© 2000 American Heart Association, Inc.
Thrombosis |
Lifestyle and Hemostatic Risk Factors for Ischemic Heart Disease
The Caerphilly Study
From the Department of Epidemiology and Public Health (J.W.G.Y.), Queen’s University, Belfast, UK; the Medical Research Council Epidemiology Unit (P.M.S.), Cardiff, UK; and the Department of Medicine (A.R., G.D.O.L.), University of Glasgow, Glasgow, UK.
Correspondence to John W.G. Yarnell, Department of Epidemiology and Public Health, Queen’s University of Belfast, Mulhouse Building, Royal Victoria Hospital Site, Grosvenor Road, Belfast BT12 6BJ, UK. E-mail h.porter{at}qub.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract— We have recently shown that fibrin D-dimer, tissue plasminogen activator (tPA) antigen, von Willebrand factor antigen, fibrinogen, plasma viscosity, and white cell count are associated with subsequent ischemic heart disease (IHD) in men aged 49 to 65 years in the Caerphilly Study from South Wales. We now report the contribution of major lifestyle factors to plasma levels of these new risk predictors for IHD. Results were available for up to 2188 men. The contribution of factors associated with lifestyle (smoking, alcohol, body mass index, leisure and work activity, social class, and use of prescribed medicines) to variation in plasma levels of 8 hemostatic variables was examined. All results were adjusted for other lifestyle variables, age, and time of day. Most hemostatic variables increased with age and smoking habit. Increasing levels of alcohol consumption were associated with increases in tPA and plasminogen activator inhibitor (PAI-1) activity and with decreases in fibrinogen and white cell count. tPA, PAI-1, fibrinogen (nephelometric), and viscosity were positively associated with body mass index. Increasing levels of leisure activity were inversely associated with D-dimer, von Willebrand factor, nephelometric fibrinogen, and viscosity. Use of prescribed medicines (a marker for chronic illness) was associated with adverse levels of D-dimer, fibrinogen, plasma viscosity, and white cell count. tPA, PAI-1, and plasma viscosity were associated with blood pressure, cholesterol, and triglycerides but not with lipoprotein(a) or homocysteine. We conclude that several lifestyle factors are associated with hemostatic risk predictors for IHD. Lifestyle modifications may reduce IHD risk partly by altering hemostatic function; large intervention studies are required to test this hypothesis.
Key Words: heart disease • hemostatic factors • lifestyle • epidemiological study
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We have recently shown that several hemostatic variables are associated with incident ischemic heart disease (IHD) in a population sample of men from South Wales (the Caerphilly Study). Measures of fibrinolytic activity included fibrin D-dimer (a marker of fibrin turnover), tissue plasminogen activator antigen (tPA), and plasminogen activator inhibitor activity (PAI-1).1 D-dimer appeared an independent predictor of IHD. Plasma tPA was also associated with increased risk of IHD, but this association was largely explained by the association of tPA antigen with lipid levels. The association of PAI-1 activity with IHD was nonsignificant. A marker of endothelial dysfunction, von Willebrand factor antigen (vWF), was also independently associated with subsequent risk of IHD.2 Plasma fibrinogen, viscosity, and white cell count were also associated with incident IHD.3 Fibrinogen has been previously shown to be a risk factor for IHD in numerous prospective studies4 and has been previously associated with smoking habit,5 alcohol consumption,6 and levels of habitual physical activity.7 We have reported that a heat-precipitation nephelometric assay of fibrinogen was a better predictor of IHD than the Clauss assay of clottable fibrinogen (Sweetnam et al8 ).
Several personal characteristics, both fixed and modifiable, are known or suspected to be associated with cardiovascular disease.9 These are often broadly grouped under the heading "lifestyle factors" and include smoking habit, alcohol consumption, body mass index, social class, and habitual physical activity, both at work and during leisure. In this present study, we examine the contribution of these lifestyle factors to the variation in plasma levels of these hemostatic variables in a sample of middle-aged men. We also consider the effects of age, the time of blood sampling, and the use of prescribed medication as an index of chronic illness.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Populations and Design
The original cohort of 2512 men aged 45 to 59 years was recruited between 1979 and 1983, and since then they have been reexamined at 5-year intervals. The men who are the subject of this report are those who were seen at the first reexamination between 1984 and 1988, when they were aged 49 to 65 years. Men of the same age who had moved into the defined geographical area since the original recruitment were also eligible to be examined. A total of 2398 men attended the evening clinic, and a fasting blood sample was obtained from 2223 (93%) of them.
