Dane Cook's analysis of exercise data of the CDC's MCAM study

[ME/CFS Skeptic]

1) The data reported by Dr. Dane Cook in this CDC call from 13 May 2021 is pretty interesting.

He was able to analyze the results of exercise testing in the large Multi-Site Clinical Assessment of ME/CFS study (MCAM).

2) Previous meta-analyses have shown that ME/CFS patients have lower peak VO2 and cardiac responses (chronotropic intolerance) than controls.

3) Cook found something similar in the data of 179 ME/CFS patients and 169 controls from the MCAM study. But when patients and controls were properly matched for fitness these differences mostly disappeared.

4) He said: “When you match on fitness, the oxygen consumption and cardiac differences for the most part go away” and “… We saw very little evidence of overt chronotropic incompetence.”

5) Interestingly, something else showed up when patients and controls were matched for fitness.

ME/CFS patients were breathing slower but deeper.

6) Cook said: “they have a deeper ventilatory response and a slower ventilatory response. This is a unique and inefficient breathing pattern for exercise, and it can't be explained by fitness because it only showed up when we matched for fitness.”

7) He added: “We see for the entire sample that the ME/CFS throughout exercise have higher values for their ventilatory equivalents for both VO2 and VCO2. And if you switch down to the matched subsamples, you see those differences remain even when we match for fitness.”

8) Cook said: “So we think that this has something to do with the pathophysiology of ME/CFS because it cannot be explained by having low fitness.”

He said that these ventilatory responses suggest poor perfusion and a problem with gas exchange.

9) He added that he only knows of one other study that has examined this in veterans with Gulf War Illness and it showed the same thing.

He also said that these findings are consistent with some of David Systrom's work on poor delivery of oxygenated blood to the muscle.

10) In the talk Dr. Cook, who holds a Ph.D. in Exercise Science, also stressed that :

“ME/CFS is not a disease of low aerobic fitness. That is a false narrative. That has been propagated by non-exercise scientists…”

11) “… In my opinion, it's been damaging to the ME/CFS community, and it's presented a lot of noise in the research that is really unnecessary. I can't think of a plausible biological reason why someone who is low fit would have a heterogenous and complex disease like ME/CFS.”

12) I know too little about exercise physiology to comment on the biological aspect but, the study used multiple clinical sites and the analyses were performed “independent of who conducted the exercise test and blind to clinical status.”

 

[Hoopoe]

I'm happy to see actual experts commenting. This comes at the right time for the NICE roundtable.

I got this illness for no apparent reason while I was pretty fit, and I continued to remain fit for a while after getting it. At least in my case it's obvious low fitness cannot have a causal role.

 

[Trish]

I hope this research will be published soon. It sounds really interesting.

 

[Peter]

1) The data reported by Dr. Dane Cook in this CDC call from 13 May 2021 is pretty interesting.

He was able to analyze the results of exercise testing in the large Multi-Site Clinical Assessment of ME/CFS study (MCAM).

2) Previous meta-analyses have shown that ME/CFS patients have lower peak VO2 and cardiac responses (chronotropic intolerance) than controls.

3) Cook found something similar in the data of 179 ME/CFS patients and 169 controls from the MCAM study. But when patients and controls were properly matched for fitness these differences mostly disappeared.

4) He said: “When you match on fitness, the oxygen consumption and cardiac differences for the most part go away” and “… We saw very little evidence of overt chronotropic incompetence.”

5) Interestingly, something else showed up when patients and controls were matched for fitness.

ME/CFS patients were breathing slower but deeper.

6) Cook said: “they have a deeper ventilatory response and a slower ventilatory response. This is a unique and inefficient breathing pattern for exercise, and it can't be explained by fitness because it only showed up when we matched for fitness.”

7) He added: “We see for the entire sample that the ME/CFS throughout exercise have higher values for their ventilatory equivalents for both VO2 and VCO2. And if you switch down to the matched subsamples, you see those differences remain even when we match for fitness.”

