The fibrinolytic system plays a central role in regulating the formation and removal of thrombi. Recent studies have reported that reduced fibrinolytic activity is associated with an increased risk of myocardial infarction and stroke (8,17,30). The incidence of unstable angina, myocardial infarction, stroke, and sudden cardiac death follow a circadian rhythm with a peak for all four in the morning(25). The fibrinolytic system also has a prominent circadian rhythm, with the lowest level of activity and the least ability to limit thrombus formation in the morning coinciding with the peak in thrombotic heart disease (1). This morning trough in fibrinolysis is a result of decreased levels of active tissue plasminogen activator (t-PA) due to increased inhibition of t-PA by plasminogen activator inhibitor 1 (PAI-1)(4).
Regular physical exercise is associated with a decreased risk of cardiovascular disease, and has been recommended as a method to reduce cardiovascular risk (3,28). While exercise produces potentially beneficial changes in blood pressure, insulin resistance and lipid profiles, much of the protective effect of fitness is due to as yet unknown mechanisms. Since the final common pathway for most forms of cardiovascular disease is acute arterial thrombosis, part of the protective effect of exercise may be through reducing the risk of thrombus formation.
A number of studies have suggested that endurance training increases resting fibrinolytic activity in blood, and that this increase in fibrinolysis may account for some of the as yet unexplained beneficial effects of endurance training on thrombotic cardiovascular disease(12,16,27,31,33-35). Other, mostly older, studies reported no change or a decrease in resting fibrinolytic activity after endurance training(11,13,14,19,24,29,37). Coming to a general conclusion as to the effect of endurance training on the circadian rhythm of fibrinolysis was difficult, as prior studies suffered from a number of limitations including: measurement of fibrinolytic factors at only one time during the day, study of only men or no separation of male and female data, use of nonspecific assays to determine plasminogen activator activity such as the euglobulin lysis time, training times of only 4-6 wk, and retrospective comparisons of exercising versus sedentary groups or evaluation of an exercise group only without nontrained controls.
The purpose of this study was to determine the effect of endurance training on the circadian rhythm of fibrinolysis in older men and women. Our study was designed to eliminate problems found in prior studies by prospectively evaluating both men and women, measuring fibrinolytic activity every 2 h from 8 p.m. to 8 a.m., using modern, specific assays to measure the changes in t-PA activity (6), total t-PA antigen(18), and PAI-1 activity (7,9), and prospectively evaluating subjects randomly assigned to 6 months of either an endurance training or stretching control group.
MATERIALS AND METHODS
Studies on human subjects were carried out according to the principles of the Declaration of Helsinki and the policies of the American College of Sports Medicine. Informed consent was obtained from all participants and the study was approved by the University of Washington Human Subjects Review Committee.
All subjects were in good health: entry criteria included no history of angina, myocardial infarction, stroke, chronic pulmonary disease, diabetes, hypertension, exercise-limiting orthopedic impairment, psychiatric illness, or sleep disorders. Entry laboratory requirements included a normal hematocrit, fasting blood glucose, total cholesterol, triglycerides, and resting and treadmill exercise electrocardiogram. After screening, a total of 53 subjects were initially enrolled in the study (32 male, 21 female) and randomly assigned to an endurance training group (17 males, 11 females) or stretching control group (15 males, 10 females). Of this total, 9 subjects were removed during the study: 2 males (controls) and 3 females (2 endurance, 1 control) due to difficulty obtaining adequate blood samples during the second circadian study; 2 males (1 endurance, 1 control) were removed when they were found to have an elevated C-reactive protein during one of the circadian studies(indicating an acute-phase response); 1 male (control) was removed when he developed sleep apnea during the circadian study; and 1 female (control) failed to complete the training program.
