthoseaged 40yearsand older.The aver-
ageof thesum of subscapular and triceps skinfold alsoincreased from 15-17mm in
1958to40mm in 1989,showing remarkable anthropometric changes.The frequency
ofdiastolichypertension (diastolic pressure >95mmHg) gradually increased up to
20%in 1982,in parallel with theincreaseinobesity.Subsequently, however, a trend
downward wasobserved, inpart due toan 8%increasein thoseunder anti-hyper-
tensive medication.
Average serum cholesterol level(Anderson-Keys method) inmen of the original
cohort,aged 40-64,was 150141mg/dl at entry (1958)and remained unchanged
during 10yearsoffollow-up (149±30mg/dl in 1968). Theaveragecholesterol levels
(enzymaticmethod) in thesubsequent new cohorts aged 40-64increased rapidly to
161±32mg/dl in 1977,to 178±32mg/dl in 1982,and to 188+37mg/dl in 1989.The
increase wasgreatest in theagegroup40-44years.Thesechanges in Body Mass
Index,sum ofskinfolds,diastolicblood pressure,and serum cholesterol wereattrib-
uted in part toadeclineof physical labor,and widespread useofcarsand automat-
ed farming machines.Theshift away from thetraditionalJapanesediet could also
acceleratethesechanges.

Changesindietarypattern in Tanushimaru.
Theanalysisof data obtained by24-hour dietary recallshowed that total caloric
intakewashighest,2,837Kcal/day, in 1958, presumably due toregular strenuous
Physicallabor.Thetotal caloricintakedecreased to2,000-2,200 Kcalin 1968,and
then remained level,afinding consistent with theaverageintakederived from the
Japanesenational survey.Thenutrient pattern alsochanged considerably.
Carbohydrate, in percent ofcalories,markedly decreased from 78.1% in 1958to
60.6%in 1989. Thisdecrease contrasted with remarkable increases inprotein intake
from 10.9%to 15.6%and fat intakefrom 10%to21.6%.

Comparison of10-yearmortalityand incidence rates ofstrokeandmyocardial infarction in

Tanushimaru (1958-1968and 1977-1987).
The 10-yearmortality and incidenceratesfor strokeand myocardial infarction were
compared between cohort 1(participants in 1958)and cohort 2(participants in1977)
ln
Tanushimaru. Theage-adjusted death ratefrom all-causesdeclined tohalf, from
15
-2/l,000/year incohort 1to7.3/1,000/year incohort 2.Among these,therewasa
dramatic reduction of strokemortality from 3.8/1,000/year incohort 1to
0-3/1,000/year incohort 2.Death ratesfrom infectious diseases including tubercu-
losisand pneumonia, or thosefrom other causes,alsoshowed a considerable
declinefrom 6.6/1,000/year incohort 1 to1.8/1,000/yearincohort2.On the other
hand,death rates from cancer,myocardial infarction orsudden death showed no
significant change.Inanalysisof incidencerates,a50%reduction of stroke

147
occurred, while therewas noappreciable trend in theincidenceof myocardial
infarction: 0.6/1,000/year incohort 1 and 0.9/1,000/year incohort2.

Epilogue
Asobserved inTanushimaru, there hasbeen aremarkable reduction in stroke
deaths(cerebral hemorrhage inparticular) inJapan,whilemortality from myocar-
dialinfarction isstillvery low.Thereseems littledoubt that thesetrends incardio-
vascular diseasemortality havebeen due tosocio-economic development of this
country.Thedeficient food supply before 1960isnow converted toexcess.
Strenuous physical laborisnowreplaced byautomated farming machinesand cars,
leading toan increasein theobesepopulation due tolackof physical activity.
Nevertheless,Japanesecurrently enjoy thegreatest longevity intheworld, with
onlyaminimalincrease,sofar, incoronary heart diseasedeaths.Thelessons from
theSevenCountries Study suggest that thislongevity maybeattributed tothe tra-
ditional eating pattern ofJapanese,which depends on riceasthemajor sourceof
energy and effectively limitsthefat intakeat 25%.Weconclude from the Seven
Countries Study that thecurrentJapanese diet maybeoptimal toprevent coronary
artery diseaseand stroke,but careful surveillance isneeded due tothe increasing
intakeof saturated fatty acids.

148
Publications
I• Kimura N,MoriF.Ahintoncholesterol
determination ofsurvey for cardiovascular epi-
demiology.JpnCircJ1963;27:392.
2« Kimura N.Afarming and fishing villagein
Japan.Tanushimaru and Ushibuka.In:
Epidemiological studies related tocoronary heart
disease:characteristics ofmenaged 40-59inseven
countries.KeysA,etal(Eds).Acta Med Scand
l%7;460(Suppl):231.
3. Kimura N,KeysA.RuralSouthern Japan.
In:Coronary heartdiseaseinseven countries.
KeysA(Ed).Circulation 1970;41(Suppl1V.101.
*• KeysA,Kimura N.Dietsof middle-aged
farmers inJapan.AmJClin Nutr 1970; 23:212.
'• Kimura N,Nakayama N.Natural historyof
heart diseasefrom epidemiological investigation.
JpnCircJ1972;36:ll.
"• Kimura N,Toshima H,NakayamaY,
MizuguchiT,Takayama K,Yoshinaga M,Fukami
T.TashiroH,Katayama F,AbeK,ArimaT,
Yokota Y,Minagawa E,Tanaka R,AkiyoshiT,
Soejima K,Yamada K,MizunoeA,Nakamura K,
Oshima F,Tanaka K,Akusu K,NiizakiT,Ikeda
H,NakamichiE,Ageta M,MiikeY,InoueT,
NakagawaT,Nanbu S,Tanioka T,ShimadaS,
FukumotoT.Population survey on cerebrovascu-
larand cardiovascular disease.The 10yearsexpe-
rienceinthefarming villageofTanushimaru and
thefishing villageofUshibuka.Jpn HeartJ
W2;13:119.
'• Kimura N,Toshimà H,NakayamaY,
MizuguchiT,Takayama K,Yoshinaga M,Fukami
T
»TashiroH,Katayama F,AbeK,ArimaT,
Yokota Y,Minagawa E,Tanaka R,AkiyoshiT,
Soejima K,Yamada K,MizunoeA,Nakamura K,
°shima F,Tanaka K,Akusu K,NiizakiT,Ikeda
H,Nakamichi E,Ageta M,MiikeY,InoueT,
Nakagawa T,Nanbu S,TaniokaT,ShimadaS,
FukumotoT.Epidemiological studyoncerebro-
an
d cardiovascular disease inTanushimaru and
Ushibuka.JpnJMed1972;11:62.
Kimura N.Apopulation surveyoncerebro-
Va
scularand cardiovascular diseases in Kyushu
Japan.SingMedJ1973;14:230.
9. Kimura N,Nakayama Y,Nanbu S,Gohda
H.Prevalenceofplasma lipoprotein abnormalities
inthefarming villageofTanushimaru and fishing
villageofUshibuka. Fromthe epidemiological
aspects.JpnCircJ1975;39:299.
10. Shigiya R,Kimura N,KomachiY,Isomura
K,Kojima S,WatanabeT.Physiological adaptabil-
ityand nutritional statusof theJapanese:
Ecologicalbackground forCVAand CHDin
Japan.Human Adaptability 1975;3:127.
11. Kimura N,Nakayama Y.Physiological
adaptabilityand nutritionalstatusof the
Japanese:population survey inrural Kyusyu,
Japan.Human Adaptability1975;3:165.
12. Kimura N,Toshima H,Nanbu S,Tanaka K,
Ooshima F,Gohda H,Ageta M,KogaY,IshidaS.
Relationof lipoprotein metabolism todevelop-
ment of ischemicheart diseaseinJapan.JpnJMed
1975;14:42.
13. Kimura N,Nakayama Y,TashiroH.The15
year follow-up population surveyoncerebrovas-
culardiseaseinrural Kyushu,Japan.JpnJMed
1977;16(2)142-144.
14. Kimura N.Study of theprevention ofmyo-
cardial infarctions (1976PrizeoftheJapan
Medical AssociationClinicalSection).AsianMed
J1977;20(5)269-285.
15. Kimura N.Atherosclerosis inJapan.
Epidemiology.Atherosclerosis Rev1977;2:209-
221.
16. Kimura N.Epidemiological studies inJapan
onsmokingand cardiovascular disease.Volume2
of theproceeding of the3rd World Conference on
smoking and health (USA)Department of Health,
Education,and Welfare. DHEWPublication no
(NIH)1977;77-1413:185-198.
17. TakagiM.Serum uricacid asarisk factor
for strokeinafishing villageofrural Southern
Japan.JapCircJ1982;46(2):131-136.
18. TashiroH.Nanbu S,TakagiM,Hori H,
SumieM,TsuikiT,UekiK,Furuta Y,Nagata H,
KitanoT,Hiyamuta K,Kinoshita E,YamashitaY,
Hamamura Y,KumagaiE,SakaiS,SenouT,
Toshima H.Changesintheprevalenceof hyper-
tension and obesity inarural area ofJapan.
KurumeMedJ1983;30(2):57-99.
149
 19. Toshima H,TashiroH,SumieM,KogaY,
Kimura N.Changesinrisk factors and cardiovas-
cularmortality and morbidity within
Tanushimaru 1958-1982.In:Nutritional preven-
tion ofcardiovascular disease.LovenbergE,
YamoriY (Eds).AcademicPress,Orlando.
1984:203-210.

150
 13
DIETARY SURVEYS I N
THE SEVEN COUNTRIES STUDY
F. Fidanza and D. Kromhout

rrom thebeginning of theSevenCountries research program, diet

wasthought tobean important determinant ofcoronary heart disease.Already in
the 1950sitwas suggested that differences indietary fat could explain differences in
mortalityfrom coronary heartdisease,with serum cholesterol asan intermediate.
Dietary intervention studiesshowed that manipulation of theamount and kindof
fat influenced predictably thecholesterol concentration in theblood.Itwas there-
fore decided that thecollection of dietary data should beapart of theSeven
CountriesStudy. Intotal,12,763middle-aged men wereenrolled inthestudy. With
thelaborious dietary survey method commonly used at that time,the seven-day
record method, itwas impossible tosurveyallmen.Therefore, subsamples were
selected for detailed dietary surveys.

Dietary Survey Methods (F. Fidanza)

When Iwas inMinnesota in 1953,Sadye F. Andelson (USDA-Washington) was car-
ryingout adietary survey on Minnesota businessand professional men participat-
inginalong-term study ofagingconducted bytheLaboratory of Physiological
Hygieneof theUniversity ofMinnesota.Therecord-by-weight, or food record
method,was used for twoconsecutive weeks.Itwasauseful experience to spend
timewith her and the five nutritionists orhomeeconomistsinvolved inthat study.
Thesame forms, with minor modifications, were then used indietary surveys in
Naples.
InFinland,theweighing method for dietary surveyswas incommon use,
including the 1956-57studiesonfood consumption of rural families inEast and
WestFinland. Iparticipated in thediet-serum cholesterol studiesin Finland and
had theopportunity tovisit Paavo Roineand Maija Pekkarinen attheold building
oftheDepartment of Nutritional Chemistry of theUniversity ofHelsinki,Viiki,
Helsinki.Theyexplained ingreat detail themethods theyused, later sending me
theforms translated into English.

151
 Iquotea paragraph from anunpublished document by PaavoRoine:'The diet-
ary surveysin Finland,Greece,Italy,and Yugoslavia werecarried out by the weigh-
ingmethod, sinceitwasconsidered in theprevailing conditions togivethe most
accurateand reliabledata on thequality and quantity of the food consumed, and
particularly on theconsumption oftheindividual men surveyed.Sincetheweigh-
ingwasdone byoutside investigators,the families could bechosen by random
sampling.Accurate information wasthus alsoobtained on thefood consumption of
such families and/or individuals who would not havebeen abletoestimate reliably
or tokeep recordsor their own food consumption. Itisalsotobenoted that the
weighing method provides data ontheamount offood actually eatenby the people
becausealltheinediblematerial, thetablewasteand theleft-over food are carefully
weighed.' IntheSevenCountries Study,after considering thelimitations of this
method and providing detailson theprocedure,chemicalanalysison a subsample
of food composites was recommended tocheck resultsobtained bycalculation, and
especially todetermine theintakeof fatty acids.
Inthethreeareasof Italy weused thismethod and procedure.Thesurvey was
carried out bynursesof theItalian Ministry of Health (Maria Giulivi Pessoli,Alba
Donnini,Dianora Mengoni,Emma Montevecchi,and Maria Organo).They were
trained in nutrition and dietary surveysand involved ina pilot study in
Montegiorgio in November 1959. Thesurvey wascarried out in threedifferent sea-
sonsof theyear 1960,and inJanuary 1961,on99families.
Thenurses did awonderful joband left anexcellent impression on the surveyed
families, which was very helpful for future work. InNicotera,in thesouth, the
selected group of30subjects was reduced to24becauseonenurse fell sick.Then,
seven subjects refused tocooperate with thesecond season survey and were substi-
tuted by 13new subjects with similar characteristics.Thefinal result was that 17
subjects wereexamined inallthreeseason surveys.Theanalysisof variance
showed no statistical difference between the 17and 7subjects in thefirst survey.
Even asubsample of 1%canberepresentative ifthepopulation has relatively
homogeneous habits.Thecomputation ofdietary data of 1,251 subjects for seven
dayswould taketoomuch time,considering thesimple,slowand 'noisy7 calcula-
torsavailableat that time.
Forthe subsample of Romerailroad men,theseven-day food diary method was
used inJune-July 1969becausewe had gained experience with thismethod and it
wasmorepractical for that particular group of subjects.
InCretethedietary survey wascarried out by Helen Sdrin (teacher at theSchool
of Home Economics inAthens) and herstaff.Iwasinvolved in thepreparationof
food composite samples in theheadquarters inthekitchen of Herakleion Hospital.
Thecook,GeorgeArniotakis,was very helpful ingrinding thefood composite with
a largevegetable grinder, thefood having arrived theeveningbefore in covered

152
Preparation of aliquots of foods at the market of Zrenjanin, 1963.

enamel jars.Becausesome subjects consumed pomegranates, itwas aproblem to

grind theseeds,solved by pounding theseedsinamortar. During thiswork, the
subjects, mostly farmers, speaking Venetian-Italian fluently, told methat their
breakfast early in themorning was aglassof oliveoil!Georgewas formerly acook
forKing Farouk; webecame friends and at theend of thework hecooked an excel-
lent 'stiffado' (ragout ofbeef with bigonions cooked for several hours) for us.
Iwasalso involved inYugoslavia inpreparation and analysis of food compos-
ites.Ratko Buzina's associates,BrankaTiefenbach (called Seka)and Agneza Horvat
from the Institute of Public Health of Zagreb,were helpful; Seka had worked with
meinNaples for atimesothat comparable results were obtained.
Inorder toplan thepresentation ofresultsondietary surveysat theSixth
International Congress of Nutrition in Edinburgh on August 1963,1 organized a
meetingin Milan from February 10to 13,1963.Intheprovisional program for the
Congress Isuggested the following speakers:Paavo Roine(methods of dietary sur-
veysin Finland,Greece,Italy,and Yugoslavia),Maija Pekkarinen (resultsof dietary
surveys in Finland),DemetriosGalanos (results ofdietary surveys inGreece),
myself (results of dietary surveys in Italy),Ratko Buzina (results ofdietary surveys
mYugoslavia),and Cornelis (Kees)den Hartog (methodsand resultsofdietary sur-
veysin theNetherlands). Atthemeeting, held atthe Board Room of the Laboratório
BiologicoZanoni,Keesden Hartog, Paavo Roine,and myself werepresent fora
fruitful discussion and a pleasant time.Wedecided topresent theavailable results

153
on dietary surveysin asession of theInternational Congress ofNutrition in
Edinburgh and topublish allpapers in theNetherlandsJournal of Nutrition,
'Voeding'.Inaddition, Den Hartog suggested collecting all thesepapers inabook-
let,nowthefamous so-called 'Red Book':DietarySurveysand Epidemiologyof
Heart Disease (1). Thisbookbecameastandard research reference in nutritional
epidemiology.Themost rewarding result of theMilanmeeting was my good
friendship with Keesden Hartog that lasted until hedied recently.
Theweekbefore theInternational Congress ofNutrition inEdinburgh,John
Durnin organized,in Glasgow,aWorkshop on DietarySurveys Methodology.I
presented apaper on 'DietMethodology-EpidemiologicalAspects',considering the
advantages and disadvantages of themethods used.Theodora van Schaik illustrat-
ed thedietary history method alsoused inZutphen (TheNetherlands) in1960.
During free timeattheGlasgow University Guest Houseshedefended the dietary
history method and Idefended theweighing method. Ihave not changed my posi-
tion,but inthefirst follow-up in 1965of thetworural Italiancohorts (Crevalcore
and Montegiorgio) wealsoused thedietary history method on the 1,536 subjects
examined. Retrospectively thiswas afortunate decision,becausewefound nodif-
ference between the twomethods in regard tomean population food and nutrient
intake.Moreover,with thedietary history method,awider scopeof dietary data is
possible.Accordingly, in thesubsequent follow-ups of theItalian rural cohorts,
both methods were used.

Processing and Chemical Analysis of Cross-cultural Food Intake Data

(D. Kromhout)
Fourteen ofthesixteendietary surveysinsubsamplesof theSeven Countries
cohorts took placebetween 1959and 1964.Twosurveys,RomeRailroad and
Ushibuka (Japan),were held later,around 1970. Theseven-day food record was
used in 14of the 16cohorts,whileone-day records wereused intheU.S.Railroad
and four-day recordsinUshibuka. Participants recorded what they ateand drank
during theperiod and theamounts consumed wereweighed aswell.In13ofthe16
surveys,foods wererecorded astheedible part of theraw products and,in3of the
16,asprepared products.Tocompare thedifferent cohorts,allquantities of thepre-
pared products wereconverted intoquantities of raw products ina standardized
way.Thiswas donebyonedietitian in 1985and 1986,AnnemarieJansen from the
Netherlands,inclosecollaboration with investigators from thedifferent countries.
Allfoods consumed bymeninthedifferent cohortswereclassified in 15homo-
geneous food groups.The16thgroup was heterogeneous.Theaverage consump-
tionof these 16food groups wascalculated,per person,per day,for each cohort,
and theresults published (2).Characteristic differences in food consumption pat-

154
terns in the different countries had been observed in the 1960s. In Finland, the
intake of milk, potatoes, edible fats, and sugar products was very high. A similar
but lower intake pattern was observed in the Netherlands. Fruit, meat, and pastry
consumption was high in the United States;cereal and alcohol consumption were
high in Italy; and bread consumption was high in Croatia and Serbia, except for
those in Belgrade. In Greece, the intake of olive oil and fruit was high while the
Japanese cohorts were characterized by a high consumption of fish, rice,and soy
products.
Food tables with detailed information on the fatty acid composition of foods in
the seven countries were lacking in the 1960s.Therefore the fatty acid composition
of food composites was determined for 13of the 16cohorts. These analyses were
carried out by Dr.Joseph T. Anderson at the Laboratory of Physiological Hygiene,
University of Minnesota and Flaminio Fidanza at the Human Physiology Institute,
University of Naples (Italy). The results showed a sevenfold difference in saturated
fatty acid intake between eastern Finland and Japan (3). Later, however, the interest
of the investigators became broader than for fatty acids. Therefore, it was decided in
1987to attempt to construct, retrospectively, composites representing the average
food intake of the 16cohorts during thebaselinesurvey. These equivalent composites
were purchased from local markets by two Dutch dietitians, Annemarie Jansen and
Ester Goddijn, in close collaboration with the local investigators. The foods were
transported in coolers to the laboratory of the Department of Human Nutrition,
Agricultural University, Wageningen, the Netherlands (Martijn B.Katan, Ph.D.).
There the foods were cleaned and equivalent composites prepared according to the
average consumption patterns of the cohorts. The foods were homogenized and fro-
zen at -20°C until chemical analysis of the different nutrients took place. The chemi-
cal analyses were carried out in 1987and 1988,the macronutrients and minerals
determined at the Department of Human Nutrition; the vitamins and trace elements
and non-nutritive substances at the Department of Micronutrients and Natural
Toxins, DLO, State Institute for Quality Control of Agricultural Products,

Unpacking of foods sent to the central laboratory in

Wageningen, The Netherlands, 1987

155
Wageningen, (Ir.PeterC.H.Hollman),and traceelementsat theLaboratoryof
Analytical Residue Research,National Institute ofPublicHealth and Environmental
Protection, Bilthoven(Huub Vaessen Ph.D.).Thesedata willbeused toanalyze,at
thepopulation or cohort level,relationsbetween habitual nutrient intakeat baseline
and 25-year mortality ratesfrom chronicdiseases.

