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

[Robert 1973]

Thanks, Simon. Really useful and clear summary, as always.

However, I think there is a bigger concern. The idea is that endothelial dysfunction means not enough oxygen gets to tissues and that's why people with ME don't have enough energy. Specifically, without enough oxygen, the body can't burn fuel efficiently and produces lactate as a result.

Unfortunately, the evidence of people with ME producing more lactate is weak at best.

This seems like something of a paradox. But this type of paradox can lead to exactly the type of insights we need. It’s a concern but also a potential clue.

Can anyone think of any possible explanation(s) as to how this type of endothelial dysfunction could not cause a significant increase in lactic acid production? Is there some way that lactic acid production could be blocked despite hypoxia?

I also wonder if anyone can think of any possible ways in which the results of this study (combined with the lack of evidence of increased lactic acid production in others studies) might relate to Hanson’s recent study on Urine Metabolomics.

Of course, the results from either or both studies may prove to be unreliable. But I find both if them intriguing and encouraging. This endothelial study seems to support findings from previous studies in the same field and the urine study is encouraging to me because the result was so stark and unexpected, and makes intuitive sense. Both studies also suggest numerous possibilities for further studies in the same areas – so I hope the grant applications will be flooding in. And approved.

It would also be fascinating to try to replicate both these studies in one combined study using the same patients and controls but I guess that may be a logistical bridge too far at this stage.

Do others agree that these are currently the two most promising avenues of research based on published studies? Are there any other published studies which suggest similarly promising avenues to explore at this stage?

Obviously we hope that DecodeME will lead to many more promising avenues but that is some way off yet.

 

[Hutan]

The absence of lactate would be not that surprising if the 'burning' of glucose is dialled back, either intentionally by the body in response to an infection to starve the pathogen, or due to some problem. I think it would fit with the itaconate shunt hypothesis.

source

e.g. The role of itaconate in host defense and inflammation

This Review focuses on itaconate’s emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome.

A key mechanism of itaconate is the modification of thiol-reactive cysteines, many of which have been identified by proteomic screens. Targets include the glycolytic enzymes aldolase A (ALDOA; ref. 76), lactate dehydrogenase A (LDHA; ref. 11),

Qin et al. (76) reported that itaconate decreases ALDOA enzyme activity, glucose consumption, and lactate production

The diagram in that paper is good.

 

[SNT Gatchaman]

On the other hand, if endothelial dysfunction is really driving the illness, then we should expect a strong association with severity measures, and a study of even this size should probably pick that up.

I think the endothelial dysfunction will be part of the disease (and may explain the orthostatic intolerance for example). While it could reduce oxygen delivery to tissues and further contribute to metabolic impairment, I don't think it's driving the disease. Rather the metabolic impairment upstream may cause downstream endothelial dysfunction. See Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone (2023).

If this model is true then symptom severity (overall: esp cognitive/neuro, muscular) may be predicated on the degree of metabolic dysfunction, and this would be partly de-coupled from the endothelial dysfunction and resulting cardiovascular and orthostatic symptoms.

 

[Ravn]

I think this is the same drug used in POTS tests?

During the Tilt Table test NTG is sometimes administered. Not sure how frequent this is as I have had the TTT with and without.

My expertise a TTT was that my BP went down and my HR up with NTG. I became very nauseous and faint. It felt the same for me as a bad POTS attack in hot weather.

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

 

[hinterland]

Haven't read, but various trials of grape seed extract in this context referenced in The impact of grape seed extract treatment on blood pressure changes: A meta-analysis of 16 randomized controlled trials (2021).

European Food Safety Agency published MegaNatural®-BP grape seed extract and maintenance of normal blood pressure: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 (2021). Concluding —

Thanks. It's not clear what product the EFSA ruling is concerning. The application is from Praline i Čokolada j.d.o.o., who, so far as I can tell are (or were) a company manufacturing sweets and chocolate bars in Croatia. It translates as praline and chocolate. So one imagines it might relate to health claims being made for grape seed extract as an added ingredient to confectionary. Praline i Čokolada appear to now be insolvent.

In the meta analysis Zhang et al 2016 conclude that

Our findings demonstrate that grape seed extract exerted a beneficial impact on blood pressure, and this impact was more obvious in younger or obese subjects, as well as in patients with metabolic disorders. In view of the small sample size involved, we agree that confirmation of our findings in a large-scale, long-term, multiple-dose randomized controlled trial, especially among hypertensive patients is warranted.

