Microvascular Dysfunction and Basal Membrane Thickening in Skeletal Muscle in ME/CFS and Post-COVID, 2025, Slaghekke et al

[Jonathan Edwards]

There is a study of iCPET with 10 patients, post COVID exercise intolerance, 9 had mild infection, on average 11 months after positive PCR
and 10 age- and sex-matched control participants.

Patients demonstrated impaired systemic oxygen extraction (0.49 0.1 vs 0.78 0.1; P < .0001)

I do not understand the detail of this but judging by discussions we have had here in the past there is considerable debate even amonsgt those who claim to understand. The defect looks similar to that in the second day PET results said to be typical of ME/CFS. But capillaries do not thicken overnight, so that cannot be the explanation there.

I do not see why these results cannot be explained by a change in muscle usage pattern due to neural events.

 

[butter.]

If there was central hypoxia then people with ME/CFS would be blue, as people with central hypoxia are, and their sats would show it. Moreover, it would make the vessel thickness theory redundant.

That seems like an oversimplified take, and I don’t mean any disrespect in saying that.

You can have cellular hypoxia without hypoxemia when oxygen is in the blood but tissues can’t use or access it (e.g., anemia, poor circulation, or mitochondrial 'poisoning' like with cyanide/H₂S or other mitochondrial and OXPHOS defects), and in such cases cyanosis may not appear.

I’m a bit concerned that your perspective might not fully reflect the patient experience of those who are moderate or more severely affected. I could be wrong, but some of your comments in this and other threads give me the impression that you may not have had much exposure to this part of the patient population or the patient population as an MD or caretaker in general. This might result in quite a bit of bias.

(I am very severe (no lung or heart disease), my standard oxygen saturation is between 90-92%, I have blue lips regularly. Many other patients have this too, especially in a crash situation. Also, patients are described as having a yellowish-gray skin tone.)

 

[butter.]

I do not understand the detail of this but judging by discussions we have had here in the past there is considerable debate even amonsgt those who claim to understand. The defect looks similar to that in the second day PET results said to be typical of ME/CFS. But capillaries do not thicken overnight, so that cannot be the explanation there.

I do not see why these results cannot be explained by a change in muscle usage pattern due to neural events.

I don't know if the thickening is a real finding and/or relevant, but that cellular hypoxia and reperfusion (caused by the thickening and increased demand of a CPET) could have delayed effects wouldn't be all that surprising?

'Neural events' could certainly cause the issues seen in ME/CFS without (some form of) hypoxia, but they could also be dowstream of it.

 

[Jonathan Edwards]

You can have cellular hypoxia without hypoxemia when oxygen is in the blood but tissues can’t use or access it (e.g., anemia, poor circulation, or mitochondrial 'poisoning' like with cyanide/H₂S or other mitochondrial and OXPHOS defects), and in such cases cyanosis may not appear.

Yes but you said central hypoxia, which means hypoxaemia. If there is anaemia the patient is pale, too, so that doesn't count. Mitochondrial poisoning is not hypoxia. It is something different, which needs a different discussion. Cahnging the argument gets us nowhere.

I’m a bit concerned that your perspective might not fully reflect the patient experience of those who are moderate or more severely affected.

I have spent several hours every day for ten years listening to what patients of all degrees of severity write about their experiences. That is why I am here. I am probably the one professional who has had most exposure to patient experience. I base my analysis absolutely on what I hear. It doesn't sound to me like hypoxia.

(I am very severe (no lung or heart disease), my standard oxygen saturation is between 90-92%, I have blue lips regularly.)

My understanding is that lip colour reflects arterial haemoglobin saturation, because the vermillion does not itself use much oxygen. And if arterial oxygen saturation is low then the problem is not capillary thickness but either lung gas transfer or cardiac output, pretty much by definition. Again, I think we get nowhere if the argument keeps changing.

 

[butter.]

Yes but you said central hypoxia, which means hypoxaemia. If there is anaemia the patient is pale, too, so that doesn't count. Mitochondrial poisoning is not hypoxia. It is something different, which needs a different discussion. Cahnging the argument gets us nowhere.



I have spent several hours every day for ten years listening to what patients of all degrees of severity write about their experiences. That is why I am here. I am probably the one professional who has had most exposure to patient experience. I base my analysis absolutely on what I hear. It doesn't sound to me like hypoxia.



My understanding is that lip colour reflects arterial haemoglobin saturation, because the vermillion does not itself use much oxygen. And if arterial oxygen saturation is low then the problem is not capillary thickness but either lung gas transfer or cardiac output, pretty much by definition. Again, I think we get nowhere if the argument keeps changing.

I am not changing my argument, I think both central hypoxia (=hypoxemia =lack of oxygen supply; existing CBF studies might strengthen that argument; blue lips, extremely cold nose and ears, cold sweat, might be indicators too) and cellular hypoxia could be part of ME/CFS, and they could certainly reinforce each other. Not only that, all this could only be somewhat localized in/to certain parts of the brain at certain times and hence difficult to detect.

EDIT:
Also, let me add that before it became impossible for me, I had workups in some of the best clinics in Europe and even in the US. No heart or lung issues were found that could explain my low saturation. So your definition is at best incomplete. The vague answer I always got was, “It’s probably a central and/or neuromuscular issue.” What makes matters worse, though, is that it’s not the kind of neuromuscular issue that specialists in neuromuscular disorders would typically recognize as such. What I have is more akin to something like post-polio syndrome, but distinct from it.

