Relation of Cigarette Smoking to 25-Year Mortality in Middle-aged Men with Low Baseline Serum Cholesterol
The Chicago Heart Association Detection Project in Industry
Lucila Blanco-Cedres,,
Martha L. Daviglus,
Daniel B. Garside,
Kiang Liu,
Amber Pirzada,
Jeremiah Stamler and
Philip Greenland
1 Department of Preventive Medicine, Northwestern University Medical School, Chicago, IL.
2 Department of Preventive Medicine, Medical School, Central University of Venezuela, Caracas, Venezuela.
 |
ABSTRACT
|
---|
It has been suggested that smoking does not influence risk of cardiovascular diseases in populations with low serum cholesterol levels. To determine whether cigarette smoking is an independent risk factor among men with low levels of serum cholesterol, data on 25-year coronary, cardiovascular, and all-cause mortality for 8,816 middle-aged men screened between 1967 and 1973 by the Chicago Heart Association Detection Project in Industry were examined. With Cox multivariate proportional hazards regression, relative risks of coronary heart disease and cardiovascular disease mortality associated with smoking for the two subcohorts with favorable levels of serum total cholesterol, that is, less than 180 and 180199 mg/dl, were of the same magnitude as those for men with elevated serum cholesterol, that is, 200239 and 240 mg/dl. In the two lower strata of cholesterol, the absolute risk and absolute excess risk of mortality for current smokers at baseline were substantially higher compared with men who never smoked, with all-cause death rates of 423.0 and 428.0 per 1,000 and absolute excess rates of 209.8 and 225.7 per 1,000. These translate to estimated shorter life expectancies of 5.3 and 5.7 years, respectively. Adverse effects of smoking on risk of coronary, cardiovascular, and all-cause mortality prevail for men with lower as well as higher serum cholesterol levels.
cardiovascular diseases; cholesterol; mortality; smoking
Abbreviations:
CHA, Chicago Heart Association Detection Project in Industry; CHD, coronary heart disease; CVD, cardiovascular disease; ECG, electrocardiogram; ICD-8, International Classification of Diseases, Eighth Revision; SE, standard error
 |
INTRODUCTION
|
---|
Cigarette smoking is one of the major risk factors responsible for the cardiovascular disease (CVD) epidemic raging in most of the world. A current concern is the escalation of coronary heart disease (CHD) incidence and mortality in some countries, especially those undergoing rapid economic change. For example, atherosclerotic CVD became the leading cause of death in South Korea in the early 1990s and is the main cause of death in China (1
3
). Many Asian countries, previously known to have low serum cholesterol levels, are also experiencing lifestyle changes, including increased prevalence of cigarette smoking and/or changing dietary patterns leading to the development of unfavorable CHD risk factor profiles (4








14
). Although it has been demonstrated that the relation of cigarette smoking to CVD risk is continuous, graded, strong, and independent (15
), there remains a divergence of opinion about this risk relation in populations with low serum cholesterol levels. Based on results from some epidemiologic studies, it has been suggested that smoking is less important to CHD mortality in such populations (16
18
). However, for some of these studies, duration of follow-up was short or statistical power was limited to detect an association between smoking and cardiovascular mortality at low levels of serum cholesterol.
This report examines this matter, based on 25 years of follow-up, for a cohort of 8,816 middle-aged men screened between 1967 and 1973 by the Chicago Heart Association Detection Project in Industry (CHA). It also assesses the interactive effects of smoking and serum cholesterol on CHD, CVD, and all-cause mortality. In particular, it analyzes whether cigarette smoking is a major independent risk factor for mortality among men with favorable levels of serum total cholesterol (<180 and 180199 mg/dl).
 |
MATERIALS AND METHODS
|
---|
Published reports on the CHA cohort detail its baseline screening methods (19
, 20
). In brief, from late 1967 to early 1973, the CHA surveyed 39,572 men and women aged 18 years and older who were employed by 84 Chicago-area companies and organizations. All employees, totaling about 75,000 people, were invited to participate; the response rate was approximately 55 percent. In this study, only data from middle-aged men were analyzed; men and women aged 1839 years and women aged 4059 years at baseline were not included because of the small number of deaths from CHD and CVD observed for the two categories of low serum total cholesterol (<180 and 180199 mg/dl). The number of men aged 4059 years screened at baseline examination was 9,267. Of these, 451 were excluded for the following reasons: missing data on relevant variables at baseline or on follow-up (n = 220); baseline electrocardiographic evidence of prior myocardial infarction (n = 62); or previous diagnosis of diabetes mellitus (n = 169). Thus, the data in this study are for 8,816 men aged 4059 years without a clinical diagnosis of diabetes or myocardial infarction and with complete baseline data on all relevant variables. Screening involved collection of demographic information, including education and ethnicity, data on past and present smoking status, medical history, and medical treatment ascertained by questionnaire; measurement of height and weight, used to calculate body mass index (weight (kg)/height (m)2); one supine blood pressure measurement; resting electrocardiogram (ECG); and venipuncture for blood chemistry measurements. Serum total cholesterol was determined by an automated adaptation of the method of Levine and Zak (21
). Criteria of the national cooperative Pooling Project and the Hypertension Detection and Follow-up Program were used to code ECG abnormalities (22
).
