Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study

Abstract

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18–65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5–13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7–21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343–4,334) vs. healthy individuals 1,886 p.u. (range 808–8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.

Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…This is consistent with recent hypotheses describing vasoconstriction in muscle and brain as a principal element of ME/CFS ( 42 – 46 ), and findings of cerebral hypoperfusion ( 47 – 49 ) and intracranial hypertension ( 50 ) in ME/CFS patients. It is also consistent with studies that have shown that endothelial function is impaired in ME/CFS ( 51 , 52 ), both in large vessels and in the microcirculation ( 53 , 54 )—associated with redox imbalance ( 51 ). Finally, it is consistent with a new hypothesis for ME/CFS which suggests that endothelial senescence underpins ME/CFS by disrupting the intestinal barriers and BBBs ( 55 ), as well as with suggestions that leakage from dysfunctional blood vessels could explain many of the symptoms in ME/CFS ( 56 ).…”

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

“…An autoantibody-mediated mechanism may influence, indirectly or directly, the fine-tuned autoregulation of blood flow required to meet the metabolic demands of tissues. Endothelial dysfunction has been shown in patients with ME/CFS (65,66), and this was also supported in substudies linked to the CycloME and RituxME trials (67). The reduced levels of certain arachidonic acid derivatives seen in the present study may impact the vascular tone and blood flow (68).…”

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

“…In our previous study of 35 ME/CFS patients, peripheral ED assessed by RH-PAT was observed in half of the patients and was associated with disease severity [ 9 ]. A recent study of postinfectious ME/CFS confirmed these findings by demonstrating ED through both RH assessment and flow-mediated dilatation [ 11 ]. ED resulting in muscle and cerebral hypoperfusion are considered key pathomechanisms in ME/CFS [ 7 , 12 , 42 ].…”