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Circulation. 1997;96:2128-2136

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(Circulation. 1997;96:2128-2136.)
© 1997 American Heart Association, Inc.

Articles

The Münster Heart Study (PROCAM)

Total Mortality in Middle-Aged Men Is Increased at Low Total and LDL Cholesterol Concentrations in Smokers but Not in Nonsmokers

Paul Cullen, MD, FRCPI; Helmut Schulte, PhD; ; Gerd Assmann, MD

From the Institutes of Arteriosclerosis Research (P.C., H.S., G.A.) and Clinical Chemistry and Laboratory Medicine (G.A.), University of Münster (Germany).

Correspondence to Gerd Assmann, MD, Institute of Arteriosclerosis Research, University of Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany. E-mail cullen{at}uni-muenster.de


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
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Background Some large epidemiological studies have shown an increase in mortality at low levels of total and LDL cholesterol. It has been speculated that low cholesterol levels may play a causative role in this association. To investigate this question, we analyzed all deaths occurring among middle-aged men in the Münster Heart Study (PROCAM), one of the largest prospective epidemiological studies of coronary heart disease risk markers in Europe.

Methods and Results In the Münster Heart Study, 10 856 men aged 36 to 65 years at study entry (46.8±7.3 years [mean±SD]) were followed for 4 to 14 years (7.1±2.4 years). During this period, 313 deaths occurred-46 from myocardial infarction, 48 from suspected or definite sudden cardiac death, 14 from cerebrovascular disease, and 10 from other diseases of the circulatory system. There were 121 deaths from cancer and 33 deaths from violent causes (injuries in 16, suicide in 14, and homicide in 3 cases). Death in 29 cases occurred from other causes and was unexplained in 12 cases. Total cholesterol, LDL cholesterol, and the LDL/HDL ratio showed a J-shaped relationship with total mortality. At high total and LDL cholesterol concentrations, increased mortality was due to increased coronary deaths. At low total and LDL cholesterol concentrations, increased mortality was seen in smokers only and was explained by an increase in smoking-related cancer deaths.

Conclusions The increase in mortality at low levels of total and LDL cholesterol among middle-aged men in the Münster Heart Study is explained by an increase in smoking-related cancer deaths among smokers.


Key Words: cholesterol • lipoproteins • mortality • coronary heart disease • smoking


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Several large epidemiological studies have provided data showing a conclusive link among the major coronary risk factors of high LDL and total cholesterol, low HDL cholesterol and high triglycerides, and CHD incidence and mortality.1 2 3 4 5 6 A worrying feature of the mortality data, however, is the finding in several epidemiological studies of a U- or J-shaped relationship between total and LDL cholesterol and all-cause mortality with an excess of deaths primarily among men with total cholesterol levels below a cutoff of {approx}200 mg/dL or LDL cholesterol levels below a cutoff of {approx}130 mg/dL in both community-based1 4 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 and occupational22 23 24 25 26 27 28 29 30 31 cohorts. This finding is not universal, however, and was not detected in a number of studies performed in younger32 33 34 35 and in healthy36 or nonsmoking37 middle-aged cohorts.

The association between low cholesterol and increased mortality has attracted particular attention in the case of several primary and secondary intervention trials, in which slight excess overall mortality occurred among the treated groups despite a reduction in coronary mortality.38 39 40 41 Although more recent large secondary42 and primary43 intervention trials have provided convincing evidence of a reduction in total mortality on cholesterol lowering, the excess mortality detected in earlier trials remains unexplained.

A number of hypotheses have been proposed to explain the excess of mortality seen at low cholesterol levels in such trials, including an increase in the incidence of injury, homicides, and suicides44 45 46 and an association with adverse lifestyle characteristics such as heavy smoking and drinking.45 47 48 49 50 Several forms of cancer are associated with hypocholesterolemia,12 51 52 and low cholesterol levels also occur in other chronic diseases, such as the acquired immunodeficiency syndrome53 54 55 and chronic obstructive lung disease.25 A recent careful study in middle-aged British men found that the excess mortality at low cholesterol concentrations was due to preexisting preclinical cancer and other noncardiovascular conditions such as chronic bronchitis, peptic ulcer disease, or gallbladder disease56 and could find no evidence of a causal effect of low cholesterol in increasing mortality.

We therefore analyzed the causes of mortality among the participants in the Münster Heart Study (formerly known as the PROCAM study), a large prospective epidemiological investigation performed among the working population in Münster and the northern Ruhr regions of Germany. Our data confirm the existence of a J-shaped relationship between overall mortality and total cholesterol but show that the excess mortality is seen at low cholesterol concentrations in smokers only and is explained by an increase in cancer mortality in these subjects.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The Münster Heart Study is a prospective epidemiological study of people at work in the northwestern German regions of Münster and the Ruhr valley. Recruitment was started in 1979 and completed in 1991, during which a total of 23 616 individuals were enrolled.

Employees of 52 companies and local government authorities were examined for cardiovascular risk factors and then kept under observation to record mortality, as well as nonfatal cardiovascular events, including myocardial infarction and stroke. The examination at study entry included case history using standardized questionnaires, measurement of blood pressure and anthropometric data, a resting ECG, and collection of a blood sample after a 12-hour fast for the determination of >20 laboratory parameters. The examination was carried out during paid working hours. Participation was voluntary, and between 40% and 80% (on average, 60%) of available employees took part. Apart from the loss of working time, participation was free of charge to both the volunteers and their employers. All findings were reported to the participants' general practitioners, and the volunteers were informed whether the results of the examination were normal or a check-up by the general practitioner might be necessary. The investigators neither carried out nor arranged for any intervention. Subjects with a prior history of myocardial infarction or stroke were excluded from the present analysis.

