Sickle Cell Trait Carriers Research Articles

Autonomic Response to Hypoxia and Isometric Exercise in Sickle Cell Trait Subjects

AbstractAbstract 3241Loss of cardiac beat to beat variability reflected by high frequency power (HFP) is a strong predictor of death in patients with cardiovascular disease. Similar autonomic dysfunction is found in patients with Sickle Cell Anemia (SCA) and can be induced by a 30 second period of hypoxia during five breath nitrogen exposure (1,2). Some data suggest that Sickle Cell Trait (SCT) carriers also exhibit autonomic dysfunction. In light of the recent attention to sudden death in young athletes with SCT we examined the autonomic response to transient hypoxia and isometric exercise in subjects with SCT and matched controls.Autonomic responses to hypoxia induced by a five-breath nitrogen exposure and intense isometric exercise resulting from handgrip to exhaustion were measured. Autonomic parasympathetic tone and sympathetic-vagal balance were measured using respiratory-adjusted time-varying heart rate variability (HRV). High frequency power (HFP) reflects parasympathetic tone and low-high ratio (LHR), sympathetic-vagal balance (1,2).Ten African American SCT carriers (7 female, 35.7 yrs + 2.8) and 11 age, and ethnicity matched controls (CTRL, 8 female, 30.5 yrs + 2.8) were studied. No difference in resting heart rate (HR, SCT 67.1 + 5.1, CTRL 65.9 + 5.5), cardiac output (CO, SCT 6.17 + .57, CTRL 7.31 + .52), mean arterial pressure (MAP, SCT 101.49 + 4.61, CTRL 101.49 + 4.96) or LHR (SCT, 1.16 + .38, SCT 1.44 + .37) was observed.Five-breath nitrogen exposure produced nearly identical minimal arterial saturation (SaO2, SCT 84.1% ± 1.3%, CTRL 83.1% ± 1.3%) with compensatory tachycardia (DRRI, SCT −6.5% ± 1.2%, CTRL −4.79 ± 1.15%) and increased cardiac output (DCO, SCT 4.7% ± 1.7, CTRL 6.0% ± 1.6%). No change from baseline was observed in the population means of HFP or LHR for CTRLs or SCT subjects.Following ten minutes of recovery, handgrip to exhaustion was performed at 60% maximum voluntary contraction. No differences were observed in maximum handgrip or duration between SCT and CTRL. Men produced higher maximal response but women maintained contraction nearly twice as long, independent of diagnosis. Handgrip exercise increased heart rate, cardiac output (SCT +13.4% ± 5.4%, CTRL +13.9% ± 5.0%), mean arterial pressure (SCT +19.6% ± 2.5%, CTRL +16.0% ± 2.3%), systolic pressure (SCT +14.6% ± 2.2%, CTRL +10.7% ± 2.1%), and diastolic pressure (SCT +22.5% ± 2.9%, CTRL +18.5% ± 2.6%). No population differences were observed in these responses. LHR increased similarly in both populations as well (SCT +78.9% ± 35.7%, CTRL +68.5% ± 32.9%), but SCT carriers had a much larger drop in HFP that was significantly different from baseline and trended lower than the control population (SCT −58% ± 18%, CTRL −9% ± 17%, p<.063).Our laboratory has previously demonstrated hyper-reflexic parasympathetic withdrawal in response to transient hypoxia in patients with SCA (1,2). SCT subjects did not demonstrate parasympathetic withdrawal to hypoxia. However, we found exaggerated parasympathetic withdrawal in response to handgrip exercise in SCT subject and not in matched controls. Even though the biophysical properties of the sickle trait red cell are not sufficient to result in major hemolysis or vaso-occlusion, they are sufficient to alter autonomic balance. It will be important to determine whether this response impacts the distribution of ventricular repolarization, potentially increasing risk of arrhythmia, or is reproduced in other autonomic axes such as mental stress. [Display omitted] [Display omitted] Disclosures:Coates:Apopharma: Consultancy; Novartis: Speakers Bureau. Wood:Novartis: Honoraria, Research Funding; Apotex: Consultancy, Honoraria; Shire: Consultancy; Ferrokin Biosciences: Consultancy.

Who Counsels Parents of Newborns Who Are Carriers of Sickle Cell Anemia or Cystic Fibrosis?

