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

Abstract

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises 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. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Graphical abstract

Figure 1.

Thermal stimulus protocol showing the timing and order of the different thermal stimuli after a baseline recording period. Red signal with the pulses represents the thermode temperature, showing the pattern of thermal stimuli. During the verbal instructions, the participant was informed of upcoming thermal stimuli, but there was minimal interaction thereafter.

Figure 2.

Microvascular blood flow during baseline and thermal stimulation cycles in all subjects. There was a significant decrease in MBF from baseline with thermal stimulation. Mean ± SEM. Repeated-measures ANOVA from baseline MBF. *P = .027; **P < .0001.

Figure 3.

Log-transformed percentage of change in mean MBF with thermal stimulation in patients with SCD and controls. For all thermal stimuli, patients with SCD showed a significantly greater decrease in MBF (multivariate repeated-measures ANOVA, P = .019), as depicted on the y-axis. Patients with SCD had significantly higher PASS scores than controls (P = .013) as depicted on the x-axis. By multivariate analysis, the PASS score was a significant predictor of MBF response (P = .026). *Log₁₀ (x + 1) transformed data.

Figure 4.

Time to vasoconstriction with thermal stimulation in patients with SCD and controls. By multivariate repeated-measures analysis, patients with SCD showed significantly faster vasoconstriction responses (P = .033) to thermal stimulation as depicted in the y-axis.

Figure 5.

Individual variability in vasoconstrictive tone with thermal stimulation. (A) Top signal represents thermode temperature; next 2 signals depict microvascular blood flow in the finger of 2 representative subjects. Subject 1 shows vasoconstriction during each cycle of 4 thermal pulses, with good recovery of blood flow to baseline between cycles (Pre-CD, Pre-HD, Pre-HP, and Pre-CP). Subject 2 shows vasoconstriction during each cycle of thermal pulses, with poor recovery of blood flow between stimuli and progressive decrease in flow. (B) Linear slopes depicting microvascular blood flow between thermal stimuli (Pre-CD, Pre-HD, Pre-HP, and Pre-CP) for controls and patients with SCD subjects. The patients (red) showed poor recovery with a progressive decrease in blood flow between thermal stimuli compared with controls (blue) who mostly showed good recovery of the blood flow to baseline between thermal stimuli. (C) The mean recovery slope for SCD and control individuals (Student t test of mean slope values, P = .042). CD, cold detection; CP, cold pain; HD, heat detection; HP, heat pain.

Figure 6.

Heart rate variability responses to thermal stimulation in all participants. A significant increase in log LFP (sympathetic+parasympathetic component) (A) and in log LHR (sympathovagal balance) (B) with painful stimuli compared with baseline.