Systolic and diastolic readings were taken on the left arm with the subject seated and the arm at heart level. One measurement was taken at the start of the interview by the examining physician, and one was taken at the end of the interview. The second measurement was recorded. A participant was considered hypertensive if a diagnosis of hypertension was known or if the systolic blood pressure was >=160 mm Hg and/or the diastolic blood pressure was >=95 mm Hg. The smoking history was obtained during the examination and used to divide participants into the following six classes: class 1, never smoked any form of tobacco; class 2, ex-smokers of pipe and/or cigars (in each case, "ex" implies >=1 year of abstinence), never smoked cigarettes; class 3, current smokers of pipe and/or cigars, never smoked cigarettes; class 4, current smoker of pipe and/or cigars, ex-cigarette smoker; class 5, current nonsmoker, ex-cigarette smoker; and class 6, current cigarette smoker. A participant was considered diabetic if a diagnosis of diabetes mellitus was known or the fasting plasma glucose level was >120 mg/dL as measured using the glucose oxidase method (coefficient of variation in our laboratory, <3%).57 Total serum cholesterol, triglycerides, and HDL cholesterol were measured using enzymatic assays58 and (for HDL cholesterol) a precipitation method from Boehringer-Mannheim59 with an Hitachi 737 autoanalyzer (coefficient of variation for all three methods in our laboratory, <5%). These methods are validated by regular analyses of reference sera supplied by the national German INSTAND proficiency testing program and the international quality assurance program of the US Centers for Disease Control and Prevention. LDL cholesterol was calculated by the Friedewald formula providing the level of triglycerides was <400 mg/dL. Clottable fibrinogen was determined according to Clauss60 using thrombin and control plasma from Behringwerke and a plasma pool (coefficient of variation in our laboratory, <8%).

Follow-up
Questionnaires were sent to the participants every 2 years to determine the occurrence of myocardial infarction, stroke, or death. At the initial examination, participants were told that they would obtain a questionnaire every 2 years. The response rate to these questionnaires was 96% after an average of two reminders per person by mail and telephone. The death certificates of all deceased study participants were reviewed. In each case in which evidence of morbidity or mortality was entered in the questionnaire, hospital records and records of the attending physician were reviewed, and in the case of deceased study participants, an eyewitness account of death was sought. These data were then reviewed by the Critical Event Committee to verify the diagnosis or the cause of death; committee members Prof K. Kochsiek (Würzburg, Germany), Prof B.E. Strauer (Düsseldorf, Germany), Prof U. Gleichmann (Bad Oeynhausen, Germany), and Prof E. Köhler (Bad Salzuflen, Germany). The initial examination was repeated after 6 to 7 years.

The relationship between a variable and mortality was described by dividing the patient series into quintiles of the studied variable and then calculating the age-standardized death rate for each quintile. To ensure comparability of results between smokers and nonsmokers, a cohortwide set of cut points was used to identify all quintiles in both groups.


*    Results
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 *Results
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Recruitment and Demographics
The study began in 1979, and the first recruitment phase was completed at the end of 1985 after the recruitment of 19 698 participants aged 16 to 65 years. In a second round of recruitment between 1986 and 1991, an additional 3918 individuals were included; thus, 23 616 individuals were followed up. The mean age of the 16 288 men in the study was 5 years more than that of the 7328 women (40.5±11.3 versus 35.8±12.3 years, P<.001).

Mortality
At the latest evaluation, only 66 deaths had occurred in women, a number that was too small to allow risk factor–based analysis of total mortality or any of its components. Only 25 deaths (including 12 deaths from injury) occurred among the one third of male participants younger than 36 years at study entry. Therefore, the analysis described here was confined to a subgroup of 10 856 male participants aged 36 to 65 years (mean, 46.8±7.3 years). A description of the study population is provided in Table 1Down. Within a follow-up period of 4 to 14 years (mean, 7.1±2.4 years), 313 deaths occurred. Because of the age at study entry and the individual follow-up periods, 456 deaths would have been expected based on German vital statistics as recorded by the Federal Statistics Office; therefore, only 69% of this expected number of deaths was observed. Possible explanations for this finding are that the study group was selected from the population at work, who tend to be healthier than the overall or the nonworking population (healthy worker effect), and the fact that men with a history of myocardial infarction or stroke were excluded from the analysis.


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  		Table 1. Description of Participants in Münster Heart Study Investigated in Present Report (10 856 Men Aged 36 to 65 y)

Total, Coronary Heart Disease, and Cancer Mortality in Men Aged 36 to 65 Years
The causes and total numbers of deaths, as well as the age-specific death rates, are shown in Table 2Down. Ninety-four men died from CHD, and 33 died from injuries, suicide, or homicide. Of the 121 cancer deaths among these men, 26 occurred within 3 years and 39 occurred 3 to 5 years after the initial examination (Table 3Down). By far the most common primary tumor was carcinoma of the bronchus, followed by carcinoma of the rectum or large bowel, malignant neoplasia of the brain, and carcinoma of the pancreas. The details of the sites of primary tumors and the ages at which they caused death are shown in Table 4Down. The incidence of cancer death among cigarette smokers (56 of 3478, or 1.6%) was almost twice that among non–cigarette smokers (65 of 7378, or 0.9%). However, smokers of a pipe and/or cigars also showed an increased incidence of all-type and, particularly, smoking-related cancer (Table 5Down). When pipe/cigar smokers were included among smokers, the incidence of smoking-related cancers in smokers (smoking classes 3, 4, and 6) was 8.7 times that of nonsmokers (smoking classes 1, 2, and 5). The incidence of carcinoma of the bronchus was 10.5 times more common in smokers (classes 3, 4, and 6) than in nonsmokers (classes 1, 2, and 5).


