(Circulation. 1999;99:1165-1172.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Sex, Age, Cardiovascular Risk Factors, and Coronary Heart Disease
A Prospective Follow-Up Study of 14 786 Middle-Aged Men and Women in Finland
From the National Public Health Institute, Department of Epidemiology and Health Promotion, Helsinki, Finland.
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Abstract |
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Background—Coronary heart disease (CHD) is markedly more common in men than in women. In both sexes, CHD risk increases with age, but the increase is sharper in women. We analyzed the extent to which major cardiovascular risk factors can explain the sex difference and the age-related increase in CHD risk.
Methods and Results—The study cohort consists of 14 786 Finnish
men and women 25 to 64 years old at baseline. The following
cardiovascular risk factors were determined: smoking,
serum total cholesterol, HDL cholesterol, blood
pressure, body mass index, and diabetes. Risk factor measurements were
done in 1982 or 1987, and the cohorts were followed up until the end of
1994. The Cox proportional hazards model was used to assess the
relation between risk factors and CHD risk. CHD incidence in men
compared with women was 
3 times higher and mortality was 5 times
higher. Most of the risk factors were more favorable in women, but the
sex difference in risk factor levels diminished with increasing age.
Differences in risk factors between sexes, particularly in HDL
cholesterol and smoking, explained nearly half of the
difference in CHD risk between men and women. Differences in serum
total cholesterol level, blood pressure, body mass index,
and diabetes prevalence explained about one-third of the
age-related increase in CHD risk among men and 50% to 60% among
women.
Conclusions—Differences in major cardiovascular risk factors explained a substantial part of the sex difference in CHD risk. An increase in risk factor levels was associated with the age-related increase in CHD incidence and mortality in both sexes but to a larger extent in women.
Key Words: aging • epidemiology • coronary disease • sex • risk factors
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Introduction |
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There is a marked difference in coronary heart disease (CHD) risk between sexes.1 2 3 4 5 6 7 8 Among middle-aged people, CHD is 2 to 5 times more common in men than in women, and this sex ratio varies between populations.8 In both sexes, the risk of CHD increases markedly with age.1 5 7
Lipid abnormalities, high blood pressure, and smoking are major risk factors for CHD.9 10 11 12 13 14 15 Obesity and diabetes also contribute to CHD risk.16 17 18 The role of major cardiovascular risk factors in the development of CHD is well established among men. Among women, the data are less extensive. Reasons for the sex difference in CHD risk are not fully understood. Even though in most populations, cardiovascular risk factor patterns are more favorable among women than among men,8 very limited data are available to assess the extent to which cardiovascular risk factors can explain the observed sex difference in CHD risk.
The aim of this study was to assess (1) whether the association of smoking, total cholesterol, HDL cholesterol, HDL cholesterol/total cholesterol ratio, blood pressure, diabetes, and obesity with CHD risk is similar in men and women; (2) the extent to which differences in these risk factors can explain the sex difference in CHD incidence and mortality; and (3) how much the changes in the risk factor levels by aging explain the difference in CHD risk between age groups.
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Methods |
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Participants and Surveys
Baseline surveys were carried out in North Karelia and Kuopio provinces in eastern Finland and in the Turku-Loimaa region in southwestern Finland in 1982 and 1987.19 In both years, age- and sex-stratified random samples were taken from the age group of 25 to 64 years according to the international World Health Organization (WHO) MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) project protocol.20 In this study, the 1982 and 1987 cohorts were combined. The samples included 9789 men and 9538 women. The participation rate was 79% among men and 85% among women. The 168 subjects who participated in both surveys were included only in the 1982 survey cohort. Excluded were 261 subjects because of their previous history of myocardial infarction and 611 because of incomplete data on
1 risk factors. Thus, 7090 men and 7696 women were included
in the present analyses.