The final study group consisted of 27 males and 17 females ages 60 to 79(mean 66 ± 5 yr). The only medications used were aspirin and estrogen replacement in a small number of subjects. Overall, four subjects were taking on average 160 mg of aspirin per day (1 male endurance, 2 male controls, 1 female endurance), and 5 were taking on average at least 320 mg of aspirin per day (2 male controls, 3 female controls). Aspirin was usually taken in the morning. Estrogen supplementation was being taken by two women in the endurance group and by four women in the control group. For subjects using aspirin or estrogen, the same dosage and schedule used prior to starting the program was maintained during the training and circadian studies. All subjects in the final study groups had C-reactive protein levels less than 11 mg·1-1 at the time of each circadian study, indicating there was no evidence of an acute-phase response that might transiently change PAI-1 and t-PA levels.
Human glu-plasminogen and one-chain melanoma-derived t-PA (512 U·μg-1) were obtained from American Diagnostica Inc.(Greenwich, CO). Human fibrinogen, cyanogen bromide (CNBr), and Triton-X-100 were obtained from Sigma Chemical Co. (St. Louis, MO). CNBr-cleaved human fibrinogen fragments were prepared as previously described(6). Enzyme-linked immunosorbent assay (ELISA) kits for measuring human t-PA/PAI-1 complex and total t-PA antigen were obtained from American Bioproducts Inc. (Parsippany, NJ). Chromogenic substrate d-valyl-phenylalanyl-lysyl-p-nitro-analide (S-2390) was obtained from Kabi Pharmacia Inc. (Franklin, OH). All other materials not described below were reagent or analytical grade.
Subjects were initially screened using a standard Bruce treadmill exercise test with 12-lead electrocardiogram. Subjects had previously been introduced to this test by walking on the treadmill. Thereafter, maximal aerobic power(˙VO2max) was determined by indirect calorimetry using a branching protocol as previously described (32). ˙VO2max was again determined at the completion of the 6-month training period.
Endurance Training and Circadian Sampling Protocol
In the exercise group, 16 males and 9 females participated in 6 months of supervised endurance training 3 times per week. Endurance training sessions lasted 90 min, beginning with stretching and a 10-min warm-up period, and ending with a 10-min cool-down period. The subjects began walk/jog/bike endurance training for 30 to 45 min at 50 to 60% of their heart rate reserve, as calculated from their maximal exercise test. Subjects were gradually increased (at two weekly intervals) to exercising for 45 min at 85% of heart rate reserve. All subjects reached this final level of exercise intensity by the 4th month of the training program. Pulse rates were continually monitored electronically at each session during the entire endurance training program.
The control group consisted of 11 males and 8 females who performed supervised relaxation, slow stretching, and flexibility exercises 3 times per week, 90 min per session, for 6 months. Stretches were similar to those done by the exercise group, but done slowly to minimize any aerobic training effect.
Before and at the end of training, subjects were placed on a 2-wk constant composition diet to stabilize their weight. During this period all meals were prepared by a research dietitian. Subjects spent a total of three nights at the University of Washington Clinical Research Center from 7 p.m. to their usual awakening time. Subjects followed their normal daily routine, but did not exercise during this assessment period. Blood samples for fibrinolytic studies were collected 72 h after the last training session. On the third night an intravenous line was started in a forearm vein. Ringer's solution was slowly infused in the line to keep it open. Prior to drawing samples for fibrinolytic analysis, the intravenous line was flushed by drawing 10 ml of blood through it. Blood samples were remotely drawn every 2 h from 8 p.m. to 8 a.m. without disturbing the subject. Prior studies have shown that intravenous lines do not alter the level of fibrinolytic factors measured in blood(1,5,15).
Blood for fibrinolytic studies was anticoagulated by the addition of 4.5 ml whole blood to 0.5 ml of 130 mmol·l-1 sodium citrate. To stabilize t-PA activity, 0.5 ml of citrate-anticoagulated whole blood was mixed with 0.25 ml of 0.5 mol·l-1 sodium acetate, pH 4.2, within 1 min after each sample was drawn (6). All samples were centrifuged for 10 min at 2500 × g at room temperature. Plasma and acidified plasma were then removed and frozen at -70°C until analyzed.
t-PA activity was measured in acidified plasma using an amidolytic method as previously described (6). Total t-PA antigen was measured in citrated plasma using an ELISA method(18).
