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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:386-391

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:386-391.)
© 1996 American Heart Association, Inc.

Articles

The Acute Rise in Plasma Fibrinogen Concentration With Exercise Is Influenced by the G-453-A Polymorphism of the ß-Fibrinogen Gene

Hugh E. Montgomery; Peter Clarkson; O.M. Nwose; D.P. Mikailidis; I.A. Jagroop; Clare Dollery; James Moult; Ferdaous Benhizia; John Deanfield; Mick Jubb; Michael World; Jean R. McEwan; Anthony Winder; Stephen Humphries

From the Hatter Institute for Cardiovascular Studies, Department of Cardiology (H.E.M., C.D., J.M., J.D., J.R.M.), and the Rayne Institute, Division of Cardiovascular Genetics, Department of Medicine (F.B., S.H.), University College London Medical School; the Department of Vascular Studies, Great Ormond Street Children's Hospital, London (P.C.); the Department of Chemical Pathology, The Royal Free Hospital, Hampstead, London (O.M.N., D.P.M., I.A.J., A.W.); the Army Training Regiment, Bassingbourn, Hertfordshire (M.J.); and the Royal Army Medical College, Millbank, London (M.W.), UK.

Correspondence to Dr Hugh Montgomery, University College London Medical School, The Hatter Institute Department of Academic and Clinical Cardiology, University College Hospital, Grafton Way, London WC1E 6DB, UK.


*    Abstract
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Abstract We have investigated the effects of chronic physical training and acute intensive exercise on plasma fibrinogen levels and the relationship of these responses to ß-fibrinogen G-453-A polymorphism genotype. One hundred fifty-six male British Army recruits were studied at the start of their 10-week basic training, which emphasizes physical fitness. Cohorts were restudied between 0.5 and 5 days after a major 2-day strenuous military exercise (ME) undertaken in their final week of training. Changes in fibrinogen concentration were adjusted for the effects of age, body mass index, and smoking history. Compared with baseline values, fibrinogen concentrations were significantly lower (11.9%, P=.04) at day 5 after ME, consistent with the beneficial effect of training. However, they were higher on days 1 through 3 after ME (suggesting an "acute-phase" response to strenuous exercise) and were maximal on days 1 and 2 (27.2%, P<.001 and 37.1%, P<.001, respectively). Fibrinogen genotype was available in 149 individuals. As expected from previous studies, men with one or more fibrinogen gene A-453 alleles had plasma fibrinogen concentrations slightly but not significantly higher at baseline (4.5%, P=.11). During the acute-phase response (days 2 and 3), however, the degree of rise was strongly related to the presence of the A allele, being 26.7±5.4% (mean±SE), 36.5±11.0%, and 89.2±30.7 for the GG, GA, and AA genotypes, respectively (P=.01). These results confirm that chronic exercise training lowers plasma fibrinogen levels, that intensive exercise generates an acute-phase rise in levels, and that this acute response is strongly influenced by the G/A polymorphism of the ß-fibrinogen gene.


Key Words: exercise • training • fibrinogen • G/A polymorphism


*    Introduction
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Fibrinogen and its products penetrate the vascular wall1 and contribute to the pathogenesis of atherosclerotic disease2 3 through effects on the endothelium1 4 5 and vascular smooth muscle cells.1 6 Indeed, increasing plasma fibrinogen concentration is a risk factor for ischemic heart disease,7 8 9 10 11 12 occlusive peripheral arterial disease,13 and cerebrovascular disease.12 13 14 15 16

Lack of physical fitness is an independent risk factor for cardiovascular mortality,17 and a dose-response relationship18 exists between regular physical exercise19 20 and reduced cardiovascular risk.21 22 23 This relationship applies to primary ischemic heart, cerebrovascular,24 25 and peripheral vascular disease,26 as well as to secondary prevention.27 28 Some of the benefit of regular exercise is lost, however, if the exercise undertaken is very intense.29 Further, an episode of very intense exercise may acutely elevate the risk of a subsequent myocardial infarction,30 and this risk is greater in those with a sedentary lifestyle.31

The effects of exercise on cardiovascular risk may be partly mediated through alterations in plasma fibrinogen concentration.32 However, the few studies of the effects of chronic exercise training33 34 or acute intense exercise35 36 on plasma fibrinogen have examined only small numbers of individuals (often <12).

