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Papers
Low grade inflammation and coronary heart disease:
prospective study and updated meta-analyses
John Danesh, Peter Whincup, Mary Walker, Lucy Lennon, Andrew Thomson, Paul Appleby,
J Ruth Gallimore, Mark B Pepys
Abstract
Objective To assess associations between baseline
values of four different circulating markers of
inflammation and future risk of coronary heart
disease, potential triggers of systemic inflammation
(such as persistent infection), and other markers of
inflammation.
Design Nested case-control comparisons in a
prospective, population based cohort.
Setting General practices in 18 towns in Britain.
Participants 506 men who died from coronary heart
disease or had a non-fatal myocardial infarction and
1025 men who remained free of such disease until
1996 selected from 5661 men aged 40-59 years who
provided blood samples in 1978-1980.
Main outcome measures Plasma concentrations of C
reactive protein, serum amyloid A protein, and serum
albumin and leucocyte count. Information on fatal
and non-fatal coronary heart disease was obtained
from medical records and death certificates.
Results Compared with men in the bottom third of
baseline measurements of C reactive protein, men in
the top third had an odds ratio for coronary heart
disease of 2.13 (95% confidence interval 1.38 to 3.28)
after age, town, smoking, vascular risk factors, and
indicators of socioeconomic status were adjusted for.
Similar adjusted odds ratios were 1.65 (1.07 to 2.55)
for serum amyloid A protein; 1.12 (0.71 to 1.77) for
leucocyte count; and 0.67 (0.43 to 1.04) for albumin.
No strong associations were observed of these factors
with Helicobacter pylori seropositivity, Chlamydia
pneumoniae IgG titres, or plasma total homocysteine
concentrations. Baseline values of the acute phase
reactants were significantly associated with one
another (P <0.0001), although the association
between low serum albumin concentration and
leucocyte count was weaker (P =0.08).
Conclusion In the context of results from other
relevant studies these findings suggest that some
inflammatory processes, unrelated to the chronic
infections studied here, are likely to be involved in
coronary heart disease.
Introduction
Circulating concentrations of C reactive protein, serum
amyloid A protein, and serum albumin and the leuco-
cyte count can fluctuate widely during acute responses
to tissue damage or infection. Plasma concentrations of
C reactive protein and serum amyloid A protein can
each rise 10 000-fold; the leucocyte count can increase
about threefold; and the concentration of serum albu-
min can fall by about 20%.12 In recent years these
“acute phase reactants” have been studied as potential
markers of more subtle and persistent systemic altera-
tions that may be loosely called low grade inflamma-
tion. If the sharp short term fluctuations are ignored,
then long term circulating concentrations of these fac-
tors show a similar year-to-year consistency within
individuals to levels of some more extensively studied
risk factors such as blood cholesterol concentration
and blood pressure.23Moreover,highly sensitive assays
for C reactive protein and serum amyloid A protein are
now available that can detect low grade inflammation
that would previously have been unnoticed.45
Several reports have suggested that plasma C reac-
tive protein and other possible markers of low grade
inflammation can predict increased risks of coronary
heart disease, but it is not known whether the associa-
tions are causal.26A variety of mechanisms by which C
reactive protein might directly promote vascular
disease have been proposed,7but none is proved.
