Orthostatic Intolerance in PwME (POTS?/NMH?)

I understood that POT was defined as in the absence of orthostatic hypotension.

I would have thought that the relevant blood pressure was ongoing over a period of many minutes, not immediately after standing, which might easily drop temporarily.

 

I may be wrong here but I thought Dr David Systrom’s invasive CPET findings were quite interesting showing poor systemic oxygen extraction in a subset despite preserved cardiac output and BP despite ubiquitous “pre-load failure”. He proposes arteriovenous shunting due to SFN in the periphery as a cause of poor oxygen extraction or a mitochondrial defect or both. But the actual mechanism hasn’t been fully elucidated and are just hypotheses based on his iCPET findings.

Could it be some aberrant neurovascular signalling defect which occurs in the periphery in the same way it does in the CNS causing excessive vasoconstriction?

I don’t really understand the term neurovascular decoupling but I know that’s been thrown around by a few researchers.

 

Except that venous pooling with preload failure would indicate failure of vasoconstriction rather than excess vasoconstriction.

I guess it might be possible to put all these things together into a single coherent story but I have a strong suspicion that we have what is called an embarras de richesses of findings and explanations that don't actually make sense. That would be par for the course in clinical physiology where people repeatedly get things wrong.

 

I wasn't referring to the NIH findings. I was referring to how one makes a coherent physiological story around the implication of POT in ME/CFS.

Maybe the problem is that other people have been convinced of what they are going to find without having thought through whether it adds up in terms of an explanation.

 

Sorry but that is simply not the case. The arguments I was making made no reference to NIH data. I don't know anything about their POTS data and wouldn't make use of it anyway, considering the other flaws in the study.

There is no coherent story that I can see. Either it is preload failure, but then to produce cerebral hypo perfusion with a normal BP you would need additional cerebral vasoconstriction and there seems to be no reason why, or it isn't preload failure after all but an inappropriate cerebrovascular regulatory response. Personally I think it much more likely that the OI symptoms do not reflect cerebral hypo perfusion but autonomic symptoms generated in the way that things like nausea are generated by perceived threats. But then we have data from other people showing reduced cerebral perfusion.

As indicated already, it seems to me there are too many bits of information that do not fit into a single plausible story and as someone who has worked and published on fluid compartment physiology that is something I am only too familiar with. I may be wrong but you haven't answered any of my doubts so far.

 

The other thing is that a high proportion of people with ME/CFS have OI yet do not show POT on testing. So there are good reasons to think POT isn't the real problem.

 

We were discussing the more general relevance of POT. In fact EndME set up a new thread as a result of that side discussion. I am being consistent in not referring to the NIH study. Sorry there was a typo in the last post that may have possibly confused. I am talking about the body of studies over the years on POT - which as I understand it is symptomatic tachycardia in the absence of hypotension on standing.

I am saying it doesn't make sense on the basis of trying to make sense of it and finding a whole list of inconsistencies. That is how I always used to do my research and had some success in finding alternative more consistent explanations. Oedema in lupus nephritis used to be put down to nephrotic protein loss but I was able to show that the patients have a significant increase in generalised capillary permeability which explains the clinical state much more satisfactorily.

This is how we do science!!

 

If you look at my posts you will see that that is precisely my point,. POT doesn't seem to be mostly what is causing OI in ME/CFS patients. But that is how POT is defined.

Sorry you are having a hard time, but I thin you are making things harder for yourself than needed.

 

Indeed there is this contradiction in the data. Is it an oversimplification to think you can get peripheral vasoconstriction so poor perfusion of exercising muscle in an attempt to maintain cardiac pre-load due to excessive venous pooling? With Midodrine on board, compression stockings and adequate hydration my otherwise freezing cold and clammy hands become warm and I have less hot flushes from sympathetic excess. I’m not sure if what is happening on a microvascular level in this disease reflects what is happening in the larger vessels.

I assume if the small nerve fibres are affected this could impact blood flow regulation in the periphery and centrally similarly? As to what is driving the small fibre nerve dysfunction nobody knows. There seems to be some research like microneurography I had done at King’s to show spontaneous nerve depolarisation compared to controls. But no replication of data let alone an answer as to why the the nerve fibres are “hyperexcitable”.

