David Systrom, a Harvard pulmonologist, uses invasive CPET tests to find that oxygen extraction problems at the muscle level are common in ME/CFS.

Chronic fatigue syndrome (ME/CFS) has a reputation for falling through the cracks. Test after test is run to no avail.  From the unusually devastating effects on functionality to the fact that exercise makes people worse rather than better, ME/CFS has been a disease that defies medical dogma.


The exercise problem in ME/CFS is different from that of other disorders. Only now is it starting to be understood.

Workwell’s two-day exercise test results, for instance, have run up against the dogma in exercise physiology that even if you have serious diseases like heart disease or kidney failure, exertion just doesn’t reduce your ability to produce energy. Something, exercise physiologists have even asserted, must be wrong with Workwell’s machine to produce that kind of result in ME/CFS. (Workwell’s findings have been replicated by other researchers.)

The first sentence in the abstract of David Systrom’s new study sums up our dilemma perfectly:

“The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked.”

If you have a problem with exercise, the first places doctors and researchers look are the heart and the lungs. If those are operating fine – as they generally are in chronic fatigue syndrome (ME/CFS) – the investigation ends. That’s kind of been the story in ME/CFS.  After the usual suspects are checked, the investigation ends.

It’s not the end of the story, anymore, with exercise. This is where our two great hopes – better technology and bold researchers – comes in. Systrom’s been focused on exercise intolerance for years and he has a sophisticated machine (invasive cardiopulmonary exercise) that’s been blowing the lid off the dogma involving exercise intolerance – and ME/CFS.

The Study

European Journal of Applied Physiology https://doi.org/10.1007/s00421-019-04222-6 Unexplained exertional intolerance associated with impaired systemic oxygen extraction. Kathryn H. Melamed1 · Mário Santos2,6 · Rudolf K. F. Oliveira3 · Mariana Faria Urbina2,6 · Donna Felsenstein4 · Alexander R. Opotowsky5,6 · Aaron B. Waxman2 · David M. Systrom2,6

Exertional intolerance has many causes…The authors

Invasive CPET test

Invasive CPET Test. (from Eur J Prev Cardiol, 24 (11), 1190-1199 Jul 2017)

Kathryn Melamed (the first author) and David Systrom gathered enough exercise intolerant people to produce an exercise study the size of which boggles the mind: 313 exercise intolerant people underwent a difficult (and very expensive) invasive cardiopulmonary test (iCPET) between March 2011 and October 2013.

In contrast to the CPET test we’re so used to, the iCPET measures both the oxygenated blood going out to the muscles and the venous blood which returns from the muscles. Besides other things, those two readings tell us how much oxygen the muscles are taking up during exercise.

This study was different in that no healthy controls were involved.  Apparently, invasive CPETs are such nasty tests that it’s not considered ethical to put healthy controls through them. All the results should be viewed on a sliding scale then.  If healthy controls had been included, the results probably would have been significantly worse.


The study subsets.

First, Melamed and Systrom winnowed their big group down. Of the 312 people, 56 had heart valve or other issues, or didn’t exert to their maximum during the test and were excluded from the study. One hundred and eighty five others found to have pulmonary hypertension or heart failure were dropped from it as well.

That brought the study down to the mystery patients – 72 people with unexplained exercise intolerance. This was the putative ME/CFS group and it was this group that made up this study.

Note that this is not a small group: the 72 mystery patients made up approximately a quarter of all the patients that had been referred to Systrom over two years.

The group was next broken up into several different subsets: first, into two major subsets which either had or didn’t have problems with systemic oxygen extraction (SOE).

Then, those groups were broken up: the SOE group was broken up into subsets with primarily mitochondrial or hyperventilation issues, and the normal oxygen extraction subset was broken up into another hyperventilation subset and a completely normal subset.

The Impaired Systemic Oxygen Extraction (SOE) Group

Almost 45% of the study participants (without an identifiable problem such as heart failure, pulmonary hypertension, etc.) had reduced systemic oxygen extraction (SOE). (This was defined as <80% of predicted VO2 max, plus increased venous blood oxygen levels relative to arterial blood oxygen level during maximal exercise). The oxygen concentration of their blood after it had passed through their working muscles was higher than normal.

Oxygen extraction is a big deal because our main source of clean energy – aerobic energy production – relies entirely on oxygen. Basically, this group’s muscles were not extracting the oxygen from their blood that was needed to power their muscles during exercise – hence their exercise intolerance, and their low VO2 max.

Their hearts were pumping out their blood just fine. In fact, in what was probably a compensatory attempt to shove more blood into their muscles, this group’s hearts were pumping out larger than normal amounts of the blood.

Every patient in this group met the criteria for chronic fatigue syndrome (ME/CFS).

Side Note – Oxygen Extraction Problems Present Even During Rest


Having an exercise stressor just makes everything easier for ME/CFS researchers (if not for the patients in their studies), and it did in this case. More results were abnormal once the participants got on the bike and started exercising.