Our objective was to describe: 1) physicians' knowledge of whether genetic counseling is provided to parents of newborns with sickle cell trait (SCT) or who are cystic fibrosis carriers (CFC), and 2) the prevalence of genetic counseling provided by primary care physicians. We conducted a cross-sectional descriptive survey of 600 randomly-sampled Michigan-based pediatricians and family physicians, assessing physician knowledge of where and whether genetic counseling is received by parents whose newborns are carriers. Chi-squared testing determined associations between genetic counseling location and physician demographic characteristics. Our response rate was 62%: 298 (84%) provided infant well care (183 pediatricians, 115 family physicians). Most respondents were non-Hispanic White (65%). Virtually all physicians believed parents whose newborns are carriers of either SCT or CFC should receive some genetic counseling (from the physician and/or another source), yet 20% reported that parents of newborns with SCT did not receive counseling. Parents of infants with CFC received more counseling overall (92% vs. 80%; p < 0.01) and were counseled more frequently by genetic counselors or specialty centers than parents of newborns with SCT (85% vs. 60%; p < 0.01). Although physicians agreed that parents whose newborns are carriers should receive genetic counseling, fewer parents of newborns with SCT than with CFC received counseling from any source. This finding strongly suggests the need for further education and investigation of this apparent health disparity.

Effects of regular physical activity on skeletal muscle structural, energetic, and microvascular properties in carriers of sickle cell trait

To assess the effects of regular physical activity on muscle functional characteristics of carriers of sickle cell trait (SCT), 39 untrained (U) and trained (T) hemoglobin (Hb)AA (CON) and SCT subjects (U-CON, n = 12; U-SCT, n = 8; T-CON, n = 10; and T-SCT, n = 9) performed a graded exercise and a time to exhaustion (T(ex)) test, and were subjected to a muscle biopsy. Maximal power, total work performed during T(ex), citrate synthase and cytochrome c oxidase (COX) activities, respiratory chain complexes I and IV content, and capillary density (CD), diameter (COD), and surface area (CSA) were upregulated by the same proportion in T-CON and T-SCT compared with their untrained counterparts. These proportionally similar differences imply that the observed discrepancies between U-SCT and U-CON remained in the trained subjects. Specifically, both CD and COX remained and tended to remain lower, and both COD and CSA remained and tended to remain higher in T-SCT than in T-CON. Besides, carriers of SCT displayed specific adaptations with regular physical activity: creatine kinase activity; complexes II, III, and V content; and type I fiber surface area and capillary tortuosity were lower or unchanged in T-SCT than in U-SCT. In summary, our results show that 1) carriers of SCT adapted almost similarly to CON to regular physical activity for most of the studied muscle characteristics, 2) oxidative potential remains altered in physically active carriers of SCT compared with HbAA counterparts, and 3) the specific remodeling of muscle microvascular network persists in the trained state.

Effects of hydration and water deprivation on blood viscosity during a soccer game in sickle cell trait carriers

The present study compared the changes in blood viscosity, hydration status, body temperature and heart rate between a group of sickle cell trait (SCT) carriers and a control (Cont) group...

A functional promoter polymorphism of the δ‐globin gene is a specific marker of the Arab‐Indian haplotype

A functional promoter polymorphism of the δ‐globin gene is a specific marker of the Arab‐Indian haplotype

Effect of α‐thalassaemia on exercise‐induced oxidative stress in sickle cell trait

Alpha-thalassaemia is known to reduce intra-erythrocyte HbS (sickle haemoglobin) concentration in sickle cell trait (SCT) subjects. Because HbS was shown to increase oxidative stress, the purpose of this study was to assess the effects of the coexistence of α-thalassaemia and SCT on oxidative stress markers and nitric oxide (NO) metabolism after an acute physical exercise. Forty subjects (age: 23.5 ± 2.21 years), SCT carriers (HbAS) or healthy subjects (HbAA), with (-αT) or without (-NαT) an associated α-thalassaemia took part in the study. Plasma markers of oxidative stress [advanced oxidation protein products (AOPP), protein carbonyl, malondialdehyde (MDA) and nitrotyrosine], anti-oxidant defences and NO metabolism (NOx) were measured at rest (T(rest)), immediately following an incremental maximal exercise test (T(ex)) and during recovery (T(1h), T(2h) and T(24h)). Malondialdehyde expressed as the percentage of changes from baseline was significantly higher in the HbAS-NαT compared with HbAS-αT during recovery (+36.3 ± 14.1% vs. -1.8 ± 13.2% at T(1h), P = 0.02; +36.6 ± 13.4% vs. -11.4 ± 12.5% at T(2h), P = 0.004 and +24.1 ± 12.3% vs. -14.4 ± 11.5% at T(24h), P = 0.02 in HbAS-NαT vs. HbAS-αT). Compared with HbAS-NαT, HbAS-αT had a higher NOx change from baseline at T(ex) (-23.4 ± 20.6% vs. +57.7 ± 19.3%, respectively; P = 0.005) and lower nitrotyrosine change from baseline at T(1h) (+7.2 ± 22.2% vs. +93.5%±29.3%, respectively; P = 0.04). All these data suggest that the presence of α-thalassaemia may blunt the higher level of oxidative stress and the impaired bioavailability of NO observed in the SCT carriers.