8) Cook said: “So we think that this has something to do with the pathophysiology of ME/CFS because it cannot be explained by having low fitness.”

He said that these ventilatory responses suggest poor perfusion and a problem with gas exchange.

9) He added that he only knows of one other study that has examined this in veterans with Gulf War Illness and it showed the same thing.

He also said that these findings are consistent with some of David Systrom's work on poor delivery of oxygenated blood to the muscle.

10) In the talk Dr. Cook, who holds a Ph.D. in Exercise Science, also stressed that :

“ME/CFS is not a disease of low aerobic fitness. That is a false narrative. That has been propagated by non-exercise scientists…”

11) “… In my opinion, it's been damaging to the ME/CFS community, and it's presented a lot of noise in the research that is really unnecessary. I can't think of a plausible biological reason why someone who is low fit would have a heterogenous and complex disease like ME/CFS.”

12) I know too little about exercise physiology to comment on the biological aspect but, the study used multiple clinical sites and the analyses were performed “independent of who conducted the exercise test and blind to clinical status.”

I'm happy to see actual experts commenting. This comes at the right time for the NICE roundtable.

I got this illness for no apparent reason while I was pretty fit, and I continued to remain fit for a while after getting it. At least in my case it's obvious low fitness cannot have a causal role.

Exiting.

Couldn’t agree more. Same here. I was very fit when coming down. No way fitness-issues or detoriation has anything to do with ME.

“Living ME” I resonate with the poor gas exchange-theory and poor supply of oxygenated blood. Immune system initially hammered, and lack of oxygen to muscles and whole organism probably always been a major problem ever since.

 

[Grigor]

Cook said: “they have a deeper ventilatory response and a slower ventilatory response. This is a unique and inefficient breathing pattern for exercise, and it can't be explained by fitness because it only showed up when we matched for fitness.”

7) He added: “We see for the entire sample that the ME/CFS throughout exercise have higher values for their ventilatory equivalents for both VO2 and VCO2. And if you switch down to the matched subsamples, you see those differences remain even when we match for fitness.”

Did this become more apparent/pronounced on the second day or was this based on a single CPET?

 

[Ryan31337]

Hyperventilation of this variety is commonly seen with POTS patients. Had the same result myself on CPETs, breathing rate far slower than normal but with very excessive volume, at rest and during pedalling. Breathing got a little disordered around VO2max but that may be unrelated.

I always realised something was a bit odd with my breathing, on several occasions I tried guided breathing exercise recordings or apps to relax. Even at their slowest settings they would try to make me breathe faster than I felt comfortable, I figured it was because I have been a keen swimmer and scuba diver in years past and had well trained lungs...

A tilt test made it abundantly clear to me that something was actually wrong with my respiratory drive, after feeling those acute sensations I now recognise the milder drive to breathe excessively deeply that's consistent during orthostasis and some other stressors.

 

[Mij]

Are they measuring pwME/POTS and pwME w/o POTS?

I never had issues with my breathing when I was exercising with ME.

The gas exchange is interesting. This is what Mark Van Ness discusses in his videos.

 

[Snow Leopard]

I'm not sure this is a meaningful finding. Participants who have not exercised intensely in a long time and/or are unfamiliar with riding a bike, adopt less mechanically efficient pedalling cadence and breathing rate the first time they do such activity in a long time.

This is one of the reasons why there is a slight learning effect on CPETs (increase in performance on subsequent tests).

Genuine differences in breathing for a given level of performance as described by Dane Cook would result in differences in parameters like O2pulse (alteration in regulation between heart rate and ventilation), but other studies have not consistently found such differences, eg https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1836-0/tables/2

 

[Trish]

Participants who have not exercised intensely in a long time and/or are unfamiliar with riding a bike, adopt less mechanically efficient pedalling cadence and breathing rate the first time they do such activity in a long time.