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  		Table 2. Observed Deaths According to Cause in Men in Age Groups 36 to 45 y (n=4509), 46 to 55 y (n=4419), and 56 to 65 y (n=1928) in Münster Heart Study


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  		Table 3. Cancer Death Rates and Absolute Number of Deaths Among Male Smokers (n=3478) and Nonsmokers (n=7378) Aged 36 to 65 y After 3, 5, and >5 y of Follow-up in Münster Heart Study


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  		Table 4. Types of Primary Tumor and Total Number of Deaths From Cancer in Each Group Among 10 856 Male Participants Aged 36 to 45 y (n=4509), 46 to 55 y (n=4419), and 56 to 65 y (n=1928) in Münster Heart Study


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  		Table 5. Age-Standardized Overall Death Rate and Death Rates From Coronary Heart Disease, Cancer (All Types), and Smoking Among Male Participants Aged 36 to 65 y in Münster Heart Study

Relationship of Risk Factors to Mortality From Coronary Heart Disease, Cancer, and All Causes
Mortality and Smoking
For the following analyses, only participants in smoking class 6 (current cigarette smokers) were considered to be current smokers. Participants in groups 4 and 5 were classed as ex-smokers. Persons who had never smoked cigarettes, including those who smoked only pipe and/or cigars (groups 1 through 3), were classified as nonsmokers. This classification was chosen to avoid difficulties in assessment of tobacco exposure in persons who smoke only a pipe and/or cigars and to prevent generating subgroups that are too small to analyze. Total and cancer mortality rates were doubled in smokers compared with nonsmokers, whereas CHD mortality was increased threefold (Fig 1Down).



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  		Figure 1. Age-standardized total, cancer-related, and coronary heart disease (CHD) death rates in male participants aged 35 to 65 years in the Münster Heart Study (PROCAM) by baseline cigarette smoking status. Number of deaths: total, 313; cancer, 129, CHD, 94.

CHD Mortality
A continuous and graded relationship was observed between CHD mortality and total cholesterol (Fig 2aDown), triglycerides (Fig 2bDown), LDL cholesterol (Fig 2Down c), HDL cholesterol (inverse relationship, Fig 2dDown), the LDL cholesterol/HDL cholesterol ratio (Fig 2eDown), and fibrinogen (Fig 2fDown). In contrast, the relationships between CHD mortality and systolic blood pressure (Fig 2gDown) and between CHD mortality and body mass index (Fig 2hDown) were apparently J-shaped, although this relationship was not statistically significant.



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  		Figure 2. Age-standardized total, cancer-related, and coronary heart disease (CHD) death rates in male participants aged 35 to 65 years in the Münster Heart Study (PROCAM) according to total cholesterol (a), triglycerides (b), LDL cholesterol (c), HDL cholesterol (d), LDL cholesterol/HDL cholesterol ratio (e), fibrinogen (f), systolic blood pressure (g), body mass index (h), and risk of CHD as estimated by multiple logistic function (MLF; footnote 1)61 (2). Population indicates number of men on whom data were available as shown; total, total number of deaths; cancer, number of deaths from cancer; and CHD, number of deaths from CHD.1 The MLF used to calculate global risk takes the form I=1[(1+exp(-y)], where y is -12.3199+(age [in years]x0.1001)+(systolic blood pressure [in mm]x0.0118)+(LDL cholesterol [in mg/dL]x0.0152)+(HDL cholesterol [in mg/dL]x-0.45)+(ln [triglycerides {in mg/dL}]x0.3346)+(history of cigarette smoking {yes=1, no=0]x0.9266)+(diabetes mellitus [yes=1, no=0]x0.4015)+(family history of myocardial infarction [yes=1, no=0]x0.4193)+(angina pectoris [no=0, yes=1]x1.319).

Total and Cancer Mortality
The J-shaped relationships were observed between both total and cancer mortality and total cholesterol, LDL cholesterol, LDL cholesterol/HDL cholesterol ratio, and body mass index. The increase in total and cancer death rates in men with low LDL cholesterol/HDL cholesterol ratios or low body mass index was most pronounced in smokers (Figs 3aDown and 4aDown). High total and cancer death rates were observed in smokers with LDL cholesterol or body mass index levels in the lowest quintile. In particular, age-adjusted cancer death rates within the first 3 years of follow-up were highest in male smokers with low levels of LDL cholesterol or in the lowest body mass index quintile. The association between increased cancer mortality and low levels of total or LDL cholesterol was no longer observed more than 5 years after recruitment. In nonsmokers with low LDL cholesterol/HDL cholesterol ratios or in the lowest body mass index quintile, in contrast, the rate of death from cancer was increased only very slightly (Figs 3bDown and 4bDown). Higher levels of triglycerides, fibrinogen, or systolic blood pressure were all associated with higher overall mortality.



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  		Figure 3. Age-standardized total, cancer-related, and coronary heart disease (CHD) death according to quintiles of LDL cholesterol/HDL cholesterol ratio in male smokers (a) and nonsmokers (b) aged 35 to 65 years in the Münster Heart Study (PROCAM). Population indicates number of men on whom data were available as shown; total, total number of deaths; cancer, number of deaths from cancer; and CHD, number of deaths from CHD.



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  		Figure 4. Age-standardized total, cancer-related, and coronary heart disease (CHD) death according to quintiles of body mass index in male smokers (a) and nonsmokers (b) aged 35 to 65 years in the Münster Heart Study (PROCAM). Population indicates number of men on whom data were available as shown; total, total number of deaths; cancer, number of deaths from cancer; and CHD, number of deaths from CHD.

