A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS),,,,,

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A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS):
Recognitions from the finding of autoantibodies against ß2-adrenergic receptors


Has anybody read this?
I thought we tended more to low blood pressure than high (please correct me?). I understand there are only 'types' of ME/CFS, not one big group.


Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.

We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.

Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
 

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6. Conclusion ß2AdR dysfunction may be an important risk factor in the pathophysiology of ME/CFS potentially caused by dysfunctional autoantibodies to ß2AdR, polymorphisms and desensitization of ß2AdR by (chronic) high sympathetic tone. High sympathetic tone in the presence of endothelial or vascular dysfunction, to which dysfunctional ß2AdR contribute, may lead to an excessive vasoconstrictor stimulus in skeletal muscles, which is opposed by the metabolically stimulated generation of endogenous algesic vasodilators in the process of functional sympatholysis. Metabolic stimulation of the generation of algesic vasodilators is strongly favored by the poor background energetic situation in skeletal muscle which is due to a still enigmatic metabolic disturbance (probably a mitochondrial disturbance). Spillover of such excessively generated algesic vasodilators into the circulation could explain the unfavorable CV situation causing hypovolemia, inhibition of renin production and preload failure further raising sympathetic (vasoconstrictor) tone. The appearance of algesic Journal Pre-proof Journal Pre-proof 19 vasodilators in the systemic circulation may explain many of the enigmatic symptoms of ME/CFS including pain, hyperalgesia, intestinal complaints, flu-like symptoms, sore lymph nodes and others.
 

pattismith

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These findings are only for a small subgroup of CFS/ME patiënts. Most of them also have POTS.
For this group I think the main cause have been found.
I don't have POTS, I don't have OI, I don't have beta adrenergic receptor auto-antibodies, but still suffer from ME/CFS/fibro and autonomic failure.

Brain hypoperfusion could be the common pathophysiology of our different subgroups, mainly from autonomic vascular dysfunction, either from auto-antibodies or from central or peripheral autonomic nerve lesions.

It would be nice if they could do a mouse model with beta 2 adrenergic receptor dysfunction to see if they would show some ME/CFS symptoms...
 

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To me it sounds like the group is stretching evidence for a small subset of ME to make it sound like it's the majority subset, or even the basis for all ME. It makes me want to ignore it. I'm unaware of having any vascular issues such as they describe.

My guess is that it's written to maximize potential funding, deserved or not.
 

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One of the two named authors works for a pharma company.
I've looked at more of the paper and understand it to say that in MECFS there is increased sympathetic activity and hence the vasiconstricion.
In response to sustained vasiconstricion, sympatholysis occurs via endogenous vasodilators! That means to counteract the sympathetic effect , the body makes vasodilators.
Vasodilation can result in things like low standing blood pressure and heart issues.
In response to these unhelpful effects of vasodilators, sympathetic tone is increased more.
And on the circle goes !
I read a bit of the paper and think they make it clear that it's only a subset of patients, but unless a person is well practiced with reading ME science , it could be misleading and look like it's about all MECFS.
I for one would like the antibody test.
How do I get one is my next puzzle 😁😁😁
 

sb4

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I find the idea that vasoconstriction is causing vasodialation interesting. I read somewhere that edema causes endothelial cells to swell and this causes the small capilaries to constrict leading to poor nutrient delivery to cells yet the bigger vessels to vasodialate leading to blood pooling. The edema would also cause hypovoliemia. I constantly feel a little swelled up so it's interesting.
 

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Theories like this should be easily testable. Give a PWME some vasodilators and see if they feel better. If not, please file the theory in the round filing cabinet and move on to something new.
 

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Theories like this should be easily testable. Give a PWME some vasodilators and see if they feel better. If not, please file the theory in the round filing cabinet and move on to something new.
Ive read the paper further, and they are actually saying constriction leads to dilation. Give a person vasocontrictors and see what happens. It works. But not all constrictors are equal. Some work for me, some dont, off label does.
 
