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Habitual Physical Activity and Endothelial Activation in Sickle Cell Trait Carriers


Medicine & Science in Sports & Exercise: November 2010 - Volume 42 - Issue 11 - p 1987-1994
doi: 10.1249/MSS.0b013e3181e054d6
Clinical Sciences

Purpose: It remains unclear whether habitual physical activity in sickle cell trait (SCT) carriers modulates the levels of resting and postexercise vascular adhesion and inflammatory molecules.

Methods: Plasma levels of pro-inflammatory (interleukin (IL)-4, IL-5, IL-8, sCD40L, and tumor necrosis factor α) and anti-inflammatory (IL-10) cytokines and adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), sP-selectin, or sE-selectin) were assessed at rest and in response to an incremental exercise to exhaustion in untrained (UT: no regular physical activity) and trained (T: soccer players, 8 h·wk−1 minimum) SCT and control (CON) subjects (n = 8 per group; age = 23.5 ± 0.35 yr).

Results: sVCAM-1 levels were significantly higher in the UT-SCT group than that in T-SCT group (+43.5%) at rest, at the end, and at 1, 2, and 24 h after the end of the exercise. For the other molecules, no differences emerged among the groups at rest, but in response to exercise plasma, sICAM-1, sVCAM-1, sE-selectin, and sCD40L increased in all groups, and sP-selectin only increased in the UT group. All values that increased with the acute exercise returned to their respective baseline levels 1 h after the end of the exercise.

Conclusions: A physically active lifestyle in SCT carriers may decrease endothelial activation and may limit the risk for vascular adhesion events in the microcirculation of SCT subjects.

1Center of Research and Innovation on Sports, University Claude Bernard of Lyon 1, University of Lyon, Lyon, FRANCE; 2Laboratory of Physiology, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, CAMEROON; 3Laboratory of Exercise Physiology, University Jean Monnet of Saint Etienne, Saint Etienne, FRANCE; 4Laboratory of Exercise Physiology, University of Savoie, Chambéry, FRANCE; 5Unit of Hemoglobin Molecular Pathology, Edouard Herriot Hospital, Lyon, FRANCE; 6Cellular and Molecular Integrative Physiology, University Claude Bernard of Lyon 1, University of Lyon, Lyon, FRANCE; 7Department of Pediatrics, University of Louisville, Louisville, KY; 8Department of Pediatrics, University of Chicago, Chicago, IL; and 9National Institute of Youth and Sports, Yaoundé, CAMEROON

Address for correspondence: Cyril Martin, Ph.D., Centre de Recherche etd'Innovation sur le Sport (CRIS EA647), Université Claude Bernard Lyon 1, Université de Lyon, Campus La Doua, Bat Raphael Dubois, 27-29 bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France; E-mail:

Submitted for publication July 2009.

Accepted for publication March 2010.

Sickle cell disease (SCD) is the most common genetic disease in the world and is caused by a unique mutation in the sixth codon of the β-globin gene (hemoglobin A (HbA) into hemoglobin S (HbS)) (31). This mutation leads to polymerization of HbS and to sickling of red blood cells (RBC) in response to physical stresses such as hypoxia, acidosis, dehydration, or hyperthermia (20). Recurrent painful vaso-occlusive crises because of an accumulation of low deformable RBC in the microcirculation are among the major symptoms of the SCD (20). In SCD, the severity of these crises is related to endothelial dysfunction. SCD endothelium is characterized by a higher expression of vascular adhesion molecules (namely, endothelial activation), the most important being vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin (23). This activation is mediated by some pro-inflammatory cytokines such as interleukin-8 (IL-8), which mediates the inflammation through enhanced leukocyte adhesion (23), or tumor necrosis factor α (TNF-α), which up-regulates the expression of VCAM-1 (23).

Sickle cell trait (SCT), the heterozygous form of SCD, is characterized by <45% of HbS. Although SCT is usually asymptomatic and usually considered a benign condition (29), an increasing number of studies have reported diminished exercise tolerance (13), impaired RBC deformability (26), existence of hypercoagulable states (41), and higher circulating levels of adhesion molecules in basal conditions and in response to exercise among SCT carriers (27,28). Some authors have in fact recently proposed to reclassify the SCT as a disease (3) because in some circumstances, such as physical exercise or hypoxic stress, SCT subjects may develop vaso-occlusive painful crises and other complications that can ultimately lead to death (11).