Physical activity blunts oxidative stress response to exercise in sickle cell trait carriers

Sickle cell trait (SCT) is characterized by hemorheological and endothelial abnormalities, possibly related to an increase in oxidative stress. Habitual exercise training has been shown to decrease oxidative stress through an up‐regulation of antioxidant defences. The aim of this study is therefore to test if regular physical activity can affect oxidative stress and nitric oxide (NO) metabolism in SCT carriers compared to sedentary counterparts. Plasma levels of 4 oxidative stress markers, antioxidant enzymes activities (SOD and GPX), NO metabolism (NOx) and adhesion molecules were assessed at baseline and following a maximal incremental exercise test (Tex) in 40 trained (T) or sedentary (S) subjects, carriers (SCT) or not (CON) of the sickle cell trait. At Tex, T‐SCT had a lower level of all the oxidative stress markers compared to the 3 others groups. Regardless the disease status (SCT or CON), trained subject had a higher activity of SOD, GPX and NOx at Tex. Finally, the changes in oxidative stress induced by exercise were correlated positively with changes in adhesion molecules and negatively with changes in NOx. Our findings indicate that regular physical training can decrease oxidative stress and improve nitric oxide metabolism and vascular adhesion in response to exercise in sickle cell trait carriers. This is likely explained by the improvement of antioxidant enzymes activities in trained subjects.

Research in athletes with sickle cell trait: just do it

the sickle cell trait (SCT) genotype, a condition found in an estimated 300 million people worldwide and 8–9% of African Americans is characterized by the heterozygous inheritance of a single defective beta globin gene. Inherited in the homozygous form, the beta globin gene mutation leads to

Exercise training blunts oxidative stress in sickle cell trait carriers

The aim of this study was to analyze the effects of exercise training on oxidative stress in sickle cell trait carriers. Plasma levels of oxidative stress [advanced oxidation protein products (AOPP), protein carbonyl, malondialdehyde (MDA), and nitrotyrosine], antioxidant markers [catalase, glutathione peroxidase (GPX), and superoxide dismutase (SOD)], and nitrite and nitrate (NOx) were assessed at baseline, immediately following a maximal exercise test (T(ex)), and during recovery (T(1h), T(2h), T(24h)) in trained (T: 8 h/wk minimum) and untrained (U: no regular physical activity) sickle cell trait (SCT) carriers or control (CON) subjects (T-SCT, n = 10; U-SCT, n = 8; T-CON, n = 11; and U-CON, n = 11; age: 23.5 ± 2.2 yr). The trained subjects had higher SOD activities (7.6 ± 5.4 vs. 5.2 ± 2.1 U/ml, P = 0.016) and lower levels of AOPP (142 ± 102 vs. 177 ± 102 μM, P = 0.028) and protein carbonyl (82.1 ± 26.0 vs. 107.3 ± 30.6 nm/ml, P = 0.010) than the untrained subjects in response to exercise. In response to exercise, U-SCT had a higher level of AOPP (224 ± 130 vs. 174 ± 121 μM, P = 0.012), nitrotyrosine (127 ± 29.1 vs.70.6 ± 46.6 nM, P = 0.003), and protein carbonyl (114 ± 34.0 vs. 86.9 ± 26.8 nm/ml, P = 0.006) compared with T-SCT. T-SCT had a higher SOD activity (8.50 ± 7.2 vs. 4.30 ± 2.5 U/ml, P = 0.002) and NOx (28.8 ± 11.4 vs. 14.6 ± 7.0 μmol·l(-1)·min(-1), P = 0.003) in response to exercise than U-SCT. Our data indicate that the overall oxidative stress and nitric oxide response is improved in exercise-trained SCT carriers compared with their untrained counterparts. These results suggest that physical activity could be a viable method of controlling the oxidative stress. This could have a beneficial impact because of its involvement in endothelial dysfunction and subsequent vascular impairment in hemoglobin S carriers.