Methods of follow-up to ascertain vital status have included local procedures and use of Social Security Administration and National Death Index records. With a mean follow-up of 25 years, vital status has been determined for more than 99 percent of the cohort. For each decedent, the underlying cause of death was coded by a trained staff professional using the International Classification of Diseases, Eighth Revision (ICD-8), adapted for use in the United States (23
). Coders were blinded to baseline data. Deaths from all CHD were defined as ICD-8 codes 410.0414.9 and those from all CVDs as codes 400.0445.9.
Age-adjusted mortality rates per 10,000 person-years of follow-up and per 1,000 men were calculated for each mortality endpoint. Mortality rates were computed by smoking status at baseline within each of four strata of serum cholesterol: less than 180, 180199, 200239, and greater than or equal to 240 mg/dl. These levels were selected based on criteria of the US National Cholesterol Education Program (24
) and findings on the large cohort of men screened for the Multiple Risk Factor Intervention Trial (15
). Rates were age adjusted by the direct method to the overall cohort age distribution.
Cox multivariate proportional hazards regression was used to assess effects of baseline current smoking on cause-specific and all-cause mortality at every level of serum total cholesterol, with control for other risk factors (age (years), race (African-American or not), education (years), body mass index, systolic blood pressure, and presence of ECG abnormalities). With use of Cox analysis, possible interaction of smoking with serum cholesterol level was also tested with terms for current smoking (yes/no), cholesterol, and a corresponding interaction term.
For each cause of death, in each cholesterol stratum, absolute excess death rates, number of excess deaths, and percent of all excess deaths for smokers compared with never smokers were calculated by subtracting rates of never smokers from smokers by using age-adjusted mortality rates per 1,000 in 25 years. Cox multivariate proportional hazards regression coefficients for the association of cigarette smoking with all-cause mortality were used to estimate years of shorter life expectancy for men who smoked at baseline compared with never smokers. Detailed methods for these computations have been published (20
).
 |
RESULTS
|
---|
Table 1 gives baseline descriptive characteristics by smoking status. Of the 8,816 men, 41.5 percent were current cigarette smokers and 36.9 percent had a total cholesterol level of less than 200 mg/dl. On average, this sample of middle-aged employed men was overweight, had systolic and diastolic blood pressures above desirable levels (i.e., above 120/80 mmHg), and was hypercholesterolemic. The group of smokers was less educated and had a higher percentage of African Americans, a higher percentage with any electrocardiographic abnormality, and a high consumption of cigarettes/day (23.7/day).
Of the 8,816 men aged 4059 years at baseline, 2,975 (33.7 percent) died during the 25-year follow-up period (table 2). CHD and CVD were the underlying causes of death for 32.0 and 45.7 percent of all decedents, respectively.
View this table:
[in this window]
[in a new window]
|
TABLE 2. Baseline cigarette smoking and 25-year mortality from coronary heart disease, cardiovascular diseases, and all causes by serum total cholesterol categories for men aged 4059 years at entry, CHA* study, 19671973
|
|
Table 2 presents age-adjusted mortality rates by cigarette smoking status at baseline for each of four strata of serum cholesterol. At every level of serum cholesterol, smoking was related to a higher risk of CHD, CVD, and all-cause mortality. Relative risks from smoking throughout the range of serum cholesterol categories ranged from 1.57 to 2.78. For example, for men in the two strata with serum cholesterol levels of less than 180 and 180199 mg/dl, risk ratios for smokers compared with never smokers were 1.78 and 2.78 for CHD mortality, respectively.