The general design and methods of the Caerphilly Study have been described elsewhere.10 11 Briefly, at each examination, the men were invited to attend an afternoon or evening clinic at which a detailed medical and lifestyle history was obtained, the London School of Hygiene and Tropical Medicine chest pain questionnaire12 was administered, a full 12-lead ECG was recorded, and height, weight, and blood pressure were measured. Alcohol consumption was determined by the use of a self-administered questionnaire checked at the clinic and converted from standard units of volume to milliliters of pure alcohol per week.13 Habitual physical activity was assessed for work-related activity by use of the Health Insurance Plan questionnaire,14 and a detailed questionnaire derived from the Minnesota Leisure Time Activity questionnaire15 was used to estimate the mean daily leisure time energy expenditure. The men were then invited to return, fasting, to an early morning clinic at which a blood sample was taken.
Blood Collection, Storage, and Analysis
Blood was taken between 7:00 AM and 10:00
AM for 91% of the men, before 7:00 AM for 7%,
and between 10:00 AM and 11:00 AM for 2%.
Centrifugation of citrated blood was carried out within
1 hour, and samples were stored at -70°C. For D-dimer, tPA, vWF,
PAI-1, and clottable fibrinogen, assays were carried out with the use
of these stored samples. One batch of samples was unavailable for the
present analysis, so that D-dimer and tPA antigens were
measured for a total of 1998 fasting samples. Another batch had been
thawed on one occasion and was therefore unsuitable for PAI-1 activity,
which was measured for 1569 samples. The measurements were made during
1994, when the plasma had been stored for between 6 and 10 years.
ELISAs were used for measurement of D-dimer (AGEN) and tPA (Biopool).
PAI-1 activity was measured by use of a chromogenic assay
(Chromogenix). Clottable fibrinogen was later measured by an automated
Clauss assay in a Coag-A-Mate X 2 coagulometer (Organon Teknika) with
the use of a separate stored plasma sample. One third of these samples
had previously been used for another purpose, so that a total of only
1378 samples were available.
Fresh dipotassium edetate–anticoagulated samples were used to measure nephelometric fibrinogen, plasma viscosity, and white cell count as described previously.5
Lipoprotein(a) [Lp(a)] was measured by using a 2-site
immunoradiometric assay (Pharmacia).16 Homocysteine was
measured by high-performance liquid
chromatography.17
2-Macroglobulin or
1-antitrypsin was measured nephelometrically
with Beckman antisera kits. Lipid measurements were made by using
enzymatic assays as described previously.11
Statistical Methods
The 8 hemostatic factors were used, in turn, as the dependent
variables in a series of multiple regression analyses. In
each, the independent variables were age, time of blood sample, and
each of the lifestyle factors. Therefore, the analyses show how
the level of each hemostatic factor varies with any particular
lifestyle factor after adjusting for age, time of day, and all the
other lifestyle factors. The results are presented, in Tables 2 to 8
, as the adjusted means of each hemostatic factor at
various levels of the particular lifestyle factor. For the categorical
lifestyle factors, such as smoking habit and the use of prescribed
medicines, clearly defined categories of adequate size were used. For
the continuous variables, such as body mass index and alcohol
consumption, the levels were obtained by dividing the variable into
5 equally sized groups. The one exception was age, which was divided
into 3 groups: <55, 55 to 59, and 
60 years.
|
|
|
|
|
|
|
The distributions of all 8 hemostatic factors have a positive skew, and
all were transformed to logarithms. For each, this transformation
produced a more nearly symmetric gaussian distribution and stabilized
variances. The means in Tables 2 to 8
are thus geometric means.
For the categorical variables, tests of significance compared each
adjusted mean value with that for a baseline group, such as the men who
had never smoked or were taking no prescribed medicine. For the other
variables, a test for trend was obtained by replacing the grouped
variable with the original continuous value. These were tests for
linear trend, with the exception of body mass index, for which a
quadratic trend was also fitted.
No measure of the variation in the geometric means is given in Tables 2 to 8 in an attempt to retain clarity. Instead, Table 1, which presents the basic characteristics of each
hemostatic factor, also gives the 95% CI for geometric means based on
100, 400, and 900 men. These numbers cover the range of sizes of the
subgroups, most of which contain 
400 men. These CIs assume that the
variance in the subgroup is the same as in the whole cohort. This
assumption generally holds well after the variance-stabilizing
logarithmic transformation. The descriptive statistics shown in Table 1 are given for the maximum number of results available from
fasting blood samples for each of the hemostatic tests.
|
The regression analyses are based on 2166 men who had no missing values for any of the nine lifestyle factors and had given a fasting blood sample. Measurements of hemostatic factors were not available for all 2166 men; the numbers available were 2131 for white cell count, 1946 for D-dimer, 1527 for PAI-1, and 1346 for clottable fibrinogen. The numbers for plasma viscosity and nephelometric fibrinogen were similar to those for white cell count, and the numbers for tPA and vWF were similar to those for D-dimer.