Moderate endurance exercise is not a risk for rhabdomyolysis or renal failure in sickle cell trait carriers

This study tested the hypothesis that trained sickle cell trait (SCT) carriers are not subjected to greater risk of rhabdomyolysis or renal failure in response to moderate submaximal exercise than subjects with normal hemoglobin (CONT). Blood markers in 11 trained SCT carriers and 12 control counterparts were measured before and after 40 min of exercise at 55% of peak power output (Ppeak) conducted in thermoneutral environment. Body weights decreased with exercise in the same proportion in the two groups (from 65.1 ± 7.0 kg to 64.1 ± 7.0 kg and from 70.2 ± 6.6 to 68.6 ± 6.6 kg at the end of exercise in SCT and CONT, respectively). Heart rate and rectal temperature increased in the two groups in response to exercise, but the groups remained closely matched. Serum urea, CRP, CK and LDH were similar in the two groups and remained unchanged in response to exercise. Creatinine, Na(+), K(+), Cl(-) and myoglobin concentrations increased above baseline in response to exercise, with changes of the same magnitude in the two groups. In summary, the results of the present study suggest that moderate submaximal exercise is not unsafe from a biochemical point of view for sportsmen carrying SCT.

Co-Inheritance of Delta Thalassemia Might Contribute to the High Fetal Hemoglobin in Sickle Cell Anemia Patients with the Saudi-Indian Haplotype

Abstract 1056Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Province of Saudi Arabia have a fetal hemoglobin (HbF) level of about 20% that is associated with a mild clinical phenotype. Their HbS gene is on the Saudi-Indian (SI) haplotype characterized by an Xmn1 restriction site at position −158 5’ to HBG2 (rs7482144), a Hinc2 site 5’ to HBE (rs3834466) and other polymorphisms in the HBB gene-like cluster. However, the functional elements within the HBB gene-like cluster and elsewhere in the genome causing high HbF are yet to be determined. In a previous study we found that Saudi HbS homozygotes with the SI haplotype had a common region of autozygosity that spanned about 126 kb and included the complete HBB cluster. We have sequenced 13.6 kb in the HBD-HBG1 intergenic region (chr11:5255683-5269326, HG19), the region of the Corfu deletion. We found a SNP at position −68 bp 5’ to HBD (c.-118 C>T) only in individuals with a SI haplotype. This SNP was not present in dbSNP build 132 or the 1000 Genomes databases. No other mutation in HBD was identified. This same SNP was recently associated with δ thalassemia (Phylipsen et al. Int. J. Lab. Hematol. 2011, 33: 85–91). Homozygotes for the −68 HBD SNP, who were not on hydroxyurea, had a mean HbF of 23%, range 12.1%-33.4% and mean HbA2 of 2.1%, range 1.2%-3%. We did not find the −68 HBD SNP in 15 African Americans with sickle cell anemia selected because of their unusually high HbF (mean HbF 17.2%, range 11%-28.9%). Parents and sickle cell trait carriers from the families of Saudi Eastern Province patients were heterozygous for the −68 HBD mutation (mean HbF 1.6%, range 0–4.2% and mean HbA2 2.7%, range 2.4%-3.2%) and one normal sibling did not carry this mutation (HbF 0 and HbA2 2.9%). Thirty patients with sickle cell disease indigenous to the Southwestern Province of Saudi Arabia, with the HbS gene on an African origin haplotype, (mean HbF 15.5%, range 4.5%-23% and mean HbA2 2.9%, range 2.1%-3.4% in HbS homozygotes) and 13 normal Saudi controls were examined and none carried the −68 HBD mutation. We also sequenced HBD and its promoter in 8 Southwestern Province HbS homozygotes with a Benin haplotype, 4 with HbF <5% and 4 with HbF >15%, and none had the −68 HBD SNP or any other mutation in HBD. Inverse relationships between percent HbF level and percent HbA2 was seen in 3 groups of HbS homozygotes:1) SI haplotype homozygotes; 2) Benin haplotype homozygotes from the Southwestern Province; 3) African Americans with diverse HbS haplotypes. The increased HbF in sickle cell anemia with δ thalassemia might involve both post-translational and transcriptional mechanisms. Increased HbF levels might in part be due to the preferential post-translational assembly of αγ dimers compared with αδ and αβS dimers. When δ thalassemia reduces available δ-globin chains, this might further favor preferential binding of less positively charged γ-globin subunits to positively charged α-globin compared with more positively charged δ-globin subunits. Perhaps more importantly, at the transcriptional level, the −68 HBD δ+-thalassemia promoter mutation might favor the interactions of transcription complexes with HBG promoters. The stimulus of hemolytic anemia and expanded erythropoiesis might be required before the favorable genetic milieu for increased HbF production can be fully utilized with the achievement of clinically significant increases in HbF that modulates the course of disease. For example, increased HbF levels of only 3.3%-4.7% have been reported in some hematologically normal individuals with homozygous δ0 thalassemia (Ohta et al. Hemoglobin 1980, 4: 417–425). High HbF levels in SI haplotype HbS homozygotes might involve the interactions of one or more HBG regulatory regions linked to the HBB gene-like cluster, like the −68 HBD SNP, perhaps with trans acting elements. Although the −68 HBD δ+-thalassemia mutation is associated with the SI haplotype and high HbF, functional studies are needed to establish causation. Disclosures:No relevant conflicts of interest to declare.