PAI-1 activity was measured in citrated plasma as previously described(7,9,34). In this assay active PAI-1 in plasma was converted into t-PA/PAI-1 complexes by addition of excess active one-chain t-PA (final concentration 50 U·ml-1) followed by incubation for 20 min at 37°C. The concentration of t-PA/PAI-1 complex was measured in the plasma before and after the addition of excess t-PA using an ELISA method(9). PAI-1 activity in the sample was equal to the difference in t-PA/PAI-1 complex before versus after addition of excess active t-PA. Active PAI-1 levels in μg·l-1 were converted to activity units using a specific activity for PAI-1 of 900 U·μg-1 (7).
Group distributions are presented as the mean ± standard error of the mean (SEM), unless otherwise noted. The probability of significant differences in fibrinolytic variables at different times during the day was determined using repeated measures analysis of variance (ANOVA) followed bypost-hoc analysis using the Tukey HSD test. The probability of significant interactions among different factors in the study was determined using between-group ANOVA.
Training-induced changes in fibrinolytic variables were evaluated in two ways. First we determined the average level of each factor over the 12-h study period (Tables 1 and 2). The paired two-tailedt-test was used to compare these average values before, versus after, training. Second, we determined whether the circadian rhythm of the factor changed, including whether changes occurred in the overall rhythm for the 12-h period; which portions of the rhythm showed the largest changes, and whether changes were significant during only a limited portion of the rhythm. Statistica/Mac™ software (Stat-Soft™, Tulsa, OK) was used for all statistical calculations.
The endurance and stretching control groups were well matched prior to starting the training sessions (Table 1). There were no significant differences in age, ˙VO2max, weight, PAI-1 activity, t-PA activity, or total t-PA antigen between the endurance training versus stretching control groups of either healthy older men or healthy older women.
There was no significant difference in the average age of the older men versus older women. ˙VO2max was 39% higher (P < 0.0001) and weight 14% higher (P < 0.003) in older men as compared with older women prior to training. PAI-1 activity, t-PA activity, and total t-PA antigen all had significant circadian variations(Fig. 1) in older men and older women (ANOVA P< 0.000001). At baseline, older men and older women had similar circadian rhythms for PAI-1 activity and t-PA activity, but different rhythms for total t-PA antigen (ANOVA P < 0.003). PAI-1 activity was lowest between 8 p.m. and 10 p.m., rising rapidly to a peak from 4 a.m. to 8 a.m.(P < 0.0001) that was on average 6-fold higher than at 10 p.m. It should be noted that PAI-1 activity showed the greatest variation among subjects of all the factors studied. At 8 a.m. PAI-1 activity ranged from a low of 1.1 U·ml-1 to a high of 54.7 U·ml-1.
t-PA activity peaked at 8 p.m., falling significantly through the night to a nadir at 6 a.m. (P < 0.0001), then rising again at 8 a.m. In older men, total t-PA antigen levels did not significantly change from 8 p.m. to 4 a.m., then rose to a peak at 8 a.m. (P < 0.0002). In older women, total t-PA antigen fell significantly from 8 p.m. to 10 p.m.(P < 0.003), did not change significantly between 10 p.m. and 6 a.m., then rose again at 8 a.m. (P < 0.01). Total t-PA antigen levels were significantly lower in older women than older men from midnight to 6 a.m. (P < 0.01). Prior to training, total t-PA antigen levels were on average 20% lower in older women compared with older men.
Changes in Maximum Oxygen Uptake and Weight
As shown in Table 1, ˙VO2max significantly increased in both older men (average 15%) and older women (average 18%) after 6 months of endurance training, indicating a substantial training effect had occurred. There was no significant difference in the average change in˙VO2max for older men versus women. While the average˙VO2max increased after endurance training, not all subjects in the endurance groups demonstrated significant increases. In the older male endurance group, 12 of 16 subjects increased their ˙VO2max by more than 2 ml·kg-1·min-1 after 6 months of endurance training. In the older female endurance group, 7 of 9 increased˙VO2max by more that 2 ml·kg-1·min-1. No change in ˙VO2max was observed for either older men or older women in the stretching control group.