Total mortality increased at lower HDL cholesterol levels and at higher values of a multiple logistic function constructed using the variables age, LDL cholesterol, log-transformed triglycerides, HDL cholesterol, systolic blood pressure, cigarette smoking, diabetes mellitus, angina pectoris, and family history of premature myocardial infarction (Fig 2iUp),61 despite the fact that the relationships between total mortality and levels of some risk factors were J- or even U-shaped.

Statistical Analysis
Statistical testing for quadratic relationships was performed using a logistic multivariate model. For the entire population (smokers and nonsmokers), statistically significant relationships were seen for the relationships between body mass index and overall mortality (Fig 2hUp, P<.04), LDL/HDL ratio and overall mortality (Fig 2eUp, P<.01), and LDL/HDL ratio and cancer mortality (Fig 2eUp, P<.05) but not between body mass index and cancer mortality (Fig 2hUp, P=.09). Among smokers, significant relationships were seen between the LDL/HDL ratio and total mortality (Fig 3aUp, P<.02), between body mass index and overall mortality (Fig 4aUp, P<.03), but not between body mass index and cancer mortality (Fig 4aUp, P=.11). Despite the presence in some cases of an apparent U-shaped profile, none of the other relationships depicted in Figs 2 through 4UpUpUp achieved statistical significance.

The mean age of death among the individuals dying of cancer was 52±6 years (mean±SD) and did not differ among the individuals falling into each percentile of total cholesterol, LDL cholesterol, or body mass index, indicating that the increased death rate from cancer among smokers with low cholesterol was not due to the so-called dependent competing risks effect in which a lower CHD death rate among persons with low cholesterol levels led to their survival to an age at which cancer mortality becomes more prevalent.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The principal result of the present analysis was the demonstration that the increase in total mortality at low cholesterol concentrations in men aged 35 to 65 was almost entirely accounted for by an increase in cancer deaths in smokers with low cholesterol. As noted above, difficulties in the assessment of tobacco exposure in pipe and cigar smokers led us to classify such men as nonsmokers in many analyses (Figs 1Up, 3Up, and 4Up). This classification does not weaken the conclusions of this report; rather, it is likely that we have underestimated the magnitude of the smoking-related increase in cancer deaths among men with low cholesterol (see Table 5Up).

An increase in overall mortality at low cholesterol concentrations has been a feature of many observa- tional1 4 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 and several interventional1 38 39 40 41 studies. A number of hypotheses have been proposed that posit a causative role for low cholesterol in this increase in cancer- and non–cancer-related mortality, including deleterious effects on cell membrane function and immune surveillance.62 In addition, low cholesterol levels have been linked to depression, violence, and antisocial behavior63 64 65 66 67 68 69 70 and were associated in two cohort studies with an increased risk of death from injury or other violent death.71 72 In a review of 10 cohort studies, a significant relative risk of death from injuries or violence of 1.29 was found in six studies done in community settings, although no increased risk was observed in four cohorts of employed men.47 The results of these studies have not surprisingly led to considerable debate and uncertainty in the medical73 74 75 and lay76 77 78 79 press with respect to the desirability of strategies to lower blood cholesterol.

In interpreting the results of the present study, it is important to remember that the Münster Heart Study was carried out in persons at work and that individuals with known CHD were at entry into the study not included in the present analysis. Thus, our study sample is likely to be healthier than the overall population, and hence our results are likely to underestimate populationwide risks of mortality from CHD, cancer, or other causes. This is reflected in the fact that overall mortality in our population was less than that predicted for a group of this size using national German mortality statistics.

Death from cancer is rare in young persons. Because increased mortality at low cholesterol concentrations appears to be due mainly to cancer, it is not surprising that several studies in young persons have found no link between low cholesterol and higher death rates. In a study of 1017 male medical students (average age at recruitment, 22 years) followed for 27 to 42 years, there was no evidence of a J-shaped relationship between mortality and serum cholesterol.32 However, the association between total mortality and a difference in the serum cholesterol of 36 mg/dL (difference between 25th and 75th percentiles, interquartile range) in this study was significant only for men dying before the age of 50 and not for men above this age, suggesting that in older men, confounding factors served to weaken the relationship. A further study in employed healthy men aged 18 to 39 also showed decreased all-cause mortality at low cholesterol concentrations.34

Several studies in the middle-aged have also failed to show increased mortality at low cholesterol concentrations, but these have excluded either persons with malignancy36 or smokers35 37 for calculation of mortality in the low-cholesterol cohorts. Thus, in the final report of the WHO clofibrate trial,36 which followed healthy (excluding men with cerebrovascular disease, malignancy, cirrhosis, or renal disease) middle-aged men for >10 years, the all-cause mortality was 29% lower and the cancer death rate was 12% lower in men with low (181±29 mg/dL) cholesterol than in men with high (247±29 mg/dL) cholesterol. In the 19-year follow-up of the Chicago Heart Association Detection Project, all-cause mortality was lower in nonsmokers aged 30 to 69 years with baseline cholesterol of <200 mg/dL.35 Similarly, in the 16-year follow-up of 353 340 men aged 35 to 57 years in the Multiple Risk Factor Intervention Trial, nonsmokers with total cholesterol of <203 mg/dL also showed reduced all-cause mortality.37 Data on mortality in smokers with low cholesterol are not available for either of these studies at present.

In both the Framingham study80 and the Honolulu Heart Program,81 an association between low cholesterol levels and cancer was seen in participants who smoked. Similar results were found in a study among male civil servants in Albany, NY,82 in the National Health and Nutrition Examination Survey I21 and in the British regional heart study of middle-aged men.56 In the Multiple Risk Factor Intervention Trial, an excess risk of lung cancer was confined to smokers with low cholesterol levels.1 In their analysis of 33 prospective studies that examined the association between low serum cholesterol and the incidence of cancer, Law and Thompson83 also raised the possibility that this association may be explained by confounding from heavy smokers.