These markers of inflammation might, however, be
indicators of chronic infective processes possibly
correlated with risk of coronary heart disease, such as
infection by Chlamydia pneumoniae or chronic gastric
infection with Helicobacter pylori.8Alternatively, the
markers might be mainly indicators of classic vascular
risk factors (such as smoking and obesity) or of the
extent of pre-existing disease (since atherosclerosis
may be partly an inflammatory lesion6). If so, the mark-
ers themselves would not be of causal relevance to dis-
ease. Long term prospective studies with data collected
on many possible confounders or mediators can help
to distinguish among these different possibilities since
this approach is generally less influenced than
retrospective studies by any effect of pre-existing
disease itself on the factors being investigated.9
We report one of the largest and most prolonged
prospective studies of “inflammatory” factors and cor-
onary heart disease so far, with updated meta-analyses
of previous relevant studies to put our findings in con-
text. We measured four circulating markers of
inflammation (C reactive protein, serum amyloid A
Tables showing
distribution of risk
factors in the
control population
are available on the
BMJ’s website
Editorial by Koenig
Clinical Trial
Service Unit and
Epidemiological
Studies Unit,
University of
Oxford, Radcliffe
Infirmary, Oxford
OX2 6HE
John Danesh
clnical research fellow
Department of
Public Health
Sciences,
St George’s
Hospital Medical
School, London
SW17 0RE
Peter Whincup
professor
Departments of
Medicine and
Population Sciences
and Primary Care,
Royal Free and
University College
Medical School,
London NW3 2PF
Mary Walker
senior lecturer
Lucy Lennon
research assistant
Andrew Thomson
computer programmer
J Ruth Gallimore
research officer
Mark B Pepys
professor of medicine
Imperial Cancer
Research Fund
Cancer
Epidemiology Unit,
Oxford OX2 6HE
Paul Appleby
statistician
Correspondence to:
J Danesh
BMJ 2000;321:199–204
199BMJ VOLUME 321 22 JULY 2000 bmj.com
protein, leucocyte count, and albumin10), which should
help to determine whether there is some underlying
process related to inflammation (rather than any one
marker by itself) that might be relevant to disease. Most
previous studies could not make such assessments
because they typically reported on only one marker of
inflammation.
Methods
Cases and controls
During 1978-80, 7735 men aged 40-59 (response rate
78%) were randomly selected from general practice
registers in each of 24 British towns. Nurses
administered questionnaires, made physical measure-
ments, recorded an electrocardiogram, and, for 5661
men in 18 of the towns, collected non-fasting venous
blood samples, which were stored at −20°C for subse-
quent analysis.11 Additional questionnaires on car own-
ership and childhood social circumstances (father’s
social class and childhood household amenities) were
posted to participants five years (98% response among
survivors) and 12 years (90% response among
survivors) after entry.
All men have been monitored subsequently for all
cause mortality and for cardiovascular morbidity, with
a loss to follow up of less than 1% to date. A total of 507
men with available samples had major coronary heart
disease events between the beginning of follow up and
December 1995 (223 deaths and 284 non-fatal
myocardial infarctions). Deaths from coronary heart
disease were ascertained through NHS central
registers on the basis of a death certificate with ICD-9
codes 410-414, and the diagnosis of non-fatal myocar-
dial infarction was based on reports from general
practitioners, supplemented by regular reviews of gen-
eral practice records, and diagnosed in accordance
with World Health Organization criteria. We selected
1026 controls who were “frequency” matched to cases
on town of residence and age in five year bands from
among men who had survived to the end of the study
period without a myocardial infarction. One potential
case and one potential control were found not to have
a serum sample available. In previous interim analyses
data were reported on albumin concentration and cor-
onary heart disease in only 97 of the 507 cases
included here12 and on leucocyte count and coronary
heart disease in only 235 cases.13
Laboratory methods
Laboratory workers blind to the case-control status of
participants measured concentrations of C reactive
protein and serum amyloid A protein using sensitive
enzyme immunoassays.45The C reactive protein assay
was standardised on the WHO international reference
standard, and the results of the serum amyloid A pro-
tein assay were used to establish the WHO inter-
national reference standard for this protein.14 Albumin
was measured with bromocresol green, and leucocyte
counts were done with Coulter counters at the time of
blood collection.11 The coefficients of variation within
each of these assays was 2-4%; the variation between
the assays was about 6-8%. Measurements were also
made of concentrations of serum IgG antibodies to
Helicobacter pylori (by enzyme linked immunoassay,
Meridian Diagnostics, Cincinatti, Ohio), IgG antibodies
to Chlamydia pneumoniae (whole organism antigen by
time resolved fluorimetry15) and serum lipids, plasma
homocysteine, glucose, insulin, and markers of renal
function (by standard assays11).
Statistical methods
Case-control comparisons were made by unmatched
stratified logistic regression fitted by unconditional
maximum likelihood (Stata Corporation, Texas, USA).
Analysis of concentrations of C reactive protein, serum
amyloid A, and albumin and of leucocyte count was
prespecified to be by thirds of values in the controls.
