Endothelial dysfunction in ME/CFS patients, 2023, Sandvik, Mella, Fluge et al

[Robert 1973]

I don’t think this is what Jo was referring to but his comment reminded me that a medic and a scientist in my family have both suggested that I have a distinctive gate that they have observed in at least one other moderate/severe ME patient

Gate / gait (?)

Ha! Actually, I was referring to my distinctive art nouveau garden gate, and I was wondering if such taste may be a common feature of severe ME/CFS

 

[Jonathan Edwards]

@Jonathan Edwards Just giving you a nudge in case you didn’t see these questions.

Thanks, my flagging system seems a bit arbitrary.
I wouldn't think it was a bad option. Signals can be blocked either in nerve tissue or elsewhere.
We are getting to the stage when almost any malfunction can potentially be corrected with genes or monoclonals or whatever.

 

[Kitty]

If we do not accumulate lactate acid what causes the deep burning, acid in the muscles and bones feeling you get with ME?

I've often wondered whether this is connected to theories about endothelial issues and blood supply. If muscle fibres had been operating rather short on oxygen-rich blood and then the supply came back on line once they were at rest, it might feel like this. A sort of reperfusion injury, but in the individual fibres of a tissue type (muscle) that tends to shout very loudly when damaged but is able to recover from it quickly.

This is only how I imagine it working, I've no idea whether it's really plausible.

 

[Robert 1973]

If we do not accumulate lactate acid what causes the deep burning, acid in the muscles and bones feeling you get with ME?

I may be atypical but I’ve never had this sensation. I get terrible all over pain but I never describe it as muscle pain as such, and it feels quite different to the feeling I used to get when I was well and lactic acid would build up when I did anaerobic exercise.

Having said that, there are definitely similarities with the sort of pain I remember from school PE when we were told to lie on our backs and try to hold our feet in the air with legs straight for as long as possible. For me, it’s a bit like that, but without the burning. The pain gets to the point when I would have had to put my legs down. But it happens when I’m doing nothing, there is no way I have found to relieve it, and it can persists for weeks or months at very high intensity.


I remember when I was first ill saying it feel like something else was building up in my muscles, similar to the way lactic acid builds up, but different, more toxic feeling, and much slower to clear – if it ever cleared at all.

It has always felt to me like there is some type of tissue hypoxia, but I appreciate there may be other explanations.

I also appreciate that people use different language to describe the same symptoms, but I would be surprised if anyone experiencing the same type of pain that I get described it as muscle pain – unless they just ran out of alternative vocabulary.

 

[Amw66]

Ha! Actually, I was referring to my distinctive art nouveau garden gate, and I was wondering if such taste may be a common feature of severe ME/CFS

Certainly will at least look organic ...

 

[Andy]

They put an ultrasound probe on the upper arm, 5-10 cm above the elbow, looking at the brachial artery. They measure the vessel diameter at rest and following blowing up a blood pressure cuff on the forearm (enough to stop arterial blood flow below where the probe is). This should make the brachial artery above the temporary occlusion dilate up. Healthy controls do, ME/CFS don't (so much).

Apologies if I'm duplicating anything but I wonder if what they did in this study might have some relation to Dr Alan Moreau's new, low-stress protocol for provoking PEM.[Thoughts?], which also involves an arm pressure cuff.

The thought was inspired by spotting this, Preprint: Altered Tissue Oxygenation in Patients with Post COVID-19 Syndrome 2023 Schäfer et al which also involved testing with an arm cuff.

 

[SNT Gatchaman]

Both this study and the preprint you posted @Andy use an arterial occlusion protocol, whereas Alain Moreau's protocol as described in thread and linked video ("a very gentle pulse", 0-4 PSI) would only be intermittently? modestly? at all? impairing arterial inflow.

It is a deliberately "low stress" approach using a gentle arm massage from an inflatable cuff, similar to a blood pressure cuff but using about a 10th of the pressure

I don't know whether this could be physiologically significant on vascular side - probably not in normals but maybe in those with endothelial dysfunction. However, perhaps the massage cuff is gently "damaging" muscles over time, similar to what happens normally with the mechanical provocation of exercise that needs to be repaired and shows as an immune and inflammatory response (or not).

 

[rvallee]

Apologies if I'm duplicating anything but I wonder if what they did in this study might have some relation to Dr Alan Moreau's new, low-stress protocol for provoking PEM.[Thoughts?], which also involves an arm pressure cuff.

The thought was inspired by spotting this, Preprint: Altered Tissue Oxygenation in Patients with Post COVID-19 Syndrome 2023 Schäfer et al which also involved testing with an arm cuff.

Definitely not enough to cut, or even reduce, arterial blood flow. Moreau used about the lowest pressure possible. It inflates and deflates in a rhythm, but at its strongest it's no more than a slightly tight shirt.

