EDITORIAL
International Studies of Cardiovascular Disease
Differences in mortality rates for coronary heart disease (CHD) and stroke among countries have intrigued epidemiologists, pathologists, and other professional and lay observers for many years. There are currently eight- to twelvefold differences in CHD mortality rates between countries with high rates (e.g. Scotland and Finland), and countries with low rates (e.g. France and Japan). Numerous ecologic analyses of available data and epidemiologic studies have been designed to evaluate and attempt to explain this international variation. Among the best known studies are the Seven Countries study (l), the NI-HON-SAN study (2), and its continuing components, the Honolulu Heart Program and the studies of Japanese men in Japan (3). The Puerto Rico (4) and Yugoslavia (5) studies were designed to provide data for countries with low CHD death rates and to be comparable to the Framingham Heart Study (6). There have also been studies of migrants, for example, from Britain and Norway to the United States and from Ireland to Boston (7, 8), to try and distinguish genetic from environmental influences. More recently, attention has been given to the variable trends in CHD mortality among different countries, some experiencing declines, some increases, and some stable rates (9-11). Two reports in this issue of the Ann& of Epidemiology provide information on coronary heart disease and associated risk factors in Iceland and in Augsburg, Germany (12, 13). R a fn sson reports on mortality from ischemic heart disease (IHD) in Iceland from 1951 to 1985 and concludes that death rates from IHD have not peaked yet in his country, whereas rates in many countries, including neighboring Scandinavian countries, have fallen. Denominators for the mortality rates were derived from censuses done in 1950, 1952, 1960 and 1982; numerators are based on death certificate entries since 1951. Because the population of Iceland is small (69,000 aged 35-64 years in 1983-1985), death rates fluctuate from year to year for the five-year age groups. Spearman correlation coefficients of mortality with calendar year vary in magnitude and direction, being significantly positive in men for the period 1951-1985 but negative for half the age groups and not significant for the combined age groups for later time periods ( 1966- 1985 and 1976- 1985). In women, the pattern was similar but there were fewer significant positive correlations for the 1951-1985 interval, and they were present only for 75-79 year old women for 1976-1985. Most correlations were negative for 1976-1985 in women. The graphs also suggest that correlations may be influenced by the choice of years to begin the two more recent time periods. The extent to which the accuracy of the population estimates for intervening years, especially between 1960-1982, influences the findings is not discussed. The author points out that improvements in the diagnosis of IHD may have contributed to the apparent trends in mortality over the 35-year interval. It would be interesting to know whether death rates for other types of heart disease, stroke, and total cardiovascular disease have changed. One remarkable feature of these data is that two pathologists have coded all death certificates, but the author’s belief that this resulted in uniform registration of IHD deaths is open to question. The author’s conclusion that mortality rates from IHD among Icelanders have not yet peaked may not be true for National
Heart,
Lung and Blood Institute
0 Mihcent Higgins. MD
of the Natmnal
Institutes
of Health
568
Higgins EDITORIAL
AEP Vol. I, No. 6 November 199J : 567-569
younger men or for women; however, trends in incidence, case fatality, risk factors and medical care derived from the Icelandic cohort of the MONICA (Multinational Monitoring of Trends and Determinants of Cardiovascular Disease) project may clarify the situation once that study is completed. In the second article, by Eberle and colleagues, associations between change in weight and change in total cholesterol and change in HDL cholesterol are reported for members of the Augsburg cohort component of the MONICA study (13). MONICA is a lo-year, WHO sponsored project whose goals are to measure the trends in cardiovascular mortality and coronary heart disease and stroke morbidity and to assess the extent to which these trends are related to changes in known risk factors, daily living habits, health care or socioeconomic characteristics in 39 geographically defined communities in 27 different countries (14). Approximately 2500 men and women aged 25-64 were examined in 1984-85 and re-examined three years later. Weight gain resulted in increases in total cholesterol and decreases in HDL cholesterol in young women and to a greater extent in men. The authors interpret their findings as suggesting that beneficial effects of weight loss on lipid levels will be greater in men than women, especially at older ages. After controlling for lipid levels at baseline and changes in cigarette use and alcohol intake, the authors found that change in body mass index (BMI) was positively and significantly correlated with changes in total cholesterol in men, and in women under, but not over, 45 years of age. Correlations of changes in BMI and changes in HDL-cholesterol were negative and significant in men in each decade and in 25-34 year old