Download Risk of acute coronary events according to

Risk of acute coronary events according to serum concentrations
of enterolactone: a prospective population-based case-control
study
Meri Vanharanta, Sari Voutilainen, Timo A Lakka, Manon van der Lee, Herman Adlercreutz, Jukka T Salonen
Summary
Background The lignan enterolactone, produced by the
intestinal microflora from dietary precursors, has been
implicated in protection against cancer. We investigated the
association of serum enterolactone concentration with the
risk of acute coronary events in a prospective nested casecontrol study in middle-aged men from eastern Finland.
Methods Enterolactone was measured by time-resolved
fluoroimmunoassay in serum from 167 men who had an
average 7·7 years of follow-up to an acute coronary event and
from 167 control men. Both cases and controls were from a
cohort of 2005 men who had no clinical coronary heart
disease (CHD) at baseline. The controls were matched for
age, examination year, and residence. Acute coronary events
were registered prospectively.
Findings The mean baseline serum enterolactone
concentration was lower among the cases than the controls
(18·2 [SD 21·1] vs 23·5 [18·2] nmol/L, p=0·001). The men in
the highest quarter of the enterolactone distribution (>30·1
nmol/L) had a 58·8% (95% CI 24·1–77·6, p=0·005) lower risk
of acute coronary events than men in the lowest quarter. After
adjustment for the nine most strongly predictive risk factors,
men in the highest enterolactone quarter had a 65·3%
(11·9–86·3, p=0·03) lower risk than men in the lowest
quarter.
Interpretation Healthy men with high serum concentrations of
enterolactone had a lower risk of acute coronary events than
men with lower concentrations. These findings support the
hypothesis that plant-dominated fibre-rich food lowers the risk
of CHD.
Lancet 1999; 354: 2112–15
Introduction
Lignans have been postulated to have a role in protection
against both cancer and coronary heart disease (CHD).1
Mammalian lignans are synthesised when plant lignans
(phyto-oestrogens) are modified by intestinal bacteria.2
The most abundant mammalian lignan is enterolactone.
There is evidence that enterolactone influences
metabolism of sex hormones and proliferation of
malignant cells, inhibits the human aromatase enzyme,
and inhibits the metabolism of growth-promoting steroid
hormones.1,3–5 These effects of enterolactone provide
potential mechanisms for a postulated preventive influence
in CHD.
Many common foodstuffs, such as seeds, cereals (rye,
barley, and wheat), berries, and some vegetables, contain
plant lignans.1 However, most mammalian lignan
precursors may still be unknown.1
We aimed to test the hypothesis that a high serum
enterolactone concentration is associated with a low risk of
acute coronary events in middle-aged men with no
previous atherosclerotic vascular diseases.
Methods
Study population
The Kuopio Ischaemic Heart Disease Risk Factor Study is a
population-based study of risk factors for CHD, atherosclerosis,
and other related outcomes.6 The study protocol was approved by
the Research Ethics Committee of the University of Kuopio. The
study population is a random sample of men living in the city of
Kuopio or neighbouring rural communities, stratified and
balanced in four strata: exactly 42 years, 48 years, 54 years, or
60 years old at the baseline examination. The baseline
examinations were carried out between 1984 and 1989. Of 3235
eligible men, 2682 (82·9%) participated. Men with prevalent
CHD at baseline (n=677) were excluded. Prevalent CHD was
defined as a history of acute coronary events or angina pectoris,
angina pectoris on effort, or use of glyceryl trinitrate tablets at least
once a week.7 Thus, this study is based on a cohort of 2005 men
without CHD.
Design and procedures
Research Institute of Public Health (M Vanharanta BSc,
S Voutilainen MSc, T A Lakka DrMedSci, Prof J T Salonen DrMedSci) and
Department of Public Health and General Practice
(Prof J T Salonen), University of Kuopio, Kuopio; and Institute for
Preventive Medicine, Nutrition and Cancer, Folkhälsan Research
Center and Department of Clinical Chemistry, University of
Helsinki, Helsinki (M van der Lee BSc, Prof H Adlercreutz DrMedSci),
Finland
Correspondence to: Prof Jukka T Salonen, Research Institute of
Public Health, University of Kuopio, PO 1627, 70211 Kuopio, Finland
(e-mail: [email protected])
2112
Acute coronary events that occurred between 1984 and 1992 were
registered as part of the multinational MONICA (Monitoring of
Trends and Determinants in Cardiovascular Disease) Project.8
Data on coronary events between 1993 and 1996 were obtained
by record linkage from the national computerised hospitaldischarge registry. The diagnostic classification used was identical
to that of the MONICA project. The cohort was followed up on
average for 10 years. According to the diagnostic classification of
the events,8 there were 81 definite and 55 possible acute
myocardial infarctions and 31 typical long episodes of chest pain.