Individual Dietary Data in Netherlands, Italy, and Finland

AllmeninZutphen (Netherlands) weresurveyed with thedietary history method
in I960,1965,and 1970. Thismethod wasalsoused in Crevalcoreand Montegiorgio
(Italy)in 1965and again inCrevalcore in 1970.In 1969Finnish colleagues also
decided tousethedietary history in the third round of theEast-West Study.
Therefore aunique data setcould beconstructed with dietary information collected
with thesamemethod inabout 3000men in threedifferent cultures.Ittook about20
years,however,before thesedata becameavailable foranalysis,due tothedevelop-
ment of modern computers.
In 1987Daan Kromhout,Alessandro Menotti,Leena Räsänen,and Maija
Pekkarinen decided tocodethesedata inauniform way.Food groups were com-
posed and computerized food tables,containing thefoods used in the 1960sand
their nutrient content,wereprepared for thethreecountries.Adata baseis current-
lyavailable containing 33food groups and 24nutrients.Thiswillbeused to study
diet -disease relations on theindividual levelin thesefive cohorts.Thedietary data
collected between 1960and 1970can thenberelated tomortality from different dis-
easesduring 15-25years of follow-up. Thegreatadvantage of thisdata baseisthe
largevariation indietary patterns,among which itwillbeeasier tofind associations
between dietary variablesand diseaseoutcomes than among homogeneous popula-
tionswithin a country.
Becauseof theavailability of individual dietarydata collected in theperiod 1960-
1970,itwasdecided togather information with thesamemethodology in the30-
year follow-up surveys.Thiswillmakeitpossibletostudy changes indietary pat-
terns intheaging cohortin different European cultures.In 1989,for example,aran-
dom samplewas surveyed of227of the524men whowerestillalivein Finland.In
1990,560men were surveyed in theNetherlands and in 1991,421men inItaly.
Thesedata willbeused todescribedifferences and changes indietary patterns and
nutrient intakeinmenaged 70-90,and toexaminecross-sectional associations
between diet and health.Later,thesedata willbeused tostudy associations pros-
pectively at theindividual and population level.

156
Publications

I• DenHartogC,Buzina R,Fidanza F,KeysA, 3. KeysA.Thediet.In:Coronary heart disease

RoineP.Dietary studiesand epidemiology of insevencountries.KeysA(Ed).Circulation
heart diseases.Stichting tot wetenschappelijke 1970;41(Suppl1):162-183.
Voorlichting opVoedingsgebied, TheHague,The
Netherlands 1968:1-157.

2. Kromhout D,KeysA,AravanisC,BuzinaR,
Fidanza F,GiampaoliS,Jansen A,MenottiA,
Nedeljkovic S,Pekkarinen M,SimicBS,Toshima
H.Food consumption patterns inthenineteen six-
tiesinSevenCountries.AmJClin Nutr
1989;49:889-894.

IS7
 14
MAJOR RESULTS OF
THE SEVEN COUNTRIES STUDY
H. Blackburn and A. Menotti

D e m o n s t r a t i o n of Feasibility
Prior totheSevenCountries Study (SCS)noonehad attempted tocompare cardio-
vascular disease (CVD)frequency and riskbetween defined populations ina
systematic manner.TheSCSdemonstrated that with goodwill,planning,and hard
work,leadership and collaboration could befound, funding obtained, and research
carried out,despite many difficulties.

P o p u l a t i o n D i f f e r e n c e s : Cross-sectional
TheSCSwas thefirst toestablish credibledata onCVDprevalence rates in contrast-
ingpopulations,with differences found on theorder of five to 10fold in coronary
heartdisease (CHD).TheSCSwasthefirst todocument population differences in
themeans and distributions ofserum cholesterol,with thedramaticexample of the
almost non-overlapping valuesbetween men of thesameageinJapan and eastern
Finland ofthe 1960s.TheSCSdemonstrated remarkabledifferences in composition
ofdiet inotherwise similar rural,stable,agricultural-pastoral populations: between
3and 22%for saturated fatty acid caloriesdaily and 9to407ctotal fat calories.
Detailed,deciled distributions werereported for thefirst timeof skinfolds;
height,weight and relativebody weight;systolic and diastolicblood pressure, and
serum cholesterol for allareas ofallseven countries.
Theconcentration ofblood serum cholesterol atentry showed greater differ-
encesamong the 16cohorts than any other risk factor. Themean ranged from 160
rng/dl orlessinSerbia andJapan,to260mg/dl in Finland.Therewasalow order
individual correlation of serum cholesterol with age,blood pressure,and body
massindex.
Entry surveys found lackof individual correlation between electrocardiologic
findings of left axisdeviation and major riskcharacteristics,and strong correlations
between:high amplitude Rwaveson ECGand systolicblood pressure; negative
T-wavesand systolicblood pressure;post exerciseSTdepression and sum of skin-

IS9
folds and systolicblood pressure.Therewere negativeassociations ofexerciseST
changesand cigarettesmoking;strong positive associations of left ventricular
hypertrophy and heavy work;and strong relationships of infarct Qwaves to serum
cholesterol and systolicblood pressure.

Population Differences: Follow-up

TheSCSwas thefirst toestablish credibledata onCVDincidencerates in contrast-
ingpopulations,withdifferences on theorder ofsixtoeightfold inCHD.The5-year
follow-up found favorable all-causedeath ratesinGreece,Japan,and Italy com-
pared withthe other areas,aswellasalower incidencerateofcoronary disease and
new electrocardiographic findings inthoseareas.
Aremarkable excesswas found of5-yeardeathsamong thosewith an old infarc-
tion,intheorder of 10-to 20-fold.
Ecologiecorrelation wasweak between CHD incidenceand theproportion of the
population sedentary, overweight, orobese,orwith elevated systolic pressure>160
mmHg.Diastolicpressure >95showed, however, astrong relationship with CHD.
Thestrongest consistent relationship wasbetween thepopulation prevalenceof
entry serum cholesterol valuesgreater than 250mg/dl and CHD incidence.There
was alsoastrong correlation ofCHD incidence with saturated fatty acid intake at
entry.
LowCHDratesinacohort werenot compensated byan excessof other death
causes.Total,all-causesdeath ratereflected well thedeath ratesfrom CHD.
Therewasan indication overall of theimportance ofblood pressure and serum
cholesterol inindividual prediction of 'hard criteria' ofcoronary death and infarc-
tion,alackof significance ofbody weight,significance of smoking habits inU.S.but
not inEuropean cohorts,and weak relationships ofCHDwith physical activity.
Inthe 10-yearfollow-up experience,among the 12,000-mancohort free of CVD
atentry, the 10-year totaldeath ratewas lessthan 75/10,000 inCrete,Japan, and
Croatia and was250or greater for Finland,U.S.Railroad,Zutphen,and Serbia.
Correlation ofCHDdeath ratesinSevenCountries cohorts withWHOvital sta-
tisticson coronary deaths was 0.98;for all-causesdeath rates thecorrelation was
0.86,indicating thatSCScohort data havegeneralizability toregional and national
experience.
Ahigher death rate from neoplasms innorthern Europeans wasdue toathree-
fold excessof lung cancer.
Itwas found that agestandardization bysingleyearsofageisrequired inanalysis,
due tothestrong influence ofageon incidenceofCHD.Forexample,the difference
of oneyearofagein 10-yearCHDincidencewas5to6%.
Theindividual correlation ofagewithmajor riskfactors wastrivial,butage was

160
thestrongest risk predictor for CHDincidenceand death from all-causes. However,
despite thegreat difference inCHDrates,theforce ofageitself,in regard to the
incidenceof hard CHD,was similarbetween northern and southern Europe.
Inallareas,men in thetop20%of theage-specific distribution ofblood pressure
atentry had twicetheincidenceofCHD,and thiswassimilar for all areas.
All-causesdeath rateswereonly slightly correlated with average serum choles-
terol level,while therewasahighly significant correlation ofcholesterol level with
10-yearCHDdeaths and anegative correlation with allcausesof death other than
CHDcombined.Thus,theSCSwasoneof thefirst studies todemonstrate the
inverserelationshipbetween serum cholesterol level and non-cardiovascular dis-
easerisk.
Serum cholesterol concentration wasa particularly important individal risk fac-
tor for CHDat levels greater than 220mg/dl, while atlessthan 200mg/dl, decreas-
ingcholesterol concentrations tended tobeassociated with increasing ratesof non-
coronary death.
Strongprognostic power was found of theECG,particularly for ischemic and
junctional typeSTdepression after exercise,for negativeTwavesindependent ofST
depression, and for post-exercisearrhythmias.Theprognostic importance was
shown of major Qand QSwaves,and of negativeTwaves and atrial fibrillation.
Aremarkable finding was that in Italy,Greece,andJapan cigarettesmoking was
aminor risk factor for all-causesand CHDdeaths,in part due tofew CHDevents.
Intheother cohorts therewasastrong individual relationship ofsmoking tocoron-
aryand non-coronary causesofdeath,and theriskofcancerroselinearly withcig-
arette smokingdose.

Weight and Physical Activity

Cohort differences in 10-yearCHDdeath rateswerenot significantly related to
averagerelativeweight orobesity.Within noneof theareaswas relative overweight
orobesity associated with excessriskof all-causesdeath.Infact, total deaths were
inverselyrelated torelativebody weight and obesity in Finland,Croatia, Italy,
Greece,Serbia,andJapan.Ten-year incidenceofcoronary heart diseasewas not sig-
nificantly related tobody mass,and theprobability of death (allcause) in 10years
was least for men with greater than average relativeweight or fatness.
Distributions of physical activity ofoccupation did not explain cohort differ-
encesin theincidenceofCHD.Wherephysical activity wasimportant in predicting
individual risk ofcoronary diseaseorearlydeath,itseemed tobedue to interrela-
tionswith other riskfactors. However, few of theoccupations represented in the
SCSinvolved heavy,anaerobic work.

161
Other Characteristics
Resting heart ratewassignificantly lower inmen active physically,and 10-year
death rate was linearly related totheentry pulse rate.
An increase ofone year inagewas associated with an averagedecreaseof 1% in
vitalcapacity and 1.4% decrease in3/4 second FEV.Timed vitalcapacity was signifi-
cantly and inversely related toall-causesdeaths,though CHDwasunrelated toentry
vitalcapacity.Timed vitalcapacity wasmore prognostic than total vital capacity.
For diet,within-individual variation in thesame cohort wasof thesame order as
between-individual variation.Thisprovided another demonstration of statistical
theory:under such conditions,individual serum cholesterol and nutrient composi-
tionofdiet cannotbefound correlated without repeated surveys toreduce the
effects of intra-individual variation.

Multivariate Analyses
Partialcorrelation analysis,including dietary saturated fatty acid content,found no
significant correlation between dietary sucroseand CHDincidence.Cohort compar-
isonsshowed thestrongest correlation of milk and cheesewith CHD incidence.
Onlytwoentry riskvariablesweresignificantly related todifferences in CHD
incidence among cohorts:blood pressure and blood cholesterol,accounting for40
and 42%of thevariance inCHDdeath rate.Together, they accounted for about
two-thirds of thevariance.
Therisk of 10-year deaths from all-causeswasleast for men aboveaverage in
relativebody weight and skinfolds in multivariate analysis,including other major
risk factors.
Inmultivariate analysis,habitual physical activity and resting heart rateat entry
weresignificant predictors of all-causesdeath and coronary death in Europe.
Systolicand diastolicblood pressure werehighly significant risk factors for
death and CHDincidencein multiple logisticanalyses,but neither was superior.
Multivariate discriminatory power of risk factors for CHDdeath was far superi-
or totheir prediction of all-causes death.
Multivariate solutions from experience inonearea gavegenerally good predic-
tionof relativeCHDrisk inother areasbut gross errors inprediction of absolute
risk.The 'southern solution', for example,greatly underestimated theabsolute risk
of coronary deathsin northern European cohorts.Thesemultivariate analyses
acrosscultures lead totwopossibleconclusions:1)at entry,measurements were not
representative of long-term characteristics of men in thedifferent areas,or2)
unidentified variables,unrelated tothoseconsidered intheSCS,contributed to the
increased risk ofAmericans and northern Europeans,or alternatively, were
'protective' insouthern Europeans and theJapanese.

162
 Inall European areas therewasasignificant riseinmean serum cholesterol in
thefirst 10yearsof theSCS.Thistrend upward incholesterol was moremarked in
southern than innorthern Europe,more marked intheyounger men than in the
older and was presumably based on dietary changeson-going in Europe.
Thespecter that a lowincidenceofCHDnecessarily involvesatrade-off with
other,lessacceptable causesofdeath,waslaid torest.TheSCSgave clear demon-
stration of thecontrary that CHD deaths aregenerally unrelated todeath rates from
othercausesin theserelatively developed countries.Theconclusion isthat effective
prevention ofCVDdoesnot necessarily lead toenhancement of other causesof
death,but rather, canresult inlower age-specific death ratesoverall!

design and Method Innovations

TheSCSwas probably the first, and certainly the first incardiovascular disease
(CVD)epidemiology, tocarry out cross-sectional surveysofpopulations contrasting
indiet,insamplesadequate todemonstrate differences inprevalence and early-
year incidence,aswell astocombinethiswithcohort follow-up for incidence and
mortality,for up to30years inmany areas.
TheSCSdemonstrated thevalidity ofdietary survey methods tocharacterize the
dietsofwholepopulations,and made important contributions tothe measurement
ofindividual and population diets.
TheSCSmadebasiccontributions,aswell,tothemethodology of population
studieswith respect toelectrocardiographic classification, clinical procedures, risk
factor measurement,blood lipid analyses,and skinfold measurement.
Inaddition,contributions weremade tosampling for epidemiological surveys.
Lessthan perfect response ratesdo not necessarily mean biased samplesin regard
tophysical characteristics.Moreover,complete responses inrural villages mayre-
present thegenerality of rural men ofanentire country.
Manycontributionsweremade,aswell,tothepracticalities offieldwork, includ-
ln
g thenumber ofpeople per day examined,number of daysor number ofweeks in
thefield, timingof thefieldwork in regard tolocalconditions,establishing a roster,
en
gaging localassistants,transportation, and training and organization of the field
team.
Methodological deficiencies werefound of occupational classifications in respect
tophysical activity.

Population Correlations
TheSCSwasthefirst tocompute population (ecologie)correlationsbetween risk
actorsand disease incidence,demonstrating significant population correlations as

163
wellas thresholds for atheroscleroticdiseases and establishing theprecision with
which CHDdeath ratescanbe predicted byknowledge oftheaverageserum cho-
lesterol levelof apopulation, and theincreasing precision of that prediction overa
15-year follow-up.
Italsodemonstrated theremarkable departure from theprediction linefor par-
ticular populations such asEastFinland, whereCHDrateswere greater than pre-
dicted bythe mean serum cholesterol values and theisland ofCrete,where the rates
were lessthan predicted by those values,opening important new questions about
causation.

The Force of Risk Factors

TheSCSwas thefirst CVDstudy toapply partial correlation coefficients derived
from relationships between risk and disease incidence found inonecountry or
groupofcountries tothoseinanother.Thisshowed theuniversality of risk factors
aspredictors of individual relativeCHD riskin widely contrasting cultures.But the
SCSwasalsothefirst todemonstrate thedifferent force of arisk factor in popula-
tionsand inindividuals,finding theslopeof theindividual risk factor-CHD rela-
tionshipapproximately twiceasgreatin theUnited Statesasin Europe,and in
northern asinsouthern Europe.

Risk Factor Changes

TheSCSwas among thefirst todemonstrate dramatic changes inadecade in both
directions (inmeansand distributions ofrisk characteristics inwhole populations),
confirming theoverwhelming roleofculture and environment indetermining dif-
ferences and changes inchronicdiseaserisk,particularly cardiovascular diseases.
TheSCSwasamong thefirst todemonstrate thepredictiveimportanceof change
in riskcharacteristics,suggesting theparticular importance of population change in
cholesterol and blood pressure levelsin theriskofcardiovascular diseases.

Long-term Prediction
TheSCSwasoneof thefirst toexamine,inprolonged cohort follow-up study, the
relationshipbetween baseline riskcharacteristicsduring health and subsequent lon-
gevity,variously defined assurvival for 25years,or toage75,or 85. Itshowed the
importance of cigarettesmoking inlong-term survival,thelesser contribution of
blood pressure,and theverylittlecontribution of serum cholesterol and body mass
index.

164
 TheSCSwasoneof thefirst toillustrate thevariety and complexity of the rela-
tionshipbetween body weight,body massand obesity,and diseaserates, including
total mortality and survival.Theshape was highly different between cultures, from
absolutely flat relationships,for example,of weight measures with CHD,to
U-shaped or inverted U-shaped, tomonotonielinear positiverelationships,and in
occasional cases,even inverse relationships.Themorerecent findings of Keyssug-
gest that insomecultures longevity and survival areactually greater inthose who
gain weight inmiddle agethan inthosewhodo not gain,orwho lose weight.
Fifteen-year mortality follow-up confirmed theexperience of the 10-year follow-
up inallregards:risk functions of northern Europeand theU.S.overestimated the
coronary mortality ofsouthern Europe,and half of thearea differences in CHD
death ratewere explained byaverageblood totalcholesterol levelalone,with little
added contribution from theother major risk factors.
Population (ecologie)correlations among the 16cohortsof theratioof mono-
unsaturated tosaturated fatty acidswereinversely related toCHD,cancer, and
all-cause mortality.
Twenty-year follow-up mortality revealed that 81% of thedifference among
cohorts inCHDdeathscould beexplained by mean saturated fatty acid intake.
Individual correlations revealed thatageand blood pressureweretheonlycon-
sistent universal predictors ofindividual riskofCHDand all-causesdeath.An in-
versecorrelation was found between blood cholesterol levelsand stroke mortality.
Thetimeintegral of thechanging levelof risk factors during the first three sur-
veys,largely independent of theinitial level,enhanced prediction of subsequent
mortality.
Twenty-five year follow-up revealed areduced predictive power ofentry choles-
terollevel for long-term CHDmortality.Thislong-term follow-up found re-
ordering among thecohorts' ranking of coronary mortality rates,with Zrenjanin
(Vojvodina) eventually achieving thehighest rates.Absoluteand relative increase in
coronary mortality wasgreatest inZrenjanin and Velika Krsna (Serbia),ac-
companied byvery large increases inaverage cholesterol levels,especially in
Zrenjanin, far greater than inother southern European cohorts.Thiscontrasted to
n
o change,or todecreased cholesterol levels,innorthern Europeand theU.S.

Public Health Implications

Frederick Epstein has,in thisvolume,summarized elegantly thepublic health
lrr
>plicationsof theseSCSresults.Itisfitting that thisbedoneby aperson outside
theinvestigators group,yet aperson having alongstanding professional interest
and asupportive roleinSeven Countries undertakings.

165
 Clearly,amajor result of theSCShasbeen theconcept ofpopulation causes and
phenomena involved inmassdiseases such asCHD,hypertension, and stroke.We
havecometoappreciate that wearedealing with mass cultural phenomena that
influence already widespread individual susceptibility and lead totheheavy popu-
lation ratesofdisease.Thisconcept has played thecentral roleindevelopment of
the population strategy of prevention,complementing theindividual medical strat-
egy.Ithasstimulated theresearch on population causesand on community-wide
preventive strategies which characterizes theon-going work of Seven Countries
investigators.

