• Question: When does a graded exercise study explain why graded exercise is not helpful for chronic fatigue syndrome (ME/CFS)?
  • Answer: when it employs an exercise test with it.

Just as NICE was pulling back on graded exercise therapy (GET) a GET study was published showing why it doesn’t work. The authors did conclude that GET works for some patients but not others but an analysis of the study suggests that may have been understating things:  the study may actually have shown why GET doesn’t work in almost all people with chronic fatigue syndrome (ME/CFS).

GET This! NICE Pulls the Plug on Graded Exercise Therapy and CBT as Treatments for ME/CFS

The first of a two part series of studies “The Impact of a Structured Exercise Programme upon Cognitive Function in Chronic Fatigue Syndrome Patients” used a graded exercise therapy (GET) protocol similar to that NICE formerly recommended. It was designed to test the idea that GET was able to enhance cognition in ME/CFS.

As with other GET studies, It was based on the idea that deconditioning was holding people with ME/CFS back. The idea was that gradual deconditioning over time made everything in ME/CFS more effortful and ushering in a vicious circle of continuing decline.

The difference was that a maximal exercise test was included to produce a heart rate the participants were supposed to match. In other words it was a physiological GET study – and that changed everything.

Home exercise was prescribed at least five days a week, 16 weeks in total, with the initial 3 sessions lasting approximately 10 minutes. The participants began with 10 minutes of exercise at 30–40% of their HRMax (maximum heart rate). That was increased to 20 minutes at a 10% higher HRMax. Stretching exercises were added. The intensity and duration was increased until the participants were exercising at 70–80% of HRMax for 40 min at least five days a week at the end of 4 months.


It should be noted that these were probably the strongest of the strong. For one they agreed to enroll in a graded exercise trial. Secondly they agreed to do two maximal exercise tests.

Fifty-three patients did the graded exercise protocol. Of those, 64% completed it and 36% dropped out. Those who finished the study did appear to make some cognitive gains, which, however did not survive a test called false discovery rate (FDR) correction. While noting that many of the participants (50%) did not complete the study, the authors concluded the study supported the hypothesis that GET could improve cognition.

The exercise test results suggested that the sympathetic nervous system may have been putting the squeeze on the blood vessels of those who couldn’t tolerate GET.

The most interesting part of the study “Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients” came when the researchers attempted to use the exercise data to understand why so many people didn’t make it through the study. They found that “greater sympathetic drive” in their blood vessels, a poorer reaction time on a visual stimulation test, and lower maximal heart rate levels were all associated with a greater risk of dropping out.

The patients able to complete the exercise protocol were able to reach, on average, a 93% of age-predicted peak heart rate during the exercise test, while the non-completers were only able to reach 86% of their age-predicted peak heart rate.

An inability to get your heart rate up to snuff during exercise is called chronotropic incompetence (CI). That reduced heart rate made it more difficult to pump blood to the muscles. Plus the “high sympathetic drive” may have been vasoconstricting or narrowing the blood vessels”. Either way, the dropouts had two conditions that may have impaired blood flows to their muscles.

Incompetence – Chronotropic or Otherwise

Unfortunately, the authors never dug into the past chronotropic incompetence findings in ME/CFS and, in particular, never referred to a landmark publication on that subject which had recently been published. The 2019 Todd Davenport/Workwell Overview “Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?” won the 2019 California Physical Therapy Association (CPTA) research publication award.

It was easy to see why the paper won an award. Dense and detailed, the paper noted the five different criteria used for CI, assessed the different ways to determine exertion level, examined CI in the context of other diseases, assessed the CI results in ME/CFS, etc. It also compared heart rate responses to exercise, single vs two-day exercise tests, evaluated the role gender played and estimated the effect cardiovascular impairment had on heart rate responses. In other words, it was a tour de force.

Right away, we can see how the graded exercise study might have gone wrong. An analysis of 22 ME/CFS exercise studies found that the healthy controls typically were able to hit 94.0% of their age-predicted maximum heart rate. People with ME/CFS, on the other hand, were able to hit only 82.2% (81.9–82.5%) of their age-predicted maximum HR.

Workwell found that on average people with ME/CFS reached only 82% of their age predicted maximum heart rates. Put another way they had 11 less heart beats per minute.

Note that the heart rates of the “ME/CFS” patients who were able to complete the graded exercise study matched those of the healthy controls (93% – 94%) participating in past ME/CFS studies. Given their near normal chronotropic competence, it was perhaps not surprising that they were able to complete the study. The bigger question was whether they had ME/CFS.

The patients who were unable to complete the graded exercise study looked more like the ME/CFS patients found in past studies. The dropouts hit 86% of their projected heart rates – just a bit above the 82.2% Workwell found typical of ME/CFS patients in past studies.