The cases were 167 men who had their first acute coronary event
by the end of 1996. To ensure the comparability of the controls,
one control was matched for each case according to age (42, 48,
54, 60), examination year (1984–1989) and place of residence
(the same municipality out of ten), and were drawn from the same
cohort as the cases. The follow-up time for the 334 participants
varied between 1 month (to event) and 12·8 years. Serum samples
THE LANCET • Vol 354 • December 18/25, 1999
n*
Cases
(n=167)
Controls
(n=167)
p
Age (years)†
334
54·2 (3·9)
54·2 (3·9)
Physical characteristics
Height (cm)
Weight (kg)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
··
332
334
332
332
171·7 (6·8)
80·9 (13·3)
140 (17)
92 (11)
173·3 (6·1)
80·3 (10·8)
134 (17)
88 (10)
0·02
0·74
0·001
0·002
Lifestyle
Smokers
Pack-years
Alcohol consumption (g/week)
334
328
334
72 (43%)
12·9 (18·8)
83 (126)
45 (27%)
7·5 (15·2)
60 (119)
0·005
0·01
0·04
Diabetes
334
20 (12%)
5 (3%)
0·003
Maximum oxygen uptake in
exercise test (mL kg21 min21)
284
28·4 (6·2)
31·6 (8·1)
<0·001
Biochemistry
Serum enterolactone (nmol/L)
Serum apolipoprotein B (mg/L)
Serum HDL cholesterol (mmol/L)
Serum HDL2 cholesterol (mmol/L)
Serum LDL cholesterol (mmol/L)
Serum triglycerides (mmol/L)
Serum ferritin (mg/L)
Serum transferrin receptor to
ferritin ratio
Plasma fibrinogen (g/L)
Plasma ascorbic acid (mg/L)
Blood glucose (mmol/L)
Urinary excretion of nicotine
metabolites (mg/24 h)
Dietary intake
Calcium (g/day)
Sodium (g/day)
Iron (mg/day)
Potassium (g/day)
Magnesium (g/day)
334
316
328
324
326
320
334
330
18·2 (21·1)
521 (586)
1·21 (0·27)
0·77 (0·26)
4·40 (1·04)
1·37 (0·79)
190 (176)
19·0 (23·3)
23·5 (18·2)
0·001
391 (533)
<0·001
1·31 (0·30) 0·003
0·86 (0·28) 0·003
4·18 (1·05) 0·02
1·29 (0·71) 0·32
151 (143)
0·02
25·3 (41·0)
0·06
276
328
334
234
3·1 (0·6)
7·0 (4·1)
5·03 (1·38)
8·18 (10·5)
3·0 (0·5)
0·1
8·2 (4·2)
0·006
4·73 (0·68) 0·38
4·40 (8·03) <0·001
324
324
324
324
324
1·4 (0·5)
3·4 (1·4)
18·7 (5·9)
4·57 (1·13)
0·44 (0·11)
1·4 (0·5)
3·3 (1·1)
18·5 (5·5)
4·58 (1·06)
0·44 (0·10)
0·24
0·35
0·83
0·98
0·98
Data are mean (SD) or number of participants. *Total for whom data were available.
†Matched variable.
Table 1: Risk factors
drawn at baseline were stored at –20ºC on average for 11·9 years
(range 8·4–14·2) from sampling to enterolactone measurements.
The measurement method was based on time-resolved
fluoroimmunoassay with a europium chelate as a label,9 with slight
modifications: serum was diluted only 1 in 2 instead of 1 in 11
with buffer before hydrolysis, and there were two ethyl-ether
extractions (each with 1·5 mL). 59-O-carboxymethylyenterolactone was synthesised and coupled to bovine serum albumin and
used as antigen to immunise rabbits. The tracer with the
europium chelate was synthesised from the same 59-derivative of
enterolactone. After enzymic hydrolysis and ether extraction, the
immunoassay was carried out with the Victor 1420 multilabel
counter (Wallac, Turku, Finland). No antiserum cross-reactivity
with available lignans, isoflavonoids, or flavonoids could be
detected. The working range of the assay was 1·5–540 nmol/L.