Anaerobic storage of red blood cells: the need for caution regarding donor red cells with sickle cell trait.

Dear Sir, We concur with observations made by Dr. Ahmed in his letter “Anaerobic storage of red blood cells: the need for caution regarding donor red cells with sickle cell trait”1 about the potential unsuitability of anaerobic conditions for the storage of sickle cell trait (SCT) blood. Blood containing HbAS is well known to clog up leucoreduction filters and to enable unacceptable levels of leucocytes to escape during the filtering process2. At sufficiently low pO2, pH and high mean corpuscular haemoglobin concentration, HbAS in red blood cells (RBC) of SCT carriers polymerises. Although SCT is considered benign, symptoms and pathology suggesting occurrences of serious sickling events have been reported in numerous cases involving healthy SCT carriers placed under extremely demanding anoxic conditions3. Polymerisation of HbAS is well underway at a pO2 below 35 Torr for RBC with an HbS content of 40% or less, reducing RBC deformability and resulting in the well-described obstruction of leucoreduction filters2. In order to obtain significant anti-oxidative and metabolic benefits, we target anaerobic red blood cells to have less than 3% haemoglobin oxygen saturation (%SO2) before placing units in storage, and then maintain this low SO2 state throughout the storage period4. The pO2 required to achieve an SO2 below 3% is less than 5 Torr at 4 °C, and under such a low pO2, HbAS would polymerise. Even if it was permissible, inclusion of anti-sickling agents would be insufficient to prevent HbAS polymerisation, and storing RBC under a highly sickled state is known to be unacceptable because of prolonged mechanical stress to the cells and resulting haemolysis. If successful collection and storage of SCT blood is specifically desired, a test to exclude units with HbAS will be necessary to avoid subjecting these collected RBC to the anaerobic treatment. Further investigation will be required to determine the feasibility of storing SCT blood with a low HbS content. The AABB guidelines for transfusing erythrocytes containing sickle haemoglobin recommend avoiding transfusion of HbAS blood to foetuses and neonates, as well as to patients with sickle cell disease, but there is no definitive clinical evidence indicating a necessity to exclude RBC units containing HbAS for general transfusion5. Despite the fact that RBC containing HbAS are diluted in the recipient upon transfusion, under anoxic conditions that may exist in the recipient’s capillaries, these RBC may become rigid due to gelation of HbAS resulting in compromised oxygen delivery. Furthermore, RBC sickling in anoxic capillaries may result in capillary plugging and further harm the tissues. The safety of HbAS blood in the context of the general blood supply is an issue that lies outside the scope of Dr. Ahmed’s letter. For the reasons stated above however, we believe it is one that merits further careful scrutiny. In routine transfusion practice, we do not expect any harm to come from transfusing anaerobic blood to recipients, since infused RBC will be fully oxygenated at their first pass through the pulmonary capillaries. The effects of transfusing anaerobic blood to sickle cell disease patients will also need careful investigation.

