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The Blood Vessel Crunch: A Unifying Hypothesis for ME/CFS

This is another hypothesis paper that gives one hope – and makes one wonder if the authors might have a handle on what’s happening with chronic fatigue syndrome (ME/CFS). The paper proposes that a tantalizingly simple problem – an autoimmune attack on just one receptor – out of hundreds of potential receptors –  could be causing virtually all the symptoms of ME/CFS.


Could an autoimmune process attacking the B2 adrenergic receptor be causing the symptoms of ME/CFS?

Receptors dotting the surface of a cell don’t seem impressive, but they’re actually the key to the activity of our cells. Lock onto a receptor and you make the cell change. Most drugs don’t target cells – they target the receptors on cells.

Could just one messed up receptor, though, produce the symptoms of ME/CFS? If it’s an important enough receptor found in enough places – yes, it can, and the receptor in question in this paper –  the beta-2 adrenergic receptor or B2AdR is indeed a heavy duty receptor.

Found in the blood vessels in the brain, the skeletal muscles and the heart, it is a downstream mediator of the sympathetic nervous system (fight or flight system)  which among other things, controls blood flows.

The evidence for B2AdR dysfunction in ME/CFS is building. It’s not overwhelming – it’s not a done deal, but it’s pointing in a very intriguing direction.

One study from a Simmaron collaborator has found elevated levels of B2AdR autoantibodies (antibodies that attack the receptor) in ME/CFS and another is believed on the way. Small mutations in the genes that produce the receptors have been found as well. Plus, similar mutations have been associated with a kind of mild ME/CFS-like state as well. Finally, Scheibenbogen’s work suggests that ß2AdR autoantibodies stimulate the ß2R signaling, but in a subset of ME/CFS patients their functioning has been blunted.

Simmaron Research collaborated with Carmen Scheibenbogen in a pilot study of B2AdR autoantibodies in ME/CFS by contributing patient samples and funding in 2018.

Unifying Hypothesis?

That was enough evidence for Klaus Wirth MD and Carmen Scheibenbogen MD in Germany to believe they had to get the word out and in doing so built a grand, indeed a “Unifying” hypothesis 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. Klaus Wirtha, Carmen Scheibenbogen, Autoimmunity Reviews, 2020

Numerous documented problems in ME/CFS including low heart rate variability, chronotropic incompetence (inability of the heart rate to increase appropriately during exercise), something called QTc shortening (shortened ventricular repolarization)

The ß2AdR’s in the blood vessels play an important role in opening or dilating the blood vessels  enough during exercise to accommodate up to 20-fold increases in blood flows muscles will see.  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.


Carmen Scheibenbogen has been studying autoantibodies in ME/CFS for several years

During exercise the body also needs to send blood to the active areas and shunt it away from non-exercising areas. The arteries clamp down to send the blood forcefully to the small blood vessels in the muscles which in turn must open to receive and use the large quantities of blood they need. This process of clamping down on the blood vessels in one end and opening them up on the other is called “functional sympatholysis”.

The authors believe that the heightened sympathetic nervous system activity clamps down hard on the arteries. Meanwhile the B2AdR dysfunction impairs the ability of the small blood vessels to dilate. This dysbalance between vasoconstrictor and vasodilator forces – with the vasoconstrictors winning – triggers the release of  painful vasodilating substances in an attempt to open the blood vessels. The entire process is, in turn, enhanced by the metabolic/energetic problems in the muscles.

In what appears to be a rough blood vessel equivalent  (i.e. leaky small blood vessel syndrome?) this enormous production of vasodilators leak into the interstitial spaces found between the blood vessels, the lymph and the cells.  This happens because one of them, bradykinin,  also happens to be pretty good at enhancing microvascular (small blood vessel) permeability. So now you have some potent peptides in a place they shouldn’t be – which is always a recipe for problems.

Throw that together with a balky energy production system in the muscles and you have a three way mess. The muscles aren’t, in what appears to be a low oxygen (hypoxic) environment, producing enough energy. The bigger blood vessels, on the other hand, are clamped down tight. The small blood vessels stuck in the middle pump out scads of vasodilators which, when they leak out into the tissues exact a price.

This process occurs in dysmenorrhea (menstrual cramps) when tissues in a hypoxic (low oxygen) and hyper-contracted uterus pour vasodilators into the blood causing fatigue, flu-like symptoms, fever, pain and even the sleep disturbances. (Dysmennorhea or endometriosis has been found increased in ME/CFS.)

The situation is a little different in ME/CFS – the authors believe it’s the blood vessels that are in a hypercontractile state – not the muscles. In fact, with the vasodilators pouring out, the authors don’t believe the muscles in ME/CFS are necessarily in a strongly hypoxic state at all.

If a hypercontractile or hypoxic uterus sounds bad, though, consider what hypoxic, hypercontractile blood vessels in the skeletal muscles across the body might be like – maybe something like ME/CFS.