But if the pwME were matched for fitness with the healthy controls, wouldn't that be true for the sedentary healthies too?

 

[Snow Leopard]

But if the pwME were matched for fitness with the healthy controls, wouldn't that be true for the sedentary healthies too?

No, because most patients tend to pace themselves and avoid all circumstances of intense exercise, whereas healthy people may occasionally do it.

edit - further comments - the "fitness matching" seems suspicious, because cardiopulmonary fitness is based on VO2peak in mL/(kg·min). But this doesn't mean the VE and Watt curves would be matched - yet they are, and of the sample as a whole. There is the possibility that fitness matching wasn't correct as patients didn't actually reach their true VO2Max. Notably the resting heart rate of "matched" controls was substantially lower, suggesting that perhaps fitness wasn't actually well matched.

Hyperventilation of this variety is commonly seen with POTS patients.

Hyperventilation is typically associated with increased breathing frequency and reduced tidal volume, which is the opposite of what was observed by Dane Cook... VE itself was similar to controls which technically means this is not a relative hyper, nor hypo ventilation compared to controls.

Did this become more apparent/pronounced on the second day or was this based on a single CPET?

It was a single CPET study. There was also some mention of cognitive testing by Unger, so perhaps we'll see an effect of a single CPET on cognitive function.

 

[Mij]

Could there also be differences between riding a bike and running? I can run and was able to use my stair master (years ago) without being out of breath, but riding my stationary bike put me out of breath quickly.

 

[Snow Leopard]

Could there also be a difference between riding a bike and running? I can run and was able to use my stair master (years ago) without being out of breath, but riding my stationary bike put me out of breath quickly.

Yes, at submaximal power output, sub optimal pacing/cadences and variations in mechanical efficiency can cause differences at a given level of effective power output. Though VO2Max itself should be similar, if the participant is able to reach it on both tests.

 

[ukxmrv]

Hyperventilation of this variety is commonly seen with POTS patients. Had the same result myself on CPETs, breathing rate far slower than normal but with very excessive volume, at rest and during pedalling. Breathing got a little disordered around VO2max but that may be unrelated.

I always realised something was a bit odd with my breathing, on several occasions I tried guided breathing exercise recordings or apps to relax. Even at their slowest settings they would try to make me breathe faster than I felt comfortable, I figured it was because I have been a keen swimmer and scuba diver in years past and had well trained lungs...

A tilt test made it abundantly clear to me that something was actually wrong with my respiratory drive, after feeling those acute sensations I now recognise the milder drive to breathe excessively deeply that's consistent during orthostasis and some other stressors.

This doesn't sound like the hyperventilation described to me by the doctor I saw early on who claimed it was at the "root" of our problems. He described rapid and shallow breathing.

It's interesting to contrast what happens in real people and what "they" think we are doing.

 

[Sasha]

I seem to be always barely breathing! Shallow breaths, and slow.

 

[borko2100]

“ME/CFS is not a disease of low aerobic fitness. That is a false narrative. That has been propagated by non-exercise scientists…”

OK if that's the true then I don't have CFS, but something else since I have been trying for decades now to improve my fitness and I still get out of breath with burning & drained muscles after less than 2 min of jogging or 5 min of biking. Either this researcher got it terribly wrong or there must be subsets of sufferers with some having normal aerobic fitness and others, like me, reduced. Very strange.

EDIT: Reading it again, maybe he meant, "not a disease of deconditioning" which is of course true and I agree with, but I don't think that's what he meant.