 

That sounds complicated. Excessive venous pooling would presumably be due to vasodilation rather than constriction? Maybe venodilation in the presence of arterial constriction but if muscles are being used I would have thought blood would be pumped back to the heart OK.

I am also not sure how it fits with sympathetic status. Midodrine is a sympathetic stimulator (a-adrenergic agonist). Sympathetic drive is part of the response to low blood volume and presumably includes venoconstriction. Maybe things really are more complicated.

I am not sure how this relates to POT though?

 

The problem (for some) is indeed excessive vasodilation and I've seen more than a few people who swear by Midodrine for significantly improving their function.

I suffered from severe orthostatic intolerance when recovering from GBS, so I suggest that impairment of autonomic afferents are involved.


https://link.springer.com/article/10.1007/s10286-018-0542-y
https://www.neurology.org/doi/10.1212/WNL.98.18_supplement.2511
https://www.autonomicneuroscience.com/article/S1566-0702(22)00129-1/abstract

 

I'm no fan of this NIH paper, but that is not what was reported.

 

Jo's comments in this thread are critically important, as we don't understand this properly at all, though like Tantalus, it feels is if the understanding is just beyond our grasp. We're generally looking at this assuming the problem is low blood volume and potential compromise of blood flow to the brain on standing. But as Jo says it doesn't hang together coherently and the rest is hand-waved away.

If it's true (per Systrom) that low right/left atrial filling pressures are ubiquitous in ME: why do we see chronotropic incompetence on exercise challenge? Shouldn't HR be higher than healthy controls? (To maintain or increase cardiac output in the presence of relatively fixed reduced stroke volume).

How might you have orthostatic intolerance, with demonstrable reduction in cerebral blood flow (per van Campen), without orthostatic hypotension (regardless of tachycardia)?

Cerebral perfusion pressure depends on mean arterial pressure and intracranial pressure (CPP = MAP - ICP). JVP is not going to be high in us by definition (low RA/LA filling pressures), so we can stick with ICP. ICP does not rise on standing - in fact the opposite. Cerebral blood flow is dictated by cerebral perfusion pressure, mediated by cerebral autoregulation.

So if we have shown from multiple studies (in ME, POTS and other conditions) that you can have OI and reduced CBF with unchanged MABP (and ICP even went down a bit), then it suggests that cerebral autoregulation is the thing that's determining reduced CBF on orthostatic challenge. As Jo says —

This may be nonsense but here's a starter for ten. What if it's an appropriate cerebrovascular regulatory response?

Could there be an explanation that's essentially in reverse, that the neurovascular mechanisms are deliberately trying to slow flow down in the brain (capillaries) in order to extract more oxygen as a metabolic compensation. That might leave things vulnerable with regard to the homeostatic mechanisms of orthostasis as you're now operating much closer to the danger zone of inadequate cerebral perfusion, with less safety margin.

The tachycardia may be an inappropriate response (in this context) that occurs in some who have either intact (rather than down-regulated) or otherwise dysfunctional sensors and effectors. Perhaps this takes effect regardless of peripheral low blood volume, low right and left atrial filling pressures — and those findings are a correlation but a separate issue. Or perhaps the low blood volume occurs as part of the brain-dictated compensation (trying to reduce MABP and CPP) but the brain's needs and the body's needs are then in contention.

---

Altered brain perfusion and oxygen levels relate to sleepiness and attention in post-COVID syndrome (2024, Annals of Clinical and Translational Neurology)

Brain Frontal-Lobe Misery Perfusion in COVID-19 ICU Survivors: An MRI Pilot Study (2024, Brain Sciences)

Reduced Cerebrovascular Oxygenation in Individuals with Post-Acute COVID-19 Syndrome PACS “long COVID” (2023, SpringerLink)

Cerebral hypoperfusion in post-COVID-19 cognitively impaired subjects revealed by arterial spin labeling MRI (2023, Nature Scientific Reports)

 

It's a clever idea but I don't think it quite flies, does it?
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.