Risk Factor Assessment
A self-administered questionnaire was sent to the participants
in advance. Current smoking status was assessed by a set of
standardized questions. At the study site, height, weight, and blood
pressure were measured according to the WHO MONICA project
protocol.20 Body mass index (BMI,
kg/m2) was used as a measure of relative body
weight. Total and HDL cholesterol were determined from
fresh serum samples by an enzymatic method (CHOD-PAP,
Boehringer Mannheim). On the questionnaire, the subjects were
asked to report the presence of diabetes. The data were complemented by
information from the Social Insurance Institution's register on
persons receiving free-of-charge medication for diabetes.
Prospective Follow-Up
Mortality data were obtained from the Central Statistical Office
of Finland. Data on nonfatal coronary events were received from
the national hospital discharge register. The International
Classification of Diseases, Injuries, and Causes of Death (ICD, 8th and
9th revisions) codes 410 to 414 were classified as coronary
deaths and ICD codes 410 to 411 in the hospital discharge register as
nonfatal acute coronary events.
Two separate end points, an incident case of CHD and CHD death, were analyzed. An incident CHD event was defined as either the first acute nonfatal coronary event or CHD death without a preceding nonfatal coronary event. The follow-up of each subject in our present analyses continued through the end of 1994. During the follow-up, 156 095 person-years were accumulated. The numbers of incident CHD events were 520 among men and 208 among women, and the numbers of CHD deaths were 231 and 63, respectively.
Statistical Analyses
ANOVA was used to test the difference in risk factors between
sexes. Multivariate analyses were performed by
use of a Cox proportional hazards model.21 All models were
adjusted for age, study year, and area. To assess whether the
association of risk factors with CHD risk is different in men than in
women, first-level interactions between sex and risk factors were
tested. To assess the extent to which the sex difference in the risk of
CHD may be explained by differences in the risk factors, a model was
built including data for both sexes and using sex as an explanatory
variable. The model was then completed by addition of the other
risk factors. The proportion of the excess risk of CHD in men compared
with women that was explained by the differences in risk factors was
estimated by comparing the risk ratios of CHD associated with sex
before and after adjustment for the other risk factors
[(RR0-RR1)/(RR0-1),
where RR0 is age-, area-, and study
year–adjusted risk ratio and RR1 is age-, area-,
study year–, and risk factor–adjusted risk ratio]. A similar
procedure was used to analyze the extent to which the
age-related changes in risk factors may explain the difference in CHD
risk between the age groups. The statistical analyses were
performed with the SAS statistical programs.22
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Results |
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CHD incidence and mortality were 786 and 339 per 100 000 person-years among men and 256 and 76 per 100 000 person-years among women, respectively (Table 1
).
Relative difference in CHD risk between sexes was largest among the
youngest subjects, 25 to 49 years old, and smallest among the oldest
subjects, 60 to 64 years old. The absolute difference in CHD risk,
however, was largest in the oldest age group.
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Smoking was more common, total cholesterol and blood
pressure were higher, HDL cholesterol was lower, and BMI
was higher among men in both the 25- to 64- and 25- to 49-year age
groups (Table 2). In the age group 50 to
59 years, systolic blood pressure of women nearly reached that
of men, and serum total cholesterol and BMI were already
higher in women. In the age group 60 to 64 years as well,
systolic blood pressure was higher in women. The HDL/total
cholesterol ratio was higher among women, but this
difference diminished with increasing age. Diabetes prevalence was
fairly similar and increased similarly with age in both sexes.
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The above-mentioned risk factors, except BMI, predicted the risk of CHD
in both sexes (Table 3). In
univariate analyses, BMI and CHD risk had a
statistically significant association (risk ratio, 1.04
[P=0.002] for incidence and 1.04 [P=0.024]
for mortality in men and 1.04 [P=0.002] for incidence and
1.08 [P=0.002] for mortality in women), but the
association disappeared when the other risk factors were included in
the analyses. BMI and diabetes had a stronger association with
coronary mortality in women than in men. Otherwise, the
association of risk factors with CHD incidence and mortality was
similar in both sexes.