Weird Cardiovascular Findings

The authors propose that  ß2AdR dysfunction could also be responsible for the weird cardiovascular situation found in ME/CFS. Calling the cardiovascular findings in ME/CFS “unique and not found in any other condition or disease”, the authors listed them: hypovolemia (low blood volume), reduced preload (reduced blood flows to the heart), low cardiac output at rest, small hearts, and the kicker – the low renin-angiotensin-aldosterone system (RAAS) activity.

A big and never answered – and rarely asked – question about ME/CFS is: why is the blood volume low? That brings up another more recently asked but similar question:  why are low venous blood flows to the heart consistently found as well? In other words, where the heck has the missing blood gone?

RAAS - Wikimedia

An underactive RAAS system in ME/CFS is a mystery given the low blood volume present. The authors have an idea why.

It’s a big question. For one thing, low blood volume alone could cause the sympathetic nervous system to go onto hyperdrive and put the vagus nerve (the rest and digest system) to sleep.

The real mystery, though, involves what’s going on with the renin-angiotensin-aldosterone system (RAAS) in ME/CFS. Low blood volumes should automatically activate that system to increase the blood volumes, but paradoxically, instead of being increased, RAAS activity appears to be reduced in this disease.

Because, as noted above, low blood volume sends the sympathetic nervous system into overdrive, the inability of the RAAS to do its job could play a major role in ME/CFS. For some reason the RAAS has hardly ever been looked into in this disease.

Wirth and Scheibenbogen have certainly been looking. They turned, once again, to a vasodilator – bradykinin – for a possible answer. While bradykinin attempts to open the blood vessels, it may also be inhibiting RAAS activity and blood volume enhancement at the same time.

The Spillover Effect

The authors don’t believe that these problems are just happening in the muscles. They believe that just about every symptom in ME/CFS could be caused when vasodilatory substances spill over into the general circulation, around the muscles, the lymph nodes, the gut and the bladder.

Provided that enough of these vasodilatory substances were present, every stress on the cardiovascular system could result in fatigue, pain, flu-like systems etc.

Even mental stress, they believe, could cause pain by triggering the sympathetic nervous system to clamp down further on the blood vessels of the skeletal muscles, causing them to emit vasodilators in an attempt to get more blood, and producing pain, flu-like symptoms, etc. For me, personally, this could explain the muscle pain and flu-like symptoms I often experience simply sitting in a chair while doing mental work.


The authors focused on bradykinin – a vasodilator which can also cause pain and increase vascular permeability

The chief vasodilator  – bradykinin – a seemingly all purpose peptide, could also open the blood-brain barrier, and contribute to the intracranial hypertension, small fiber neuropathy, sleep apnea and sleep problems present. Given the low blood volume and preload failure predicted by the spillover of vasodilatory substances, orthostatic intolerance (trouble standing) would be a natural outcome.

An add-on factor in ME/CFS may be a dysfunction of the endothelial cells lining the blood vessels. Autoantibodies to B2AdR receptors could be keeping the blood vessels in ME/CFS from dilating enough.

The chronicity of it all could play a role as well. Given enough cardiovascular stress the B2AdR receptors will simply disappear.

A local TV report triggered Klaus Wirth's interest in ME/CFS

A local TV report triggered Klaus Wirth’s interest in ME/CFS

Mystery Man

But what about Klaus Wirth? We’ve never heard his name before, yet here he is the co-author of a major hypothesis paper on ME/CFS. Wirth, it turns out, an experimental pharmacologist focused on cardiovascular research in Sanofi-Aventis Deutschland in Frankfurt.

During his investigations into small blood vessel diseases he realized how important activation of the beta adrenergic receptors were for blood flows through both the small and large blood vessels. In 2018 his work suggested that beta adrenergic activation plays a vital role in brain blood flows.

Then in March 2018 he happened to turn on a TV show:

In March 2018 I saw a short report on our local TV on a father whose son was bedridden by ME/CFS. He was interviewed for his activities in politics to enhance funding for ME/CFS research. I had no idea of what ME/CFS was and I made a Google search that evening. Next day I went into pubmed. The second abstract I saw was that of Carmen’s group on autoantibodies against ß2-adrenergic receptors. I immediately felt that there might a problem with cerebral and skeletal muscle perfusion and a fundamental and underlying cardiovascular problem. Although I immediately felt that I might be able to understand the pathophysiology it was very tiring to put the pieces of this puzzle together. It took us 1-1.5 years.


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, of 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 BSAdR 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.

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  • Issie

    May 10, 2020 at 1:32 pm - Reply

    I have all the issues spoken of here. All found with many visits to Mayo. But, these symptoms go along with HyperPOTS. I have said for years that I need to vasodilate and not vasoconstrict. Which is the “traditional ” approach with POTS (to constrict). Doing that made me so much worse. And they did find hypovolume blood issues and blood pooling. The one thing we found later, is genetic issues with too thick blood. So if blood consistency is too thick and blood vessels too clamped down, there is definitely a blood flow, volume issue. We are thinning my blood with enzymes and herbs and that does seem to help.