Adjustment was made for age; cigarette smoking
(never, former, current); daily cigarette consumption;
non-fasting blood concentrations of total cholesterol,
high density lipoprotein cholesterol, and triglycerides;
current social class (registrar general’s 1980 classifi-
cation with separate category for armed forces11);
housing tenure (owner, private rent, council rent);
marital status; current car ownership; and father’s
occupation (manual, non-manual), family car owner-
ship, bathroom in house, hot water tap in house, and
bedroom sharing. H pylori seropositivity, C pneumoniae
IgG titres, and concentrations of non-fasting blood lip-
ids, plasma homocysteine, and other blood compo-
nents were investigated as possible correlates of levels
of each of the acute phase reactants.
We have previously described the methods for
meta-analyses of prospective studies of non-fatal myo-
cardial infarction or death from coronary heart disease
with over a year’s follow up.2The meta-analysis was
updated to include all studies identified with data avail-
able in March 2000. Most studies related risk of coron-
ary heart disease to baseline measurement of risk
factors, even though the levels of each factor can fluc-
tuate within individuals over time. Our comparisons of
those in the top third of baseline values with those in
the bottom third have therefore been corrected for
such regression dilution16 by use of self-correlation
coefficients derived from other studies.2Results of
studies were combined by using inverse variance
weighted averages of log odds ratios. Heterogeneity
was assessed by standard ÷2tests. Odds ratios are given
with 95% confidence limits, and two sided probability
values are used.
Results
The mean age at coronary heart disease event among
cases was 62 years (mean duration of follow up 9.5
years). There were highly significant differences
between cases and controls with respect to known vas-
cular risk factors such as smoking, obesity, blood pres-
sure, and blood lipids concentrations (table 1).
Associations among different acute phase reactants
In controls without evidence of coronary heart disease
at baseline, the correlation coefficients of the
associations between plasma C reactive protein and
serum amyloid A protein, leucocyte count, and
albumin were 0.58, 0.33, and −0.19 respectively
(P < 0.0001 for each), and the correlation coefficients
between serum amyloid A protein and leucocyte count
and albumin were 0.19 and 0.14 respectively
(P < 0.0001 for each). These associations among the
four acute phase reactants were not adjusted for values
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200 BMJ VOLUME 321 22 JULY 2000 bmj.com
of one another to avoid overadjustment since they may
reflect a common underlying process (see tables on
BMJ ’s website). Leucocyte count and serum albumin
concentration were not strongly related (R=−0.06,
P = 0.08).
Acute phase reactants, classic vascular risk factors,
and other characteristics
C reactive protein concentration was strongly associ-
ated with cigarette smoking, body mass index, and low
forced expiratory volume in one second (P < 0.0001
for each), and the associations were little changed by
adjustments for age, town, smoking, and indicators of
socioeconomic status. Associations of C reactive
protein with high density lipoprotein cholesterol,
triglyceride, urate, and insulin, however, weakened sub-
stantially after such adjustments (table A on BMJ ’s
website). There were strong and highly significant asso-
ciations of serum amyloid A protein with body mass
index and total cholesterol (P < 0.0001) and with low
forced expiratory volume (P < 0.001) which remained
significant after adjustment for possible confounders,
but such adjustment substantially weakened the associ-
ation with high density lipoprotein cholesterol (table B
on website). Strong adjusted associations were
observed between leucocyte count and cigarette smok-
ing and packed cell volume (P < 0.0001 for each, table
C on website) and between low albumin and age and
cigarette smoking (P < 0.0001 for each, table D on
website) and between albumin and blood pressure,
total cholesterol, and packed cell volume (P< 0.0001
for each). Possible associations existed between
albumin and high density lipoprotein cholesterol, trig-
lycerides, and serum markers of renal function. No
consistent associations were observed of these acute
phase proteins with H pylori seropositivity, C pneumo-
niae IgG titres, plasma total homocysteine concentra-
tions, or a range of childhood or adult indicators of
socioeconomic status.