Multivariate-adjusted relative risks for smoking from Cox regression analyses are shown in table 3. The impact of smoking on mortality was of almost the same magnitude in each of the four categories of serum cholesterol. The relative risk associated with current smoking for those with optimal levels of serum cholesterol (<180 mg/dl) was similar to that for those with hypercholesterolemia (
240 mg/dl), with relative risks for CVD mortality of 1.58 and 1.49, respectively, and those for CHD mortality of 1.74 and 1.50, respectively. For the subcohort with favorable levels of serum cholesterol (180199 mg/dl), current smoking was associated with the same risk for CHD and CVD mortality as for those with unfavorable levels of serum cholesterol (200239 mg/dl)relative risks ranged from 1.95 to 2.18and with greater risk for CHD and CVD mortality than for those with hypercholesterolemia, with relative risks of 2.18 and 1.95 compared with 1.50 and 1.49, respectively (table 3). Throughout the range of serum total cholesterol, current smoking at baseline was associated with increased risk of all-cause mortality (i.e., relative risks of
1.78) compared with never smoking.
View this table:
[in this window]
[in a new window]
|
TABLE 3. Multivariate-adjusted relative risk and absolute excess risk per 1,000 in 25 years and percent of all excess deaths in smokers compared with never smokers, CHA* men aged 4059 years at baseline, 19671973
|
|
From the lowest to the highest category of serum cholesterol, baseline averages of 22.4, 23.3, 23.9, and 24.6 cigarettes/day translated into shorter estimated life expectancies of 5.3, 5.7, 5.7, and 6.2 years, respectively, compared with never smoking. Cox multiple regression coefficients used to estimate these shorter life expectancies due to smoking were, for the lowest to the highest strata: age, 0.095 (0.010 standard error (SE)), 0.093 (0.010 SE), 0.095 (0.007 SE), 0.080 (0.009 SE), and those for cigarettes per day were 0.026 (0.004 SE), 0.026 (0.003 SE), 0.026 (0.007 SE), and 0.023 (0.003 SE).
In Cox proportional hazard regression models that tested for interactions between current smoking (yes/no) and total cholesterol level (<180 vs.
180 mg/dl), no significant interactions were observed (p for interaction = 0.54, 0.30, and 0.90 for CHD, CVD, and all-cause mortality, respectively). Other total cholesterol levels were also tested for interaction: less than 200 versus 200 mg/dl and less than 200 versus 200239 versus 240 mg/dl; additionally, an interaction term was added to the continuous multivariate models; none of these was statistically significant.
For men with optimal (<180 mg/dl) and desirable (180199 mg/dl) levels of serum cholesterol, the absolute excess risks for CHD mortality were 34.4 and 62.7 per 1,000 in 25 years, respectively, and the absolute excess risks for all-cause mortality were 209.8 and 225.7 per 1,000 in 25 years, respectively. The excess risk of mortality due to smoking was also substantial, accounting for 30 percent of excess CHD deaths, 28 percent of excess CVD deaths, and 36 percent of excess deaths from all causes for men in these two strata. Men with unfavorable levels of serum cholesterol (200239 and
240 mg/dl) had absolute excess risks from smoking ranging from 57.1 to 226.5 per 1,000 in 25 years; smoking accounted for a substantial proportion of excess CHD, CVD, and all-cause deaths; for example, for these two strata, 70 percent of excess CHD deaths and 64 percent of excess deaths from all causes were attributed to smoking (table 3).
The results also showed the beneficial effects of quitting smoking throughout the range of serum total cholesterol; risk of CHD, CVD, and all-cause mortality for exsmokers was attenuated to almost the same level as that of never smokers (table 2).
 |
DISCUSSION
|
---|
The main results here were that 1) the independent effect of cigarette smoking on risk of CHD and CVD mortality was demonstrated throughout the range of serum total cholesterol. For the two subcohorts with favorable levels of serum cholesterol, relative risks due to smoking were of the same magnitude as those for men with elevated serum cholesterol; 2) for men with the lowest serum cholesterol levels, cigarette smoking accounted importantly for absolute risk, absolute excess risk, and for CHD and CVD mortality; 3) the risk relation of smoking to all-cause mortality was of similar magnitude for each of the four cholesterol subcohorts, with relative risks ranging from 1.78 to 2.19. These risk estimates for total mortality are similar to those estimated for smokers in the United States and other countries (15
, 25
, 26
); and 4) in the two strata with low levels of serum cholesterol, smokers had shorter life expectancies, by about 5 years, compared with never smokers. These results are most likely underestimates due to misclassification of persons with only a single measurement of serum cholesterol (regression dilution bias) (27
).
