© 2001 American Heart Association, Inc.
Thrombosis |
C-Reactive Protein, Fibrin D-Dimer, and Incident Ischemic Heart Disease in the Speedwell Study
Are Inflammation and Fibrin Turnover Linked in Pathogenesis?
From the University Department of Medicine (G.D.O.L., A.R.), Royal Infirmary, Glasgow; the Department of Epidemiology and Public Health (J.W.G.Y.), The Queen’s University of Belfast, Belfast; Gwent Health Commission (D.B.), Mamhilad, Pontypool, Gwent; and the MRC Epidemiology Unit (P.M.S.), Llandough Hospital, Penarth, South Glamorgan, UK.
Correspondence to Professor G.D.O. Lowe, University Department of Medicine, Third Floor, Queen Elizabeth Building, Royal Infirmary, Glasgow, G31 2ER Scotland. E-mail gdl1J{at}clinmed.gla.ac.uk
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Abstract |
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Abstract—Plasma levels of C-reactive protein (CRP, a marker of the reactant plasma protein component of the inflammatory response) and of fibrin D-dimer (a marker of cross-linked fibrin turnover) have each been associated in recent studies with the risk of future ischemic heart disease (IHD). Previous experimental studies have shown that fibrin degradation products, including D-dimer, have effects on inflammatory processes and acute-phase protein responses. In the Speedwell Prospective Study, we therefore measured CRP and D-dimer levels in stored plasma samples from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75±4 months (mean±SD) and studied their associations with each other, with baseline and incident IHD, and with IHD risk factors. CRP and D-dimer levels were each associated with age, plasma fibrinogen, smoking habit, and baseline evidence of IHD. CRP was associated with D-dimer (r=0.21, P<0.00001). On univariate analyses, both CRP and D-dimer were associated with incident IHD. The incidence of IHD increased with CRP independently of the level of D-dimer (P=0.0002) and also increased with D-dimer independently of the level of CRP (P=0.048). In multivariate analyses, inclusion of D-dimer and conventional risk factors reduced the strength of the association between CRP and incident IHD; likewise, inclusion of CRP and conventional risk factors reduced the strength of the association between D-dimer and incident IHD. We conclude that although these respective markers of inflammation and fibrin turnover show modest association with each other in middle-aged men, they may have additive associations with risk of incident IHD. Further larger studies are required to test this hypothesis.
Key Words: C-reactive protein • fibrin D-dimer • ischemic heart disease
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Introduction |
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C-reactive protein (CRP), a marker of the reactant plasma protein component of the inflammatory response, has been associated with the risk of future ischemic heart disease (IHD), not only among patients with stable and unstable angina1 2 and high-risk subjects3 but also among population samples of apparently healthy middle-aged men4 5 and elderly men and women.6 A recent meta-analysis7 of these prospective studies found a combined risk ratio for IHD of 1.7 (95% confidence interval [CI], 1.4 to 2.1) for subjects in the top third of the distribution of CRP compared with the bottom third. There was no evidence of heterogeneity between these studies.
Fibrin D-dimer, a marker of cross-linked fibrin turnover, has also been shown in recent studies to be associated with the risk of future IHD in persons with and without baseline evidence of vascular disease.8 9 10 11 12 13 14 15 16 Local fibrin formation and lysis are part of the inflammatory response, and fibrin degradation products, including D-dimer, have been shown to have diverse effects on inflammatory processes and acute-phase responses, including neutrophil and monocyte activation; secretion of cytokines, including interleukin-6 and interleukin-1; and hepatic synthesis of acute-phase proteins, including fibrinogen and CRP.17 18 19 20
We therefore hypothesized that (1) plasma levels of CRP and D-dimer and their associations with incident IHD in the general population might be linked; (2) linkage might result from focal, vessel wall–related fibrin formation and lysis and an inflammatory response associated with unstable atherosclerotic plaque activity21 22 ; and (3) CRP and D-dimer might be related to IHD risk factors associated with thrombogenesis and inflammation, particularly cigarette smoking. We are unaware of previously published studies of CRP and D-dimer considered jointly. We tested these hypotheses by studying the mutual relationships of CRP, D-dimer, incident IHD, and risk factors (especially smoking habit) in the middle-aged men of the Speedwell population cohort.