Acute phase reactants and incident coronary heart
disease
The odds ratio for coronary heart disease was 3.46
(95% confidence interval 2.59 to 4.62; ÷2= 71,df = 1) in
men in the top third compared with those in the
bottom third of baseline C reactive protein concentra-
tion (tertile cut offs, > 2.4 v< 0.9 mg/l). The odds ratio
fell to 2.13 (1.38 to 3.28;÷2= 11.8, df = 1) after smoking,
vascular risk factors, and indicators of socioeconomic
status were adjusted for (table 2). Comparisons
between the top and bottom thirds of the other factors
gave the following adjusted odds ratios for coronary
heart disease: 1.65 (1.07 to 2.55) for serum amyloid A
protein ( > 9 v< 6 mg/l); 1.12 (0.71 to 1.77) for leuco-
cyte count ( > 7.8 v6.4×109/l); and 0.67 (0.43 to 1.04)
for albumin ( > 46 v< 44 g/l). These results were not
Table 1 Baseline characteristics of men with coronary heart
disease and of controls matched for age and town. Values are
mean (SD) unless stated otherwise
Characteristic
Cases
(n=507)
Controls
(n=1026) P value
Questionnaire
Age (years) 52.2 (5.3) 52.2 (5.3) Matched
No (%) current smokers 268 (53) 436 (42) <0.0001
No (%) with evidence of coronary
disease*
177 (35) 204 (20) <0.0001
No (%) with treated diabetes 12 (2) 15 (1) NS
No (%) >2 drinks alcohol/day 110 (22) 232 (23) NS
No (%) in non-manual occupation 112 (22) 280 (27) 0.03
No (%) of home owners† 275 (64) 667 (69) 0.03
Physical measurements
Body mass index (kg/m2) 25.8 (3.4) 25.3 (3.3) 0.008
Height (cm) 171 (6.4) 172 (6.5) 0.002
Weight (kg) 76.3 (11.4) 75.8 (11.2) NS
Systolic blood pressure (mm Hg) 151 (21) 147 (21) <0.0001
Diastolic blood pressure (mm Hg) 86 (14) 83 (13) <0.0001
Forced expiratory volume (l) 308 (68) 326 (77) <0.0001
Blood sample
Total cholesterol (mmol/l) 6.63 (1.10) 6.20 (0.99) <0.0001
HDL cholesterol (mmol/l) 1.10 (0.28) 1.15 (0.29) 0.0003
Triglyceride (mmol/l) 2.26 (1.33) 1.93 (1.22) <0.0001
*Evidence of ischaemia on baseline electrocardiogram or reported history of
angina or myocardial infarction.
†Information on home ownership was available for only 431 cases and 964
controls.
Table 2 Odds of coronary heart disease in men who had values of inflammatory factors in top third of distribution of controls relative to those who had
values in bottom third of this distribution
Factor (tertile cut offs)
No of cases No of controls Odds ratio (95% CI) adjusted for:
Top Middle Bottom Top Middle Bottom Age and town
Age, town, and
smoking
Age, town,
smoking, and risk
factors*
Age, town, smoking,
risk factors,
socioeconomic status†
All 506 cases and 1025 controls
C reactive protein
(2.4 and 0.9 mg/l)
268 150 88 347 298 380 3.46 (2.59 to 4.62) 3.32 (2.47 to 4.47) 2.92 (2.13 to 4.01) 2.13 (1.38 to 3.28)
Serum amyloid A protein
(9 and 6 mg/l)
255 144 107 362 351 312 2.12 (1.60 to 2.80) 2.13 (1.61 to 2.82) 1.66 (1.22 to 2.26) 1.65 (1.07 to 2.55)
Leucocyte count
(7.8 and 6.4×109/l)
212 168 110 332 329 330 1.89 (1.43 to 2.51) 1.69 (1.25 to 2.28) 1.46 (1.06 to 2.00) 1.12 (0.71 to 1.77)
Albumin (46 and 44 g/l) 174 141 191 348 347 327 0.83 (0.63 to 1.10) 0.90 (0.68 to 1.20) 0.61 (0.44 to 0.83) 0.67 (0.43 to 1.04)
329 cases and 820 controls without evidence of coronary heart disease at entry
C reactive protein
(2.4 and 0.9 mg/l)
164 95 70 265 234 321 2.93 (2.10 to 4.09) 2.74 (1.95 to 3.85) 2.61 (1.81 to 3.77) 2.31 (1.42 to 3.76)
Serum amyloid A protein
(9 and 6 mg/l)
163 87 79 284 288 248 1.90 (1.37 to 2.64) 1.93 (1.38 to 2.68) 1.50 (1.05 to 2.16) 1.67 (1.02 to 2.74)
Leucocyte count
(7.8 and 6.4×109/l)
142 104 71 253 261 277 2.19 (1.56 to 3.07) 1.87 (1.30 to 2.68) 1.57 (1.07 to 2.30) 1.34 (0.80 to 2.27)
Albumin (46 and 44 g/l) 115 95 118 282 266 269 0.90 (0.64 to 1.26) 1.0 (0.71 to 1.41) 0.65 (0.45 to 0.95) 0.75 (0.45 to 1.25)