The GET’s study use of physiological markers, then, which I believe is a rarity for these kinds of studies, revealed something about the participants.

Being able to hit your age-predicted maximum heart rate matters. Workwell reported that getting to only 82% of your age-predicted maximum heart corresponds to eleven less heart beats per minute; e.g. that’s eleven less opportunities every minute to flood the muscles with blood during exercise.

That was during a single exercise test – a test which we know fails to adequately demonstrate the metabolic problems found in many people with ME/CFS. When the stress of one maximal exercise test is added to another one the day after, Workwell found the age-predicted maximum heart rates decline by about 5 more points in the ME/CFS patients on the second test – and either remain the same, or even increase, in healthy controls.

Workwell’s 2003 study, “Subclassifying chronic fatigue syndrome through exercise testing“, fleshed out the exercise intolerance and heart rate issues like no other study has, and introduced even more serious declines in predicted maximal heart rates.

Examining the exercise data of a large number (n=179) of ME/CFS patients, it found (using peak volume of O2) that about 11% of ME/CFS patients had no discernible impairment; 37% had “mild” impairment, 40% had moderate impairment, and 11% had severe impairment.

It turns out that “mild” was not so mild after all. While the ME/CFS patients with no impairment were able to achieve a pretty robust 91% of their age-predicted maximum heart rate, those with mild impairment were only able to reach 83% of their predicted heart rate. Things slid downhill rapidly from there. Those with “moderate” impairment were able to manage just 75% of their predicted heart rate, while those with severe impairment bottomed out at staggeringly low 67% of their predicted heart rate.

The authors pointed to four potential causes of the reduced heart rates. Interestingly, given that the heart rate is under sympathetic nervous system (SNS) control, they speculated that an inhibition of the SNS – something spoken of in ME/CFS  – may be responsible. The potential causes included:

  • Reduction of the ß1 and/or ß2 adrenoreceptors resulting in adrenergic receptor insensitivity
  • Sympathetic fiber dysfunction resulting in decreased norepinephrine levels
  • Diminished sympatho-adrenal-medullary activation causing smaller than normal rises in epinephrine
  • Vagus nerve dominance blunting the effects of epinephrine and norepinephrine and heart rate increases.

Finally, it should be noted that an inability to reach normal maximum heart rates during exercise is just one of the many things which have been found to go awry when researchers have put people with ME/CFS on a bike and told them to pedal away.

Not everyone with ME/CFS has chronotropic incompetence (CI). Studies suggest that a wide variety of cardiovascular problems are found in ME/CFS.  I know someone who has an excellent maximal heart rate, lung capacity and ventilation (they are apparently getting oxygen into their blood and pumping it out well) but they reach their anaerobic threshold very quickly, presumably because the oxygen in their blood is not being taken up by their muscles. Their functionality is very impaired, which shows up in other physiological measures.


First, it should be noted that graded exercise therapy (GET) trials are probably usually skewed to healthier patients. This GET trial was probably doubly skewed because it required that two maximal exercise tests be done. It was probably triply skewed because its own physiological data suggested that many of the participants either didn’t have ME/CFS or were in that small subset of patients who do not have cardiovascular issues.

question mark

Did 2/3rds of the GET study participants not have typical ME/CFS? (Image-by-Gerd-Altmann-from-Pixabay)

About half the participants failed to complete the trial – some because they feared doing the maximal exercise test. Of those completing the exercise test, 36% failed to complete the study.

It turned out that the dropouts had a significantly lower age-predicted maximal heart rate than those participants who completed the study. There was also evidence of increased sympathetic drive, which may have vasoconstricted, or narrowed, the blood vessels of the dropouts. This was quite valuable as it pointed at physiological reasons for the exercise intolerance seen in ME/CFS – perhaps a first for a GET study. Plus these possibilities have been brought up again and again.

Both of these factors could have impaired the amount of blood flowing to the muscles – making it more and more difficult to exercise as the amount and intensity of the prescribed exercise increased.

An analysis suggested that age-predicted maximal heart rates of the “ME/CFS patients” who able to complete the GET trial were near normal – and almost identical to those of the healthy controls in past ME/CFS studies (93-94%). That suggested that either these weren’t ME/CFS patients or they were in that small subset of patients with no discernible cardiovascular impairments.

The age-predicted maximal heart rates of the participants unable to complete the GET trial were quite similar, on the other hand, to the ME/CFS patients in past exercise studies (86-82%). They looked like typical, albeit “mildly” impaired ME/CFS patients. (Workwell’s 2003 study suggests that much greater impairment is seen in many people with ME/CFS).

When assessed in the context of past exercise study results, the GET trial suggests that GET is likely to be a failure for a typical ME/CFS patient because of the difficulty these patients have in getting blood and oxygen to their muscles. It also brings into question what kind of patients this and perhaps other GET trials have employed.


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