Habitual Physical Activity and Endothelial Activation in Sickle Cell Trait Carriers

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. 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 minimum) SCT and control (CON) subjects (n = 8 per group; age = 23.5 ± 0.35 yr). 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. 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.

Hemorheology and exercise: effects of warm environments and potential consequences for sickle cell trait carriers

The relationship between blood rheology and hemodynamics is complex, and the following review presents several aspects of exercise hemorheology, with the focus on both cycling and running as exercise. The scientific literature assessing the effects of warm environment on exercise hemorheology is presented and the potential consequences for a specific population, sickle cell trait carriers, are discussed.

Effects of hydration and dehydration on blood rheology in sickle cell trait carriers during exercise

This study compared the hemorheological responses of a group of sickle cell trait (SCT) carriers with those of a control (Cont) group in response to 40 min of submaximal exercise (exercise intensity, 55% aerobic peak power) performed in two conditions: one with water offered ad libitum, i.e., the hydration (Hyd) condition, and one without water, i.e., the dehydration (Dehyd) condition. Blood and plasma viscosities, as well as red blood cell rigidity, were determined at rest, at the end of exercise, and at 2 h recovery with a cone plate viscometer at high shear rate and 37 degrees C. The SCT and Cont groups lost 1 +/- 0.7 and 1.6 +/- 0.6 kg of body weight, respectively, in the Dehyd condition, indicating a significant effect of water deprivation compared with the Hyd condition, in which body weight remained unchanged. Plasma viscosity increased with exercise and returned to baseline during recovery independently of the group and condition. As previously demonstrated, resting blood viscosity was greater in the SCT carriers than in the Cont group. Blood viscosity increased by the end of exercise and returned to baseline at 2 h recovery in the Cont group in both conditions. The blood viscosity of SCT carriers did not change in response to exercise in the Dehyd condition and remained elevated at 2 h recovery. This extended hyperviscosity, in association with other biological changes induced by exercise, could be considered as a risk factor for exercise-related events in SCT carriers, similar to vasoocclusive crises, notably during the recovery. In contrast, the Hyd condition normalized the hyperviscosity and red blood cell rigidity of the SCT carriers, with blood viscosity values reaching the same lower values as those found in the Cont group during the recovery. Adequate hydration of SCT carriers should be strongly promoted to reduce the clinical risk associated with potential hyperviscosity complications.

Skeletal muscle structural and energetic characteristics in subjects with sickle cell trait, α-thalassemia, or dual hemoglobinopathy

Previous studies have shown that subjects with sickle cell trait (SCT), alpha-thalassemia (alpha-t), and the dual hemoglobinopathy (SCT/alpha-t) manifest subtle, albeit significant, differences during exercise. To better understand such differences, we assessed skeletal muscle histomorphological and energetic characteristics in 10 control HbAA subjects (C), 5 subjects with alpha-t (alpha-t), 6 SCT carriers (SCT) and 9 SCT carriers with alpha-t (SCT/alpha-t). Subjects underwent a muscle biopsy and also performed an incremental maximal exercise and a time to exhaustion test. There were no observable differences in daily energy expenditure, maximal power output (Pmax), or time to exhaustion at 110% Pmax (Tex) among the groups. Blood lactate concentrations measured at the end of the Tex, muscle fiber type distribution, and mean phosphofructokinase (PFK), lactate dehydrogenase (LDH), beta-hydroxyacyl-CoA-dehydrogenase (HAD), and citrate synthase (CS) activities were all similar among the four groups. However, SCT was associated with a lower cytochrome-c oxidase (COx) activity in type IIa fibers (P<0.05), and similar trends were observed in fiber types I and IIx. Trends toward lower creatine kinase (CK) activity (P=0.0702) and higher surface area of type IIx fibers were observed in SCT (P=0.0925). In summary, these findings support most of the previous observations in SCT, such as 1) similar maximal power output and associated maximal oxygen consumption (VO2max) values and 2) lower exercise performances during prolonged submaximal exercise. Furthermore, performances during short supramaximal exercise were not different in SCT. Finally, the dual hemoglobinopathy condition does not seem to affect muscle characteristics.

