Stovall et al. (2022)
- Authors: M. Stovall, P. Joseph, R. Pari, A. Warren, S. Miller, J. Squires, W. Xiao, A. B. Waxman, D. M. Systrom.
- Institutes: Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, United States; Pulmonary, Critical Care, and Sleep Medicine, Yale New Haven Hospital, New Haven, CT, United States; Internal Medicine, University of Rochester Medical Center, Rochester, NY, United States; Surgery, Science and Bioengineering, Massachusetts General Hospital, Boston, MA, United States.
- Publisher: Am J Respir Crit Care Med
- Link: DOI
Summary
This study provides strong evidence for a specific physiological problem in ME/CFS known as “preload failure,” where impaired blood vessel function reduces blood return to the heart during exercise. The drug pyridostigmine 💊 appears to temporarily correct this issue, leading to improved exercise capacity. Importantly, the worsening performance of the placebo group on the second test offers an objective measurement that mirrors the clinical phenomenon of post-exertional malaise. This research identifies a key mechanism of the disease and points to a class of existing drugs that could be further investigated as a potential treatment.
What was researched?
This study investigated whether a single 60mg dose of pyridostigmine 💊, a reversible acetylcholinesterase inhibitor, could acutely improve exercise tolerance in ME/CFS patients. Researchers measured changes in peak oxygen uptake ( max) and other cardiovascular functions during back-to-back invasive exercise tests.
Why was it researched?
The study was motivated by the observation that about one-third of ME/CFS patients have small fiber neuropathy (SFN), which can cause neurovascular dysregulation. The researchers hypothesized that impaired blood vessel constriction during upright exercise reduces blood flow back to the heart and creates a mismatch between blood supply and muscle demand, and that pyridostigmine 💊 could correct this by improving vascular regulation.
How was it researched?
This was a randomized, placebo-controlled clinical trial involving 45 ME/CFS patients, of whom 39 (all women) were included in the final analysis. All participants first underwent an invasive cardiopulmonary exercise test (iCPET) to confirm low filling pressures in the heart. Eligible subjects were then randomly and blindly given either 60mg of pyridostigmine 💊 or a placebo, followed by a second iCPET after a 50-minute rest period to assess the drug’s effect.
What has been found?
The group receiving pyridostigmine 💊 showed a significant increase in peak oxygen consumption ( max) during the second exercise test compared to the placebo group. In the treatment group, key measures of cardiovascular function like oxygen uptake (), cardiac output (Qt), and right atrial pressure (RAP) increased significantly from the first test to the second, whereas these measures tended to decrease in the placebo group, indicating a worsening of function after the first exertion.
Discussion
As an abstract, the paper does not contain a detailed discussion of limitations. However, it notes that while 38% of subjects had objective evidence of small fiber neuropathy (SFN), there was no statistically significant difference in the prevalence of SFN between the treatment and placebo groups, suggesting the drug’s beneficial effects may not be exclusive to patients with confirmed SFN.
Conclusion & Future Work
The authors conclude that these findings suggest neurovascular dysregulation is a fundamental cause of acute exercise intolerance in ME/CFS. The study also provides new evidence that prior exertion worsens this vascular dysregulation, offering a physiological insight into post-exertional malaise (PEM), a hallmark symptom of the disease.