Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Chest. 2021 Aug;160(2):642-651. doi: 10.1016/j.chest.2021.01.082. Epub 2021 Feb 10.

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.

Research question: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study design and methods: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles.

Results: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.

Interpretation: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Keywords: dysautonomia; dyspnea; exercise testing; physiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Exercise Test / methods*
  • Fatigue Syndrome, Chronic / physiopathology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Small Fiber Neuropathy / physiopathology*