166
Selected Seven Countries Publications
1. Blackburn H, Keys A,Simonson E,
Rautaharju PM, Punsar S.The electrocardiogram
in population studies. A classification system.
Circulation 1960;21:1160-1175.
2. Keys A, Blackburn HW, Van Buchem FSP,
Buzina R,Djordjevic BS,Dontas AS,Fidanza F,
Karvonen M],Kimura N, Lekos D, Monti M,
Puddu V,Taylor HL Epidemiological studies
related to coronary heart disease: characteristics
of men aged 40-59 in seven countries. Acta Med
Scand 1967;460(Suppl 180):l-392.
3- Den Hartog C, Buzina R, Fidanza F,Keys A,
Roine P, Eds. Dietary studies and epidemiology of
heart disease. Stichting tot wetenschappelijke
Voorlichting op Voedingsgebied. The Hague
1968:1-157.
*• Keys A, Blackburn H, Menotti A, Buzina R,
Mohacek I, Karvonen MJ, Punsar S,Aravanis C,
Corcondilas A, Dontas AS,Lekos D, Fidanza F,
Puddu V,Taylor HL, Monti M, Kimura N, Van
Buchem FSP,Djordjevic BS,Strasser T, Anderson
JT, Den Hartog C, Pekkarinen M, Roine P, Sdrin
H. Coronary heart disease in Seven Countries.
Circulation 1970;41(Suppl 1):1-211.
5- Keys A, Aravanis C, Blackburn H, Van
Buchem FSP,Buzina R, Djordjevic BS,Fidanza F,
Karvonen MJ, Menotti A, Puddu V,Taylor HL.
Coronary heart disease :overweight and obesity
as risk factors. Ann Intern Med 1972;77:15-27.
"• Keys A, Aravanis C, Blackburn H, Van
Buchem FSP,Buzina R,Djordjevic BS,Fidanza F,
Karvonen M, Menotti A, Puddu V,Taylor HL.
Probability of middle-aged men developing coro-
nary heart disease in five years. Circulation
1972;45:815-828.
'• Keys A, Aravanis C, Blackburn H,
Djordjevic BS,Dontas AS,Fidanza F, Karvonen
MJ,Menotti A,Taylor HL. Lung function as a risk
«actor for coronary heart disease. Am ] Publ
Health 1972;62:1506-1511.
"• Keys A, Fidanza F,Karvonen MJ, Kimura N,
Taylor HL. Indices of relative weight and obesity.
JChron Dis 1972;25:329-43.
'• Rautaharju PM, Punsar S, Blackburn H,
Warren J, Menotti A. Waveform patterns in Frank
lead rest and exercise electrocardiogram of
healthy elderly men. Circulation 1973;48:541-548.
10. Rose GA, Blackburn H, Keys A,Taylor HL,
Kannel WB, Paul O, Reid DD,Stamler J. Colon
cancer and blood cholesterol. Lancet 1974;1:181-83.
11. Menotti A,Capocaccia R,Conti S, Farchi G,
Mariotti S, Verdecchia A, Keys A, Karvonen MJ,
Punsar S.Identifying subsets of major risk factors
in multivariate estimation of coronary risk.J
Chron Dis 1977;30:557-565.
12. Keys A, Aravanis C, Blackburn H, Buzina R,
Djordjevic BS,Dontas AS,Fidanza F, Karvonen
MJ, Kimura N, Menotti A,Mohacek I, Nedeljkovic
S, Puddu V, Punsar S,Taylor HL, Van Buchem
FSP.Seven countries. A multivariate analysis of
death and coronary heart disease. Harvard
University Press,Cambridge Mass and London,
1980:1-381.
13. Farchi G, Capocaccia R,Verdecchia A,
Menotti A, Keys A. Risk factors changes and coro-
nary heart disease in an observational study. IntJ
Epidemiol 1981;10:31-40.
14. Keys A, Aravanis C, Van Buchem F,
Blackburn H, Buzina R, Djordjevic BS,Fidanza F,
Karvonen MJ, Kimura N, Menotti A, Nedeljkovic
S, Puddu V,Taylor HL.The diet and all causes
death rate in the Seven Countries Study. Lancet
1981;2:58-61.
15. Mariotti S,Capocaccia R, Farchi G, Menotti
A, Verdecchia A, Keys A. Differences in the inci-
dence rate of coronary heart disease between
North and South European cohorts of the Seven
Countries Study. Eur Heart J 1982;3:481-487.
16. Keys A, Menotti A, Aravanis C, Blackburn
H, Djordjevic BS,Buzina R, Dontas AS,Fidanza F,
Karvonen MJ,Kimura N, Mohacek I, Nedeljkovic
S, Puddu V,Punsar S,Taylor HL,Conti S,
Kromhout D,Toshima H. The Seven Countries
Study :2,289 deaths in 15years. Prev Med
1984;13:141-154.
17. Keys A, Aravanis C, Blackburn H, Buzina R,
Dontas AS,Fidanza F,Karvonen MJ, Menotti A,
Nedeljkovic S,Punsar S,Toshima H. Serum cho-
lesterol and cancer mortality in the Seven
Countries Study. Am JEpidemiol 1985;121:870-
883.
167
18. Keys A, Menotti A, Karvonen MJ, Aravanis
C, Blackburn H, Buzina R, Djordjevic BS, Dontas
AS, Fidanza F,Keys M, Kromhout D, Nedeljkovic
S, Punsar S,Seccareccia F,Toshima H. The diet
and 15-year death rate in the Seven Countries
Study. Am JEpidemiol 1986;124:903-915.
19. Mariotti S,Capocaccia R, Farchi G, Menotti
A,Verdecchia A, Keys A. Age, period, cohort and
geographical area effects on the relationship
between risk factors and coronary heart disease
mortality. 15-year follow-up of the European
cohorts of the Seven Countries Study. ]Chron Dis
1986;39:229-242.
20. Menotti A, Keys A, Aravanis C, Nedeljkovic
S,Seccareccia F.Hypertension and atherosclero-
sis:epidemiological aspects.The experience from
Southern Europe. In: 'Hypertension and
Atherosclerosis'. Satellite Meeting, VIII
International Symposium on Atherosclerosis.
Florence, Italy, 1988.CIC Edizioni Internazionali.
Roma 1988:53-58.
21. Menotti A, Keys A, Nissinen A, Kromhout
D, Seccareccia F.The Seven Countries Study: 25
year experience in three countries. In:
'Epidemiology of Atherosclerosis'. Satellite
Meeting, VIII International Symposium on
Atherosclerosis. Porto Cervo, 1988.CIC, Edizioni
Internazionali. Roma 1988:19-25.
22. Keys A, Karvonen MJ.The diet and 15-year
death rate in the Seven Countries Study. Am J
Epidemiol 1988;128(1):238-241.
23. Kromhout D, Keys A, Aravanis C, Buzina R,
Fidanza F,Giampaoli S,Jansen A, Menotti A,
Nedeljkovic S, Pekkarinen M, Simic BS,Toshima
H. Food consumption patterns in the 1960s in
Seven Countries. Am JClin Nutr 1989;49:889-894.
24. Menotti A, Keys A, Aravanis C, Blackburn
H, Dontas AS,Fidanza F,Karvonen MJ,
Kromhout D, Nedeljkovic S,Nissinen A,
Pekkanen J, Punsar S,Seccareccia F,Toshima H.
Seven Countries Study. First 20 year mortality
data in 12cohorts of the Seven Countries. Ann
Med 1989;21:175-179.
25. Menotti A, Keys A, Blackburn H, Aravanis
C, Dontas AS,Fidanza F,Giampaoli S, Karvonen
MJ, Kromhout D,Nedeljkovic S,Nissinen A,
Pekkanen J,Punsar S,Seccareccia F,Toshima H.
Twenty-year stroke mortality and prediction in
twelve cohorts of the Seven Countries Study. IntJ
Epidemiol 1990;19:309-315.
168
26. Menotti A, Keys A, Kromhout D, Nissinen
A, Blackburn H, Fidanza F,Giampaoli S,
Karvonen MJ, Pekkanen J, Punsar S,Seccareccia F.
Twenty-five-year mortality from coronary heart
disease and its prediction in five cohorts of mid-
dle aged men in Finland, the Netherlands, and
Italy. Prev Med 1990;19:270-278.
27. Kromhout D,Nissinen A, Menotti A,
Bloemberg BPM, Pekkanen J,Giampaoli S. Total
and HDL cholesterol and their correlates in elder-
ly men in Finland, Italy and the Netherlands. Am
J Epidemiol 1990,131:855-863.
28. Menotti A, Keys A, Kromhout D, Nissinen
A, Blackburn H, Fidanza F,Giampaoli S,
Karvonen MJ, Pekkanen J, Punsar S,Seccareccia F.
All cause mortality and its determinants in mid-
dle-aged men in Finland, the Netherlands and
Italy in a 25-year follow-up. J Epidemiol Comm
Health 1991;45:125-130.
29. Menotti A, Keys A, Blackburn H, Karvonen
M, Punsar S,Nissinen A, Pekkanen J, Kromhout
D,Giampaoli S,Seccareccia F,Fidanza F,
Nedeljkovic S, Aravanis C, Dontas AS, Toshima
H. Blood pressure changes as predictors of future
mortality in the Seven Countries Study. J Hum
Hypertension 1991;5:137-144.
30. Kromhout D, Katan MB,Menotti A, Keys A,
Bloemberg BPM. Serum cholesterol and long-term
death rates from suicide,accidents or violence.
Lancet 1992;340:317 (Letter to the editor).
31. Menotti A, Keys A, Kromhout D, Blackburn
H, Aravanis C, Bloemberg B,Buzina R,Dontas A,
Fidanza F,Giampaoli S,Karvonen MJ,Lanti M,
Mohacek I,Nedeljkovic S,Nissinen A, Pekkanen
J, Punsar S,Seccareccia F,Toshima H. Inter-cohort
differences in coronary heart disease mortality in
the 25-year follow-up of the Seven Countries
Study. Eur JEpidemiol 1993;9:527-536.
32. Kromhout D,Keys A, Menotti A, Aravanis
C, Blackburn H, Bloemberg BPM, Buzina R,
Dontas AS,Fidanza F,Giampaoli S,Jansen A,
Karvonen M, Katan M, Pekkarinen M, Punsar S,
Räsänen L,Simic B,Toshima H. Dietary saturated
and trans fatty acids,cholesterol and 25-year mor-
tality from coronary heart disease. The Seven
Countries Study. Submitted.
 15
PUBLIC HEALTH IMPLICATIONS
OF THE SEVEN COUNTRIES STUDY
F.H. Epstein

Ancel Keysnever wroteor talked much about publichealth as

such but rather contributed toitsmission and success.However, itis interesting
and important that 'public health' ispart of thetitleofahistorical paper,based ona
lecturepresented in 1953,inwhich hepresented, for thefirst time,hisviewson the
relationship between cholesterol and thediseasesdue toatherosclerosis (1).In the
introduction, hepointsout that thefrequently narrow concept of public health
should beextended towider horizons, 'toprevent ordecrease the incidenceofall
forms ofillnessand disability,not merely thosethat areinfective oroccupational in
origin'.Keysstates that major publichealth attention isrequired when there are
largenumbers of thepopulation suffering disability and death from diseases for
which private medical practiceismaking littleheadway, and when thereis hope
that measures applicable tothegeneral population canbefound toalter theinci-
denceof thesediseases;headds that coronary heart diseasefulfills these conditions.
Itisclear,therefore, that Keyshad thepublichealth implications of hiswork in
mind from thevery beginning.TheSeven Countries Study is,asKeysstatesin his
own contribution tothisbook,theculmination of work whichbegan in Minnesota
in 1947.Butittook some 10yearsfor themajor project togetunder way after com-
pletion of themany exploratory investigations in theintervening years.
Thedefinition of publichealth isnot asevident asitmight seem.One proposal is
that it '...consistsofallthethingsweasasociety docollectively toassure thecondi-
tionsinwhich peoplecanbehealthy' (2). Thisdefinition has thesanction of aspe-
cialcommittee of theInstituteof Medicineof theNational Academy ofSciencesof
theU.S.A.;itisappealing inbeingbroad,broad-minded, and functional. Itwill
servethepresent purpose very well.Under thisdefinition, itisunnecessary to
debate towhat extent research into thecausesofdisease falls within thedomainof
publichealth,or whether theapplication oftheresults of thisresearch isentirely
within itsrealm.Allthat mattersishow thetargetscanbereached most effectively
and efficiently! Along thisroad thereisacontinuum from observational studies,
liketheSevenCountries Study,totesting theresults for causalitybetween predis-

169
posing factors and diseaseriskby meansof intervention studies,and applying the
knowledge and understanding gained toward prevention. TheSeven Countries
Study standsat thebeginning of thischain but has had adecisive influence all the
wayalong itscourse.Thepresent assessment isconcerned with thefinal link, trying
toevaluate theimpactof thestudy at thepublichealth level.
Before proceeding further, itgoeswithout saying that nostudy isanisland, like
'noman isan island'. Theroleofeach study must beviewed within thecontextof
thecontributions ofalltheinvestigations which,over theyears,have helped to
build up theavailable knowledge on,inthiscase,cardiovascular disease epidemi-
ology.Anattempt hasbeen made tosummarize the saga ofthissuccessstory (3). In
thecaseoftheSevenCountriesStudy thetask issomewhat simplified by the fact
that,among thestudieswhich permit international comparisons,itreally has no
equal.Inpart, itisanecological study which makes itpossible torelatedisease inci-
dence,notjust mortality from national statistics,torisk factors and lifestyles, meas-
ured bycomparable methods;thisecologicalcomponent hasapartial counterpart in
theMONICA Project. There isnocounterpart totheprospective component
because,innoother study,haveincidenceasrelated tolifestyles and risk factors
been measured according tothesamestudy protocol by thesame, standardized
methods.Therearemany separateprospectiveinvestigationsofcoronary heartdis-
easeinanumber ofcountries which attest totheuniversal validity of therisk factor
concept inregard tocholesterol,blood pressure,and smoking,but the incidence
data arenot comparable asthediagnosticcriteria arenot thesame.Another unique
feature of theSevenCountries Study isthat itcombines theadvantages of ecological
and cohort studies,whilelargely avoiding thepitfalls of the 'ecological fallacy' since
data based on individuals areavailable atthesame time.
No finding from theSevenCountries Study had agreater impact than the
sequence leading from dietary habits,especially intermsof dietary fats, tothe lipid
content ofblood,in particular cholesterol,and from there tocoronary heart disease
risk.Inmost epidemiological investigations,data ondiet arelackingand, ifavail-
able,arelimited intheir usefulness for characterizing individuals,onaccountof
measurement error and variability.IntheSevenCountries Study,ecological dietary
comparisons ofgroups aresupplemented by thedietary investigations of individu-
alsunder controlled conditions,carried out independently by theLaboratoryof
Physiological Hygiene.Drawing on allsourcesof data,thestudy hasprovided the
strongest existingevidence that therisk ofcoronary heart diseaseislinked to the
consumption of saturated fat, and that thisrelationship ismediated by serum cho-
lesterol.This,of course,isthebasisfor thecurrent conviction that reduction of satu-
rated fat intakewilllead toareduction ofcoronary heart diseaserisk.Firm support
comesfrom preventive trials,but theseareconfined tohigh-risk groups and mostly
usedrugs rather than dietary modification for lowering serum cholesterol.The

170
results from theSeven Countries Study permit, more than any other data singly or
collectively,important though they are,theextrapolation from high-risk groups to
thepopulation at large.They areacornerstone,therefore, of thepopulation strategy
of prevention related todiet and serum lipids.
Beyond serum cholesterol and itsdeterminants,theSeven Countries Study has
contributed important cross-cultural data onblood pressure which isrelated todis-
easerisk in alltheareas.Thesamedoesnot apply tosmoking orphysical activity.
Thisdoesnot in any way suggest that they arenot important,but indicates that the
constellations of risk factors which add up tototal coronary heartdisease risk may
notbeexactly thesameindifferent parts of theworld. Furthermore,evidence from
other studies must betaken intoaccount,aswell as thestatistical power inherent in
different studies.No singlestudy can answer allquestions,but therearefew if any
studies which havecontributed at thesame timetoasmany answers,definite or
tentative,astheSevenCountries Study.Inthepresent context,from the all-impor-
tant point of view of coronary heart diseaseprevention, theoutstanding finding is
thedemonstration that countriescanbegraded alongascaleofdiseaserisk, and
that thisrisk isrelated toaseriesoflifestyles and risk factors.Without theSeven
CountriesStudy,thisknowledge would have tobepieced together from a varietyof
sources which often lackcomparability or reliability.These studies alsogiveeach
participating country ameasure of itsown risk statusand thefactors which influ-
enceit.From this,high-risk countriescandraw thelesson how tobecomea low-risk
country and low-risk countries can learn how tobecomeor not tobecomea high-
riskcountry.Examples of theformer are theU.S.A.,Finland,and the Netherlands
that showed largedecreasesinCHDmortality during thelast twodecades.An
exampleof alow-risk population thatbecameahigh-risk population isthe Serbian
cohortZrenjanin (Vojvodina).Thelatter lesson isofprimeimportancetothedevel-
oping part of theworld. Itwould bevery unfortunate if theSeven Countries Study
wereviewed only within itsown confines,without realizing that itsfindings can be
extrapolated tocountries resembling thosewhich areincluded init.Thisisoneof
itsgreat strengths!
Thebearing of thestudy on thepopulation strategy of prevention has already
been pointed out.Foroptimal prevention on thecommunity level,the high-risk
strategy must supplement it.Whilepracticing physicians must beinvolved inboth
strategies,their immediate roleistheprotection ofpeopleat high risk.AncelKeys
had striking successinenlisting thecollaboration ofclinicians,many of them lead-
er
s in theirown countries,both intheSevenCountries Study and, importantly, in
thefield studies which preceded itin thelate 1940sand inthe 1950s.Through them,
theseedsof thinking in termsofepidemiology and prevention, and of becoming
er
>gaged inthesefields, wereplanted inagood many countries,both within and
outside theSevenCountriesStudy.Itwould beimpossible togauge theinfluenceof

171
thesephysicians and their publications,separately and with theMinnesota team,
but,empirically,the 'spirit of prevention' seems tobe,on theaverage,morealivein
their countries.Acertain international halo-effect of theseactivities alsoappears to
beevident. Perhaps oneof themessagesof theStudy isthat medical people support
epidemiology and prevention morestrongly if they get themselves involved in their
pursuit.Oneoftheobstacles topublichealth action in coronary heartdiseasepre-
vention isthefrequently passiveornegative attitudeof themedical profession.
Practicing physicians areessential 'agentsof change' in promoting prevention and
theSeven CountriesStudy hashad an impact on these developments.
Theinfluence of theSeven Countries Study,along with thetotaleffort of the
Laboratory of Physiological Hygiene,on research intothecausesand prevention of
atherosclerosis and itsconsequences isimmense.Inhisintroduction tothe first
AncelKeysLecture,Blackburn hastersely and impressively addressed this point
(4).Itisnot only amatter of thehugeamount of work donebut havingopened,in
many ways,anew world which stimulated an immeasurable amount of work car-
ried outbyothers.Tothismust beadded theleadership which Ancel Keysand his
senior associatesassumed nationally and internationally tofurther epidemiological
research,and toapply theresults in thecauseof prevention.Thereisnodoubt that
allof thisdedicated and successful effort played amajor roleininitiating and inten-
sifying epidemiological research,including thebig intervention studies,and the
development of national programs for theprevention and control of cardiovascular
diseases,both in theUnited Statesand someother countries.
How does research lead toaction on thepublic health level?Cardiovascular dis-
ease,being ahealth burden of epidemic proportions,demands preventive action
encompassing thewholepopulation.Therequired action needscollaboration of all
people in thepopulation,whether or not atelevated risk,thephysicians in thecom-
munity, thehealth agencies from thelocaltothenational level,professional so-
cieties,themedia,research workers and organizations,and policymakers.This
chapter isconcerned with thepublichealth implications of theSeven Countries
Study.Has itinfluenced preventive action onallof theselevels?Most likely ithas,
but itwould behard toarrange thetargets inorder of theimpact which the Study
had on them.Doesitmatter? Canwedo morethan giveour best indoing good
research and seetoitthat thoseinaposition toturn itinto action areaware of the
scientific evidence and itsimplications? IntheSeven Countries Study,allof this has
been done!
TheSevenCountries Study hasnot only provided crucial evidence for the poten-
tialofcoronary heartdiseaseprevention;ithasalsocreated anew model and
approach for studying geographical differences in thefrequency of non-communi-
cablediseasesand searching for theircauses.Inhisreview ofAncel Keys'sbook on
theSevenCountries Study,Stallones writes:'Keys's contributions tothe epidemi-

172
ologyofcoronary heart diseaseareenormous,but thisreport suggests that what he
hasbegun may befar greater even than what hehasdone.' (5)Thepublic health
implications of thismonumental work, therefore, will inallprobability,extend to
horizonswhich cannot yetbeseen.

173
References

1. KeysA.Atherosclerosis:aproblem in newer 4. Blackburn H.Introduction toAncelKeys

publichealth.JMtSinai Hosp 1953;20:118-139. Lecture.AncelKeys,Pioneer.Circulation1991;
84:1402-1404.
2. Remington RD.Roleoforganized public
health incardiovascular diseaseprevention. In: 5. Stallones RA.Patternsof healthrisk-Seven
Coronary Heart DiseaseEpidemiology, from Countries.Science1980;208:1138-1139.
Aetiology toPublicHealth (Marmot M,ElliottP,
Eds)Oxford UnivPress,Oxford, 1992:515-524.

