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P. Shah et al.
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Figure 6. Autonomic nervous system responses to mental stress. (A) R-to-R interval (sec) and (B) high frequency power (sec2/Hz, shown on a log scale) in response to the N-Back and Stroop tasks in all subjects. There is a significant decrease in R-to-R interval and parasympathetic withdrawal during mental stress tasks compared to baseline. SE: standard error of mean; HFP: high frequency power.
hyperreactivity by enhancing the sympathetic nervous system and dampening the parasympathetic system in SCD subjects compared to non-SCD individuals.16,17 Sympathetic and parasympathetic responses have been related to clinical vaso-occlusion in SCD, through ANS modulation of regional blood flow.15,17 SCD is probably the best example of a disorder in which decreased microvas- cular perfusion can be directly related to the pathology of the disorder, because the increase in transit time from decreased blood flow promotes entrapment of rigid red cells in small vessels.3,5 To our knowledge, this is the first study to quantify regional blood flow modulated by ANS reactivity under mental stress in SCD.
Our data show that experimental mental stress caused a decrease in regional blood flow in all participants. While we thought that SCD subjects would exhibit stronger vasoconstriction because of their hyperresponsiveness to sympathetically induced stimuli, such as sighing,28 we did not detect a difference in stress-induced vasoconstriction between SCD patients and controls. We did find a signifi- cantly higher anxiety response score (P=0.03) in subjects who were exposed to the more difficult mental stress test first (Stroop). We also found that the degree of vasocon- striction was proportional to the magnitude of the stress. Subjects reported that overall the Stroop task was more stressful: accuracy scores were lower and there was also a greater decrease in blood flow with this cognitive stressor task. However, different sublevels of difficulty within a task type did not correlate with levels of vasoconstriction. This finding suggests that consecutive stressful events could make SCD patients more vulnerable to vaso-occlu- sion. We think that variability in the vasoconstriction response to stress may account in part for differences in clinical severity among SCD patients who have the same hemoglobin phenotype. The frequency of VOC and inten- sity of pain are higher among patients found to have high anxiety and stress scores on standard psychological assess- ments.8,41,42 We tried to correlate the vasoconstrictive response with clinical severity. As our SCD patients were either on chronic transfusion or hydroxyurea, the number of VOC was too low to detect differences in this current relatively small sample.
Along with a strong vasoconstriction response, signifi- cant autonomic reactivity was seen in all subjects. The Stroop test was consistently more stressful, and induced greater vasoconstriction as well as greater autonomic reac- tivity. There was both sympathetic activation as well as parasympathetic withdrawal during this cognitive task. Mental stressors are known to influence autonomic func- tion by sympathetic or parasympathetic tone alterations. Higher anxiety induces atherosclerosis via enhanced sym- pathetic modulation, increasing the risk of cardiovascular disease.43 In addition, mental stress and anxiety have been linked to impaired endothelial function via autonomic dysfunction.43–45 Endothelial function, quantified by flow mediated dilation, decreases as a result of mental stress tasks.46 Similarly, in SCD, a synergistic interaction between impaired local vascular function and the exagger- ated neurally mediated vasoconstrictive response could further reduce peripheral blood flow, setting the stage for VOC.
Consistent with the findings of our previous study,18 anticipation of pain caused significant vasoconstriction and this response was quantitatively greater than that of the calibrated experimental stress tasks (Figure 3). We do not have strong evidence to conclude that the presence of SCD alone influences mental stress-induced vasoconstric- tion but anxiety seems to be a modifying factor. Interestingly unlike control subjects, SCD subjects who were highly anxious had less vasoconstriction during the PA task and vice versa. We think that this pattern of response occurred because highly anxious subjects were already vasoconstricted at baseline and this limited the magnitude of further vasoconstriction. So the fact that SCD subjects have less change in the vasoconstriction response to the stressors than controls actually reflects their chronically vasoconstricted state. Although not sta- tistically significant, the trend of lower baseline blood flow with high anxiety in SCD can be seen in Online Supplementary Figure S1, which also shows the significant variability in baseline measures. Photoplethysmogram and microvascular perfusion signals from Perimed do not have absolute units, so measurements made as percent changes from baseline are more reliable, basically correct-
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haematologica | 2020; 105(1)