Studies of the effect of acute exercise on a background of chronic training are scarce and conflicting,37 38 39 and the time course of the acute response remains ill defined. Further studies have been advocated.34 Fibrinogen levels increase with advancing age40 and are related to other cardiovascular risk factors, being higher in diabetics and smokers.12 16 41 42 43 They are also influenced by genetic determinants.44 45 The fibrinogen molecule comprises two subunits, each composed of three polypeptide chains (Aa, Bß, and y) encoded by a different gene (FGA, FGB, and FGG, respectively) clustered on chromosome 4. Synthesis of the Bß chain is the rate-limiting step in the synthesis of fibrinogen46 and is responsive to cytokines such as IL6.47 Environmental factors may thus interact with genetic factors, such as polymorphisms of the fibrinogen gene locus, in the control of fibrinogen levels.48 Several such polymorphisms have been identified that are associated with differences in fibrinogen levels at baseline.40 44 45 49 Of these, the G-A substitution in the 5' flanking promoter sequence of the ß-fibrinogen gene has been consistently associated with differences in fibrinogen levels,40 49 50 and recent data suggest that it interacts strongly with factors such as gender, and hormonal and environmental factors.51 This being so, it might be that the acute-phase response of fibrinogen to physiological stress may also be partly determined by this polymorphism.

We sought to clarify these issues by investigating the fibrinogen response to chronic exercise training and to acute severe exercise in fit individuals and the role of the G/A polymorphism of the fibrinogen gene in regulating these responses.


*    Methods
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Study Population
With Army Medical Ethical Committee approval, we studied consecutive cohorts (October 1994 to March 1995) of male recruits to the Army Training Regiment Bassingbourn, where new British Army recruits undergo 10 weeks of intensive training. Sixty-nine 40-minute periods are specifically dedicated to physical training, with much of the remaining time involving physical activity. The last week of training includes an exhausting 2-day ME, comprising prolonged and intensive physical exertion. Written informed consent was obtained from recruits. Height, weight, medical, drug, and smoking history were recorded. The mean of three manually recorded BPs taken 1 minute apart after 5 minutes of supine rest was documented, and a venous blood sample was drawn. Cohorts of troops were studied at intake and again in the last week of training, when fitness had improved greatly. This final assessment was staggered, with five cohorts of troops (A through E) studied at different time points in relation to ME (see the TableDown).


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  		Table 1. Change in Mean Plasma Fibrinogen Concentration in Different Cohorts After Severe Exertion

Fibrinogen Assay
Venous whole blood was collected (9 mL blood+1 mL 3.8% trisodium citrate), centrifuged (300g for 15 minutes), and platelet-poor plasma derived. Assay of plasma fibrinogen was performed by the Clauss (nephelometric) method adapted for an ACL 300 (Research) instrument (IL Laboratories). Normal laboratory range was 200 to 350 mg/dL.

Fibrinogen Genotype
Venous blood (5 mL) was taken into EDTA sample tubes, stored at -20°C, and DNA extracted by the "salting out" method.51 Genotype at the G-445-A position was determined by polymerase chain reaction using oligonucleotides and conditions as previously described.51 DNA was digested with Hae III, and fragments were separated by electrophoresis on a 3% agarose gel.49

Statistical Analysis
Data were expressed as F1, F2, and FCF. Analysis was performed using the SPSS-PC package. No data transformation was required, as fibrinogen levels were normally distributed within the sample. Data for each of the groups A through E were analyzed separately. F1 and F2 within groups were compared using paired t tests, and differences in FCF between groups by one-way ANOVA and Fisher's exact test. To examine the effect of genotype on FCF and plasma fibrinogen levels F1 and F2, data were adjusted by multiple linear regression analysis for the effects of age, BMI (kg/m2), and reported smoking habit (coded as 0=nonsmoker, 1=smoker, 2=ex-smoker). Effects of genotype were estimated on the adjusted data by ANOVA. The correlation between fibrinogen levels at F1 and F2 was estimated using the Spearman correlation coefficient. Values of P<.05 were taken to be statistically significant.