3. Epstein FH.Contribution of epidemiology

tounderstanding coronary heartdisease.In:
Coronary Heart DiseaseEpidemiology, from
Aetiology toPublicHealth (Marmot M,ElliottP,
Eds)Oxford Univ Press,Oxford, 1992:20-34.

174
 16
THE FUTURE OF
THE SEVEN COUNTRIES STUDY
D. Kromhout, A. Menotti and A. Nissinen

Itisalmost 40years sincethe first ideasfor an international colla-

borative study on theepidemiology ofcardiovascular diseases weredeveloped. In
1958thefieldwork was started inDalmatia. Inalmost allcohorts,threeroundsof
fieldwork werecarried out every fifth year.After the third round, mortality follow-
up wascontinued inall 16cohorts.The25-year mortality follow-up of all cohorts
was terminated in 1989. Thedata on 12,763men,originally 40-59yearsofage,were
collected between 1958and 1989and arenowavailable for analyses.In Finland,
Italy,and theNetherlands additional surveyswerecarried out after 25and 30years
offollow-up, and a35-year follow-up isbeing planned for these threecountries.
After 25yearsof follow-up, themen were65-84yearsold and therefore the study
was extended intoabroad gerontological survey.Fortunately,25-year follow-up
surveys werecarried out in thethreeSerbian cohortsof theSevenCountries Study,
and itishoped that studieson thesecohortscanberealized in the future.
Theaimsof theoriginal Seven Countries Study weredescribed byAncelKeyson
page315of the 1980monograph: 'tocompare theincidenceofcoronary heart dis-
easeindiversepopulations,tofind and evaluate relationships between the inciden-
ceofthediseaseand thecharacteristics of menbefore clinicaldiseasewas evident,
and toexamine theuniversality,orvariability,of these relationships in contrasting
populations.' On page 162of the 1970monograph hestated that 'from the inception
of theresearch program,animportant focus wason thedietand itspossible rela-
tionship totheetiology ofcoronary heart disease.'
Themajor resultsof theSevenCountriesStudy havebeen described in Chapter
14and thepublic health implications inChapter 15.However,in mostof the analy-
sescarried out,onlybaselinedata of the 16cohorts havebeen related to 10or15
years' mortality experience.Thedata of there-examinations collected in the second
and third round have notbeen fully explored. Therefore, much isstilltobe learned
from thedata collected during 25yearsof follow-up, including theseexamplesof
current orplanned analyses.
Menottiand co-workers havealready shown that,besidestheentry levelof

175
blood pressure,changes inblood pressure areindependent individual predictorsof
CVDrisk.Similar analyses willbecarried out for changes inbody weight and
serum cholesterol.Currently, thereisagreat interest in therelation between serum
cholesterol level and non-cardiovascular diseases.TheSeven Countries Study data
provide thepossibility tostudy theseassociations indifferent culturesand throw
light on thiscomplicated issue.Inall cohortsinformation on lung function wascol-
lected atleast once.Thisinformation willbeused tostudy associations between
lung function, mortality from chronicdiseases,and all-causes deaths.
Individual dietary data werecollected inZutphen (TheNetherlands) in I960,
1965,and 1970,inCrevalcore (Italy) in 1965and 1970,inMontegiorgio (Italy) in
1965,and inEastand West Finland in 1969. Thedietary survey method used inall
thesecohorts was thedietary history.Therefore aunique data set isavailableof
about 3,800men,aged 40-69,atbaselinewhowerefollowed during 15-25yearsin
relation tomortality experience.Thesedata willbeused tostudy individual asso-
ciationsbetween diet and chronicdiseasesin threedifferent European cultures.A
topicof special interest istheeffect of measurement error on therelation between
diet and chronicdiseases.Another topictobedealt with indetail isthe relation
between diet and chronic non-specific lung diseases (CNSLD).Evidence isaccumu-
lating thatnutritiveand non-nutritive dietary anti-oxidantsplayaroleintheetiolo-
gyofCNSLD.Thedietary data baseof theSevenCountries Study provides thepos-
sibility toanalyze these associations.
Since 1984more than 2,300men aged 65-84in Finland,Italy,and the
Netherlands havebeen examined ingerontologiesurveys.Besidesthe traditionally
collected data in theSevenCountries Study,information isalsocollected on:gluco-
setolerance,hemostatic factors, diet,physical activity,psycho-social variables,and
different aspects of health.Thisprovides aunique data setwith information on risk
factors and health intheelderly.Currently analyses arebeingcarried out on:
• Functional status of the elderly.
• Development ofadisability index.
• Predictive valueof classicalrisk factors in the elderly.
• Relationbetween diet and health inthe elderly.
• Physical activity and health in the elderly.
• Diet,glucose tolerance,and hyperinsulinemia in the elderly.
• Dietand hemostatic factors in the elderly.
Theseanalyses should provide insight into theassociationsbetween risk factors
and,not only chronicdiseases,but alsohealth ingeneral (of great interest for aging
populations).Nowadays,information on factors that influence disease-freelifeex-
pectancy ismost welcomebyhealth policy makersand thistypeof information can
onlybeobtained from prospective epidemiologic studies.TheSeven Countries
Study can playan important rolein thiscontextbecause theoriginally middle-aged

176
men have now been followed for 35years,and much information hasbecome and
will become availableon factors that influence health inold age.
Thereisstillmuch tobelearned about thecausesof health and disease.Theepi-
demiologic approach should therefore bebroadened, aswe have tried todo in the
last decade.This was foreseen by AncelKeysin thethird monograph of theSeven
Countries Study that appeared in 1980.Weclosebyquoting the last paragraph of
that monograph: The period of epidemiological exploration of these matters isnot
over,and there isstill alot tobelearned from the study ofthe experiments of natu-
re.Theneed for more and better epidemiological studies hasnever been more
obvious.Untilnow,allprospectivestudiesincluding theSevenCountries Study,
have dealt with toofew persons;thestandard errorsof themeans and ratesare too
large.Theinstability of lifestyle in many populations greatly complicates thecollec-
tion of representative data and theiranalyses,but perhaps theinstability itself
should beincluded in theanalysis asa risk factor. Moreover, thealmost universal
assumption that risk isa linear function of thecharacteristics of interest must give
way toless restrictive ideasand mathematical models.Finally,besides our great
concern about the incidenceof coronary heart disease,new epidemiological pro-
grams should be more broadly concerned with all diseaseand death.'

Picture of the authors taken at the international symposium 'Lessons for Science from the Seven Countries
Study'. November 30, 1993, Fukuoko, Japan.
From left to right:
Upper row: H. Toshima, H. Blackburn, D. Kromhout, A. Menotti, A. Nissinen, S. Nedeljkovic, F. Epstein
Lower row: R.Buzina, C. Aravanis, A. Keys, F. Fidanza, M. Karvonen, A. Dontas

177
 17
A B O U T THE INVESTIGATORS
A N D AUTHORS

Aravanis, Christos J Professor

Education
MedicalSchool,University of Athens M.D. 1948 Medicine
Doctorate inMedicine D.Sc. 1959

Professional Experience
Served inthearmy asaMedical Officer, 1949-1952.
Clinical Assistant inmedicine,University Hospitals,Athens,1953.
Intern,JerseyCity Medical Center and College,1954.
Resident and Clinicaland Research Associate,University of Health Sciences,Chicago
MedicalSchool,1954-1960.
Senior Registar,Department of Cardiology, University of Athens,1960-1962.
AssociateProfessor of Cardiology, University of Athens,1963.
Senior Attending Cardiologist, University Hospital,Athens,1963-1973.
Professor of Physiology and Biophysics (cardiology),University of Health Sciences,Chicago
Medical School,1973.
Director,Department ofCardiology, 'Evangelismos' Hospital Medical Center, Athens,
1975-1986.
Director,Department ofCardiology, Medical Center of Athens,1987-present.

Special Experience
Directorand Responsible Investigator for thestudy of CHDinGreeceunder USPHS,NIH,
1960-1972.
Visiting Lecturer,University of Belgrade,Yugoslavia,1965.
Visiting Professor, ChicagoMedical School,1969and 1970.
Visiting Lecturer, Instituteof Health,Finland,1971.
VisitingScientist,University of Perugia, Italy, 1971.
VisitingScientist,Northwestern University, (Department of Community Health),
Chicago,1974.
VisitingScientist,Oak Forest Hospital, Illinois,1973and 1974.
VisitingScientist,University of Minnesota (Schoolof Public Health),1974.

178
C o m m i t t e e s and Offices
Member, Scientific Councils on Thrombosis, Epidemiology, Blood Pressure, and Basic
Sciences, American Heart Association.
Member, Editorial Board, Journal of Electrocardiography, USA.
Member, Editorial Board, Journal of Vascular Diseases, USA.
Member, various Greek Medical Societies.
Member, various Editorial Boards,Greek Scientific Journals.
Secretary, Hellenic Heart Association, 1966.
Secretary, 5th European Congress of Cardiology, Athens, 1968.
Founder and General Secretary, Greek Society for the Study of Atherosclerosis, 1960-present.
President, Greek Ileart Association, 1969-1971.
Regent for Greece, American College and Academy of Chest Physicians, 1983-1993.

Selected Publications
KeysA,AravanisC,Sdrin H.Thedietsof middle
aged men in two rural areasofGreece.Voeding
1966;27:575-86.
AravanisC,DontnsAS,LekosD,KeysA.Rural
populations inCreteand Corfu, Greece.In:
Epidemiological studies related tocoronary
heart disease:characteristicsof menaged 40-59
inSeven Countries.KeysA,etal(Eds).Acta
MedScand 1967;460Suppl:209-230.
KeysA,AravanisC,Blackburn H,VanBuchem
FSP,Buzina R,Djordjevic BS,Fidanza F,
Karvonen M,Menotti A,Puddu V,TaylorHL.
Probability of middle-aged men developing
coronary heartdiseaseinfiveyears.Circulation
1972;45:815-828.
AravanisC,Corcondilas A,Dontas AS,LekosD,
KeysA.TheGreek islandsofCreteand Corfu.
In:Coronary Heart DiseaseinSeven Countries.
Circulation, 1970;41(Suppl1):88-100.
Ar
avanisC.TheGreek Islands Heart Study. Proc
'iter Congresson the Biological ValueofOlive
°'l-1976;1:315-319.
AravanisC.Theclassicrisk factors for coronary
heartdisease.Experience inEurope. Preventive
Med 1984;2:125-135.
AravanisC,Mensink R,KaraliasN,
Christodoulou B,Katan M.Serum lipids,apo-
proteinsand nutritional intakeinrural Cretan
boysconsuming higholiveoildiets.JClin
Epidemiol 1988;41:1117-1123.
AravanisC,Mensink R,Corcondilas A,Ioanides
P,FeskensE,Katan M.Riskfactors for coronary
heart disease inmiddle-aged men inCretein
1982.InternJEpidemiol1988;17:779-783.
Menotti A,KeysA,AravanisC,Blackburn H,
Dontas AS,Fidanza F,Karvonen M],Kromhout
D,Nedeljkovic S,Nissinen A,PekkanenJ,
PunsarS,Seccareccia F,Toshima H.Seven
CountriesStudy.First20-year mortality data in
12cohortsof sixcountries.Ann Med
1989;21:175-179.
Menotti A,KeysA,Blackburn H,AravanisC,
Dontas AS,Fidanza F,Giampaoli S,Karvonen
MJ,Kromhout D,NedeljkovicS,Nissinen A,
PekkanenJ,PunsarS,Seccareccia F,Toshima H.
Twenty-year strokemortality and predictionof
twelvecohortsof theSevenCountries Study.
InternJEpidemiol 1990;19:309-314.
Sandker GW,Kromhout D,AravanisC,
BloembergBPM,Mensink RP,KaraliasN,
KatanMB.Serum cholesterol ester fatty acids
and their relation with serum lipids inelderly
men inCreteand TheNetherlands.EurJClin
Nutr 1993;47:201-208.

179
Blackburn, Henry Professor

Education
University ofMiami,FL B.S. 1947 Chemistry
TulaneUniversity,New Orleans,LA M.D. 1948 Medicine
University of Minnesota, Minneapolis,MN M.S. 1956 Medicine

Professional Experience
Intern,Northwestern WesleyHospital,Chicago,IL,1948-1949.
Resident,American Hospital of Paris,Paris,France,1949-1950.
MOC,USPHS,Salzburg and Munich,1950-1953.
Fellow,Department of Medicine,University ofMinnesota,1953-1956.
Chief Resident,Internal Medicine,Ancker Hospital,St.Paul,MN,1956.
Research Fellow,1956-1958. Assistant Professor, 1958-1961.Associate Professor, 1961-1968.
Professor, 1968-present.Director, 1972-1983, Laboratory of Physiological Hygiene,Schoolof
PublicHealth,University of Minnesota, Professor, Department of Medicine,Universityof
Minnesota,1972-present.
Professor and Director, 1983-1990.MayoProfessor of PublicHealth, 1990-present.Divisionof
Epidemiology,Schoolof PublicHealth,University of Minnesota.

Special Experience
Project Officer, SevenCountriesStudy,1958-1974.
Faculty,AHAand ISFCSeminarsonCardiovascular Epidemiology, 1968-present.
Member,World HealthOrganization ExpertWorkingGroups,1970,1971,1981.
Principal Investigator,MRFIT,1972-1977;Minnesota Heart Health Program,1980-1990.
Minnesota HeartSurvey,1987-1993.
Visiting Professor, University ofGeneva, 1970;University ofSydney, 1982; Universityof
South Horida, 1987,1993.DelegateUS-USSRHealth Treaty 1973;US-Japan Health Treaty
1982-present.

Committees and Offices

Chairman,CouncilonEpidemiology,American Heart Association,1971-1973.
Nutrition Committee,American Heart Association,1978-1983.
SteeringCommittee,Coronary Drug Project,NHLBI,1968-1975.
Epidemiology and DiseaseControlStudy Section,NIH, 1977-1981.
Chairman,CouncilonEpidemiology and Prevention, International Societyand Federationof
Cardiology,1986-1990.
Member,Committee on Dietand Health,National Academy of Sciences,1986-1989.
Member, Advisory Council,NHLBI,1988-1992.
Chairman, MedicalSection,American Association for Advancement ofSciences,1991-1992.

Editorial Boards
Journal of PublicHealth Policy,1980-1985.
Journal ofChronicDiseases,1967-1985.
Circulation,AssociateEditor,1967-1970.Board, 1978-1987;1993-.
AmericanJournal ofCardiology,1976-1986.
American HeartJournal, 1978-1981.
Journal ofCardiacRehabilitation,1979-1990.
Hypertension,1986-1988.
Nutrition, Metabolism and Cardiovascular Diseases,1989-present.
International Journal of Cardiology,1988-present.

180
Honors
Alpha Omega Alpha, 1948.
Thomas Francis Award In Epidemiology, University of Michigan, 1975.
Eleanor Naylor Dana Award in Preventive Medicine, New York, 1976.
Louis Bishop Award in Cardiology, Miami, 1979.
Phi Kappa Phi Scholar of the Year, Minnesota Chapter, 1981.
Doctor Honoris Causa, University of Kuopio, Kuopio, Finland, 1982.
Langmuir Lecture in Epidemiology, CDC, 1982.
Honorary Fellow, American College of Chest Physicians, Chicago, 1983.
Delta Omega, Honorary Society of Public Health, 1983.
Gold Heart Award, American Heart Association, 1990.
Ancel Keys Lecture, American Heart Association, 1991.
Research Achievement Award, American Heart Association, 1992.

Selected Publications
Blackburn H,KeysA,Simonson E,Rautaharju P,
PunsarS.Theelectrocardiogram in population
studies.Aclassification system. Circulation
1960;21:1160.
Blackburn H.BrozekJ,Taylor HL.Commoncir-
culatory measurements insmokersand non-
smokers.Circulation1960;22:1091.
RoseGA,Blackburn H.Cardiovascular Survey
Methods.WHOMonograph Seriesno. 56,
WHOPress,Geneva,1969.
Blackburn H.Multifactor preventive trialsincor-
onary heart disease.In:Trendsin epidemiology.
StewartGT(Eds).ThomasCC,Springfield, 1972.
Blackburn H.Diet,masshyperlipidemia and cor-
onary heartdisease.Apublichealth approach.
In:Nutrition,Lipidsand Coronary Heart
Disease.Raven PressPublishers,NewYork,
1978.
Blackburn H.Determinants ofindividual and
population blood lipoprotein levels:nutritional-
geneticinteractions.In:GeneticFactorsin
Nutrition.VelasquesA,BourgesH(Eds).New
York,AcademicPress,1984.
Blackburn H,JacobsDRJr.Physicalactivity and
theriskofcoronary heartdisease.(Editorial) N
EnglJMed 1988;319(18):1217-1219.
Blackburn H,JacobsDRJr.Theongoing natural
experiment ofcardiovasculardiseaseinJapan.
(Editorial)Circulation 1989;79:718-720.
Blackburn H.Community programme inCHD
prevention and health promotion: Changing
community behaviour.In:Coronary Heart
DiseaseEpidemiology. From Aetiology to
PublicHealth.MarmotM,EliottP(Eds). Oxford
University Press,1991:495-514.
Blackburn H.TheAncelKeysLecture.Thethree
beauties:bench,clinical,and population
research.Circulation1992;86:1323-1331.

181
V a n Büchern, Frans SP Professor
BornNovember 30,1897
Died August 1,1979

Education
University ofLeiden M.D. 1921 Mediane
UniversityofLeiden Ph.D. 1924

Professional Experience
Resident internal medicine,KlevarieHospital,Maastricht,1921-1925.
Chief Resident internal medicine,University ofGroningen,1925-1929.
Chief,Dept. internal medicineandChief Physician,StElisabeth Hospital,Tilburg,1929-1945.
Professor internal medicine,University ofGroningen,1945-1959.

Special Experience
Resident,Dept.ofCardiology,Vienna,Austria,1924.
Member ofWHOinternational medical team,visitsto:Calcutta (India),Rangoon (Burma),
Calabo (Ceylon),1952.
Principal Investigator, Zutphen Study,1960-1974.

Committees and Offices

Member oftheBritishInstituteofRadiology,1938.
Honorary memberoftheCardiological SocietyofIndia,1953.
FellowoftheAmericanCollegeofChestPhysicians,1954
MemberoftheFrenchCardiologieSociety,1950.
Member oftheRoyalDutch Academy ofScience, 1958.
Member oftheNetherlands Health Council,1958.
Fellow International Angiological Society,1963.
Honorary memberoftheDutch MedicalSociety,1968.
Member oftheBelgiumCardiologieSociety,1968.
Member Council onEpidemiology andPrevention, International SocietyofCardiology,1968.

Editorial Boards
NetherlandsJournal ofMedicine (NTvG), 1951.
Acta Medica Scandinavica,1951.

182
Selected Publications
Van Buchem FSP.Pepticulcerof thegreater cur-
vatureof thestomach.BrJRadiol1939;11:667.
Van Buchem FSP,NieveenJ. Thebasisof the
treatment of diabetesmellitus.ActaMed Scand
1952,142:190.
Van Buchem FSP.Dilatation of the pulmonary
artery.Circulation 1956;8:719.
VanBuchem FSP.Primary aldosteronism due to
adrenocortical hyperplasia. Lancet1956,11:335.
Van Buchem FSP.Theelectrocardiogram and
potassium metabolism.AmJMed 1957;23:376.
Van Buchem FSP,PolG,DeGierJ,BöttcherCJF,
PriesC.Congenital ß-lipoprotein deficiency.
AmJMed 1966;40:794.
Van Buchem FSP,Dalderup LM.Thetownof
Zutphen, theNetherlands.In:Epidemiological
studiesrelated tocoronary heart disease:
Characteristics ofmen aged 40-59inseven
countries.KeysA,etal(Eds).Acta Med Scand
1967;460Suppl:191.
Van Buchem FSP. Zutphen,a town in the
Netherlands.In:Coronary heart diseasein
seven countries.KeysA(Ed).Circulation
1970;41(SuppIl):I-76.
Van Buchem FSP,SchermersTG,Vanden Berg
JW.Theclinicalsignificance ofaorticsclerosis.
AmHeartJ1970;80:831.
Van Buchem FSP.Hyperostosiscorticalis genera-
lisata.(VanBuchem'sdisease). Monograph
Elsevier,Amsterdam,1976.
183
Buzina, Ratko Professor

Education
MedicalSchoolUniversity ofZagreb,Croatia M.D. 1944 Medicine
SchoolofPublicHealth,University Zagreb, D.P.H. 1951-1953 Public health
Croatia nutrition
UniversityofZagreb,Croatia Sc.D. 1963 Medicine

Professional Experience
Chief,Community Health Services,1947-1950.
Assistant Professor (Nutrition),InstituteofPublicHealth Zagreb,Croatia,1950-1956.
Associate Professor (Nutrition),MedicalSchool,University ofZagreb,Croatia,1956-1963.
Professor (Nutrition)MedicalSchool,UniversityofZagreb,Croatia, 1963-present.
Chief,Nutrition Department, InstituteofPublicHealth,Zagreb,Croatia,1973-1985.

