You are here: Simmaron ResearchUncategorizedPOTS Rising! Research & Advocacy Producing Breakthroughs in Neglected Disease

POTS Rising! Research & Advocacy Producing Breakthroughs in Neglected Disease

April 28, 2018

Remarkable Progress

It’s rare that a clear cause of disease like postural orthostatic tachycardia (POTS) or chronic fatigue syndrome (ME/CFS) or fibromyalgia (FM) shows up, but that appears to be what’s happening in POTS.

focus - POTS

Researchers are increasingly focusing on autoimmune aspects of POTS

The progress is all the more notable in POTS given the newness of the disease.  The name was only coined in 1993 and the disease still lacks a dedicated funding stream at the NIH (but see below). Nor does the NIH track POTS funding the way it does other diseases.  It was only recently that the World Health Organization created an ICD code specifically for POTS. While the disease is mostly an afterthought at the NIH, it affects a large number of people (1-3 million in U.S.)

Despite its humble beginnings remarkable progress in understanding the disease is being made.  That’s good news for people with ME/CFS given the high incidence of POTS (11-40%) in the disease. Plus it shows that even a small research community can make significant strides in a disease if they target the right area.

Autoimmune Disorder

With its female dominance and often an infectious trigger, POTS, like ME/CFS, has always been a candidate for classification as an autoimmune disease.  In fact, autoimmunity has been showing up in orthostatic intolerance in general lately. Plus it’s shown up in an array of cardiovascular diseases including hypertension, cardiomyopathy, myocarditis and cardiac arrhythmias, each of which can cause problems standing.

Orthostatic Hypotension

It turns out there are many ways to mess with our circulatory systems.  A University of Oklahoma group has been driving the findings in mostly small studies. In 2012 that group reported that people with orthostatic hypotension, who experience severe drops in blood pressure while standing, commonly had autoantibodies to the receptors on the outside of cells that regulate autonomic nervous system activity. Remarkably, autoantibodies  were found in no less than 75% of the study participants.

The adrenergic (B1AR, B2AR) and muscarinic (M2R, M3R) receptors identified affected blood flow across the body. Different symptoms appear to result depending on which receptor is involved.

People with severe blood pressure drops within a few minutes of standing, for instance, tended to harbor B2AR and M3R autoantibodies which affect the vasodilation of our blood vessels. Because our blood vessels constrict or narrow when we stand in order to halt the gravitational flow of blood to our limbs, vasodilation during standing is exactly the wrong strategy.

Other people with dramatic heart rate increases while standing tended to harbor M2R and/or β1AR autoantibodies.

POTS

In 2014 the Oklahoma group’s study in the Journal of American Heart Association found evidence of three autoantibodies in POTS. This time the Oklahoma group predicted they would find autoantibodies to a receptor (α1 adrenergic receptor – α1AR) that causes our blood vessels to contract.

They found that, but in a twist, they also found additional autoantibodies: to the β1AR receptor in all the POTS patients, and vasodilatory autoantibodies to the β2AR receptor in half of them. They believe that these autoantibodies enhance norepinephrine’s effect on the heart; i.e. they increase the heart rate problems in POTS.

Autoimmunity POTS

Autoimmune processes that affect the blood vessels may define disorders that produce problems with standing.

They posit, interestingly, that problems with blood pressure not heart rate increases are the primary problem in POTS. They believe that when POTS patients stand, their α1AR autoantibodies smack the αIAR receptors, causing problems with blood vessel contraction. That allows blood to drain from POTS patients’ brains into their lower bodies causing fatigue, dizziness, etc. In order to compensate, they jack up their sympathetic nervous system activity with norepinephrine in order to maintain blood pressure.

Unfortunately, since POTS patients also harbor autoantibodies which cause them to increase their heart rates, the result is sometimes astonishingly high heart rates while standing. Since a heart beating too fast has the same effect as a heart beating too low (reduced blood flow), the ploy doesn’t work and POTS patients experience dizziness, fatigue, etc. upon standing.

In effect the POTS patients struck out on two levels; not only did they have autoantibodies that might be imperiling their ability to maintain their blood pressure while standing, they also had autoantibodies that dramatically increased their heart rates.