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The risk ratio of CHD associated with sex (men versus women) was 3.38
for incidence and 5.00 for mortality (Table 4). The risk ratios decreased to 2.31 and
3.20 after smoking, HDL/total cholesterol ratio,
systolic blood pressure, BMI, and diabetes were introduced into
the model. Thus, 45% of the excess CHD risk of men was associated
with the sex differences in cardiovascular risk
factors. This proportion was highest, 60% for both CHD incidence
and mortality, in the age group 25 to 49 years. The corresponding
proportions were 47% and 46% in the age group 50 to 59 years and 35%
and 39% in the age group 60 to 64 years. In all age groups, the sex
difference in the HDL/total cholesterol ratio explained
most of the risk factor–associated excess CHD risk. Smoking was the
second most important determinant of the sex difference in CHD
risk.
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Age-related change in risk factors explained about one-third in men and
over half in women of the higher CHD risk in the age group 50 to 64
years compared with the age group 25 to 49 years (Table 5). A decrease in the HDL/total
cholesterol ratio and increase in systolic blood
pressure contributed most to the risk factor–associated increase of
CHD risk by aging. Also, the increase in BMI and diabetes prevalence
was associated with the increase of CHD incidence and mortality by
aging.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The role of major cardiovascular risk factors in the development of CHD was fairly similar in both sexes. Among young subjects, the overall risk factor level was more favorable in women. With age, however, this advantage of women diminished markedly.
CHD incidence among men was 3-fold and mortality 5-fold greater
than in women. The sex differences in the measured
cardiovascular risk factors explained nearly half of
the observed sex difference in CHD incidence and mortality. The
difference in the HDL/total cholesterol ratio was the major
determinant of the sex difference in CHD risk. In addition, differences
in smoking rate contributed markedly to the excess CHD risk of men. The
role of smoking in the sex difference in CHD risk may be even larger
than estimated in our analyses, because smoking may also
decrease HDL cholesterol level.23
In both sexes, the risk of CHD increased markedly with age. In most populations, serum total cholesterol increases as age increases. In men, this increase usually levels off around the age of 45 to 50 years, whereas in women, the increase continues sharply until the age of 60 to 65 years.24 Like serum cholesterol, blood pressure also tends to increase with age, and more prominently in women than in men.25 The increase in blood pressure and its different relations to age in men and women are probably explained in part by obesity.25 26
In the 1970s, on the basis of Framingham data, Johnson27 analyzed the role of cardiovascular risk factors on sex difference in CHD risk. His conclusions were that differences in smoking, serum total cholesterol, blood pressure, and the occurrence of left ventricular hypertrophy and glucose intolerance did not explain the observed sex difference in CHD risk. The shortcoming of the study, however, was that HDL cholesterol was not included in the analyses.
In the early 1990s, Larsson and colleagues28 analyzed whether sex differences in smoking rate, serum total cholesterol, blood pressure, BMI, and waist-to-hip ratio could explain the sex difference in CHD incidence among 54-year-old Swedish men and women. Their conclusion was that differences in waist-to-hip ratio explained practically all of the sex difference in CHD risk and that the other risk factors included in the analyses altered the results only marginally. This study did not include HDL cholesterol in the analyses, either. Another problem was that waist-to-hip ratio largely depends on anatomic structure, which differs markedly between sexes. Therefore, it is questionable whether the same reference values can be applied in both men and women.
The WHO MONICA Project and ARIC Study researchers recently analyzed the contribution of sex differences in cardiovascular risk factors to sex differences in CHD mortality between 46 communities.8 In this study, communities were used as the unit of the analyses. Sex differences in CHD mortality between communities were correlated with sex differences in the following risk factors: smoking, obesity, high blood pressure, high total cholesterol, and low HDL cholesterol. Approximately 40% of the variation in the sex ratios of CHD mortality could be explained by differences in the sex ratios of the 5 risk factors examined.