Because of the large number of subjects, even very weak associations between the hemostatic and lifestyle factors are statistically significant at the usual 5% level. We have also carried out many tests of statistical significance. To minimize these effects and to try to make the pattern of associations clearer, we have chosen the 1% level as our level of statistical significance. Where a probability is <1%, the exact probability is given, unless P<0.0001. If the probability is >1%, it is deemed to be not statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Table 1
shows the descriptive data
for the 8 hemostatic variables.
The Figure summarizes the data shown in
Tables 2 to 8 but relates to individual hemostatic factors
rather than to individual lifestyle variables. All lifestyle
variables shown in the Figure were significantly related to
each individual hemostatic factor after adjustment for age, time of
blood sampling, and all other lifestyle factors.
|
Table 2 shows that all variables
considered (with the exception of white cell count) were associated
with age. The majority increased with age, but PAI-1 activity
decreased.
Venous blood samples were taken after an overnight fast. In order
not to disrupt the normal lifestyle of working men, such samples were
taken between 4:00 AM and 11:00 AM, giving
rise to possible variation in values due to differing circadian
rhythms. Table 3 shows that only tPA
antigen and plasma viscosity were significantly associated with time of
blood sampling; early samples were associated with lower values.
Table 4 shows the variation in hemostatic
factors with smoking habit. The majority of variables were strongly
associated with smoking habit; the strongest associations were for
white cell count, fibrinogen, viscosity, and tPA. There were weaker
associations with D-dimer and PAI-1. Dose-dependent relations between
the amount of tobacco smoked were usually weaker or absent. Larger
effects were seen between lifetime abstainers and exsmokers.
Table 5 shows that associations between
the hemostatic factors and alcohol consumption are variable both in
magnitude and direction. The strongest associations were the positive
ones with tPA and PAI-1. Negative associations were seen with both
clottable fibrinogen and white cell count and, to a lesser extent, with
nephelometric fibrinogen.
Body mass index is examined in Table 6.
Strong positive linear associations were shown for plasma viscosity,
nephelometric (but not clottable) fibrinogen, and PAI-1. tPA showed
both strong linear and quadratic associations; the quadratic components
reflected the tendency for the rate of increase of tPA to decrease with
increasing body mass index. vWF showed only a nonlinear
association.
Only 2 factors, D-dimer and vWF, showed a statistically significant
association with leisure activity as assessed by the Minnesota Leisure
Time Activity questionnaire (Table 7).
Both decreased as leisure time activity increased. Fibrinogen and
plasma viscosity also both decreased as activity increased, but the
changes were small and not statistically significant. Work-related
physical activity showed no independent relation to any of the
hemostatic factors studied (data not shown).
Table 8 shows the mean values for the
hemostatic factors in subjects who were taking prescribed medicines and
in those who were not. Such a measure may be used as a proxy measure
for any subjects with long-standing (or, less frequently, short-term)
illness, which may affect the variables. This shows that the
majority of variables, with the exception of tPA, PAI-1 activity,
and vWF, were affected by use of prescribed medication or by the
underlying pathology or by both.
The relation between social class and hemostatic variables was also examined. Only fibrinogen, measured nephelometrically, and plasma viscosity showed a significant trend with social class (data not shown).
To examine the relation between hemostatic factors and other
cardiovascular risk markers, we calculated bivariate
Pearson correlation coefficients for these variables. Table 9 shows these results.
|
Both tPA and PAI-1 activity were strongly associated with all major
cardiovascular risk factors, whereas D-dimer and vWF
showed almost no such associations. The acute phase reactants,
2-macroglobulin and
1-antitrypsin, showed associations with all
hemostatic factors except PAI-1; tPA correlated only with
2-macroglobulin. Lp(a) correlated only with
clottable fibrinogen, whereas homocysteine showed only weak
correlations with D-dimer, PAI-1, vWF, and white cell count. The values
of the correlation coefficients are given after logarithmic
transformation but are very similar for untransformed data.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
These results show a series of statistically and clinically significant associations between several modifiable lifestyle variables and certain hemostatic variables, which are both risk predictors for IHD and biologically relevant to its pathogenesis. The advantages of our data set are as follows: (1) it comes from a well-defined cohort study, comprising the majority of middle-aged men in a defined geographical area, Caerphilly10 11 ; (2) the hemostatic variables studied have all been related to risk of incident IHD in this cohort1 2 3 ; and (3) the relations between individual lifestyle variables and hemostatic variables have been clarified by statistical adjustment for other lifestyle variables and also for age, time of blood sample, and prescribed medications. The 95% CIs shown in Table 1
provide a guide for
the relative strengths of the trends shown in Tables 2 to 8.