New Study – New Autoantibody

In a follow up 2018 study published in the Journal of the American Heart Association, the group looked at an entirely different type of autoantibody – the angiotensin II type 1 receptor (AT1R) that regulates blood pressure via the renin-aldosterone system. The renin-aldosterone system also regulates blood volume, which is often low in ME/CFS.

The study was again small (17 POTS patients) plus 16 controls, but once again the results were highly significant with 12/17 POTS patients but none of the controls exhibiting autoantibodies to AT1R. Plus all the POTS patients also had autoantibodies to either or both of the AT1R and the α1‐adrenergic receptor.

Because the renin-angiotensin-aldosterone system works more slowly than the aforementioned responses, it appears that many POTS patients may suffer from both a rapid and a more prolonged dysregulation of their circulatory systems.  When placed in a rabbit model, the ATIR autoantibody effectively duplicated the effects of the α1AR autoantibody – it stopped the blood vessels from constricting properly, again resulting in blood pooling in the lower extremities – and in humans feelings of fatigue, dizziness, etc.

In a nice fit, several POTS studies have documented problems with the renin-angiotension-aldosterone system, which could be caused by autoantibodies like ATIR. One study, which found elevated Ang II levels and low aldosterone levels, suggested that receptor problems were interfering with transformation of Ang II to aldosterone. The authors of this study suggested that the autoantibody found could indeed be the missing link.

Another Autoantibody (!)

We’re still not done with autoantibodies in POTS. A recent presentation which found a fourth autoantibody (to the M1 receptor) suggested POTS patients may be swimming in autoantibodies which negatively affect their circulatory systems.

Spectrum Disorder?

These investigators believe POTS is part of a spectrum of diseases (OH, POTS, cardiovascular diseases, (ME/CFS?)), all of which harbor autoantibodies that interfere with blood vessel contraction/dilation and the heart rate.

Dysautonomia International – Moving Forward on POTS

Since being co-founded in 2012 by Lauren Stiles, Dysautonomia International has grown rapidly and is now providing substantial funding for POTS research. A very dynamic organization, I was glad to have the opportunity to ask its President about its POTS work, where we are on autoimmunity and POTS, and DI’s recent advocacy work.

What kind of POTS funding has Dysautonomia International provided? 

Dysautonomia International

Dysautonomia International has grown rapidly in just five years.

Dysautonomia International has funded over $300,000 in POTS Research Fund grants to support the work of Dr. David Kem and colleagues at University of Oklahoma, exploring the role of autoimmunity in POTS, seeking to identify diagnostic biomarkers, and eventually the development of targeted immune therapies. Dr. Kem’s recent publication documenting the presence of angiotensin receptor antibodies in POTS was one of several important publications that resulted from these grants, and there are additional autoimmune POTS related studies still in progress at the University of Oklahoma. We have also funded autoimmune POTS related studies at Mayo Clinic and University of Texas Southwestern, which are in progress.

How far are we from establishing that at least a major subset of POTS patients have an autoimmune disease?

Most POTS experts acknowledge that a subset of POTS patients have an autoimmune problem. Defining what percentage of patients that is depends on how we define what we mean by “an autoimmune problem.”

For example, the largest cohort study on POTS to date with over 4,000 patients enrolled (lead by Dysautonomia International, Vanderbilt University and University of Calgary), found that 16% of POTS patients report being diagnosed with a known autoimmune disease, most often Hashimoto’s, Sjogren’s, lupus and celiac.

Then there is a larger group of POTS patients who have positive blood tests on common antibody tests, such as TPO, ANA or SS-A, but they don’t meet the criteria for a known autoimmune disease.

POTS patients have signs of an autoimmune disease but larger studies are needed to validate them.

Then we have several small cohort studies, usually 40 patients or less, showing that nearly all POTS patients have antibodies to various cell surface receptors that play a role in regulating the autonomic nervous system (adrenergic, muscarinic and angiotensin antibodies).

This last category of antibodies are also present in other medical conditions, several of which are associated with autonomic dysfunction, such as orthostatic hypotension, Sjogren’s syndrome, Chagas disease, dilated cardiomyopathy, and ME/CFS.

We need a lot of additional research before we can go from “we found these interesting antibodies that might play a role in POTS” to “we’re sure POTS is an autoimmune disease,” but that research is happening at several universities. The antibody tests are being refined. The small cohort studies are being repeated on larger cohorts. Researchers are starting to look at immune modulating treatments too.