The really interesting thing, though, was how many times Systrom found abnormalities during rest.  It sometimes takes two maximal exercise tests to show a significant difference between VO2 max or other measures during a non-invasive cardiopulmonary exercise test (CPET).


The oxygen extraction problems Systrom found during his more sensitive testing, however, didn’t need exercise to manifest themselves. Even during rest, when the participants’ energy systems were not being stressed, oxygen extraction problems – and hence energy production problems – were present in many people.

The SOE Triad

oxygen extraction issues

The triad of conditions believed responsible for the oxygen extraction problems in ME/CFS. (From the study).

The authors believed the three core issues – all of which were likely interacting with each other – resulted in the reduced oxygen usage problem:

  • skeletal muscle mitochondrial defect
  • hyperventilation
  • limb muscle microcirculatory dysfunction.

Each will be examined below.

The SOE Subsets

The systemic oxygen extraction problem was primarily caused in two ways: by mitochondrial dysfunction and/or hyperventilation.

The Messed Up Mitochondria Group


A significant subset of patients appear to have a mitochondrial problem.

Twenty-two percent of the group without heart or lung problems appeared to have mitochondrial problems that prevented them from taking up normal amounts of oxygen. Oxygen extraction problems are the hallmark of mitochondrial disease (mitochondrial myopathy). The authors believed this group probably had higher lactate levels as well.

The cause of this mitochondrial breakdown was unclear, but several possibilities exist. A genetic weakness, which only showed up in full force in adulthood, could be present. (Birch has found evidence of some “inborn errors of metabolism” in ME/CFS.) Infection or autoimmune processes could also have damaged the mitochondria later in life.

The Hyperventilation and Systemic Oxygen Extraction Group

Twenty-two percent of the group without obvious heart or lung problems had systemic oxygen extraction problems produced by hyperventilation during exercise. (Systrom describes this form of hyperventilation as “pathologic”; i.e. in this case, it’s biological – not a psychological condition.)

This group had higher serum bicarbonate levels, but their normal lactate levels suggested their mitochondria were doing just fine.

This group then had a breathing problem. We breathe more rapidly and deeply during exercise to get rid of the toxic levels of CO2 accumulating in our cells and to bring more oxygen to our muscles. This group was simply breathing more rapidly and/or deeply than was necessary to get rid of the CO2 their muscles were creating.

That breathing pattern was producing a less acidic environment in their capillaries. Because oxygen offloads better from our red blood cells in a more acidic environment, the hyperventilation was essentially reducing the amount of oxygen available to the muscles. It may also be reducing blood flows to the muscles by diverting blood from the exercising skeletal muscles to the muscles working the lungs.

The women in this group also had the greatest “systemic vascular resistance” found, suggesting that narrowed or vasoconstricted blood vessels could also be impairing blood flows to their muscles. Since men didn’t have this problem, the authors suggested estrogen may be playing a role in women.

This group was also taking the vast majority (75%) of beta-blockers and 100% of the ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics used. (If you’re taking these drugs, you may fit this subset.)

Why the hyperventilation is occurring is unclear. The authors suggested that the skeletal muscle metaboreceptors, which assess the byproducts of exercise, may not be feeding the proper signals to the lungs and heart. It’s also possible that autonomic nervous system problems may be reducing blood flows to the muscles.

Microcirculatory Problems

Looming over all of this are microcirculatory problems that may be impairing blood flows to the muscles in both groups.  Microcirculatory problems have been questioned in ME/CFS for years and appear to be present in  POTS and other forms of dysautonomia.  Melamed and Systrom believe they play an important role in many people with ME/CFS.

Could Poor Microcirculation Be Causing Chronic Fatigue Syndrome (ME/CFS)?

The “Normal” Oxygen Extractors 

Fifty-five percent of the people with exercise problems – but without any heart or lung problems – had normal oxygen extraction. This group was broken up into the hyperventilators and the normals.

The Hyperventilation Group

Ph scale

The hyperventilation was alkalinizing their blood – preventing oxygen from off-loading readily from their red blood cells.

This group’s mitochondria appeared to be functioning normally and their hyperventilation did not prevent their muscles from taking up sufficient amounts of oxygen. The blood acid levels were, however, significantly higher – indicating they were hyperventilating.

This group may not have been as normal as it seemed, however. Compared to the normals, this group had reduced aerobic capacity and systemic oxygen extraction.

If this group had been compared to healthy controls, the differences might have been more dramatic; i.e. they may be normal only in the context of this iCPET study which only involved exercise intolerant individuals. Let’s call them the not-quite-normal normals.

The Normals (the real Mystery Group)

Fifteen percent of the participants displayed exercise intolerance without any evidence of heart or lung disease or any of the issues noted above. The cause of their exercise intolerance is a mystery.


A large subset of ME/CFS patients (at least 20-25%) appear to have mitochondrial issues that are keeping their muscles from extracting normal amounts of oxygen from their blood.

