Orthostatic Intolerance in PwME (POTS?/NMH?) - discussion thread

Jonathan Edwards said:
Slowing down blood could increase the oxygen extraction from a given volume of blood but what possible compensatory function could that have? To extract more oxygen over time you want faster flow and return to lungs as quick as possible for new oxygen.
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If I'm not mistaken, that may not be the case. I need to read some more but I believe that we actually have more oxygen per unit volume of blood delivered to the brain than it can use in normal circumstances. That is the principle of fMRI and BOLD (blood oxygen level dependent) imaging. Because the brain doesn't have a fuel reserve and increase in demand requires tight neurovascular coupling. So with a lag of 2-6 seconds we see an increase in blood flow in brain regions which is a surrogate of increased neuronal activity. But what we measure is the rise in oxygenated Hb in that brain volume because the neurons can't use it all.

So in fMRI (BOLD) increased oxyHb is a surrogate for increased blood flow which is a surrogate for increased neuronal activity.

Why the O2 overshoot in normal circumstances? I think it's been suggested that the increased neuronal activity produces metabolic waste and that needs to be cleared. So it's not simply about the O2 and glucose inputs, it's also the waste outputs.

A few things might follow, but there are still some holes.

Slowing blood flow to the brain generally — perhaps for the benefit of certain regions in particular — might have the consequence of reducing the clearance of metabolic waste. Then you might have a little more waste needing to be cleared via the glymphatic system, which might explain enlarged perivascular spaces that are commonly seen.

In this model cognitive-induced PEM may relate to further reduced clearance of waste products, leading to increased neuro symptoms; and systemic cardiovascular effects, leading to increased body symptoms.

If it's true that the brain wants slower flow to allow it to extract more O2 than it it would or could in normal circumstances, then the brain could try and influence this by aiming to reduce circulating blood volume and putting us in a near shock state, to try and keep MABP down.

That could explain reduced or undetectable vasopressin levels (aka anti-diuretic hormone, from the hypothalamus).

Could also explain the RAAS (renin-angiotensin-aldosterone) paradox as again the hypothalamus could be adjusting the HPA axis, although I don't have a handle on potential mechanisms.

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One problem though, in me and others, is that my BP is now high. Admittedly a bit of a hand-wave for now, but maybe that results from the contention between brain requests and body requests of the cardiovascular system.

(I don't get brain fog and maybe my brain compensation mechanisms are doing a better job at holding the line, at the cost of body symptoms.)

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PS if this were true then it puts a knife into the TPJ findings in the NIH paper, as BOLD imaging can not be regarded as at all reliable in this scenario.
 
SNT Gatchaman said:
I need to read some more but I believe that we actually have more oxygen per unit volume of blood delivered to the brain than it can use in normal circumstances.
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I am absolutely sure that is the case. But slowing the blood won't help the brain metabolically. And if neurone are very active they may want the oxygen tension to be well up near optimal even in the venules. It may not at all like draining all the oxygen out. A bit like a Chinese paintbrush. It needs to be full of ink right through the stroke, not half dry half way through. You don't get good chrysanthemum petals that way.

It might mean more blood could be sent to kidneys though.
 
Jonathan Edwards said:
I agree. I was thinking of writing almost exactly the same post.

So far nobody seems to have worked out a plausible mechanism of origin for POT. It isn't just autonomic failure. It is very unclear to me where it is supposed to start off. I suspect it may not be a very good way of categorising things especially in the context of ME/CFS. NIH may have confirmed a sound suspicion that OI in ME/CFS isn't usefully classified that way.
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I spoke to Satish Raj about this at a conference.

POT doesn't come with the syndrome. It's possible that POT is highlighting tachycardia that can effectively compensate and maintain blood flow (especially CBF). POTS might be when the tachycardia happens but isn't effective enough to maintain blood flow (especially CBF).

I personally wonder if adrenaline used to initiate the tachycardia has off-target effects that are creating symptoms in POTS vs POT. I note that several co-morbidities that exacerbate ME/CFS seem to initiate an adrenaline dump (POT, MCAS, allergy). What if it's the inappropriate reaction to adrenaline in other places that is underlying symptoms in some patients?
 
Great discussion in here.

A lot of focus on oxygen delivery, I think too much focus actually. More interested in CO2 and its impact on blood flow. Additionally, blood flow is important in removing and providing metabolites. The removal process is underrated here, it could actually be the critical problem of reduced CBF.
 