women; correlations were negative, smaller and not significant in 35-54 year old women and absent in older women. There is less information about effects of gaining and losing weight on cardiovascular risk factors and on clinical events than there is on associations between adiposity and obesity and risk factors measured at the same time. Associations between change in weight and change in serum cholesterol, blood pressure, blood glucose, serum uric acid, and fibrinogen have been reported in the Framingham Heart Study and obesity, especially upper body or abdominal obesity, has been implicated as an independent risk factor for cardiovascular disease, diabetes and other conditions (15, 16). A strength of the Augsburg study is that it provides information for women as well as men, and presents data for four age groups separately. Age is a potentially important confounding factor which must be considered in evaluating relationships between weight change and morbidity or mortality. Unintentional weight loss carries a poor prognosis, especially at older ages; causes of weight gain and weight loss were not ascertained. Eberle and colleagues did control changes in smoking and drinking habits which also influence weight and change in weight (16). The prevalence of obesity is very high, especially in women and certain minority populations in the United States, and it is increasing. Once established, obesity is difficult to treat, and repeated cycles of weight gain and weight loss may be harmful. Further information from observational and intervention studies is badly needed to guide policy and develop recommendations with respect to body weight. This article on a MONICA center illustrates some of the strengths and some of the limitations of international studies of cardiovascular disease. Within each collaborating center, local information which might not otherwise have been available is providing new insights into the frequency, distribution and determinants of CHD, its risk factors and management. New investigators have been recruited into CVD epidemiology and trained in the use of standardized methods and quality control procedures. Experienced and less experienced epidemiologists, statisticians, cardiologists
Higgins EDITORIAL
AEP Vol. I, NCJ.6 November 1991: 567-569
and laboratory col, collect
scientists
have worked
the data and participate
Limitations
of international
quantity of available data, information. Participation some centers
low enough
together in analysis
studies
to design
in general
such as demographic, rates in population to raise questions
the study,
and interpretation include
develop
the proto-
of the results.
the variable
medical record sample surveys
569
quality
and
and death certificate are variable, and in
of bias, generalizability
and comparability
of results. However,
international
tive for a wider tions, country
risk factors
range
studies of cardiovascular
of disease
and medical
as large and diverse
rates and trends,
care than
disease provide socio-economic
in exist in any individual
as the United
a unique
perspec-
and living country
condi-
including
a
States. Millicent
Higgins,
MD
REFERENCES 1. Keys A, ed. Coronary heart disease in seven countries, Circulation. 1970;41(Suppl l):l-211. 2. Kagan A, Harris BR, Winkelstein W, Jr, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Demographic, physical, dietary and biochemical characteristics, J Chron Dis. 1974;27:345-64. 3. Yano K, MacLean CJ, Reed DM, et al. A Comparison of the 12-Year Mortality and Predictive Factors of Coronary Heart Disease Among Japanese Men in Japan and Hawaii, Am J Epidemiol. 1988;127:476-87. 4. Gordon T, Garcia-Palmieri MR, Kagan A, Kannel WB, Schiffman J. Differences in coronary heart disease in Framingham, Honolulu and Puerto Rico, J Chron Dis. 1974;27:329344. 5. Kozarevic D, Pirc B, Racic Z, Dawber TR, Gordon T, Zukel WJ. The Yugloslavia cardiovascular disease study, Am J Epidemiol. 1976;104:133-140. 6. Levy D, Kannel WB. Cardiovascular risks: New insights from Framingham, Am Heart J. 1988;116:266-272. 7. Rogot E. Cardiorespiratory disease mortality among British and Norwegian migrants to the United States, Am J Epidemiol. 1978;108:181-191. 8. Kushi LH, Lew RA, Stare FJ, et al. Diet and 20.year mortality from coronary heart disease: The Ireland-Boston Diet-Heart Study, N Engl J Med. 1985;312:811-18. 9. Higgins M, Luepker RV, eds. Trends and Determinants of Coronary Heart Disease Mortality: International Comparisons, Int J Epidemiol. 1989;18(Suppl 1). 10. Thorn TJ. International mortality from heart disease: Rates and trends, Int J Epidemiol. 1989;18(Suppl 1):520-B. 11. Higgins M, Thorn T. Trends in CHD in the United States, Int J Epidemiol. 1989;18(Suppl l):S58-S66. 12. Rafnsson V. Mortality from ischemic heart disease in Iceland 195 1-1985. Ann Epidemiol. 1991;l: 13. Eherle E, Doering A, Keil U. Weight change and change of total cholesterol and HDL-cholesterol: Results of the (MONICA) Augsburg Cohort Study, Ann Epidemiol. 1991;l: 14. WHO MONICA Project: Objectives and Design. Int J Epidemiol. 1989;18(Suppi l):S29-S37. 15. Higgins M, Kannel W, Garrison R, Pinsky J, Strokes J III. Hazards of obesity-The Framingham Experience, Acta Med Stand. 1987;723(Suppl):23-26. 16. Health Implications of Regional Obesity. In: Bjomtorp P, Smith U, Lonnroth P, eds. Acta Medica Scandinavia Symposium Series No. 4. Stockholm: Almqvist and Wiksell International; 1988:
International Studies of Cardiovascular Disease
Differences in mortality rates for coronary heart disease (CHD) and stroke among countries have intrigued epidemiologists, pathologists, and other professional and lay observers for many years. There are currently eight- to twelvefold differences in CHD mortality rates between countries with high rates (e.g. Scotland and Finland), and countries with low rates (e.g. France and Japan). Numerous ecologic analyses of available data and epidemiologic studies have been designed to evaluate and attempt to explain this international variation. Among the best known studies are the Seven Countries study (l), the NI-HON-SAN study (2), and its continuing components, the Honolulu Heart Program and the studies of Japanese men in Japan (3). The Puerto Rico (4) and Yugoslavia (5) studies were designed to provide data for countries with low CHD death rates and to be comparable to the Framingham Heart Study (6). There have also been studies of migrants, for example, from Britain and Norway to the United States and from Ireland to Boston (7, 8), to try and distinguish genetic from environmental influences. More recently, attention has been given to the variable trends in CHD mortality among different countries, some experiencing declines, some increases, and some stable rates (9-11). Two reports in this issue of the Ann& of Epidemiology provide information on coronary heart disease and associated risk factors in Iceland and in Augsburg, Germany (12, 13). R a fn sson reports on mortality from ischemic heart disease (IHD) in Iceland from 1951 to 1985 and concludes that death rates from IHD have not peaked yet in his country, whereas rates in many countries, including neighboring Scandinavian countries, have fallen. Denominators for the mortality rates were derived from censuses done in 1950, 1952, 1960 and 1982; numerators are based on death certificate entries since 1951. Because the population of Iceland is small (69,000 aged 35-64 years in 1983-1985), death rates fluctuate from year to year for the five-year age groups. Spearman correlation coefficients of mortality with calendar year vary in magnitude and direction, being significantly positive in men for the period 1951-1985 but negative for half the age groups and not significant for the combined age groups for later time periods ( 1966- 1985 and 1976- 1985). In women, the pattern was similar but there were fewer significant positive correlations for the 1951-1985 interval, and they were present only for 75-79 year old women for 1976-1985. Most correlations were negative for 1976-1985 in women. The graphs also suggest that correlations may be influenced by the choice of years to begin the two more recent time periods. The extent to which the accuracy of the population estimates for intervening years, especially between 1960-1982, influences the findings is not discussed. The author points out that improvements in the diagnosis of IHD may have contributed to the apparent trends in mortality over the 35-year interval. It would be interesting to know whether death rates for other types of heart disease, stroke, and total cardiovascular disease have changed. One remarkable feature of these data is that two pathologists have coded all death certificates, but the author’s belief that this resulted in uniform registration of IHD deaths is open to question. The author’s conclusion that mortality rates from IHD among Icelanders have not yet peaked may not be true for National
Heart,
Lung and Blood Institute
0 Mihcent Higgins. MD
of the Natmnal
Institutes
of Health
568
Higgins EDITORIAL
AEP Vol. I, No. 6 November 199J : 567-569
younger men or for women; however, trends in incidence, case fatality, risk factors and medical care derived from the Icelandic cohort of the MONICA (Multinational Monitoring of Trends and Determinants of Cardiovascular Disease) project may clarify the situation once that study is completed. In the second article, by Eberle and colleagues, associations between change in weight and change in total cholesterol and change in HDL cholesterol are reported for members of the Augsburg cohort component of the MONICA study (13). MONICA is a lo-year, WHO sponsored project whose goals are to measure the trends in cardiovascular mortality and coronary heart disease and stroke morbidity and to assess the extent to which these trends are related to changes in known risk factors, daily living habits, health care or socioeconomic characteristics in 39 geographically defined communities in 27 different countries (14). Approximately 2500 men and women aged 25-64 were examined in 1984-85 and re-examined three years later. Weight gain resulted in increases in total cholesterol and decreases in HDL cholesterol in young women and to a greater extent in men. The authors interpret their findings as suggesting that beneficial effects of weight loss on lipid levels will be greater in men than women, especially at older ages. After controlling for lipid levels at baseline and changes in cigarette use and alcohol intake, the authors found that change in body mass index (BMI) was positively and significantly correlated with changes in total cholesterol in men, and in women under, but not over, 45 years of age. Correlations of changes in BMI and changes in HDL-cholesterol were negative and significant in men in each decade and in 25-34 year old women; correlations