In the endurance group, 11 of 16 older men lost weight (average of 2.6 kg) during the training program, while 6 of 9 older women lost weight (average of 3.3 kg). In the endurance subgroups showing an increase in ˙VO2max greater than 2 ml·kg-1·min-1, 10 of 12 older males lost weight (average of 2.6 kg), while 5 of 7 older women lost weight (average of 3.9 kg). The overall weight decrease was significant for the older male endurance group, but did not reach statistical significance in the older women. There was no change in weight for older men or older women in the stretching control group.
Changes in Fibrinolytic Variables
Endurance training altered the average levels and circadian curves of each fibrinolytic factor to different extents and at different times. Changes were often significant during only a limited portion of the circadian period studied (Fig. 2). In older men, endurance training had no effect on average PAI-1 activity from 8 p.m. to 8 a.m. (P = 0.056,Table 1), but did significantly reduce PAI-1 activity(P = 0.023) between 8 p.m. and 6 a.m. The biggest change to the circadian rhythm of PAI-1 activity in older men was a 37% decrease between midnight and 6 a.m. (P = 0.034). Changes in PAI-1 activity were more dramatic in the subset of older men showing a greater than 2 ml·kg-1·min-1 increase in ˙VO2max; this group had a 51% decrease in average PAI-1 activity (P = 0.015,Table 2).
While endurance training in older men had no effect on the average level or circadian rhythm of t-PA activity, it reduced average total t-PA antigen levels 11% overall, and 15% in men, showing a greater than 2 ml·kg-1·min-1 increase in ˙VO2max. As with PAI-1 activity, the largest change in the circadian rhythm of total t-PA antigen in older men occurred between midnight and 6 a.m. (18% decrease,P = 0.0003).
In older women (Fig. 3) endurance training had no effect on the average level or circadian rhythm of PAI-1 activity and had no effect on the average level t-PA activity, but did significantly increase t-PA activity between 8 p.m. and 4 a.m. (P = 0.017). The biggest change to the circadian rhythm of t-PA activity in older women was a 20% increase between 10 p.m. and 4 a.m. (P = 0.027). Endurance training in older women increased average total t-PA antigen 28% in the entire group, and 53% in women, showing a greater than 2 ml·kg-1·min-1 increase in ˙VO2max, with the major changes to the circadian rhythm of total t-PA antigen occurring between 10 p.m. and 4 a.m. (55% increase,P = 0.007).
After 6 months of endurance training, there were no significant differences in the average levels or circadian rhythms of PAI-1 activity, t-PA activity, or total t-PA antigen in older men versus older women.
The older male control group showed no change in the average level or circadian rhythm of PAI-1 activity or total t-PA antigen after 6 months of stretching, but did show a 12% decrease in average t-PA activity. The decrease in t-PA activity occurred primarily at 8 p.m. and 8 a.m. (P < 0.02) with no change between 10 p.m. and 6 a.m.
The older female control group showed no change in the average level or circadian rhythm of PAI-1 activity, t-PA activity, or total t-PA antigen after 6 months of stretching.
Aspirin and Estrogen Use
Aspirin use was not associated with changes in the baseline levels of any of the fibrinolytic factors tested either in older men or older women. Analysis of variance indicated there were no significant interactions between aspirin use and the effects of training (exercise or stretching).
The number of older women taking estrogen replacement was not significantly different (chi-squared test) in the exercise versus control groups. Estrogen use was not associated with changes in the baseline levels of any of the fibrinolytic factors tested. Analysis of variance indicated there were no significant interactions between estrogen replacement and the effects of training (exercise or stretching).
Reduced plasminogen activator activity is associated with an increased risk of thrombotic cardiovascular disease(8,17,30). Endurance training may reduce the risk of thrombotic heart disease in part by enhancing fibrinolytic activity(12,16,27,31,33-35). All prior studies of endurance training evaluated fibrinolysis at only one time during the day. In contrast, we evaluated the plasminogen activator system from 8 p.m. to 8 a.m. Evaluating the effect of endurance training on the circadian rhythm of the plasminogen activator system was important for two reasons. Plasminogen activator activity in blood appears to be linked to both short-term and long-term patterns of thrombotic cardiovascular disease risk. Depressed plasminogen activator activity, as indicated by reduced t-PA activity, increased PAI-1 activity, and elevated total t-PA antigen, is associated with an increased long-term risk of arterial thrombosis(8,17,30). Over the short term, both the incidence of thrombotic cardiovascular disease and the plasminogen activator system follow circadian rhythms with the peak in thrombosis and nadir in plasminogen activator activity occurring in the morning(1,2,5).