    The POTS docs have been looking into this and that receptor for awhile. But, seems few are realizing that some of us have too constricted veins and we don’t need to clamp them down more.

    I also have near no renin or aldosterone, at the kidney level. Angiotensin falls in the middle of that process. But, angiotensin can be made in the heart and brain too. So possibly renin and aldosterone is there too. Renin and aldosterone regulate volume of fluids. So it can affect things like dehydration and volume.

    One possible good thing, in light of current virus (and in debate among doctors), is this virus goes in on ACE2. If we have low angiotensin, good chance we may have a milder case of it than someone with higher levels. I found a study with docs trying to determine whether or not to pull people off ACE inhibitors.


    May 10, 2020 at 1:50 pm - Reply

    Yes I agree with this, my blood vessels
    are always swollen and this makes my legs heavy. BUT WHAT TO DO ABOUT IT?

  • Learner1

    May 10, 2020 at 2:00 pm - Reply

    Like Issie, I have hyper POTS and thick blood due to a genetic issue. I don’t have beta adrenergic antibodies, but I do have alpha a1 adrenergic and m4 muscarinic antibodies. At my sickest, I had very low aldosterone and very high prostaglandin D2. And, like several other ME/CFS patients, I have AMPD1 SNPs which cause adenosine buildup with exercise.

    Is there a variant on this hypothesis?

    Thanks for an interesting article.

  • acacia

    May 10, 2020 at 2:09 pm - Reply

    This makes so much sense! Although I can’t comment on the detailed technical aspects and I have not had any of the detailed tests named here these findings could be explanatory.
    I have had a finding through echocardiograph of narrowed diameter of inferior vena cava, leading to inference of low blood volume. I also find a hot shower of some relief.
    I hope this research is followed up! A question to be answered is also why there is often a delay in our worst symptoms. Is there a cascade effect in these chemicals?

  • Kathy Bungard

    May 10, 2020 at 2:18 pm - Reply

    Issie, could you share which enzymes and herbs you are using?

    As I’ve read this and another article on bradykinin I do think they are on the right track.

    I’ve had months of SEVERE pain that develops soon after I get up each morning – after about an hour I begin to get a very painful tightness on my lower right back that starts near my spine and then grows outward and around my rib cage and after an hour or two it is so intense I feel like there is an iron vice around my ribs that is literally crushing them. I believe I have developed inflammation in the cartilage attaching the ribs to spine and sternum so one would think it is something like costo chondritis, however the pain lessens with application of heat – hot baths, sauna, heating pad – and I can get relief for as long as the dilation from the heat sources last.

    So what now? What can be done if their theory is correct?

  • Issie

    May 10, 2020 at 2:33 pm - Reply

    There are a couple enzymes I rotate between. Serrapeptase and Empiral labs, Vascuzyme. I’m also using Ginger which not only thins blood but helps pain too. Occasionally use Turmeric. Gingko and Ginger is in a formula I use to help brain fog issues and functioning. It helps blood flow to brain and reperfusion issues. That one is called Clari T.

  • Wendy

    May 10, 2020 at 3:06 pm - Reply

    I wish this article were more lay friendly as I barely understand it. It’s interesting because so much of my cfs/Lyme is about orthostatic hypotension (not quite POTS) and exercise intolerance…I hope i catch the upcoming article

    • Cort Johnson

      May 10, 2020 at 4:29 pm - Reply

      I’m afraid this article is about laymen friendly as it’s going to get. These are simply difficult, complex concepts.
      The core things to remember, though, are:

      • that an overactive fight or flight system is clamping down on the arteries (big blood vessels).
      • The small blood vessels near the muscles need to dilate or open up in order to get more blood to the muscles during exertion (you can’t get much liquid through a small tube). They’re under a lot of pressure to do that because the blood vessels leading to them have been constricted.
      • Past studies suggest that the receptors which dilate those blood vessels are damaged in ME/CFS.
      • That means they’re stuck – you already have these narrowed arteries and now you can’t dilate the small blood vessels enough to get blood to the muscles. How does the body compensate for that? By producing it’s own vasodilators – substances which make the blood vessels bigger – allowing at least some blood to get through the muscles.
      • Unfortunately, there is often a cost to an compensatory effort. In this case so many vasodilators are produced that they cause fatigue, pain, cognitive problems, etc.
      • There are two needs: turn the fight/flight system off and repair the receptors that have been damaged.
  • lisa

    May 10, 2020 at 3:35 pm - Reply

    Is this the beta adrenergic receptor from the cell trend panel? Because only a subset of patients were found to have autoantibodies against it and their immunoadsorption study to remove those autoantibodies have not been that successful I think.