The increases with age (between 49 and 65 years) for most variables
shown in Table 1 are consistent with the literature for
D-dimer,18 19 tPA antigen,18 20 vWF
antigen,18 21 fibrinogen,6 and plasma
viscosity.22 The lack of increase in white cell
count22 and small decrease in PAI-1
activity18 20 are also consistent with previous
data. Diurnal variations (Table 3) in tPA antigen have also been
reported.20 These effects of age and time of blood sample
were adjusted for in analyses of lifestyle variables and
hemostatic factors.
The increases with smoking habit shown in Table 4 are also
consistent with the literature for D-dimer,19 tPA
antigen,23 PAI-1 activity,6 23 24 vWF
antigen,21 fibrinogen,4 5 6 18 22
viscosity,5 18 22 and white cell
count.5 18 22 In longitudinal analyses, however,
D-dimer,1 tPA,1 vWF,2
fibrinogen,3 4 10 viscosity, and white cell
count3 were associated with subsequent IHD, independent of
smoking habit. It has been previously suggested that the association
between smoking habit and subsequent IHD may be mediated, at least in
part, by these hemostatic variables,25 especially
fibrinogen.26,27 The present data suggest
that the increases in D-dimer, tPA, PAI-1, fibrinogen, viscosity, and
white cell count are partly reversible in exsmokers and that these
changes are not due to concurrent changes in other lifestyle
variables. If so, then the reductions in thrombotic tendency and
plasma viscosity may partly explain the rapid reduction in IHD risk
that follows cessation of smoking and cannot be attributed to
regression of coronary
atherosclerosis.28
Moderate alcohol consumption decreases the risk of IHD; however, heavy
alcohol consumption increases the risk of
cardiovascular disease, including
stroke.29 The effects of increasing alcohol consumption on
hemostatic variables (Table 5) suggest possible explanations
for these epidemiological findings. Alcohol consumption was
independently associated with decreasing levels of fibrinogen and white
cell count, which are consistently associated with IHD
risk.3 30 On the other hand, heavy alcohol consumption was
independently associated with increased levels of tPA antigen, as in 2
previous reports from the US Physicians Study31 and the
Edinburgh Artery Study.32 These 2 studies have also
reported that tPA antigen levels are associated with incident
stroke,33 34 and a recent report has associated increased
levels of tPA–PAI-1 complexes with incident stroke, especially
hemorrhagic stroke.35 Our finding that PAI-1 activity is
also related to alcohol consumption, in a manner similar to tPA antigen
(Table 5), is consistent with a previous
study,36 raising the possibility that tPA–PAI-1 complexes
are related to alcohol consumption. Fibrin D-dimer levels were
unrelated to alcohol consumption, suggesting that the increased levels
of tPA and PAI-1 in high consumers do not result in increasing turnover
of cross-linked fibrin in vivo. However, the association of high-dose
exogenous tPA as thrombolytic therapy for acute
myocardial infarction with hemorrhagic stroke37 suggests a
possible role for alcohol-elevated endogenous tPA in
hemorrhagic stroke. On the other hand, it should be noted that raised
tPA antigen levels probably do not correlate with functional tPA
activity and may relate more to endothelial cell
disturbance (such as found with vWF).
Overweight and obesity, assessed by body mass index, are risk factors
for IHD and maturity-onset diabetes mellitus.38 Table 6 confirms that both tPA antigen and PAI-1 activity are strongly
related to body mass index, in accordance with the
literature.39 40 41 In the present study, obese men
(body mass index >30 kg/m2) had an 50%
increase in PAI-1 activity compared with men of "ideal" body mass
index (<25 kg/m2), when adjusted for other
lifestyle variables. This was accompanied by an 30% increase in
tPA antigen and with no increase in cross-linked fibrin turnover in
vivo, as assessed by fibrin D-dimer levels. There is some evidence that
weight reduction reduces PAI-1 and tPA levels,41
suggesting a causal relation. Increasing body mass index was also
associated with increasing levels of fibrinogen and plasma viscosity,
consistent with the literature,4 6 16 39 40 42
although, overall, there is little evidence that weight reduction
reduces fibrinogen or viscosity levels.42 Interestingly,
body mass index was associated with total (nephelometrically assayed)
fibrinogen rather than clottable fibrinogen (Table 6), which may
be relevant to our finding that the former assay was a better predictor
of incident IHD than the latter in this cohort.8
Many cohort studies indicate that physical activity, particularly
during leisure time, is a protective lifestyle activity against IHD,
even in moderate doses.43 Previous reports from the
present cohort7 and from others43 44 have
associated leisure activity with decreasing fibrinogen levels. In the
present study, adjustment for other lifestyle variables reduced
this association to nonsignificance at the 1% level. Likewise, the
association between fibrinogen and physical activity was no longer
statistically significant after adjustment for smoking and social class
in the Scottish Heart Health Study.44 In combination with
the conflicting data from intervention studies,42 a causal
association between leisure activity and fibrinogen remains to be
proven by further studies. We observed no significant independent
association of leisure activity with tPA or PAI-1 levels, which again
is consistent with data from intervention
studies.45 In contrast, we observed independent
associations of leisure activity with decreased levels of fibrin
D-dimer and vWF (Table 7). These novel findings suggest the
possibility that leisure activity may reduce IHD risk by decreasing
cross-linked fibrin turnover and endothelial
disturbance in vivo. However, this hypothesis requires testing
in randomized intervention trials of increased leisure activity.