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Cort just posted a write up of this paper here on SimmaronResearch:
Conclusion

Given the vast reach of the cardiovascular system it’s a natural place to look for a cause of ME/CFS, but nobody has looked at it in ME/CFS patients in quite this way before. Banking on studies showing that autoantibodies to the B2AdR receptors are present in a significant subset of ME/CFS patients, the authors draw a vast model of cardiovascular dysfunction which could produce many, if not all, the symptoms of ME/CFS.

At its core the hypothesis is simple – there’s an imbalance between vasoconstriction and vasodilation in the blood vessels. It starts with a vasoconstriction crunch produced by an overactivated sympathetic nervous system. Damage to [B2AdR] receptors leaves the small blood vessels near the muscles struggling to open up enough to get the blood they need. With limited blood flows, and with the energy deprived muscles screaming for more blood, the authors envision pain and fatigue provoking vasodilators pouring out in an attempt to open up those blood vessels.

So many vasodilators pour out that they get into the general circulation and leak into the interstitial spaces – the spaces between the blood vessels, the lymph and the tissues – causing pain, fatigue and other symptoms – as well as low blood volume, preload failure and sympathetic nervous system hyperactivity.

One vasodilator, bradykinin, may be responsible for a host of effects including the inability of the renin-angiotensin-aldosterone system to increase blood volume to the proper levels, intracranial hypertension, small fiber neuropathy, sleep apnea and sleep problems.

It’s a grand, unifying hypothesis, indeed. The authors, in fact, see three mechanisms by which these beta adrenergic receptors could be damaged in ME/CFS: autoantibodies (autoimmune attack), polymorphisms (e.g. mutations) in the gene that produces the receptor, and desensitization to chronic cardiovascular stress. Plus, problems with the endothelium (smooth muscle cells lining the blood vessels) or another form of vascular dysfunction could also strongly contribute.

Stay tuned. A second hypothesis paper focusing on the energy problems in the muscles is coming.

So, yeah, auto-immunity for ß2AdR (acetylcholine receptors) causing hyper-constriction of small vessels in skeletal muscles (that can need up to 20x more flow when working) and heart and brain are mentioned too.

Vasodilator peptides (particularly bradykinin) released locally in excess, to try to compensate, that spill into whole blood and cause a bunch of problems.

So I'd assume these molecules should have been detected in ME/CFS serum metabolomics studies (if in excess)... But if this mechanism is only applicable to a sub-set (as Cort fails to make clear in his article), then I guess that increase might have failed to hit statistical significance, overall. (Or might have been filtered out at a patient selection stage?)​

Excess bradykinins are also a common cause of dry cough in those taking ACE inhibitors for high blood pressure (no idea of the relative concentrations - if in a similar range or not).​

Sympathetic nervous system overdrive to constrict arteries, more than the normal, to push blood out into the small vessels where oxygen is needed. Can boost heart rate excessively too.

Then, what I find co-incidentally interesting is tying the renin-angiotensin system in (to account for low blood volume in ME/CFS). I was just posting about angiotensin (due to central role in MedCram's hypothesis for severe Covid-19 problems) and wondering why we've not heard more about it before in relation to ME/CFS...
Cropper2020-05-08-21-56-11-4221916.jpg
 
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For me, I can believe small brain vessels aren't opening up enough, dynamically, to enable shifts in brain activity needed for complex thinking. But mostly just during fatigue reaction 'crashes'.

And lack of opened up muscle vessels might make sense for rapid muscle burn, e.g. after only 20s of stirring a pot, or something. (Although thankfully I don't get fibromyalgia/pain generally.)

Also, when I used to be able to play racket sports (back before dietary exclusions shifted my symptoms around), it would take me 5-10 minutes of dragging my body about before something opened up and my body got working properly. I thought of it being more like adrenaline clearing counteracting the sickness signal (of cytokines or histamine). But maybe small vessels opening up by the compensatory mechanisms...??

I've also been interested in acetylcholine receptors a little (though not read up much) because Alpha-GPC's had boosted me a bit. As per Diana Driscol in an interview with her by The Low Histamine Chef.