*Blood pressure, total cholesterol, high density lipoprotein cholesterol, triglycerides, body mass index
†Occupation, housing tenure, marital status, car ownership, and childhood socioeconomic factors (father’s occupation, family car ownership, bathroom in house, hot water tap in house,
bedroom sharing, height).
Analyses of acute phase reactants and coronary heart disease were not adjusted for values of other inflammatory markers to avoid possible overadjustment (see results).
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201BMJ VOLUME 321 22 JULY 2000 bmj.com
materially changed in analyses restricted to the 329
cases and 820 controls with no evidence of coronary
heart disease at baseline (table 2) or in analyses
restricted to the 227 cases and 779 controls who had
complete information on childhood socioeconomic
status. The findings were also unaffected by varying the
prespecified cut-off levels for analysis of each factor.
Discussion
Our prospective study in the general British male
population shows that baseline values of four acute
phase reactants are associated with one another as well
as with future risk of coronary heart disease. These
data support the idea that there are some underlying
processes related to inflammation that are relevant to
coronary heart disease. To determine what factor(s)
might be triggering such low grade inflammation years
in advance of disease, we studied classic risk factors,
plasma homocysteine concentration, serological evi-
dence of chronic infection with C pneumoniae or H
pylori, and a range of possible other triggers. None,
however, was strongly related to inflammatory mark-
ers, suggesting that these factors cannot fully account
for the associations observed with coronary heart
disease. Even though the strength of the association of
coronary heart disease with baseline concentrations of
C reactive protein and serum amyloid A protein seems
comparable with that for some more extensively stud-
ied risk factors (such as blood fibrinogen concentra-
tion2), several uncertainties remain. We discuss below
the strengths and limitations of the available evidence
on coronary heart disease and each of these factors in
the context of updated meta-analyses of other relevant
studies.
C reactive protein
A previous meta-analysis of seven prospective studies
of C reactive protein, with a total of 1053 cases,
indicated a risk ratio for coronary heart disease of 1.7
(95% confidence interval 1.4 to 2.1) in individuals in
the top third compared with those in the bottom third
of baseline measurements.2Since the publication of
that review, six additional prospective studies of C
reactive protein have been identified, including an
additional 994 cases of non-fatal myocardial infarction
or death from coronary heart disease.17–22 All used sen-
sitive assays and adjusted for smoking and some stand-
ard vascular risk factors. In aggregate, the 14 available
prospective reports (including the present study of 506
cases) include 2557 cases with a weighted mean age at
entry of 58 and weighted mean follow up of eight
years.17–28 There was no significant heterogeneity
among them (÷2= 6.9, df = 13; P > 0.1), and a compari-
son of individuals with C reactive protein concentra-
tions in the top third with those in the bottom third at
baseline gave a combined risk ratio of 1.9 for coronary
heart disease (1.5 to 2.3; fig 1) with a similar risk ratio of
2.0 (1.6 to 2.5) in the 11 studies of the general popula-
tion (test for heterogeneity, ÷2= 5.8, df = 10; P > 0.1).
The estimated mean usual log C reactive protein values
in the top third and bottom thirds were 0.38 and 0.02
mg/l in the general population, which correspond to
mean estimated usual values of 2.4 and 1.0 mg/l.