Special Experience
Postgraduate TraininginBiochemistry andVitaminology. Department of Biochemistry,
Medical Faculty,University ofBasel,Switzerland,1950-1951.
Research Fellow,LaboratoryofPhysiological Hygiene,MedicalSchool,University
Minnesota, Minneapolis USA,1955-1956.
Research Fellow,Department ofNutrition, Medical SchoolVanderbilt University, Nashville
USA,1956
Coordinator (Croatia) International StudyontheEpidemiology ofCoronary Heart Disease,
1958-1985.
Nutritional Advisor totheWorld Health Organization forSouth EastAsia inNewDelhi,
India,1959-1962.
WHOShortTermConsultant (Nutrition) toIndia,Burma,SriLanka andThailand,1963-1981.
Consultant (Nutrition) WHOHeadquarters Geneva,Switzerland, 1989-present.

Committees and Offices

Member,Croatian Medical Association.
Member,Croatian Nutrition Society(President 1983-1987).
Member,American SocietyofClinical Nutrition.
Member,American Instituteof Nutrition.
Member,American Public Health Association.
Member, Hungarian Nutrition Society.
Member,International SocietyandFederation ofCardiology.
Board Member,International Society forTraceElement ResearchinHumans,1986-present.
Member,GroupofEuropean Nutritionists (GEN)andVice-president, 1988-present.
Member,World HealthOrganization PanelonNutrition, 1963-present.
President,International UnionofNutrition Sciences,1981-1985,Honorary President since1985.
Member,Scientific Committee (Nutrition) oftheCommunity Alpe-Adria.

184
Selected Publications
BrozekJ,Buzina R,MikicF.Population studieson
serum cholesterol and dietary fat inYugoslavia.
AmJClin Nutr 1957;5:279-285.
Buzina R,KeysA.Blood coagulation after a fat
meal.Circulation 1956;14:854-858.
KeysA,Buzina R,Grande F,AndersonJT.The
effects of mealsofdifferent fatson blood coagu-
lation.Circulation 1957;15:214-219.
Buzina R,Ferber E,KeysA,BrodarecA,
Agneletto B,Horvat A.Dietsofrural families
and headsof families in tworegionsof
Yugoslavia.Voeding1964;27:629-639.
Buzina R,KeysA,BrodarecA,AndersonJT,
Fidanza F.Dietary surveysinrural Yugoslavia.
IIChemicalanalysisof dietsinDalmatia and
Slavonia.Voeding1966;27:31-36.
Buzina R,KeysA,BrodarecA,AndersonJT,
Fidanza F.Dietary surveysinrural Yugoslavia.
IIIComparison ofthreemethods.Voeding
1966;27:99-105.
Buzina R,KeysA,Mohacek1, Hahn A,BrozekJ,
Blackburn H.Rural men in Dalmatia and
Slavonia,Yugoslavia. In:Epidemiological stud-
iesrelated tocoronary heart disease:
Characteristics of men aged 40-59inSeven
Countries.KeysAetal. (Eds).Acta Med Scand
1967;460:147-168.
Buzina R,KeysA,Mohacek I,MarinkovicM,
Hahn A,Blackburn H.In:Coronary Heart
DiseaseinSevenCountries.Five-year follow-
up in Dalmatia and Slavonia.KeysA(Ed).
Circulation 1970;41(Suppl 1):40-51.
Buzina R,Suboticanec K,SaricM.Diet patterns
and health problems:Diet inSouthern Europe.
Ann Nutr Metab 1991;(SuppI l):32-40.
Buzina R.Recentevaluation of food habitsin
Mediterrarean populations.In:Forabetter
nutrition in the21thcentury.Leathwood P,
Horrisberger M,JamesWPT(Eds)NestleNutr
WorkshopSeries,Raven Press1993;27:67-74.
I8S
D j o r d j e v i c , B o z i d a r Svetislav Professor
BornJanuary 5,1910
Died April 11,1986

Education
MedicalSchool,Universityof Belgrade M.D. 1934 Medicine
Residency inInternal medicine, 1934-1938
TraininginCardiology, Paris 1949

Professional Experience
Assistant Professor, Internal Medicine,Medical Faculty Belgrade,1936.
AssociateProfessor, Medical Faculty Belgrade,1949.
Professor of Internal Medicine,Medical Faculty Belgrade, 1953.
FullProfessor of Internal Medicine,Medical Faculty Belgrade,1958.
Founder and Chief,Postgraduate SchoolofCardiology, Medical Faculty Belgrade,1965-1978.
Deputy Dean,Medical Faculty Belgrade,1952-1956.
Prorector and Rector, BelgradeUniversity,1957-1967.

Special Experience
Principalinvestigator and director of theSerbian part of theSevenCountriesStudy,1962-1986.
Principal investigator 'Organization ofcardiological health,research and educational service
inSerbia',1960-1970.
Director,Medical Research Institute,Serbian AcademyofScienceand Arts,1962-1963.
Chief,Department of Internal Medicine,and CardiologicalTeam,1952-1978.
Director,MedicalClinic B,1974-1976.
Consultant, InstituteofCardiovascular Rehabilitation, Niska Banja, 1974-1986.
Board member for inauguration and opening of new medical faculties inSerbia:Novi Sad,
Vojvodina, Pristina,Kosovoand Nish.
Associate toFull Member,Serbian Academy of Scienceand Arts,1963-1986.

Committees and Offices

Secretary,Serbian MedicalSociety,1946-1950.
Founder,Serbian SocietyofCardiology,1957.
GeneralSecretary,Yugoslav Medical Associations,1954-1960.
President, Yugoslav Medical Associations,1960-1964.
Member, American CollegeofCardiology,1963-1986.
Board Member, European Societyof Cardiology.
VicePresident,Yugoslav SocietyofCardiology,1957-1969.

Honors
BelgradeOctober Award.Contribution toscienceand arts for therealization of theSerbian
part of theSevenCountries Study,1970.
Serbian National DayAward 'Seventh ofJuly*.Contribution toscienceand health promotion
inSerbia.
BelgradeOctober Award.Contribution toscienceand arts for themonograph 'Congenital
Heart Disease',1974.
Decoration for 'Services tothepeoplewith golden wreath',1965.
Brotherhood and Unitywith Silver Wreath,1970.
Medalof Labor with Red Flag,1974.
Medalof the 'Legion of Honor' and medal 'Fenix' from France.
French International Cardiology Meetings (ledby FrenchcardiologistCamilleLian).

186
Selected Publications
Djordjevic' B.,Nedeljkovic S.Variabilité des
données electrocardiographiques dans trois
groupes epidemiologiques différents
(Recherchessur l'epidemiologiede la maladie
coronaire).ActualitésCardiologiques et
AngeiologiquesInternationales1965;14(4):281-
286.
Djordjevic'B, Simic'B,SimicA,StrasserT,
Josipovic"V,MacarolV,KlincI,NedeljkovicS,
Todorovic'P.Dietarystudiesinconnection with
epidemiology of heart diseases:resultsin
Serbia.Voeding 1965;26:117-127.
Djordjevic'B, Josipovic"V,StrasserT, Nedeljkovic
S,LambicI,BalogB,StojanovicG,MacorolV,
Simic'B,Simic'A,Slavkovic'V,Milutinovic'P,
KlincI,Jovanovic"M:Lespremiersrésultatsdes
recherchessur l'epidemiologiedela maladies
coronairedans troisgroupesdifférants depo-
pulation enSerbie.Actualités Cardiologiques
et Angeiologiques Internationales1966;15(1):
15-21.
Djordjevic"B,Josipovic"V,Nedeljkovic"S,Strasser
T,Slavkovic'V,Simic'B,KeysA,Blackburn H.
Men inVelika Krsna,ASerbian village.In:
KeysA,etal (Eds).Epidemiological studies
related tocoronary heart disease.
Characteristicsofmenaged 40-59inSeven
Countries.ActaScand 1967;Suppl460:267-277.
Djordjevic'B,Balog B,Bozmovic'LJ,Josipovic'V,
Nedeljkovic'S, LambicI,Sekulic'S,Slavkovic'V,
Stojanovic"G,Simic1A,Simic"B,StrasserT,
Blackburn H,KeysA.Threecohortsof men fol-
lowed five yearsinSerbia.In KeysA(Ed).
Coronary heartdiseaseinSevenCountries.
Circulation 1970;41(Suppl1):123-137.
Nedeljkovic S,Djordjevic B,StojanovicG.Follow
upballistocardiographic findings inan
epidemiological study ofcardiovascular diseas-
esinYugoslavia, Ballistocardiography,Bibl
Cardiol,Krager,Basel1973;31:237-244.
KeysA,AravanisC,Blackburn H,DjordjevicB,
Dontas A,Fidanza F,Karvonen M,MenottiA,
Taylor H.Lungfunction asariskfactor for cor-
onary heart disease.AmJPubl Hlth
1972;62(11):1506-1511.
KeysA,AravanisC,Blackburn H,VanBuchem
FSP,Buzina R,Djordjevic B,FidanzaF,
Karvonen M,Menotti A,Puddu V,Taylor H.
Coronary heart disease:overweight and obesity
asriskfactors. Ann Intern Med 1972;77:15-27.
KeysA,Menotti A,AravanisC,Blackburn H,
Djordjevic B,Buzina R,DontasA,FidanzaF,
Karvonen M,Kimura N,Mohachek I,
Nedeljkovic"S,Puddu V,PunsarS,TaylorH,
ContiS,Kromhout D,Toshima H.TheSeven
CountriesStudy:2.289deathsin 15years.Prev
Med 1984;13:141-154.
KeysA,MenottiA,KarvonenM,AravanisC,
Blackburn H,Buzina R,Djordjevic B,DontasA,
Fidanza F,KeysM,Kromhout D,NedeljkovicS,
PunsarS,Seccareccia F,Toshima H.
Thediet and 15yeardeath ratesin theSeven
CountriesStudy.AmJEpidemiol
1986;124(6):903-915.
187
D o n t a s , Anastasios S. Professor

Education
University of Athens,Greece M.D. 1946 Medicine
University ofAthens,Greece 1948 Physiology
University of Michigan M.S. 1952

Professional Experience
Head,Center ofStudiesof AgeRelated Changes inMan;AthensHomefor theAged,
1966-present.
Head, Department Medicine,AccidentHospital.Kifissia, 1970-1986.

Special Experience
Expert Adviser onproblemsofhealth of theelderly,WHO,1984-1988.
Visiting Professor, University of Minnesota,1978,1982,1989.
Chief (and Co-)Investigator for Greecefor the following programmes:
TheSevenCountriesStudy (NIH),1960-1979.
Renal Function intheAged,WHO,R/00073,1965-1968.
Health Careof theElderly (WHO), 1978-1981.
TheElderly in ElevenCountries (EEC),1987-1989.

Committees and Offices

General Secretary,HellenicAssociationGerontology,1977-present.
Chairman, Hellenic National Committee,World Assembly onAging,UN,1982.

Editorial Boards
Mechanisms of Agingand Development, 1972-1979.
International Journal ofTechnology and Ageing,1989-present.
European Journal ofGerontology, 1991-present.
GeriatricNephrology and Urology, 1991-present.

Honors
FirstEmbiricosAward inMedicine(with associatesMarketosSG,Papanayiotou P), 1970.
Academy of Athens Award for textbook The Third Age',1984.
Second Don Goodchild Lecturer;3rd National Symposium on Microbial Diseasein
Nephrology, London,1985.
Sandoz Foundation ofGerontological Research Grantee,1989.

188
Selected Publications
DontasAS,KeysA,Anthopoulos L,SchulzN.
Effects ofageon thecarotid pulse in twoGreek
populations.Circulation 1970;42:529-539.
AravanisC,Corcondilas A,DontasAS,LekosD,
KeysA.TheGreek islandsofCreteand Corfu.
In:Coronary heart diseaseinseven countries.
KeysA(Ed).Circulation 1970;41(Suppl1):
88-100.
Papanayiotou P,Dontas AS.Waterloadingtestin
bacteriuria. NEngl]Med 1972;287:531-534.
Dontas AS,Kasviki-Charvati P,Papanayiotou P,
MarketosSG.Bacteriuria and survival inold
age.N EnglJMed 1981;304:939-943.
Dontas AS,JacobsD,Corcondilas A,KeysA,
Hannan P.Longitudinal versus cross-sectional
vital capacity changesand effecting factors.
JGerontology 1984;39:430-438.
DontasAS,Paraskaki I,PetrikkosG,Giamarellou
H.Diuresisbacteriuria inphysically dependent
elderly women.Ageand Ageing1987;16:
215-220.
TziasV,Dontas AS,PetrikkosG,
Papapetropoulou M,Dracopoulos H,
Giamarellou H.Three-day antibiotictherapy in
bacteriuria ofold age.JAntimicr Chemother
1990;26:705-711.
Dontas AS,Tzonou A,GeorgiadesGL,Christakis
G,Kasviki-Charvati P,Trichopoulos D.Survival
inaresidential home.JAmGeriatrSoc 1991;
39(7):641-649.
DontasAS.Dilemmasof prolonging lifeof elderly
patientsinterminal system failure. Geriatric
Nephrol Urol 1991,1:9-12.
Dontas AS,Giamarellou H,Staszewska-Pistoni M,
PetrikkosG,lakovou M,TziasV.Short vslong
cotrimoxazolecoursesineradicating bacteriuria
in theelderly.JChemotherapy 1992;4:114-118.
189
Epstein, Frederick H Professor

Education
University ofCambridge, England B.A. 1940 Medicine
University ofCambridge, England M.A. 1944 Medicine
UniversityofCambridge, England M.B.Bchir 1944 Surgery
University ofCambridge,England M.D. 1956 Medicine

Professional Experience
Resident Physician,England,1943-1947.
New YorkUniversity Collegeof Medicine,1948-1956.
ResidentLecturer,Research Associate,AssociateProfessor, University of Michigan,
Schoolof PublicHealth,Ann Arbor,Michigan,1956-1963.
Professor of Epidemiology, University of Michigan,Schoolof PublicHealth,Ann Arbor,
Michigan,1963-1973.
Professor of Preventive Medicine,University of Zurich,Switzerland, 1973-present.

Committees and Offices

Member, RoyalCollegeofSurgeons,London,1943.
Chairman,Council onEpidemiology and Committee onCriteria and Methods, American
Heart Association.
Member, ExecutiveCommittee,Council on Epidemiology and Prevention, International
Societyand Federation of Cardiology.
Editor,International Epidemiology Newsletter,International Societyand Federationof
Cardiology.
Director,Center for Research inDiseasesof theHeart and Circulation and other disorders,
University ofMichigan,1968-1973.
Member, Panel of ExpertsonCardiovascular Diseases,World Health Organization,
1973-present.
Member, Committee on Epidemiology and Veterans Follow-upStudies,National
Academy-National Research Council.
Member,Scientific Advisory Board,SwissSocietyofSocialand Preventive Medicine,
1979-present.
Member,Scientific Expert,HeartSpecial Projects Committee,National Heart, Lung and
Blood Institute, 1978-1991.
Member,TaskForceonGenetics,NationalHeart,Lungand Blood Institute.
Fellow,RoyalCollegeof Physicians,London,1990.

Honors
ResearchCareerAward,National Heart, Lungand Blood Institute,National Institutesof
Health,1962-1973.
Salomon Neuman Medal,German SocietyofSocialMedicine.
MacArthur Postgraduate Lecture,University of Edinburgh,1965.
GeorgeC.Griffith Scientific Lecture,LosAngeles, 1971.
Doctor HonorisCausa,University of Heidelberg,Germany,1979.
ThomasFrancisJr.Memorial Lecture,University of Michigan,1982.
AncelKeysLecture,American Heart Association,1993.

190
Editorial Boards
Circulation
American Journal of Epidemiology
Atherosclerosis
Preventive Medicine
Sozial-und Praeventivmedizin (SwissJournal of Social-and Preventive Medicine)
Nutrition Metabolism and Cardiovascular Disease
Cardiology
Cor etVasa
Selected Publications
Epstein FH,BoasEP,Simpson R.Theepidemiolo-
gyofatherosclerosisamongarandom sample
ofclothing workersofdifferent ethnicoriginsin
New YorkCity.JChron Dis1957;5:300,329.
Epstein FH.Theepidemiology ofcoronary heart
disease;areview.JChron Dis1965;18:735.
Epstein FH,Ostrander LD,Johnson BC,etal.
Epidemiological studiesofcardiovascular dis-
easeinatotalcommunity; Tecumseh,
Michigan.Ann IntMed 1965;62:1170.
Epstein FH.Hyperglycemia -arisk factor incor-
onary heart disease.Circulation 1967;36:609.
Epstein FH.Coronary heart disease epidemiology
revisited -clinical and community aspects.
Circulation 1973;48:185.
Epstein FH.Preventive trialsand the diet-heart
question:wait for resultsoract now?
Atherosclerosis.1977;26:515.
Epstein FH,Holland WW.Prevention of chronic
diseasesinthecommunity -one-disease versus
multiplediseasestrategies.IntJEpidemiol
1983,12:135.
Epstein FH.Cholesterol,coronary heart disease,
cancerand diet.Atherosclerosis Rev 1983;11:1-
28.
Epstein FH,Pyörälä K.Perspectives for thepri-
mary prevention of prematurecoronary heart
disease.Cardiology 1987;74:316.
Epstein FH.Lowserum cholesterol,cancer and
other non-cardiovascular diseases.
Atherosclerosis1992;94:1.
191
Fidanza, Flaminio Professor

Education
University of Naples (Italy) M.D. 1945 Medicine

Professional Experience
Assistant Professor, Institute of Biochemistry,MedicalSchool,University of Naples(Italy),
1946-1955.
Rockfeller Fellow,Laboratory ofPhysiological Hygiene,University of Minnesota,1952-1953.
Assistant Professor, Instituteof Human Physiology, MedicalSchool,University of Naples,
1955-1965.
Professor inchargeof Nutrition and FoodScience,MedicalSchool,University of Naples,
1961-1964.
FullProfessor ofNutrition and Food Science,1965-1990;Outside of tenureuntil retirement,
1990-present;
Director, 1965-present,Instituteof Nutrition and Food Science,Faculty of Pharmacy,
University of Perugia.

Special Experience
Principal Investigator, Italian Section,Seven Countries Study,1958-1967.
Member, Food and Agriculture Organization Expert Working Groups,1977,1979,1981,1985.
Member,World Health Organization Expert Working Groups,1977,1979,1981,1985.

Committees and Offices

Member,Committee on Diabetes and Cardiovascular Diseases,International Unionof
Nutritional Sciences(IUNS),1968-1972.
Member,Commission on Nutrition Education and Training,IUNS, 1970-1975.
Chairman,Commission on Nutritional Education and Training,IUNS,1975-1982.
Permanent Representative of IUNStoFAO,1972-1990.
Secretary General,Group of European Nutritionists,1971-1978.
Vice-President and President,Group of European Nutritionists,1978-1988.
President,Italian Association ofClinical and Preventive Nutrition,1986-present.
Editorial Boards
Nutritio etDieta,1966-1976.
International Journal for Vitamin and Nutrition Research,1971-present.
ProgressinFood and Nutrition Science, 1975-1981.
Diabetes,Nutrition & Metabolism,1988-present.
Nutrition, Metabolism and Cardiovascular Diseases,1991-present.
ItalianJournal of Clinicaland Preventive Nutrition,editor, 1991-present.

Honors
PavesiAward inNutrition Research,1964.
Diploma of Merit ofSchool,Culture and Artof Italian Republic,1986.

