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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
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
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Abstract |
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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
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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
200 mg/dL or LDL cholesterol
levels below a cutoff of 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.
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Methods |
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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.
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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 1
. 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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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 2. 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 3). 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 4. 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 5). 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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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 1).
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CHD Mortality
A continuous and graded relationship was observed
between CHD mortality and total cholesterol (Fig 2a), triglycerides (Fig 2b),
LDL cholesterol (Fig 2 c), HDL cholesterol
(inverse relationship, Fig 2d), the LDL
cholesterol/HDL cholesterol ratio (Fig 2e), and fibrinogen (Fig 2f). In contrast, the relationships between
CHD mortality and systolic blood pressure (Fig 2g) and between
CHD mortality and body mass index (Fig 2h) were apparently
J-shaped, although this relationship was not statistically
significant.
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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 3a and 4a).
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 3b and 4b). Higher
levels of triglycerides, fibrinogen, or systolic
blood pressure were all associated with higher overall mortality.
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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 2i
),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 2h, P<.04), LDL/HDL ratio and
overall mortality (Fig 2e, P<.01), and LDL/HDL ratio and
cancer mortality (Fig 2e, P<.05) but not between body mass
index and cancer mortality (Fig 2h, P=.09). Among smokers,
significant relationships were seen between the LDL/HDL ratio and total
mortality (Fig 3a, P<.02), between body mass index and
overall mortality (Fig 4a, P<.03), but not between body
mass index and cancer mortality (Fig 4a, P=.11). Despite the
presence in some cases of an apparent U-shaped profile,
none of the other relationships depicted in Figs 2 through 4 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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 1
, 3, and 4). 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 5). 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 3). 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.
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Acknowledgments |
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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.
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