Hence, this updated meta-analysis indicates a similar
risk ratio to the previous review, but the scope for the
play of chance is now substantially reduced because
there are more than twice as many cases reported.
For two main reasons, however, it remains
uncertain whether C reactive protein is an independ-
ent risk factor for coronary heart disease. Firstly, the
odds ratio in our study was reduced from 3.46 to 2.13
after baseline confounding factors were adjusted for.
This substantial reduction suggests that more exact
adjustment for the usual long term concentrations of
these and other factors might produce a greater
reduction
—
for example, we did not measure blood
fibrinogen concentration. Secondly, although experi-
mental studies suggest that C reactive protein might
directly contribute to vascular damage (such as its fre-
quent detection in atherosclerotic plaques,29 its ability
to stimulate tissue factor production by macrophages,30
and its enhancement of complement activation after
binding partly degraded, non-oxidised low density
lipoprotein cholesterol31 32), no direct evidence exists
for such involvement.7Additional studies are also
needed to determine the relevance of apparently
sustained falls in C reactive protein concentrations
after the use of lipid lowering statin drugs3as well as
apparently sustained increases after postmenopausal
hormone replacement therapy.33
Serum amyloid A protein
Only three previous studies have reported on serum
amyloid A protein and incident coronary heart
disease,22 28 34 including two cohorts defined on the
basis of pre-existing coronary heart disease. They com-
prised 551 cases in total (fig 2). Our 506 cases in the
general population almost double the available
evidence. In aggregate, these four studies include 1057
cases, with a weighted mean age at entry of 56 and
weighted mean follow up of 10 years. There was no
significant heterogeneity among them (÷2= 0.3, df = 3;
P > 0.1),and a comparison of individuals with values in
the top third with those in the bottom third at baseline
Type of cohort
and source
No of
cases
99% or
2.0 (95% CI 1.6 to 2.5)
1.5 (95% CI 1.1 to 2.1)
1.9 (95% CI 1.5 to 2.3)
0.51248
95% limits
Degree of
adjustment
Risk ratio and confidence limits
(top third vs bottom third)
Population based
Present study
Ridker et al, 1997
Koenig et al, 1999
Kuller et al, 1996
Lowe et al, 1999
Tracy et al, 1997
Tracy et al, 1997
Witherell et al, 1999
Ridker et al, 1998
Agewall et al, 1998
Roivainen et al, 2000
Subtotal
Pre-existing vascular disease
Ridker et al, 1998
Toss et al, 1997
Haverkate et al, 1997
Subtotal
Total
506
246
53
246
165
150
145
100
85
16
241
1953
391
138
75
604
2557
++++
++++
++++
+++
+++
+++
+++
+++
++++
+++
++
+++
+++
+++
Fig 1 Prospective studies of C reactive protein and coronary heart disease. Risk ratios
compare top and bottom thirds of baseline measurements. Black squares indicate the risk
ratio in each study, with the size of square proportional to number of cases. The combined
risk ratio and its 95% confidence interval are indicated by unshaded diamonds for subtotals
and shaded diamond for total. All studies adjusted for age, sex, smoking, and some other
standard vascular risk factors; the first three studies also adjusted for markers of
socioeconomic status
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202 BMJ VOLUME 321 22 JULY 2000 bmj.com
gave a combined risk ratio of 1.6 for coronary heart
disease (1.1 to 2.2; fig 2).The estimated mean usual log
values in these groups were 1.00 and 0.68 mg/l, which
correspond to mean values of 10.0 and 4.7 mg/l. Fur-
ther studies are needed to determine whether this
association is independent of possible confounders.
Leucocyte count and serum albumin
The adjusted odds ratio for coronary heart disease in
our study was 1.12 (0.71 to 1.77) in men with leucocyte
counts in the top third compared with those in the bot-
tom third of baseline measurements. Although this
odds ratio is not significant, it is consistent with a com-
bined risk ratio for coronary heart disease of 1.4 (1.3 to
1.5) reported in a previous meta-analysis of 19
prospective studies of leucocyte count including a total
of 7229 cases, with top and bottom thirds correspond-
ing to mean usual leucocyte counts of 8.4 and
5.6×109/l, respectively.2We also observed an adjusted
odds ratio for coronary heart disease of 0.67 (0.43 to
1.04) in men in the top third compared with those in
the bottom third of baseline albumin measurements.