I’m proud to say that Dysautonomia International is very much part of this effort, not only funding many of the studies, but also facilitating the larger cohort studies at our annual conferences, and connecting researchers who should be talking to each other together.

The NIH didn’t have a dedicated funding platform for POTS research but now things are looking up. What happened?

After Dysautonomia International’s July 2017 Lobby Day and our first Congressional Briefing on POTS in October 2017, Congress adopted our requested language directing the NIH to “stimulate the field’ of POTS research and “develop strategies that will increase our understanding of POTS and lead to effective treatments.” We’re continuing to meet with NIH to see what this will lead to in 2018, which we hope will be NIH’s first POTS specific call for proposals. Find additional details on our blog.

Conclusion

The POTS autoimmune finding are helpful for ME/CFS in several ways.  For one they show that researchers even in greatly underfunded diseases can make substantial progress if they target the right area. Secondly they’re beginning to demonstrate a strong autoimmune basis for a disease which produces similar symptoms to ME/CFS and which has a substantial overlap with it. Finally some of the same autoantibodies (and other ones) have been found in ME/CFS and interest in ME/CFS as an autoimmune disorder is picking up.  A recent review paper presented evidence that at least a subset of ME/CFS patients have an autoimmune disease. That will be covered in a future blog.

Print Friendly, PDF & Email

20 Comments

  • Eimear

    April 28, 2018 at 8:01 pm - Reply

    I can’t wait to hear of treatments…orthostatic intolerance is a big issue for me. Cort, if ME is an autoimmune disease, then this does not fit with the metabolic trap theory or the cortene theory, is that correct? We have alot of theories!! You will think I am nuts but I dreamt last night I got a present in the post. It was a collection of all Cort’s posts on ME/CFS up to 2020…I was opening the pack and I woke up…pretty disappointing!!! Anyway, back to my question. Are these theories all seperate, I don’t see how cortene/suramin/metabolic trap and autoimmunity tie in together?

    • Cort Johnson

      April 29, 2018 at 2:11 pm - Reply

      🙂 That’s funny! Up to 2020. I wonder what was in there! 🙂

      Check this out. One of the possibilities of Robert Phair’s metabolic trap hypothesis is that it could also help explain how autoimmunity starts. We’re a ways from showing that – that’s for sure – but it’s nice to see that possibility just pop out of his models…

      Other than that I don’t know how they all tie together. They may or they may not: the best thing for me is that different credible possibilities are being generated.

  • dejurgen

    April 28, 2018 at 8:50 pm - Reply

    Impressive results for 300,000 dollar: a breakthrough on a bargain price!

    Good news for the POTS community indeed! Now there is a target for drugs. And now there is no single sane reason left to not take the POTS community serious and act accordingly.

    Good news for ME/CFS too: if 11-40% of ME patients has POTS and 75% of POTS patients has clear measurable auto-antibodies then around 8 to 30% of ME patients should have clear measurable auto-antibodies too. Let’s hope ME patients with POTS do not make up that other 25% ;-).

    And there are many more ME/CFS patients with other forms of OI, so the percentage with detectable auto-antibodies likely will further go up.

    The auto-antibody on the renin-angiotensin-aldosterone system looks promising to me:
    “When placed in a rabbit model, the ATIR autoantibody effectively duplicated the effects of the α1AR autoantibody – it stopped the blood vessels from constricting properly, again resulting in blood pooling in the lower extremities – and in humans feelings of fatigue, dizziness, etc.”

    Imagine it would both cause low blood volume and blood pooling in the lower extremities. Many of us could have “undetectable” blood pooling in a way that our legs get 90% of normal blood volume and our head 60% to make up for a 75% of normal blood volume. It would fit perfectly with our “fight or flight” response: huge adrenaline levels would be needed to re-prioritize blood to go to the brain.

    Great research! Great news even if it means possibly having an auto-immune disease. Many thanks to the researchers and the people at Dysautonomia International!!! Thanks for following this and the clear write-up Cort!

