I think the shunting is a different category to the low right atrial filling pressures not the cause. Most have low RAP but some seem to have a peripheral limitation of oxygen reaching or being used by the muscles.
Microvascular Dysfunction and Basal Membrane Thickening in Skeletal Muscle in ME/CFS and Post-COVID, 2025, Slaghekke et al
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I think the shunting is a different category to the low right atrial filling pressures not the cause. Most have low RAP but some seem to have a peripheral limitation of oxygen reaching or being used by the muscles.
Jonathan Edwards
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It could be in a non-equilibrium state but it would not explain a baseline state of low right atrial pressure I don't think. I find it hard to see how it would explain poor muscle perfusion.
The low right atrial pressure only occurs when upright and undergoing the exercise challenge. Whatever is going on it seems like gravity is a critical factor in driving the lower RAPs.
If there is increased venous compliance couldn't that cause a larger drop off in venous pressure back to the heart leading to low filling pressures? There is only so much blood in the body. So if more fluid is sitting in the veins below the heart then would it not be the case that without an increase in pressure less would be returning to the heart? It would be interesting to compare the fluid dynamics of ME/CFS to what happens to patients with blood loss.
He also showed some data showing that saline solution directly before the exercise challenge helps increase the RAP and cardiac output during the upright exercise.
The poor muscle perfusion is inferred by measuring atrial and venous oxygen content. A smaller difference between atrial and venous oxygen concentrations suggests that oxygen is not being extracted efficiently during exercise. He says that this is often found in atrial septal defects but in this case must be occurring outside of the heart. Maybe caused by shunting in smaller arteries such that more blood never reaches the muscle. I think this can occur with low RAP but is not caused by the low RAPs. Maybe the shunting acts to increase blood flow back to the heart but because of the increased venous compliance RAP are still low and there is additional poor perfusion.
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Snow Leopard
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I wonder whether the shunting itself is a compensation mechanism for low RAP.
Jonathan Edwards
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Do we have any guarantee that the control V02max and arteriovenous differences are representative of a population? If you ask for volunteers for a CPET study I think you are pretty certain to get recruits mostly from people who do more sprt. My guess is that there will be a 25% of the population who will not volunteer because they are embarrassed by their lack of physical prowess.
Add that 25% in to the graph and it is identical to ME/CFS.
Moreover, even without this caveat most ME/CFS subjects have values within the range of people who consider themselves fit and well. There is no way that these measurements can represent the cause of ME/CFS symptoms.
Interatrial shunting is a quite different process from AV shunting so if Systrom is quoting that it is merely confusing things I think.
I hve never heard of AV shunting as a mechanism to overcome low CVP/RAP. I am not sure that it would serve any biological purpose since the whole point is to maintain tissue oxygenation.
Add that 25% in to the graph and it is identical to ME/CFS.
Moreover, even without this caveat most ME/CFS subjects have values within the range of people who consider themselves fit and well. There is no way that these measurements can represent the cause of ME/CFS symptoms.
Interatrial shunting is a quite different process from AV shunting so if Systrom is quoting that it is merely confusing things I think.
I hve never heard of AV shunting as a mechanism to overcome low CVP/RAP. I am not sure that it would serve any biological purpose since the whole point is to maintain tissue oxygenation.
Snow Leopard
Senior Member (Voting Rights)
I'm not sure. The fact is that almost all of the study results tend to show very low maximum heart rates for the VO2Peak suggesting these people are not used to exercising at a high V02 level and are not actually reaching their VO2Max. Poor oxygen extraction (and poor fitness) itself doesn't limit VO2Max because that is a heart limitation (or lung limitation in maximally trained athletes, or those with pulmonary problems), but it does make it much harder to actually achieve VO2Max in terms of effort.
But the studies also don't include any severe patients at all.
The hypothetical purpose would be to maintain sufficient RAP so that sufficient blood pressure can be maintained in the brain.
My own experience of maximal CPET testing was I lost my vision for about 15 seconds when I reached what was presumably my true VO2Max.
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Jonathan Edwards
Senior Member (Voting Rights)
Yes, but the usual way to do that is to shut down all circulatory paths other than to brain - as in the peripheral whiteness of shock. Opening up shunts would drop arterial pressure, which is ultimately what needs holding up.
I find it hard to piece together a story that works for the situation of pwME/CFS exercising.
I know there are multiple discussions going on on more than one paper but I thought I'd add some comments because I think it is worth discussing.
Systrom used controls who had some exercise intolerance but who didn't have ME/CFS or another condition is known to alter those parameters. So I highly doubt these were sporty people but it does raises other potential concerns.
"A control cohort assembled for comparison purposes comprised 36 patients who had undergone iCPET for exertional intolerance but who had normal results. Specifically, there was no exercise or resting pulmonary hypertension, heart failure, or decreased aerobic capacity"
There is also some discussion that the lower RAP and higher cardiac output found in people with ME/CFS is the opposite of what happens in deconditioning.
I agree that it can't be the cause of all ME/CFS symptoms. But I think it could explain the symptoms of OI.
It was only brought up in the context that interatrial shunting can result in higher venous oxygen saturation in the heart but that is clearly not what is going on here so there must be another explanation.
Jonathan Edwards
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This sounds worryingly like doing science backwards - allocating to controls those who did not show changes.
The worry about representing a population was for the Slaghekke set.
Jonathan Edwards
Senior Member (Voting Rights)
I still think a shunt and venous pooling ar two different issues. Venous pooling could be relevant to OI but not sure about shunting.
I think that is a very good point. I wonder if the bodies response to low cardiac output and low RAP are different. But I find it hard to produce a single story too.
I do think the results of low RAP during exercise are so pronounced that if they hold up they must be somehow related to ME/CFS.
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Yes, I don't know if all the controls are like that or just this study. My understanding is they get referrals for all sorts of exercise intolerance not just ME/CFS. And out of the group that doesn't meet the criteria for ME/CFS they use some of them for controls. So I don't think it is as bad as allocating those that don't show change as controls but still a worry.
Does this research confirm the findings with your moxy measurements @SNT Gatchaman ?
DMissa
Senior Member (Voting Rights)
Yes one of the academics instrumental in this was from my department
I'm certainly following this research with interest. I should reiterate that my observations would be crude, not rigorously methodological and I was using a commercial unit (Moxy). However, I suspect my severity level is greater than the cohort used here (I don't frequently make 1000 steps/day unless a very good day), but who knows what biological confounders are in my n=1. They also are doing things I hadn't tried, in particular the arterial occlusion/recovery component which they state measures vasodilatory capacity.
On their EM findings, reduced capillaries, abnormal endothelial cells and basement membrane thickening / duplication I screen-grabbed in post #48 look to replicate findings (not universal in that n=11 cohort) in Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles (2023) —