Again, despite a lack of conventional significance, this
odds ratio is compatible with a combined risk ratio of
0.7 (0.6 to 0.8) reported in a meta-analysis of eight pro-
spective studies including a total of 3770 cases, with top
and bottom thirds corresponding to mean usual albu-
min concentrations of 42 and 38 g/l, respectively.2The
strongly positive associations of serum albumin values
with blood pressure and serum lipid concentrations
indicate that these variables cannot account for the
association between low serum albumin and coronary
heart disease
—
rather the reverse in fact.
Conclusions
We found that baseline levels of four circulating mark-
ers of low grade inflammation were associated with
one another and with future risk of coronary heart dis-
ease. The markers, however, were not associated with
some chronic infective processes possibly related to
coronary heart disease. These findings
—
in the context
of results from other relevant studies
—
suggest that low
grade inflammatory processes may be relevant to cor-
onary heart disease.
We thank H Refsum and P Ueland for the homocysteine assays;
M Thomas, Yuk-ki Wong and M Ward for C pneumoniae
serology; J Atherton and C Hawkey for H pylori serology; and J
John for valuable help. Professor AG Shaper established the
British Regional Heart Study
Contributors: The study was designed and conducted by the
British Regional Heart Study collaborative group. All the named
authors contributed to the analysis and interpretation of these
data and to writing the paper. JD and PW are the guarantors.
Funding: The British Regional Heart Study is a British Heart
Foundation research group and also receives support from the
Department of Health. JD is supported by Merton College and
the Frohlich Trust. MBP is supported by the UK Medical
Research Council.
Competing interests: None declared.
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16 Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, et
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Type of cohort
and source
No of
cases
99% or
0.51248
95% limits
Degree of
adjustment
Risk ratio and confidence limits
(top third vs bottom third)
Population based
Present study
Ridker et al, 2000
Pre-existing vascular disease
Ridker et al, 1998
Haverkate et al, 1997
Total
506
85
391
75
1057
++++
++++
+++
+++
1.6 (95% CI 1.1 to 2.2)
Fig 2 Prospective studies of serum amyloid A protein concentration and coronary heart
disease. Risk ratios compare top and bottom thirds of baseline measurements. Black squares
indicate the risk ratio in each study, with the size of square proportional to number of cases.
All studies adjusted for age, sex, smoking, and some other standard vascular risk factors; our
study also adjusted for markers of socioeconomic status
What is already known on this topic
Plasma concentrations of C reactive protein and
other sensitive markers of systemic inflammation
may be correlated with future risk of coronary
heart disease in the general population
It is not known whether these associations are
causal or merely due to confounding by classic
risk factors, chronic infective processes, or early
disease
What this study adds
Baseline values of C reactive protein, serum
amyloid A protein, leucocyte count, and serum
albumin were associated with one another as well
as with future risk of coronary heart disease
Values of these factors were not associated with
markers of chronic infective processes
These findings suggest that low grade
inflammatory processes may be relevant to
coronary heart disease
Papers
203BMJ VOLUME 321 22 JULY 2000 bmj.com
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C-reactive protein and risk of ischaemic heart disease: the Speedwell
study. Blood Coagul Fibrin 1999;10 (suppl 1):S92-3.
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19 Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective
study of C-reactive protein and the risk of future cardiovascular events
among apparently healthy women. Circulation 1998;98:731-3.
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JH. Helicobacter pylori infection, C-reactive protein, and risk for myocar-
dial infarction: a prospective study.Gastroenterology 1999;116:A355.
21 Roivainen M, Viik-Kajarnder M, Palosuo T, Sacks F Braunwald E.
Infections, inflammation,and the risk of coronary heart disease. Circula-
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22 Ridker PM, Rifai N, Pfeffer MA, Toivanen P,Leinonen M, Saikku P,et al.
