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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/881    most recent expphysiol.2005.030718v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kulaputana, O. Articles by Hagberg, J. M Search for Related Content PubMed PubMed Citation Articles by Kulaputana, O. Articles by Hagberg, J. M

¹ Department of Kinesiology, University of Maryland, College Park, MD 20742, USA ² Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA ³ Geriatric Research, Education, and Clinical Center, Baltimore VA Medical Center, Baltimore, MD 21201, USA ⁴ Division of Gerontology, University of Maryland School of Medicine, Baltimore, MD 21201, USA

	Abstract

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Endurance exercise training improves fibrinolysis, but this training-induced adaptation may differ somewhat between men and women. We sought to determine whether the potential gender differences in training-induced changes in selected fibrinolysis measures were related to changes in adiposity and/or plasma lipoprotein lipid levels. Seventeen men and 28 women, 50–75 years old, who were generally overweight to obese, were assessed for plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) activity, t-PA antigen and plasma lipoprotein-lipid levels, and body composition before and after 6 months of endurance exercise training while on a low-fat diet. At baseline, there were no differences in fibrinolytic measures between the men and women. Baseline levels of these fibrinolytic markers in both men and women were primarily related to other fibrinolytic measures and body composition, with a smaller contribution from plasma high-density lipoprotein cholesterol (HDL-C) levels. Exercise training reduced t-PA antigen levels in both men and women, but the reduction was significantly greater in men (–1.6 ± 0.3 versus –0.5 ± 0.2 ng ml^–1, P = 0.007). Exercise training decreased PAI-1 activity more in men than in women (–2.6 ± 1.4 versus +0.9 ± 0.9 IU ml^–1, P = 0.03). Men and women both showed increased t-PA activity with exercise training to the same extent (+0.38 ± 0.12 versus +0.36 ± 0.24 U ml^–1). The changes in fibrinolytic measures with exercise training in men and women were correlated with changes in other fibrinolytic measures, although in men abdominal fat changes were a strong predictor of fibrinolytic changes with training. These findings suggest that training-induced improvements in endogenous fibrinolysis markers are somewhat greater in men compared to women and may be more strongly associated with abdominal obesity in men.

(Received 26 April 2005; accepted after revision 22 August 2005; first published online 23 August 2005)
Corresponding author J. Hagberg: Department of Kinesiology, University of Maryland, College Park, MD 20742–2611, USA. Email: hagberg{at}umd.edu

	Introduction

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Fibrinolysis is the result of several enzymes working in concert to lyse fibrin clots. Of these enzymes, the most important are tissue plasminogen activator (t-PA) and its main inhibitor, plasminogen activator inhibitor-1 (PAI-1). Elevated t-PA antigen level, which primarily reflects inactive circulating t-PA bound to PAI-1, is an independent risk factor for cardiovascular (CV) disease and stroke in men and women (Ridker et al. 1993, 1994; Thompson et al. 1995; Macko et al. 1999). Endurance exercise training improves fibrinolysis, along with other CV disease risk factors involved in the regulation of fibrinolysis (Ponjee et al. 1996; Dunstan et al. 1999). While little is known regarding the gender specificity of training-induced fibrinolytic system adaptations, some evidence suggests that men and women may differ in terms of their fibrinolytic enzyme responses to training (Chandler et al. 1996). Therefore, we hypothesized that men would respond to exercise training with greater improvements in selected fibrinolytic measures than women.

A number of studies show strong relationships between adiposity, particularly visceral adiposity, and impaired fibrinolysis (Almer & Janzon, 1975; Vague et al. 1986, 1989; Landin et al. 1990; McGill et al. 1994; Calles-Escandon et al. 1996; Cigolini et al. 1996; Alessi et al. 1997; Janand-Delenne et al. 1998). Recent evidence indicates that adipose tissue is a source of PAI-1 and that visceral fat produces more PAI-1 than subcutaneous fat (Shimomura et al. 1996; Alessi et al. 1997). Markers of endogenous fibrinolysis, including PAI-1 activity, are also associated with circulating lipoprotein lipid levels, particularly triglyceride (TG) levels (Juhan-Vague et al. 1989; Sundell et al. 1989; Landin et al. 1990; Keber et al. 1994; Bard et al. 2001), and improved fibrinolytic markers are related to reductions in plasma lipoprotein lipids induced by medications (Keber et al. 1994) and weight loss (Folsom et al. 1993; Calles-Escandon et al. 1996). We hypothesized that there would be gender differences in training-induced fibrinolysis changes and that these differences would be related to changes in adiposity and/or plasma lipoprotein lipid levels.