Smoking is undoubtedly a major cause of illness and premature death. Worldwide, about 3 million deaths a year are attributed to smoking, and it is estimated that this number will rise to more than 10 million by the year 2025 (1
, 4
). Currently, most of these deaths occur in developed countries, but it is projected that 7 million of the 10 million deaths will occur in developing countries by the year 2025 (5
). Asian countries have the highest prevalence of smoking in the world: 72 percent in Korean men, 63 percent in Chinese men, and 58 percent in Japanese men (3
). For some of these Asian populations, it has been reported that smoking is less important as a risk factor for cardiovascular mortality than in Western populations. In the Seven Countries Study, cigarette smoking was less predictive of coronary heart disease and death from all causes in southern Europe and Japan than in the United States and northern Europe in 10 years of follow-up (18
). Moreover, some studies have reported that populations of smokers with low serum total cholesterol levels appear to be protected from CHD (28
). Absence of significant risk of mortality with smoking was reported by studies in Puerto Rico (16
) and Japan (17
). However, lack of significance in these studies could reflect short duration of follow-up and limited statistical power to detect an association between smoking and cardiovascular mortality at low levels of serum cholesterol (table 4).
View this table:
[in this window]
[in a new window]
|
TABLE 4. Characteristics of populations studied for the relation of cigarette smoking to mortality at low serum cholesterol levels in six populations
|
|
In contrast, prospective investigations with larger numbers of deaths or longer years of follow-up have yielded different results (table 4). Yuan et al. (29
) conducted a prospective study of male residents of Shanghai, China, with average cholesterol levels less than 180 mg/dl. They found significant relative risks of 2.1 for CHD and 1.4 for all-cause mortality for smokers compared with never smokers. Analyses on smoking and mortality were adjusted only for age and alcohol intake. Likewise, Jee et al. (3
) demonstrated that in a large prospective study of Korean men with a mean cholesterol level of 194.2 mg/dl, smoking was a major independent risk factor for CHD and CVD morbidity and mortality. Significant relative risks from current smoking of 3.3 and 1.6 were reported for CHD and CVD, respectively. This study included persons with antecedent atherosclerotic CVDs. Another cohort study in Xi'an, China, found that smoking was a major risk factor for CHD and all-cause mortality in a population with a mean serum cholesterol level of 179 mg/dl. Relative risks of CHD and all-cause mortality for smokers were 3.6 and 2.4, respectively, after adjustment for other major cardiovascular risk factors (26
). Similarly, a cohort of Western men screened for the Multiple Risk Factor Intervention Trial, with a mean serum cholesterol level of 163.7 mg/dl and 12 years of follow-up, were reported to have an age-adjusted risk ratio of CHD mortality for smokers compared with never smokers of 2.0 (15
, 30
).
In summary, our results demonstrate that cigarette smoking is a major risk factor for CHD-CVD mortality at every level of serum total cholesterol in an employed US population. This has important public health policy implications, underscoring the need for a multifactorial approach for the primary prevention of CVDs. While population-wide strategies for the primary prevention of CVDs (particularly lifestyle improvements) have been implemented in many industrialized countries, in some Asian countries, habitual tobacco usage combined with adverse lifestyle changes (especially adverse dietary changes) has caused adverse trends in mean levels of cardiovascular risk factors in the last few decades (10


14
, 31
). As our results show, favorable mean serum cholesterol levels in a population do not protect against the risks of CHD and CVD mortality conferred by cigarette smoking. Strategies for primary prevention targeting cigarette smoking and all other major risk factors for CHD (adverse blood pressure and serum cholesterol levels and adverse diet) should therefore play an important role in the health policies of these countries.
 |
ACKNOWLEDGMENTS
|
---|
Supported by the American Heart Association and its Chicago and Illinois affiliates; the Illinois Regional Medical Program; the National Heart, Lung, and Blood Institute (HL21010); the Chicago Health Research Foundation; and private donors.
The work of the CHA study was accomplished thanks to the invaluable cooperation of 84 Chicago-area companies and organizations and their officers, staff, and employees whose volunteer efforts made the project possible. Acknowledgment is also gratefully extended to all the Chicago Heart Association staff and volunteers serving the project. Many of these persons are cited by name in references 19 and 20.
 |
NOTES
|
---|
Correspondence to Dr. Martha L. Daviglus, Department of Preventive Medicine, Northwestern University Medical School, 680 N. Lake Shore Drive, Suite 1102, Chicago, IL 60611-4402 (e-mail: daviglus{at}northwestern.edu).