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Methods |
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Study Population
The Speedwell Study began in 1979. It was based on all men who were registered with any of 16 general practitioners from 2 group practices in East Bristol and who were between 45 and 59 years old on September 1, 1978. A total of 2550 men were eligible for inclusion, and 2348 (92%) attended the first examination between 1979 and 1982. At that time their ages ranged from 45 to 63 years. The cohort was reexamined on 3 further occasions at intervals of 3 to 4 years. The current study uses as its baseline the second examination conducted between 1982 and 1985, at which time men were aged 49 to 67 years. Of the 2348 men seen at the first examination, 106 had died, 28 had moved out of the area or emigrated, and 9 were too ill to be seen. Of the 2205 eligible for the second examination, 2055 (93%) attended.
Survey Methods
The general design and procedures have been described
in detail
elsewhere.23 24
In brief, at each examination the men were invited to attend a clinic
where a detailed medical and lifestyle history was obtained; the London
School of Hygiene and Tropical Medicine chest pain
questionnaire25 was
administered; a full 12-lead ECG was recorded; and height, weight,
and blood pressure were measured. Current or last occupation was
recorded, and from this information, social class was coded
according to the Registrar General’s
Classification.26 A personal
history of diabetes and a family history of myocardial infarction among
first-degree relatives were included in the medical
history.
Blood Collection, Storage, and
Analysis
At the first examination, the men returned after an
overnight fast to an early morning clinic to give a blood sample.
Standard methods were used for the estimation of
lipids.27 At the second
examination, a nonfasting blood sample was taken from 2016 (98%) of
the men seen. Fibrinogen was measured by heat precipitation
nephelometry.24 Lipids were
not remeasured on this nonfasting sample, and hence, the fasting levels
of total cholesterol from the first examination are used in
this report.
Plasma samples from dipotassium edetate–anticoagulated blood at the nonfasting second examination were stored at -20°C. CRP and D-dimer levels were measured on these samples in 1997, when the samples had been stored for between 12 and 15 years. CRP was measured by a sensitive nephelometric assay (Behring) and D-dimer, with an ELISA (Biopool). One batch of samples was unavailable for the current analysis, so CRP was measured for 1690 men, who were a subset of 1719 men for whom D-dimer was measured first. Another batch containing 17% of the samples was thawed on 1 occasion due to freezer failure. Levels of CRP and D-dimer were both significantly higher (P<0.001) among these thawed samples. However, it is not certain that the measurements were affected by thawing of the samples. Fibrinogen, measured on the fresh, prestorage samples, and even fibrinogen and total cholesterol, as measured at the first examination, were all higher among the subjects whose stored, second-examination sample thawed. This suggests that the subjects whose samples had been thawed were, by chance, not a representative sample of the whole group. Further support for this explanation comes from the Caerphilly study.12 When D-dimer was measured there, 1 batch of samples had also previously been thawed, and D-dimer levels were slightly but not significantly lower among the thawed samples. It was thus decided not to exclude the results from the thawed samples but to include them in all analyses with an adjustment for the effect of thawing.
Incident IHD
Incidence of IHD was measured between the second
examination (the baseline for this report) and the fourth examination,
which took place between 1988 and 1991. At that fourth examination, the
men were seen in the same order as far as possible, and the average
follow-up period was 75 months (mean±SD, 75±4). All men were entered
on the National Health Service Central Registry, and all of the death
certificates were coded by 1 of us (J.W.G.Y.). Death coded as 410 to
414 according to the 9th revision of the International Classification
of Diseases (ICD) was used as the definition of fatal IHD. Questions
about admission to hospital with severe chest pain and lists from
hospital activity analysis of all men admitted with a diagnosis
of ICD 410 to 414 were used as the basis for a search of hospital notes
for events meeting standard World Health Organization
criteria28 for acute
myocardial infarction (MI). Finally, the appearance on any follow-up
ECG of major or selected moderate Q waves (Minnesota codes 1.1 [any],
1.2.1 to 1.2.5 or 1.2.7) when there were no Q waves (1.1 [any], 1.2
[any]. or 1.3 [any]) on either the first or the baseline
second-examination ECG was also taken as evidence that an MI had
occurred during the follow-up period.
Under these definitions, there were 191 major IHD events of which 72 were fatal. The average annual incidence rate was 1.5%. Among the 1690 men with a measurement for CRP, there were 162 major IHD events, whereas among the 1719 for whom a D-dimer measurement was available, there were 165 such events.