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MelbME said:
A lot of focus on oxygen delivery, I think too much focus actually. More interested in CO2 and its impact on blood flow. Additional, blood flow is important in removing and providing metabolites. The removal process is underrated here, it could actually be the critical problem of reduced CBF.
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OK, so rather than my question up-thread as to whether capillary flow is being deliberately slowed to allow more O2 extraction as a metabolic compensation, perhaps a better hypothesis could be that cerebral autoregulation etc is principally aiming to preserve and protect the BBB. If it's damaged that might prompt the brain to use all the tools at its disposal to try and reduce CBF to repair or protect against further damage. That could include the other aspects beyond autoregulation: chemoregulation, neuronal regulation, and endothelium-dependent regulation (reviewed here). Eg why do we seem to have "dysfunctional breathing" — the brainstem could direct hyperventilation, causing hypocapnia leading to cerebral vasoconstriction.

Reducing vasopressin, HPA modulation of the RAAS, increasing brain-derived natriuretic peptide could all reduce blood volume in an attempt to reduce MABP. Standing lowers ICP which would act to increase CBF. Lying down does the opposite. When I was improving from severe, even if not obviously dizzy with OI I "knew" I had to lie down and couldn't tolerate sitting but I didn't know why. I felt sick and nauseous, "must... lie... down...".

Increased sympathetic activity will cause cerebral vasoconstriction and there are inputs via the trigeminal nerve too. Maybe reduced parasympathetic inputs reduces cerebral vasodilatation. Effects of each may be small, but the brain has quite a few mechanisms to use in parallel.

Could there be other mechanisms that are beyond the brain and even more indirect? Eg could the brain be causing reduced RBC deformability, leading to slowing flow through capillaries and decreasing CBF? (endothelial interactions??, nNOS??) The side effect of any of these measures might then be increased oxygen extraction from these more slowly moving, but initially normally saturated RBCs.

It might neatly explain orthostatic intolerance following head injury.

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Preliminary Evidence of Orthostatic Intolerance and Altered Cerebral Vascular Control Following Sport-Related Concussion (2021, Frontiers in Neurology)

Post-Concussive Orthostatic Tachycardia is Distinct from Postural Orthostatic Tachycardia Syndrome POTS in Children and Adolescents (2022, Child Neurology Open)

Symptoms upon postural change and orthostatic hypotension in adolescents with concussion (2021, Brain Injury)
 
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SNT Gatchaman said:
OK, so rather than my question up-thread as to whether capillary flow is being deliberately slowed to allow more O2 extraction as a metabolic compensation, perhaps a better hypothesis could be that cerebral autoregulation etc is principally aiming to preserve and protect the BBB. If it's damaged that might prompt the brain to use all the tools at its disposal to try and reduce CBF to repair or protect against further damage. That could include the other aspects beyond autoregulation: chemoregulation, neuronal regulation, and endothelium-dependent regulation (reviewed here). Eg why do we seem to have "dysfunctional breathing" — the brainstem could direct hyperventilation, causing hypocapnia leading to cerebral vasoconstriction.

Reducing vasopressin, HPA modulation of the RAAS, increasing brain-derived natriuretic peptide could all reduce blood volume in an attempt to reduce MABP. Standing lowers ICP which would act to increase CBF. Lying down does the opposite. When I was improving from severe, even if not obviously dizzy with OI I "knew" I had to lie down and couldn't tolerate sitting but I didn't know why. I felt sick and nauseous, "must... lie... down...".

Could there be other mechanisms that are beyond the brain and even more indirect? Eg could the brain be causing reduced RBC deformability, leading to slowing flow through capillaries and decreasing CBF? (endothelial interactions??, nNOS??) The side effect of any of these measures might then be increased oxygen extraction from these more slowly moving, but initially normally saturated RBCs.

It might neatly explain orthostatic intolerance following head injury.

---
Preliminary Evidence of Orthostatic Intolerance and Altered Cerebral Vascular Control Following Sport-Related Concussion (2021, Frontiers in Neurology)

Post-Concussive Orthostatic Tachycardia is Distinct from Postural Orthostatic Tachycardia Syndrome POTS in Children and Adolescents (2022, Child Neurology Open)

Symptoms upon postural change and orthostatic hypotension in adolescents with concussion (2021, Brain Injury)
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CO2 is produced from the TCA cycle in mitochondria. It's a byproduct but it plays a lot of important role. Less TCA cycle gets you less CO2. Hyperventialtion pushes our more CO2. Both things happen in ME, both would work to reduce CO2.