Maybe you are right that this is a normal compensatory response. Maybe it is equivalent to compensated haemorrhage shock. In compensated shock the blood pressure tends to be maintained very late, with pulse rising. (What we may be missing is that with a rising pulse the average perfusion pressure may get closer to systolic.) It would make sense for the autonomic system, when detecting low blood volume, to constrict inflow to all organs a bit, even brain, to make sure kidneys got enough as well.

What I think does not fit for me is the idea that the functional low blood volume on standing would be due to autonomic neurovascular control failure. I have been involved in the care of people with peripheral neuropathy affecting autonomic nerves. The limbs, and especially the calves, tend to be warm, pink and puffy - often very swollen. In diabetes the situation is complicated by long standing vascular damage but for acute neuropathies the picture is sufficiently typical for me to have been able to confound a ward round by making the diagnosis from three yards from the bed.

Which makes me wonder whether the problem might be some form of autonomic neurovasscular failure that is not part of a typical neuropathy pattern. Again, I just wonder about acetylcholine endings. If it were a defect that simply does not occur in any other context then it could explain the inconsistent picture. There seems no doubt that the situation is complicated. After all, when most people get OI from standing too long (typically on interminable hospital ward rounds in the 1970s) they usually end up fainting suddenly and I suspect with a vasovagal bradycardia.

What I think is important, though is to keep sight of the fact that most people with ME/CFS seem to have OI without the official picture of POT and quite a few normal people have POT without symptoms. As has already ben said, POT may not be the right marker for the problem seen generally in ME/CFS.

 

For the reasons given in the post above. I am clinically familiar with that situation and it doesn't apply to people with ME/CFS - they do not have warm pink swollen legs in that way. But maybe there is a specific defect that does not occur in other circumstances.

 

I would agree that the mechanisms going on are likely complex. How can we explain the significant dependent acrocyanosis seen in many people with POTS? It’s hypothesised that it’s due to reduction in blood flow to the skin by the small blood vessels potentially due to a defect in nitric oxide signalling.

I seem to have many symptoms of dysregulated blood flow. Excessive chest flushing, bright red palms especially after eating, a very warm burning bright red ear that gets randomly triggered off that I didn’t have pre-covid. But then at times I have dependent acrocyanosis, very blue and pale lips, freezing cold peripheries hands, tip of nose etc and have been told it’s due to SFN/dysfunctional autonomic neurovascular control. I appreciate the clinical picture looks quite different to that seen in length dependent neuropathies like diabetes.

I also wanted to add that my tachycardia could be brought on by merely lifting my head off the pillow in the morning or turning over in bed when not treated pharmacologically so in theory it didn’t require a big postural change and excessive blood pooling. It felt like the nerves were incredibly hypersensitive and overactive as it would coincide with intense burning pain.

It’s also hypothesised that the pre-load failure could also be due to excessive splanchnic pooling and underlying neurohormonal mechanisms. I would significantly “crash” after eating which has been prevented with Midodrine and abdominal binders.

Like you I struggle to piece this all together scientifically and wonder what the role of neuropeptides like cgrp or neurotransmitters like acetylcholine have in this context.

 

I like this idea. My orthostatic symptoms do sometimes feel how I would imagine it is to bleed out. On my tilt table test, as my heart rate increased my blood pressure was much more variable than when supine. To me this could suggest that the body is struggling to compensate for gravity and while average blood pressure stays the same, it is acting like it is in a stake of shock. Although, if this were the case I think you would expect vasocontraction. However, my feet and hands turn purple which seems to indicate increased blood volume in those areas.

Systrom has looked at Saline infusions during CPET testing. He found that filling pressures, Vo2 max, cardiac output and stroke volume all increase with saline which I guess makes sense if blood volume is low.

Does anyone know if it is possible for blood pressure to be different in different vessels? While the system is all connected, perhaps pressure can be increased in certain compartments. As long as the volume of blood into and out of the heart is the same, couldn't pressures be different in different areas?

Agreed, I have never thought that the tachycardia itself was the problem. Its just something measurable that seems to indicate and orthostatic abnormality.

 

Very interesting, that is something I haven't seen before. While it does seem like a crude measure with many cofounding variables, I too would be interested in what ranges occur in heathy people v POTS & or ME. On my tilt table a while back I got up to 1.2.