Coefficients of variation within and between assays at three
different concentrations varied from 4·5% to 9·2% and from 5·9%
to 9·1%, respectively. The correlation coefficient for 44 samples
between this method and our reference method (isotope dilution
gas-chromatography and mass spectrometry) was 0·82
(p=0·0004), the mean values being 31·2 nmol/L for the reference
assay and 31·0 nmol/L for the fluoroimmunoassay. The
reproducibility coefficient for a single measurement of serum
enterolactone was 0·55 (95% CI 0·41–0·69).10
Demographic variables, medical history and medications,
family history of diseases, ischaemic findings in the baseline
exercise test, smoking, and blood pressure were assessed as
described previously.7,11 The collection of blood samples and the
measurement of serum lipids, lipoproteins, and ferritin, plasma
fibrinogen and ascorbic acid, maximum oxygen uptake,11 24 h
urinary excretion of nicotine metabolites, and sodium excretion
have been described previously.7,12–15 Diabetes was defined as a
previous diagnosis of diabetes or fasting blood glucose
concentrations of 6·7 mmol/L or higher.
The consumption of foods was assessed at the time of blood
sampling with an instructed 4-day food recording by household
measures.16 The instructions were given and the completed food
records were checked by a nutritionist. The intake of nutrients
and total energy intake were estimated with Nutrica software. The
databank of Nutrica mainly uses Finnish values for the nutrient
values of foods.
Statistical analysis
Differences in risk factors between the cases and controls were
tested for significance with Wilcoxon’s signed-rank test or with
McNemar’s test for two related samples; those between quarters
of the serum enterolactone distribution were tested with KruskalWallis ANOVA. Odds ratios for acute coronary events, adjusted
for risk factors, were estimated by stepwise and forced conditional
multivariate logistic-regression modelling in paired data. 95% CI
were estimated on the assumption of asymptotic normality of
estimates of the Egret for Windows software (version 1.0).
Missing values in urinary nicotine excretion were imputed by
means of linear regression on the basis of the self-reported number
of cigarettes smoked daily. The self-reported number of cigarettes
daily had a correlation with the urinary nicotine excretion of 0·57
before imputation and 0·72 after the imputation. Missing values in
other covariates were replaced by means, separately for cases and
controls.
Results
The distributions of the major known coronary risk factors
in the cases and controls are shown in table 1. The mean
serum enterolactone concentration was 25·1% lower
among the cases than among controls (95% CI 4·1–46·2],
p=0·001 for difference).
In a univariate logistic model, the risk of acute coronary
events was decreased on average by 1·4% per unit
(nmol/L) of serum enterolactone (0·2–2·6, p=0·016). The
Model 1*
Model 2†
Odds ratio (95% CI)
p
Odds ratio (95% CI)
p
Enterolactone
Fourth quarter (>30·10 nmol/L)
Third quarter (15·11–30·10 nmol/L)
Second quarter(7·21–15·10 nmol/L)
0·33 (0·14–0·76)
0·69 (0·31–1·57)
1·11 (0·50–2·45)
0·01
0·38
0·80
0·35 (0·14–0·88)
0·75 (0·31–1·81)
1·22 (0·51–2·96)
0·03
0·53
0·51
Other risk factors
Serum apolipoprotein B (per 100 mg/L)
Dietary iron intake (mg/day)
Family history of coronary heart disease (yes vs no)
Ischaemic findings on exercise test (yes vs no)
Dietary calcium intake (per 100 mg/day)
Urinary excretion of nicotine metabolites (mg/day)
Diabetes (yes vs no)
Systolic blood pressure (per 10 mm Hg)
Maximum oxygen uptake (L kg21 min21)
··
··
··
··
··
··
··
··
··
··
··
··
··
··
··
··
··
··
1·31 (1·12–1·53)
1·12 (1·05–1·21)
2·80 (1·40–5·46)
3·23 (1·36–7·66)
0·89 (0·83–0·97)
1·05 (1·01–1·10)
5·82 (1·36–24·98)
1·26 (1·02–1·54)
0·94 (0·88–0·99)
<0·001
0·001
0·004
0·008
0·01
0·02
0·02
0·03
0·03
*A logistic model including three highest enterolactone quarters.