Red blood cell deformability and aggregation, cell adhesion molecules, oxidative stress and nitric oxide markers after a short term, submaximal, exercise in sickle cell trait carriers

The present study investigated the hemorheological and endothelial alterations in sickle cell trait (SCT) carriers in response to a submaximal exercise. Eleven SCT carriers and 11 subjects with normal hemoglobin performed submaximal exercise for 15 min. Blood was sampled at rest, at the end of exercise, and at 2 and 24 h of recovery. Hemorheological alterations observed in the SCT group were as follows: 1) lower RBC deformability at high shear stress at all time-points, with no relation to oxidative stress, 2) higher disaggregation threshold at all time-points, suggesting RBC hyper-aggregation, and 3) higher blood viscosity at the end of exercise and during recovery. Exercise had a specific influence on the levels of the soluble cell adhesion molecules P and L-selectin in the SCT carriers, with higher P-selectin levels at all time-points and a greater increase in L-selectin levels during recovery. SCT carriers had slightly decreased nitrite levels at 24h of recovery, which might be clinically insignificant. In conclusion, the hemorheological alterations in association with lower NO production found in the SCT carriers are probably not sufficient to explain the medical complications sometimes reported in SCT carriers after exercise.

New fundamental and applied mechanisms in exercise hemorheology

The present article summarizes recent data presented at the Exercise and Hemorheology symposium during the 15th Conference of the European Society for Clinical Hemorheology and Microcirculation (June 28-July 1, Pontresina, Switzerland, 2009). The review starts with several unresolved paradoxes in exercise hemorheology. Then, we focus on the potential hemorheological and immunological mechanisms involved in the adverse events sometimes reported in exercising sickle cell trait carriers, and the role of habitual physical activity. In a fourth part, new results on the effects of acute hypoxia on blood rheology are presented. Finally, we will discuss recent experimental evidences on the role of exercise on the regulation of nitric oxide synthesizing mechanisms in red blood cell.

Remodeling of skeletal muscle microvasculature in sickle cell trait and α-thalassemia

The influence of sickle cell trait and/or alpha-thalassemia on skeletal muscle microvascular network characteristics was assessed and compared with control subjects [hemoglobin (Hb) AA] in 30 Cameroonian residents [10 HbAA, 5 HbAA alpha-thalassemia (alpha-t), 6 HbAS, and 9 HbASalpha-t] matched for maximal work capacity and daily energy expenditure. Subjects performed an incremental exercise to exhaustion and underwent a muscle biopsy. Muscle fiber type and surface area were not different among groups. However, sickle cell trait (SCT) was associated with lower capillary density (P < 0.05), lower capillary tortuosity (P < 0.001), and enlarged microvessels (P < 0.01). SCT carriers had reduced counts of microvessels <5-microm diameter, but a higher percentage of broader microvessels, i.e., diameter >10 microm (P < 0.05). alpha-Thalassemia seemed to be characterized by a higher capillary tortuosity and unchanged capillary density and diameter. Thus, while SCT is a priori clinically benign, we demonstrate for the first time that significant remodeling of the microvasculature occurs in SCT carriers. These modifications may possibly reflect protective adaptations against hemorheological and microcirculatory dysfunction induced by the presence of HbS. The remodeling of the microvascular network occurs to a lesser extent in alpha-thalassemia. In alpha-thalassemic subjects, increased capillary tortuosity would promote oxygen supply to muscle tissues and might compensate for the lower Hb content often reported in those subjects.

Lactate Removal Ability and VO2 Recovery Kinetics in Sickle Cell Trait Carriers Compared with Normal Haemoglobin Subjects: Preliminary Data

Because of the reduced affinity of haemoglobin S to oxygen and the altered blood rheological profile of sickle cell trait carriers (AS), it is often thought that exercise physiological responses should differ between AS and subjects with normal haemoglobin (AA). The present study aimed to compare the ability to remove blood lactate and the characteristics of oxygen uptake (VO2 kinetics were not significantly different between the two groups (P > 0.05). No significant relationship was observed between  2 and A2 (r = 0.04; P > 0.05) or between  2 and  2 (r = -0.44; P > 0.05) in all groups. It seems that the ability to recover or to remove lactate after a short supramaximal exercise does appear unaltered by sickle cell trait. It is possible that the elevated blood viscosity reported several times in AS could have promoted greater vasodilatation which in turn may favour exercise recovery to a similar level observed in subjects with normal haemoglobin. Our findings may suggest that AS and AA subjects need similar recovery after exhausting exercise. However, it is also known that AS may be prone to medical complications in response to exercise. So, the presence of clinical sign should justify to prolong recovery or to stop exercise in AS.