	Methods

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Sedentary healthy men and women aged 50–75 years were screened by medical history, blood biochemistry evaluation and general physical examination to ensure they had no liver, renal or haematological disorders. A graded exercise test with ECG monitoring was used to exclude individuals with CV disease. Subjects were excluded if they had body mass index (BMI) > 35 kg m^–2, uncontrolled hypertension (blood pressure (BP) > 160/90 mmHg), or orthopaedic problems that would interfere with exercise training. All women were postmenopausal for > 2 years. Women on hormone replacement therapy (HRT) continued this for the duration of the study; those not on HRT remained off treatment for the duration of the study. Written informed consent that conformed with the Declaration of Helsinki was obtained during the first screening visit. The study was approved by the University of Maryland College Park and Baltimore Institutional Review Boards.

Subjects then completed a 6 week dietary stabilization programme during which they were instructed on the American Heart Association step I diet (Krauss et al. 1996). Food records and food frequency questionnaires were administered before, during and after training. Subjects could not lose > 5% body weight during the study.

Blood samples to assess plasma lipids and fibrinolysis were drawn after a 12 h overnight fast. A questionnaire assessing recent infection/inflammation was administered before obtaining the blood samples. Blood was only drawn from subjects reporting no infections/inflammation for > 2 weeks. Antecubital venipuncture with a 21 gauge butterfly needle was performed with minimal venostasis after subjects rested for 20 min. To determine PAI-1 and t-PA activities, blood was drawn directly into an acidified citrate anticoagulant to prevent on-going in vitro inactivation of t-PA and inactive PAI-1 release. To determine t-PA antigen levels, blood was directly collected into vacuum tubes containing trisodium citrate. PAI-1 activity was measured from platelet-poor plasma by the chromogenic method (Spectrolyse/pL PAI, Biopool, Umeå, Sweden); intra- and interassay coefficients of variation were 5.8 and 8.6%, respectively. t-PA activity was measured by the direct amidolytic activity method (Coaset t-PA, Chromogenix, DiaPharma, West Chester, OH, USA); intra- and interassay coefficients of variation were 1.8 and 5.5%, respectively. t-PA antigen was measured from platelet-poor plasma by ELISA (Asserachrom, Diagnostica Stago, Parsippany, NJ, USA); intra- and interassay coefficients of variation were 2.8 and 3.9%, respectively. Samples for plasma lipoprotein lipids were drawn, processed and stored using standard procedures. Total cholesterol and triglycerides (TG) were measured by standard enzymatic methods. Plasma HDL-C was analysed after precipitation of apolipoprotein B (ApoB)-containing lipoproteins with dextran sulphate-MgCl₂. Plasma low-density lipoprotein cholesterol (LDL-C) was calculated according to the Friedewald equation.

Body composition was analysed using dual energy X-ray absorptiometry (DPX-L, Lunar Corp., Madison, WI, USA) and L4–L5 visceral and subcutaneous adipose tissue areas were quantified using a standardized computerized tomography (CT) protocol (Nicklas et al. 1996). Maximum rate of O₂ uptake was measured during a graded treadmill protocol at the speed that elicited 70% of peak heart rate (Wilund et al. 2002). Oxygen uptake was measured throughout this test (Wilund et al. 2002). A true was considered to have been achieved if standard criteria were exceeded (Wilund et al. 2002).