A further important personal characteristic of middle-aged men is the
prevalence of prescribed medication. Such medication may be prescribed
for both acute and chronic illnesses, including symptoms of
cardiovascular disease. Table 8 shows that
fibrinogen, viscosity, white cell count, and D-dimer were all
significantly higher in the men receiving prescribed medication. These
findings may reflect effects of the underlying illness, effects of
medication, or both. The effects of the underlying illness are probably
most important, because all these hemostatic variables are
recognized "acute-phase reactants," which increase nonspecifically
in both vascular and nonvascular illnesses, which are common in
comprehensive samples of the general population such as the present
cohort. The associations of these variables with the acute-phase
reactant proteins, 2-macroglobulin and
1-antitrypsin (Table 9), are
consistent with this suggestion. Adjustment for prescribed
medication (received by almost 50% of men in this cohort, Table 8) is therefore important when considering the effects of
lifestyle variables.
Table 9 shows that tPA, PAI-1, nephelometric fibrinogen, and
viscosity are correlated with blood pressure and lipids. These findings
are consistent with the literature4 6 22 39 40 41
and may partly account for the associations of these hemostatic
variables with correlated lifestyle variables such as alcohol,
obesity, and leisure activity. However, a causal role for blood
pressure and lipids in elevation of hemostatic variables remains to
be established by large randomized controlled trials of the effects of
blood pressure and lipid reduction on hemostatic variables.
Lp(a) may be a risk factor for IHD, and it has been suggested that this
may be mediated by effects on hemostatic variables: in particular,
decreased lysis of intravascular fibrin may result from elevated Lp(a),
which competes with plasminogen for binding to
fibrin.46 However, Table 9 shows no significant
associations of Lp(a) with fibrinolytic variables; in particular,
there was no association with fibrin D-dimer, a marker of turnover of
cross-linked fibrin in vivo. The only association of Lp(a) was with
clottable (but not nephelometric) fibrinogen, but the degree of
association is small. Plasma homocysteine may also be a risk factor for
IHD in the general population, possibly, in part, because of
endothelial disturbance.47 In the
present study, homocysteine correlated weakly with vWF, D-dimer,
and white cell count (Table 9). Although consistent with
an effect of raised homocysteine on endothelial
disturbance, fibrin turnover in vitro, and an inflammatory
response, these associations were very weak.
In conclusion, our findings are consistent with the hypothesis that lifestyle risk factors for IHD and stroke (smoking, alcohol consumption, obesity, and leisure activity) may operate partly through changes in hemostatic variables that are risk predictors for cardiovascular events. Further large intervention studies are required to examine this hypothesis. In the meantime, these findings suggest that lifestyle modifications may result in decreased thrombotic tendency in the blood and increased ability of blood to flow. This may be relevant to the early decreased risk of cardiovascular events with lifestyle change, which precedes changes in atherosclerosis.
|
Acknowledgments |
|---|
We thank the British Heart Foundation and the Medical Research Council for financial support.
Received March 26, 1999; accepted August 7, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lowe GDO, Yarnell JWG, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischemic heart disease in the Caerphilly study. Thromb Haemost. 1998;79:129–133.[Medline] [Order article via Infotrieve]
2. Rumley A, Lowe GDO, Sweetnam PM, Yarnell JWG, Thomas HF, Ford RP. Factor VIII, von Willebrand factor and the risk of major ischemic heart disease in the Caerphilly Study. Br J Haematol.. 1999;105:110–116.[Medline] [Order article via Infotrieve]
3.
Yarnell JWG, Baker IA, Sweetnam PM, Bainton D,
O’Brien JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity and white
cell count are major risk factors for ischemic heart disease.
Circulation. 1991;83:836–844.
4. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993;118:963–965.
5.
Yarnell JWG, Sweetnam PM, Rogers S, Elwood PC, Bainton
D, Baker IA, Eastham R, O’Brien JR, Etherington NW. Some long term
effects of smoking on the hemostatic system: a report from the
Caerphilly and Speedwell Collaborative Surveys. J Clin
Pathol. 1987;40:909–913.
6. Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. BMJ. 1979;1:153–156.
7.