What is the nature of the link between low cholesterol and excess mortality in our and other studies? Possible explanations include chance, regression dilution bias, competing risks, cause-effect, effect-cause, and confounding.44 Based on the large amounts of data with reasonably small confidence intervals,45 84 chance does not appear to be the explanation. Regression dilution bias also is not the explanation because this error tends to underestimate the size of any real association. Dependent competing risks might explain the excess in noncoronary deaths if a decrease in the death rate from CHD led to an increase in the death rate from, for example, cancer. However, in our study, the mean age of death from cancer was similar in men with low and high levels of cholesterol. As noted above, it has been suggested that low serum cholesterol in some way affects cellular function, leading to an increased incidence of neoplasia. However, in tissues other than the spleen, endogenous synthesis is the main source of cholesterol.85 Moreover, in human neonates, plasma total cholesterol levels of 77 mg/dL are compatible with growth and cell division, and mean levels of <116 mg/dL are normal in healthy Chinese adults.84 Furthermore, in studies of human mononuclear cells and fibroblasts, cell membrane fluidity and cholesterol content were not altered, even during incubation in the presence of very low levels of LDL.85

Thus, the two most likely reasons for the observed association between low cholesterol levels and increased mortality are an effect-cause relationship (ie, low cholesterol concentrations are the result of the illness, such as cancer, causing increased mortality) and confounding bias. In the Honolulu Heart Study, falling levels of total cholesterol were accompanied by increased overall and cancer mortality.86 In contrast, there was no increase in overall mortality among men with stable low cholesterol levels. Among the Finnish cohorts of the Seven Countries Study, a significant inverse relationship between cholesterol and non-CHD deaths was seen within 10, but not within 15, years of follow-up.3 In the Multiple Risk Factor Intervention Trial study, the association of cholesterol and cancer continued to diminish after 12 years of follow-up.44 In an analysis from the American National Health and Nutrition Examination Survey I, Harris et al19 also found that the risk of mortality associated with low serum cholesterol persisted only up to 10 years. It has been proposed that the hypocholesterolemia associated with cancer and other chronic diseases is related to cytokine release87 and that the low cholesterol level reflects preclinical disease. In the present study, the increased mortality at low levels of LDL or total cholesterol in smokers was explained almost entirely by an increase in cancer. In our population, the association between increased cancer mortality and low levels of total or LDL cholesterol was no longer observed >5 years after recruitment, which supports the hypothesis that latent cancer predated and was responsible for the low level of serum cholesterol observed in many of the smokers.

In addition, increased mortality at low total cholesterol and LDL cholesterol levels or in the lowest body mass index quintile was seen only in smokers. This increase in mortality is therefore unlikely to reflect a causal relationship between hypocholesterolemia or low body mass index per se and the risk of death but is probably due to complex interactions involving a smoking-related increased incidence of cancer. This is reflected in the distribution of cancer types. The mortality rate due to carcinoma of the bronchus, the most common cancer in our study, was four times greater among cigarette smokers (class 6) than among nonsmokers (and 11 times greater if cigar/pipe smokers were included among smokers [classes 3 + 4 + 6]). Mortality due to carcinoma of the urinary bladder, the etiology of which is also smoking related, was eight times greater among cigarette smokers than among nonsmokers (Table 3Up). It is also possible that smoking may not have been the only contributor to the increased mortality in men with low cholesterol levels. In several studies, low cholesterol concentration has been associated with excess noncardiovascular, noncancer deaths related to smoking or heavy drinking, two features of lifestyle that often occur together.1 9 48 84 In addition, smoking may have contributed to an increase in noncardiovascular, noncancer mortality by other mechanisms. In the North Karelia project, for example, smoking was strongly associated with mortality from injuries, suicide, and other violent deaths, and the association was graded.88 The number of deaths that occurred in the present study is too small, however, to allow statistically meaningful analysis of these issues.


*    Acknowledgments
 
This authors express their gratitude to the Landesversicherungsanstalt Westfalen and Landesversicherungsanstalt Rheinland for their support of this project.