Subjects performed three training sessions per week for 6 months (Wilund et al. 2002). Exercise duration and intensity were gradually increased until subjects performed 40 min of 70% exercise by week 9. At week 10 subjects added a moderate intensity exercise session during the weekend. Training intensity and frequency were then held constant for the remainder of the programme.

Subjects continued their training until all final tests were completed. Blood samples after training were drawn after a 12 h overnight fast and 24–36 h after a normal training session.

Data are presented as means ± S.E.M. Statistical significance was set at P 0.05. Student's paired t tests were employed to determine the effect of exercise training. Independent t tests were used to determine the significance of differences between the responses of men and women. Pearson correlation coefficients were used to assess the relationships between fibrinolytic and other variables. Stepwise multiple regression analyses were used to identify predictors for baseline and changes in fibrinolytic variables with exercise training.

	Results

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Baseline characteristics (Table 1)

The men and women in this study were generally overweight to obese, as indicated by their initial BMI values of 27.1 ± 0.9 and 29.1 ± 0.8 kg m^–2, respectively, with very few of them having initial BMI values in the normal range (< 25 kg m^–2). At baseline, there were no differences in age, fibrinolytic measures, BMI or CT intra-abdominal fat area between the 17 men and 28 women who comprised the final study population. However, there were baseline differences between men and women for body weight (P = 0.048), percentage body fat (P < 0.001), CT subcutaneous fat (P < 0.001), CT intra-abdominal to total CT fat ratio (P = 0.001) and (P < 0.001). There were no initial differences in LDL-C or TG between the men and women, but the women initially had higher total cholesterol (P = 0.023) and HDL-C levels (P = 0.001).

In men baseline PAI-1 activity correlated significantly, with some of the relationships being positive and others negative, with t-PA activity, t-PA antigen levels, HDL-C levels, BMI and percentage body fat, with t-PA antigen levels, and percentage body fat being significant in the multivariate regression model. Baseline t-PA activity in men correlated with PAI-1 activity, HDL-C levels, body weight, BMI, percentage body fat, CT intra-abdominal fat and CT subcutaneous fat, with all of the relationships except that with HDL-C being negative; however, only percentage body fat had a significant independent relationship in the multivariate analyses. t-PA antigen levels correlated significantly with PAI-1 activity, CT intra-abdominal fat and , with PAI-1 activity levels, and body weight having significant independent relationships in the multivariate analyses.

Changes with training (Table 1)

Both men and women demonstrated significant increases in following training. Men had significant reductions in body weight, BMI, percentage body fat, CT intra-abdominal fat and CT intra-abdominal to total CT abdominal fat ratio with exercise training. In addition, men had a significant increase in HDL-C levels, whereas no other significant changes in any lipoprotein lipids were evident after training. In women, training also significantly decreased body weight, BMI, percentage body fat, CT intra-abdominal fat and CT intra-abdominal to total CT abdominal fat ratio. Women also demonstrated a significant increase in HDL-C and a reduction in TG levels, with no changes in total cholesterol or LDL-C levels with training.

The differences in training-induced changes in PAI-1 activity between men and women were significant (P = 0.03), with men tending to show a decrease in PAI-1 activity with training (–2.6 ± 1.4 IU ml^–1) while women tended to show an increase in PAI-1 activity with training (+ 0.9 ± 0.9 IU ml^–1). Men and women both showed a significant decrease in t-PA antigen levels with exercise training, but the reduction in t-PA antigen levels was significantly greater in men compared to women (–1.6 ± 0.3 versus –0.5 ± 0.2 ng ml^–1, P = 0.007). The exercise training-induced increases in t-PA activity were not significantly different between men and women (+0.38 ± 0.12 versus +0.36 ± 0.24 U ml^–1, respectively).

Predictors of exercise training-induced fibrinolysis changes

In men, PAI-1 activity changes with exercise training were significantly correlated with the training-induced t-PA antigen level changes (r = 0.75, P < 0.01). In men, the changes in t-PA antigen levels and CT intra-abdominal to total CT fat ratio demonstrated significant independent relationships with PAI-1 activity changes in multivariate analyses. The exercise training-induced increase in t-PA activity in men was not significantly correlated with training-induced changes in aerobic capacity, body composition, lipoprotein lipid, or the other fibrinolytic measures. The training-induced decreases in t-PA antigen levels in men correlated significantly only with training-induced changes in PAI-1 activity (r = 0.75, P < 0.01), with changes in PAI-1 activity and CT intra-abdominal to total CT fat ratio having significant independent relationships in multiple regression models.