Elwood PC, Yarnell JWG, Pickering J, Fehily AM,
O’Brien JR. Exercise, fibrinogen, and other risk factors for
ischemic heart disease: Caerphilly Prospective Heart Disease
Study. Br Heart J. 1993;69:183–187.
8. Sweetnam PM, Yarnell JWG, Lowe GDO, Baker IA, O’Brien JR, Rumley A, Etherington MD, Whitehead PJ, Elwood PC. The relative power of heat-precipitation nephelometric and clottable (Clauss) fibrinogen in the prediction of ischemic heart disease: the Caerphilly and Speedwell studies. Br J Haematol. 1998;100:582–588.[Medline] [Order article via Infotrieve]
9. Poulter N, Sever P, Thom S, eds. Cardiovascular Disease: Risk Factors and Intervention. Oxford, UK: Radcliffe; 1993.
10.
Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD,
Baker IA, Elwood PC. Fibrinogen, viscosity and the 10-year incidence of
ischemic heart disease. Eur Heart J. 1996;17:1814–1820.
11.
Bainton D, Miller NE, Bolton CH, Yarnell JWG, Sweetnam
PM, Baker IA, Lewis B, Elwood PC. Plasma triglyceride and
high density lipoprotein cholesterol as predictors of
ischemic heart disease in British men: the Caerphilly and
Speedwell collaborative heart disease studies. Br Heart
J. 1992;68:60–66.
12. Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular Survey Methods. 2nd ed. Geneva, Switzerland: World Health Organization; 1982.
13. Yarnell JWG, Fehily AM, Milbank JE, Sweetnam PM, Walker CL. A short dietary questionnaire for use in an epidemiological survey: comparison with weighed dietary records. Hum Nutr Appl Nutr. 1983;37A:103–112.
14. Shapiro S, Weinblatt E, Frank CW, Sager RV. The H.I.P. study of incidence and prognosis of coronary heart disease: preliminary findings on incidence of myocardial infarction and angina. J Chronic Dis. 1965;18:527–558.[Medline] [Order article via Infotrieve]
15. Taylor HL, Jacobs DR, Schucker B, Knudsen J, Leon AS, de Backer G. A questionnaire for the assessment of leisure time physical activities. J Chronic Dis. 1978;31:741–755.[Medline] [Order article via Infotrieve]
16. Durrington PN, Ishola M, Hunt LP, Arrol S, Bhatnagar D. Apolipoproteins (a), A-I, and B, and parental history in men with early onset ischemic heart disease. Lancet. 1988;1:1070–1073.[Medline] [Order article via Infotrieve]
17. Ubbink JB, Vermaak WJH, Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr. 1991;565:441–446.[Medline] [Order article via Infotrieve]
18. Rumley A, Lowe GDO, Lee AJ, Tunstall-Pedoe HD. Effect of age, sex and menopause on fibrinolytic variables. Fibrinolysis. 1992;6(suppl 3):73. Abstract.
19.
Lee AJ, Fowkes GR, Lowe GDO, Rumley A. Determinants of
fibrin D-dimer in the Edinburgh Artery Study. Arterioscler Thromb
Vasc Biol. 1995;15:1094–1097.
20. Eliasson M, Evrin P-E, Lundblad D, Asplund K, Ranby M. Influence of gender, age and sampling time on plasma fibrinolytic variables and fibrinogen. Fibrinolysis. 1993;7:316–323.
21. Conlan NG, Folsom AR, Finch A, Davis CE, Sorlie P, Marcucci G, Wu KK. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost. 1998;79:129–133.
22. Lowe GDO, Smith WCS, Tunstall-Pedoe HD, Crombie IK, Lennie SE, Anderson J, Barbenel JC. Cardiovascular risk and haemorheology: results from the Scottish Heart Health Study and the MONICA Project, Glasgow. Clin Hemorheol. 1988;8:518–524.
23. Eliasson M, Asplund K, Evrin P-E, Lundblad D. Relationship of cigarette smoking and snuff dipping to plasma fibrinogen, fibrinolytic variables and serum insulin: the Northern Sweden MONICA Study. Atherosclerosis. 1995;113:41–53.[Medline] [Order article via Infotrieve]
24. Allen RA, Kluft C, Bronmer EJP. Effect of chronic smoking on fibrinolysis. Arteriosclerosis. 1985;85:443–450.
25. Yarnell JWG. The role of hemostatic factors in cardiovascular disease: a review. Primary Cardiol. 1992;18:68–74.
26. Meade TW, Imeson J, Stirling Y. Effect of changes in smoking and other characteristics on clotting factors and the risk of ischemic heart disease. Lancet. 1987;2:986–988.[Medline] [Order article via Infotrieve]
27. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham study. Am Heart J. 1987;113:1006–1010.[Medline] [Order article via Infotrieve]
28. Royal College of Physicians. Smoking or Health? London, UK: Pitman; 1983.
29. Beaglehole R, Jackson R. Alcohol, cardiovascular diseases and all causes of death: a review of the epidemiological evidence. Drug Alcohol Rev. 1992;11:275–290.