  • Proff

    May 10, 2020 at 3:37 pm - Reply

    I find it interesting that Bradykinin is being linked to ME/CFS.

    HAE (Hereditary Angioedema) is a diagnose that has a C1-inh-protein error that gives Bradykinin-issues. Fatigue is a big symptom under a swelling attack, caused by HAE. Patients with HAE often have a second serious condition too, as ME/CFS, Lupus, Fibromyalgia, Ankylosing spondylitis, IBS, pain disorders etc. You rarely find a adult HAE patient with just HAE.

    I’m NOT saying that there is a direct link between ME/CFS and HAE, but as I first said, I find this common denominator (Bradykinin) very interesting, and also relevant. Maybe this hypothesis is a long shot in the dark, but I absolutely see the possibility for something good is coming out of this. I’m looking forward for more about this.

  • ZeroGravitas

    May 10, 2020 at 4:07 pm - Reply

    Odd co-incidence…!: Just a couple days ago I was posting (on PR) about MedCram’s hypothesis of severe Covid-19 illness being caused by intense oxidative stress from an imbalance of Angiotensin II (not being converted to Angiotensin (1-7) due to the virus destroying ACE2 surface enzyme in lungs):
    The post was originally about the overlap with common ME/CFS supplements and those recommended for immune system support and Covid treatment. But it got me wondering why I’d not heard about ME/CFS research on this angiotensin system ever before… Especially as MedCram was saying that ATII increases oxidation and AT(1-7) has an anti-oxidant effect. Something I’ve no idea how it works…
    Also! Is there a potential link between this work and the paper you posted about in your last article?:

    In that, it listed HSV’s possible antigen mimicry as *acetylcholine receptors*. And in this paper: “We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients”
    Serendipity or mere coincidental overlap?

  • ElizabethKay

    May 10, 2020 at 4:43 pm - Reply

    On a related note: VEGH – Vascular Epithelial Growth Hormone – may be intermittently out of whack in our ME/CFS population. Is anybody here familiar with this or looking into this?

    Kathy, your description of pain like an iron vice around the ribs – I get pain like that too. This definitely rings a bell! And while we’re thinking about vaso-dilators
    and -constrictors, and uterus-centric pain… Often my pain feels eerily like migraine pain – but the pain seems to be a full body migraine.

    And speaking from my own experience of natural childbirth & labor, quite often I’ve noticed my pain has felt like the same kind of pain that I had during natural labor – although my fibro-cfs pain is full body as compared to uterus/cervix centric.

    I’ve been curious for years about the, ahem, impressive similarities of this bodily pain – curiously very similar to migraine or labor.

  • Cort Johnson

    May 10, 2020 at 4:48 pm - Reply

    This is from Nikolai:

    Years ago, back in the mid-80s, I was in a research project in UCLA. I was
    on an exercycle. First time, on room air. Minimum time on the bike, and the next
    day, I hurt like hell.

    One week later, same experiment, only this time I was on 100% oxygen
    Lasted 40 minutes, no pain later. I concluded that my muscles were not getting
    any oxygen! Then, I learned that one help for migraines was Niacin. A potent
    vasodilator! It worked, I even helped a Christian Scientist man get rid of his
    migraine with it! His religion did not object to vitamins or supplements for what
    body needed anyway.

    BTW, I hate this format! Too hard to stay within the field. I’ve been ill with
    ME?CFS/FMS since June 1981. Before that, I was an active person, scuba diving and
    going on mountain hikes, often. Loved to walk and run. Gave up most physical
    activity. “Graduated exercise’ was a disaster!

    Now I am 82 years old, and one good thing about this disease: apparently, it does not shorten your life span. It also helps that I never did drink, smoke, do drugs or abuse my medications.

  • Nikoli McCracken

    May 10, 2020 at 4:54 pm - Reply

    Way back in the mid-80s, (I got sick June 1981) I participated in an experiment at UCLA. Riding a
    medical bicycle, I exercised on room air. Very short time, was painful all the next few days. Next time, was on 100% O2, lasted 40 minutes, no pain afterward. I concluded I was not getting any oxygen to my muscles!
    I also discovered that niacin, a potent vasodilator, would stop a migraine. I even helped a man who was Christian Science, get rid of his migraine with that. His religion did not keep him from taking vitamins or minerals.
    I tried to follow doctor’s orders for ‘graduated exercise.’ It nearly killed me. Formerly a scuba diver and mountain hiker, i was reduced to doing no extra exercise. Not going to stick my hand in that fire again! The only exercise I can still do is swimming. That doesn’t hurt me. But I
    CANNOT SCUBA dive anymore. Even using the fins kills the muscles in my legs.
    This sounds like the new idea we have all needed for so long.
    There is one good bit of news about the damned disease:: Apparently, it doesn’t shorten your life span. I am 82 years old! It helps that I never drank, smoke, did drugs, or abuse my medications. I am very encouraged by this new idea. I think it is wonderful that a person with
    “New Eyes” came up with new ideas.