Statistical Methods
The distributions of CRP and D-dimer both had a
marked, positive skewness. In all analyses where they were used
as continuous variables, they were transformed to (natural)
logarithms. The transformations produced distributions that were close
to gaussian, with back-transformed geometric means of 1.57 mg/L for CRP
and 42.0 ng/mL for D-dimer.
Adjusted mean differences in CRP and D-dimer between men who developed IHD and those who did not were obtained by ANCOVA by using standard multiple regression techniques. The remainder of the analysis was performed by using multiple logistic regression with the occurrence or not of any of the 3 types of incident IHD as the dependent variable. Logistic regression takes no account of the duration of follow-up, but this factor is likely to be immaterial because follow-up was at a nearly constant interval of 75 months, with an SD of only 4 months. Furthermore, any model such as the Cox proportional-hazards model that involves the time to the event would face the problem that no time to event is available for the ECG-defined MIs. These would either have to be excluded or allocated an arbitrary time to event.
In the logistic regression analyses, CRP and D-dimer were first divided into 5 equally sized groups by using 4 cutpoints: 0.6, 1.1, 2.0, and 4.2 mg/L for CRP and 26, 37, 47, and 63 ng/mL for D-dimer. Results were then presented as the odds of IHD in each group relative to the odds in the 20% of men with the lowest levels. Tests for trend were obtained by entering CRP or D-dimer as logarithmically transformed continuous variables, and the trends were summarized by standardized relative odds (SROs): the odds associated with a 1-SD increase in the logarithm of CRP or D-dimer.
Evidence of ischemia at baseline was assessed from the chest pain questionnaire and the ECG. Three categories, namely angina; history of at least 1 episode of prolonged, severe chest pain; and ECG ischemia were defined in a standard manner.29 Among the 2055 men, 486 (24%) had some evidence of ischemia at baseline. This prevalence is slightly lower than that found by the British Regional Heart Study30 for men of similar age. These men were not excluded from the analysis. Exclusion of such a large group, among whom 42% of the incident events occurred, does not seem satisfactory. Neither does the usual practice of excluding just a very small percentage (<5%) of men for whom there is good evidence of a previous MI. Instead, we have chosen to include all men and to adjust for the presence of ischemia at baseline by including the 3 standard measures of confounders in the logistic regression analyses.12
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Results |
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Baseline Characteristics
The baseline characteristics of the 191 men who developed major IHD are compared in Table 1
with those of the 1864 men who did not.
Those who developed IHD were slightly older
(P<0.001) and had higher total
cholesterol
(P=0.001), body mass index
(P=0.029), and systolic
(P<0.001) and
diastolic (P=0.002)
blood pressures. They were more likely to be smokers
(P=0.001), to be diabetic
(P=0.003), and to have a family
history of MI (P=0.024). The
proportion from the manual social classes was similar in the 2
groups.
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Univariate Analyses of CRP,
D-Dimer, and Incident IHD
In
Table 2, the data show that mean CRP and D-dimer levels
were each higher among the men who developed IHD. The age- and
thawing-adjusted mean difference between the 2 groups was highly
significant for CRP (P=0.00008)
and significant for D-dimer
(P=0.017).
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In
Table 3, the data show that the incidence of IHD increased
steadily from 5.7% in the 20% of men with the lowest levels of CRP to
15.5% among the 20% with the highest levels. Unadjusted, the
corresponding relative odds increased steadily to 3.07 (95% CI, 1.80
to 5.22) in the top 20% of the distribution. This trend was highly
statistically significant
(P<0.00001), and the SROs, the
relative odds associated with a 1-SD increase in CRP, were 1.48.
Adjusting for age slightly reduced the relative odds in the top 20% to
2.73 (95% CI, 1.60 to 4.67) and the SRO to 1.41, but the trend was
still highly significant
(P=0.00005). Further adjustment
for whether or not the sample had been thawed during the freezer
failure had no material effect on these relative odds
(Table 3).
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The incidence of IHD increased from 7.0% in the 20% of men
with the lowest levels of D-dimer to 12.0% and 11.2% in the fourth
and fifth highest quintile groups, respectively
(Table 3
). Unadjusted, the corresponding relative odds
increased steadily to 1.68 (95% CI, 1.00 to 2.82) in the top 20% of
the distribution. This trend was highly statistically significant
(P=0.0018), and the SROs were
1.27. Adjusting for age slightly reduced the relative odds in the top
20% to 1.44 (95% CI, 0.85 to 2.45) and the SRO to 1.22, but the trend
was still significant
(P=0.012). Adjustment for
thawing had only a minor effect
(Table 3).
