THE SEVEN COUNTRIES STUDY A scientificadventure in cardiovasculardisease epidemiology THE SEVEN COUNTRIES STUDY A scientific adventure in cardiovasculardisease epidemiology Editors: Daan Kromhout Professor, Director Division of Public Health Research National Institute of Public Health and Environmental Protection P.O.Bo x 1,372 0B ABilthoven ,Th e Netherlands Alessandro Menotti Professor, Director Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanita VialeRegin a Elena 299,1-00161Rome ,Ital y Henry Blackburn Mayo Professor, Division of Epidemiology University of Minnesota Suite300,130 0Sout h Second Street, Minneapolis, MN55454-1015 ,US A THE SEVEN COUNTRIES STUDY A scientificadventure in cardiovascular disease epidemiology Editors: Daan Kromhout, Alessandro Menotti and Henry Blackburn Investigators and Contributors: Ancel Keys,Christo sAravanis , Henry Blackburn, Frans SPva n Buchem*, Ratko Buzina, BozidarS Djordjevic" , Anastasios SDonta s Frederick H Epstein, FlaminioFidanza , Martti JKarvone n Noboru Kimura*,Daa n Kromhout, Alessandro Menotti,Sreck o I Nedeljkovic Aulikki Nissinen, Maija Pekkarinen ,Vittori o Puddu",Sve n Punsar Leena Räsänen, Henry L Taylor*,Hironor i Toshima *decease d Cover/design: Anne-Claire Alta bNO,RIVM ,Bilthoven ,Th e Netherlands Production: Marjan Nijssen-Kramer, Studio RIVM,Bilthoven ,Th e Netherlands Printing: Brouwer Offset bv, Utrecht,Th e Netherlands Thepublication ofthis bookwas made possible bygenerous grants ofthe Centre for the Fight against Infarction, Rome,Italy . Division of Epidemiology, University of Minnesota, School of Public Health,Minneapolis ,Minnesota ,U.S.A . Finnish Heart Foundation, Helsinki, Finland. National Institute of Public Health and Environmental Protection, Bilthoven,Th e Netherlands. Netherlands Heart Foundation,Th e Hague,Th e Netherlands. North Karelia Project Research Foundation,Joensuu , Finland. Third Department of Medicine,Kurum e University School of Medicine, Kurume,Japan . ISBN90-6960-048- x All rights reserved. No part of thispublicatio n may bereproduced , stored in anautomati c retrieval system,o r transmitted inan y form or by any means,electronic ,mechanical ,photocopying , recording or otherwise,withou t the prior permission of theeditors . 7 ToAncel Keys onhis 90th birthday PREFACE I he fieldwork for the Seven Countries Study began in1958 . During the past 35year s a tremendous amount of work has been carried out in that study, under the leadership of Ancel Keys.Thre e monographs and a countless number of papers have been published. Nevertheless, there isn o publication sum­ marizing how the study developed in the different countries, nor are the major results of the study and their public health implications available in one place. Therefore the idea arose in connection with the international symposium, 'Lessons for Science from theSeve n Countries Study' (held on October 30,1993,i n Fukuoka, Japan, organized by Professor H.Toshima) ,t oassembl e this history. An editorial committee was formed, consisting of Daan Kromhout, Alessandro Menotti, and Henry Blackburn and all principal investigators of the cohorts participated in this undertaking. Professor Frederick Epstein kindly provided a chapter on the public health implications of the study. All these made this document possible, from the personal perspectives of the investigators. Thisboo k provides an overview of a study that has greatly influenced science and the public health as well asou r own careers. It would not have seen daylight without the administrative support of Anke Roccuzzo,Kari n Bruineman and Nola Fortner. Wegratefull y acknowledge their contribution. The Editors December 1993 ACKNOWLEDGMENTS I hePrincipa l Investigators acknowledge the gracious cooperation of the study communities, participants and field teams over the past 35year s as wella s achievements of the coordinating centers: Laboratory of Physiological Hygiene and Division of Epidemiology, University of Minnesota, School of Public Health, Minneapolis, Minnesota, U.S.A.. Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanitâ, Rome, Italy. University of Leiden and theNationa l Institute of Public Health and Environmental Protection, Bilthoven,Th e Netherlands. All these played a crucial role in realizing the study. The many sources of financial support that carried the Seven Countries Study through the entry examinations and the five and 10years ' follow-up surveys have been acknowledged in the 1967,1970an d 1980monographs . The 25-year mortality follow-up was realized mainly through local grants.Th e research of the 25-an d 30- year follow-up data from Finland, Italy,an d The Netherlands was partly made pos­ sible through a grant from the National 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 - WEST STUDIES 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 ƒ 78 10 INTRODUCTION The Editors I he Seven Countries Study (SCS)ha s become a classici n science for its pioneering effort in cardiovascular disease (CVD) epidemiology and for its powerful lesson toscience :tha t mass phenomena determine the population rates and the preventive strategies of CVD.Th e idea of the SCSaros e in various forms in the minds of imaginative individuals capable of integrating laboratory, clinical, and population evidence.Th e study was given substance and direction by itsleader , our colleague,Ance l Keys. TheSC Sdevelope d out of arich set of observations made by a number of clini­ cians and investigators. It emerged in embryonic form in each of the seven coun­ tries.Ther ewas ,i n thelat e 1950s,a readiness for theideas ,alon g with preparedness for effective research among disciplines and across cultures. Ancel Keys and the Minnesota group, who had participated in physiological studies during and after World War II,ha d found the importance of nutrition and lifestyle in human biology (which they called physiological hygiene),an d had recognized early that cardiovas­ cular diseases were amajo r new public health concern. Keys and colleagues were also prepared with quantitative thinking and computational skills,abl e to link ide­ as,bridg e disciplines, and apply methods appropriate to the scientific question. Taylor and colleagues at Minnesota in 1957initiate d U.S.effort s for theSC Si n a study of CVDrate s in railway occupations that required different levels of physical activity. At the same time,researcher s in several parts of the world were examining similar issues:Karvone n and the Finnish group, Fidanza and Puddu of the Italian group, Buzina and Djordjevic with the Croatian and Serbian groups,Aravani s and Dontas and the Greek group, Kimura and Toshima and theJapanes e group, and Van Buchem and Dalderup and the Dutch group. Each had already begun explora­ tions of population phenomena in CVD,testin g hypotheses about the causal roleo f diet, physical activity,an d lifestyle. Backi n Minnesota, Keys,Grande , and Ander­ son also made crucial systematic metabolic experiments in the precise serum choles­ terol effects of diet changes.Essentia l to the whole were the observations of Paul Dudley White and Noboru Kimura, who put into bold and simple terms the differ­ ences in CVDfrequenc y and arterial pathology seen around the world. Meetings between all these remarkable people were stimulated by Ancel Keys;th e ideas for collaborative research rapidly took hold, and active work began. Pilot studies with the Finns in 1956,an d the Italians and Greeks in 1957,demonstrate d feasibility of the SCSi n the field. The central coordinating grant toProfesso r Keys from NIH allowed the definitive cohort surveys tobegi n in Croatia in 1958, while theU.S . Railroad Study had proceeded in 1957unde r a separate grant to Henry Taylor. "Fortunatel y for the SCS,nationa l Heart Foundations and other groups were ready tosuppor t the early phases of these activities.Th e U.S.Railroa d Study profit­ ed from the support of the new National Heart Institute (NHI).Ance l Keys, of course,playe d the crucial role of putting all the ideas together in a clear proposal to theNH I for collaborative research among theseve n countries. He had the interna­ tional contacts, the vision,an d the experience tomov e this major project forward. Finally, thespecia l experience and knowledge of each of the SCSprincipa l inves­ tigators about their professional fields, and about the geography and culture of their lands,alon g with their clinical contacts and political clout, enabled the wholeSC S operation