I'd also suppose it possible that GSE could have an effect on the endothelium and regulation of blood flow despite inconsistent evidence on blood pressure.

 

[Simon M]

The absence of lactate would be not that surprising if the 'burning' of glucose is dialled back, either intentionally by the body in response to an infection to starve the pathogen, or due to some problem. I think it would fit with the itaconate shunt hypothesis.

That’s an interesting explanation for the lack of lactate production (I didn’t know about the lactase dehydrogenase issue)).

But I don’t think it can explain the single maximal exercise test. One of the slightly surprising, but consistent findings is that the maximal exercise results for people with ME are pretty much as expected, given the level of activity: lower than sedentary controls, but not massively so.

they are much higher than people with, for example, known mitochondrial disorders. If glucose metabolism was inhibited at a substantial level, I think would be seen how much bigger difference between ME and controls.

Also, that Dane Cook study found, I think, over a quarter of people with with ME were metabolically fitness matched with healthy controls. Again, we wouldn’t expect to see that if glycolysis was throttled back at significant scale.

I feel the challenge for any hypothesis relating to reduced energy production is to explain single maximal exercise test results: neither VO2 mac nor lactate levels look surprising, despite people suffering from severe fatigue.

 

[Robert 1973]

I feel the challenge for any hypothesis relating to reduced energy production is to explain single maximal exercise test results: neither VO2 nor lactate levels look surprising, despite massive fatigue problems.

@Jonathan Edwards Any thoughts on this? And/or more generally on this paper and the other studies which suggest there may be endothelial dysfunction?

 

[Jonathan Edwards]

@Jonathan Edwards Any thoughts on this? And/or more generally on this paper and the other studies which suggest there may be endothelial dysfunction?

I very much agree with Simon's analysis. This study may show an abnormality of signalling that, maybe amongst other things, is involved in vascular tone. I agree that to link that to reduced energy output is implausible in view of the single CPET data, and, indeed, to my mind, the very nature of ME symptomatology.

I see the lack of ability to do things in ME as much more likely due to some inhibitory signal - maybe similar to that which makes us unable to get up when we have 'flu' or even stops us from running when in a bad dream. NO is a fast acting signal that may bridge the gap between most hormonal signalling and neural signalling. I suspect that there is an ongoing audit of activity capacity going on in the body from second to second all the time and if there is a signal mismatch the immediate effect is to put all action on hold.

I think we are looking for an inhibitory signal, that for inflammatory disease would be TNF alpha or gamma interferon but which in ME is something else. It is not simply going to be too much or too little NO but it might be something linked in to NO signalling.

 

[Kitty]

maybe similar to that which makes us unable to get up when we have 'flu

In my experience at least, that is exactly what PEM feels like.

 

[JemPD]

In my experience at least, that is exactly what PEM feels like.

mine too.
I know the yuppie flu term was derogatory and awful, but i still prefer it to chronic fatigue, at least it vaguely resembled my experience

 

[Hutan]

I agree that to link that to reduced energy output is implausible in view of the single CPET data, and, indeed, to my mind, the very nature of ME symptomatology.

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? If that itaconate shunt evolved to help a sick animal starve out a pathogen, there would be an evolutionary advantage for the animal to be able to override that mechanism when necessary to attempt to evade a predator.

 

[Jonathan Edwards]

I just don't see PWME as having the sort of problem I have been used to seeing in people with heart failure or other organ system failure where ATP mediated energy supply is limited.

I don't see people with ME in the clinic but I have got to know quite a number of people with mild or moderate ME on committees. I go up and down stairs, or even along the street, and sit with them in a room going about activities for a couple of hours. I perceive that they are limited, on the alert for symptoms, but nothing reminds me of people with heart failure or dermatomyositis or something where muscles simply stop operating.

When energy delivery fails, movements change. I don't see that in ME, I see distress and I see tentativeness and perhaps impending disorientation. The movements executed are always normal. It reminds me a bit of people mobilising after major surgery - doing anything has a cost, but it is not that the movement changes shape. Rather, something has been switched on which is there to inhibit activity to protect. In convalescence it works to good effect but in ME it is an aberration.

I may be wrong but this is a view strongly endorsed by a colleague who works full time with people with mitochondrial disease. He said the picture was quite different.