 

[Robert 1973]

Thanks, my flagging system seems a bit arbitrary.
I wouldn't think it was a bad option. Signals can be blocked either in nerve tissue or elsewhere.
We are getting to the stage when almost any malfunction can potentially be corrected with genes or monoclonals or whatever.

Thanks.

Sorry to be persistent but could you answer my other 2 questions:

If it was a neural signalling problem, would you expect there to be abnormal physiological effects of those faulty signals which could be objectively identified?

Apologies if this is a dumb question (as you know, I’m not a scientist) but do you think it’s plausible there may be something as yet unidentified which is interfering with the signals – ie that there is a signalling problem but it’s not primary?

 

[Jonathan Edwards]

I guess I didn't answer those questions because I don't know the answers. To the first: maybe not. To the second, maybe, but it is hard to think what would lie behind a persistent signalling problem without showing itself some there way.

 

[Robert 1973]

I guess I didn't answer those questions because I don't know the answers. To the first: maybe not. To the second, maybe, but it is hard to think what would lie behind a persistent signalling problem without showing itself some there way.

Thanks. Better to know what we don’t know than to not know what we don’t know, I guess.

The reply you gave to Hutan (below) seems to imply that there would be measurable physiological effects. I’m struggling to envisage how a signalling problem which did not result in any measurable physiological effects could cause PEM (ie not only the malaise but the inability to override the faulty signal)

But there's a cost. If it was just faulty signalling (which sounds rather like the central sensitisation theory) then people should be able to push past the signalling, and suffer no ill effects. That's not what happens. It took a couple of weeks to get back to my baseline level of functioning after those two day

But to me faulty signalling makes much more sense than lack of ATP. Lack of ATP should last for a minute or two, maybe twenty minutes after a marathon run. If the faulty signalling involves hormonal signals or sleep centre cycles or other systems that audit activity over longer periods then delayed recovery makes a lot of sense to me.

If I exercise more than usual I may well be aware of the effects for several days. Signals bring in macrophages to muscle for several days. Growth hormone effects that mediate bone responses work over an extended period, and so on. And that is the normal situation.

it is hard to think what would lie behind a persistent signalling problem without showing itself some there way

Whatever the cause(s)/mechanisms of ME/CFS it is clearly something which is hard to think what it is, otherwise someone would have thought of it by now.

Is it conceivable that some sort of pathogen which has thus far evaded detection could be interfering with signalling? For example, is it conceivable that commensal microbes could overgrow when the immune system is under stress from infection, and then remain undetected at a steady but pathogenic state which interferes with signalling post infection?

Alternatively, is it conceivable that there could be an undetected brain infection? As far as I’m aware we still can‘t detect prions in the blood, so it doesn’t seem inconceivable to me that there may be some type of undetected infection in ME/CFS which interferes with signalling.

I’m not suggesting that either of these is necessarily likely. I’m just trying to understand if they, or similar scenarios, are possibilities. And I know that I don’t know enough to answer these questions myself.

 

[Jonathan Edwards]

One reason why I doubt hidden microbes are involved is that if they were I would expect at least an occasional case where the microbe showed itself in terms of 'winning' rather than just hiding away causing a nuisance. Most hidden infections can become overt in people who for some other reason have their defences reduced.

 

[Hutan]

That's a good point.

But, there is the example of rickettsias. There is an Australian study that found a high level of latent rickettsial infection in people with ME/CFS symptoms. (I also have tested positive to rickettsias.) Brill-Zinsser disease does occur occasionally, as a reactivation of a rickettsial infection, but it doesn't seem to happen often, and, when it does, it can be decades later. Given that the reactivation is typically milder and doesn't necessarily cause a rash, just a fever that responds to doxycycline, it might not even be identified as a reactivation. It's damn hard to get tested for rickettsias.

Brill-Zinsser Disease in Moroccan Man, France, 2011

Since 1970, reports of only 8 cases of Brill-Zinsser disease have been published (9,10). In all cases, known risk factors were present (overcrowding, poor hygiene, or contact with flying squirrels). Brill and Zinsser described that stress or waning immunity could reactivate R. prowazekii infection (2). Corticosteroids can trigger recurrence of R. prowazekii in mice (2), but no such observations were made in humans. In the case presented here, we found no stress factor, no immunosuppression, and no medical history of epidemic typhus.

Brill-Zinsser disease can develop >40 years after acute infection. The mechanism of R. prowazekiilatency has not been established. A recently explored reservoir for silent forms of R. prowazekiiinfection is adipose tissue because it contains endothelial cells, which are the target cells for R. prowazekii infection, and because of its wide distribution throughout the body (2). Brill-Zinsser disease should be considered as a possible diagnosis for acute fever in any patient who has lived in an area where epidemic typhus is endemic.

 

[Robert 1973]

One reason why I doubt hidden microbes are involved is that if they were I would expect at least an occasional case where the microbe showed itself in terms of 'winning' rather than just hiding away causing a nuisance. Most hidden infections can become overt in people who for some other reason have their defences reduced.