Associations With
Cardiovascular Risk Factors
The data in
Table 4 show how CRP and D-dimer varied with cigarette
smoking habit and with evidence of IHD at baseline. Current smokers had
geometric mean levels of CRP that were nearly double those among men
who had never smoked. Among those current smokers, the lowest geometric
mean level (1.87 mg/L) was found among the lightest smokers, and even
this lowest level was significantly
(P<0.001) higher than that
found among the men who had never smoked. There was no clear dose
response among current smokers, but among ex-smokers there was a clear
trend with the length of time since quitting. Even those who gave up
more than 10 years ago had a geometric mean CRP of 1.36 mg/L, which was
still higher (P=0.037) than the
geometric mean of 1.13 mg/L among the men who had never smoked. The
average length of time since quitting among these men was nearly 23
years, with a range from 10 to 48 years. Current smokers also had
higher D-dimer levels than men who had never smoked
(P=0.046), with no dose
response. Again, there was a clear trend with the length of time since
quitting; 5 to 9 years after quitting, their D-dimer levels returned to
the levels observed in nonsmokers.
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All manifestations of IHD at baseline were associated with
higher geometric mean levels of CRP. Men with angina from the Rose
chest pain questionnaire had levels of CRP nearly double those of men
without angina. CRP was raised by 
50% among men with a history of
prolonged, severe chest pain or with evidence of ischemia on
ECG. All of these differences were highly statistically significant
(P<0.001). D-dimer levels
compared with CRP showed less elevation in men with evidence of
ischemia, but these elevations were still statistically
significant for men with a history of severe chest pain
(P=0.014) or with evidence of
ischemia on ECG
(P<0.001). CRP was also raised
by 50% among the small number (2.8%) of diabetics. Among the much
larger proportion (26%) of men with a first-degree relative with a
history of MI, CRP was raised by 17%
(P=0.011). There was no
association between CRP and social class. D-dimer was not significantly
associated with diabetes, family history of MI, or social
class.
CRP increased with age (r=0.15) and showed positive associations with other conventional cardiovascular risk factors such as total cholesterol (r=0.08), diastolic blood pressure (r=0.07), and body mass index (r=0.14). All of these were statistically significant (P<0.01) but modest in size. There was a much stronger association with fibrinogen (r=0.42). D-dimer also increased with age (r=0.15, P<0.01) and fibrinogen (r=0.16, P<0.01) but not with total cholesterol (r=0.01), diastolic blood pressure (r=0.03), or body mass index (r=0.00).
There was a positive correlation between CRP and D-dimer (r=0.21, P<0.00001). This association did not arise simply because both were positively associated with age, smoking habit, baseline evidence of IHD, and fibrinogen. On adjusting for all of these factors, the partial correlation declined to only 0.17 and remained statistically significant (t=5.29, P<0.00001).
Incidence of IHD With Increasing CRP and
D-Dimer
The data in
Table 5 show that the incidence of IHD increased with CRP
at each level of D-dimer and that it also increased with D-dimer at
every level of CRP. The trend for incidence of IHD to increase with CRP
independently of the level of D-dimer was statistically significant
(P=0.00015), as also was the
trend for incidence to rise with D-dimer independently of the level of
CRP (P=0.048). There was no
evidence that the association between IHD and CRP was different at
different levels or D-dimer or that the association between IHD and
D-dimer differed with level of CRP (test for interaction,
2 (2 df)=3.54,
P=0.17).
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Multivariate Analysis
for CRP
In
Table 6 are shown the results of a series of multiple
logistic regression analyses that examined the change in
association between CRP and incident IHD as groups of
cardiovascular risk factors were successively added to
the regression model. In the first model, which adjusted only for age
and the thawing (or not) of the sample, the relative odds of IHD rose
to 2.49 (95% CI, 1.44 to 4.30) among men in the top 20% of the
distribution of CRP, and the SROs were 1.37
(P=0.0002). These figures
differ from those in
Table 3 only because those in
Table 3 were based on all 1690 men with a measurement of
CRP, whereas the figures in
Table 6 were based on the 1595 men who had a complete set
of data for all of the variables included in the models of
Table 6.