 

[voner]

I don't see that in ME, I see distress and I see tentativeness and perhaps impending disorientation. The movements executed are always normal. It reminds me a bit of people mobilising after major surgery - doing anything has a cost

that is a useful observation. Do you get to see these people 24, 48 etc. hours later and what are your observations then?

 

[JemPD]

I just don't see PWME as having the sort of problem I have been used to seeing in people with heart failure or other organ system failure where ATP mediated energy supply is limited.

I don't see people with ME in the clinic but I have got to know quite a number of people with mild or moderate ME on committees. I go up and down stairs, or even along the street, and sit with them in a room going about activities for a couple of hours. I perceive that they are limited, on the alert for symptoms, but nothing reminds me of people with heart failure or dermatomyositis or something where muscles simply stop operating.

When energy delivery fails, movements change. I don't see that in ME, I see distress and I see tentativeness and perhaps impending disorientation. The movements executed are always normal. It reminds me a bit of people mobilising after major surgery - doing anything has a cost, but it is not that the movement changes shape. Rather, something has been switched on which is there to inhibit activity to protect. In convalescence it works to good effect but in ME it is an aberration.

I may be wrong but this is a view strongly endorsed by a colleague who works full time with people with mitochondrial disease. He said the picture was quite different.

Presumably though, if those are people who are well enough to be in the meetings with you, they are not yet in PEM. Perhaps i'm barking up the wrong tree but it just occurs to me to mention that my carers have often commented that my body appears to work differently and the movements of my body all look what they call "odd" when i am "bad" as they call it - ie when i'm in PEM. So its not just that i struggle to have the strength to stand, but that i also 'walk funny'. I'm aware of it but i cant make my legs move in normal way.
A nurse who knew me also commented when she visited me for something else while i happened to be in a bad bout of PEM but had to see her anyway, she was shocked at the change at the time, & when i saw her again she commented how my movements had looked strange on that day.

I'd always taken in for granted that this was just a standard aspect of PEM that everyone experiences at the more severe end of things?


Perhaps this is something different than what you're talking about, forgive me if i'm barking up wrong tree.

 

[Hutan]

I'm having a day where it is hard to think and write coherently, so apologies if my posting reflects that.

Previously, but after the onset of ME/CFS, I worked on 2 consecutive days of full-day video calls where there was a lot of information to process and points to argue. I fortified myself with a lot of coffee. I don't think anyone would have known I had ME/CFS if they had not been told. Stimulants do seem to allow greater function.

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 days.

If I walk too far, walking starts to require conscious thought, limbs become heavier and more clumsy. The best way I can explain it is that I feel like when I was at high altitudes when I was healthy.

 

[Kitty]

When energy delivery fails, movements change.

I broadly agree with that. The effects of PEM in mild/moderate ME include clumsiness and tremor, and sometimes movements resembling drunk people who kind of fling their limbs instead of controlling them smoothly, but it's not the same as non-functioning muscle.

I have weakness in my legs caused by something other than ME, and whether I'm in PEM or not, I can't manage a normal gait because I have to truncate the movement. I can't lift my thighs up far and I compensate by using more hip rotation, giving me a sort of rolling gait. I have to take small steps, too, as I can't sustain longer ones.

My arm and shoulder muscles are only affected by ME, and on a better day I could move them through one set of ballet positions as smoothly and fully as I did before I ill. On a PEM day I'd be a bit unbalanced even if I were sitting down, I'd be rushing through the movement, I'd move jerkily if I were asked to slow it down, and I'd probably need to stop for a rest (you quickly start to get the numb feeling as if the blood supply's been reduced), but I could still make the full trajectory after a fashion. That's never possible with my legs.

 

[Robert 1973]

Jo, If ME/CFS was a signalling problem would that be something that would be detectable in the blood as with TNF? Or are there other types of signalling problem that could be occurring?


Some more thoughts on comments above:

– 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. The first time they met the other patient they said they instantly recognised the gate. I don’t know if anyone has ever studied this. As a severe patient, I think I am probably in a PEM-type state all or most the time, although it gets worse if I try to do more.

– Again, I’m not sure if this is the type of movement that Jo was referring to but my leg frequently flaps about quite violently when I am trying to rest. I can usually stop it if I try hard enough but it is less effort to let it happen. It is very unpleasant and distressing. I also get a lot of rapid involuntary hand flapping when I am in a half-conscious state.