But I've no idea if this paper's theory is likely to hold water; at this point our ME/CFS research has pulled in pretty much every system in the body...


Oh, and this paper, that Cort blogged the other day (and I posted about in the Prusty thread) hypothesised the possibility of acetylcholine receptor autoantibodies courtesy of mimicry by HSV (herpes simplex).
Don't know if there a potential relationship there, between the 2 hypotheses. Or if that would even be the same receptor...?
 

sb4

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And lack of opened up muscle vessels might make sense for rapid muscle burn, e.g. after only 20s of stirring a pot, or something. (Although thankfully I don't get fibromyalgia/pain generally.)
It's interesting you also get this almost instant lactic acid build up from minimal exertion. I think the most likely reason is poor blood flow / autonomic dysfunction not supplying muscles the nutrients they need fast enough. If you also have PDH issues then a lot of that nutrition would then be used very inefficiently making lactic acid in the process.

This at least makes sense with my symptoms of heart pounding, some tachycardia, blood pooling in feet, feeling like I am in constant sympathetic mode (dry mouth, inability to relax), etc.
 

Pearshaped

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Even though I have POTS and severe OH I have been tested negative for both of these auto-antibodies.
Its probably not as simple as it seems.
I pray for a real breakthrough which will help us all in one way or another.
 
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instant lactic acid build up from minimal exertion
It's not that bad for me, just certain motions like that, or brushing hair, where it becomes noticeable. Can generally be on my feet for an hour or so, grocery shopping, cooking. Legs not hitting a limit.

Even though I have POTS and severe OH I have been tested negative for both of these auto-antibodies.
Hmm, so certainly seems like it might be a very niche group, if anyone then. (Or apply counter-intuitively to other groups.)

I don't have tachycardia or OH (to a notable degree)...

Excuse me if I'm a little hyper, running about the web, playing dot-to-dot with the various research. Obviously each piece of research isn't going to be entirely correct. But even a wrong hypothesis can teach us something when disproven - why something *doesn't* go wrong. And most end up applying to some degree, to some niche circumstance. So, I think it's all worthwhile doing. I mean, academic expertise isn't always that transferable, past a certain point of specialism, so abandoning one avenue doesn't necessarily allow investigating another. Of course there's plenty of scope to grow the field, in terms of funding - that's the main thing. (Wow, my sidetracks....)


Anyway, Cort's also says:
In order to do that the blood vessels release a wide variety of vasodilators such as adenosine, ATP, prostaglandins, (PGEs), prostacylin (PCI), bradykinin (BK) and protons.
So, purinergic signaling (with ATP and adenosine) is used for vasodilation, too... Is that right? Edit: apparently so [Wikipedia]:
The regulation of vascular tone in the endothelium of blood vessels is mediated by purinergic signalling. A decreased concentration of oxygen releases ATP from erythrocytes, triggering a propagated calcium wave in the endothelial layer of blood vessels and a subsequent production of nitric oxide that results in vasodilation.
I wonder how that plays out in conjunction with (Naviaux's) cell danger signalling, using the same molecules...? :confused:
 

sb4

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I should also mention that I had beta adrenergic receptor 1 & 2 antibody test as well as muscarinic 1-5. They all came back normal. In fact they all came back really low except M3 and 4 which where almost in the at risk range. Why these where more elevated than the rest and if it is at all relevant IDK.

I will say that having negative antibodies doesn't mean the whole theory has to be scrapped. A very similar mechanism could be occuring that leads these effects. It might be that those with bAR2 just have different symptoms.
 

pattismith

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I find the idea that vasoconstriction is causing vasodialation interesting..
We can find similar theory for ErythroMelalgia and Raynaud Phenomenon, happening mainly in hands and feet.
I Wonder if ME/CFS or Fibro could be a kind of EM or RP hapening in the muscle and brain instead of skin!
 

sb4

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We can find similar theory for ErythroMelalgia and Raynaud Phenomenon, happening mainly in hands and feet.
I Wonder if ME/CFS or Fibro could be a kind of EM or RP hapening in the muscle and brain instead of skin!
I dont know how relevant or common this is but when I was a kid my hands would turn a sort of orange and dotted blue color when cold.
 

lenora

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Hi sb4......Well, you can't say that you don't get some pretty fast answers on here.

OK, I'm 73 yrs. old, female, and until menopause I had incredibly low blood pressure. I'm talking I should have been on the floor low pressure. Now after menopause I've gone the other way. So I have incredibly low pressure in the a.m. and quite the opposite in the p.m. One night I was over 300 and went to the hospital. That was a wasted exercise since they weren't able to get it down either. I think "normal" is just flat abnormal for most of us. I'd be interested in hearing from anyone else with this problem. Out of interest, I do have a cousin who suffers from it, but his is to such a degree that he'll go from low to high in a matter of minutes. The Dr.'s at The Cleveland Clinic had never seen anything like it. Anyway, we're treated the same way....with a cocktail of drugs that change from time to time and we've both had serious heart problems. So, obviously some of this is genetic...but how much, and why does it change form?

I also think circulatory problems are fairly common among us. I know that I have to wear gloves in the winter (tops of fingers not on gloves), and that helps because, as you know, this can be fairly painful when circulation is that low. As in everything else in my life, my l. side is worse than my r. I don't have any color changes, but wouldn't be surprised if they do show up. Of course in the summer, it's the reverse.

I've been fortunate that I don't have blue hands, or hands like yours. Of course you could have a skin condition and perhaps the first stop is your GP or a dermatologist. I would probably ask both....our dermatologist is somewhat useless and I am planning to change this year. I have no idea why I tolerated him for all the years I did. See, we're all capable of making excuses and dragging our feet. Now I'll have even more forms to fill in! Good luck in getting your answer....you're certainly off to a roaring good start. Yours, Lenora
 
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I think that this research signifies a major breakthrough in understanding the cause of ME/CFS.

A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors

The paper describes how dysfunction of certain cell receptors in the autonomic nervous system results in lack of blood supply to skeletal muscles and the brain, causing exercise intolerance and brain fog. The paper further ties this dysfunction to the cardiac effects found by Dr Systrom and the association of ME/CFS with craniocervical instability and related problems of skull-to-neck junction.

I. To better understand the science, I recommend educational videos that explain the autonomic nervous system and the receptors thereof.
Adrenergic Receptors This is a link to a video aimed at medical school students. You can skip over the parts where he explains the chain reaction within the cell caused by activation of the receptor, but then pay attention to the way the beta-2 receptor affects blood supply to different parts of the body. There is another video by the same people that explains the autonomic nervous system more generally. The specific anatomy of the nerves and their ganglia are not relevant here, but otherwise the overview may be helpful.

II. This explanation really resonated with my experiences. I have experienced a gradual onset, with fatigue as my primary symptom. The disease has continued to worsen from the time, a few years ago, when I could no longer hold a job. My only other comorbidities (other ailments) are allergies and allergic asthma.
Here are the things that seem to fit for me in particular

  • Asthma: My albuterol inhaler (ProAir) seems to have little or no effect: Albuterol is a Beta 2 agonist so if the beta2 receptors are defective, as the theory asserts, then the inhaler would have an attenuated effect at best.
  • Gynecological issues: I have a history of heavy periods and even severe hemorrhaging from the uterus for no apparent reason. When I gave birth, my very first contractions were relentless, without any pauses in between. This resulted in record-fast deliveries. This could be explained by the fact that the beta 2 receptors are responsible for moderating uterine contractions, and my beta 2 receptors are not working.
I would love to hear if this fits for others. I am still studying the paper, so there are likely more aspects that I have not yet absorbed.

Other good news. Although the paper does not address possible clinical implications, IMHO, this may result in new treatments!

Also, I don't understand why Dr Systrom prescribes a drug that increases the availability of Acytlcoline. If you have any insights, let me know!