*    Results
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*Results
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Effects of Exercise on Plasma Fibrinogen Levels
Two hundred forty-five subjects were initially studied, of whom 156 (mean±SE age, 18.8±0.11 years; height, 175.4±0.5 cm; weight, 67.9±0.6 kg; BMI, 22.2±0.12 kg/m2) completed training and were subsequently reassessed. All were male, normotensive (initial BP, 119/72±0.85/0.74 mm Hg; final BP, 120/70±0.84/0.85 mm Hg), free of cardiovascular disease, and had a similar low level of cardiorespiratory fitness at entry. Demographic data and initial fibrinogen concentrations were similar in all groups and genotypes.

Fibrinogen concentrations (see the TableUp and Fig 1Down) rose significantly from baseline values on days 1 through 3 after the intensive physical effort of the 2-day ME (27.2%, P<.001; 37.1%, P<.001; 19.9%, P=.04, respectively) and were lower at day 5 (11.9%, P=.04). There was no significant change in fibrinogen concentration at 12 hours after ME and at 4 days after ME. The peak percentage rise in fibrinogen concentration on day 2 was significantly greater than at any other time point (P<.05 for all comparisons) (see the TableUp and Fig 1Down).



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  		Figure 1. The mean percentage change in plasma fibrinogen concentration from pretraining levels with time after an intensive 2-day ME (see text). *P<.05; **P<.001 by paired t test.

Influence of G/A Polymorphism
Fibrinogen G/A genotype was determined in 224 subjects at entry and was available in 149 of the 156 with paired (pretraining and posttraining) fibrinogen levels. The relative frequency of the A allele (0.192) was not significantly different from that reported for individuals in the United Kingdom,49 51 and genotype distribution was consistent with Hardy-Weinberg equilibrium.

The relationship between genotype and fibrinogen levels F1 and F2 was examined by ANOVA. Fibrinogen levels were slightly higher (but not statistically significant) in the combined group of men with one or more A alleles compared with those homozygous for the G allele, being 4.2% and 4.5% higher for F1 and F2, respectively (TableUp). Plasma fibrinogen concentration rose maximally in groups B and C (days 1 and 2), after which the response began to decline. Any association between G/A polymorphism and the acute-phase response to exercise would therefore be expected to be most evident on these days. There was a significant rise in fibrinogen concentration overall (P<.001), but the degree of rise was genotype dependent (Fig 2Down), being (mean±SE) 26.7±5.4%, 36.5±11.0%, and 89.2±30.7% for GG, GA, and AA genotypes, respectively, P=.01; and 26.7±5.4% versus 50.9±12.9% for GG versus those with one or more A allele, P<.05. The effect of the A allele remains if the data for the group showing maximal rise (day 2, group C) are examined alone (FCF, 29.5% [n=24], 37.1% [n=6], and 108.9% [n=2]; P=.016). However, the effect is weakened by the inclusion of a group in whom the acute fibrinogen response is already declining (ie, days 1, 2, and 3) in which rise in fibrinogen was 25.8±4.6% for those of the GG genotype compared with 35.1±9.1% (P=.14).



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  		Figure 2. The mean of percentage in fibrinogen concentration changes from pretraining levels during the acute-phase response to severe exercise by fibrinogen gene G-453-A polymorphism (see text for details).


*    Discussion
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*Discussion
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An acute rise in plasma fibrinogen occurs in response to intensive exercise, lasts several days, and is strongly influenced by the G/A polymorphism of the fibrinogen gene.