A similar subset of ME/CFS patients hyperventilate during exercise, which, by altering the acidic environment in their small blood vessels, makes it more difficult to extract oxygen from their red blood cells. Autonomic nervous system issues that propel blood away from their exercising muscles, may be present as well.

Both these issues could explain why many people with ME/CFS have so much trouble with exercise and/or movement.

A significant percentage (55%) of patients with unexplained exercise intolerance have lower than normal levels of oxygen extraction – but not as low as the other patients. One group that hyperventilates exhibits lower energy production during exercise – but the cause of that is unclear. About fifteen percent of the patients are a complete mystery.

Systrom’s results suggest that some of the inconsistent mitochondria results in ME/CFS could be explained by the inclusion of different kinds of ME/CFS patients in the study; i.e. those with mitochondrial issues and those without them.

Treatment Takeaways 

The authors did not mention potential treatments but here are some ideas:

  • Systrom has, however, been successful in treating some patients (the hyperventilation group??) with Mestinon. Check out one longtime ME/CFS patient who did great on Mestinon.
  • While blood volume enhancers would not solve the oxygen extraction problem, they might help ameliorate it a bit by providing more blood to the working muscles.
  • Mitochondrial enhancers might be helpful for the mitochondrial group. The catch is that we don’t know what’s gone wrong with the mitochondria.
  • One wonders if techniques that increase oxygen levels like hyperbaric oxygen could temporarily help.
  • Could breathing exercises help with the hyperventilation?
  • Given the problem with oxygen extraction in almost half the participants, exercises which don’t stress the aerobic system would clearly be preferable.

The Gist

  • David Systrom, Harvard pulmonologist, used an invasive cardiopulmonary exercise test to, among other things, assess how much oxygen was being used up during exercise in people with a mysterious case of exercise intolerance.
  • Oxygen provides the fuel we need for sustained exercise.
  • Systrom found that the muscles of 45% of the people in his study – all of whom met the criteria for chronic fatigue syndrome (ME/CFS) – were unable to extract normal amounts of oxygen from their blood.
  • The inability to extract enough oxygen from their red blood cells could explain why people with ME/CFS have so much trouble with exercise; i.e. their muscle cells simply aren’t getting the fuel (the oxygen) they need to engage in exercise.
  • The oxygen extraction issues were found even during rest.
  • Two subsets of ME/CFS patients with oxygen extraction problem were found. One subset has mitochondrial issues, the other hyperventilates during exercise.
  • Inborn errors of metabolism, a pathogen or an autoimmune disease could be causing the mitochondrial issues.
  • Problems with muscle metaboreceptors or with the diversion of blood from the working muscles could be occurring in the hyperventilation subset.
  • Three conditions, often occurring in all these patients, were present: mitochondrial myopathy, dysautonomia and issues with the microcirculation in the blood.
  • Just over half the participants did NOT have oxygen extraction issues. One subset which hyperventilated had reduced energy production. The ICPET test did not uncover any problems in the other group (the normals).
  • Systrom is collaborating with Ron Tompkins of the Harvard Collaborative ME/CFS Center, Anne Oaklander, Michael VanElzakker and others.


Systrom is just where we want him – in Boston – right in the middle of a group of ME/CFS researchers. He’s working with Ron Tompkins and the OMF-funded Harvard Collaboration, Anne Oaklander (SFN), Michael VanElzakker, and others. A donor funneled Solve ME a grant to fund some of Systrom’s work in ME/CFS work, plus Tompkins and the Harvard Collaboration are doing a deep dive into the molecular facets of his ME/CFS samples. (They just received almost $400,000 in funding from the Open Medicine Foundation.) Tompkins is confIdent they’ll uncover evidence of the immune, metabolic and other issues that are going wrong during exercise in ME/CFS.

Everything in Systrom’s findings is pointing to the muscles; the blood vessels are not providing enough blood to them, and/or the mitochondria in the muscles are not taking up enough oxygen from the blood; and/or muscle metaboreceptors are sending the wrong signals to the lungs (causing hyperventilation – and reduced oxygen availability). In some people, perhaps many people with ME/CFS, all these processes may be exacerbating each other.

The important thing is that it appears to be happening around the muscles, and that’s where Tompkins and the OMF-funded Harvard Collaboration come into play.

Tompkins is doing a deep dive into the omics and structural properties of ME/CFS patients’ muscles. He won’t be able to do that before and after exercise – that study is hopefully coming next – but it’s notable that Systrom’s systemic extraction oxygen subset demonstrated notable problems even at rest.

Systrom relied on data gathered from patients he saw from 2011 to 2013. Over time, one suspects he’s been able to gather many more samples. It’s possible, in fact, that Systrom has one of the largest ME/CFS sample collections in the country. Systrom and Melamed promised more was to come as they continue to build and analyze their data. Expect a larger report on the exercise subsets in ME/CFS in the future.

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