†A stepwise model (p for entry 0·05); the second and third enterolactone quarters are forced into the model.
Table 2: Strongest risk factors for acute coronary events in conditional multivariate logistic regression models
THE LANCET • Vol 354 • December 18/25, 1999
2113
There was significant heterogeneity in systolic and
diastolic blood pressure between quarters of the
enterolactone distribution (table 3). The mean
concentrations of total, HDL, and LDL cholesterol and
apolipoprotein B did not differ significantly between these
quarters (table 3).
Serum enterolactone concentration had a positive
correlation (r=0·08, p=0·15) with fibre intake. The
correlation was stronger (r=0·12, p=0·03) when fibre
intake was expressed in relation to bodyweight. The
dietary intake of fibre had, however, no consistent
association with the risk of acute coronary events.
Discussion
Unadjusted and risk-factor-adjusted odds ratios for acute
events according to quarters of baseline serum enterolactone
concentration
decrease in risk was 2·3% per nmol/L serum enterolactone
(0·7–3·7, p=0·004) after adjustment for the nine other
most strongly predictive risk factors (table 2, model 2).
The covariates were selected by stepwise analysis (p<0·05
for entry). Men with high serum enterolactone (above
median, 15·11 nmol/L) had a 52·0% (9·4–74·6, p=0·02)
lower risk of acute coronary events than men with lower
serum enterolactone concentrations.
To examine the dose-response relation, we grouped the
participants into quarters of the serum enterolactone
distribution. Men in the highest quarter (>30·10 nmol/L)
had a 58·8% (24·1–77·6, p=0·005) lower risk of acute
coronary events than men in the lowest quarter (figure).
After adjustment for the nine most strongly predictive risk
factors (table 2, model 2), men in the highest quarter had a
65·3% (11·9–86·3, p=0·03) lower risk of acute coronary
events than men in the lowest quarter. The linear trend in
risk of acute coronary events across quarters of the
enterolactone distribution was significant (p=0·01).
To test the association between enterolactone and the
risk of acute coronary events in men with neither clinical
nor subclinical CHD, we excluded 37 pairs because
electrocardiography showed ischaemia on the exercise test
for either the case or the control. The association of
enterolactone with the risk of acute coronary events was
stronger than for all pairs. The unadjusted odds ratio for
men in the highest quarter of enterolactone was 0·33
(0·14–0·76, p=0·01) compared with those in the lowest
quarter.
Since smokers are under increased oxidative stress, the
impact of antioxidative nutrients on CHD is expected to
be greater in smokers. In an unadjusted unpaired logistic
regression analysis, the relative benefit in the highest
quarter was 79·3% (37·8–93·1, p=0·005) among smokers
and 47·0% among non-smokers (216·5 to 75·9, p=0·11).
The difference was not significant.
Enterolactone is a diphenolic compound of dietary origin
that has been associated with a reduced risk of cancer.1,17,18
A role of enterolactone in protection against CHD has
been suggested previously.1 Although enterolactone may
be simply a biomarker of healthy fibre-rich food, there are
mechanisms through which enterolactone itself could
actively protect against cardiovascular diseases.
Plasma enterolactone concentration depends on the
intake of lignan-containing food and the activity of the
intestinal microflora. For example, antibiotic treatment
decreases the production of enterolactone for weeks.
There is an increasing amount of evidence that the
initiation of atherosclerosis is related to the oxidative
modification of LDL. Lipid peroxidation is associated with
accelerated atherosclerotic progression.19 Like all phenolic
compounds, enterolactone is likely to inhibit lipid
peroxidation.1
Cigarette
smoke
increases
lipid
peroxidation.19,20 Because smokers are under high oxidative
stress, they are likely to benefit from additional
antioxidants,21 such as enterolactone. We found higher
relative benefits from high serum enterolactone for
smokers than for non-smokers.
Intracellular enterolactone could also protect against
lipid peroxidation. Because of the interaction between
lignans and the sex-hormone-binding globulin (SHBG),
enterolactone is carried to the target cells.22 Enterolactone
passes freely into the cell4 and could protect against
oxidative damage due to intracellular free radicals.