192
Selected Publications
Fidanza F,KeysA,Anderson JT.Density of body
fat inman and other mammals.
JAppl Physiol 1953;6:252-256.
KeysA,Fidanza F,Scardi V,etal. Studieson
serum cholesterol and other characteristicson
clinically healthy men inNaples.Arch Intern
Med 1954;93:328-336..
Fidanza F,Fidanza-Alberti A,Ferro-Luzzi G,
Proja M.Dietary surveysinconnection with the
epidemiology ofheartdisease:ResultsinItaly.
Voeding1964;25:502-509.
Fidanza F.Dietsand dietary recommendations in
ancientGreece and Romeand theschoolof
Salerno.Prog Food NutrSei1979;3:79-99.
FarchiG,MariottiS,Menotti A,Seccareccia F,
TorselloS,Fidanza F.Dietand 20-year mortal-
ityintworural population groupsof middle-
aged men in Italy.AmJClin Nutr1989;
50:1095-1103.
Fidanza F.TheMediterranean Italian diet:Keysto
contemporary thinking.
ProcNutr Soc1991;50:519-526.
Fidanza F(Ed).Nutritional statusassessment.A
manual for population studies.
Chapman &Hall,London1991.
BorrelliR,SimonettiMS,Fidanza F.Inter-and
intra-individual variability infood intakeof
elderly peopleinPerugia (Italy).
BritJ Nutr 1992;68:3-10.
FarchiG,Fidanza F,MariottiS,MenottiA.
Alcohol and mortality in theItalian rural
cohortsof theSevenCountriesStudy.
IntJEpidemiol1992;21:74-81.
Fidanza F.Nutrition and cardiovascular risk:
Thebiological markersofdietary intake.
BiblNutr Diet1992;49:59-65.
193
Karvonen, M a r t t i J. Professor, Major General M C

Education
Helsinki University M.D. 1945 Medicine
Universityof Cambridge Ph.D. 1950 Physiology
Specialist inClinical Physiology 1964
Specialist inOccupational Health 1970

Professional Experience
Demonstrator, Instituteof Physiology,Helsinki University, 1945-1950.
Lecturer ofSport Medicine,Instituteof Physiology, Helsinki University,1950-1956.
Director,Department of Physiology,InstituteofOccupational Health, Helsinki,1950-1967.
Docentof Physiology,Helsinki University,1951-1968.
SurgeonGeneral of theAirForce,1956-1966.
Professor of Physiology,Collegeof Veterinary Medicine,Helsinki,1966-1970.
Director,Institute of Occupational Health,Helsinki,1970-1974.
Surgeon General of the Armed Forcesof Finland,1974-1978.

Special Experience
Principal Investigator,TheFinnish East-West Project of theSeven Countries Study,
1956-1980.
RegionalOfficer for Occupational Health and Rehabilitation, WHORegionalOffice for
Europe,Copenhagen, 1966-1967.
Visiting Professor, University of Dortmund, 1978-1980.
WHO Consultant:
Egypt,1981,
Indonesia 1981,1983,
WHORegionalOffice for the Eastern Mediterranean, Alexandria,1982,
WHOHeadquarters,Geneva,for theMONICA Project,1982-1983.
UNConsultant for Occupational Health inPoland,1972.

Committees and Offices

President, Finnish Society for SportsMedicine,1957-1962.
Member, Expert Advisory Panelon Cardiovascular Diseases,WHO,1962-present.
President, Finnish Medical Association,1963-1965,1969.
Rector,Collegeof Veterinary Medicine,Helsinki,1969-1970.
Vice-President, Finnish HeartAssociation,1971-1975.
Chairman,StateBoard onCleanAirand NoiseProtection,1973-1974.
President, Finnish Society for Research inSportsSciences,1975-1977.
Chairman,StateCommittee inHealth Education,1975-1976.

Editorial Boards
AmericanJournal ofCardiology,1958-1967.
ScandinavianJournal ofWork,Environment and Health,1972-1984.
ScandinavianJournal ofSportsSciences,Editor inChief, 1979,Editorial Board,1980-1989.
International ArchivesofOccupational and Environmental Health,1979-1986.
European Journal of Applied Physiology,1980-1984.

194
Honors
Ruhemann-plaquette, German Association of Sports Medicine, 1966.
Corresponding Member, German Association for Occupational Health, 1972-present.
Doctor Honoris Causa, Helsinki University, Helsinki, Finland, 1981.
Doctor Honoris Causa,Jyväskylä University, Jyväskylä, Finland, 1982.
Honor Award, American College of Sports Medicine,1991.
Honorary memberships:
J. Purkinje Medical Society,Czechoslovakia, 1961.
Finnish Society for Sports Medicine, 1969.
Finnish Medical Association, 1978.
Finnish Aerospace Medical Association, 1984.
Finnish Sauna Society, 1988.
Finnish Cardiological Society, 1988.
Finnish Society for Clinical Physiology, 1993.

Selected Publications
JoklE,Karvonen MJ,KihlbergJ,KoskelaA.
Sports inthecultural pattern of the world.
Helsinki:InstituteofOccupational Health,
1956,116pp.
Karvonen MJ,Kentala E,Mustala O.Theeffects of
training on heart rate.Ann Med ExpBiolFenn
1957;35:307-315.
Karvonen MJ,Telivuo LJ,Järvinen EJK.
Sphygmomanometer cuff sizeand theaccuracy
of indirect measurement ofblood pressure.
AmJCardiol1964;13:688-693.
Hasan J,Karvonen MJ,Piironen P.Physiological
effects ofextremeheatasstudied in the Finnish
'sauna' bath.Part I.AmJPhysMed
1966;45:296-314.Part II.AmJPhysMed
1967;46:1227-1245.
Pyörälä K,Karvonen MJ,Taskinen P,TakkunenJ,
Kyrönseppä H,PeltokallioP.Cardiovascular
studieson former enduranceathletes.
AmJCardiol 1967;20:191-205.
Karvonen MJ,Klemona H,Virkajarvi J,Kekkonen
A.Longevity ofendurance skiers.MedSei
Sports1974;6:49-51.
Turpeinen O,Karvonen MJ,Pekkarinen M,
Miettinen M,ElosuoR,Paavilainen E.Dietary
prevention ofcoronary heartdisease:
TheFinnish Mental Hospital Study.IntJ
Epidemiol 1979;8:99-118.
Karvonen MJ.Physical activity and cardiovascu-
larmorbidity.ScandJWork Environ Health
1984;10:389-395.
Karvonen MJ,Mikheev MI(Eds).Epidemiology
ofOccupational Health.Copenhagen. World
Health Organization, RegionalOffice for
Europe,1986:1-392.
Karvonen MJ.Determinantsof cardiovascular
diseases intheelderly.Ann Med1989;
21:3-14.

195
Keys, A n c e l Professor/Director

Education
University ofCalifornia, Berkely,USA B.A. 1924 Biology
UniversityofCalifornia, Berkely,USA M.A. 1928 Biology
University of California, Berkely,USA Ph.D. 1930 Biology
KingsCollege,Cambridge,UK Ph.D. 1936 Physiology

Professional Experience
USNational Research FellowinCopenhagen,1930-1931.
Rockefeller Foundation Fellowin King'sCollege,Cambridge University,1931-1932.
Instructor of Physiology Cambridge University, 1932-1933.
Instructor inBiochemistry Harvard University 1933-1936.
Staff member, MayoClinic1936-1937.
Assistant Professor, Associate professor, Professor of Physiology,University of Minnesota,
Medical School,1937-1940.
Professor and Director Laboratory of Physiological Hygiene,University of Minnesota, School
of Public Health1940-1972.
Professor emeritus 1972-present.

Special Experience
Special Assistant totheSecretaryof Defense,1939-1943.
Visiting Professor Magdalen College,Oxford University 1951-1952.
Visiting Professor Department of PhysiologyNaplesUniversity 1963-1964.

Committees and Offices

Chairman,Committee on Food and Nutrition, Food and Agriculture Organization, World
HealthOrganization,1951.
Chairman, Research Committee,International Societyof Cardiology,1954-1958.

Honors
Honorary citizen of GioiaTauroand ofNicotera, Italy.
Member Academy of Finland.
TheAmerican Heart Association established theannual Ancel Keyslectureship in1989.
BristolMeyersSquibbaward for research innutrition,1993.

196
Selected Publications
KeysA.Physical performance inrelation todiet.
Fed Proc1943;2:164-187.
KeysA,BrozekJ,Henschel A,Mickelson O,
Taylor HL.Thebiology of human starvation.
Minneapolis MN,University of Minnesota
Press,Minneapolis,MN,1950:Vol.1-2:1-1385.
KeysA.Thecholesterol problem. Voeding
1952;13:539-555.
KeysA,BrozekJ.Bodyfat inadult man.Physiol
Rev1953;33:245-325.
KeysA,Anderson JT,Grande F.Predictionof
serum cholesterol responsesof man tochanges
in fats in thediet.Lancet1957;2:959-966.
KeysA,Anderson JT,Grande F.Serum choleste-
rolresponse tochangesinthediet.IV.
Particular saturated fatty acidsin thediet.
Metabolism 1965;14:776-787.
KeysA,Blackburn HW,VanBuchem FSP,Buzina
R,Djordjevic' BS,DontasAS,FidanzaF,
karvonen MJ,Kimura N,LekosD,MontiM,
Puddu V,Taylor HL.Epidemiological studies
related tocoronary heart disease:characteristics
ofmenaged 40-59inSevenCountries.Acta
Med Scand 1967;460(Suppl 180):l-392.
KeysA.Coronary heart diseaseinSeven
Countries.Circulation 1970;41(Suppl 1):1-211.
KeysA,AravanisC,Blackburn H,Buzina R,
Djordjevic"BS,DontasAS,Fidanza F,Karvonen
MJ,Kimura N,Menotti A,MohachekI,
Nedeljkovic'S,Puddu V,PunsarS,TaylorHL,
VanBuchemFSP.Seven countries.Amultivari-
ateanalysisofdeathand coronary heartdis-
ease.ACommonwealth Fund Book,Harvard
University Press,Cambridge Massand London,
1980:1-381.
KeysA,Menotti A,Karvonen MJ,AravanisC,
Blackburn H,Buzina R,Djordjevic BS,Dontas
AS,Fidanza F,KeysM,Kromhout D,
Nedeljkovic S,PunsarS,Seccareccia F,Toshima
H.Thedietand 15-yeardeath rateintheSeven
CountriesStudy.AmJEpidemiol 1986;124:
903-915.
197
Kirnura, N o b o r u Professor
BomAugust 4,1911
Died September 9,1983

Education
Kyushu University, Faculty of Medicine M.D. 1936 Medicine

Professional Experience
Resident,the 1stDepartment of Internal Medicine,Kyushu University Hospital,1936.
Fellow,the 1stDepartment of Internal Medicine,Kyushu University Hospital,1942.
Lecturer,the 1stDepartment of Internal Medicine,Kyushu University,1943.
AssociateProfessor, the 1stDepartment of Internal Medicine,Kyushu University,1945.
Professor, Kyushu University Medical College,1945.
Exchange Research Fellow,Rockefeller Foundation,1951.
Lecturer, the3rd Department of Internal Medicine,Kurume University Schoolof Medicine,
1957.
Professor, the3rd Department of Internal Medicine,Kurume UniversitySchoolofMedicine,
1958-1977.
Director,theInstituteofCardiovascular Diseases,Kurume University Schoolof Medicine,
1959-1977.
Dean,Kurume University School of Medicine,1972-1973.
Vice-president,Saga MedicalCollege,1976-1979.
President, Kurume University,1980-1982.

Special Experience
Member,SevenCountries Study Group
Member,WHOProfessional Consultant Committee,1955.
VisitingLecturer,Department of Internal Medicine,Kyushu University,1958.
Member, ScienceCouncil ofJapan,1969.
Member, Board of Directors,Japan Heart Foundation,1970-1983.
Vice-president, the 1stSouth-East AsianConference ofCardiovascular Disease Prevention,
1973.
Member,National Survey onChronicNon-communicable DisordersofAdult Population,
1971.
President, Kimura Memorial Heart Foundation,1977.

Committees and Offices

President, the32ndScientific Session,JapaneseCirculation Society,1968.
President, the 14thScientific Session,JapaneseSocietyof Rheumatic Disease,1970.
President, the 11thScientific Session,Japanese Societyof Medical Electronics, 1971.
Member,OrganizingCommittee,International Societyof Nutrition,1974.
Director,Japan Atherosclerosis Society,1974.
Vice-president, the8thWorld Congressof Cardiology,1975.
Chairman,Societyof Human Dock,1975.
President, the75thScientific Session,JapaneseSocietyof Internal Medicine,1976.
President, the list Scientific Session,JapaneseAssociation for Cerebro-Cardiovascular
DiseaseControl,1976.
Chairman, ExecutiveCommitteeofAsian-Pacific Hypertension Conference, 1976.

198
Honors
J a p a n M e d i c a l Association A w a r d , 1976.
H o n o r a r y Professor, K u r u m e U n i v e r s i t y , 1977.
Selected Publications
Kimura N, Fukumura I,Nawata Y,Oishi K,
Matsumoto M, Masaki H, Utsu N, Kawazoe K,
Toshima H, Mori F,Mori I,Shikata H,
Fukumoto A, Akasu M, Nakakura S.
Electrocardiographic and vectorcardiograph«:
studies of proved mitral valvular disease. Jpn
CircJ1961;25:872.
Kimura N,Toshima H, Nakakura S,Fukumoto A,
Akasu M, Yamaguchi K.The component of
right ventricular hypertrophy in QRS complex-
es. Observation on electrocardiographic chang-
es after commissurotomy in pure mitral steno-
sis.Jpn CircJ 1962;26:885.
Kimura N, Ueda H, Donomae I,Kimura E,
Maekawa M, Niitani H,Okinaka S,Saito M,
Sano T,Tasaka S,Takatsu T,Takayasu M.
Prognostic value of various electrocardiograph-
ic features. The report of the committee on the
criteria of the heart disease and electrocardio-
gram. Jpn Heart J 1963;4:239,
Kimura N, Toshima H. Essential differences
between vectorcardiogram and electrocardio-
gram. Jpn Circ J 1963;27:61.
Kimura N,Toshima H, Mori F,Kodama A, Abe K,
Outsuka Y,Arima T,Oki Y,Yokota Y. Studies
on the metabolism of carbohydrate, lipids and
contractile protein in myocardium and on the
hemodynamics in the dogs with experimentally
produced aortic valvular lesions.Jpn CircJ
1967;31:1916.
Kimura N,Toshima H, Takayama K, Nakayama
Y,Abe K, Matoba T.Comparative study of
angiogram, electrocardiogram and vector-
cardiogram on the disease with left ventricular
diastolic loading. Jpn CircJ1967;31:1878.
Kimura N, Keys A. Rural Southern Japan. In:
Coronary heart disease in seven countries. Keys
A (Ed).Circulation 1970;41(Suppl 1):101.
Kimura N, Toshima H, Takayama K,Shimada S,
Soejima K. Clinical usefulness of the vectorcar-
dioagraphic pattern difference using the
Kimura- and Frank-Lead System. Jpn J Med
1971;10:50.
Kimura N,Toshima H, Nakayama Y, Mizuguchi
T,Takayama K, Yoshinaga M, Fukami T,
Tashiro H, Katayama F,Abe K, Arima T,
Yokota Y,Minagawa E,Tanaka R,Akiyoshi T,
Soejima K,Yamada K, Mizunoe A, Nakamura
K,Oshima F,Tanaka K,Akusu K, Niizaki T,
Ikeda H, Nakamichi E,Ageta M, Miike Y, Inoue
T,Nakagawa T, Nanbu S,Tanioka T, Shimada
S,Fukumoto T. Epidemiological study on cere-
bro and cardiovascular disease in Tanushimaru
and Ushibuka. Jpn JMed 1972;11:62.
Kimura N. Epidemiological studies inJapan on
smoking and cardiovascular diseas. Volume 2
of the proceeding of the 3rd World Conference
on smoking and health (USA).Department of
Health, Education, and Welfare. DHEW
Publication no (NIH) 1977;77-1413:185-198.
199
Kromhout, Daan Director/Professor

Education
M.Sc. 1974 Human
Agricultural University Wageningen, NL nutrition
Ph.D. 1978 Human
Agricultural University Wageningen, NL nutrition
M.P.H. 1981 Epidemiology
University ofMinnesota,Minneapolis,MN

Professional Experience
Research Assistant, Dept.Hematology, Karolinska Hospital,Stockholm,Sweden,1972.
Ph.D.student,Dept.Human Nutrition Agricultural UniversityWageningen, Netherlands,
1974-1978.
Assistant Professor, Dept.ofSocialMedicine,University of Leiden,Netherlands,1977-1982.
AssociateProfessor, Dept.ofSocialMedicine,University ofLeiden,Netherlands,1982-1988.
Professor inNutritional Epidemiology,University of Leiden,Netherlands,1984-present.
Head, Department of Epidemiology,National Instituteof PublicHealth and Environmental
Protection,Bilthoven,Netherlands, 1988-1991.
Director,Division of PublicHealth Research,National Instituteof PublicHealth and
Environmental Protection,Bilthoven,Netherlands,1991-present.
Special Experience
Principal Investigator of theZutphen Study,1978-present.
Member ExecutiveCommittee of theINTERSALTstudy,1982-1988.
Member ExecutiveCommitteeof theSevenCountries Study,1986-present.
VisitingProfessor University of Helsinki,1987.
Principal Investigator of theMonitoring Project onCardiovascular Diseases in the
Netherlands,1987-1992.
Principal Investigator of thescenarioproject onchronic diseases,1988-1992.
Temporary Advisor of theWHOstudy group on 'Diet,nutrition and prevention of non-com-
municable diseases',1989.

Committees and Offices

Member,Committee onNutrition and Atherosclerosis.Nutrition Council,1978-1982
Member,Committee onDietand Coronary Heart Disease,Nutrition Council,1979-1982.
Member,Committee onDietand Cancer,Nutrition Council,1982-1986.
Chairman,Foundation QualityControl ChemicalAnalyses,1986-1990.
Member,Nutrition Council, 1984-present.
Member and Vice-Chairman,Committee Socio-economic Health Differences, 1987-present.
Chairman,CommitteeNutritional Surveillance,Nutrition Council,1988-1992.
Secretary and Chairman,Working group Nutrition of theNetherlandsOrganization for
Research, 1991-present.

Honors
TravelGrantNetherlands Organization for Scientific Research for one-year stayat the
Laboratory of Physiological Hygiene,University of Minnesota,Minneapolis,MN,USA,1980.
Liga Nutrition Award of theNetherlands Nutrition Foundation,1989.
Annie B.Cunninglecture,RoyalAustralasian Collegeof Physicians,Melbourne,1990.
Keynotelecture,Tercentenary Charter Celebration,RoyalCollegeof Physiciansof Ireland,
Dublin,1992.

