Systrom has dramatically deepened our understanding of what’s occurring during exercise in ME/CFS.

David Systrom, the Harvard pulmonologist, is digging ever deeper into his ME/CFS patients. In “Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” Systrom and company assessed the records of 160 people retrospectively diagnosed with ME/CFS. – and in doing so became the first group to assess small fiber neuropathy (SFN) in this disease.

The first major finding was that mean peak V02 – the highest level of oxygen extraction that occurred during the exercise – was significantly lower in ME/CFS. Since energy is mostly a function of oxygen extraction, this indicated the ME/CFS patients were unable to produce as much energy as the healthy controls. Under that broad brush, though, several subsets were about to pop out.

The Gist

  • David Systrom and his invasive cardiopulmonary exercise testing are testing the blood before it gets to the muscles and after it leaves the muscles during exercise.
  • The ME/CFS group as a whole had reduced peak oxygen uptake; i.e. they were unable to produce as much energy as expected.
  • Approximately 30% of ME/CFS patients had small fiber neuropathy.
  • Systrom identified low-flow and a hi-flow groups. The low flow group had low cardiac output, high levels of venous oxygen and reduced preload. This group likely appears to exhibit “venous pooling”; i.e. blood is pooling in the veins – possibly, in some cases, due to a small fiber neuropathy – and then getting lost into the body before it reaches the heart. That reduces blood flows to the heart and the muscles.
  • The high flow group has plentiful blood flows but the blood is either not getting to the muscles (possibly because of a small nerve fiber problem), or damaged mitochondria are not taking it up. This group has reduced oxygen extraction.
  • The authors declared that deconditioning is “definitively” not causing the problems they’re seeing.
  • Ron Tompkins of the OMF funded Harvard ME/CFS Collaborative Center is doing cytokine, metabolomics and proteomics analyses of the blood Systrom is collecting. He reported the cytokine analyses are finding high cytokine levels in the ME/CFS patients.
  • The fact that similar low-flow and high-flow findings occur in POTS suggests that POTS and ME/CFS share a similar pathophysiology.
Two radically different kinds of ME/CFS showed up. One set of patients had high cardiac output (high-flow) during exercise – their hearts are pumping out a lot of blood; the other had low cardiac output (low-flow) – their hearts aren’t pumping out much blood at all

  • Low-Flow -Reduced cardiac output is usually caused by problems in the heart (heart failure) or the lungs (pulmonary hypertension), but neither of these were present. Instead, their heart output was reduced because their hearts weren’t getting enough blood in the first place. Studies of this group in POTS indicate they have high vascular resistance; i.e. narrowed down blood vessels that are impeding blood flows.
  • High-Flow – Despite their plentiful blood flows, the high-flow group had the lowest oxygen extraction of the group; i.e. less oxygen was being extracted from their blood than the other group. They also had the highest venous oxygen tension (vPO2); i.e. they had higher levels of oxygen in their venous blood. (Oxygenated blood flows from the hearts to the arteries, into the muscles, then out of the muscles into the veins, where it returns to the heart.) In short, this was the impaired oxygen extraction group. The authors proposed that either blood is being shunted away from their muscles and/or a mitochondrial problem is preventing them from taking up the oxygen in their blood. Systrom noted that this kind of shunting has been associated with small fiber neuropathy before.

Small Fiber Neuropathy (SFN) (Finally) Found in Chronic Fatigue Syndrome (ME/CFS)

It was good to see, 8 years after the first fibromyalgia (FM) small fiber neuropathy (SFN) study and dozens of FM SFN studies later, SFN FINALLY getting assessed in ME/CFS. For one thing, it will help people with ME/CFS get their doctors to assess them for this condition if that’s something they want to do.

small fiber neuropathy

In small fiber neuropathy the small nerve fibers in the skin, cornea’s and probably elsewhere are disappearing. This was the first study to assess SFN in ME/CFS.


Optic Nerve Thinning Suggests Fibromyalgia is “Neurodegenerative” Disease

About a third of the ME/CFS patients – just a bit below the @ 40% generally seen in FM studies – had small fiber neuropathy (SFN) in their skin. SFN occurs when the very small autonomic/sensory nerve fibers in the skin or elsewhere have become damaged. Studies have also found SFN in the corneas of the eyes of fibromyalgia patients, and in POTS. Both Systrom and Oaklander have proposed that small nerve fibers may be damaged elsewhere such as the blood vessels or the gut.

SFN was found in both low-flow and high-flow ME/CFS patients. The authors speculated how SFN might be causing problems in either group.