That makes sense. But if microbes overgrew to the extent that they were “winning” might that not result in a different presentation and a different or new diagnosis? I’m wondering if ME/CFS could be a steady pathogenic state where neither the microbe(s) nor the immune system is winning. If the immune system wins, the patient recovers. If the microbe wins, the presentation and diagnosis changes. Could it be that ME/CFS only occurs when there is a stalemate?

 

[JemPD]

That makes sense. But if microbes overgrew to the extent that they were “winning” might that not result in a different presentation and a different or new diagnosis? I’m wondering if ME/CFS could be a steady pathogenic state where neither the microbe(s) nor the immune system is winning. If the immune system wins, the patient recovers. If the microbe wins, the presentation and diagnosis changes. Could it be that ME/CFS only occurs when there is a stalemate?

was just thinking the similarly thing that if the microbes ever win the person is simply assumed to have been misdiagnosed. And perhaps it hasnt alerted us because it isnt always the same one? I'm very foggy though so that might be sheer drivel

 

[Jonathan Edwards]

Could it be that ME/CFS only occurs when there is a stalemate?

It could but in the long term many people eventually get a loss of immune defences - maybe 5-10% will develop a condition that lowers resistance, such as diabetes. So we would expect 5-10% of PWME to eventually suffer from overt infection with the hidden agent.

An analogy would be herpes zoster. About 10% of people will develop shingles in later life as a reactivation of their hidden chicken pox virus. In the past re-emergence of TB was another example - still seen commonly in poorer communities when people are given anti-TNF drugs.

 

[Robert 1973]

Do we have any reliable epidemiological data on causes of death in people with ME/CFS? I know suicide rates have been studied (and are high) but I don’t know if there is reliable data on other causes. It would be interesting to know if there are any statistically significant differences with other groups which can’t be explained by the limitations imposed on patients by the disease.

If the stalemate idea was true, presumably it could either be caused by a particular type of ME/CFS specific microbe which has a tendency to evade detection by leading to a stalemate (possibly not a bad evolutionary “strategy”), or alternatively it might be that it could be caused by any one of a multitude of different pathogens. If the latter were the case and there were enough different pathogens capable of causing a stalemate then presumably that might not not show up in epidemiological data as the causes of death in the cases where immune comprised patients had lost to the pathogen would be as diverse as the pathogens themselves.

Thinking about all the above also makes me think how useful it would be if we had a post-mortem tissue bank for ME/CFS, as the MEA is trying to establish.

[edit: changed some of the wording and grammar to try to make my point clearer.]

 

[SNT Gatchaman]

Replication study by another group, extending to compare LC (short duration) and ME/CFS (long duration). Identical findings in both groups.

People With Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Exhibit Similarly Impaired Vascular Function (2023)

 

[RobH]

That makes me wonder, for those of us with POTS or other forms of OI, wouldn't a vasodilator be expected make things worse? As in more blood rushing to the feet more quickly?

So could the reduced vasodilation simply be a downstream compensatory effect of some sort?

Which sounds like a lose-lose situation. Too little vasodilation potentially means too little oxygen gets to some tissues like the muscles. But increasing vasodilation with drugs potentially means too little oxygen gets to the brain

I have mild ME/CFS with dysautonomia symptoms including OH.

I have tried supplementing with Citrulene and beet root extract, both are vasodialators. What you describe is my N=1 set of symptoms. I get increased OH from the supplements.

I also understand that a primary drug treatment for OH is Midodrene. That is a vaso-constrictor if I am not mistaken.

 

[RobH]

You may well be right about the inhibitory signal. But, I'm not sure why the ability of people with mild ME/CFS to perform normally on a single CPET when well-rested indicates that there is no problem with the ability to sustainably produce ATP. Why do you think that?

I think we have seen a bit of evidence that there are problems with the production of ATP, although admittedly the literature is very messy, with small samples and focused on cells that are normally quiescent.

Could there not be an ability to produce enough ATP for a short burst of exercise, maybe assisted by adrenalin or something, but an inability to sustain that production for longer and without substantial consequences?

This fits my experience. I try to be a competitive masters swimmer despite my mild ME/CFS. I can maximally sprint 25 yards in about 12 to 14 seconds (nationally competitive times for my age group) with no limitations except catching my breath afterwards. I can, but struggle to sprint 50 yards, which takes me 25 to 30 seconds. I definitely feel impairment during last half of that distance. I have put my body into complete shutdown trying to race 100 yards, hitting a proverbial wall at about 70 yards. I have a very significant decline of speed as distance increases.

My understanding of body energy systems is that PCr is the primary energy source for about 15 seconds. After that, we start using increased amounts of glucose metabolism which is processed in the mitochondria and requires blood flow to operate. Oxygen must be delivered and metabolites must be removed. Both energy systems create significant metabolites that, if not removed, can cause system failure. The breathlessness from exertion could certainly be explained by increased levels of CO2 (metabolites not being removed quickly enough).