Received March 26, 1997; accepted May 3, 1997.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Neaton JD, Blackburn H, Jacobs D, Kuller L, Lee DJ, Sherwin R, Shih J, Stamler J, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Med. 1992;152:1490-1500.[Abstract]
  2. Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration and ischemic heart disease in observational studies: data from the BUPA Study. BMJ. 1994;308:363-366.[Abstract/Free Full Text]
  3. Pekkanen J, Nissinen A, Punsar S, Karvonen MJ. Short- and long-term association of serum cholesterol with mortality: the 25-year follow-up of the Finnish cohorts of the Seven Countries Study. Am J Epidemiol. 1992;135:1251-1258.[Abstract/Free Full Text]
  4. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham Study. JAMA. 1987;257:2176-2180.[Abstract]
  5. Assmann G, Schulte H. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Munster Study. Am J Cardiol. 1992;70:10H-13H.[Medline] [Order article via Infotrieve]
  6. Wilson PFW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality: the Framingham Study. Arteriosclerosis. 1988;8:737-741.[Abstract/Free Full Text]
  7. Williams RR, Sorlie PD, Feinleib M, McNamara PM, Kannel WB, Dawber TR. Cancer incidence by levels of cholesterol. JAMA. 1981;245:247-252.[Abstract]
  8. Garcia-Palmieri MR, Sorlie PD, Costas R, Havlik RJ. An apparent inverse relationship between serum cholesterol and cancer mortality in Puerto Rico. Am J Epidemiol. 1981;114:29-40.[Abstract/Free Full Text]
  9. Kozarevic D, McGee D, Vojvodic N, Gordon T, Racic Z, Zukel W, Dawber T. Serum cholesterol and mortality: the Yugoslavia Cardiovascular Disease Study. Am J Epidemiol. 1981;114:21-28.[Abstract/Free Full Text]
  10. Salmond CE, Beaglehole R, Prior IAM. Are low cholesterol values associated with excess mortality? BMJ. 1985;290:422-424.
  11. Martin MJ, Browner WS, Wentworth D, Hulley SB, Kuller LH. Serum cholesterol, blood-pressure, and mortality: implications from a cohort of 361 662 men. Lancet. 1986;2:933-936.[Medline] [Order article via Infotrieve]
  12. Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF. Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley Survey. BMJ. 1989;298:920-924.
  13. Kagan A, McGee DL, Yano K, Rhoads GG, Nomura A. Serum cholesterol and mortality in a Japanese American population: the Honolulu Heart Program. Am J Epidemiol. 1981;114:11-20.[Abstract/Free Full Text]
  14. Stemmermann GN, Chyou PH, Kagan A, Nomura AMY, Yano K. Serum cholesterol and mortality among Japanese-American men: the Honolulu (Hawaii) Heart Program. Arch Intern Med. 1991;151:969-972.[Abstract]
  15. Frank JW, Reed DM, Grove JS, Benfante R. Will lowering population levels of serum-cholesterol affect total mortality? Expectations from the Honolulu Heart Program. J Clin Epidemiol. 1992;45:333-346.[Medline] [Order article via Infotrieve]
  16. Kark JD, Smith AH, Hames CG. The relationship of serum cholesterol to the incidence of cancer in Evans County, Georgia. J Chron Dis. 1980;33:311-322.
  17. White AD, Hames CG, Tyroler HA. Serum cholesterol and 20-year mortality in black and white men and women aged 65 and older in the Evans County Study. Ann Epidemiol. 1992;2:85-91.[Medline] [Order article via Infotrieve]
  18. Higgins M, Keller JB. Cholesterol, coronary heart disease, and total mortality in middle-aged and elderly men and women in Tecumseh. Ann Epidemiol. 1992;2:69-76.[Medline] [Order article via Infotrieve]
  19. Harris T, Feldman JJ, Kleinman JC, Ettinger WH, Makuc DM, Schatzkin AG. The low cholesterol mortality association in a national cohort. J Clin Epidemiol. 1992;45:595-601.[Medline] [Order article via Infotrieve]
  20. Schatzkin A, Taylor PR, Carter CL, Licitra LM, Hoover RN, Ziegler RG, Larson DB. Serum cholesterol and cancer in the NHANES-I epidemiologic follow-up study. Lancet. 1987;2:298-301.[Medline] [Order article via Infotrieve]
  21. Schatzkin AS, Hoover RN, Taylor PR, Ziegler RG, Carter CL, Albanes D, Larson DB, Licitra LM. Site-specific analysis of total serum cholesterol and incident cancer in the National Health and Nutrition Examination Survey I epidemiologic follow-up study. Cancer Res. 1988;48:452-458.[Abstract/Free Full Text]
  22. Cowan LD, Oconnell DL, Criqui MH, Barrettconnor E, Bush TL, Wallace RB. Cancer mortality and lipid and lipoprotein levels: the Lipid Research Clinics Program mortality follow-up study. Am J Epidemiol. 1990;131:468-482.[Abstract/Free Full Text]
  23. Iso H, Naito Y, Kitamura A, Sato S, Kiyama M, Takayama Y, Iida M, Shimamoto T, Sankai T, Komachi Y. Serum total cholesterol and mortality in a Japanese population. J Clin Epidemiol. 1994;47:961-969.[Medline] [Order article via Infotrieve]
  24. Goldbourt U, Yaari S, Neufeld HN. High density lipoprotein and total cholesterol as predictors of 7-year mortality from coronary heart disease, cancer and all causes. Am J Cardiol. 1981;47:486.
  25. Smith GD, Shipley MJ, Marmot MG, Rose G. Plasma cholesterol concentration and mortality: the Whitehall Study. JAMA. 1992;267:70-76.[Abstract]
  26. Rose G, Shipley MJ. Plasma lipids and mortality: a source of error. Lancet. 1980;1:523-526.[Medline] [Order article via Infotrieve]
  27. Yaari S, Goldbourt U, Evenzohar S, Neufeld HN. Associations of serum high density lipoprotein and total cholesterol with total, cardiovascular, and cancer mortality in a 7-year prospective study of 10 000 men. Lancet. 1981;1:1011-1015.[Medline] [Order article via Infotrieve]