  • Troon Harrison

    May 10, 2020 at 5:01 pm - Reply

    It would be interesting to know what this means for ME patients who have hypertension. Are ACE inhibitors and beta blockers thus helpful to them, or would those meds make ME symptoms worse, according to this new theory?

  • ZeroGravitas

    May 10, 2020 at 5:27 pm - Reply

    You’ve written “BSAdR” in concludion one time, instead of B2AdR.

    [Delete again, hank you! Much love. 😉 ]

  • Pamela

    May 10, 2020 at 5:44 pm - Reply

    I like it! Thank you for posting this, Cort, and for all your hard work.

    This seems to make sense of my ACE (angiotensin-converting enzyme) and CK (creatine kinase) test anomalies like nothing else. The heart-brain-muscle associations leading to our seemingly unique kind of fatigue that Klaus made also makes sense to me of the way I (now) experience fatigue (it feels heart failure-like-oriented) and certain muscle and brain symptoms.

    ACE and CK were included in an array of labs I was given for the first time in 2006, I believe. Thereafter the few times they were tested again they were always mysteriously elevated; I had no medical condition that would commonly explain them.

    I do not have POTS and I have never had high blood pressure, but my muscles rapidly fatigue causing pain and/or weakness, shakiness or numbness to one degree or another. The effect ranges from annoying awareness to restricting to occasionally debilitating. These muscle symptoms only became apparent in the later years of my illness after other symptoms had also developed or worsened. I notice it, for instance, within seconds of elevating my arms for any activity now — painting a ceiling (which I can no longer practically do for that reason), washing hair in the shower, changing a ceiling light bulb, holding a phone to my ear…It can feel as though the blood has drained from my arms. Pain is activated within a matter of seconds, or weakness, or shaking, or numbness depending on the position of my arm or leg or neck, and length of time. It has caused my voice to get shaky, too, if I had to talk for too long The fatigue I experience has had a more pronounced feeling of heart failure in recent years.


    Elevated CK:

    For what it’s worth, I was completely “cured” of ME for the short duration (about two weeks) following a large post-surgical dose of prednisone, after which it came back and progressed.

  • Nancy

    May 10, 2020 at 6:08 pm - Reply

    A few years ago I proactively asked my primary care doctor for Diamox to prevent altitude sickness. While taking, I felt good and was able to exercise more than I usually can. In Seattle, I have not found a doctor who understands or follows current research on ME/CFS and I”m not sure what type of doctor would be best to discuss this with.

  • Rose

    May 10, 2020 at 7:11 pm - Reply

    Vessels in my toes and fingers often painfully burst for no reason at all. I wonder if there is a connection to the above. I’ve been diagnosed with ME/CFS 20 years ago.

  • Carole

    May 10, 2020 at 7:21 pm - Reply

    Issie- This also sounds like my issues . My BP is all over the place. 100/40 hr may be up or down But when I get this-I am almost immobile Weak and dizzy /can’t think or concentrate . Have to be still and lie down if possible. What meds where rec for you or just natural remedies?. Problem is finding a Dr to address this.

  • Carole

    May 10, 2020 at 7:34 pm - Reply

    Cort- Great Post. I used to be an Athlete until 1987. When I contracted Epstein Barr and CMV. Now I did get back to exercising with Immune Globulin and B-12 injections. This as years ago. In the last 2-3 years. Heart fluctuations and crazy BP all over the place have stopped everything but Yoga and stretching. Even my cardiologist cannot determine what is causing my low BP like 100/40 and Hr varies from 40-70? I get so weak I have to lie down. Have given up trying to drive. If the vasodiloters -Gingko, Tumeric would help at all-wondering??? I am also on a Cpap Machine at night??

  • Issie

    May 10, 2020 at 8:43 pm - Reply

    There are a lot of different types of dysautonomia. First doc to see may be a neurologist. And then a cardiologist next. Both address it from different angles.

    Be careful with vasodilating with hypotension, (low blood pressure). Can drop it more.

  • Nancy B.

    May 10, 2020 at 8:59 pm - Reply

    Cort, wow! I’m very excited about this news, especially being someone with Ehlers-Danlos! First, 80-95% of EDSers present with pain and FATIGUE. About 50% have or will acquire small fiber neuropathy (the nerves actually die off, and this translates to fibromyalgia-like pain). And the real kicker is that a very large percent of us have autonomic dysfunction and it’s mostly POTS.

    I’m new to understanding the RAAS system but this theory makes so much sense.

    For myself, with wildly fluctuating BP and HR from low to high, I’m fairly confident I have Hyperadreneric POTS (a subset of POTS) where our flight or fight is way out of control. I have defective connective tissue (read that muscles, tendons, BLOOD VESSELS,etc.) which do not respond in a normal way (possibly also because I am lacking some of the receptors or even structure necessary for the RAAS feedback to work).

