© 1995 American Heart Association, Inc.
Articles |
Effects of Exercise Training and Deconditioning on Platelet Function in Men
From the Department of Physiology, National Cheng-Kung University Medical College, Tainan, Taiwan, ROC.
Correspondence to Professor Hsiun-ing Chen, PhD, Department of Physiology, National Cheng-Kung University Medical College, Tainan, Taiwan 701, Republic of China. E-mail hichen@mail.ncku.edu.tw.
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Abstract Platelets play an important role in the pathogenesis of cardiovascular disease. It has also been noticed that regular exercise can reduce the risk of cardiovascular disease. This is the first study to demonstrate that endurance exercise training may suppress platelet adhesiveness and aggregation and that deconditioning may reverse the training effects. Healthy male sedentary subjects were randomly divided into control and training groups. The trained men were trained on a bicycle ergometer at about 60% of maximal oxygen consumption for 30 minutes per day, 5 days per week for 8 weeks, then deconditioned for 12 weeks. During the experimental period, blood samples of the trained subjects were collected before and immediately after a progressive exercise test every 4 weeks. The same experiments were applied to the controls at the beginning of this study and 8 weeks thereafter. A tapered parallel-plate chamber was used to assess platelet adhesiveness. Platelet aggregation induced by ADP was evaluated by the percentage of reduction in single platelet count. Our results showed that (1) platelet adhesiveness and aggregability were increased by short-term strenuous exercise in both control and trained groups, but the enhancement of platelet aggregability was decreased after exercise training in the trained subjects; (2) at rest and immediately after strenuous exercise, platelet adhesiveness and aggregability were decreased by training, whereas they were unchanged in the control group; and (3) deconditioning reversed the training effects on resting and postexercise platelet adhesiveness and aggregability back to the pretraining state. These results suggest that platelet adhesiveness and aggregability may be depressed by exercise training but be reversed back to the pretraining state after deconditioning.
Key Words: long-term exercise • deconditioning • platelets
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Introduction |
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Pathological and clinical studies have indicated that platelets play an important role in the pathogenesis and progression of cardiovascular diseases.1 2 3 A prospective study has also suggested that there is a relation between blood platelet concentration and aggregability and long-term incidence of fatal coronary heart disease in apparently healthy men.4 Furthermore, antiplatelet agents have been shown to reduce the incidence of cardiovascular ischemic events in some therapeutic trials.5 6 Epidemiological studies have suggested that regular exercise seems to play an important role in the prevention and treatment of several cardiovascular diseases.7 8 9 An animal study also showed that regular exercise may reduce the tendency toward thrombosis induced by laser injury of the blood vessels.10
Previous studies have suggested that the risk of primary cardiac arrest
is transiently increased during vigorous exercise, whereas habitual
physical exercise is associated with an overall decreased risk of
primary cardiac arrest.11 12 Therefore, it is important to
distinguish physiological events that occur between
short-term bouts of exercise and physical conditioning. Our
previous study suggested that platelet adhesiveness and
aggregability but not release may be sensitized by short-term
strenuous exercise and may be suppressed by short-term moderate
exercise and that the effects of short-term exercise tend to be
more pronounced in sedentary men than in active men.13
However, the exercise training effects on platelet adhesiveness
have not been studied yet. Moreover, the training effects on
platelet aggregation are either controversial or
incomplete,14 15 16 and deconditioning effects on
platelet function have not been studied. To answer these questions,
we conducted this study to clarify the effects of
moderate-intensity exercise training (about 60%
O2max) and deconditioning
on various platelet functions in healthy men. To specifically
assess platelet adhesiveness in vitro, a tapered parallel-plate
chamber (ie, linear shear-stress flow chamber), which provided a
range of shear stress covering the entire
physiological range in human circulation, was
used.13 The ADP-induced disappearance of single
platelets in PRP due to aggregation was used as an index for the in
vitro assay of platelet aggregability.
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Methods |
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Subjects, Exercise Training, and Deconditioning
The protocol had been previously reviewed and approved by an institutional committee for the protection of human subjects. The procedures followed were in accordance with institutional guidelines. Twenty-three young and healthy men were studied after they had given their informed consent and understood the experimental procedures. These subjects were randomly divided into control (n=12) and training (n=11) groups. There were no significant differences in their anthropometric data: age, 21.7±0.6 versus 21.0±0.7 years; height, 170.4±1.5 versus 170.6±1.4 cm; and weight, 65.4±2.4 versus 69.5±3.8 kg for the control and training groups, respectively. None of these subjects were engaged in any regular physical activity for at least 1 year before the study. To prevent the confounding effect of smoking,17 all of the subjects were nonsmokers. They did not take any medication for at least 2 weeks before the first progressive exercise test and continued to abstain from any medication throughout the training-deconditioning program. Before the actual study, subjects were familiarized with exercise on a bicycle ergometer (Corival 400) to eliminate the novel effects of a new experience. They completed the medical history form and a physical activity questionnaire. The subjects in the training group then came to our laboratory to receive an exercise training program for 8 weeks; the controls were not trained during the experimental period.
The men in the training group were trained on a bicycle ergometer for
30 minutes per day, 5 days per week for 8 weeks, followed by 12 weeks
of deconditioning. The training intensity was adjusted to about 60% of
O2max.
Exercise Test and Blood Collection
At the beginning, a progressive exercise test was performed in
each subject. During the experimental period, exercise tests were
repeated every 4 weeks in the training group until the end of
deconditioning. In contrast, the control group received two progressive
exercise tests, at the beginning and 8 weeks later. All subjects
arrived at 1:30 PM to perform the exercise tests to avoid
possible diurnal influence as mentioned in a previous
study.18 To avoid the short-term effects of exercise,
the training group performed a progressive exercise test 48 hours after
exercise training. After the subject had arrived at the laboratory and
rested for 30 minutes, blood samples were drawn from a forearm vein for
baseline data on platelet function. The first 2 mL was discarded;
then the remaining blood sample was used for the measurement of
platelet function. Immediately after the progressive exercise test,
another blood sample was collected for the measurement of postexercise
platelet function.
Exercise tests began at 3 PM. The exercise protocol
consisted of 2 minutes of unloaded pedaling, followed by a continuous
increment of work load, 15 to 30 W every 3 minutes, until exhaustion.
During exercise, the electrocardiogram was continuously
monitored by a Gould ECG/Biotach, recorded on a four-channel
polygraph (Gould 2400S portable ink recorder), and converted to a
digital display of the HR (Gould digital display). Resting blood
pressure was monitored with a sphygmomanometer (Nitirin). The subject
breathed through a large two-way valve (Hans Rudolph) into a 5-L
mixing chamber. The fractional concentrations of O2 and
CO2 in the mixed expired gas were continuously measured by
an oxygen analyzer (Ametek S3A/1, Applied Electrochemistry) and
a CO2 analyzer (SensorMedics LB-2). In addition,
the inspiratory airflow was monitored by a pneumotachometer (Hans
Rudolph), and the signal was passed to a carrier amplifier (Gould).
Then, the airflow signal was electronically integrated to measure tidal
volume by an integrator (Gould). Therefore, the data of HR,
I, O2, and
CO2 for every minute were obtained
during the resting and the exercise periods as described
previously.19
Platelet Adhesion
A tapered parallel-plate chamber, which provided
shear-stress values covering the entire
physiological range in human circulation, was used
to assess platelet adhesiveness as described in a previous
study.13 The linear shear-stress flow chamber
consisted of four components: a stainless steel cover plate, a glass
slide plate, a PTFE gasket, and a plastic distributor. The glass slide
was coated with 3 mg/dL human fibrinogen (Kabi). After the chamber had
been assembled, it was then placed on the stage of an inverted
microscope equipped with a CCD video camera (Hamamazu). The inlet of
the chamber was connected to a perfusion system. PRP was gently infused
into the chamber and kept there for 12 minutes to allow platelet
settlement on the fibrinogen-coated surface. The flow chamber was
then flushed with Tyrode's-HEPES buffer (NaCl, 0.128 mol/L, and
[mmol/L] KCl 2.7, MgCl2 0.5, CaCl2 2,
NaH2PO4 0.36, NaHCO3 12, HEPES 10;
pH 7.4) for 5 minutes at a flow rate of 0.027 mL/s, which provided the
range of shear stress from 55 to 0 dyne/cm2. This flow
chamber can generate a linear shear field with a constant
shear-stress gradient over the entire length of the chamber. Ten
field locations along the center line were observed at intervals of 5
mm from the downstream end with approximately zero shear stress, and
the number of remaining platelets per 0.16 mm2 was
counted at each location. Theoretically, no platelet could be
flushed away from the surface at the outlet apex of the flow channel,
where the local shear stress is zero. Therefore, the platelet
density extrapolated to this apex region was considered to be 100% and
was used as the denominator for obtaining the percentage of remaining
adherent platelets at various locations. A simple linear regression
line for adhered platelets, indicated as percentage of attached
platelets at the outlet, at various shear-stress fields was
obtained. The slope of attached platelet percentage versus shear
stress was used as an index of platelet adhesiveness (ie, the less
negative the slope, the greater the platelet adhesiveness).
Platelet Aggregation
Platelet aggregation induced by ADP was evaluated by the
percentage of reduction in single platelet count as described in a
previous study.13 Blood samples (20 mL) were transferred
into polypropylene tubes containing sodium citrate (3.8 g/dL, 1 vol for
9 vol of blood). PRP was prepared by centrifugation at
120g for 10 minutes at room temperature.
Platelet-poor plasma was obtained after
recentrifugation at 1600g for 10
minutes. The kinetics of platelet aggregation in PRP was measured
with a platelet aggregometer (Hema Tracer 2, NKK) after addition of
various concentrations of ADP (Sigma) (ie, 0.125, 0.25, 0.5, 1, 2, and
4 µmol/L in final concentration). After the sample optic density had
reached a steady value for at least 1 minute, the test tube was then
removed from the aggregometer and kept at rest for 90 minutes, allowing
the sedimentation of platelet aggregates. Plasma (40 µL) was
removed from the upper suspension of the PRP for single platelet
counting. Our preliminary study showed that once these ADP-induced
platelet aggregates fell to the bottom of the tube, mostly within
30 minutes, sedimented platelets could no longer float to the upper
layer without mixing. What remained in the upper layer was single
platelets, as had been verified by light microscopy. After
aggregated PRP samples were allowed to settle for 90 minutes, the
"single platelet counting" of an upper suspension of PRP
measured by a cell counter was quantitatively validated with a
hemocytometer. Results were expressed as the percent ratio of
aggregated platelets to total platelets: ie, (single
platelet count before ADP minus single platelet count after
ADP)/single platelet count before ADP times 100%. The
dose-response curves for ADP-induced platelet aggregation were
obtained by logistic fitting. The geometric means of
(ADP)ED50 were then analyzed.
Statistics
The statistical software packages of SPSS-PC+ and IBS were used for analysis of our
data. The comparison of body weight, HR, blood pressure, exercise
performance, and platelet function in both trained and
control groups at the beginning of this study and 8 weeks later were
analyzed by ANOVA followed by Fisher's multiple range test. To
compare the differences of various parameters as mentioned
above in the training group along with the experimental period, the
results were analyzed by the randomized block ANOVA and
Tukey's multiple range test. Differences were considered significant
at P<.05. The results were expressed as mean±SEM.
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Results |
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After an 8-week training period, the body weight of the trained group was decreased from 69.5±3.8 to 67.1±3.2 kg (P<.05), whereas it was unchanged in the control group (65.4±2.4 kg before versus 66.0±2.6 kg after 8 weeks).
Heart Rates and Blood Pressures
Before the experiments, resting and maximal HRs and systolic and
diastolic blood pressures at rest were not significantly
different between control and trained groups. However, the trained
group had significantly lower resting HRs and systolic pressures
compared with the control group at the end of 8 weeks of training.
Moreover, resting HRs and diastolic and systolic pressures
of the trained group were lowered by exercise training. Nonetheless,
the training effects were reversed back to the pretraining state after
12 weeks of deconditioning (Fig 1
).
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Exercise Performance
The trained subjects increased their ET, Wmax,
Imax,
O2max, and
CO2max after 4 or 8 weeks of exercise
training. However, the training effects were reversed back to the
pretraining state after deconditioning (Fig 2). They
also had remarkably higher ET, Wmax,
O2max, and
CO2max than the control subjects after
8 weeks of training. In contrast, the control group did not alter
exercise performance after 8 weeks of the experiment (Fig 2).
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Platelet Adhesiveness and Aggregability
Fig 3 demonstrates an example of training and
deconditioning effects on platelet adhesiveness in one trained and
one control subject. Our results showed that resting and postexercise
platelet adhesiveness, indicated as the slope, was decreased after
4 or 8 weeks of training in the trained group (Fig 4).
Conversely, platelet adhesiveness was not altered in the control
group after 8 weeks of this experiment. Moreover, the trained group
also had remarkably lower platelet adhesive slope than the control
group after 8 weeks of training. However, the training effects on
platelet adhesiveness were reversed back to the pretraining state
after deconditioning (Fig 4).
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Platelet aggregability induced by 0.5, 0.25, and 0.125 µmol/L ADP
at rest and by 2, 0.5, and 0.25 µmol/L ADP after strenuous exercise
was decreased by 8 weeks of training. An example is demonstrated in Fig 5a and 5b. In contrast, ADP-induced platelet
aggregability was not altered in the control group (an example is shown
in Fig 5c and 5d). The results were grouped together in Fig 6 using (ADP)ED50 as the aggregability
index. Preexercise and postexercise (ADP)ED50 increased
after training, whereas the control group did not show any significant
(ADP)ED50 variation after 8 weeks of the experiment (Fig 6). Moreover, the training effects on platelet aggregability in the
trained group were reversed back to the pretraining state after
deconditioning (Fig 6).
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The short-term effects of strenuous exercise in both trained and
control subjects showed an increase in platelet adhesiveness during
the experimental period (Fig 4
; P<.05). In comparison,
although the sensitivity of ADP-evoked platelet aggregability was
elevated by a short-term bout of strenuous exercise at the
beginning of this study (Fig 6, P<.05), it was not changed
by short-term exercise after 4 weeks of training. This training
effect on the response to short-term exercise was also reversed by
deconditioning; ie, (ADP)ED50 was decreased by strenuous
exercise after a 12-week deconditioning period (Fig 6,
P<.05). In contrast, (ADP)ED50 of the control
subjects was significantly decreased by severe exercise at the
beginning of the study and at 8 weeks thereafter (Fig 6,
P<.05).
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Discussion |
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Our results demonstrated that (1) the trained men increased their aerobic capacities after 8 weeks of exercise training, but these effects disappeared after deconditioning; (2) resting and postexercise platelet adhesiveness and aggregability were decreased after exercise training; (3) platelet aggregability and adhesiveness were increased by short-term strenuous exercise, but the enhancement of platelet aggregability disappeared after exercise training; and (4) deconditioning reversed the training effects on resting and postexercise platelet function back to pretraining states.
Although physical activity seems to play an important role in the prevention and treatment of several cardiovascular diseases,7 8 9 10 its underlying mechanisms are still not resolved. Our study is the first report to clearly demonstrate that platelet adhesiveness and aggregability may be depressed by moderate exercise training and be reversed back to pretraining states after deconditioning. Rauramaa et al14 found that regular physical activity of low to moderate intensity might reduce resting platelet aggregability in vitro in middle-aged, overweight, mildly hypertensive men. Their findings were consistent with part of our results. However, they did not investigate the effect of exercise training on platelet adhesiveness, which was another important cellular reaction of platelets during hemostasis and thrombus formation. Moreover, the influence of deconditioning on platelet function has not yet been studied.
Our data showed that moderate exercise training could decrease platelet adhesiveness and aggregability, which might in turn reduce the risk of thrombotic events. This may explain, at least in part, why regular exercise can protect us against cardiovascular diseases. Moreover, the enhanced platelet activity in short-term severe exercise was diminished after exercise training. This may reduce the risk of primary cardiac arrest during vigorous exercise in trained subjects.4 Therefore, it is plausible to consider moderate exercise training as a "safe" exercise dosage to reduce the risk of cardiovascular complication to a minimum by eliciting beneficial physiological changes. However, the training effect was reversed back to the pretraining state after a 12-week deconditioning period.
Adhesion, aggregation, and secretion are the major platelet reactions during hemostasis and thrombosis. Although platelet aggregation and secretion were widely used as platelet functional assays, the measurement of platelet adhesion was much less popular until recent advances in technology became available. Moreover, in other studies, platelet adhesion assays were not able to distinguish adhesion from aggregation.20 21 In our platelet adhesiveness assay, we were able to observe and quantify platelet adhesiveness to a fibrinogen-coated surface exposed to a wide range of shear stress without the confounding effect of aggregation, as described in our previous study.13 The wall shear stress in human blood circulation, ranging from >1.5 to <56 dyne/cm2,22 is completely covered by our linear shear-stress flow chamber. During the assessment of platelet adhesiveness, platelets in PRP were allowed to settle on the surface by gravity and were subsequently flushed by buffer. Platelet-platelet collision, a requirement for platelet aggregation, is absent under these circumstances. In addition, due to the small thickness (0.12 mm) of our flow channel, only a few platelets had the chance to fall on top of one another, as evidenced from scanning electron microscopic observations.23 Therefore, the complication of platelet aggregation during platelet adhesion assay, seen in other studies, does not happen in our static-adhesiveness assay. As for the validation of our platelet aggregation method, we have found that little sedimentation occurred in ADP-free specimens during a 90-minute waiting period.13 The disaggregation of existing platelet aggregates usually occurs in the presence of shear force, such as happens in the mixing chamber of a conventional aggregometer. Our preliminary study showed that once these ADP-induced platelet aggregates fell to the bottom of the tube, mostly within 30 minutes, sedimented platelets could no longer float to the upper layer without mixing. What remained in the upper layer was single platelets, as verified by light microscopy. The "single platelet counting" of an upper suspension of PRP measured by a cell counter after aggregated PRP samples are allowed to settle for 90 minutes has been quantitatively validated by a hemocytometer, as described in "Methods."
Our results showed that the platelet adhesive slopes of resting and postexercise conditions were decreased by exercise training but were reversed back to the pretraining state after deconditioning. Similar results were observed in resting and postexercise platelet aggregation induced by ADP. The findings of short-term exercise effects were consistent with our previous study13 ; ie, platelet adhesiveness on a fibrinogen-coated surface and ADP-induced platelet aggregability were increased by short-term strenuous exercise in all subjects. Moreover, the enhancement of platelet aggregability by short-term exercise was decreased after exercise training.
Previous studies on the effect of exercise training on platelet aggregation have provided contradictory results.14 15 16 Our findings of reduced resting platelet aggregation after training were consistent with some of the previous studies.14 15 In addition, we observed that the enhanced platelet aggregability in severe exercise was diminished after exercise training. These findings are also consistent with recent reports that strenuous exercise in sedentary subjects, but not in physically active subjects, can either sensitize or activate platelets.13 24 However, Davis et al16 showed that exercise training did not change resting platelet aggregability. In their study, only six subjects (three men and three women) were trained 3 days a week for 12 weeks, and platelet aggregation was estimated by the slope of agonist-induced platelet aggregation. Therefore, the effect of exercise on platelet aggregability may be related to different exercise protocols, various fitness levels of the subjects, and different techniques for the evaluation of platelet function.
It is known that short-term exercise causes hemoconcentration, whereas exercise training leads to hemodilution. If changes in hematocrit are significant, there will be a relatively increased concentration of anticoagulant in blood samples immediately after short-term exercise and a relatively decreased concentration of anticoagulant in resting blood samples after training. Since we found that platelet function was increased by short-term strenuous exercise and decreased by training, it was possible that we underestimated the effects of exercise on platelet functions. Therefore, the changes in hematocrit could not explain our results.
Short-term severe exercise-induced change in platelet activation may be due to an increase in the endogenous release of adrenaline, since adrenaline release can be increased by short-term exercise25 and adrenaline can activate platelets.26 27 28 In contrast, exercise training can decrease resting and short-term exercise-induced plasma catecholamine levels.29 30 The different effects of short-term versus long-term exercise on platelet aggregation, therefore, may be partially explained by the alteration of plasma catecholamine levels. Moreover, Lehmann et al30 indicated that the platelets of endurance-trained athletes at rest may be less sensitive to adrenaline-induced aggregation than those of non–endurance-trained athletes. In our experience, exercise training reduced platelet sensitivity to ADP. Therefore, platelets from trained subjects may be less sensitive to the physiological stimuli as a whole. This viewpoint is further supported by our previous animal study indicating that exercise training causes an elevated prostacyclin level and a reduced thromboxane level.31 Moncada and Vane32 suggested that the ratio of prostacyclin to thromboxane might have an important role in determining the extent of platelet aggregation; ie, the lower the ratio, the greater one's predisposition toward platelet aggregation.
In addition, some studies have reported that EDRF may inhibit platelet aggregation and adhesion.33 34 Previous reports found that exercise training could enhance endothelium-dependent vasodilatation to agonists via the stimulated EDRF release.35 36 37 These findings suggest that platelets may be desensitized by an enhanced release of EDRF/NO after training.
Some studies have suggested that atherogenic lipoproteins may modulate platelet function and alter the susceptibility of platelets to different stimulating agents.38 39 40 High levels of LDL and VLDL increased platelet aggregability, secretion, and thromboxane A2 release from activated platelets. It had been reported that LDL and VLDL levels were decreased by exercise training combined with loss of body weight.41 Exercise training could increase HDL and decrease lipoprotein lipase activity and lipogenesis. Therefore, the changes of platelet function induced by exercise training seen in this study might be partially explained by the alteration of lipoproteins after training.
The underlying mechanisms of deconditioning effects on platelet function are unclear. A previous study showed that the decreased peripheral vascular resistance and the enhanced blood flow during exercise training were attenuated after a deconditioning period.42 Langille and O'Donnell43 indicated that a long-term decrease in blood flow led to a reduction in blood vessel diameter, and this change appeared to be mediated by low levels of EDRF.44 In addition, the training-evoked alteration of lipoprotein patterns was returned to the pretraining state after deconditioning. Therefore, we speculate that the enhanced release of EDRFs and changes in lipoprotein induced by exercise training may be attenuated by deconditioning, which returns platelet function to the pretraining state.
In conclusion, platelet adhesiveness on fibrinogen-coated surfaces and ADP-induced platelet aggregation may be diminished by exercise training. Moreover, the enhanced platelet activity induced by short-term severe exercise can be decreased after long-term exercise. However, these training effects will be reversed back to the pretraining state after deconditioning. These findings give new insight into the possible protective effects of moderate exercise training against the risk of cardiovascular disease.
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Acknowledgments |
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This study was supported by the National Science Council of Taiwan, Republic of China (grants NSC82-0412-B006-088 and NSC83-0412-B006-097). The authors would like to thank the volunteers for their enthusiastic participation in this study.
Received January 27, 1995; accepted July 25, 1995.
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