were negative, smaller and not significant in 35-54 year old women and absent in older women. There is less information about effects of gaining and losing weight on cardiovascular risk factors and on clinical events than there is on associations between adiposity and obesity and risk factors measured at the same time. Associations between change in weight and change in serum cholesterol, blood pressure, blood glucose, serum uric acid, and fibrinogen have been reported in the Framingham Heart Study and obesity, especially upper body or abdominal obesity, has been implicated as an independent risk factor for cardiovascular disease, diabetes and other conditions (15, 16). A strength of the Augsburg study is that it provides information for women as well as men, and presents data for four age groups separately. Age is a potentially important confounding factor which must be considered in evaluating relationships between weight change and morbidity or mortality. Unintentional weight loss carries a poor prognosis, especially at older ages; causes of weight gain and weight loss were not ascertained. Eberle and colleagues did control changes in smoking and drinking habits which also influence weight and change in weight (16). The prevalence of obesity is very high, especially in women and certain minority populations in the United States, and it is increasing. Once established, obesity is difficult to treat, and repeated cycles of weight gain and weight loss may be harmful. Further information from observational and intervention studies is badly needed to guide policy and develop recommendations with respect to body weight. This article on a MONICA center illustrates some of the strengths and some of the limitations of international studies of cardiovascular disease. Within each collaborating center, local information which might not otherwise have been available is providing new insights into the frequency, distribution and determinants of CHD, its risk factors and management. New investigators have been recruited into CVD epidemiology and trained in the use of standardized methods and quality control procedures. Experienced and less experienced epidemiologists, statisticians, cardiologists
Higgins EDITORIAL
AEP Vol. I, NCJ.6 November 1991: 567-569
and laboratory col, collect
scientists
have worked
the data and participate
Limitations
of international
quantity of available data, information. Participation some centers
low enough
together in analysis
studies
to design
in general
such as demographic, rates in population to raise questions
the study,
and interpretation include
develop
the proto-
of the results.
the variable
medical record sample surveys
569
quality
and
and death certificate are variable, and in
of bias, generalizability
and comparability
of results. However,
international
tive for a wider tions, country
risk factors
range
studies of cardiovascular
of disease
and medical
as large and diverse
rates and trends,
care than
disease provide socio-economic
in exist in any individual
as the United
a unique
perspec-
and living country
condi-
including
a
States. Millicent
Higgins,
MD
REFERENCES 1. Keys A, ed. Coronary heart disease in seven countries, Circulation. 1970;41(Suppl l):l-211. 2. Kagan A, Harris BR, Winkelstein W, Jr, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Demographic, physical, dietary and biochemical characteristics, J Chron Dis. 1974;27:345-64. 3. Yano K, MacLean CJ, Reed DM, et al. A Comparison of the 12-Year Mortality and Predictive Factors of Coronary Heart Disease Among Japanese Men in Japan and Hawaii, Am J Epidemiol. 1988;127:476-87. 4. Gordon T, Garcia-Palmieri MR, Kagan A, Kannel WB, Schiffman J. Differences in coronary heart disease in Framingham, Honolulu and Puerto Rico, J Chron Dis. 1974;27:329344. 5. Kozarevic D, Pirc B, Racic Z, Dawber TR, Gordon T, Zukel WJ. The Yugloslavia cardiovascular disease study, Am J Epidemiol. 1976;104:133-140. 6. Levy D, Kannel WB. Cardiovascular risks: New insights from Framingham, Am Heart J. 1988;116:266-272. 7. Rogot E. Cardiorespiratory disease mortality among British and Norwegian migrants to the United States, Am J Epidemiol. 1978;108:181-191. 8. Kushi LH, Lew RA, Stare FJ, et al. Diet and 20.year mortality from coronary heart disease: The Ireland-Boston Diet-Heart Study, N Engl J Med. 1985;312:811-18. 9. Higgins M, Luepker RV, eds. Trends and Determinants of Coronary Heart Disease Mortality: International Comparisons, Int J Epidemiol. 1989;18(Suppl 1). 10. Thorn TJ. International mortality from heart disease: Rates and trends, Int J Epidemiol. 1989;18(Suppl 1):520-B. 11. Higgins M, Thorn T. Trends in CHD in the United States, Int J Epidemiol. 1989;18(Suppl l):S58-S66. 12. Rafnsson V. Mortality from ischemic heart disease in Iceland 195 1-1985. Ann Epidemiol. 1991;l: 13. Eherle E, Doering A, Keil U. Weight change and change of total cholesterol and HDL-cholesterol: Results of the (MONICA) Augsburg Cohort Study, Ann Epidemiol. 1991;l: 14. WHO MONICA Project: Objectives and Design. Int J Epidemiol. 1989;18(Suppi l):S29-S37. 15. Higgins M, Kannel W, Garrison R, Pinsky J, Strokes J III. Hazards of obesity-The Framingham Experience, Acta Med Stand. 1987;723(Suppl):23-26. 16. Health Implications of Regional Obesity. In: Bjomtorp P, Smith U, Lonnroth P, eds. Acta Medica Scandinavia Symposium Series No. 4. Stockholm: Almqvist and Wiksell International; 1988:
