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Stress and vasoconstriction in SCD and controls
ing for baseline variability and allowing detection of the differences seen in Figure 5. These findings may be related to pain catastrophization and increased psychophysical pain sensitivity due to frequent pain episodes.7,47,48 Over the years, pain catastrophization may increase the fre- quency of pain and severity of pain crises.47,49 From a standpoint of neural physiology, repeated acute pain cre- ates a central neural pathological pain connectome50 that leads to baseline chronic pain and chronic vasoconstric- tion. Although baseline blood flow was not statistically significantly lower, probably due to insufficient study power, we suspect that the above-described phenomenon is the explanation for our findings and warrants further study.
We showed that neurally mediated vasoconstriction is a biophysical marker of mental stress in SCD patients and controls. Mental stress has been identified as a trigger for pain crises in SCD and its connection with a decrease in microvascular perfusion seems to make a causal link to VOC. The probability of vaso-occlusion is predicted to be related to the relation between time to polymerization of deoxy HbS and microvascular flow.3,5 Obviously, HbS is the major pathology in SCD. However, neurally mediated changes in microvascular flow certainly play a significant and unappreciated role. Individual variation in patterns of vasoconstriction with different ANS reactivity may offer a possible biological explanation for the variability in the fre- quency of VOC in SCD patients with similar hemoglobin phenotype. Identifying the high-risk individuals who show a phenotype of chronic vasoconstriction and repeat- ed pain crises, and targeting them with neuro-modulatory cognitive-based therapies may improve vascular and neu- ral physiology in SCD. In the primary stage of a crisis,
implementing these learned cognitive-based therapies or distraction and relaxation techniques will help to improve the prognosis during acute pain. Microvascular flow in response to stress may also serve as an important surrogate endpoint for therapy in SCD and other diseases in which small vessel blood flow and reactivity are important.
Some limitations of this study should be acknowledged. One limitation was that the small sample size did not allow us to detect a difference in the magnitude of vaso- constriction between groups and correlate it with a clinical outcome such as VOC. Since the concept that mental stress causes vasoconstriction has not been studied in SCD, prior effect size was not known to permit sample size cal- culation. Another reason for lack of difference between groups is that over 90% of our patients are on hydroxyurea or chronic transfusion and thus clinical crises are relatively uncommon. Any real magnitude differences would be more likely to emerge in studies with larger samples and untreated patients. However, the primary aim of this study was to understand the changes in peripheral and car- diac responses to mental stress. The fundamental study design presented here was able to detect changes in phys- iological signals with millisecond accuracy and clearly showed vasoconstriction responses and ANS reactivity due to mental stress in all subjects. We think that the conse- quences of these findings are mechanistically related to the pathophysiology of sickle cell vaso-occlusion.
Acknowledgments
This work was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute (U01 HL117718). The authors thank Justin Abbott for his con- tribution to the data collection.
References
1. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757): 2018-2031.
2. KassimAA,DeBaunMR.Sicklecelldisease, vasculopathy, and therapeutics. Annu Rev Med. 2013;64(1):451-466.
3. Christoph GW, Hofrichter J, Eaton WA. Understanding the shape of sickled red cells. Biophys J. 2005;88(2):1371-1376.
4. EatonWA,HofrichterJ.Sicklecellhemoglo- bin polymerization. In: Advances in Protein Chemistry. Elsevier; p63-279.
5. Eaton WA, Hofrichter J, Ross PD. Editorial: Delay time of gelation: a possible determi- nant of clinical severity in sickle cell disease. Blood. 1976;47(4):621-627.
6. MurrayN,MayA.Painfulcrisesinsicklecell disease--patients’ perspectives. BMJ. 1988;297(6646):452-454.
7. Bhatt RR, Martin SR, Evans S, et al. The effect of hypnosis on pain and peripheral blood flow in sickle-cell disease: a pilot study. J Pain Res. 2017;10:1635-1644.
8. Gil KM, Carson JW, Porter LS, et al. Daily stress and mood and their association with pain, health-care use, and school activity in adolescents with sickle cell disease. J Pediatr Psychol. 2003;28(5):363-373.
9. Levenson JL, McClish DK, Dahman BA, et
al. Depression and anxiety in adults with
sickle cell disease: the PiSCES project.
Psychosom Med. 2008;70(2):192-196. 407.
10. Thomas LS, Stephenson N, Swanson M, Jesse DE, Brown S. A pilot study: the effect of healing touch on anxiety, stress, pain, pain medication usage, and physiological measures in hospitalized sickle cell disease adults experiencing a vaso-occlusive pain episode. J Holist Nurs. 2013;31(4):234-247.
11. Jain D. Mental stress, a powerful provoca- teur of myocardial ischemia: Diagnostic, prognostic, and therapeutic implications. J Nucl Cardiol. 2008;15(4):491-493.
12. Wei J, Rooks C, Ramadan R, et al. Meta- analysis of mental stress-induced myocar- dial ischemia and subsequent cardiac events in patients with coronary artery disease.. Am J Cardiol. 2014;114(2):187-192.
13. Porter LS, Gil KM, Sedway JA, Ready J, Workman E, Thompson RJ. Pain and stress in sickle cell disease: an analysis of daily pain records. Int J Behav Med. 1998;5(3):185–203.
14. Porter LS, Gil KM, Carson JW, Anthony KK, Ready J. The role of stress and mood in sick- le cell disease pain: an analysis of daily diary data. J Health Psychol. 2000;5(1):53-63.
15. Connes P, Coates TD. Autonomic nervous system dysfunction: implication in sickle cell disease. C R Biol. 2013;336(3):142–147.
16. Pearson SR, Alkon A, Treadwell M, Wolff B, Quirolo K, Boyce WT. Autonomic reactivity
17. Treadwell MJ, Alkon A, Styles L, Boyce WT. Autonomic nervous system reactivity: chil- dren with and without sickle cell disease. Nurs Res. 2011;60(3):197-207.
18. Khaleel M, Puliyel M, Shah P, et al. Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain. Am J Hematol. 2017;92(11):1137-1145.
19. Sangkatumvong S, Khoo MCK, Kato R, et al. Peripheral vasoconstriction and abnormal parasympathetic response to sighs and tran- sient hypoxia in sickle cell disease. Am J Respir Crit Care Med. 2011;184(4):474-481.
20. Chalacheva P, Khaleel M, Sunwoo J, et al. Biophysical markers of the peripheral vaso- constriction response to pain in sickle cell disease. PLoS One. 2017;12(5):e0178353.
21. Connes P. Altered autonomic nervous sys- tem function in sickle cell disease. Am J Respir Crit Care Med. 2011;184(4):398-400.
22. Goor DA, Sheffy J, Schnall RP, et al. Peripheral arterial tonometry: a diagnostic method for detection of myocardial ischemia induced during mental stress tests: a pilot study. Clin Cardiol. 2004;27(3):137-141.
23. The State-Trait Anxiety Inventory (STAI).
and clinical severity in children with sickle
cell disease. Clin Auton Res. 2005;15(6):400-
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