In women, PAI-1 activity changes with training were significantly and independently associated with the training-induced change in t-PA antigen levels (r = 0.65, P < 0.001). t-PA activity changes with training in women were not significantly associated with the training-induced changes in any fibrinolysis, body composition, plasma lipoprotein lipid or measures. In women, the decrease in t-PA antigen levels with exercise training was positively and independently correlated only with the training-induced changes in PAI-1 activity (r = 0.65, P < 0.001).

	Discussion

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We found that generally overweight to obese men and women respond to endurance exercise training with improvements in their fibrinolytic systems. However, some of the training-induced changes in fibrinolytic measures differed between men and women. With exercise training, men improved fibrinolysis by an increase t-PA activity to the same degree as women, a decrease in t-PA antigen levels to a greater degree than women, and a reduction in PAI-1 activity levels to a greater degree than women. Furthermore, in men but not in women, the training-induced decrease in CT intra-abdominal to total CT fat ratio was a positive predictor of changes in both PAI-1 activity and t-PA antigen levels after adjustment for changes in other fibrinolytic markers, lipoprotein lipid, CV fitness and other body composition measures.

The results of other studies are not consistent with regard to the effect of exercise training on the fibrinolytic system (Suzuki et al. 1992; Chandler et al. 1996; van den Burg et al. 1997; Vaisanen et al. 1999). It is difficult to draw a definitive overall conclusion relative to exercise training-induced changes in the fibrinolysis system because the exercise training protocols, the study designs and the fibrinolytic markers assessed in these studies vary markedly. Most of these previous studies assessed the effects of exercise training on fibrinolysis only in men (van den Burg et al. 1997; Vaisanen et al. 1999) or in combined groups of men and women (Suzuki et al. 1992). However, Chandler et al. (1996) reported that PAI-1 activity and t-PA antigen levels appear to decrease with exercise training in men while, with the same training, t-PA activity and t-PA antigen levels increased in women. Our study showed a significant increase in t-PA activity, a significant decrease in t-PA antigen levels and a tendency to decrease PAI-1 activity in the men, all of which are consistent with improved endogenous fibrinolysis profiles. However, while exercise training elicited the same increase in t-PA activity in men and women, women had a significantly smaller reduction in t-PA antigen levels than men, and less of a decrease in PAI-1 activity levels than men. These gender-specific differences in training-induced fibrinolytic responses occurred despite the fact that both men and women underwent an identical exercise training programme. Our findings that exercise training resulted in somewhat different improvements in the fibrinolytic system in men and women add substantially to the literature, since we had more than three times as many women as in the previous study that assessed the possibility that there might be gender differences in exercise training-induced fibrinolytic responses (Chandler et al. 1996).

Numerous metabolic and body composition factors may affect plasma fibrinolysis measures (Almer & Janzon, 1975; Vague et al. 1986, 1989; Landin et al. 1990; McGill et al. 1994; Calles-Escandon et al. 1996; Cigolini et al. 1996; Alessi et al. 1997; Janand-Delenne et al. 1998). Fibrinolysis markers have been associated with adiposity and various body fat distribution measures including BMI, waist-to-hip ratio and visceral fat (Vague et al. 1989; Cigolini et al. 1996; Janand-Delenne et al. 1998). Associations between fibrinolytic markers and levels of various plasma lipoprotein lipids have also been reported (Juhan-Vague et al. 1989; Sundell et al. 1989; Landin et al. 1990; Bard et al. 2001).