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Addition of a set of conventional cardiovascular risk factors (smoking habit, body mass index, diastolic blood pressure, total cholesterol, and evidence of ischemia at baseline) reduced the relative odds in the top 20% of the distribution of CRP to 1.60 (95% CI, 0.90 to 2.83) and the SROs to 1.20. The test for trend was still just significant at the conventional 5% level. The further addition of fibrinogen and then D-dimer to the model reduced the relative odds in the top 20% of the CRP distribution to 1.45 (95% CI, 0.79 to 2.66) and the SROs to 1.15. The test for trend (P=0.16) was no longer statistically significant.
A stepwise multiple logistic regression analysis was
then performed for CRP
(Table 7). The variables considered for inclusion in the
stepwise regression were all those cardiovascular risk
factors appearing in the models of
Table 6. The base model again consisted of age and whether
or not the sample had been thawed, as well as CRP. At each stage of the
stepwise procedure, the cardiovascular risk factor that
produced the largest reduction in the SROs of IHD was added to the
model. First to be so added was evidence of ischemia at
baseline, which caused the SROs to decline from 1.37 to 1.27, but the
test for trend remained significant
(P=0.008). At the next stage
the addition of smoking habit caused the largest further reduction to
1.21 (P=0.033). Thereafter the
addition of fibrinogen and then D-dimer reduced the SROs first to 1.19
(P=0.084) and then to 1.16
(P=0.13). No individual risk
factor then caused any further substantial reduction in SROs. The joint
addition of body mass index, diastolic blood pressure and
total cholesterol only reduced the SROs to 1.15
(P=0.16) as shown in
Table 6. When family history of MI instead of social class
and whether or not the subject was a diabetic were added jointly to the
model, the SROs declined only from 1.16
(P=0.13) to 1.14
(P=0.17).
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Multivariate Analysis
for D-Dimer
The data in
Table 6 show that addition of the set of
cardiovascular risk factors reduced the relative odds
in the top 20% of the distribution of D-dimer to 1.15 (95% CI, 0.65
to 2.05) and the SROs to 1.17. The test for trend after this adjustment
was nonsignificant and was reduced further by adjustment for fibrinogen
and CRP. Stepwise multiple logistic regression showed that the
confounding factor that most reduced the association of D-dimer with
IHD was CRP, followed by evidence of ischemia at baseline and
fibrinogen
(Table 7).
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Discussion |
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To our knowledge, this is the first report to compare CRP (a marker of the reactant plasma protein component of the inflammatory response) with D-dimer (a marker of fibrin turnover) in the prediction of incident IHD in a population cohort. The inflammatory and the thrombotic components of coronary atherosclerosis and IHD are of current interest in pathophysiology,21 22 31 and there is some experimental evidence that they may be linked.17 18 19 20 Because both CRP and D-dimer are easily measured in stored plasma (or serum) samples, their potential use in risk stratification for IHD merits a comparison.
We observed that in this population cohort of men aged 49 to 67 years, plasma CRP and D-dimer levels showed a moderate correlation (r=0.21, P<0.00001). On adjusting for potential confounders (age, smoking, baseline evidence of IHD, and fibrinogen), the association was reduced but remained highly statistically significant (r=0.17, P<0.00001). This correlation supports our hypothesis that there may be a link between these respective markers of inflammation and fibrin turnover in middle-aged men, which may be due in part to their associations with asymptomatic and symptomatic arterial lesions. However, the correlation is not strong, which suggests that other factors have different effects on plasma levels of these 2 variables.
As expected, we found that cigarette smoking habit had
important, reversible effects on both
CRP7 32 33
and D-dimer.34 35
The elevations of CRP and D-dimer in current cigarette smokers were not
dose dependent but were reversible after quitting
(Table 4). Mean plasma CRP was approximately doubled in
current smokers compared with never-smokers and may partly reflect
elevations in smokers of interleukin-6, which is a major regulator of
the reactant plasma protein component of the inflammatory
response.36 Although plasma
CRP levels fell progressively with time since quitting smoking, they
remained significantly elevated 10 years after quitting compared with
those in never-smokers
(Table 4). In contrast, the elevation in mean plasma D-dimer
in current smokers was only 10% and fell to levels seen in
nonsmokers, 5 to 9 years after quitting
(Table 4). These data suggest that the "inflammatory"
effect of cigarette smoking is both larger in magnitude (10-fold) and
longer-lasting than its effect on cross-linked fibrin turnover. The
relationships of these observations to underlying smoking-related
pathology in the arteries, respiratory tract, and other organs and to
the time course of reduction of IHD risk in smokers who quit merit
future study.