 

[Jonathan Edwards]

“It’s probably a central and/or neuromuscular issue.”

Are you talking about arterial saturations? If so I cannot see how a 'best clinic' could attribute low values to a neuromuscular issue.

 

[butter.]

Are you talking about arterial saturations? If so I cannot see how a 'best clinic' could attribute low values to a neuromuscular issue.

Yes, arterial.

Really? You don’t think it’s possible to have low oxygen saturation due to a lack of central drive or dysfunction of the diaphragm and thoracoabdominal respiratory musculature? Maybe I am confusing/missing things here, but I don't think so.

 

[Jonathan Edwards]

You don’t think it’s possible to have low oxygen saturation due to a lack of central drive or dysfunction of the diaphragm and thoracoabdominal respiratory musculature?

In that sense it is theoretically possible, yes, and may be relevant to sleep apnoea, but I have not come across it mentioned as a daytime phenomenon.

 

[Utsikt]

There is a study of iCPET with 10 patients, post COVID exercise intolerance, 9 had mild infection, on average 11 months after positive PCR
and 10 age- and sex-matched control participants.

Patients demonstrated impaired systemic oxygen extraction (0.49 0.1 vs 0.78 0.1; P < .0001)

• DOI: 10.1016/j.chest.2021.08.010

Thread here:

https://www.s4me.info/threads/persistent-exertional-intolerance-after-covid-19-insights-from-invasive-cardiopulmonary-exercise-testing-2021-singh-systrom-et-al.21821/

 

[jaded]

My understanding is that lip colour reflects arterial haemoglobin saturation, because the vermillion does not itself use much oxygen. And if arterial oxygen saturation is low then the problem is not capillary thickness but either lung gas transfer or cardiac output, pretty much by definition.

I don’t want to derail the thread but I also experience blue lips only since my ME has further worsened post covid with the development of cranial neuropathic symptoms.

Aren’t the lips rich in small fibre nerves which regulate vascular tone and so local vasoconstriction can result in the discolouration?

This is the same theory proposed by Dr Systrom at a microvascular level in exercising muscle with ateriovenous shunting occurring. So there could be local hypoxia taking place. The poor oxygen extraction problems happens at baseline on the first CPET in his cohort of patients. Yes we need better controls published by Dr Systrom but he should have enough experience from doing invasive CPET testing in patients with cardiac and lung pathology where these problems are not seen.

Then there’s the preliminary data showing an improvement in oxygen extraction after a single dose of pyridostigmine enhancing nerve transmission.

Kindly explain why this neuropathic dysregulation can’t be the cause of symptoms for a least a subset of PwME? You were speculating about the role of acetylcholinesterase and CGRP at one point.

 

[Jonathan Edwards]

It all seems much too complicated and disconnected to me. I am unclear what neuropathic dysregulation would mean. If there is vasoconstriction everywhere where is the shunting occurring? People seem to be trying desperately hard to attribute symptoms to hypoxia when the evidence we have does not confirm that and the clinical picture does not look particularly like that. The trouble is the researchers used to a particular technique or set of explanations will tend to apply those to all problems and hope to find something that fits with them.

Having experience with a technique is no use unless you do rigorous blinded controls and make sure your sampling is not biased.

And as you say, this is all peripheral to the question about capillary thickness impairing oxygenation. If we think Systom's idea is valid it is a bit strange that we now have a second explanation on top of it. William of Ockham would not be pleased.

 

[Formerhuman]

It all seems much too complicated and disconnected to me. I am unclear what neuropathic dysregulation would mean. If there is vasoconstriction everywhere where is the shunting occurring?

This is how Anne Louise Oaklander explains shunting:

Other SFN symptoms are caused by neuropathic microvasculopathy that
leaves tissues unable to augment perfusion during peak demand. Pathology
studies clearly demonstrate impaired sympathetic motor activity causing microvascular
dysregulation. In one skin biopsy study, gaping arteriovenous shunts
dumped arterial blood directly into venules, bypassing tissue capillaries and
reducing oxygen exchange permitting premature hypoxia, anaerobic metabolism,
and hypercapnia.22 A study of perivascular innervation in skin and muscle
biopsies found denervation of the capillaries supplying primarily proximal
skeletal muscles (e.g., quadriceps). This likely explains the reduced capacity
for exertion and deep aching pain (from premature anaerobic metabolism and
lactic acidosis) many SFN patients report.23

Redirecting

People seem to be trying desperately hard to attribute symptoms to hypoxia when the evidence we have does not confirm that and the clinical picture does not look particularly like that.

I haven't understood yet why you don't like iCPET data on decreased oxygen extraction that can imply perfusion or diffusion issues. And I would disagree that clinical picture doesn't look like that. I see in patients' communities that muscle fatigability and especally leg muscle symptoms are not rare.

 

[Jonathan Edwards]

This is how Anne Louise Oaklander explains shunting:

That seems to be just a scattershot of statements based on odd observations here and there, with very speculative interpretation. In my experience neuropathies usually lead to vasodilatation.

I haven't understood yet why you don't like iCPET data on decreased oxygen extraction that can imply perfusion or diffusion issues.

Partly because the time course makes no physiological sense and partly because we never see cases severe enough to show overt ischaemia with necrosis. Nobody is doubting that people with ME/CFS have muscle symptoms. The question is whether they are plausibly attributable to hypoxia. I don't see any good evidence for that and yet researchers seem time after time to assume that is what they are looking for.