Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels... 2022, Wirth and Lohn

[Sly Saint]

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?
Wirth and Lohn

Abstract
:
Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI).

These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS). OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection.

The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID.

We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels.

We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability), also affects the vasa vasorum to impair the function of the capacitance vessels. In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.

https://www.mdpi.com/1648-9144/58/12/1807

 

[RedFox]

This is a hypothesis paper, meaning it's a new perspective on existing research. The idea that OI is caused by a specific sort of vascular dysfunction is pretty novel and interesting. What types of experiment could help confirm or disprove it?

 

[belbyr]

This is actually one of the first papers I've read in a while that seems to make sense. Going to start shooting this over to other sources to get thoughts.

 

[rvallee]

This is a hypothesis paper, meaning it's a new perspective on existing research. The idea that OI is caused by a specific sort of vascular dysfunction is pretty novel and interesting. What types of experiment could help confirm or disprove it?

Is it? I thought this was a pretty old hypothesis. Just that, a hypothesis, but I'm pretty sure I've seen it described this way before. It makes a lot of sense, the sum of all capillaries is actually huge, even a small reduction in their ability to do their job will have a huge impact since it's hugely multiplied. They cover a lot of space.

I'm not sure how much it explains reduced blood flow to the brain, though. Maybe that's just a compensatory mechanism. Unless it also affects the main arteries. There's probably a few dynamic feedback looks involved to explain the whole thing.

 

[Hutan]

I'm not sure how much it explains reduced blood flow to the brain, though.

Upon assuming the upright position, patients experience a worsening of symptoms and a decrease in cerebral blood flow occurs, while hypotension and orthostatic tachycardia are less consistent findings.

I'm not sure, but I think the research on reduced blood flow to the brain in ME/CFS is a bit equivocal. The Rowe paper found it, even in people with ME/CFS without overt OI symptoms, but there was another paper that used BOLD imaging that didn't find evidence of reduced blood flow. The idea of reduced blood flow in the brain makes sense to me as a cause of at least some of my symptoms, but, yeah, I'm not sure the evidence base is solid yet.

 

[RedFox]

Darn it, I wish there was at least ONE aspect of ME pathology that had rock solid research, meaning replicated multiple times. I'm tired of the lack of research into a condition that's so profoundly disabling.

 

[Hutan]

Some notes as I read

As background: here's an image of the vasa vasorum. Capillaries help supply oxygen and nutrients to the cells of the arteries and veins. They are particularly important in veins, because the veins are carrying blood that is low in oxygen and nutrients and the blood is under less pressure - so the cells in the veins need other supply mechanisms. The idea seems to be that anything affecting capillaries will also necessarily affect the vasa vasorum, and therefore veins and vascular regulation.





Capacitance vessels (background from other sources)
"Vascular capacitance refers to degree of active constriction of vessels (mainly veins) which affects return of blood to the heart and thus cardiac output."
"Veins are known as capacitance vessels because they are capable of storing a significantly larger volume of blood than arteries due to their large lumen and high compliance"

 

[Hutan]

Smooth muscle cells in the media of capacitance vessels actively contract when being stimulated by alpha-adrenergic receptors during OR and for adaptation of the cardiovascular system to exercise (raising preload of the heart). Inflammation, malnutrition and hypoxia, as a consequence of disturbed microcirculation, may affect the contractile function of the smooth muscle cells to cause not only OD but also maladaptation of the cardiovascular system to exercise by the inability to raise cardiac preload and, thereby, cardiac output. Aortic inflammation was found after COVID-19 infection with 18-Fluorodeoxyglucose investigation [42]. This, together with the microcirculatory disturbance in skeletal muscle itself, may affect muscular perfusion to cause fatigue. Skeletal muscle hypoperfusion, as a result of those vascular disturbances, together with mitochondrial dysfunction in skeletal muscle, which we assume is due to an ionic disturbance of sodium and calcium handling, could explain the high fatigability, loss of force and skeletal muscle complaints like myalgia [43,44].

