Abstract

Abstract 3244

Introduction:

The United States Armed Forces estimate that sickle cell trait (SCT) conveys a 30-fold risk of sudden cardiac death and a 200-fold risk of rhabdomyolysis following exertion in recruits during basic training. Catastrophic cardiovascular collapse in African Americans with SCT has been the leading cause of death in NCAA football players in the last decade, prompting the NCAA to make testing for SCT mandatory in all Division-1 athletes. We hypothesized that in SCT subjects that abnormal RBC metabolic reserves lead to abnormal muscle blood flow supply in exercising muscle. We tested this hypothesis in 11 subjects with SCT and 10 age, sex, and ethnicity matched controls.

Methods:

Patients were instrumented with pulse oximetry and beat-to-beat blood pressure recording apparatus in the nondominant hand; near infrared spectrometry measurements were performed over the extensor and flexor compartments of the dominant arm. Maximum voluntary contraction (MVC) was assessed by handgrip dynamometer in the dominant arm, following by placement of an intravenous catheter in the antecubital fossa. Baseline CBC, red cell amino acids, plasma amino acids and glutathione metabolites were collected and appropriately processed. Patients then maintained 60% MVC exercise until exhaustion. Following 8 minutes of recovery, a venous blood gas and repeat glutathione metabolites were drawn.

Table 1
Pre HandgripPost Handgrip
CTLSCTpCTLSCTp
O296.3 ± 0.5 96.3 ± 0.8 0.43 96.1 ± 0.6 96.4 ± 0.7 0.16 
NIRS % 56.1 ± 8.5 53.4 ± 6.2 0.65 62.1 ± 10.8 61.7 ± 2.7 0.97 
Heart Rate 63.5 ± 10.5 67.3 ± 18.7 0.82 61.8 ± 10.7 65.3 ± 18.1 0.76 
Systolic BP 143.3 ± 22.2 133 ± 21.4 0.38 146 ± 24 139 ± 22 0.84 
Diastolic BP 76.5 ± 11.9 76.9 ± 12.5 0.58 75.7 ± 12.5 78.2 ± 11.9 0.21 
Cardiac Index 3.5 ± 0.4 3.3 ± 0.4 0.56 3.6 ± 0.5 3.5 ± 0.5 0.93 
Hemoglobin 12.3 ± 0.85 12.5 ± 0.6 0.56    
Hematocrit 37.4 ± 2.4 36.4 ± 1.8 0.28    
MCHC 32.9 ± 1.1 34.4 ± 0.6 0.003    
Glutamine 280 ± 68 253 ± 40 0.35    
Glutamate 170 ± 26 198 ± 30 0.11    
GLN/GLM ratio 1.73 ± 0.58 1.30 ± 0.21 0.14    
Citrulline 24.1 ± 9.3 32.2 ± 8.7 0.05    
GSH 8.76 ± 1.17 7.57 ± 1.82 0.05 8.34 ± 1.75 7.35 ± 1.84 0.26 
GSSG 2.95 ± 1.27 2.15 ± 0.75 0.17 2.99 ± 0.78 2.49 ± 0.81 0.38 
Glutathione 14.7 ± 3 11.7 ± 3 0.04 20.4 ± 4.1 19.9 ± 3.4 0.21 
pH    7.36 ± 0.03 7.36 ± 0.02 0.36 
pCO2    49 ± 4.7 42 ± 5.3 0.54 
pO2    34.1 ± 11.7 22.4 ± 5.8 0.004 
HCO3    27.3 ± 1.6 29.2 ± 1.9 0.07 
base excess    1.1 ± 1.3 2.8 ± 1.5 0.035 
O2 saturation    56.6 ± 19.9 35.6 ± 13.8 0.007 
Lactate    9.3 ± 7.1 13.9 ± 3.5 0.009 
Pre HandgripPost Handgrip
CTLSCTpCTLSCTp
O296.3 ± 0.5 96.3 ± 0.8 0.43 96.1 ± 0.6 96.4 ± 0.7 0.16 
NIRS % 56.1 ± 8.5 53.4 ± 6.2 0.65 62.1 ± 10.8 61.7 ± 2.7 0.97 
Heart Rate 63.5 ± 10.5 67.3 ± 18.7 0.82 61.8 ± 10.7 65.3 ± 18.1 0.76 
Systolic BP 143.3 ± 22.2 133 ± 21.4 0.38 146 ± 24 139 ± 22 0.84 
Diastolic BP 76.5 ± 11.9 76.9 ± 12.5 0.58 75.7 ± 12.5 78.2 ± 11.9 0.21 
Cardiac Index 3.5 ± 0.4 3.3 ± 0.4 0.56 3.6 ± 0.5 3.5 ± 0.5 0.93 
Hemoglobin 12.3 ± 0.85 12.5 ± 0.6 0.56    
Hematocrit 37.4 ± 2.4 36.4 ± 1.8 0.28    
MCHC 32.9 ± 1.1 34.4 ± 0.6 0.003    
Glutamine 280 ± 68 253 ± 40 0.35    
Glutamate 170 ± 26 198 ± 30 0.11    
GLN/GLM ratio 1.73 ± 0.58 1.30 ± 0.21 0.14    
Citrulline 24.1 ± 9.3 32.2 ± 8.7 0.05    
GSH 8.76 ± 1.17 7.57 ± 1.82 0.05 8.34 ± 1.75 7.35 ± 1.84 0.26 
GSSG 2.95 ± 1.27 2.15 ± 0.75 0.17 2.99 ± 0.78 2.49 ± 0.81 0.38 
Glutathione 14.7 ± 3 11.7 ± 3 0.04 20.4 ± 4.1 19.9 ± 3.4 0.21 
pH    7.36 ± 0.03 7.36 ± 0.02 0.36 
pCO2    49 ± 4.7 42 ± 5.3 0.54 
pO2    34.1 ± 11.7 22.4 ± 5.8 0.004 
HCO3    27.3 ± 1.6 29.2 ± 1.9 0.07 
base excess    1.1 ± 1.3 2.8 ± 1.5 0.035 
O2 saturation    56.6 ± 19.9 35.6 ± 13.8 0.007 
Lactate    9.3 ± 7.1 13.9 ± 3.5 0.009 
Results:

Patient and control groups were well age and sex matched with a mean age of 33 years [range 23.1 – 55.6] and 72% female participants. Complete blood counts were nearly identical except for higher MCHC in SCT (Table 1). Reduced and total RBC glutathione were decreased in SCT at rest. Red cell glutamine, glutamate, and glutamine/glutamate ratio were not statistically different. Plasma amino acid profiles were unremarkable except for higher citrulline in SCT. SCT and CTL subjects maintained handgrip for the same duration (105 ± 72 versus 102 ± 27 seconds); there was no correlation with handgrip time and metabolic parameters. Post handgrip blood gas demonstrated markedly lower pO2 and O2 saturation as well as increased lactate and base excess. Lactate was reciprocally related to baseline reduced glutathione concentration (r2 = 0.27, p=0.013). Post handgrip NIRS saturation increased in both groups but there was no difference between them.

Conclusion:

SCT erythrocytes are oxidatively stressed at baseline, most likely resulting from superoxide generation from hemoglobin S. Impaired redox buffering is associated with delayed lactate clearance following exhaustive handgrip exercise. Venous pO2 and O2 saturation are also markedly lower in SCT patients following handgrip, reflecting either a shift in hemoglobin dissociation curve or superoxide generation from hemoglobin S. However, the absence of significant post handgrip desaturation by NIRS is most consistent with shifted hemoglobin dissociation curve through metabolic mediators such as adenosine. Nonetheless, pO2's as low as 9 torr were observed in this relatively simple study, raising the possibility that dangerous muscular hypoxia could potentially be generated under more extreme conditions. Further work is necessary to determine the mechanisms and clinical important of the persistent post-exercise venous desaturation in SCT.

Disclosures:

Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Coates:Novartis: Speakers Bureau; Apopharma: Consultancy.

Author notes

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Asterisk with author names denotes non-ASH members.