30.
Danesh J, Collins R, Appleby P, Peto R. Association of
fibrinogen, C-reactive protein, albumin or leukocyte count with
coronary heart disease. JAMA. 1998;279:1477–1482.
31.
Ridker PM, Vaughan DE, Stampfer MJ, Glynn RJ, Hennekens
CH. Association of moderate alcohol consumption and plasma
concentration of endogenous tissue type
plasminogen activator. JAMA. 1994;272:929–933.
32. Lee AJ, Flanagan PA, Rumley A, Fowkes FGR, Lowe GDO. Relationship between alcohol intake and tissue-plasminogen activator antigen and other hemostatic factors in the general population. Fibrinolysis. 1995;9:49–54.
33. Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet. 1994;343:940–943.[Medline] [Order article via Infotrieve]
34.
Smith FB, Lee AJ, Fowkes FGR, Price JF, Rumley A, Lowe
GDO. Hemostatic factors as predictors of ischemic heart disease
and stroke in the Edinburgh Artery Study. Arterioscler Thromb
Vasc Biol. 1997;17:3321–3325.
35. Nilsson TK, Jansson JH, Boman K. t-PA–PAI-1 complex as a risk factor for the development of a first stroke. Fibrinolysis. 1998;12(suppl 1):21. Abstract.
36.
Hendriks HF, Veenstra J, Velthuis-te Wierik EJ,
Schaafsma G, Kluft C. Effect of moderate dose of alcohol with evening
meal on fibrinolytic factors. BMJ. 1994;308:1003–1006.
37.
Collins R, MacMahon S, Flather M, Baigent C, Remvig L,
Mortensen S, Appleby P, Godwin J, Yusuf S, Peto R. Clinical effects of
anticoagulant therapy in suspected acute myocardial infarction:
systematic overview of randomised trials. BMJ. 1996;313:652–659.
38.
Jousilhti P, Tuomilehto J, Vartianen E, Pekkanen J,
Puska P. Body weight, cardiovascular risk factors and
coronary mortality. Circulation. 1996;93:1372–1379.
39. Sundell IB, Nilsson TK, Ranby M, Hallmans G, Hellsten G. Fibrinolytic variables are related to age, sex, blood pressure, and body build measurements: a cross-sectional study in Nonsjö, Sweden. J Clin Epidemiol. 1989;42:719–23.[Medline] [Order article via Infotrieve]
40. Eliasson M, Evrin P-E, Lundblad D. Fibrinogen and fibrinolytic variables in relation to anthropometry, lipids and blood pressure: the Northern Sweden MONICA Study. J Clin Epidemiol. 1994;46:513–524.
41. Juhan-Vague I, Alessi MC. Fibrinolysis and risk of coronary artery disease. Fibrinolysis. 1996;10:127–136.
42. Ernst E, Resch KL. Therapeutic interventions to lower plasma fibrinogen concentration. Eur Heart J. 1995;16:47–53.
43.
Connelly JB, Cooper JA, Meade TW. Strenuous exercise,
plasma fibrinogen and factor VII activity. Br Heart J. 1992;67:351–354.
44. Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol. 1990;43:913–919.[Medline] [Order article via Infotrieve]
45. Lowe GDO, Small M. Stimulation of endogenous fibrinolysis. In: Kluft C, ed. Tissue-Type Plasminogen Activator t-PA: Physiological and Clinical Aspects, Volume II. Boca Raton, Fla: CRC Press; 1988:129–171.
46. Scanu AM, Scandiani L. Lipoprotein (a): structure, biology and clinical relevance. Adv Intern Med. 1991;36:249–270.[Medline] [Order article via Infotrieve]
47.
Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A
quantitative assessment of plasma homocysteine as a risk factor for
vascular disease. JAMA. 1995;274:1049–1057.