  28. Dyer AR, Stamler J, Paul O, Shekelle RB, Schoenberger JA, Berkson DM, Lepper M, Collette P, Shekelle S, Lindberg HA. Serum cholesterol and risk of death from cancer and other causes in three Chicago epidemiological studies. J Chron Dis. 1981;34:249-260.[Medline] [Order article via Infotrieve]
  29. Peterson B, Trell E, Sternby NH. Low cholesterol level as risk factor for non-coronary death in middle-aged men. JAMA. 1981;245:2056-2057.[Abstract]
  30. Schuit AJ, Van Dijk CEMJ, Dekker JM, Schouten EG, Kok FJ. Inverse association between serum total cholesterol and cancer mortality in Dutch civil servants. Am J Epidemiol. 1993;137:966-976.[Abstract/Free Full Text]
  31. Wald NJ, Thompson SG, Law MR, Densem JW, Bailey A. Serum cholesterol and subsequent risk of cancer: results from the BUPA Study. Br J Cancer. 1989;59:936-938.[Medline] [Order article via Infotrieve]
  32. Klag MJ, Ford DE, Mead LA, He J, Whelton PK, Liang KY, Levine DM. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med. 1993;328:313-318.[Abstract/Free Full Text]
  33. Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship of base line major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts. Cardiology. 1993;82:191-222.[Medline] [Order article via Infotrieve]
  34. Stamler J, Garside D, Dyer A, Stamler R, Liu K, Greenland P. The strong positive relationship of serum cholesterol to risk of death from coronary heart disease (CHD), all cardiovascular diseases (CVD), cancers, other diseases, and all causes in employed young adult men: findings of the Chicago Heart Association study (CHA). Circulation. 1993;88(suppl I):I-24. Abstract.
  35. Stamler J, Garside D, Stamler R, Dyer A, Greenland P, Liu K, Ruth KJ. Low risk women and men: 19 year mortality data, Chicago Heart Association detection project in industry (CHA). Circulation. 1994;89:938.
  36. Heady JA, Morris JN, Oliver MF. WHO clofibrate/cholesterol trial: clarifications. Lancet. 1992;340:1405-1406. Letter.[Medline] [Order article via Infotrieve]
  37. Stamler J, Neaton JD, Wentworth D. Mortality of low risk and other men: 16-year follow-up of 353 340 men screened for the Multiple Risk Factor Intervention Trial (MRFIT). Circulation. 1994;89:938. Abstract.
  38. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men. JAMA. 1991;266:1225-1229.[Abstract]
  39. Multiple Risk Factor Intervention Trial Research Group. Risk factor changes and mortality results. JAMA. 1982;248:1465-1477.[Abstract]
  40. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a qualitative review of primary prevention trials. BMJ. 1990;301:309-314.
  41. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237-1245.[Abstract]
  42. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]
  43. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New E J Med. 1995;333:1301-1307.
  44. Simes RJ. Low cholesterol and risk of non-coronary mortality. Aust N Z J Med. 1994;24:113-119.[Medline] [Order article via Infotrieve]
  45. Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, Neaton J, Nelson J, Potter J, Rifkind B, Rossouw J, Shekelle R, Yusuf S. Report of the conference on low blood cholesterol–mortality associations. Circulation. 1992;86:1046-1060.[Abstract/Free Full Text]
  46. Cummings P, Psaty BM. The association between cholesterol and death from injury. Ann Intern Med. 1994;120:848-855.[Abstract/Free Full Text]
  47. Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ. 1994;308:373-379.[Abstract/Free Full Text]
  48. Davey-Smith G, Shipley MJ, Marmot MG, Rose G. Plasma cholesterol and mortality: the Whitehall Study. JAMA. 1992;267:70-76.
  49. Manolio TA, Ettinger WH, Tracy RP, Kuller LH, Borhani NO, Lynch JC, Fried LP, Burke GL, Cody ME, Cruise RG, Furberg CD, Heiss G, Klopfenstein HS, Lefkowitz DS, Lyles MF, Mittelmark MB, Tell GS, Toole JF, Bommer W, Lee M, Robbins J, Schenker M, Bryan RN, Bush TL, Chabot J, Comstock GW, German PS, Hill J, Kittner SJ, Kumanyika S, Powe NR, Price TR, Rock R, Szklo M, Bonk J, Mclaughlin B, Meyer P, Newman A, Orchard TJ, Rutan GH, Schulz R, Smith VE, Wolfson SK, Antonculver H, Gardin JM, Knoll M, Kurosaki T, Wong N, Oleary DH, Polak JF, Potter J, Bovill E, Cornell E, Howard P, Enright P, Toogood S, Calhoun K, Calhoun H, Montague P, Rautaharju F, Rautaharju P, Fitzpatrick AL, Hermanson BK, Kronmal RA, Psaty BM, Siscovick DS, Shemanski L, Wahl PW, Bild DE, Savage PJ, Smith P. Epidemiology of low cholesterol levels in older adults: the Cardiovascular Health Study. Circulation. 1993;87:728-737.[Abstract/Free Full Text]
  50. Wannamethee G, Shaper AG. Blood lipids: the relationship with alcohol intake, smoking and body weight. J Epidemiol Commun Health. 1993;46:197-202.[Abstract]
  51. Winawer SJ, Flehinger BJ, Buchalter J, Herbert E, Shike M. Declining serum cholesterol levels prior to diagnosis of colon cancer. JAMA. 1990;263:2083-2085.[Abstract]
  52. McMichael AJ, Jensen OM, Parkin DM, Zaridze DG. Dietary and endogenous cholesterol and human cancer. Epidemiol Rev. 1984;6:192-216.[Free Full Text]
  53. Shorposner G, Basit A, Lu Y, Cabrejos C, Chang J, Fletcher M, Manteroatienza E, Baum MK. Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. Am J Med. 1993;94:515-519.[Medline] [Order article via Infotrieve]
  54. Constans J, Pellegrin JL, Peuchant E, Dumon MF, Pellegrin I, Sergeant C, Simonoff M, Brossard G, Barbeau P, Fleury H, Clerc M, Leng B, Conri C. Plasma lipids in HIV-infected patients: a prospective study in ninety-five patients. Eur J Clin Invest. 1994;24:416-420.[Medline] [Order article via Infotrieve]
  55. Christeff N, Lortholary O, Casassus P, Thobie N, Dalle MT, Veyssier P, Guillevin L, Nunez EA. Serum lipid concentration with reference to the clinical and immunological status of HIV-infected men. Ann Med Intern. 1995;146:490-495.
