Page 94 - 2020_01-Haematologica-web

P. Shah et al.
HbS polymerization and the subsequent flexible-to-rigid transformation. If the transit time of RBC through the microvasculature is longer than the polymerization time, sickled RBC will lodge in the microvasculature.3 Any trig- ger that decreases microvascular blood flow will prolong the transit time, promoting the entrapment of sickled RBC, resulting in vaso-occlusion. This physiology of SCD, described decades ago,4,5 is fundamental to understanding the triggering of VOC. Patients report that stress, cold, and pain itself can trigger the onset of VOC6 but the frequency of VOC is highly variable. To date, the mechanism of how such events might trigger regional vaso-occlusion has not been fully elucidated.
Psychological stress is an exacerbating factor in many chronic illnesses, such as SCD,7–10 coronary artery disease and myocardial ischemia.11,12 Stress is significantly associ- ated with increased pain intensity, reductions in social and physical activities and greater health care utilization.8,13,14 Day-to-day stressors have been associated with onset of pain and the course of VOC in SCD.9,10 Stress is well- known to modulate autonomic nervous system (ANS) activity which in turn plays a major role in the regulation of regional blood flow.15 Interestingly, SCD children with greater mental-stress-induced autonomic reactivity had more severe clinical disease.16,17 SCD subjects also have augmented ANS-mediated vasoconstriction in response to
18-20
sighing, hypoxia, and pain. Therefore, autonomic dys-
regulation in SCD represents a plausible physiological link
between mental stress and sickle RBC retention in the
16,18–21
microvasculature. Further understanding of this pro-
posed mechanism of VOC triggering would not only help to predict disease manifestations, but would also open up opportunities for therapeutic intervention in disorders such as SCD in which preservation of microvascular blood flow is important.22
To address the role of mental stress in the physiology of SCD, we objectively quantified microvascular blood flow, measured by photoplethysmography, in response to stan- dardized mental stress tasks in subjects with SCD and in controls. We also assessed cardiac ANS balance by analy- sis of heart rate variability in response to mental stress. We correlated photoplethysmogram-derived physiological indices with subjective indices of perceived stress assessed from standardized anxiety questionnaires. The aim of this study was to determine the relationship of peripheral and cardiac ANS responses with mental stress in SCD.
Methods
The study was conducted under an institutional review board- approved protocol at the Children’s Hospital Los Angeles with approved consent/assent. Twenty SCD subjects with Hb SS, S-β0, S-β+ or SC genotype and 16 age- and race-matched controls from the patients’ family and friends were recruited.
Experimental setup and study protocol
All studies were performed in an ANS laboratory under strictly controlled settings.18 Neuropsychological stress was assessed at baseline using the State-Trait Anxiety Inventory (STAI) question- naire.23 The STAI Y-1 and Y-2 evaluate “anxiety at this moment, aka state anxiety” and “how people generally feel, aka trait anxiety”, respectively.
Following 5 minutes of baseline recording, the stress induction protocol was presented through psychological software (E-prime
Figure 1. Time sequence of the study protocol. The subjects were randomly assigned to perform the N-back or Stroop test first. STAI: State-Trait Anxiety Inventory; Y-1: Sate question- naire; Y-2 Trait questionnaire.
2.0, Psychology Software Tools, USA). The protocol consisted of a memory task (N-back)24 and a conflict test (Stroop),25,26 presented in a randomized order, followed by a pain anticipation (PA) test (Figure 1). During the N-back task, the subjects were asked to respond when the current letter matched the letter from n steps (n=zero, one, two, or three back) earlier in the sequence. During the Stroop task, the participants were asked to identify the font color of a word, not the written name of the word. We measured state anxiety between tasks. During the PA task, subjects read the following sentence on their computer screen: “You will receive a maximum pain stimulus in one minute. When you cannot tolerate the pain any longer, say STOP and the device will cool down to normal level immediately”. However, no pain stimulus was actu- ally applied.
Physiological measurements and analysis parameters
All the physiological monitoring sensors were attached to the subjects’ left arm. Microvascular blood flow was measured using photoplethysmography (Nonin Medical Inc., USA) and laser Doppler flowmetry (Perimed, Sweden). Respiration (thoracic and abdominal bands, zRip DuraBelt, Philips), the electrocardiogram and continuous blood pressure (Nexfin, Amsterdam) were record- ed.
Recorded data from all devices were exported for processing and analysis in MATLAB. The photoplethysmogram amplitude was normalized to its own 95th percentile value during the full study. The average microvascular blood flow was calculated over the 5 min baseline period, the N-back, Stroop and PA tasks. The percent decrease in the amplitude of the photoplethysmogram or microvascular perfusion waveforms (Figure 2; 2nd and 3rd signals,
84
haematologica | 2020; 105(1)