Cross-sectional and epidemiological studies support the existence of a reduction in plasma fibrinogen concentration with chronic exercise training. Cardiorespiratory fitness52 and amount of exercise53 54 55 56 correlate inversely with fibrinogen levels, which are thus reduced in athletes.57 However, the effects of training are not consistent,38 and previous prospective studies, hampered by small, mixed cohorts and diverse training protocols, have produced variable results in the young.33 34 Even so, fibrinogen levels may fall with training in patients with cardiovascular disease58 59 and have decreased by more than 15% in young males with 9 weeks of training.60

We have demonstrated (Fig 1Up and TableUp) that fibrinogen levels are significantly (11.9%) reduced after 10 weeks of training if 5 days without severe exertion intervene, an effect in keeping with a beneficial effect of chronic training on fibrinogen levels.

Fibrinogen is a hepatically derived acute-phase protein,47 61 62 63 whose synthesis is responsive to cytokines.47 49 Whereas regular exercise may reduce fibrinogen levels, severe exercise might paradoxically cause an acute-phase rise,35 36 although this theory is debated.38 However, we have confirmed a prolonged rise in response to acute severe exercise (Fig 1Up and the TableUp). Fibrinogen levels at day 5 probably more closely approximate the new "basal levels" induced by chronic training. Within 12 hours of the completion of a 2-day ME, fibrinogen levels are already 14.5% higher than those at 5 days, suggesting that the acute response has already begun. The duration of the rise (at least 3 days) may be related to continued fibrinogen production or to its long plasma half-life (4.5 to 6.5 days).33 Interestingly, the time course of this response is similar to that seen after the physiological stress of myocardial infarction.63

Indices of hydration (such as hematocrit) were not documented. However, all troops had free access to fluids throughout both ME and the follow-up period. Further, any minor fluid deficits would have been most significant immediately upon return from ME and would have rapidly corrected during early follow-up. Nonetheless, fibrinogen levels continued to rise long after this. Thus the effects of fluid balance would only have acted to reduce the perceived rise.

Body composition was not assessed before and after training (although skeletal muscle mass may have been expected to rise and fat content perhaps to fall). However, this parameter is unlikely to have influenced the acute-phase rise itself.

The effects of previous training on the response to acute exercise have been disputed. Keber et al37 suggested that an acute early rise in fibrinogen concentration occurred in response to acute exercise at all levels of fitness, although Dufaux et al39 suggest that a delayed rise after prolonged severe exercise may be abolished by prior training. Our data suggest that any such "protective" effect is incomplete. Differences in study design (differing background fitness and acute exercise burden, study of early [minutes] or delayed [days] fibrinogen responses) probably account for these differing findings.

Changes in fibrinogen concentration may mediate some of the beneficial effects of exercise observed on cardiovascular risk. Fibrinogen is a cardiovascular risk factor64 perhaps as important as serum cholesterol, BMI, and BP.4 8 10 11 64 Regular physical exercise reduces cardiovascular morbidity and mortality17 19 20 22 23 in a dose-dependent fashion,18 29 an effect hard to explain by the effects on other factors such as lipid profile65 or BP.66 Just as chronic exercise lowers both fibrinogen concentration and cardiovascular risk, acute severe exercise may be procoagulant36 and raise cardiovascular risk.30 31 Some of the benefits of regular exercise are lost with very high exercise energy expenditures per week.29 As well as demonstrating a strong interaction between an environmental stimulus and fibrinogen gene expression, we have shown that this response may be strongly influenced by polymorphisms within the gene itself.

As expected from previous studies of the association between the G-453-A ß-fibrinogen gene polymorphism and fibrinogen levels,49 51 those with one or more A alleles had modestly (4.5%) higher levels at entry. A clear pattern of change in fibrinogen concentration with respect to baseline values was seen over the 5 days following a major episode of physical exercise (ME) (Fig 1Up). In groups B and C, who were examined on days 1 and 2 after ME, fibrinogen levels were rising to a peak as part of an acute response. Fibrinogen levels were 27.2% and 37.1% higher than baseline on these 2 days. Among this acute response group, fibrinogen levels rose by 26.7% for those homozygote for the G allele and by almost twice as much (50.9%) in those with one or more A alleles. Although the group was small, the differences were statistically significant, and the size of the effect is sufficient to be of biological significance. In particular, the three men homozygous for the A allele (representing 4% of the population based on the observed allele frequencies) had fibrinogen levels that had risen by more than 89% compared with their "untrained" levels and that were among the highest levels in the whole sample.