CO2 + H2O gets you HCO3- and H+
This highlights the major role for pH balance.
For digestion, the H+ is pumped in to stomach to lower pH, HCO3- is then pushed in to to intestines to increase pH and this process is used to anti-port metabolites from intestines in to bloodstream.
CO2 is important for brain blood flow.


I don't know why hyperventilation is happening but it seems important to find out.

What if ME is a disease of reduced cerebral blood flow that can't be recompensated because of an array of different factors?
 
MelbME said:
CO2 is produced from the TCA cycle in mitochondria. It's a byproduct but it plays a lot of important role. Less TCA cycle gets you less CO2. Hyperventialtion pushes our more CO2. Both things happen in ME, both would work to reduce CO2.




I don't have enough medical knowledge. Could you explain this sentence again. I understand less TCA = less CO2, but hypervertilation is reducing CO2?
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Yes during hyperventilation you breathe out more CO2. If TCA cycle is constantly slower then you'd have a mechanism of reduced CO2 production and excessive release.

CO2 is important for CBF, balancing blood pH and digestion.
 
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MelbME said:
Do ME/CFS with orthostatic intolerance remember if they had OI symptoms before ME/CFS?
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I had no OI symptoms before ME/CFS onset.

And my OI symptoms were among my very first ME/CFS symptoms.

For me, OI symptoms include feeling lightheaded, needing to fidget or move around while standing, increased heart rate, cold sweat/clammy, and probably some others I'm forgetting. Also nausea that would come on suddenly. I'd often have to abandon my shopping cart in the store and go lie down in my car.

I also remember several times waiting for an elevator where I suddenly had to sit down on the carpet. And heat made all these OI symptoms worse.

I did not realize that these symptoms were due to OI (and presumably due to dropping blood pressure in my case?) until I got these same symptoms on the tilt table test shortly before I passed out (I fainted after about 20 minutes).

I never fainted before the tilt table test. I was always able to sit down when I started getting those symptoms. I didn't know that I might faint. I thought it was some kind of weakness (or ???) that made me need to sit down.
 
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I fainted a few times as a child and young adult before ME/CFS, but the cause was identifiable, eg standing too long in hot weather, severe pain (period pain) and having needles stuck in me. These are still true since I got ME, though obviously not period pain any more, as I'm 74.

That is different from my ME OI which is not usually feeling faint or fainting, it's more lack of capacity to stay upright even at the beginning of my ME when I was still physically fit. It start with my legs feeling like they are goiing to collapse, and needing to sit, then if I sit too long, I feel increasingly unwell and need to lie down. When crashed I do have the dizziness, faintness too, and become bedbound.
 
I had no issues with orthostatic intolerance prior to my ME’s onset, and was not aware of it as an issue for some years into my ME. At first some ten years in I was aware that resting lying horizontal was more ‘restful’ than reclining at an angle or leaning back in a chair which in turn was more ‘restful’ than sitting unsupported. As it became more of an issue I became aware that it related to my relationship to the horizontal as much as the level of physical support. It was also only then that I read about the concept of orthostatic intolerance and could start to understand its impact on possible activity levels.

I then struggled to undertake any activity bending forwards, getting breathless and feeling faint, and when my ME was at its worst over 20 years in I was limited as to how long I could stay upright without feeling faint, triggering fatigue and increasing the likelihood of subsequent PEM. Although better now than my lowest point
I still have to ration how long I am upright, I need to spend much of my day horizontal and can not do anything requiring bending forward for more than a minute or so.

My orthostatic intolerance gets much worse when in PEM and being upright contributes the likelihood of any activity triggering further PEM. I have not had a tilt test or any diagnosis of POTS.
 
I’ve only ever passed out once due to violent coughing. That was during the 10 years when I had undiagnosed ME. But I don’t think is related to ME. I have hypertension which was first identified around the time of the gradual onset of my ME. But everyone in my immediate family had/has hypertension.

But I definitely have OI as I can’t stand still or queue for more than 5 minutes or so without needing to sit. I can sit upright for much longer but a long block of 4 or so hours without being able to put my feet up means I need to lie down for about an hour to get some energy back when I get home. I’ve struggled with supermarket queues when I was undiagnosed but I only realised when I started reading up on ME and even then I didn’t understand that if you didn’t pass out it could still be OI.

https://en.wikipedia.org/wiki/Orthostatic_hypertensionpresumably is what I get. I’ve never done any sort of test or raised the issue with a Dr I’m not sure there’s anything that can address it. My diastolic tends to be more above normal than systolic but it does seem to be within normal levels on the two medications when tested sitting for my annual hypertension review. And whenever the systolic has been normal but diastolic a bit high GPs not interested.
 
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