    Hypermobile EDSers have blood vessels and muscles which struggle to contract to normalize blood flow in the body and brain–especially when active or even standing upright. Low blood flow is low oxygen is low function. Low function is pain, less responsive muscles and brain fog.

    I also found Proff’s comments about HAE very provocative as EDSers may have unrecognized bradykinin issues and as a group are also very likely to have autoimmune co-morbidities like Proff mentioned.

    Also Issie’s comment about using Serrapeptase (an enzyme important for muscle, tissue and joint function) for her issues (MCAS, EDS and I’m sure some others) makes me think about the link between EDS and gastrointestinal issues. People have lots of Mast Cells and other immune cells in their digestive track and guess what, angiotensin has an effect there too!

    If I remember correctly, Ron Davis suspects it is something in the plasma and not in the blood cells or mitochondria which may be causing our CFS problems–could that something be part of the RAAS feedback? Could an illness cause a mutation on the beta-2 adrenergic receptor?

    In the meantime, to those of you who suspect they have autonomic dysfunction, is a good place to look for more advanced help. Having a misbehaving autonomic system can certainly contribute to fatigue! I don’t know if things like using compression wear, hydrating, and keeping a close eye on ones electrolytes, especially sodium, might be helpful to some of you. It is for many EDSers.

  • Ara

    May 10, 2020 at 9:58 pm - Reply

    So CFS patients are at a greater risk if they get COVID19?

  • Phillida

    May 10, 2020 at 10:28 pm - Reply

    Could this be related to the now very old finding out of Otago University, New Zealand, that showed the red blood cells were distorted into a ‘cup’ shape in ME/CFS and carried less oxygen as a result?

  • Marie scales

    May 10, 2020 at 10:51 pm - Reply

    I have the ability of relieving my symptoms with mayofascial release therapy, but since Covid 19 I am
    finding my fascia is going through calcification and I am spending a lot of time meditating. This is the only way I can relieve my vagus nerve inflamation. No doctor understands what I explain to them! Ia anyone else experiencing this?

  • Jim Kepner

    May 11, 2020 at 12:29 am - Reply

    Thanks Cort for another superb and cogent summary of some ridiculously complex biology. Your articles never look like the work of the brain fogged but I’d bet it may cost you sometimes.

    This is the most plausible organizing hypothesis I’ve seen in my 40 years of watching one after another of simplistic singular cause solutions trotted out. It’s complex enough to make sense of the upstream and downstream difficulties in multiple body systems. Fingers crossed. And, I really love the serendipity of someone with an entirely different scientific interest than the research to date got into this from watching a TV interview. I’ll look forward to your continued reporting.

  • Esther

    May 11, 2020 at 3:24 am - Reply

    Very interesting. A live blood scan showed my red blood cells were distorted. Heart is not working properly under stress…I will contact cardiologist and find out exactly what is wrong and see if it corelates. Also, very low blood pressure and thick blood have been major problems. On one visit to the Dr the nurse checked my blood pressure…pushed the machine away…said “It is broken”. A second machine… “This one is broken too! Your blood pressure cannot be that low!”. I haven’t been told that when my bp was 80/45…that was okay! Standing for any length of time makes me so sick and it takes a couple of days to recover. Looking forward to more research being done! I’ve only had this 34 years!! At least I’ve made it to 63!

  • ZeroGravitas

    May 11, 2020 at 4:18 pm - Reply

    @Issie – Regarding ACE inhibitors and ARBs (angiotensin receptor blockers), the latest Covid-19 study findings showed that it’s best to stay on them (certainly if taking them already):

  • Cort Johnson

    May 11, 2020 at 9:27 pm - Reply

    Great question about the delayed effect. I don’t know. This hypothesis is really new. I like how it takes a known problem – the narrowed blood vessels and low blood volume and the possible B2ADR problem then adds something completely new – a huge surge of vasodilators causing pain and fatigue and other symptoms.

    Whatever explains ME/CFS must be able to explain the delayed reaction issue.

  • Jessica

    May 11, 2020 at 9:28 pm - Reply

    Wobenzym is another enzyme to try that thins the blood. I follow an old Fibro protocol of 4 tabs 3 times a day.

  • Cort Johnson

    May 11, 2020 at 9:31 pm - Reply

    Me too, Jim! I love that Klaus Wirth got turned onto this by a TV program. They make a difference! Robert Phair of the Metabolic Hypothesis got turned onto ME/CFS by a campus newsletter. The more we share, the more we spread the word, the more we tell anyone in our circle what’s going on the more opportunity we will have to solve this thing.

    Wirth is in a quite specialized field and it’s great to have his contributions.

  • Cort Johnson

    May 11, 2020 at 9:37 pm - Reply

    Hi Paul, therapeutic options are, of course, being considered but must remain vague for the present. . Klaus noted, though, that “insights into disease mechanisms have always led to concrete therapeutic approaches.” Let’s hope!