  • Low-Flow SFN – The authors proposed that after the blood reached the muscles, small nerve fiber problems were impairing the veins from constricting properly – resulting in blood pooling and blood loss. The reduced blood flows to the heart that resulted caused reduced preload and low heart blood flows.
  • High-Flow SFN – The authors proposed that small nerve fiber problems were causing blood to be shunted away from the muscles prior to reaching them. Because less blood was reaching the muscles, less oxygen was being consumed, and less energy was being produced aerobically,  – causing the muscles to produce energy anaerobically – and resulting in pain, fatigue, etc. The authors suggested that small nerve fiber losses in the gut be affecting gut motility, and causing discomfort following meals and nausea.

Update! – Ron Tompkins of the Open Medicine Funded Harvard ME/CFS Collaborative Research Center is collaborating with David Systrom to dig deeper into what’s happening during exercise. Tompkins is doing the first-ever “omics’ analysis of ME/CFS patient’s blood before it gets to the muscles (where all sorts of havoc may be happening) and after it’s passed through them during exercise.

Tompkins will be analyzing cytokines and doing metabolomics (metabolism), and proteomic (proteins) in three times points (before, during and after exercise) over 100 patients and healthy controls.

Tompkins recently reported that significantly higher levels of multiple cytokines have been found this far in the ME/CFS patients. That would fit well with Dr. Klimas’s findings suggesting that exercise triggers a burst of inflammation in people with ME/CFS. To cap the Systrom study off Tompkins will also be taking muscle biopsies and creating metabolic models.

Deconditioning Hypothesis Gets Another Body Blow 

If the deconditioning angle didn’t get destroyed by Visser’s recent study (not to mention the 2-day exercise studies), it will hopefully be obliterated by this one. It’s not that deconditioning is not present in ME/CFS – it is. The question is whether deconditioning is causing these abnormal exercise results – it isn’t.

Deconditioning Denied: Could a Large ME/CFS Study Put an End to the Deconditioning Myth?

It’s a crucial question. If deconditioning is actually causing these abnormal exercise findings, then the answer for ME/CFS is simple: exercise. If, on the other hand, problems with generating energy exist – then too much “exercise” will make the situation worse.


The deconditioning hypothesis takes yet another hit. At least in the research literature it’s sinking fast.

The authors reported that the study “definitively eliminates (the) possibility” that deconditioning is causing the exercise abnormalities “because the hallmark of deconditioning is low peak exercise cardiac output” rather than the increased output they found.

Plus, instead of the high heart filling pressures seen in deconditioning, they found the opposite – low filling pressures. Plus, they noted that deconditioning doesn’t have any effect on oxygen extraction, which was low in the low-flow patients.

The ME/CFS/POTS/Fibromyalgia/Long-Hauler Mega Group

Postural orthostatic tachycardia syndrome (high heart rates, increased symptoms upon standing) and ME/CFS were linked ever closer together with the authors noting that both the low-flow and high-flow subsets found in ME/CFS are also found in POTS.

How many diseases fit into the dysautonomia, orthostatic, metabolically impaired framework?

Visser’s seminal brain blood flow study, which demonstrated that virtually every person with ME/CFS has reduced blood flows to the brain (the very definition of orthostatic intolerance) when standing, more closely links ME/CFS, orthostatic intolerance and POTS.

Given enough study – and quite a bit has already been done – fibromyalgia may fit into this group as well. With POTS and dysautonomia showing up in long COVID patients, they’re joining the club as well.

A suite of factors – dysautonomia, orthostatic intolerance, exertion problems, metabolic and mitochondrial problems – are showing up in different degrees in all these conditions. At some point, this will all hopefully merge together.

Systrom’s invasive tests are so effective and illuminating because he’s able to measure how these factors change before and after the blood feeds the muscles. Assessing ME/CFS from a whole-body perspective, Systrom is finding problems with foundational factors such as oxygen consumption, blood flows, gas levels. Workwell’s two-day exercise test (CPET) and Avindra Nath’s metabolic chambers are other ways of assessing energy production from a more macro perspective.

Muscle studies and cellular energy production studies, on the other hand, examine energy production from a more micro perspective. While the results have varied from study to study, in general, the two approaches seem to be validating each other: both the more macro and the more micro studies are finding evidence of energy production problems. The key will be in linking them together.

Check out Health Rising’s Small Fiber Neuropathy Resource Page

Small Fiber Neuropathy (SFN) Fibromyalgia and ME/CFS Resource Page


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