So, if the veins aren't able to contract because muscle cells around them aren't receiving oxygen and nutrients, then the circulatory system can't properly function to get enough blood back to the heart. Muscles generally may get fatigued and painful because they aren't receiving enough oxygen and because the mitochondria aren't working due to sodium and calcium handling problems (due to a lack of energy?).

Being unable to adequately contract, the vascular capacitance system would behave as a “flaccid tube system.” An expected consequence of this vascular failure would be a rise in sympathetic activity to compensate for the deficit. An appropriate compensation will not always be possible, sympathetic activity is expected to strongly rise and to finally overshoot. Beyond a certain level, sympathetic activation becomes counterproductive and harmful by itself, thereby worsening OD by causing excessive, mainly cerebral and skeletal muscle alpha-adrenergic receptor mediated vasoconstriction, which has the potential of causing a vicious circle and of fixing OI so that it persists. In ME/CFS, reduced cerebral blood flow was even found in a sitting position, and in severe ME/CFS, even at 20 degrees of head-up tilt [46,47]. This means that in the awake state in human everyday life, orthostatic stress is almost unavoidable in ME/CFS. Chronic orthostatic stress has the potential to desensitize β 2-adrenergic receptors, which are very important in skeletal muscle physiology, and also the alpha2-adrenergic (inhibitory) autoreceptors, whose dysfunction could cause sympathetic and adrenergic hyperactivity and hypervigilance, as described previously [44,48]. Another potential disturbance should be considered as an additional vascular mechanism contributing to OD. In Long COVID, autoantibodies have been found targeting β2- and adrenergic α1-receptors, the MAS-receptor and the angiotensin-II-type-1 receptor. The presence of these autoantibodies could be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation [49]. Such autoantibodies against vascular regulators have the potential to disturb OR as a highly coordinated vascular process. This is another argument for the idea of a vascular disturbance as the cause of OI.

They suggest that a consequence of blood not getting back to the heart is an increase in sympathetic nerve activity, and that this overshoots. (Sympathetic nerve activity happens when the body is under stress e.g. the heart rate increases and the immune system is activated.)
The authors suggest that chronic orthostatic stress has the potential to "desensitise β 2-adrenergic receptors, which are very important in skeletal muscle physiology, and also the alpha2-adrenergic (inhibitory) autoreceptors". They suggest that autoantibodies to these receptors have been found in Long Covid, but, from memory, those findings are not very robust. Still, I guess desensitisation of the receptors could be happening without autoantibodies. I note that one of the authors of this paper, Wirth, has co-authored papers with Carmen Scheibenbogen.

(I'm aware I'm just jotting things down without checking what I write. Please do comment and correct things.

 

[RedFox]

Before reading this paper, I had no idea that blood vessels had blood vessels. The human body is amazing.

 

[Hutan]

Before reading this paper, I had no idea that blood vessels had blood vessels.

Same. Of course it makes sense, but it's not something I had ever thought of.

The authors say:

From an epistemological point of view, it makes more sense starting the search or analysis of the potential causes of OI from the proven (micro)vascular disturbance than to assume a new and still vague concept like neuroinflammation.

And here's their hypothesis in a vicious cycle diagram:


I'm not sure about some of the assumptions there. For instance, what evidence is there for increased blood cell size? I'm pretty sure that my red blood cells are fine, size-wise.

They also say

A further finding in ME/CFS from investigations before COVID-19 is that hearts are smaller [50,51,52]. This may be due to the effect of a chronically low cardiac preload that is favored both by chronic hypovolemia and a disturbed capacitance vessel system unable to adequately fill the heart, which causes cardiac hypotrophy in the long run. Small hearts, in turn, may be another mechanism to contribute to the fixing of OI and maladaptation to exercise (exercise intolerance).

I'm not too sure how solid that finding, of smaller hearts, is either. Too many bad ME/CFS/LC papers have left me pathologically skeptical. The authors suggest that small hearts (an adaptation to lower preload) may be part of the cause of the persistence of symptoms beyond the triggering infection.

 

[Hutan]

I think the paper is interesting, in strengthening the potential connection between problems in microcirculation and problems in macrocirculation and OI. I think some of the statements made are a bit of a reach, given the quality of the evidence for them.