While it is likely that the short-term circadian patterns influence long-term risk, they are probably not identical. It may be important to know both the average level of fibrinolytic activity in blood as well as the nadir level in the morning in determining overall risk. For example, in a prior study we found that some individuals have no apparent circadian rhythm for PAI-1 activity, while others show up to a 10-fold variation in PAI-1 activity over 24 h (2). Thus, an individual with a constant level of 50 U·ml-1 of PAI-1 activity throughout the day may be at greater long-term risk than an individual with a peak level of 50 U·ml-1 PAI-1 activity at 6 a.m. that falls to 5 U·ml-1 at 6 p.m. (average level approximately 28 U·ml-1), even though both individuals may have a similar risk of thrombosis in the morning.
We chose to study the period from 8 p.m. to 8 a.m. for three reasons: 1) it is the period when the risk of thrombotic cardiovascular disease rises from a nadir to its peak; 2) it is the period of the major changes in the fibrinolytic system; and 3) due to roughly sinusoidal nature of the fibrinolytic rhythm (5), it provides a good estimate of the overall or average level of fibrinolytic factors. At baseline prior to training we found that older men and women had similar rhythms for PAI-1 activity and t-PA activity, but that women had a different rhythm (P< 0.003) and a lower average level of total t-PA antigen. Lower levels of t-PA have also been reported in younger women compared with younger men(36).
Endurance training enhanced plasminogen activators primarily during the early morning hours in older men and women. After 6 months of endurance training, older men showed an increase in ˙VO2max, a decrease in weight, and a significant decrease in both PAI-1 activity and total t-PA antigen between the hours of midnight and 6 a.m., but no change in t-PA activity. These results were supported by our previous work, which showed reductions in morning PAI-1 activity (58%) and total t-PA antigen (39%) after endurance training in older men (34).
In older women, endurance training produced an increase in˙VO2max, no change in weight or PAI-1 activity, and a significant increase in both t-PA activity and total t-PA antigen between the hours of 10 p.m. and 4 a.m. Changes in both older men and women were greatest when the endurance training was successful, that is, in subjects with an increase in˙VO2max greater than 2 ml·kg-1·min-1 and a decrease in body weight. After 6 months of endurance training there were no significant differences in the amplitude or rhythm of PAI-1 activity, t-PA activity, or total t-PA antigen in older men versus older women. The control group that did nonaerobic stretching for 6 months showed essentially no change in ˙VO2max, weight, or the circadian rhythm of fibrinolysis. We conclude that endurance training enhanced the fibrinolytic system of both older men and older women. To understand how these changes might be potentially beneficial we need to review how fibrinolysis is regulated.
Fibrinolysis is initiated by active t-PA binding to the fibrin surface of a thrombus and activating plasminogen to plasmin. t-PA exists in two forms in plasma, active t-PA and t-PA complexed to PAI-1 and other inhibitors. The t-PA activity assay measures functional t-PA, while the total t-PA antigen assay measures active plus complexed t-PA. As PAI-1 activity rises in plasma, more t-PA is inhibited and the ratio of active to complexed t-PA falls. Prior studies have also shown that as PAI-1 activity increases, the total amount of t-PA in the blood also rises (7). The mechanism of this parallel increase in PAI-1 activity and total t-PA antigen is unknown. In resting samples, high PAI-1 activity is associated with high total t-PA antigen but low t-PA activity. In theory, then, plasminogen activator activity might be increased in plasma by either decreasing PAI-1 secretion or increasing t-PA secretion.