200
Selected Publications
Kromhout D,Bosschieter EB,DeLezenne
CoulanderC.Dietary fibreand 10-yearmortal-
ityfrom coronary heart disease,cancerand all
causes.TheZutphen Study.Lancet1982;II:
518-522.
Arntzenius AC,Kromhout D,BarthJD,Reiber
JHC,BruschkeAVG,BuisB,VanGentCM,
Kempen-Voogd N,Strikwerda S,VanderVelde
EA.Diet,lipoproteins and coronary lesion
growth.TheLeiden Intervention Trial.NEnglJ
Med1985;312:805-811.
Kromhout D,Bosschieter EB,DeLezenne
Coulander C.Theinverserelation between fish
consumption and 20-yearmortality from cor-
onaryheartdisease.NEnglJMed 1985;312:
1205-1209.
Kromhout D.Essential micronutrientsinrelation
tocarcinogenesis.AmJClinNutr1987;45:
1361-1367.
Kromhout D,Bosschieter EB,Drijver M,De
LezenneCoulander C.Serum cholesterol and
25-year incidenceofand mortality from myo-
cardial infarction and cancer.TheZutphen
Study.Arch Intern Med 1988;148:1051-1055.
Kromhout D,KeysA,AravanisC,BuzinaR,
Fidanza F,GiampaoliS,Jansen A,MenottiA,
Nedeljkovic S,Pekkarinen M,Simic BS,
Toshima H.Food consumption patternsin the
nineteen sixtiesinSevenCountries.AmJClin
Nutr 1989;49:889-894.
Kromhout D,Nissinen A,MenottiA,Bloemberg
B,PekkanenJ,GiampaoliS.Totaland HDL
cholesterol and theircorrelatesinelderly men
inFinland,Italyand theNetherlands.
AmJEpidemiol1990;131:855-863.
Caspersen CJ,Bloemberg BPM,SarisWHM,
Merritt RK,Kromhout D.Theprevalenceof
selected physical activitiesand their relation-
shipwith coronary heartdiseaserisk factors in
elderly men:TheZutphen Study,1985.
AmJEpidemiol 1991;133:1078-1092.
Kromhout D.Dietary fats.Longterm implications
for health.Nutr Rev1992;50(II):49-53.
Kromhout D,Bloemberg BPM.Methodsinnutri-
tionalepidemiology. In:Coronary heart disease
epidemiology:Fromaetiology topublichealth.
Marmot M,Elliott P(Eds).Oxford University
Press1992:140-151.
Hertog MGL,FeskensEJM,Hollman PCH,Katan
MB,Kromhout D.Dietary antioxidant flavo-
noidsand riskofcoronary heart disease.
(TheZutphen ElderlyStudy).Lancet
1993;342:1007-1011.
201
Menotti, Alessandro Director/Professor

Education
University of Rome,Italy M.D. 1958 Medicine
University ofTurin,Italy 1960 Cardiology
University of Rome,Italy 1963 Pathology
LondonSchoolof Hygiene,London,UK 1964/1967 Medical
statistics
University of Rome,Italy Ph.D. 1971 Health
statistics

Professional Experience
Assistant, Department ofMedicine,Government Hospital ofTripoli,Libya, 1960-1961.
Research Associate,Laboratory ofPhysiological Hygiene,University of Minnesota,
Minneapolis Minnesota, USA,1962-1975
Assistant, Centerfor Cardiovascular Diseases,St.CamilloHospital,Rome,Italy,1975-1979.
Director,Unit for ChronicDiseases,Laboratory of Epidemiology and Biostatistics,Istituto
SuperiorediSanità(National Instituteof Health),Rome,Italy,1979-1989.
Director,Laboratory of Epidemiology and Biostatistics,IstitutoSuperioredi Sanità (National
Institute of Health),Rome,Italy,1989-present.

Special Experience
Memberof theCentralStaff,SevenCountriesStudyonCardiovascular Diseases,1967-1993.
Principal Investigator, Death Ratesamong Italian Railroad Employees,NIHGrant,1968-1976.
WHOMONICA Project (Monitoring Cardiovascular Diseases),Coordinator for Italy, 1981-
1993;MemberSteeringCommittee,1981-1983.
Principal Investigator, WHOEuropean Multifactor PreventiveTrialofCHD,1973-1988.
WHOERICAProject (European RiskFactorCoordinated Analysis),Member Steering
Committe,1982-1993.
Lecturer on Epidemiology,University of Rome,Italy 1972-1979,1981-1983,and Universityof
Padua atVerona,Italy,1974.

Committees and Offices

Temporary Adviser inmore than 40WorkingGroupsof theWorld Health Organization,
1966-1990.
Consultant totheHealth Service,Italian Railroad System,1978-1993.
Responsible for Cardiovascular DiseasesintheReport on theNation's Health Status
of theItalian Ministry ofHealth,1981-1984,1989.
Italian Representative intheCommittee onEpidemiology of theEuropean Community,
Bruxelles,1981-1982.
Member of theNational Committee for Cardiology and CardiacSurgery of the Italian
Ministryof Health,1981-1993.
Co-Director, Decentralized Activitiesfor Epidemiology and Prevention of Cardiovascular
Diseasesof theWorld Health Organization, Regional Office for Europe,atUniversityof
Heidelberg,Germany,1982-1989.
Member of theWorking Group onGuidelines for theItalian Diet,Italian National Instituteof
Nutrition,1985-1986.
Coordinator Sub-Project Community MedicineintheTargeted Project on Preventive
Medicine,Italian National Research Council,1989-1993.
Vice-Chairman SectiononEpidemiology and Prevention, International Societyand
Federation ofCardiology, 1978-1982,and Memberatlarge,ExecutiveCommittee,1990-1993.

202
C o m m i t t e e s and Offices Continued
Vice-Chairman, Working Group on Epidemiology and Prevention, European Society of
Cardiology, 1983-1986.
Chairman, GIEP (Italian Group for Epidemiology and Prevention Cardiovascular Diseases),
1983-1986.
Editorial Boards
Bollettino Società Italiana di Cardiologia, 1962-1968;
Cuore e Circolazione,1962-1970;
Giornale Italiano di Cardiologia, 1971-1979.
Selected Publications
Menotti A,Moschini-Antinori E,SplendianiG.
Heartdiseases inTripolitania. Aclinical and
statisticalstudy.MalatCardiov1963;4:665-675.
Puddu V,MenottiA.Ischemicheartdiseaseand
cerebrovascular accidentsmortality trendsin
theItalian regions.Theirrelationship tosome
socio-economic indexes.Acta Cardiol
1966;21:585-591.
Menotti A,Capocaccia R,ContiS,FarchiG,
MariottiS,Verdecchia A,KeysA,KarvonenMJ,
PunsarS.Identifying subsetsof major risk fac-
torsinmultivariateestimation ofcoronary risk.
JChron Dis1977;30:557-565.
ResearchGroupATS-RF2of theItalian National
ResearchCouncil (AMenotti among the
authors).Timetrendsof some cardiovascular
riskfactors inItaly.AmJEpidemiol
1987;126:95-103.
MenottiA,KeysA,Blackburn H,AravanisC,
DontasAS,Fidanza F,GiampaoliS,Karvonen
MJ,Kromhout D,Nedeljkovic S,Nissinen A,
PekkanenJ,PunsarS,Seccareccia F,Toshima H.
Twenty-year mortalityand prediction of stroke
intwelvecohortsof theSevenCountries Study.
IntJEpidemiol1990;19:309-315.
Menotti A,KeysA,Kromhout D,Nissinen A,
Blackburn H,Fidanza F,GiampaoliS,
Karvonen MJ,PekkanenJ,PunsarS,Seccareccia
F.Twenty-five yearmortalityfrom coronary
heart diseaseand itsprediction infive cohorts
of middleaged men inFinland, the Nether-
landsand Italy.PrevMed 1990;19:270-278.
ERICAResearchGroup (AMenottiamong the
authors).Prediction coronary heartdiseasein
Europe.The2nd reportof theWHO-ERICA
Project. Eur HeartJ 1991;12:291-297.
MenottiA,KeysA,Blackburn H,KarvonenM,
PunsarS,Nissinen A,PekkanenJ,Kromhout D,
Giampaoli S,Seccareccia F,FidanzaF,
Nedeljkovic'S, AravanisC,DontasAS,Toshima
H.Blood pressure changesaspredictorsof
future mortality intheSevenCountriesStudy.J
Hum Hypertension 1991;5:137-144.
MenottiA,Lanti P,Seccareccia F,GiampaoliS,
Dima F.Multivariate prediction of the first
major cerebrovascular event inanItalian sam-
pleofmiddleaged men followed-upfor25
years.Stroke1993;24:42-48.
MenottiA,Seccareccia F,LantiM,GiampaoliS,
Dima F.Timechanges inpredictability ofcor-
onary heartdiseaseinan Italianaging popula-
tion.Cardiology 1993;82:172-180.
203
Nedeljkovic, S r e c k o Professor

Education
MedicalSchool,University of Belgrade M.D. 1952 Medicine
Residency andspecialty ininternal medicine 1953-1957
Colombia University,NY 1961-1962 Biostatistics
Habilitation inmedical scienceson 1963
ballistocardiography
Subspecialty incardiology, Medical Faculty, 1965 Cardiology
Belgrade
MasterofScience M.Sc. 1967
Doctorofscience Ph.D 1969

Professional Experience
Assistant Professor ofInternal Medicine,Medical Faculty Belgrade,1959.
Associate Professor, 1970andProfessor, 1976.
FullProfessor ofInternal MedicineandCardiology, 1981-1989

Special Experience
Project Officer, Serbian cohortsoftheSevenCountries Study, 1962-1985
Principal Investigator,Serbian part oftheSevenCountries Study,1986-1993.
Co-investigator, theBelgrade 'Rakovica cardiovascular study',1972-1992.
Principal Investigator, 'Electrotherapy incardiacarrhythmias',Serbian Research Council,
1964-1972.
Principal Investigator, 'Hemodynamics incoronary heartdiseases',Serbian Research
Council,1974-1980.
SecretaryandChief,Postgraduate SchoolofCardiology,1975-1989.
Founder andChief,Cardiology Laboratory,MedicalClinicB,1962-1984.
Chief,Cardiology ClinicatMedical clinicB,1985-1986.
FounderandFirstDirector,InstituteofCardiovascular Diseases,University Clinical Centre,
MedicalFaculty Belgrade,1987-1989.
Consultant,InstituteofCardiovascular Diseases,University ClinicalCentre,1989-present.

C o m m i t t e e s and Offices
Member,Serbian MedicalAcademy, 1978.Vice-president,1990-1993.
President,Serbian SocietyofCardiology,1976-1978.
President,YugoslavSocietyofCardiology, 1985-1989.Honorary president since1992.
Member,Scientific CommitteeofMediterranean AssociationofCardiology andCardiac
Surgery, 1987-present.
Affiliated FellowAmerican CollegeofCardiology, 1965-1992.Present status emeritus.
Fellow,European SocietyofCardiology,since1988.
Organizer,twocardiology exchangemeetingsbetween BaylorCollegeofMedicine (Houston,
TX)andBelgradeMedical Faculty.InBelgrade,1981 andinHouston, 1991.
Chairman,Symposium 'Rheumatic heart diseaseinyoung' World CongressofCardiology,
Moscow,1982.

204
Honors
Belgrade October Award. Contribution to science and arts, for the realization of the Serbian
part of the Seven Countries Study, 1970.
Serbian National Day Award 'Seventh July' for the contribution to science and health promo-
tion, in relation with the 'Rakovica cardiovascular study', 1979.
Belgrade October Award. Contribution to science and arts, for the monograph 'Cardiac block
and pacemakers',1981.
Decoration for 'Services to the people with golden wreath', 1986.
Gold Medal for Services to Yugoslav Society of Cardiology, 1989.
'Yugoslav Distinguished Sportsman title for chess play achievements and two silver medals
won in European championships, 1958and 1961.
Serbian Medical Society 'Life achievement award', 1993

Selected Publications
V

Plavei?C,HidM,Nedeljkovic S.Lesmaladies des NedeljkovicS,GrujicM,Menotti A,KeysA,

artèrescoronairesenYougoslavie.Acta
Cardiologica 1959;14(Suppl8):79-86.
Djordjevicf B,SimidB,Simic'A,StrasserT,
Josipovid V,MacarolV,KlincI,NedeljkovicS,
TodorovidP.Dietarystudies inconnection with
epidemiology of heartdiseases:resultsin
Serbia.Voeding1965;26:117-127.
Nedeljkovid S,Djordjevic B,Stojanovic G.
Ballistocardiographic findings inan epidemi-
ologicalstudy ofcardiovascular diseasesin
Yugoslavia,Ballistocardiography, BiblCardiol,
Krager,Basel1968;21:16-20.
Djordjevid B,BalogB,Bo2inovicLj,JosipovidV,
Nedeljkovic S,LambicI,SekulidS,SlavkovicV,
StojanovicG,SimicA,SimicB,StrasserT,
Blackburn H,KeysA.Threecohortsof men
followed fiveyears inSerbia.InKeysA,etal
(Eds).Coronary heart diseaseinSeven
Countries.Circulation 1970;41 (Suppl1):
123-137.
Nedeljkovic'S, Djordjevic B,StojanovicG.Follow
upballistocardiographic findings inanepide-
miological study ofcardiovascular diseasesin
Yugoslavia, Ballistocardiography, BiblCardiol,
Krager,Basel1973;31:237-244.
Nedeljkovic S,Djordjevic B,Josipovid V,Bo2ino-
vic'Lj,Kozarevic'Dj,Demirovic'J,Vojvodic'N,
SiminN,Ostojid M,Grujic M,MilosevidM.
Twenty year follow up of three population
groups inSerbia:reexamination of University
professors inBelgrade.ApartofSeven
CountriesStudy.CVDEpidemiological
Newsletter 1985;38:119-120.
StojanovicG,Ostojic'M,Kromhout D.Coronary
heart diseasemortality inthreeSerbian cohorts
-partofSevenCountriesStudy followed 25
years.Abstracts.EurHeartJ1989;10:807.
Nedeljkovic S,MenottiA,KeysA,OstojidM,
Grujic M,Kromhout D,Stojanovic G.Coronary
heartdiseaseinthreecohortsofmeninSerbia
followed up for25yearsasapart ofSeven
CountriesStudy.Kardiologija 1992;13(l-2):
35-44.
Nedeljkovic'S,Ostojid M,Grujic'M,JosipovidV,
KeysA,MenottiA,Seccareccia F,LantiM,
Kromhout D.Coronary heartdiseasedeathsin
25years.TheexperienceinthreeSerbian
cohortsof theSevenCountriesStudy.Acta
Cardiologica 1993;48(l):ll-24.
Kromhout D,Nedeljkovic SI,Grujic MZ,Ostojic
MC,KeysA,MenottiA,Katan MB,Van
OostromMA,BloembergBPM.Changesin
major risk factors for cardiovascular diseases
during 25yearsin theSerbian cohortsof the
SevenCountriesStudy.IntJEpidemiol.
Accepted.

205
Nissinen, A u l i k k i M . Professor

Education
Kuopio Nursery College 1963 Nursery
Helsinki Nursery College 1965 Public health
nursery
Universityof Kuopio M.D. 1977 Medical doctor
University of Kuopio Ph.D. 1979 Public health

Professional Experience
Nurse,KuopioCentral Hospital,1963-1964.
Publichealth nurse,Cityof Helsinki,1965.
Midwife,City of Helsinki,1966.
Nurse teacher, Helsinki Nursery College,1970.
Assistant Professor inPublicHealth,University of Kuopio, 1977-1981.
Professor of PublicHealth,University of Kuopio,1981-1982.
Chief of Laboratory ofChronic Diseases,National PublicHealth Institute,Helsinki,
1983-1985.
MedicalOfficer, Cardiovascular DiseasesUnit,World Health Organization,
Geneva,Switzerland, 1986-1988.
Professor inPublicHealth,University of Kuopio,Medical Faculty,1988-present.

Special Experience
Co-principal Investigator of theNorth Karelia Project
Coordinator of WHOglobal InterHealth-project (Integrated Programme for Prevention and
Control of ChronicDiseases).

Committees and Offices

Member ofseveral scientific and administrative boards,Faculty ofMedicine,Universityof
Kuopio,1972-1982,1988-present.
Expertgroups,Ministry of Education and Medical Board of Health, Finland,1975-1985.
Member, Finnish AcademyofScience,Medical Department, 1988-present.
Member, Developing Country Research Council,1988-present.Chairperson, 1991-present.
Member, Finnish Physical ExerciseScientific Board,Ministry of Education,1988-1991,
Chairperson, 1991-present.
Member,SteeringGroup for Health by2000-program, Ministryof Health and Social Welfare,
1988-present.

206
Selected Publications
Tuomilehto J, Nissinen A,Salonen JT, Kottke TE,
Puska P.Community programme for control of
hypertension in North Karelia, Finland. Lancet
1980;2:900-904.
Puska P,lacono JM, Nissinen A, Korhonen HJ,
Vartiainen E,Pietinen P, Dougherty R, Leino U,
Mutanen M, MoisioS, Huttunen J. Controlled,
randomized trial of the effect of dietary fat on
blood pressure. Lancet 1983;l/8:l-5.
Puska P,Nissinen A,Tuomilehto J,Salonen JT,
Koskela K, McAlister A, Kottke TE,Maccoby N,
Farquhar JW.The community-based strategy to
prevent coronary heart disease: conclusions
from the ten years of the North Karelia Project.
Ann Rev Publ Hlth 1985;6:147-193.
Nissinen A,Tuomilehto J, Kottke TE, Puska P.
Cost-effectiveness of the North Karelia hyper-
tension program 1972-1977.Medical Care
1986;24(8):767-780.
Pekkanen J,Marti B,Nissinen A, Tuomilehto J,
Punsar S, Karvonen MJ. Reduction of prema-
ture mortality by high physical activity: A 20-
year follow-up of middle-aged Finnish men.
Lancet 1987;1473-1477.
Nissinen A,Tuomilehto J, Korhonen H, Piha T,
Salonen JT,Puska P.Ten-years results of hyper-
tension care in the community: Follow-up of
the North Karelia hypertension control pro-
gram. Am JEpidemiol 1988;127(3):488-199.
Lammi U-K, Kivelä S-L, Nissinen A, Punsar S,
Puska P, Karvonen MJ. Predictors of disability
in elderly Finnish men. A longitudinal study.J
Clin Epidemiol 1989;42(12):1215-1225.
Nissinen A, Wiklund I,Lahti T,Akkila J, Wilson
A, Wahl M, Puska P.Anti-anginal therapy and
quality of life. A comparison of the effects of
transdermal nitroglycerin and long-acting oral
nitrates.JClin Epidemiol 1991;44(9):989-997.
Pekkanen J,Nissinen A, Punsar S, Karvonen MJ.
Short and long-term association of serum cho-
lesterol with mortality. The 25-year follow-up
of the Finnish cohorts of the Seven Countries
Study. Am JEpidemiol 1992;135(11):1251-1258.
Tuomilehto-Wolf E,Tuomilehto J,Hitman CA,
Nissinen A, Stengârd J, Pekkanen J, Kivinen P,
Kaarsalo E, Karvonen MJ.Genetic susceptibility
to non-insulin dependent diabetes mellitus and
glucose intolerance are located in HLA region.
Br Med J 1993;307:155-159.
207
Pekkarinen, Maija Associate Professor

Education
Järvenpää College for 1942 Home
teachersof Home Economics economics
University of Helsinki M.Sc. 1952 Household
economics
University of Helsinki Lic.Agr.Sci. 1958 Nutrition
University of Helsinki D.Agr.Sci. 1962 Nutrition

Professional Experience
Home economicsexpert,TheFinnish Martha Organization,1942-1950.
Assistant Professor, Department of Household Economics,University of Helsinki,1950-1957.
Research work for Doctor'sdegree, 1958-1961.
Research Assistant and junior fellow, National ResearchCouncil for Agriculture and
Forestry,Academy of Finland,1962-1968.
AcademicDocent,University of Helsinki,1966-1968.
Associate Professor, University of Helsinki, 1968-1981.
ActingProfessor, Head of Department ofNutrition,Universityof Helsinki,1971-1977.

Committees and Offices

Board Member, Foundation for promotion of food production,1962-1981.
Member,Group of European Nutritionists,1969-present.
Board Member, National Research Council for Agricultureand Forestry,Academyof
Finland,1971-1976.
Member, Finnish FAOcommittee and chairperson, Divisionof Homeeconomicsand nutri-
tion,1974-1982.
Board Member and VicePresident, FAO/ECAworking party on women and the agricultural
family inrural development, 1972-1982.
Chairperson, Research Centrefor Home Economicsand Consumer Affairs,1972-1983.
ViceChairperson, Finnish StateCouncil onNutrition,1977-1982.

Honors
Gold Badgeof Merit,TheFinnish Martha Organization,1965.
Knight, 1stcall,Order of theWhiteRoseof Finland,1979.
Honorary member:
Finnish Martha Organization,1977.
Association of Home EconomicsTeachers,1979.
Association of Nutrition Therapists, 1981.
Association of University Home Economics,1983.