  56. Wannamethee G, Shaper AG, Whincup PH, Walker M. Low serum total cholesterol concentrations and mortality in middle aged British men. BMJ. 1995;311:409-413.[Abstract/Free Full Text]
  57. Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem. 1964;6:24-29.
  58. Röschlau P, Bernt E, Gruber Z. Enzymatische Bestimmung des Gesamtcholesterins im Serum. Z Klin Chem Klin Biochem. 1974;12:403-408.[Medline] [Order article via Infotrieve]
  59. Burstein M, Samaille J. Sur un dosage rapide du cholesterol lié aux alpha- et aux betalipoproteins du sérum. Clin Chim Acta. 1960;5:609-614.[Medline] [Order article via Infotrieve]
  60. Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957;17:237-246.[Medline] [Order article via Infotrieve]
  61. Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated levels of lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol. 1996;77:1179-1184.[Medline] [Order article via Infotrieve]
  62. Lewis B, Tikkanen MJ. Low blood total cholesterol and mortality: causality, consequence and confounders. Am J Cardiol. 1994;73:80-85.[Medline] [Order article via Infotrieve]
  63. Freedman DS, Byers T, Barrett DH, Stroup NE, Eaker E, Monroeblum H. Plasma lipid levels and psychosocial characteristics in men. Am J Epidemiol. 1995;141:507-517.[Abstract/Free Full Text]
  64. Fowkes FGR, Leng GC, Donnan PT, Deary IJ, Riemersma RA, Housley E. Serum cholesterol, triglycerides, and aggression in the general population. Lancet. 1992;2:995-998.
  65. Morgan RE, Palinkas LA, Barrett-Connor EL, Wingard DL. Plasma cholesterol and depressive symptoms in older men. Lancet. 1993;341:75-79.[Medline] [Order article via Infotrieve]
  66. Lindberg G, Larsson G, Setterlind S, Rastam L. Serum lipids and mood in working men and women in Sweden. J Epidemiol Commun Health. 1994;48:360-363.[Abstract]
  67. Virkkunen M. Serum cholesterol in antisocial personality. Neuropsychobiology. 1979;5:27-30.[Medline] [Order article via Infotrieve]
  68. Glueck CJ, Tieger M, Kunkel R, Hamer T, Tracy T, Speirs J. Hypercholesterolemia and affective disorders. Am J Med Sci. 1994;308:218-225.[Medline] [Order article via Infotrieve]
  69. Muldoon MF, Matthews KA, Wing RR. Serum cholesterol and depression in women. Circulation. 1994;89(suppl I):I-6. Abstract.
  70. Robins LN, Helzer JE, Weissman MM, Orvaschel H, Gruenberg E, Burke JD, Regier DA. Lifetime prevention of specific psychiatric disorders in three sites. Arch Gen Psychiatry. 1984;41:949-958.[Abstract]
  71. Schuit AJ, Dekker JM, Schouten EG, Kok FJ. Low serum cholesterol and death due to accidents, violence, or suicide. Lancet. 1993;341:827. Letter.
  72. Lindberg G, Rastam L, Gullberg B, Eklund GA. Low serum cholesterol concentration and short-term mortality from injuries in men and women. BMJ. 1992;305:277-279.
  73. Oliver MF. Doubts about preventing coronary heart disease: multiple interventions in middle-aged men may do more harm than good. BMJ. 1992;304:393-394.
  74. Smith GD, Pekkanen J. Should there be a moratorium on cholesterol-lowering drugs? BMJ. 1992;304:431-433.
  75. Ravnskov U. Cholesterol-lowering trials in coronary heart disease: frequency of citation and outcome. BMJ. 1992;305:15-19.
  76. Hodgkinson N. Cutting cholesterol increases danger of heart attacks: diet theories overturned by new research. The Sunday Times, 22 December 1991, page 1.
  77. Anonymous. Freispruch für einen Schurken [A villain is acquitted]. Der Spiegel, issue 45, 1990, pages 256-272.
  78. Moore TJ. The cholesterol myth. The Atlantic Monthly, September 1989, pages 37-69.
  79. Prentice T. Heart pills can increase risk of death. The Irish Times, 14 February 1992, page 4.
  80. d'Agostino RB, Belanger AJ, Kannel WB, Higgins M. Role of smoking in the U-shaped relation of cholesterol to mortality in men: the Framingham Study. Am J Epidemiol. 1995;141:822-827.[Abstract/Free Full Text]
  81. Iribarren C, Reed DM, Burchfiel CM, Dwyer JH. Serum total cholesterol and mortality: confounding factors and risk modification in Japanese-American men. JAMA. 1995;273:1926-1932.[Abstract]
  82. Baptiste MS, Nasca PC, Doyle JT, Rothenberg RR, MacCubbin PA, Mettlin C, Metzger C, Carlton KA. Cholesterol and cancer in a population of male civil service workers. Int J Epidemiol. 1992;21:16-22.[Abstract/Free Full Text]
  83. Law MR, Thompson SG. Low serum cholesterol and the risk of cancer: analysis of the published prospective studies. Cancer Causes Control. 1991;2:253-261.[Medline] [Order article via Infotrieve]
  84. Chen Z, Peto R, Collins R, Macmahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ. 1991;303:276-282.
  85. Dietschy JM. Regulation of cholesterol metabolism in man and in other species. Klin Wochenschr. 1984;62:338-345.[Medline] [Order article via Infotrieve]
  86. Iribarren C, Sharp D, Burchfiel CM, Sun P, Dwyer JH. Association of serum total cholesterol with coronary disease and all- cause mortality: multivariate correction for bias due to measurement error. Am J Epidemiol. 1996;143:463-471.[Abstract/Free Full Text]
  87. Ettinger WH Jr, Harris TB. Cytokines cause hypocholesterolemia: a mechanism to explain the association of low cholesterol with mortality from multiple chronic diseases. Cardiovasc Risk Factors. 1995;5:173-179.
  88. Puska P, Tuomilehto J, Salonen J, Nissinene A, Virtamo J, Björkqvist S, for the North Karelia Project. Community Control of Cardiovascular Diseases: The North Karelia Project. Copenhagen: WHO Regional Office for Europe; 1981.



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