 

[Snow Leopard]

So we think that these ventilatory responses are indicative of a problem with gas exchange. So VE/VCO2 is usually suggestive when you have high levels of poor perfusion. You're not able to get rid of and transfer the gases across different tissues and then expel them into the environment. The VE/VO2 is suggestive of poor extraction of oxygen to active skeletal muscle. And so you have a hard time getting rid of these byproducts,and even if you can deliver oxygen to the muscle, it's difficult for the muscle to use that oxygen. We think this unique breathing pattern may be a strategy to improve what's called alveolar ventilation. So you have these air sacs in your lungs where gas is collected and then transferred to the blood to send to active muscle. And so if you breathe slower and deeper during exercise, you might be trying to bring in as much oxygen as you can to improve ventilation. We also think it might be—another explanation would be respiratory muscle fatigue, which could lead to what's called a—what's called a metaboreflex. So the release of neurotransmitters that cause vasoconstriction at the exercising muscle, which is not what you want. You want vasodilation. You want lots of blood to be sent to those exercising muscles. And we think that you get this vasoconstriction because the respiratory muscles need more oxygen because they're becoming fatigued. This is what's called the Robin Hood effect in exercise physiology. So the system is robbing the oxygen-rich exercising muscle to pay the fatigued and poor respiratory muscles.

We saw very little evidence of overt chronotropic incompetence. Most of the cardiac differences went away with fitness matching, and none of our—none of our metrics met criteria for chronotropic incompetence.

The overall breathing pattern cannot be due to a pulmonary disorder, there was no overall difference in V̇CO2 and no difference in OUES (Oxygen uptake efficiency slope).

Assuming the observed effect is genuine, Dane's hypothesis that it is an adaptation to improve alveolar ventilation caused by ongoing metaboreflex is plausible (he states they are two different explanations, I suggest they are linked) and is consistent with all we know about the regulation of ventilatory responses to exercise.


I also suspect there is suboptimal motor unit recruitment (which also suggests altered metaboreflex) that drives the overall ventilatory inefficiency that was observed. (This also coincides with the higher rated perceived exertion - I'm actually suggesting that patients are in fact recruiting more motor units for a given level of performance, hence higher effort)

In that sense, it isn't really the breathing itself that is "inefficient", but something going on with blood flow in the muscles...

Either this researcher got it terribly wrong or there must be subsets of sufferers with some having normal aerobic fitness and others, like me, reduced. Very strange.

Correct. I still have normal aerobic fitness, but others definitely have reduced fitness, including participants in the aforementioned study.

 

[borko2100]

The overall breathing pattern cannot be due to a pulmonary disorder, there was no overall difference in V̇CO2 and no difference in OUES (Oxygen uptake efficiency slope).

Correct. I still have normal aerobic fitness, but others definitely have reduced fitness, including participants in the aforementioned study.

Interesting. Then it would seem to me that this is a quite fundamental difference between those two groups, which probably means 2 different disease processes / etiologies?

 

[Snow Leopard]

Interesting. Then it would seem to me that this is a quite fundamental difference between those two groups, which probably means 2 different disease processes / etiologies?

No, I think it means some people like me do the minimum amount of intense activity to maintain an average level of aerobic fitness.

Christine Pearson: Okay. So, this one says: "What are your thoughts on second and/or third CPET to confirm diagnosis and/or treating someone with ME/CFS?"

This reminds me of you people (you know who you are!) claiming we should do a week of CPETs to see what happens. I'm feeling horrified just thinking about it.

 

[Ryan31337]

Hyperventilation is typically associated with increased breathing frequency and reduced tidal volume, which is the opposite of what was observed by Dane Cook... VE itself was similar to controls which technically means this is not a relative hyper, nor hypo ventilation compared to controls.

Why is a comparison of VE to controls useful in knowing if patients are hyperventilating? Isn't the ratio of VE to CO2 the important factor? If the patient is producing less CO2 for the same VE they will be relatively hyperventilating?

Sorry if that's a confused question, asking to learn rather than argue!

Edited: I wanted to try and find the ref.... This is why I said its a common POTS hyperventilation pattern: "Hyperventilation in POTS is hyperpnea only, distinct from panic in which tachypnea also occurs."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442665/

 

[Blueskytoo]

I seem to be always barely breathing! Shallow breaths, and slow.

Me too.