Skin Temperature Circadian Rhythms and Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Role of Endothelin-1 in the Vascular Tone Dysregulation

{"Background": "Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder affecting over 50 million people worldwide, predominantly women. The etiology remains unknown but appears multifactorial, involving immunogenetic and environmental factors. Autonomic dysfunction is highly prevalent in ME/CFS, with symptoms including dizziness, orthostatic hypotension, palpitations, hot flashes, and night sweating. Previous research suggests an imbalance between sympathetic and parasympathetic nervous systems, with decreased parasympathetic tone and increased sympathetic output. Circadian rhythm disruptions, including impaired thermoregulation, have been implicated in ME/CFS. Endothelin-1 (ET-1), a potent endothelial vasoconstrictor, has been linked to circadian rhythm regulation and was recently reported elevated in ME/CFS. This study hypothesized that alterations in the vasoconstrictor/vasodilation process, reflected in temperature variations, would indicate dysautonomia in ME/CFS, and aimed to explore autonomic responses through hemodynamic variables, thermoregulation, and endothelial biomarkers.", "Methods": "A single-center, prospective, cross-sectional case-control study was conducted from October 2019 to March 2022, enrolling 67 consecutive females with ME/CFS (diagnosed per 2011 international consensus criteria) and 48 non-fatigued healthy controls. Participants underwent a 10-minute NASA lean test (NLT) to assess orthostatic intolerance, with blood pressure and heart rate recorded at 1-minute intervals and wrist temperature measured simultaneously using a Thermochron iButton sensor. Participants also wore an ActTrust actigraphy device on the non-dominant wrist for 7 continuous days to record skin temperature, motor activity, and light intensity at 1-minute intervals. Circadian rhythm analysis was performed using El-temps software, calculating MESOR, acrophase, amplitude, intra-daily variability (IV), Rayleigh's test (R), percentage of variance (PV), and non-parametric measures (T_M5, T_L10 for temperature; A_M10, A_L5 for activity). Fasting blood samples were collected for routine biochemistry and measurement of endothelial biomarkers (ET-1, VCAM-1, ICAM-1) using commercial ELISA kits. Self-reported outcomes included FIS-40 (fatigue), PSQI (sleep quality), HADS (anxiety/depression), COMPASS-31 (autonomic symptoms), SF-36 (quality of life), and OGS (orthostatic grading scale). Statistical analyses were adjusted for age and BMI, using ANOVA, Mann-Whitney U tests, Pearson correlations, stepwise linear regression, and discriminant analysis.", "Key Results": "ME/CFS patients had significantly higher supine systolic BP (124.18 vs. 112.95 mmHg, p<0.05), diastolic BP (78.97 vs. 70.97 mmHg, p<0.01), and heart rate (74.47 vs. 67.5 bpm, p<0.01) compared to healthy controls. ME/CFS patients showed significantly higher levels of ET-1 (1.84 vs. 1.12 pg/mL, p=0.004) and VCAM-1 (739 vs. 494 ng/mL, p<0.001), but no difference in ICAM-1 (284 vs. 285 ng/mL, p=0.611). No significant differences were found between groups in postural changes of BP, HR, or wrist temperature during the NLT. Seven ME/CFS patients and eight healthy controls met POTS criteria; four ME/CFS patients and one healthy control had orthostatic hypotension. Circadian rhythm analysis showed no significant differences in wrist temperature rhythm variables between groups, but ME/CFS patients had significantly lower motor activity MESOR (2058 vs. 2746 a.u., p<0.001), amplitude (1744 vs. 2116 a.u., p<0.009), and M10 (3390 vs. 4308 a.u., p<0.001). ET-1 levels were positively correlated with symptom severity in ME/CFS: FIS-40 (r=0.529, p=0.005), HADS (r=0.407, p=0.035), COMPASS-31 (r=0.452, p=0.018), PSQI (r=0.468, p=0.014), and negatively with SF-36 (r=-0.501, p=0.008). Stepwise regression showed that ET-1 in ME/CFS was predicted by T_PV (B=-0.034, p<0.05) and T_M5 (B=0.564, p<0.01). A discriminant analysis using supine DBP, ET-1, VCAM-1, T_PV, and T_M5 correctly classified 91.5% of participants (96% of ME/CFS patients and 85% of healthy controls; Wilks' lambda=0.372, Chi-square=53.95, p<0.0001).", "Clinical Implications": "This study provides the first evidence linking circulating ET-1 levels with both objective measures of vasoconstriction/vasodilation (wrist temperature circadian rhythm variables) and subjective autonomic symptom severity in ME/CFS. The finding that ET-1 levels correlate with worse fatigue, sleep quality, anxiety/depression, and autonomic symptoms suggests ET-1 may serve as a biomarker of illness severity. The high classification accuracy (91.5%) of a multifactorial model combining blood pressure, endothelial biomarkers, and circadian temperature variables underscores the complexity of autonomic dysfunction in ME/CFS and supports a multi-dimensional diagnostic approach. The elevated VCAM-1 levels suggest endothelial inflammation, though this did not correlate with symptom severity. The lack of association between nocturnal temperature and sleep quality in ME/CFS (present in controls) may reflect autonomic dysfunction or melatonin dysregulation. These findings point to endothelial dysfunction as a potential therapeutic target in ME/CFS, though the cross-sectional design and relatively small sample size limit causal inference. Future studies should investigate whether interventions targeting endothelial function can improve autonomic symptoms in ME/CFS."}