Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease

Abstract

Sickle cell disease (SCD) subjects exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crisis by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. As SCD subjects have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity towards vasoconstriction. We exposed 17 SCD and 16 control subjects to a sequence of predetermined threshold temperatures for cold and heat detection as well as cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand using photo-plethysmography, and cardiac autonomic balance was assessed using heart rate variability. Thermal stimuli at both detection and pain thresholds caused significant decrease in MBF in the contralateral hand within seconds of stimulus application, with SCD subjects showing significantly stronger vasoconstriction (p=0.019). Furthermore, SCD subjects showed greater progressive decrease in blood flow than controls, with poor recovery between episodes of thermal stimulation (p=0.042). SCD subjects had faster vasoconstriction than controls (p=0.033), especially with cold detection stimulus; individuals with higher anxiety also vasoconstricted faster (p=0.007). Augmented vasoconstriction responses and progressive decrease in perfusion with repeated thermal stimulation in SCD is indicative of autonomic hypersensitivity in the microvasculature. This is likely to increase red cell entrapment in response to clinical triggers like cold or stress that have been associated with vaso-occlusive crisis in SCD.

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease

“…Consistent with this finding, Willen et al 16 showed no significant association between low mean nocturnal SpO 2 and incidence of VOC in the SAC participants studied here. On the other hand, we 5,7,8,24,25 and others 26‐29 have shown significant dysautonomia in SCD. Therefore, we examined measures of cardiac ANS balance (LHR, RMSSD) but found no association with VOC rate (modesl 8‐9 Table S2).…”

Vasoconstriction Response to Mental Stress in Sickle Cell Disease: The Role of the Cardiac and Vascular Baroreflexes

“…While we found that interindividual variability of BRSv contributes to the variability in vasoconstriction responses across individuals, adjusting for differences in BRSv actually further reduced the inter-group differences in MTS-induced vasoconstriction responses (Figure 4B). This stands in contrast with the enhanced vasoconstriction responses found in SCD subjects during thermal pain stimuli (Khaleel et al, 2017;Veluswamy et al, 2020). Since there is increasing evidence that dysautonomia in SCD is associated with autonomic hyperresponsiveness, one would have expected the SCD subjects with high sympathetic tone to have displayed stronger vasoconstriction responses to MTS.…”

“…In a previous study ( Shah et al, 2020 ), we measured the cardiovascular responses of SCD and healthy subjects to MTS tasks that included N-back, Stroop, and anticipated pain tests. However, in contrast to physical autonomic stressors, such as heat pain and cold pain, where SCD subjects showed exaggerated vasoconstriction responses ( Khaleel et al, 2017 ; Veluswamy et al, 2020 ), the responses of the SCD subjects to MTS were not different from their control counterparts. However, there is substantial variability in the magnitude of the responses within the SCD and control subjects.…”

“…ANS could be modulated by pro-inflammatory states, and in turn, could exacerbate inflammatory responses creating a vicious cycle of pain ( Ballas et al, 2012 ). Our group has employed multiple laboratory stressors, such as hypoxia ( Sangkatumvong et al, 2011 ), cold face stimulation ( Chalacheva et al, 2015 ), heat pain ( Khaleel et al, 2017 ), cold pain ( Veluswamy et al, 2020 ), and orthostatic stress ( Chalacheva et al, 2019 ), to determine the resulting ANS responses in SCD and control subjects. These studies demonstrated the presence of significant abnormalities in the ANS responses of the subjects with SCD.…”

Vasomotor hyperresponsiveness in SCD

“…Chiesa et al have described excellent outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) for 712 patients with chronic granulomatous disease (CGD). This study reports the largest published cohort to date by a significant margin 1. As a young hematologist set on becoming a transplanter, I sought advice from someone more experienced than myself, and one of my colleagues replied, "Know as much as you can about the underlying disease.…”