In our study, the major cardiovascular risk factors explained nearly half of the sex difference in CHD risk. An interesting question is which factors explain the other half. The phenomenal difference between men and women is determined by the X and Y chromosomes. During the fetal period, male and female phenotypes are developed through the action of sex hormones. Among women, estrogen is the predominant sex hormone. The decrease in estrogen production after menopause changes the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level and by increasing LDL and total cholesterol, triglyceride, and lipoprotein(a) levels.29 30 In addition to the lipid effect, estrogen may have cardioprotective effects through glucose metabolism and the hemostatic system, and it may also have a direct effect on endothelial cell function.31 32
The role of the major risk factors for the sex difference in CHD risk may also be larger than estimated from our models. Because we measured the risk factors only once, we have probably underestimated the association between the risk factors and CHD risk because of regression dilution bias.33 Atherosclerosis is also a cumulative process, starting at a fairly young age.34 Even though sex differences in serum cholesterol levels and blood pressure disappeared with age, it is possible that the cumulative effects of these risk factors on arteriosclerosis remain larger in men than in women, because of the longer exposure time in men. In addition to the risk factors included in our analyses, other factors, such as family history of CHD, physical activity, nutrition, and alcohol intake, may explain part of the sex difference in CHD risk. The prevalence of positive family history of CHD and its association with CHD risk does not differ markedly between sexes.35 Even though physical activity, nutrition, and alcohol intake differ somewhat between sexes, their role in the sex difference in CHD risk is probably small.
The major clinical and public health challenges are how to reduce the risk of CHD among middle-aged men closer to that in women and how to prevent the marked increase in CHD risk with aging, particularly in women. The HDL/total cholesterol ratio was the major determinant of the sex difference in CHD risk, and the increase in risk factor levels, particularly in serum cholesterol and blood pressure, explained a substantial part of the age-related increase in CHD incidence and mortality. Both HDL and total cholesterol levels can be modified by dietary and lifestyle changes.36 37 The increase in serum cholesterol and blood pressure with age is not an inevitable physical phenomenon. It does not occur in some nonwesternized populations, and in western populations, it can be prevented.24 38 Reduction in smoking would also reduce CHD incidence and mortality markedly, particularly in men.
In addition to lifestyle changes, cardiovascular risk can be controlled by pharmacological means, such as antihypertensive and cholesterol-lowering drug treatments.39 40 41 42 Two factors, however, need to be noted when drugs are used in the primary prevention of CHD. First, the initiation of drug treatment should be based on the assessment of the expected absolute reduction in disease risk. Even though the relative risk of CHD associated with risk factors is similar or even higher in women than in men, the risk factors operate at different levels. Second, because the number of people who have only moderately increased CHD risk is large, most of the coronary events occur among them.37 43 Therefore, the public health impact of even small but population-wide risk factor reduction is usually larger than more marked risk reduction among the high-risk individuals alone.
Even though the major cardiovascular risk factors were the same in both sexes, there are also preventive strategies that are unique to women. Several studies have shown that in postmenopausal women, hormone replacement therapy reduces the risk of CHD markedly.44 45 46 47 In clinical trials, the CHD risk of women in the treatment group has decreased by 40% to 50% compared with the control group. Part of this reduction in risk has been attributed to changes in the levels of lipoproteins, but other mechanisms are also involved. Even though the evidence supporting the cardioprotective effect of hormone replacement therapy is quite strong, the overall health effects of hormone replacement therapy in women is still a controversial issue.7
In conclusion, differences in major cardiovascular risk factors, particularly in HDL cholesterol level and smoking rate, explained a substantial part of the sex difference in CHD risk. Increases in serum total cholesterol, blood pressure, relative weight, and diabetes prevalence were associated with the age-related increase of CHD incidence and mortality in both sexes but to a larger extent in women. In both sexes, CHD can be effectively prevented by reducing the levels of these risk factors.
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Footnotes |
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Reprint requests to Dr Pekka Jousilahti, National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
Received April 30, 1998; revision received November 2, 1998; accepted November 18, 1998.
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A. Colao, C. Di Somma, A. Cuocolo, L. Spinelli, W. Acampa, S. Spiezia, F. Rota, M. C. Savanelli, and G. Lombardi Does a Gender-Related Effect of Growth Hormone (GH) Replacement Exist on Cardiovascular Risk Factors, Cardiac Morphology, and Performance and Atherosclerosis? Results of a Two-Year Open, Prospective Study in Young Adult Men and Women with Severe GH Deficiency J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5146 - 5155. [Abstract] [Full Text] [PDF]
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