208
Selected Publications
RoineP,Pekkarinen M,Karvonen MJ,KihlbergJ.
Dietand cardiovascular diseasein Finland.
Lancet1958;2:173-175.
Karvonen MJ,Pekkarinen M,Metsälä P,Rautanen
Y. Dietand serum cholesterol of lumberjacks.Br
JNutr1961;15:157-163.
Pekkarinen M.Weighing method indietary sur-
veys.Voeding1964;25:26-31.
Pekkarinen M,RoineP.Studieson thefood con-
sumption oftherural population in Eastand
WestFinland.AnnMed ExpBiolFenn
1964;42:93-101.
RoineP,Pekkarinen M,Karvonen MJ.Dietary
studies inconnection withepidemiologyof
heart disease:ResultsinFinland.Voeding
1964;25:383-393.
Pekkarinen M.Chemical analysisin connection
withdietarysurveys in Finland. Voeding
1967;28:2.
Pekkarinen M,Kivioja S,Jortikka L.Acomparison
of food intakeof rural families estimated byone
day recalland preciseweighing methods.
Voeding 1967;28:470-476.
Pekkarinen M.Methodology in thecollectionof
food consumption data.World RevNutr Diet
1970;12:145-171.
Pekkarinen M.Dietary surveys inconnection with
coronary heart diseasestudiesinFinland. New
TrendsinNutrition,Lipid Research and
Cardiovascular Diseases.Alan R.LissInc.New
York, 1981:243-261.
AhoK,Pekkarinen M.Dietand physical activity
ofmeninEast and WestFinland in1969.Ann
Med1989,21:241-243.
209
Puddu, Vittorio Professor

Vittorio Puddu wasborn in 1909inAncona,theregion of Marche,central Italy,intoa family

ofSardinian origin.
After graduation inMedicineat theUniversityof Romehebecameoneof thefirst Italian
doctors whoused anelectrocardiographic machine,which put himon the track ofdevelop-
ingapeculiar interest inthestillnon-existing disciplineofcardiology. Hewas later trained in
thisdeveloping disciplineinParisand Vienna,and started what could havebeenabrilliant
university career.However, for anumber of reasons henever tookachair,alsoreflecting his
substantially independent personality.
After theSecond World War,which took himtoRussia asmedical officer in the Italian
army,hehad another term offoreign experience inParis,and camebackwith theclearbelief
that somecardiovascular diseaseswereof socialinterest due totheirlargenumber and
marked severity.Through thefinancial support of theMinistry of Health hefounded the first
Centrefor Cardiovascular DiseasesinRome,located in theUniversity Hospital of Rome-
and then in theSt.CamilloHospital of thesamecity-but completely independent from the
University itself.Initially,themain interest was focused onrheumatic heart disease,which
was theprevalent oneinthose times,whilelater coronary heart diseasebecame the major
interest.In 1956hefounded thefirst Division ofCardiology inItaly,again at theSt.Camillo
Hospital and was thechief of thatunituntil retirement in1976.
Professor Puddu wasapioneer rich ingreat intuitions.Heestablished inhiscountrya
number of firsts:hewas thefirst tolaunch epidemiological studiesinthemedicalschoolsin
search ofignored rheumatic and congenital heart diseases,and thefirst, through theSeven
Countries Study,tobeinvolved inepidemiology ofcoronary heart disease;inhisCenter and
in theDivision ofCardiology oneof thefirst cath-labs,thefirst coronarycareunit,and the
first cardiacrehabilitation center inItalywerelocated.Alargenumber of scientific papers
resulted from such intenseand varied activity.
Moreover, hewasagreat promoter ofcardiology atanational and international level.His
fluency infour languages,beyond hisnativeone,put him intheidealsituation for becoming
a leader inthisaction,culminating inhisposition asSecretaryGeneral of the International
SocietyofCardiology for many yearsand President of thesamesocietyfor one term.
Besidesallhismeritsincardiology Professor Puddu wasaneclecticperson rich in many
hobbies.Hewasanexpert gastronome with official positions ingroups and societies in this
field; hewasaskilled electro-mechanicalengineer abletodisassemble and fix anECG
machineifneeded;hewasfor someyearsarenowned champion inoutboard motorboatrac-
ingand lateravaluablecompetitor insailboatracing;hewasacollectorof archeological
specimensof smallbronzestatutesand aconstructor of flying airplane models.
Hislastyearsweresad and troubled byan aggressive Parkinson diseasewhich took him
away in1991.

211
Punsar, Sven Physician

Education
University of Helsinki,Finland M.D. 1953 Medicine
Specialist inInternal Medicine 1961
Specialist in Cardiology 1963
University of Helsinki,Finland Ph.D. 1980 Medicine

Professional Experience
MedicalOfficer, Finnish Army,1954.
Assistant Physician,SalusHospital,Helsinki,Finland,1956.
Research Fellow,Laboratory of Physiological Hygiene,Schoolof PublicHealth,Universityof
Minnesota,1957-1958.
Assistant Physician,HelsinkiUniversity Hospital,Finland, 1958-1961.
Private Physician,Helsinki,Finland,1958-1965.
Physician,Student Health Service,1962.
Assistant Physician (Cardiology),Helsinki University Hospital,1962-1965.
AssistantChief Physician, Internaland Pulmonary Medicine,LaaksoHospital,Helsinki,
1965-1985.
Chief Physician,Department of Internal Medicine,LaaksoHospital,Helsinki,1985-1986.

Special Experience
Project Officer, TheEast-WeststudiesinFinland, theSevenCountries Study,1959,1964-1980.
Consultant,TheMobileClinic,theNational Pension Institute,1965-1985.
Principal Investigator,TheEast-West StudiesinFinland, theSevenCountries Study,
1980-1984.
Docent inEpidemiology,University of Helsinki,1981-1986.

Committees and Offices

Member, theScandinavian Committee on ECGclassification, 1966.
Member,Committee for Safety"andEfficacy of Drugs,National Board of Health,1970-1982.
Secretary,Finnish InternistsAssociation,1971-1973.

212
Selected Publications
Blackburn H,KeysA,Simonson E,Rautaharju P,
PunsarS.Theelectrocardiogram in population
studies.Aclassification system. Circulation
1960;21:1160.
TheScandinavian CommitteeonECG
Classification (Punsar S).The 'Minnesota Code'
for ECGclassification. Adaptation toCRleads
and modification ofthecodefor ECG'srecord-
ed during and after exercise.Acta Med Scand
1967;Suppl 481.
Karvonen MJ,BlomqvistG,KallioV,OrmaE,
PunsarS,Rautaharju P,TakkunenJ,KeysA.
Meninrural Eastand WestFinland.ActaMed
Scand 1967;Suppl460:169.
PunsarS,Pyörälä K,Siltanen P.Classification of
electrocardiographicS-Tsegment changesin
epidemiological studiesofcoronary heartdis-
ease.Preliminary evaluation ofanew, modified
classification, with particular reference tothe
prognostic significance ofdifferent typesofS-T
segmentchanges.Ann Med Int Fenn1968;57:53.
Karvonen MJ,Orma E,PunsarS,KallioV,Arstila
M,LuomanmàkiK,TakkunenJ.Five-yearexpe-
rienceinFinland.In:Coronary heartdiseasein
sevencountries.KeysA(Ed).Circulation
1970;41(Suppl1):52.
PunsarS.Cardiovascular mortality and qualityof
drinking water.Anevaluation of the literature
from anepidemiological pointof view.Work
Environment Health1973;10:107.
PunsarS,Karvonen MJ.Angina pectorisand ECG
abnormalities inrelation toprognosisofcoro-
nary heart diseaseinpopulation studiesin
Finland.AdvCardiol1973;8:148.
PunsarS,ErämetsäO,Karvonen MJ,RyhänenA,
Hilska P,VornamoH.Coronary heart disease
and drinking water.Asearch intwo Finnish
malecohorts forepidemiologicevidenceofa
water factor. JChron Dis1975;28:259.
PunsarS,Karvonen MJ.Physicalactivity and cor-
onary heartdiseasein populations from East
and WestFinland.AdvCardiol1976;18:196.
PunsarS,Karvonen MJ.Drinking water quality
and sudden death:observations from West and
EastFinland.Cardiology 1979,64:24.
213
Räsänen, L e e n a K. Associate Professor

Education
University of Helsinki, Finland M.Sc. 1970 Nutrition
University of Helsinki, Finland Lic.Sc. 1977 Nutrition
University of Helsinki, Finland D.Sc. 1980 Nutrition

Professional Experience
Teaching Assistant, Department ofNutrition, University of Helsinki,Finland,1970-1971.
Research Associate,National Research Council for Agriculture and Forestry,Academyof
Finland,1972-1977.
Junior Research Fellow,National ResearchCouncil for Agriculture and Forestry,Academyof
Finland, 1978.
Acting AssociateProfessor of PublicHealth Nutrition, Department of Public Health,
Universityof Tampere, Finland,1979-1982.
Teacherof Nutrition, Faculty of Medicine,University of Helsinki,Finland,1979-1984.
SeniorScientist,National Research Council for Agriculture and Forestry,Academyof
Finland, 1982.
ActingProfessor of Nutrition, Department of Nutrition, University of Helsinki, Finland,
1986-1988.
SeniorScientist,National Research Council for Agriculture and Forestry,Academyof
Finland,1989-1990.
Associate Professor of Nutrition, Division of Nutrition, Department ofApplied Chemistry
and Microbiology,University of Helsinki,1982-present.

Committees and Offices

Member,Societyfor Food ScienceinFinland, 1972-present.
Member, Finnish Association of Public Health and Clinical Nutritionists,1976-present.
Member,SocietyofSocialMedicineinFinland, 1972-present.
Member of Board,Society ofSocialMedicineinFinland,1976-1981.
Member, NordicGroup for Dietary Survey Methodology,1976-1985.
Member ofCouncil,Federation of European Nutrition Societies,1979-1989.
Member,Group of European Nutritionists,1983-present.
Member, Finnish Society for Nutrition Research,1985-present.
ViceChairman, Finnish Societyfor Nutrition Research,1992-present.

214
Selected Publications
RäsänenL,Wilska M,KanteroR-L,NäntöV,
AhlströmA,Hallman N.Nutrition surveyof
Finnish rural children.IV.Serum cholesterol
values in relation todietary variables.AmJ
Clin Nutr 1978;31:1050-1056.
Räsänen L.Nutrition survey of Finnish ruralchil-
dren. VI.Methodological study comparing the
24-hour recall and thedietary history interview.
AmJClin Nutr 1979;32:2050-2057.
RäsänenL,Pietinen P.Ashort questionnaire
method forevaluation ofdiets.PrevMed
1982;11:669-676.
Moilanen T,Räsänen L,ViikariJ,Âkerblom HK,
AholaM,Uhari M,Pasanen M,NikkariT.Fatty
acid composition ofserumcholesterylestersin
3-to 18-year-old Finnishchildren and itsrela-
tion todiet.AmJClin Nutr1985;42:708-713.
Pietinen P,Hartman AM,Haapa E,RäsänenL,
HaapakoskiJ,PalmgrenJ,AlbanesD,Virtamo
J,Huttunen JK.Reproducibility and validityof
dietary assessment instruments.I.Aself-
administered food usequestionnaire witha
portion sizepicturebooklet.AmJEpidemiol
1988;128:655-666.
Räsänen L,LaitinenS,Stirkkinen R,KimppaS,
ViikariJ,Uhari M,Pesonen E,SaloM,
Âkerblom HK.Composition of thedietof
young Finnsin 1986. AnnMed 1991;23:73-80.
Virtanen SM,Räsänen L,AroA,YlönenK,
Lounamaa R,TuomilehtoJ,Âkerblom HK.The
'Childhood Diabetes in Finland' StudyGroup.
Feeding in infancy and theriskof type 1 dia-
betesmellitus inFinnish children. DiabeticMed
1992;9:815-819.
Räsänen L,Mutanen M,Pekkanen J,LaitinenS,
Koski K,Halonen S,Kivinen P,StengârdJ,
Nissinen A.Dietary intakeof70-to89-year-old
men ineastern and western Finland.JIntern
Med 1992;232:305-312.
Moilanen T,Räsänen L,ViikariJ,Âkerblom HK.
Trackingofserum fatty acid composition:a
6-yearfollow-up study of Finnish youths.AmJ
Epidemiol 1992;136:1487-1492.
LehtimäkiR,MoilanenT,Porkka K,Âkerblom
HK,Ehnholm C,Rönnemaa T,Räsänen L,
Laippala P,ViikariJ.Association ofserumlip-
idswithapolipoprotein Ephenotypeand lino-
leicacid content of serum cholesteryl estersin
theCardiovascular RiskinYoung FinnsStudy.
Nutr MetabCardiovasc Dis1993;3:61-65.
215
T a y l o r , H e n r y L. Professor
BornFebruary2,1912
Died November 10,1983

Education
Harvard College,Boston,MA B.A. 1935 Biochemistry
University of Minnesota, Minneapolis,MN Ph.D. 1941 Physiology

Professional Experience
Assistant Professor, Physiological Hygiene,University of Minnesota, 1944-1949.
AssociateProfessor, Physiological Hygiene,University of Minnesota,1949-1956.
Professor, Physiological Hygiene,University ofMinnesota, 1958-1983

Special Experience
Investigator, Aging,personal characteristics,and coronary heartdiseaseinMinnesota busi-
nessmen,1948-1983.
Principal Investigator, Epidemiology ofcoronary heartdiseaseinUSrailroad employees,
1956-1972.
Fieldwork epidemiology of coronary heart diseaseamong employeesof Italian National
Railroads,Rome,Italy,1962and 1967.
Director,Cooperativestudy of theprevalence of hyperlipoproteinemias for the Minnesota
Unit of theLipid Research Clinics,1972-1982
Co-investigator, Minnesota Clinicof theMultiple RiskFactor Intervention Trial,1973-1982

Committees and Offices

Research Committee,American Heart Association,1960-1965.
ExecutiveCommittee,Councilon Epidemiology,American Heart Association,1964-1965.
WhiteHouseConference on Food,Nutrition and Health;Consultant toPanelonAdultsinan
Affluent Society:TheDegenerative Diseasesof MiddleAge,1968.
Chairman,SteeringCommittee of theCooperative Study on theFeasibility of Physical
Activity inTrialsof Coronary Heart DiseasePrevention,1966-1969.
Member, Panel on Exercise,National Heart and Lung Institute,TaskForceon
Arteriosclerosis, 1971.
Member Division of ResearchGrants,National Institutesof Health Study Section,Applied
Physiology and Bioengineering,1972-1976.

216
Selected Publications
KeysA,BrozekJ,HenschelA,MickelsenO,
Taylor HL.Thebiologyof human starvation.
Universityof Minnesota Press,Minneapolis,
MN,1950;Vol1-2:1-1385.
Taylor HL,KeysA.Adaptation tocaloricrestric-
tion.Science1950;112:215-218.
Taylor HL,Buskirk ER,HenschelA.Maximal
oxygen intakeasanobjective measureofcar-
dio-respiratory performance. JAppl Physiol
1955;8:73-80.
TaylorHL,KlepetarE,KeysA,ParlinW,
Blackburn H,PuchnerT.Death ratesamong
physically activeand sedentary employeesof
therailroad industry.AmJPubl Hlth
1962;52:1697-1707.
KeysA,TaylorHL,Blackburn H,BrozekJ,
AndersonJT,Simonson E.Coronary heartdis-
easeamong Minnesota businessand profession-
almen followed fifteen years.Circulation
1963;28:381-395.
Taylor HL,Blackburn H,BrozekJ,ParlinRW,
Puchner T,MontiM,Puddu V,Menotti A,Keys
A.Railroad employees intheUSand railroad
employeesinRome.In:Epidemiological studies
related tocoronary heart disease:
Characteristics of menaged 40-59inseven
countries. KeysA,etal (Eds).Acta MedScand
1967;460(Suppl 180)55-115.
Taylor HL,Blackburn H,KeysA,ParlinRW,
VasquezC,PuchnerT.Fiveyear follow-upof
employeesofselected USRailroad companies.
In:Coronary heart diseaseinseven countries.
KeysA(Ed).Circulation 1970;41(SupplD.20-39.
Taylor HL,Buskirk ER,Remington R.Exercisein
controlled trialsof theprevention of coronary
heartdisease.Fed Proc1973;32:1623-1627.
Taylor HL,JacobsDR,Schucker B,KnudsenJ,
LeonAS,DeBackerG.Questionnaire for the
assessment ofleisuretimephysical activities.J
Chron Dis1978;31:741-755.
Taylor HL.Physicalactivity:Isitstillarisk factor.
PrevMed 1983,12:20-24.
217
Toshima, Hironori Professor/Director

Education
Kyushu University, Faculty of Medicine M.D. 1952 Medicine

Professional Experience
Internship,Kyushu University Hospital,1952-1953.
Residency,the 1stDepartment of Medicine,Kyushu University Hospital,1953-1958.
Research Fellow,Laboratory of Physiological Hygiene,University of Minnesota,USA,
1963-1964.
AssociateProfessor, the3rd Department ofMedicine,KurumeUniversity Schoolof
Medicine,1959-1977.
Professor, the3rd Department of Medicine,Kurume University SchoolofMedicine,
1977-present.
Director,TheInstituteofCardiovascular Diseases,Kurume University, 1977-present.

Committees and Offices

Director,JapaneseCirculation Society,1979-present.
Chairman,Idiopathic Cardiomyopathy Research Committee,Ministry of Health and Welfare
ofJapan,1980-1986.
President, the54thAnnual Scientific Meetingof theJapaneseCirculation Society,1990.
Member,Scientific Council on theRehabilitation of CardiacPatients,International Society
and Federation ofCardiology,1981-1988.
Member, Board of Directors,Japanese Heart Foundation, 1990-present.
President, the12thScientific Sessionof theJapaneseSocietyofClinical Nutrition.1990.
President, the26thScientific Sessionof theJapaneseAssociation for Cerebro-cardiovascular
DiseaseControl, 1991.
Chairman, Prevention Committee,Asian-Pacific SocietyofCardiology, 1991-present.
Chief Director,Kimura Memorial Heart Foundation, 1992-present.
Chief Director,theJapaneseAssociation for Cerebro-cardiovascular DiseaseControl, 1991-
present.

218
Selected Publications
Cueto J,Toshima H, Tuna N, Armigo G, Lillehei
CW. Vectorcardiographic studies in acquired
valvular disease with reference to the diagnosis
of right ventricular hypertrophy. Circulation
1966;33:588.
Simonson E,Tuna N, Okamoto N,Toshima H.
Diagnostic accuracy of the vectorcardiogram
and electrocardiogram. Am J Cardiol
1966;17:829.
Toshima H, Cueto J, Lillehei CW.
Vectorcardiographic studies in acquired valvu-
lar disease with reference to the diagnosis of
left ventricular hypertrophy. Circulation
1967;35:132.
Toshima H, Fukami T.Clinical features of ido-
pathic hypertrophic cardiomyopathy. Jpn CireJ
1971;35:777.
Toshima H. Prognosis of patients with rheumatic
heart disease and some aspects in its preven-
tion. Jpn JMed 1974,13:95.
Toshima H, Koga Y,Uemura S,Jinnouchi J,
Kimura N, Nakakura S. Echocardiography
study on hypertrophic cardiomyopathy. Jpn
HeartJ1976;17:275.
Toshima H, Koga Y,Yoshika H, Akiyoshi T,
Kimura N. Echocardiographic classification on
hypertensive heart disease. A correlative study
with clinical features. Jpn Heart J1976;16:377.
Toshima H, Tashiro H, Sumie M, Koga Y, Kimura
N. Changes in risk factors and cardiovascular
mortality and morbidity within Tanushimaru
1958-1982. In: Nutritional prevention of cardio-
vascular disease. Lovenberg E,Yamori Y(Eds).
Academic Press,Orlando. 1984:203-210.
Toshima H. State of the art in patient education in
Japan. In:The education of the patient with car-
diac disease in the twenty-first century. Wenger
NK (Ed).LeJacq Publishing Inc, 1986:292.
Nishi H, Kimura A, Harada H, Toshima H,
Sasazuki T. Novel missense mutation in cardiac
ß myosin heavy chain gene found in a Japanese
patient with hypertrophic cardiomyopathy.
Biochem Biophys Res Commun 1992;188(1):379-
387.
219
This highly readable monograph, composed and edited by the
investigators, is an unusual history of an unusual undertaking,
The Seven Countries Study, a landmark in cardiovascular
disease epidemiology. It is doubtful that any other major long-
term scientific enterprise, this one in its 35th year, has been
more appealingly documented by the scientists and clinicians
involved.

The introduction is by the founder of the Study, Ancel Keys,

about how it began, with the ideas of collaborators looking
beyond their clinics and laboratories to broader questions
about the origins of heart disease. The other investigators
provide delightful, personalized details of the study's
tribulations in the field, about its contributions to survey and
follow-up methodology in epidemiology, and about its
findings. An overview is given of results of the Study, along
with commentary by Frederick Epstein, long-term observer of
the scene, on the public health influence of the Study.

The Seven Countries Study was the first to carry out both
cross-sectional and longitudinal cohort studies in populations
purportedly contrasting in cardiovascular disease rates and in
lifestyle, including diet. It was the first to apply regressions
developed in one population to men of similar age in another,
demonstrating the universality of CVD risk factors but their
different forcein individuals and contrasting cultures.

Relatively short and easily read, the volume contains the

essence of the design, operation, main results, and public
health import, and much more of the flavor, of this pioneering
study in cardiovascular disease.