Endurance training enhanced plasminogen activator activity in both older men and women. In older men endurance training modified at least two of the three fibrinolytic alterations associated with thrombotic cardiovascular disease, reducing both morning PAI-1 activity and total t-PA antigen levels. This was most likely due to a decrease in PAI-1 secretion. In older women endurance training increased morning t-PA activity and total t-PA levels. This was most likely due to an increase in t-PA secretion. The final outcome was that the fibrinolytic systems of older men and women were essentially the same after endurance training.
The underlying cause of endurance training-induced changes in the resting fibrinolytic system is unknown. Juhan-Vague and others have shown that insulin resistance, obesity, and elevated triglyceride levels are associated with elevated levels of PAI-1 activity (21). Reductions in weight, reduced triglyceride levels, and increased insulin sensitivity have been associated with reductions in PAI-1 activity. In this study we found endurance training resulted in reduced weight in 11 of 16 older men and 6 of 9 older women. Prior studies from our group found that similar endurance training programs in older men resulted in an average 2.5 kg reduction in weight, 21% decrease in plasma triglyceride, 21% decrease in fasting insulin, and 36% increase in insulin sensitivity (22,32). It is possible that endurance training induced changes in the fibrinolytic system are linked to changes in the insulin and lipid regulation systems.
Modifying known fibrinolytic risk factors could be one mechanism whereby endurance training reduces cardiovascular risk. This study was not designed to determine whether endurance training-induced fibrinolytic changes were associated with a reduced incidence of thrombotic cardiovascular disease. That would require a much larger study. At best we can determine whether the fibrinolytic changes moved in a direction predicted to reduced heart disease risk.
It should be noted that the fibrinolytic changes in this study relate only to older men and older women. Studies on the effect of endurance training in young men and women indicate that the initial level of fitness may determine the response. Young men and women specifically selected for a sedentary lifestyle showed decreased PAI-1 activity after endurance training(16,27) while a more fit group did not, even though the latter group significantly increased their ˙VO2max (34). Our prior study indicated that older men tend to be less aerobically fit than young men at the start, and therefore may be more likely to show a change in fibrinolytic parameters with endurance training(34).
Two possible confounding factors in the study were the use of aspirin and estrogen in a small number of subjects. The dose of aspirin or estrogen was maintained at the same level before, during, and after the training period. Low-dose aspirin (average 160 mg or less per day) has no effect on the resting, post-venous occlusion, or post-exercise fibrinolytic system(10,23,26,38). Higher doses of aspirin(average 320 mg or more per day) reduce plasma t-PA levels 20 to 30% both at rest and after stimulation of t-PA release. In this study, endurance-trained subjects were either taking no aspirin or a low dose, and as expected there was no association between aspirin use and fibrinolytic activity before or after training. A small number of controls were taking higher doses of aspirin throughout the study, but the control groups as a whole showed no change in fibrinolytic parameters during the study, and there was no association between aspirin use and fibrinolysis in the controls. Estrogen use has been reported to decrease PAI-1 and t-PA levels (20). A small number of women in both the control and endurance training groups were taking estrogen supplementation during the study. There were no differences in the baseline or post-training levels of fibrinolytic factors in the groups taking estrogen versus those that were not. Thus, it is unlikely that aspirin or estrogen use during the study had significant effects on the final results.
While the changes in fibrinolytic factors after endurance training moved in the direction of improved fibrinolytic activation and away from the levels associated with increased cardiovascular risk in men, our data do not indicate these changes are protective in themselves. Thrombus formation is a complex interaction of platelets, coagulation factors, fibrinolysis, and the vessel wall. Little is known about the effect of endurance training on platelets or prothrombotic factors. Changes in other hemostatic factors may be more important either in improving cardiovascular risk or in offsetting the pro-fibrinolytic effects seen here. Determining which factors truly effect cardiovascular risk requires a much larger prospective study of endurance training, fibrinolysis, and thrombotic coronary artery disease. This study points out the importance of studying fibrinolytic changes in both men and women, the evaluation of changes to the circadian rhythm, and in the need to use modern specific assays in evaluating fibrinolysis, rather than older global assays.
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Keywords:©1996The American College of Sports Medicine
EXERCISE; TISSUE PLASMINOGEN ACTIVATOR