  • Issie

    May 12, 2020 at 2:09 am - Reply

    @ZeroGravitas, I watched some of that video and did a little checking on releases of last few days. There still is a bit of debate. While they are (Now) telling people to stay on them. There is still debate on the end result. Some are saying it changes the pathways of how the virus goes in on the ACE2 and maybe they would be of benefit. But most all the studies have been with mice. And the ones admitted to the hospital and ICU are mostly those with high blood pressure and on them already. So debate is still there by some. They think maybe having higher angiotensin may be a help when it goes to pneumonia and lung issues. But angiotensin is in other places than just the lungs and this virus is attacking neurological and also the heart. Both the brain and heart having angiotensin. The paper released on Medscape, sort of, is pointing this out. There is good that the medicines can do with high blood pressure and kidney issues. Angiotensin playing a strong part in that organ and pathway. But they also suggested that some who don’t want to stay on ACE or ARBS, there are other alternatives. So, I think it still isn’t that firm yet by all the doctors and researchers. A lot is still hypothesis. I guess with time, it will be sorted beyond doubt. And yes, it’s TRUE the latest papers are trying to get people to stay on them. I didn’t look to see if there is a vested interest. But that may be worth checking. It’s so hard to know what direction to take when you are dealing with the unknown. I’m sure there will be many new discoveries with this world event.

    I personally hope, lower angiotensin doesn’t put one in the high risk category as I did horrible on ACE and ARB and I have really low angiotensin at the kidney level. And initially it was thought that lower levels were a protection with less chance of the virus going in on this pathway. I guess time will tell.

  • Lora

    May 12, 2020 at 3:24 pm - Reply

    Most Excellent, Article Cort! I definitely can relate and understand the path mentioned …Great Research! Looking forward in seeing more info. along this line..

  • Lora

    May 13, 2020 at 2:22 pm - Reply

    @ Issie
    I thought I would mention to you that one of our Fibromite sis from long ago..Was having a hard time and happen to mention she had a S-Curve Spineand she had passed shortly after that…

  • Annie

    May 13, 2020 at 8:31 pm - Reply

    I’m on midodrine for orthostatic hypotension. Which is a vasoconstrictor do you think this will be making my M.E worse?

  • Tanja B

    May 14, 2020 at 12:03 am - Reply

    Does anyone know where we can get tested in the U.S. for Beta 2 adrenergic receptor antibodies? The only place I can find listed on the Internet is in Germany. The University of Colorado can’t do them for me.

    • Cort Johnson

      June 5, 2020 at 12:46 pm - Reply

      So far as I know. The only place is Germany unfortunately.

  • Issie

    May 14, 2020 at 12:20 am - Reply

    Was it someone I knew? And why did she pass?

  • Issie

    May 14, 2020 at 1:45 am - Reply

    Better PM on Healthrising forum and us not take up space on this blog. Let me know who that was. I have two people in mind.

  • Kathy Bungard

    May 14, 2020 at 2:45 am - Reply

    Great summary, Cort, thanks.

    For months I’ve been experiencing some of the most painful symptoms in the almost 40 years I’ve been ill with ME and it is all about INTENSE pain I begin to experience within an hour of getting up in the morning. I get a burning pressing feeling in one particular spot just to the right of my mid spine. It feels like the muscle is turning to stone! It tightens and tightens until my ribs ache, my throat also begins to close, my voice goes to a whisper and pain can go in shots to my shoulder and neck, up back of my head.

    Reading this article I’m inclined to believe what you are describing is what I am experiencing. As usual with this nightmare illness it is a huge relief to finally understand what is happening only to come up against the wall of – and then what do I do to stop this?

  • Tanja B

    May 14, 2020 at 7:00 pm - Reply

    Does anyone know where (in the US) we can be tested for beta 2 adrenergic receptor antibodies? I am having trouble finding a lab that can test for it.

  • Marina

    May 15, 2020 at 12:16 pm - Reply

    i was wondering if there was a link between the above and the fact that large doses of ibuprofen usually improve my symptoms to the point of feeling “normal”. I found different articles on the internet which appear to contradict each other -I read on google that it is a vaso-constrictor but a research paper, “Coronary arterial vasodilator effect of ibuprofen” (Apstein, 1982) states otherwise. It may be that I am in the wrong subset but any thoughts on this from someone more informed than I am would be welcome!

  • Angus Mackay

    May 16, 2020 at 2:55 am - Reply

    Hi Cort… you say a “unifying hypothesis”, but a. how does it explain mutiple triggers for ME/CFS… not always viral, but via trauma or chemical toxin exposure etc in the stimulation and production of specific autoantibodies required? b. they say they can detect auto antibodies to the receptor in the blood (by auto-antibodies), and yet not to the consistency or reliability to provide a ‘blood test’ for ME/CFS it would appear? Does this imply ‘subtypes’, they use the term ‘subsets’ – how do they explain those who do not produce these autoantibodies who have ME/CFS… is that ‘unifying’ enough? c. And do they explain how ‘relapses’ occur?
    Angus NZ

  • Maureen Hartnett

    May 17, 2020 at 4:58 am - Reply

    I agree that the details of this article seems to describe Postural Tachycardia Syndrome (POTS) which is a somewhat common form of dyautonomia. I wonder if they are going to share this information with Dysautonomia International?