Soluble VCAM-1 (sVCAM-1) is the plasma circulating form of VCAM-1 and reflects endothelial activation (34). Monchanin et al. recently reported that SCT carriers exhibit a higher level of plasma sVCAM-1 at rest and during recovery from a progressive and maximal exercise (27) or endurance exercise (28) compared with normal hemoglobin (HbAA) subjects. The endothelial activation and the potential existence of underlying vascular dysfunction raised further questions about the risk for blood cells/endothelium interactions and for vaso-occlusive events during and several hours after exercise. Indeed, several studies have shown that exercise training improves endothelial function in healthy men (9) as well as in patients with chronic heart failure (1,2) or type 2 diabetes (43). The beneficial roles of physical training were further demonstrated by significant reductions in circulating levels of major inflammatory cytokines (1), soluble ICAM-1 (sICAM-1) (43), and sVCAM-1 (2). However, we are not aware of any studies on the effects of regular physical activity on circulating pro-inflammatory cytokines and soluble vascular adhesion molecules in SCT carriers. On the basis of aforementioned considerations, we hypothesized that endothelial activation/inflammation would be attenuated by physical activity in SCT carriers that consequently should reduce the risks for vascular adhesion and for the potential vaso-occlusive pathologies sometimes observed in this population. To test this hypothesis, the aim of this study was therefore to investigate whether habitual physical activity affects the plasma levels of pro-inflammatory (IL-4, IL-5, IL-8, and TNF-α) and anti-inflammatory (IL-10) cytokines, sCD40L, and adhesion molecules (sVCAM-1, sICAM-1, sP-selectin, or sE-selectin) at rest and in response to a progressive and maximal exercise in SCT carriers.

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The study population consisted of 16 SCT carriers (HbAS, SCT, 34.5% HbS ± 0.81) and 16 subjects with normal Hb (HbAA, CON). Subjects were male students of the University of Yaoundé II (Soa, Cameroon). Each group was divided into two subgroups on the basis of their habitual physical activity: eight CON and eight SCT who did not engage in regular physical activity for the two preceding years were assigned to "untrained" (UT) subgroups (eight UT-CON and eight UNT-SCT). Eight CON and eight SCT who practiced soccer regularly (8 h·wk−1 minimum for several years) were included in the "trained" (T) subgroups (eight T-CON and eight T-SCT). All the subjects were volunteers and gave their written informed consent before participation in the study. The definite enrolment of the subjects took place only after a complete medical examination, including height and weight measurements and a venous blood test to detect SCT and HIV. Exclusion criteria included the presence of known chronic disease (hypertension, HIV), stroke, or recent malaria crisis. SCT subjects did not report previous sickle cell crisis or other incident related to their hemoglobinopathy.

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Protocol and exercise test.

The protocol was approved by the local ethics committee of Cameroon and was in accordance with the guidelines set by the Declaration of Helsinki. All the experiments took place at the General Hospital of Yaoundé (Cameroon). The day before the exercise test, the subjects were asked to avoid strenuous exercise. On the experimental day, all subjects performed an incremental maximal test exercise on a cycle ergometer (Monark, 818E, Stockholm, Sweden). The test began after a 5-min warm-up at 30 W. The initial 70-W work rate was increased every 3 min by 35-W steps until volitional exhaustion and therefore allowed assessment of the maximal aerobic power (MAP; W) and HRmax (beats·min−1). HR was displayed throughout the incremental exercise using a chest belt (Polar Electro, Kempele, Finland). MAP was determined by linear interpolation from the HR versus work rate curve. Blood samples were drawn from a catheterized antecubital vein of the nondominant arm and collected at rest (T rest), immediately at the end of the exercise test (T ex), and after 1, 2, and 24 h of recovery (T 1h, T 2h, T 24h, respectively) in EDTA tubes. The samples were used to measure levels of blood cells (at rest), soluble adhesion molecules (sVCAM-1, sICAM-1, sP-selectin, and sE-selectin), sCD40L, and cytokines (TNF-α IL-4, IL-5, IL-8, and IL-10) at all blood sampling time points.

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SCT confirmation, α-thalassemia detection, and hematological parameters.

For SCT confirmation, blood samples were collected in the EDTA tubes at rest, and the various Hb were isolated and quantified by ion-exchange high-performance liquid chromatography (Variant I, Beta Thal Short Program; Bio-Rad Laboratories, Hercules, CA). Positive test results for SCT were determined by the presence of HbS but <50% of the total Hb. To study the coexistent presence of α-thalassemia, the technique described by Chong et al. (7) was used. The only form of α-thalassemia found in some SCT carriers was the heterozygous one marked by a depletion of 3.7 kb of DNA, containing one of the two linked α-globin genes (αα/−α3.7). Blood for the hematological measurements was sampled at rest in EDTA tubes and was analyzed using a hematology analyzer (Abbott Cell Dyn 1800 hematology analyzer; Block Scientific, Bohemia, NY).

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Adhesion molecules and cytokines assessment.

The blood samples collected at T rest, T ex, T 1h, T 2h, and T 24h were centrifuged, and plasma was aliquoted and stored at −80°C until analysis. The measurements of plasma sVCAM-1, sICAM-1, sE-selectin, and sP-selectin were done with the use of enzyme-linked immunoabsorbent assay kits (Diaclone Systems, Besançon, France) according to the manufacturer's instructions. All samples were determined in triplicate, and the sensitivity limits were 0.6 ng·mL−1 (sVCAM-1), 0.1 mg·mL−1 (sICAM-1), 0.5 ng·mL−1 (sE-selectin), and 1.06 ng·mL−1 (sP-selectin). Cytokines were quantified at T rest, T ex, and T 2h using a Luminex® fluorescent bead-based immunoassay kit (Luminex Corporation, Austin, TX) to simultaneously measure interleukin (IL)-4, IL-5, IL-8, IL-10, sCD40L, and TNF-α. The R&D Fluorokine MAP Human Cytokine Multiplex Panel was used for this purpose (R&D Systems, Minneapolis, MN). The detection limits were 1, 4, 4, 1, 16, 64, and 1 pg·mL−1, respectively.

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Results are expressed as means ± SE and analyzed with Statistica (Version 5.5; StatSoft, Tulsa, OK). The anthropometric characteristics, the hematologic findings, the HRmax, and the MAP were compared using two-way ANOVA procedures followed by post hoc tests (UT/T and CON/SCT). Plasma levels of soluble adhesion molecules and cytokines were compared between the four groups and at different times using two-way ANOVA with repeated measurements followed by post hoc tests. Paired t-tests were used when appropriate to determine where significant differences occurred. Differences between values were considered to be statistically significant for P ≤ 0.05.

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Anthropometric, hematologic, and MAP characteristics.

As shown in Table 1, although the age was not different among the four groups, UT-CON subjects were significantly shorter than UT-SCT and T-CON subjects and significantly lighter than that in the three other groups (P < 0.05). In addition, UT-SCT subjects' height was significantly higher than that in the T-SCT group (P < 0.05). The HRmax values and the hematologic parameters were similar among the four groups, except for the following: i) the mean corpuscular volume was significantly lower in the SCT groups than that in their CON counterparts, and ii) the platelet concentrations were significantly higher in the T groups compared with the UT subjects (P < 0.05). A coexistent α-thalassemia was detected in three UT-SCT and in five T-SCT subjects. MAP (W) and relative MAP (W·kg−1) were significantly higher in T subjects than that in their UT counterparts (215.05 ± 7.0 W vs 174.9 ± 6.2 W, P < 0.001, and 3.2 ± 0.09 vs 2.74 ± 0.09 W·kg−1, P < 0.005, respectively).



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Plasma cytokines and soluble adhesion molecules at rest and after maximal exercise.

The plasma concentrations of IL-4, IL-5, IL-8, IL-10, or TNF-α did not significantly differ at rest and after the incremental exercise between the four groups (Table 2). Furthermore, no significant variations in these cytokines concentrations were obtained at T ex and T 2h compared with T rest. Although no significant intergroup differences were observed, sCD40 ligand concentrations were significantly increased at T ex compared with T rest and T 2h in all the subjects (+59.7%, P < 0.05) (Table 2).



Basal plasma concentrations of sICAM-1, sP-selectin, and sE-selectin were not statistically different among the four groups (Table 3). For sVCAM-1, ANOVA revealed that UT-SCT subjects exhibited higher concentrations than their T counterparts (1738 ± 98 vs 1248 ± 131 ng·mL−1, respectively, P < 0.05; Fig. 1). This was also the case at T ex and T 1h, T 2h, and T 24h.



FIGURE 1-Effec

FIGURE 1-Effec

Furthermore, sVCAM-1 plasma concentrations were significantly more elevated in UT-SCT than that in UT-CON (P < 0.05; Fig. 1), whereas no significant difference was observed between T-SCT and T-CON subjects (P = 0.89). Plasma sICAM-1, sVCAM-1, and sE-selectin increased significantly in all groups at the end of the strenuous exercise as compared with resting levels (+8.2%, +12.0%, and +12.2%, respectively, P < 0.05) and returned to their baseline value 1 h after the end of exercise (T 1h). When plasma sE-selectin concentrations were expressed relative to the resting values, the return to the baseline was confirmed at T 1h in T subjects (Fig. 2), whereas it occurred only 2 h after the end of exercise (i.e., at T 2h) in UT subjects (Fig. 2).

FIGURE 2-Effec

FIGURE 2-Effec

Although incremental exercise did not statistically change sP-selectin concentrations in the T groups, a significant increase in these concentrations was measured in the UT groups between T rest and T ex (+167%, P < 0.005). These concentrations returned to basal values 1 h after the end of exercise (Table 3, Fig. 3).

FIGURE 3-Effec

FIGURE 3-Effec

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The present study examined whether the training status of CON or SCT subjects affected the plasma concentrations of inflammatory and soluble adhesion molecules at rest and in response to an incremental maximal exercise. The main findings of our study were that 1) sVCAM-1 plasma concentrations were significantly lower in the T-SCT subgroups compared with the UT-SCT subgroups at rest, immediately (T ex), and 1 h (T 1h), 2 h (T 2h), and 24 h (T 24h) after the end of exercise; 2) sP-selectin significantly increased at the end of the exercise in UT, whereas no changes were observed among T group subjects; and 3) the postexercise decrease kinetics of plasma sE-selectin was faster in T than that in UT.

As shown in previous studies (27,28,40), MAP was not different among the SCT and the control subjects. However, MAP was significantly higher in the T group than that in the UT group (+23%, P < 0.001). In addition, UT-CON subjects were smaller and lighter by comparison with the three other groups. Therefore, as UT-CON and UT-SCT were matched for MAP and relative MAP; this difference should be of no consequence to the inflammatory and vascular adhesion findings.

No differences were found at rest between the four groups for hematological parameters, except for the mean corpuscular volume, which was significantly lower in the SCT carriers. This can be explained by the coexistence in half of SCT subjects (SCT-αT subjects) of α-thalassemia mutation (Table 1), which is known to diminish the RBC volume (38). Also and in accordance with Singh et al. (37), the T subjects exhibited a higher level of circulating platelets than the UT.

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Effect of habitual physical activity on circulating inflammatory and adhesive molecules at rest.

The baseline levels of all the studied molecules were similar between the four groups except for sVCAM-1. Whereas sVCAM-1 concentrations were significantly more elevated in UT-SCT subjects than that in their CON counterparts (P < 0.05), those concentrations were similar between the two trained groups (T-SCT and T-CON). The present results are in accordance with those reported by Tripette et al. (40), who did not observe significant sVCAM-1 difference in trained SCT subjects compared with subjects with normal hemoglobin (HbAA). Conversely Monchanin et al. (27,28) observed significant higher sVCAM-1 concentrations in a trained SCT population compared with a healthy trained population at rest. Our results are difficult to compare with those of Monchanin et al. (27,28) and Tripette et al. (40) because i) our subjects were not experienced in cycle ergometer (that explains the poor measured MAP) and ii) several SCT carriers presented the double mutation α-thalassemia/SCT (63.6% for the T-SCT and 42.8% for the UT-SCT), which might be considered as beneficial for this population (26-28). Because plasma sVCAM-1 is reduced in SCT-αT subjects compared with SCT-only subjects (27,28), this might explain the variability of sVCAM-1 concentrations in our cohort and the discrepancies between our findings and those of Monchanin et al. (27,28) (Fig. 1).

Nevertheless, this study is the first to show a differential effect of habitual physical activity on sVCAM-1 concentrations in SCT carriers. Higher sVCAM-1 concentrations were observed in the UT-SCT compared with the T-SCT subjects (Fig. 1). The present results extend those of Adamopoulos et al. (2), who found, in healthy subjects and in patients with chronic heart failure, that baseline sVCAM-1 plasma concentrations were reduced after an exercise training program (30 min of cycling at 70%-80% V˙O2max per day, 5 d·wk−1 during 12 wk). Furthermore, Shiu et al. (34) showed that soluble adhesion molecules at rest reflect the degree of endothelium vascular activation; thus, the present results suggest that the vascular endothelium is less activated in the T group compared with the UT group. Because VCAM-1 is involved with very late antigen-4 (VLA-4) in the interactions between leukocytes (17) and reticulocytes/endothelial cells (37,34), increased endothelial expression of VCAM-1 should lead in SCT carriers to an increased risk of blood cell aggregation and thrombus formation, that is, vaso-occlusive events (15,31). We propose that the risk for such vaso-occlusive events might be more pronounced among the SCT subjects who do not engage in regular physical activity. Because high sVCAM-1 has been associated with pulmonary hypertension, organ failure, and mortality in SCD (19), further investigations will be required to determine the potential effects of physical activity in homozygous HbS carriers.

It is now well established that physical exercise disturbs homeostasis and that one of the main results of physical training is to attenuate these perturbations. Thus, among SCT carriers, known factors that promote sickling, such as increased pH, could be less influential and contribute to limiting the polymerization process after training compared with before training. Consequently, endothelial activation and sVCAM-1 expression (33,34) as suggested in the present study would be accordingly attenuated. A putative alternative explanation would be that because training is known to restrict the inflammatory response induced by an acute exercise bout (by limiting pro-inflammatory responses and increasing the anti-inflammatory cytokine release) (32), exercise training might limit vascular activation by its anti-inflammatory pathway (32,39). This has been suggested by Tripette et al. (40), who showed increased postexercise IL-6 concentrations in trained SCT subjects. This cytokine has been demonstrated to exert anti-inflammatory effects through an inhibition of the production of TNFα and IL-1 and a stimulation of the production of IL-1ra and IL-10 (32). Further studies will have to confirm the possibility that an elevated physical activity may limit the adhesive potential in HbS carriers.

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Effects of training on incremental exercise and recovery of circulating inflammatory and adhesion molecules.

A significant increase in sVCAM-1, sE-selectin, sICAM-1, and sCD40L plasma concentrations was observed in the four groups in response to incremental exercise (Tables 2 and 3). Although these findings are in accordance with several previous studies in healthy subjects or in patients with peripheral arterial disease or SCT carriers (5,27,28,35,36), they contrast with other findings obtained in healthy subjects or in SCT carriers (27,40,42). The use of the endothelial circulating molecules to observe the effects of an acute exercise on the endothelial activation is because at rest, soluble molecules reflect the level of underlying endothelial activation (34). A postexercise increase in plasma adhesion molecules is thought to result from the shedding of these molecules from the cell surface, possibly as a result of inflammation or increase in shear stress induced by exercise (24). As shown in Figures 1 and 2, plasma sVCAM-1 and sE-selectin concentrations were raised in response to incremental exercise. These molecules are known to reflect endothelial dysfunction and mediate the interaction between leukocytes and platelets/endothelium (5) and between leukocytes and reticulocytes/endothelium (34), respectively. Similarly, the marked increase in sCD40L could reflect increased CD40L expression, primarily on lymphocytes' surface (8) but also on platelets, endothelial cells, smooth muscle cells, macrophages, dendritic cells, fibroblasts, and mast cells (42). The rise of sCD40L has been associated to the pathogenic processes of chronic inflammatory disease (42) and to the presence of increased prothrombotic activity (22). The present findings thus suggest that incremental exercise might be responsible for endothelial activation in HbAA as in HbAS subjects, independent of their habitual physical activity levels. Of note, the rise of the soluble form of ICAM-1 is difficult to interpret because ICAM-1 is expressed in many types of cells, including endothelial cells, fibroblasts, epithelial cells, and multiple cells of hematopoietic lineage (36), such that it is impossible to ascertain whether the present increase of sICAM-1 indeed results from an increase in endothelial ICAM-1. The latter possibility is unlikely because no significant increases in sICAM-1 have been reported after maximal exercise in SCT subjects (27) or in HbAA subjects (4). The sICAM-1 increase reported by Akimoto et al. (4) after endurance or downhill exercise may be attributed to muscular damage and inflammation induced by these types of exercise.

Although widely used, assessment of soluble molecules to indirectly evaluate the endothelium expression immediately after an acute exercise is controversial. Tripette et al. (40) recently argued that the postexercise increase in adhesion molecules observed in several studies may be accounted for by an exercise-induced hemoconcentration. Although water loss during a 15-min incremental exercise should be rather minor in our population (30), the "hemoconcentration hypothesis" should not be dismissed altogether. Thus, the postexercise changes described heretofore should be viewed as the result of both exercise-induced physiological responses (endothelial activation) and hemoconcentration.

No significant changes in plasma interleukins (TNF-α, IL-4, IL-5, IL-8, and IL-10) were observed in response to exercise. These results were unexpected because IL-4, IL-8, and TNF-α are pro-inflammatory cytokines that are responsible for endothelial activation and adhesion molecule expression (23,34). It is thus possible that alternative pathways such as oxidative stress (18) may be recruited.

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Differential effects of habitual physical activity on exercise-induced variations of soluble P- and E-selectin.

The different temporal trajectories among T and UT groups in sE-selectin and sP-selectin after an acute exercise are of remarkable interest. First, in accordance with some authors (10,35), a significant rise in sP-selectin was observed at the end of the incremental exercise in the UT subjects only (+167%). However, despite the present statistically significant finding concerning the sP-selectin increase, when we observe the individual results, two UT populations are distinguished. Six of the 16 UT subjects exhibit more than 50% postexercise increase (high responders). The 10 other subjects are characterized by 13%-50% postexercise sP-selectin increase (low responders). As sP-selectin is an important marker of platelet activation (42,43), our results suggest that platelet activation in response to an acute exercise is characterized by an important interindividual variability and is more pronounced in subjects with low physical activity than that in their trained counterparts. This is in agreement with the observation of Kestin et al. (21), who showed in a healthy population that strenuous exercise resulted in both platelet activation and platelet hyperactivity in sedentary subjects but not in physically active subjects. These authors further strengthened the link between platelet activation/aggregation and ischemia and emphasized the fact that sedentary subjects are more vulnerable to death during exercise (21). Chronic exercise is also known to increase fibrinolysis and to reduce platelets aggregation and activation (24), all of which may contribute to limit the thrombus formation in response to an acute exercise in T-SCT subjects. However, our hypothesis contrasts with those of Connes et al. (14), who did not find differences in the coagulation markers (prothrombin time, activated partial thromboplastin time, and antithrombin III activity) between SCT carriers and sedentary subjects in response to a maximal exercise. These authors hypothesized that the clinical complications observed in some SCT carriers during exercise are not the consequence of increased blood coagulation activity (14). In addition, no difference between T and UT was observed concerning sCD40L plasma concentrations, which are considered as prothrombotic activity marker (22). To resolve these discrepancies, the effects of habitual physical activity on platelet metabolism need to be further examined, particularly in SCT carriers.

A significant increase in sE-selectin was also observed in response to graded exercise in all groups. However, when sE-selectin is expressed relative to its resting values, slower recovery kinetics was observed in the UT group (2 h) as compared with the T subjects (1 h). This finding is in accordance with Boos et al. (6), who found that sE-selectin increased immediately after exercise in subjects with cardiovascular disease, without any decrease 30 min later (6). We hypothesize that the differences in the recovery process between the T and the UT groups might be accounted for either by better clearance of sE-selectin in the T subjects or by faster recovery of the basal plasma volume in the T group (i.e., auto-hemodilution or better hydration postexercise for the trained subject-not measured). The latter might be particularly relevant for SCT carriers because a higher hemodilution should restrict the occurrence of two factors involved in vaso-occlusive events, namely, blood viscosity (which increases shear stress and consequently the vascular adhesion activation) (27) and RBC dehydration, which would lead to an impaired RBC deformability (12).

Taken together, our results might appear contradictory compared with those of the literature presenting case reports of accidents in SCT carriers after exercise (16,25). In these earlier studies, vaso-occlusive crises sometimes leading to sudden death were reported in young athletes and military recruits, and both of these populations can be viewed as "trained." These studies suggested that these populations appear to be "at high risk" for vaso-occlusive events. However, our subjects performed an acute exercise paradigm in standardized conditions of temperature, duration, and hydration. This contrasts with the multiple "extreme" and adverse environmental conditions (e.g., altitude, temperature, dehydration, exhausting long-lasting exercises) that were present and described in the case-report studies. These differences in environmental conditions might explain the aforementioned apparent contradiction. Nevertheless, such explanations should not minimize our awareness and need for precautions, considering the many unanswered questions around SCT and exercise that need to be resolved in the future.

In conclusion, a physically active lifestyle is associated with low baseline and postexercise levels of sVCAM-1 in the SCT carrier group, with a limited plasma sP-selectin increase in response to an incremental exercise and with a rapid recovery in plasma sE-selectin. Thus, increased levels of chronic physical activity may confer beneficial effects on endothelial activation and possibly reduce the likelihood of vascular occlusions in SCT carriers. As endothelial activation and sVCAM-1 concentrations are associated with pulmonary hypertension, organ failure, and mortality in SCD (19), these results should be of interest and support further investigations in SCD patients.

This study was supported by grants from l'Ambassade de France au Cameroon in Yaoundé.

The authors thank Mrs. Gaëlle Lepape, Pr. Christophe Nouedoui, and Mrs. Philippe Stofft and François-Xavier Owona for their helpful assistance and the general direction of the Central Hospital of Yaoundé for its hospitality.

The authors also thank the financial and logistic support of the Cameroonian Ministries of Public Health and of Higher Education.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

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1. Adamopoulos S, Parissis J, Karatzas D, et al. Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. J Am Coll Cardiol. 2002;39(4):653-63.
2. Adamopoulos S, Parissis J, Kroupis C, et al. Physical training reduces peripheral markers of inflammation in patients with chronic heart failure. Eur Heart J. 2001;22(9):791-7.
3. Ajayi AAL. Should the sickle cell trait be reclassified as a disease state? Eur J Int Med. 2005;16(6):463.
4. Akimoto T, Furudate M, Saitoh M, et al. Increased plasma concentrations of intercellular adhesion molecule-1 after strenuous exercise associated with muscle damage. Eur J Appl Physiol. 2002;86(3):185-90.
5. Bartzeliotou AI, Margeli AP, Tsironi M, et al. Circulating levels of adhesion molecules and markers of endothelial activation in acute inflammation induced by prolonged brisk exercise. Clin Biochem. 2007;40(11):765-70.
6. Boos CJ, Balakrishnan B, Lip GYH. The effects of exercise stress testing on soluble E-selectin, von Willebrand factor, and circulating endothelial cells as indices of endothelial damage/dysfunction. Ann Med. 2008;40(1):66-73.
7. Chong SS, Boehm CD, Higgs DR, Cutting GR. Single-tube multiplex-PCR screen for common deletional determinants of alpha-thalassemia. Blood. 2000;95(1):360-2.
8. Chung I, Goyal D, Macfadyen RJ, Lip GYH. The effects of maximal treadmill graded exercise testing on haemorheological, haemodynamic and flow cytometry platelet markers in patients with systolic or diastolic heart failure. Eur J Clin Invest. 2008;38(3):150-8.
9. Clarkson P, Montgomery HE, Mullen MJ, et al. Exercise training enhances endothelial function in young men. J Am Coll Cardiol. 1999;33(5):1379-85.
10. Collins P, Ford I, Ball D, Macaulay E, Greaves M, Brittenden J. A preliminary study on the effects of exercising to maximum walking distance on platelet and endothelial function in patients with intermittent claudication. Eur J Vasc Endovasc Surg. 2006;31(3):266-73.
11. Connes P, Hardy-Dessources M-D, Hue O. Counterpoint: sickle cell trait should not be considered asymptomatic and as a benign condition during physical activity. J Appl Physiol. 2007;103(6):2138-40.
12. Connes P, Hue O, Tripette J, Hardy-Dessources MD. Blood rheology abnormalities and vascular cell adhesion mechanisms in sickle cell trait carriers during exercise. Clin Hemorheol Microcirc. 2008;39(1-4):179-84.
13. Connes P, Monchanin G, Perrey S, et al. Oxygen uptake kinetics during heavy submaximal exercise: effect of sickle cell trait with or without alpha-thalassemia. Int J Sports Med. 2006;27(7):517-25.
14. Connes P, Tripette J, Chalabi T, et al. Effects of strenuous exercise on blood coagulation activity in sickle cell trait carriers. Clin Hemorheol Microcirc. 2008;38(1):13-21.
15. Frenette P, Atweh G. Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest. 2007;117(4):850-8.
16. Harrelson G, Fincher A, Robinson J. Acute exertional rhabdomyolysis and its relationship to sickle cell trait. J Athl Train. 1995;30(4):309-12.
17. Hemler M. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365-400.
18. Ji L. Antioxidants and oxidative stress in exercise. Proc Soc Exp Biol Med. 1999;222(3):283-392.
19. Kato G, Martyr S, Blackwelder W, et al. Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality. Br J Haematol. 2005;130(6):943-53.
20. Kaul D, Nagel R. Sickle cell vasoocclusion: many issues and some answers. Experientia. 1993;49(1):5-15.
21. Kestin AS, Ellis PA, Barnard MR, Errichetti A, Rosner BA, Michelson AD. Effect of strenuous exercise on platelet activation state and reactivity. Circulation. 1993;88(4 pt 1):1502-11.
22. Lee SP, Ataga KI, Orringer EP, Phillips DR, Parise LV. Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Arterioscler Thromb Vasc Biol. 2006;26(7):1626-31.
23. Makis AC, Hatzimichael EC. The role of cytokines in sickle cell disease. Ann Hematol. 2000;79(8):407-13.
24. Marsh SA, Coombes JS. Exercise and the endothelial cell. Int J Cardiol. 2005;99(2):165-9.
25. Mitchell BL. Sickle cell trait and sudden death-bringing it home. J Natl Med Assoc. 2007;99(3): 300-5.
26. Monchanin G, Connes P, Wouassi D, et al. Hemorheology, sickle cell trait, and alpha-thalassemia in athletes: effects of exercise. Med Sci Sports Exerc. 2005;37(7):1086-92.
27. Monchanin G, Serpero LD, Connes P, et al. Effects of progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without alpha-thalassemia. J Appl Physiol. 2007;102(1):169-73.
28. Monchanin G, Serpero LD, Connes P, et al. Plasma levels of adhesion molecules ICAM-1 and VCAM-1 in athletes with sickle cell trait with or without α-thalassemia during endurance exercise and recovery. Clin Hemorheol Microcirc. 2008;40(2):89-97.
29. Noguchi CT, Torchia DA, Schechter AN. Polymerization of hemoglobin in sickle trait erythrocytes and lysates. J Biol Chem. 1981;256(9):4168-71.
30. O'Toole ML, Paolone AM, Ramsey RE, Irion G. The effects of heat acclimation on plasma volume and plasma protein of females. Int J Sports Med. 1983;4(1):40-4.
31. Okpala I. Leukocyte adhesion and the pathophysiology of sickle cell disease. Curr Opin Hematol. 2006;13(1):40-4.
32. Petersen A, Pedersen B. The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol. 2006;57(10 suppl):43-51.
33. Sakhalkar VS, Rao SP, Weedon J, Miller ST. Elevated plasma sVCAM-1 levels in children with sickle cell disease: impact of chronic transfusion therapy. Am J Hematol. 2004;76(1):57-60.
34. Shiu Y, Udden M, McIntire L. Perfusion with sickle erythrocytes up-regulates ICAM-1 and VCAM-1 gene expression in cultured human endothelial cells. Blood. 2000;95(10):3232-41.
35. Signorelli SS, Mazzarino MC, Di Pino L, et al. High circulating levels of cytokines (IL-6 and TNFalpha), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test. Vasc Med. 2003;8(1):15-9.
36. Silvestro A, Schiano V, Bucur R, Brevetti G, Scopacasa F, Chiariello M. Effect of propionylcarnitine on changes in endothelial function and plasma levels of adhesion molecules induced by acute exercise in patients with intermittent claudication. Angiology. 2006;57(2):145-54.
37. Singh I, Quinn H, Mok M, et al. The effect of exercise and training status on platelet activation: do cocoa polyphenols play a role? Platelets. 2006;17(6):361-7.
38. Steinberg MH, Embury SH. Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood. 1986;68(5):985-90.
39. Suzuki K, Peake J, Nosaka K, et al. Changes in markers of muscle damage, inflammation and HSP70 after an Ironman Triathlon race. Eur J Appl Physiol. 2006;98(6):525-34.
40. Tripette J, Connes P, Hedreville M, et al. Patterns of exercise-related inflammatory response in sickle cell trait carriers. Br J Sports Med. 2010;44(4):232-7.
41. Westerman MP, Green D, Gilman-Sachs A, et al. Coagulation changes in individuals with sickle cell trait. Am J Hematol. 2002;69(2):89-94.
42. Zietkowski Z, Skiepko R, Tomasiak MM, Bodzenta-Lukaszyk A. Soluble CD40 ligand and soluble P-selectin in allergic asthma patients during exercise-induced bronchoconstriction. J Investig Allergol Clin Immunol. 2008;18(4):272-8.
43. Zoppini G, Targher G, Zamboni C, et al. Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2006;16(8):543-9.


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