As with smoking, the relationships of CRP to both baseline
IHD
(Table 4) and incident IHD
(Tables
2and
3)
were stronger than those of D-dimer to baseline and incident IHD. These
relationships to IHD are consistent with the literature for
CRP7 and
D-dimer.8 9 10 11 12 13 14 15 16
We are not aware of previous studies directly comparing the predictive
value of CRP and D-dimer for
IHD. The present study suggests that measurement of
both variables may be
useful in risk stratification
(Table 5). The incidence of IHD increased with CRP
independently of the level of D-dimer and vice versa. The risk of IHD
over 6 years follow-up was 6% (ie, 1% per year) in middle-aged
men with levels in the lower third of both CRP and D-dimer compared
with almost 18% (ie, almost 3% per year) in those in the upper third
of both CRP and D-dimer. These data, combined with the practical issue
that both CRP and D-dimer are easily measured in stored plasma (or
serum) samples, suggest the need for further evaluation of both
variables in risk stratification for IHD. This suggestion has a
plausible pathophysiological basis: both
inflammation and thrombosis are important in the pathogenesis of
IHD.21 22 31
In the present study, we observed that inclusion of
conventional risk factors as well as CRP or D-dimer in multiple
logistic regression analyses of the relationships of the other
variable to incident IHD reduced the strength of the association
(Tables 5, 6, and 7).
With regard to the relationship between CRP and incident IHD, the
inclusion of fibrinogen in the model reduced the relationship to below
the conventional level of statistical significance (reduction of SROs
from 1.21, P=0.033 to 1.19,
P=0.084); however, because CRP
and fibrinogen are both measures of the reactant plasma protein
component of inflammation, the validity of this adjustment is
debatable. The addition of D-dimer to the model further reduced the
relationship (SROs of 1.16,
P=0.13), which suggests that
the relationship between CRP and incident IHD is partly confounded by
their mutual relationships to D-dimer. Conversely, with regard to the
relationship between D-dimer and incident IHD, the inclusion of CRP in
the model reduced the relationship from an SRO of 1.21
(P=0.023) to 1.15
(P=0.11). However, the limited
number of major IHD events in this study (191) results in wide
confidence intervals for estimates of the mutual relationships between
CRP, D-dimer, conventional risk factors, and incident IHD. Hence,
further prospective cohort studies and collaborative
meta-analyses are required to define these with greater
precision.
Assays of CRP and D-dimer were performed after storage at -20°C for 12 to 15 years. Although both of these proteins appear resistant to proteolysis during storage and the assays used in the current study appear sufficiently robust to withstand the effects of long-term storage (and thawing), it is also important to perform further prospective cohort studies in which these assays are performed together in samples stored at lower temperatures (-70°C or below). The effect of storage at different temperatures on CRP and D-dimer levels should also be studied prospectively by serial analyses over time. However, comparison of the distributions of CRP and D-dimer values in the present study to those obtained in previous studies in which samples were stored at -70°C or below1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 (including the Caerphilly Study, whose subjects and methods were otherwise similar to those of the Speedwell Study12 ) shows close agreement, which supports the validity of our conclusions. Furthermore, the results of the present study are very similar to the overall results in meta-analyses of CRP and D-dimer (J. Danesh, personal communication, 2000).
In conclusion, our data suggest that in a population cohort of middle-aged men, markers of inflammation (CRP) and of fibrin turnover (D-dimer) are related to each other, smoking, age, plasma fibrinogen, and baseline (as well as incident) IHD. These findings may be related to the association of inflammation and fibrin turnover in arterial lesions and at other body sites. However, measurement of both CRP and D-dimer may be a logical and practical enhancement of current risk stratification for IHD. Further studies are required to test these hypotheses.
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Acknowledgments |
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We thank the Medical Research Council (UK) for financial support. P.M.S. is currently supported by the British Heart Foundation.
Received June 27, 2000; accepted September 29, 2000.
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