  • Dawne Mowbray

    May 19, 2020 at 1:04 am - Reply

    I read this article and another one in my mailbox from Dr. Malcolm Kendrick, a UK doctor. He was writing about covid-19 and vitamin A. One of his journal references was this article:

    Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium
    Christopher C. Gibson , Chadwick T. Davis , Weiquan Zhu, Jay A. Bowman-Kirigin, Ashley E. Walker, Zhengfu Tai, Kirk R. Thomas, Anthony J. Donato, Lisa A. Lesniewski, Dean Y. Li
    Published: October 15, 2015

    This article talks about vascular dysfunction phenotypes and correlation with low vitamin D levels. It mentioned that Vitamin D protects endothelial cells (also mentioned in your article) and that Vitamin D is a modulator of inflammation.

    Just wondering if the benefits of Vitamin D (which Dr. Kendrick discussed in the context of covid-19) could be extended to the vascular and endothelial dysfunction mentioned by Wirth and Sheibenbogen.

    Thanks so much for all your work Cort. I’ve had ME/CFS since 1988.

  • martin

    May 24, 2020 at 1:40 pm - Reply

    I spoke to a PWME once online and he said his symptoms were vastly improved with a reb blood cell making drug in the bone marrow that increased his blood volume, He said his life was great for a couple of years but then he had to stop as his numbers were all over the place. Nancy Klimas did a clinical trial of this drug to see if it reduced fatigue but the trial was not successful I believe. Can’t remember the name of the drug now. Think is began with an R

  • Martin

    May 24, 2020 at 5:20 pm - Reply

    Prof Basant Puri of Imperial College London recommends taking Omega 3 Fatty Acids for CFS as it reduces inflammation so this could help with the idea in this thread.

  • Lubix

    May 30, 2020 at 8:38 pm - Reply

    Thanks for great article, all very familiar. I am diagnosed with EDS, POTS and also Lyme and Morgellons Disease. All these diseases began with Morgellons Disease 30 years ago. About 6 years ago I discovered I was heavily infected with a parasite of which little is known about but many people have discovered inside of them, it’s known as Ropeworm or Human Intestinal Rope parasite. It’s a novel infection and most research has been done by Russian biologist Gubarev and his associate Volinsky. It is a biofilm parasite, the Protozoa infection known as FL1953 is also very similar in its biofilm building capabilities (Dr Steven Fry). This biofilm parasite growso inside intestines and migrates through tissue into multi systems and organs and is known to cause atherosclerosis and constriction of blood vessels. After many years of removing unbelievable volumes of this biofilm my health has improved. It is passed through bowels, there are a few protocols involving anti parasite medications, enzymes such as serrapeptase and bowel cleansing using mimosa pumice. The Ropeworm is seen commonly in those children with Autism also.
    The more I remove the more I improve. Pain almost gone, no pain killers now. Sleep improved, thyroid health improved also oxygen levels, and overall symptoms of POTS. I wish you all well.

  • Rose Fenton

    June 5, 2020 at 10:20 pm - Reply

    I would like to reply to someone who mentioned beta-blockers. After being given this drug in 1980 for my M.E and Fibromyalgia, and high blood pressure, by a so-called Specialist, and left on it for 7 years, despite collapsing and it finishing the use of my legs, my then Dr,would not agree to stopping it. It was a locum who told me immediately to stop this drug, as he had seen this happen before, but all too late for the damage it caused. I read in an ME Book later that it is the worst drug anyone with ME could be given! it meant that I had to have a wheelchair from then on, and still so today.

    • Cort Johnson

      June 11, 2020 at 6:35 pm - Reply

      Sorry to hear about your experience. These are drugs that obviously need to be used carefully. Some people do find them quite helpful. We really need to know what different subsets are present in ME/CFS in order to treat people properly.

  • Andrew

    August 26, 2020 at 11:06 am - Reply

    Bro melanin can help reduce level of bradykinin – may be helpful

  • Andrew

    August 26, 2020 at 11:07 am - Reply

    Bromelain that is, damn you autocorrect!

    • Cort Johnson

      September 10, 2020 at 8:42 pm - Reply


  • winterwren

    September 4, 2020 at 1:22 am - Reply

    I know this is an old article now but I just can’t wait for a follow up of some kind. I just read about the covid 19 theory connecting it to bradykinin and it’s all making so much sense with ME as well. I’m excited.

    • Cort Johnson

      September 10, 2020 at 8:43 pm - Reply

      Thanks for passing that on, Winterwren!