Evidence from both basic research and cross-sectional
human population studies suggests that increased freeradical stress is associated with hypertension.23 Also, low
plasma concentrations of vitamin C and selenium have
been associated with high blood pressure.!5 We found
higher blood pressure in men with low serum enterolactone
concentrations than in those with higher values.
Lignans have weak oestrogenic activity, as a result of the
2,3-dibenzylbutane structure, which resembles synthetic
oestrogens.24 High amounts of lignans together with other
similar compounds entering the portal circulation
stimulate SHBG production.3 This is one mechanism
through which lignans could protect against atherosclerosis
Characteristic
First quarter
Second quarter
Third quarter
Fourth quarter
p for heterogeneity
Systolic blood pressure (mm Hg)*
Diastolic blood pressure (mm Hg)*
Serum total cholesterol (mmol/L)†
Serum LDL cholesterol (mmol/L)†
142 (2)
93 (1)
6·13 (0·13)
4·25 (1·13)
136 (2)
89 (1)
6·13 (0·13)
4·34 (1·03)
134 (2)
88 (1)
6·27 (0·13)
4·39 (1·02)
137 (2)
90 (1)
6·22 (0·13)
4·19 (0·99)
0·026
0·017
0·82
0·52
Serum HDL cholesterol (mmol/L)†
Serum apolipoprotein B (mg/L)†
1·24 (0·03)
478 (59)
1·28 (0·03)
350 (59)
1·26 (0·03)
447 (58)
1·28 (0·03)
0·74
519 (59)
0·22
*Adjusted for age, examination year, alcohol intake, 24 h urinary sodium excretion, and dietary magnesium intake.
†Adjusted for age, examination year, and alcohol intake.
Table 3: Mean (SE) blood pressure and serum lipid concentrations in quarters of distribution of serum enterolactone
concentrations from ANOVA
2114
THE LANCET • Vol 354 • December 18/25, 1999
and CHD. Low SHBG concentrations are associated with
smaller and denser LDL particles,25 which in turn have
been associated with increased CHD risk.26 The
oestrogenic effect of lignans on liver SHBG production
may parallel an effect on LDL synthesis resulting in larger
LDL particles that are more resistant to oxidation. In a
female population during a 12-year follow-up period, low
plasma SHBG concentrations were associated with
increased CHD mortality,27 but in men the evidence is
controversial.28
Our finding of high blood pressure in men with low
serum enterolactone concentrations needs to be retested.
We confirmed the previous finding that fibre intake
correlates only weakly with enterolactone concentration in
body fluids.1 Even though a high dietary intake of both
total fibre and cereal fibre has been associated with a lower
risk of CHD in several prospective studies,29,30 we found no
such association. Nevertheless, we cannot rule out the
possibility that there are other compounds in fibre-rich
foods that might add to the protective effect of
enterolactone or even be the protective nutrients,
enterolactone merely being a biomarker of a protective diet.
Our findings must be confirmed by further
epidemiological studies, and randomised trials testing the
effects of diets and supplements high in plant and
mammalian lignans will be warranted. A diet high in
enterolactone precursors has no conceivable harmful
effects. Eventually, these further studies could justify
changes in the current recommendations for a healthy diet.
8
9
10
11
12
13
14
15
16
17
18
Contributors
Meri Vanharanta undertook most of the data analyses and drafted the
paper, Sari Voutilainen contributed to the data analysis and checked the
food record data, Timo Lakka classified coronary events, Manon van der
Lee carried out the enterolactone assays, Herman Adlercreutz developed
and supervised the enterolactone assays, and Jukka Salonen designed the
KIHD investigation and initiated this study. All investigators contributed
to the writing of the report.
Acknowledgments
We thank Kristiina Nyyssönen for supervising part of the chemical
analyses; Esko Taskinen, Juha Venäläinen, Riitta Salonen, Hannu
Litmanen, and Rainer Rauramaa for supervising exercise tests; Jaakko
Tuomilehto, and Kalevi Pyörälä for the access to the Finmonica coronary
registry data; Plonja Kuiper for participating in the enterolactone assays;
and Sudhir Kurl and Hannu Mykkänen for useful comments.
This study was supported by research grants from the National Heart,
Lung, and Blood Institute of the USA (grant HL 44199 to George A
Kaplan) and the Academy of Finland (grants 41471, 1041086 and
2041022 to Jukka T Salonen).
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