This article has been cited by other articles:
 |
|
 |
|
  N. Sattar, G. Wannamethee, N. Sarwar, J. Chernova, D. A. Lawlor, A. Kelly, A. M. Wallace, J. Danesh, and P. H. Whincup Leptin and coronary heart disease: prospective study and systematic review. J. Am. Coll. Cardiol., January 13, 2009; 53(2): 167 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. L. Humphrey, R. Fu, K. Rogers, M. Freeman, and M. Helfand Homocysteine Level and Coronary Heart Disease Incidence: A Systematic Review and Meta-analysis Mayo Clin. Proc., November 1, 2008; 83(11): 1203 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Paczek, W. Michalska, and I. Bartlomiejczyk Trypsin, elastase, plasmin and MMP-9 activity in the serum during the human ageing process Age Ageing, May 1, 2008; 37(3): 318 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Moens, C. J. Vrints, M. J. Claeys, J.-P. Timmermans, H. C. Champion, and D. A. Kass Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H1971 - H1977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Yanbaeva, M. A. Dentener, E. C. Creutzberg, G. Wesseling, and E. F. M. Wouters Systemic Effects of Smoking Chest, May 1, 2007; 131(5): 1557 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Sattar, G. Wannamethee, N. Sarwar, J. Tchernova, L. Cherry, A. M. Wallace, J. Danesh, and P. H. Whincup Adiponectin and Coronary Heart Disease: A Prospective Study and Meta-Analysis Circulation, August 15, 2006; 114(7): 623 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Steptoe and M. Marmot Psychosocial, Hemostatic, and Inflammatory Correlates of Delayed Poststress Blood Pressure Recovery Psychosom Med, July 1, 2006; 68(4): 531 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Smith, C. Patterson, J. Yarnell, A. Rumley, Y. Ben-Shlomo, and G. Lowe Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke?: The Caerphilly Study Circulation, November 15, 2005; 112(20): 3080 - 3087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Wannamethee, G. D.O. Lowe, A. G. Shaper, A. Rumley, L. Lennon, and P. H. Whincup Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease Eur. Heart J., September 1, 2005; 26(17): 1765 - 1773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yarnell, E. McCrum, A. Rumley, C. Patterson, V. Salomaa, G. Lowe, A. Evans, and on behalf of the MONICA Optional Haemostasis Study Association of European population levels of thrombotic and inflammatory factors with risk of coronary heart disease: the MONICA Optional Haemostasis Study{dagger} Eur. Heart J., February 2, 2005; 26(4): 332 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D.O. Lowe, A. Rumley, A. D. McMahon, I. Ford, D. St. J. O'Reilly, C. J. Packard, and for the West of Scotland Coronary Prevention Study Interleukin-6, Fibrin D-Dimer, and Coagulation Factors VII and XIIa in Prediction of Coronary Heart Disease Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1529 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.D.O. Lowe, J. Danesh, S. Lewington, M. Walker, L. Lennon, A. Thomson, A. Rumley, and P.H. Whincup Tissue plasminogen activator antigen and coronary heart disease: Prospective study and meta-analysis Eur. Heart J., February 1, 2004; 25(3): 252 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Lee and G. Y. H. Lip Effects of Lifestyle on Hemostasis, Fibrinolysis, and Platelet Reactivity: A Systematic Review Arch Intern Med, October 27, 2003; 163(19): 2368 - 2392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Yu, J W G Yarnell, P M Sweetnam, and L Murray What level of physical activity protects against premature cardiovascular death? The Caerphilly study Heart, May 1, 2003; 89(5): 502 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Steptoe, S. Kunz-Ebrecht, N. Owen, P. J. Feldman, A. Rumley, G. D. O. Lowe, and M. Marmot Influence of Socioeconomic Status and Job Control on Plasma Fibrinogen Responses to Acute Mental Stress Psychosom Med, January 1, 2003; 65(1): 137 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.J. Brunner, H. Hemingway, B.R. Walker, M. Page, P. Clarke, M. Juneja, M.J. Shipley, M. Kumari, R. Andrew, J.R. Seckl, et al. Adrenocortical, Autonomic, and Inflammatory Causes of the Metabolic Syndrome: Nested Case-Control Study Circulation, November 19, 2002; 106(21): 2659 - 2665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.H. Whincup, J. Danesh, M. Walker, L. Lennon, A. Thomson, P. Appleby, A. Rumley, and G.D.O. Lowe von Willebrand factor and coronary heart disease. Prospective study and meta-analysis Eur. Heart J., November 2, 2002; 23(22): 1764 - 1770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Wannamethee, G. D.O. Lowe, P. H. Whincup, A. Rumley, M. Walker, and L. Lennon Physical Activity and Hemostatic and Inflammatory Variables in Elderly Men Circulation, April 16, 2002; 105(15): 1785 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Steptoe and M. Marmot The role of psychobiological pathways in socio-economic inequalities in cardiovascular disease risk Eur. Heart J., January 1, 2002; 23(1): 13 - 25. [Full Text] [PDF]
|
|
|
|
 |
|
 A. McEntegart, H. A. Capell, D. Creran, A. Rumley, M. Woodward, and G. D. O. Lowe Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis Rheumatology, June 1, 2001; 40(6): 640 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. O. Lowe, J. W. G. Yarnell, A. Rumley, D. Bainton, and P. M. Sweetnam C-Reactive Protein, Fibrin D-Dimer, and Incident Ischemic Heart Disease in the Speedwell Study : Are Inflammation and Fibrin Turnover Linked in Pathogenesis? Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 603 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||