– Re. lactate: I recall a private conversation a few years ago with an ME researcher who told me there was a study that showed lactate production was not abnormal but that lactate clearance was abnormally slow in ME/CFS patients (which would tie in with the recent urine metabolite study). I’m not sure if the study he was referring to was ever published. Does it ring any bells with anyone?

 

[RedFox]

I very much agree with Simon's analysis. This study may show an abnormality of signalling that, maybe amongst other things, is involved in vascular tone. I agree that to link that to reduced energy output is implausible in view of the single CPET data, and, indeed, to my mind, the very nature of ME symptomatology.

I see the lack of ability to do things in ME as much more likely due to some inhibitory signal - maybe similar to that which makes us unable to get up when we have 'flu' or even stops us from running when in a bad dream. NO is a fast acting signal that may bridge the gap between most hormonal signalling and neural signalling. I suspect that there is an ongoing audit of activity capacity going on in the body from second to second all the time and if there is a signal mismatch the immediate effect is to put all action on hold.

I think we are looking for an inhibitory signal, that for inflammatory disease would be TNF alpha or gamma interferon but which in ME is something else. It is not simply going to be too much or too little NO but it might be something linked in to NO signalling.

Contrary to most responses, I find your observations are insightful and not veering towards BPS territory. Just because we lack energy in the sense of ability to do tasks doesn't mean we lack energy in the sense of making ATP. It's certain that the subjective feeling of awfulness PEM brings is the tip of a serious biochemical iceberg, but there's probably more nervous and immune dysfunction in that iceberg than metabolic issues. As you noted, ME symptoms don't match mitochondrial dysfunction, and neither does it match the generalized fatigue from other illnesses.

 

[Hutan]

Contrary to most responses, I find your observations are insightful and not veering towards BPS territory. Just because we lack energy in the sense of ability to do tasks doesn't mean we lack energy in the sense of making ATP.

I don't think that's an accurate reading of my response here, or of any other member who has replied. I'm very happy to hear what an observant, smart and sympathetic clinician thinks, and even more so when that clinician also has a knowledge of the ME/CFS literature. I don't think anyone has said 'it must be an ATP production problem'. Who knows, it might even turn out to be central sensitisation, not that Jonathan Edwards was actually suggesting that. I think it is worthwhile considering if ME/CFS is a 'sickness response' that keeps on being turned on by activity and is turned down by rest.

It's certain that the subjective feeling of awfulness PEM brings is the tip of a serious biochemical iceberg, but there's probably more nervous and immune dysfunction in that iceberg than metabolic issues.

It's hard to imagine a neural or immune dysfunction of sufficient significance that it causes the disability we face but that doesn't leave a detectable metabolic trace.

 

[SNT Gatchaman]

I do see movement changes in myself. I've observed my gait changes - if I'm worse but still able to move around the house, I am slow and less steady, particularly going up and down steps. When better I can move much more normally and freely (over these short distances). This can vary over a single day. The background assessment that the phone/watch makes would seem to correlate with this long-term variation in my overall state. I've posted some of these graphs previously, including prior to illness. Here is the latest data, where my current status is "not too bad, generally house-bound" but not quite the best it's been during this illness.


I find for example the available strength in my limbs, eg standing up from the couch, varies, which I will compensate by boosting with my arms when required. I relate that reduced power with the reduced control and fine motor precision, but to me this doesn't seem to be a problem of neurological inputs: either central or peripheral, excitatory or inhibitory.

A few months before I developed this, some colleagues were discussing a crude test of optimum neuromuscular performance (for fit, normal weight and adequately flexible adults, potentially in to their 70s). If you can sit cross-legged on the floor, and without using arms/hands, transition to standing, then things are AOK. I could do this with ease, as could they (though they were younger and a little more graceful!). Now - no way.

The question of inhibition / protection is difficult to evaluate. From personal experience, at my worst I could not lift my arms up from the bed, or roll over. When even just a little better than that, I could almost not lift my arms and this was clear to me. However, I could push it and lift them with supreme effort, but this was slow and ponderous. It could then not be repeated for variable time (minutes to hours). I learnt there was no benefit to pushing it of course, so this could be regarded as "protective".

I interpret these experiences as variable failure of energy delivery. When just able to overcome "paralysis" I imagine this might be using backup/emergency metabolic pathways, somewhat equivalent to aerobic vs anaerobic, but they are very limited, inefficient and invoking them has a cost, with declining returns.