Inflammation, pravastatin, and the risk of coronary events after myocar-
dial infarction in patients with average cholesterol levels. Circulation
1998;98:839-44.
23 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflam-
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healthy men. New Engl J Med 1997;336:973-9.
24 Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, et al.
C-reactive protein, a sensitive marker of inflammation, predicts future
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results from the MONICA-Augsburg cohort study, 1984-1992.
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26 Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, et al.
Relationship of C-reactive protein to risk of cardiovascular disease in the
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artery disease. Circulation 1997;96:4204-10.
28 Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB. Produc-
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ble angina. Lancet 1997;349:462-6.
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1999;19:2348-54.
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(Accepted 22 February 2000)
Chlamydia pneumoniae infection and mortality from
ischaemic heart disease: large prospective study
N J Wald, M R Law, J K Morris, X Zhou, Y Wong, M E Ward
Abstract
Objective To determine whether there is an
independent association between infection with
Chlamydia pneumoniae and ischaemic heart disease.
Design Prospective study using a nested case-control
design.
Setting Medical centre in London run by BUPA, a
private medical organisation.
Participants 21 520 professional men aged 35-64
who attended for a medical examination in London
between 1975 and 1982.
Main outcome measure Death from ischaemic heart
disease.
Results The distributions of concentrations of IgG
and IgA antibodies to C pneumoniae were similar in
the 647 men who subsequently died of ischaemic
heart disease and in 1294 age matched controls who
did not. There was no material association with heart
disease irrespective of the cut-off point chosen to
define seropositivity. At a cut-off point that defines
15% of controls as positive, for example, the odds
ratios were 1.26 (95% confidence interval 0.95 to 1.68)
for IgG and 1.09 (0.82 to 1.43) for IgA.
Conclusions No material association was found
between infection with C pneumoniae and ischaemic
heart disease. The size and prospective design of the
study and the socioeconomic homogeneity of the
cohort minimise both random and systematic error.
Introduction
Several reports have linked ischaemic heart disease
with various infections, notably those caused by Helico-
bacter pylori and Chlamydia pneumoniae (also called
Chlamydophila pneumoniae).12A review in 1997 empha-
sised the problems in interpreting these associations.2
The studies showing associations tended to be small,
retrospective, and susceptible to bias or confounding.It
was concluded that large prospective studies of socially
homogeneous cohorts were needed to resolve the
issue.2We then reported a clearly negative result in
much the largest study to report on the association
between H pylori and ischaemic heart disease, with 648
deaths.3The prospective design of this study reduced
bias, and the likelihood of an indirect association aris-
ing through differences in social class (socioeconomi-
cally disadvantaged people being more likely to have
the infection and to develop heart disease regardless of
a possible causal link between the two) was minimised
by the homogeneity of the study population; the
participants were all professional men attending for a
routine medical examination. Both random and
systematic errors were therefore likely to be small.
The studies of C pneumoniae and heart disease have
generated mixed results regardless of whether IgG or
IgA was measured.1 2 4–11 For example, results from the
Caerphilly prospective study were negative for IgG
antibodies to chlamydia but suggested an association
with IgA (odds ratio for fatal ischaemic heart disease
1.83, 95% confidence interval 1.17 to 2.85).7We report
on the relation between ischaemic heart disease and
both IgG and IgA antibodies to C pneumoniae in the
BUPA study.
Participants and methods
The study design was as reported previously for
H pylori and ischaemic heart disease.3Br iefly, the BUPA
Papers
Editorial by Koenig
BUPA
Epidemiological
Research Group,
Wolfson Institute of
Preventive
Medicine, St
Bartholomew’s and
the Royal London
School of Medicine
and Dentistry,
London
EC1M 6BQ
NJWald
professor
MRLaw
reader
J K Morris
statistician
Molecular
Microbiology
Group,
Southampton
General Hospital,
Southampton
SO16 6YD
X Zhou
research assistant
Y Wong
research registrar
MEWard
professor
Correspondence to:
NJWald
n.j.wald@mds.
qmw.ac.uk
BMJ 2000;321:204–7
204 BMJ VOLUME 321 22 JULY 2000 bmj.com
