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Stress and vasoconstriction in SCD and controls
anxiety responses than did the subjects who performed the N-back task first (mean difference=10; P=0.03). Overall the accuracy score was significantly lower for the Stroop task than for the N-back task in all subjects (mean score difference=25, P<0.001).
The accuracy score for the Stroop and N-back tasks decreased as the difficulty increased from zero-back to three-back in the N-back task and from level one to level three in the Stroop task (P<0.0001) (Figure 4) but there was no further change in blood flow with increasing diffi- culty. Once the subjects manifested vasoconstriction, in comparison with baseline vascular tone, the vasoconstric- tion remained throughout the whole task regardless of the difficulty of the tasks.
Vasoconstriction response to perceived anxiety during pain anticipation
On robust regression, the effect of state anxiety on blood flow response was greater in SCD patients than in controls (P=0.03 for the interaction), suggesting that high- er anxiety at baseline (STAI Y-1) in SCD subjects is associ- ated with less change in blood flow (coefficient = -1.85, P=0.002) in response to pain anticipation (Figure 5). State anxiety had no effect on change in blood flow in control subjects. To understand why SCD subjects would have less response with high anxiety, we looked at the baseline blood flow. We found that highly anxious subjects tended to have a lower mean baseline blood flow (Online Supplementary Figure S1), meaning they were already vaso- constricted at baseline, limiting them from further vaso- constriction. This trend was not seen among controls. (Online Supplementary Figure S2A, B: high-anxiety SCD responder and low-anxiety SCD responder).
Cardiac autonomic response
Since the ANS regulates blood flow and SCD subjects have dysautonomia,15,28,31,32 we explored the effect of men- tal stress responses on cardiac autonomic balance. In com-
parison to the value at baseline, there was a significant decrease in R-to-R interval, signifying an increase in heart rate, during all tasks (P<0.0001) (Figure 6A). As for the microvascular blood flow response, the R-to-R interval was less during the Stroop task than during the N-back task (P=0.002).
There was significant parasympathetic withdrawal dur- ing the N-back and Stroop tasks as reflected by the drop in high frequency power (P=0.002 and P<0.0001, respective- ly) (Figure 6B) The Stroop task caused stronger parasym- pathetic withdrawal than the N-back task (P<0.0001). There was more sympathetic activation during the Stroop test (low-to-high power ratio: P=0.03), but not during the N-back task. We did not analyze autonomic reactivity dur- ing the PA task because the 1-minute test period was not long enough to derive spectral indices.29
Discussion
VOC is a significant complication of SCD and a major cause of morbidity and mortality.33 The frequency of VOC is related in part to hemoglobin-F content, white blood cell count, inflammatory status and other factors.34-36 However, there is still significant variability in crisis frequency among SCD subjects with otherwise similar hematologic status. Pain crises can be promoted by preceding dehydra- tion, infection, injury, exposure to cold or emotional stress.37,38 Much of the research in past decades has focused on adhesion and processes attributed to occlusion in the post-capillary venule, and to decreased flow due to nitric oxide depletion.39 While stress and cold are often men- tioned, very little attention has been paid to decreased flow due to neurally induced vasoconstriction.32,40 SCD patients undergo a tremendous amount of stress not only due to environmental challenges but also the illness-relat- ed stress of painful episodes, repeated medical procedures and life-threatening complications. Stress causes ANS
Figure 5. Relation between vasoconstriction during pain anticipation and perceived stress (state anxiety) in sickle cell disease subjects and controls. State anxi- ety was determined at baseline by the State-Trait Anxiety Inventory Y-1 questionnaire (STAI Y-1) and assessed in response to change in microvascular blood- flow during pain anticipation (PA) in sickle cell disease (SCD) subjects (closed circles, —) and controls (open diamonds, - - -). SCD subjects who were highly anxious at baseline had a smaller vasoconstriction response during the PA task than the SCD subjects who were less anxious (P=0.002); this effect was not seen among con- trols. MBF: microvascular blood flow.
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