The primary predictors of the levels of fibrinolytic markers at baseline in our study were the other fibrinolytic markers. Beyond the fibrinolytic markers, selected measures of body composition were the next most significant predictors of levels of baseline fibrinolytic profiles. In men, factors associated with baseline fibrinolysis profile markers generally included significant or near-significant relationships with all measures of body composition, including body weight, BMI, percentage body fat, and CT-measured intra-abdominal and subcutaneous abdominal fat. In women, the only significant relationship was with CT-measured intra-abdominal fat. Furthermore, in men was significantly associated with baseline levels of t-PA antigen, whereas no such relationship was evident in women. Finally, plasma lipoprotein lipid levels were associated with baseline levels of fibrinolytic markers in both men and women; however, the relationships were with total cholesterol levels in women and with HDL-C in men.

Improved endogenous fibrinolysis, particularly reduced PAI-1 activity levels, occurs with weight loss in overweight to obese individuals (Folsom et al. 1993; Calles-Escandon et al. 1996). An average body weight reduction of 9.4 kg in men and 7.4 kg in women produced 31 and 24% reductions in PAI-1 and t-PA antigen levels, respectively (Folsom et al. 1993). Previous studies suggest that subcutaneous fat is not responsible for changes in circulating PAI-1 with hypocaloric diet-induced weight loss, since subcutaneous adipose tissue expression of PAI-1 increased while a decrease in circulating PAI-1 levels was observed (Bastard et al. 2000). In contrast, Janand-Delenne et al. (1998) reported that the reduction in visceral fat induced by weight loss correlated with the decrease in PAI-1 levels in women.

Our study was designed to control changes in body weight in our subject population of generally overweight to obese individuals, with men and women showing only minimal, albeit statistically significant, decreases in body weight (2.0 and 1.4 kg, respectively) with exercise training. Accordingly, we observed reductions in BMI, total body fat and CT-measured intra-abdominal fat in both gender groups with exercise training. Of all these measures, changes in the ratio of CT intra-abdominal to total abdominal fat independently predicted changes in fibrinolysis in men, but not in women. These results suggest that the differential changes in fibrinolysis with exercise training between men and women may involve gender-specific changes in body composition despite the limited weight loss.

Plasma lipoprotein lipid levels were associated with baseline levels of fibrinolytic measures in both men and women. It is possible that changes in fibrinolysis associated with weight loss may be mediated by an improvement in plasma lipoprotein lipid profiles. Changes in TG levels resulting from a hypocaloric diet-induced 9 kg weight loss were strongly correlated with changes in PAI-1 levels (Calles-Escandon et al. 1996). However, changes in fibrinolysis markers were not associated with exercise training-induced changes in plasma lipoprotein lipid levels in our men and women. This suggests that our improvements in fibrinolysis profiles with exercise training were probably not mediated by alterations in plasma lipoprotein lipids.

In conclusion, both older men and women, who were generally overweight to obese, showed improvements in fibrinolysis with exercise training. However, the training-induced fibrinolytic improvements were gender specific. Fibrinolysis was improved in men by an increase in t-PA activity to the same extent as in women, but by a decrease in t-PA antigen levels to a greater extent than in women and a decrease in PAI-1 activity more than in women. The primary predictors of the exercise training-induced changes in these fibrinolytic markers in both men and women were the changes in the other fibrinolytic markers, though changes in body composition with training were predictors of training-induced fibrinolytic improvements in men but not women. Thus, endurance exercise training-mediated improvements in markers of endogenous fibrinolysis are more beneficial in overweight to obese men than women, and the alterations in fibrinolysis profiles of men are specifically related to a reduction in central abdominal obesity.

	References

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	Acknowledgements

 
J.M.H. and D.A.P. were supported by NIH grants AG15389 and AG17474. A.P.G. and R.F.M. were supported by the Department of Veterans Affairs Medical Research Service, the Baltimore VA Geriatric Research, Education, and Clinical Center, and the University of Maryland Claude D. Pepper Older Americans Independence Center (P60 AG12583).

This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/881    most recent expphysiol.2005.030718v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kulaputana, O. Articles by Hagberg, J. M Search for Related Content PubMed PubMed Citation Articles by Kulaputana, O. Articles by Hagberg, J. M