Phillip Joseph1, Carlo Arevalo2, Rudolf K F Oliveira3, Mariana Faria-Urbina4, Donna Felsenstein5, Anne Louise Oaklander6, David M Systrom4. 1. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale-New Haven Hospital, Yale University, New Haven, CT. Electronic address: phillip.joseph@yale.edu. 2. Department of Medicine, University of Rochester Medical Center, Rochester, NY. 3. Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil. 4. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 5. Infectious Diseases Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA. 6. Department of Neurology, Massachusetts General Hospital, Boston, MA; Department of Pathology (Neuropathology), Massachusetts General Hospital, Boston, MA.
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.
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.
Authors: Graeme Carrick-Ranson; Jeffrey L Hastings; Paul S Bhella; Naoki Fujimoto; Shigeki Shibata; M Dean Palmer; Kara Boyd; Sheryl Livingston; Erika Dijk; Benjamin D Levine Journal: J Appl Physiol (1985) Date: 2014-01-23
Authors: Phillip J Albrecht; Scott Hines; Elon Eisenberg; Dorit Pud; Deborah R Finlay; Kari M Connolly; Michel Paré; Gudarz Davar; Frank L Rice Journal: Pain Date: 2006-01-19 Impact factor: 6.961
Authors: Roy Freeman; Jennifer S Gewandter; Catharina G Faber; Christopher Gibbons; Simon Haroutounian; Giuseppe Lauria; Todd Levine; Rayaz A Malik; J Robinson Singleton; A Gordon Smith; Josh Bell; Robert H Dworkin; Eva Feldman; David N Herrmann; Ahmet Hoke; Noah Kolb; Heikki Mansikka; Anne Louise Oaklander; Amanda Peltier; Michael Polydefkis; Elissa Ritt; James W Russell; Stephen Sainati; Deborah Steiner; Roi Treister; Nurcan Üçeyler Journal: Neurology Date: 2020-10-14 Impact factor: 9.910
Authors: Alexis Boneparth; Shan Chen; Daniel B Horton; L Nandini Moorthy; Ian Farquhar; Heather M Downs; Hang Lee; Anne Louise Oaklander Journal: J Rheumatol Date: 2020-08-15 Impact factor: 4.666
Authors: Suzanne D Vernon; Sherlyn Funk; Lucinda Bateman; Gregory J Stoddard; Sarah Hammer; Karen Sullivan; Jennifer Bell; Saeed Abbaszadeh; W Ian Lipkin; Anthony L Komaroff Journal: Front Med (Lausanne) Date: 2022-06-23
Authors: James T Brown; Anita Saigal; Nina Karia; Rishi K Patel; Yousuf Razvi; Natalie Constantinou; Jennifer A Steeden; Swapna Mandal; Tushar Kotecha; Marianna Fontana; James Goldring; Vivek Muthurangu; Daniel S Knight Journal: J Am Heart Assoc Date: 2022-04-26 Impact factor: 6.106
Authors: Kari Sørland; Miriam Kristine Sandvik; Ingrid Gurvin Rekeland; Lis Ribu; Milada Cvancarova Småstuen; Olav Mella; Øystein Fluge Journal: Front Med (Lausanne) Date: 2021-03-22
Authors: Fereshteh Jahanbani; Rajan D Maynard; Justin Cyril Sing; Shaghayegh Jahanbani; John J Perrino; Damek V Spacek; Ronald W Davis; Michael P Snyder Journal: PLoS One Date: 2022-08-09 Impact factor: 3.752
Authors: Fredrik Hoel; August Hoel; Ina Kn Pettersen; Ingrid G Rekeland; Kristin Risa; Kine Alme; Kari Sørland; Alexander Fosså; Katarina Lien; Ingrid Herder; Hanne L Thürmer; Merete E Gotaas; Christoph Schäfer; Rolf K Berge; Kristian Sommerfelt; Hans-Peter Marti; Olav Dahl; Olav Mella; Øystein Fluge; Karl J Tronstad Journal: JCI Insight Date: 2021-08-23