 |
REFERENCES
|
---|
-
Mackay JL. The fight against tobacco in developing countries. Tuber Lung Dis 1994;75:824.[ISI][Medline]
-
Yao C, Wu Z, Wu Y. The changing pattern of cardiovascular diseases in China. World Health Stat Q 1993;46:11318.[Medline]
-
Jee S, Suh I, Kim IS, et al. Smoking and atherosclerotic cardiovascular disease in men with low levels of serum cholesterol. The Korea Medical Insurance Corporation Study. JAMA 1999;282:214955.[Abstract/Free Full Text]
-
Peto R, Lopez AD, Boreham J, et al. Mortality from smoking worldwide. Br Med Bull 1996;52:1221.[Abstract]
-
Mackay J, Crofton J. Tobacco and the developing world. Br Med Bull 1996;52:20621.[Abstract]
-
Chen ZM, Xu Z, Collins R, et al. Early health effects of the emerging tobacco epidemic in China. A 16-year prospective study. JAMA 1997;278:15004.[Abstract]
-
Liu BQ, Peto R, Chen ZM, et al. Emerging tobacco hazards in China. 1. Retrospective proportional mortality study of one million deaths. BMJ 1998;317:141122.[Abstract/Free Full Text]
-
Gong YL, Koplan JP, Feng W, et al. Cigarette smoking in China. Prevalence, characteristics, and attitudes in Minhang District. JAMA 1995;274:12324.[Abstract]
-
Yang G, Fan L, Tan J, et al. Smoking in China. Findings of the 1996 National Prevalence Survey. JAMA 1999;282:124753.[Abstract/Free Full Text]
-
Woo KS, Chook P, Young RP, et al. New risk factors for coronary heart disease in Asia. Int J Cardiol 1997;62(suppl 1):S39S42.
-
Shimamoto T, Komachi Y, Inada H, et al. Trends for coronary heart disease and stroke and their risk factors in Japan. Circulation 1989;79:50315.[Abstract]
-
Sakata K, Labarthe DR. Changes in cardiovascular disease risk factors in three Japanese surveys 19711990. J Epidemiol 1996;6:93107.[Medline]
-
Tao S, Li Y, Xiao Z, et al. Serum lipids and their correlates in Chinese urban and rural populations of Beijing and Guangzhou. Int J Epidemiol 1992;21:893903.[Abstract]
-
Zhou B, Rao X, Dennis BH, et al. The relationship between dietary factors and serum lipids in Chinese urban and rural populations of Beijing and Guangzhou. Int J Epidemiol 1995;24:52834.[Abstract]
-
Stamler J, Wenthworth D, Neaton JD, et al. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256:28238.[Abstract]
-
Gordon T, Garcia-Palmieri MR, Kagan A, et al. Differences in coronary heart disease in Framingham, Honolulu and Puerto Rico. J Chronic Dis 1974;27:32944.[ISI][Medline]
-
Robertson TL, Kato H, Gordon T, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii, and California: coronary heart disease factors in Japan and Hawaii. Am J Cardiol 1977;39:2449.[ISI][Medline]
-
Keys A, ed. Seven countries: a multivariate analysis of death and coronary heart disease. Cambridge, MA: Harvard University Press, 1980:13660.
-
Stamler J, Rhomberg P, Schoenberger JA, et al. Multivariate analysis of the relationship of seven variables to blood pressure: findings of the Chicago Heart Association Detection Project in Industry, 19671972. J Chronic Dis 1975;28:52748.[ISI][Medline]
-
Stamler J, Dyer AR, Shekelle RB, et al. Relationship of baseline major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts. Cardiology 1993;82:191222.[ISI][Medline]
-
Levine JB, Zak B. Automated determination of serum total cholesterol. Clin Chim Acta 1964;10:3814.[ISI]
-
Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chronic Dis 1978;31:201306.[ISI][Medline]
-
National Center for Health Statistics. International classification of diseases. Eighth Revision. (Adapted for use in the US). Washington, DC: US GPO, 1967.
-
Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA 1993;269:301523.[ISI][Medline]
-
Stamler J, Greenland P, Neaton JD. The established major risk factors underlying epidemic coronary and cardiovascular disease. CVD Prev 1998;1:8297.
-
Lam TH, He Y, Li Lan S, et al. Mortality attributable to cigarette smoking in China. JAMA 1997;278:15058.[Abstract]
-
MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:76574.[ISI][Medline]
-
Goldberg RJ. Coronary heart disease: epidemiology and risk factors. In: Ockene IS, Ockene JK, eds. Prevention of coronary heart disease. Boston, MA: Little Brown & Co, Inc, 1992:340.
-
Yuan JM, Ross RK, Wang KL, et al. Morbidity and mortality in relation to cigarette smoking in Shanghai, China. JAMA 1996;275:164650.[Abstract]
-
Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Arch Intern Med 1992;152:5664.[Abstract]
-
Hu FB, Wang B, Chen C, et al. Body mass index and cardiovascular risk factors in a rural Chinese population. Am J Epidemiol 2000;151:8897.[Abstract]
Received for publication August 24, 2000.
Accepted for publication August 15, 2001.