These finding are in accord with cross-sectional data showing an interaction between fibrinogen genotype and smoking (an inducer of the acute-phase response) in determining fibrinogen levels50 67 and support an association of the A allele with greater fibrinogen level "responsiveness."68

The molecular mechanisms underlying this association are unclear. Transcription of the ß-fibrinogen gene is the rate-limiting step in hepatocyte fibrinogen production,46 49 and the G/A polymorphism may influence the binding of transcription factors. The G/A change at position 453 is also a marker for a T/C change at position 148 of the promoter, with A and C always occurring together and G and T always occurring together in Caucasians.69 This T/C change is located within a sequence of DNA that confers responsiveness to IL6 in in vitro assays.47 This behavior raises the possibility that either the C-148 sequence alone or the A-453 plus C-148 sequence in combination have a direct effect on the control of ß-fibrinogen synthesis in response to IL6-mediated stimuli such as smoking, inflammation, and tissue damage.

The homogeneity of the study population and environment limited the confounding effects of age,34 38 40 44 57 sex,44 51 hypertension,70 diet,16 smoking history,12 16 41 42 43 71 72 background fitness, exercise nature and intensity,59 73 and season of study74 on fibrinogen levels. Initial fibrinogen concentrations were thus similar in all groups. However, our study does have limitations: it is of cohort design, and logistics of military training prevented us from repeated study of individuals over multiple time points. We were unable to plot the true baseline fibrinogen levels after chronic training (recruits disband 6 days after ME) or assess the early phases of the acute-phase response. Fibrinogen concentrations were >14% higher when first measured after ME than those at day 5 (perhaps more representative of the new posttraining baseline), suggesting that levels had already risen. Indeed, the acute response may comprise an early (within hours)36 and delayed (over days)39 component. Fibrinogen concentrations were still falling rapidly from days 2 through 5 and may well have continued doing so for some time afterward. We have assumed that the fall in fibrinogen concentration at day 5 compared with that at intake represents an effect of chronic training. We were unable to enforce complete rest over the days following ME, although no specific physical training sessions or major exercises were held during this period.

Finally, the number of patients in the genotype analysis is small, especially in the A/A group. Nonetheless, comparisons are statistically significant. A gradient of increasing acute fibrinogen response is seen across the GG, GA, and AA genotypes, respectively, consistent with a different effect attributable to each allele.

In conclusion, our data demonstrate a rise in plasma fibrinogen in response to severe exertion and show that this rise occurs even in physically fit individuals in whom chronic exercise training may have led to a background reduction in plasma fibrinogen concentration. Given that a fall in fibrinogen concentration of just 0.1 g/L might correspond to a cardiovascular risk reduction of 15%,60 at least part of the cardiovascular benefit of regular exercise (and detrimental effects of chronic and acute intensive exercise) may derive from an associated change in fibrinogen levels. The intensity of the response may be influenced strongly by polymorphisms within the gene itself, raising the possibility that individuals homozygous for the A allele may be at particular risk of a thrombotic event after an acute-phase stimulus. Once identified, such individuals may benefit from risk factor reduction.


*    Selected Abbreviations and Acronyms
 
BMI = body mass index
BP = blood pressure
F1 = initial fibrinogen concentration
F2 = final fibrinogen concentration
FCF = fractional change in fibrinogen concentration
IL = interleukin
ME = military exercise


*    Acknowledgments
 
This study was supported in part by Hoechst-Roussel and by grants from the British Heart Foundation (grant CRG16 to Dr Montgomery, Dr Humphries, and Dr Benhizia) and the Medical Research Council (Dr Dollery). We thank Hewlett Packard for furnishing transport and technical assistance; Marquette Electronics for technical support; Harry Hindle, Amanda Powell, Anne O'Donaghue, and Teresa Bull for assistance on the study days; MAJ Simon Davies and BRIG Groves; the staff and recruits of Army Training Regiment Bassingbourn; and in particular the staff of the medical center for their patience and enthusiasm.

Received September 11, 1995; accepted November 10, 1995.


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*References
 

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