I do like the fact that the hypothesis is testable and that the authors suggest what could be done:

Our assumptions for an altered capacitance vessel system explaining OD in Long COVID and ME/CFS are possibly amenable to experimental verification by comparing the diameters or volumes of large capacitance vessels in the recumbent and upright position in Long COVID and ME/CFS patients versus healthy controls.

We could also do with some more work on heart size and structure, taking into account the time people have been ill, so as to account for any adaptation over time, and also more replications of studies of cerebral blood flow under various conditions (i.e. not just lying down in an MRI machine).

 

[belbyr]

Darn it, I wish there was at least ONE aspect of ME pathology that had rock solid research, meaning replicated multiple times. I'm tired of the lack of research into a condition that's so profoundly disabling.

I think we need to keep in mind that about 30-50% of us have an underlying autoimmune disorder per most of the POTS specialists including Dr Klimas. That is why they do antibody panels, skin punch biopsies, sweat tests, etc. To see if there is any kind of ongoing neurological damage.

The rest of us may have this issue, if immune testing comes back normal...? So I don't think we will have a 'one aspect' of ME pathology, although Dr Systrom does report preload failure across the board for his ME/CFS and POTS patients, per his talk and slideshow yesterday.

 

[belbyr]

Hutan, do you see anything where treatment/medications could be applied to this issue? I wish I was more intelligent about this stuff...

 

[Hutan]

Hutan, do you see anything where treatment/medications could be applied to this issue? I wish I was more intelligent about this stuff...

Me too. Some people report feeling better with some OI medications that increase blood volume, but our thread on fludrocortisone does not suggest a great response, with a lot of people saying there was no effect or they felt worse.

An ongoing issue in microcirculation might be the problem to fix. But, as yet, we don't know if that really is the core problem or what might causing it, much less how to fix it. For example, the idea of micro clots, which these authors seem to assume are a causal factor, is far from solidly established.

 

[Jonathan Edwards]

Sorry, but reading the abstract I have to conclude that this is written by people with no clue what they talking about.

We don't even have any meaningful evidence of microvascular dysfunction in Long Covid or ME yet.

 

[belbyr]

Sorry, but reading the abstract I have to conclude that this is written by people with no clue what they talking about.

We don't even have any meaningful evidence of microvascular dysfunction in Long Covid or ME yet.

Do you think the pursuit of looking into how preload failure starts is a worthy cause, given Dr Sytrom's findings in POTS and/or CFS patients across the board?

I've really struggled with finding the right medications for my POTS/CFS, and I am beginning to wonder if being on Carvedilol for the increased heart rate is maybe the wrong way to go about it... Maybe pursue increasing the vascular 'squeezing effect' vs tamp down the autonomic response?

 

[SNT Gatchaman]

I've read through the paper and some of the proposed concepts make sense to me both from a theoretical and patient experience perspective.

Building from Hutan's post above on what capacitance vessels and the vasa vasorum are [1], the paper notes the following potential impairments —

(1) Capacitance vessels do not adequately contract when needed (behaving like a “flaccid tube system”) due to a failure to contract the smooth muscles located in the media of the vessel wall.

(2) Capacitance vessels may structurally be rigid and additionally shrunk, therefore being unable to dilate and to take up blood at rest, which then cannot be delivered in sufficient quantity into the systemic circulation during [Orthostatic Regulation] (a rigid and perhaps shrunk tube system).

(3) Inappropriate filling of the vascular system, or hypovolemia, causes [Orthostatic Intolerance] and is consistently found in ME/CFS with low renin (renin paradox).

(4) Inappropriate autonomic regulation (baroreflex, volume regulation, volume- and barosensors and vagal and sympathetic activity) occurs if autonomic [Orthostatic Regulation] is too weak, too slow or if it is exaggerated. Exaggerated sympathetic activity during OR is supposed to cause cerebral vasoconstriction. Apart from hypovolemia, autonomic dysfunction is clearly present in ME/CFS and Long COVID. Hyperventilation, which is also reported to occur in ME/CFS and Long COVID, may contribute to cerebral vasoconstriction.

They note that the large systemic veins, which form the bulk of the blood volume capacitance system, carry de-oxygenated blood and so the blood vessel wall itself is dependent of the vasa vasorum to provide oxygen-rich, "arterial" blood to allow the vessel to function in this environment: i.e. expand and contract to maintain circulatory homeostasis, esp in response to orthostatic challenge.

Since these veins have an active role in [Orthostatic Regulation] and since venous oxygen partial pressure is most likely insufficient to fully support their active contractile function, they are critically dependent on arterial blood supply from their vasa vasorum.

They start from the position that the "microclot" theory is established — and it is not.

We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability), also affects the vasa vasorum to impair the function of the capacitance vessels.

From there they propose that impaired supply to the vasa vasorum will lead to undercompensation of the (vein's) intraluminal oxygen content. This would then result in poor performance of the vessel's smooth muscle and consequent autonomic compensations —

SARS-CoV-2 induced microthrombosis of vasa vasorum would lead to hypoxic conditions in the adventitia

An expected consequence of this vascular failure would be a rise in sympathetic activity to compensate for the deficit. An appropriate compensation will not always be possible, sympathetic activity is expected to strongly rise and to finally overshoot. Beyond a certain level, sympathetic activation becomes counterproductive and harmful by itself, thereby worsening [Orthostatic Dysfunction] by causing excessive, mainly cerebral and skeletal muscle alpha-adrenergic receptor mediated vasoconstriction, which has the potential of causing a vicious circle and of fixing [Orthostatic Intolerance] so that it persists.

I would like to propose an alternative explanation that is similar but does not rely on microcirculation impairment.

It's been noted that when tested in LC patients, peripheral venous oxygen saturation is very low. (Mine has been 15%, 22% and 46% - all well below the expected 60-70%). Perhaps this much lower resulting partial pressure of oxygen it too low for the vasa vasorum to compensate for - even if they are functioning normally. It could be that a metabolic / mitochondrial process leads to this peripheral low SvO2 (and I note that central values are normal to high in Systrom's iCPET research). Also, failure of NO bioavailability may be compounding the capacitance vessel failure.

As limited as my subjective evaluation of my experience is, I suspect the tachycardia / OI symptoms are due to failure at the vascular level, rather than CNS / peripheral neural.

---
[1] Vasa Vasorum in Normal and Diseased Arteries (2014)

 

[marcjr]

As limited as my subjective evaluation of my experience is, I suspect the tachycardia / OI symptoms are due to failure at the vascular level, rather than CNS / peripheral neural.

I always felt weird how everyone clings to the term "dysautonomia", while it is not well established if the tachycardia is caused by a defective autonomic nervous system, or if it is working correctly, but jsut compensating for defective vasculature.

In my case, I am convinced that my OI is vascular in nature. None of the parasympathetic "boosters" ever had an effect on me. I have tried SGB injections, tVNS, etc.

But with all this money and time Long Covid is getting, why is that nobody is being able to validate this? It has been 3 years since the start of the pandemic and we still have close to 0% actual knowledge on why post-Covid OI happens. And I sense that more than half of recent LC papers just feel like recycled garbage.

 

[belbyr]

I always felt weird how everyone clings to the term "dysautonomia", while it is not well established if the tachycardia is caused by a defective autonomic nervous system, or if it is working correctly, but jsut compensating for defective vasculature.

In my case, I am convinced that my OI is vascular in nature. None of the parasympathetic "boosters" ever had an effect on me. I have tried SGB injections, tVNS, etc.

But with all this money and time Long Covid is getting, why is that nobody is being able to validate this? It has been 3 years since the start of the pandemic and we still have close to 0% actual knowledge on why post-Covid OI happens. And I sense that more than half of recent LC papers just feel like recycled garbage.

I've been searching around the webs and can't seem to find an article I read a while back where doctors took veins of sick patients and the veins did not react like they were supposed to. It validated that the autonomic system is fine, it's just compensating for a physical abnormality elsewhere in the body.