    • Cort Johnson

      April 29, 2018 at 2:07 pm - Reply

      Thanks for doing the calculations De Jurgen 🙂 And good point about other forms of OI in ME/CFS. We forget about Dr. Natelson’s hyperventilation finding which he found in no less than 20% of ME/CFS patients in one study. Check out a home hyperventilation test here – https://www.healthrising.org/forums/resources/a-home-postural-hypocapnic-hyperventilation-test-for-me-cfs-and-fibromyalgia.239/. Plus if I remember correctly David Systrom is finding that just about every person with ME/CFS/FM he’s tested hyperventilates when exercising.

      Plus there are those of us for whom exercise induces a temporary case of POTS – indicating something is off there. Plus there are those of us who have something wrong with the cardiovascular system but don’t meet the criteria for POTS. I can’t believe that I am not in that category.

      It’s all good news for POTS and ME/CFS and I believe FM as well.

  • Jiki Betts

    April 28, 2018 at 8:56 pm - Reply

    Very interesting!
    Thank you very much Cort.

    • Cort Johnson

      April 29, 2018 at 2:02 pm - Reply

      Thanks!

  • Chris

    April 28, 2018 at 9:49 pm - Reply

    I have a friend who has jumped through many hoops just trying to get a firm dx for her POTS. Good news!

    • Cort Johnson

      April 29, 2018 at 2:12 pm - Reply

      POTS is another disease its hard to get a diagnosis in. Thankfully there are some good dysautonomia centers and specialists out there but until you know where they are – check out Dysautonomia International for a map – it can be rough.

  • Syd

    April 28, 2018 at 10:03 pm - Reply

    Thanks much for this.

    As someone with major daily impairment from POTS, here’s hoping this leads to some effective treatment.

  • Issie

    April 29, 2018 at 4:24 am - Reply

    I’m a HyperPOTS person and have low renin and aldosterone. When I first got DX with these things I dug deep into WHY and felt this had a key role in POTS. Here is some of the discussions we had on the subject back then.

    https://www.dinet.org/forums/topic/16668-renin-aldesterone-the-article/

    https://www.dinet.org/forums/topic/15830-more-on-aldosterone-and-renin/

    I may not have had it all correct and didn’t understand it completely either – but have always felt this was a part of the picture. I also always questioned what treatments were given to POTS people and thought some of our “symptoms” and DXs were/are a compensation for the lesser evil.

    Issie

    • Cort Johnson

      April 29, 2018 at 2:13 pm - Reply

      I think that’s this group is saying….The jacked up sympathetic nervous system is there for a reason which actually fits my case just fine as when I do things that increase my energy and relax my muscles I tend to fall apart.

  • Gijs

    April 29, 2018 at 9:33 am - Reply

    I have objective POTS and fit the profile! I think that people with ME/CFS and OI with objective AB tests will get out of the ME/CFS stigma too. But it will be around the 25% i guess. So the other 75% still have a long way to go.

  • Joseph

    April 29, 2018 at 2:47 pm - Reply

    Great article Cort! This helps to explain why my ME / CFS / FM related symptoms include POTS and how POTS and my recent cardiac event are interrelated. This also explains why I have back-to-back tachycardia with immediate bradycardia (and then POTS). Super fast then super slow heart beats per my one month telemetry device report. Sadly, once cardiac issues overlap with ME / CFS / FM issues – many cardiologists will be unable to make the necessary connections.

    In fact, even though I mentioned the fact I had both CFS + FM and I do have POTS, none of my doctors had a single comment or suggestion. My point? What happens when the patients know more about the disease than the doctors? (I’m serious).

    Somehow all of these great articles you write have to be distilled and translated in a cogent manner to PCPs and a hoard of specialists. It’s great your fine work helps all of us, but now we need to educate doctors with some sort of formal ME / CFS / FM set of “CME” material.

    Otherwise, we have to take these findings and go back to the doctors and question them and prod them, then we get labelled as know-it-all patients who are difficult. Hence, many of us are in a classic catch-22 whereby if we are damned if we say nothing or if we share recent research findings. And worse yet, under our managed care model, we have about 12 – 15 minutes with the doctor and so we’ve hardly enough time to even begin to explain our vast array of medical issues.

    IMO, I feel physician CME on CFS + FM is the answer. The question is – how?

    Again, thanks for another excellent article! I’d love to know what others (and you) think about my CME comments…

    • Cort Johnson

      April 29, 2018 at 4:21 pm - Reply

      I could certainly do put something together. I guess my big concern is whether doctors will listen to something put together by a patient blogger.

      On the other hand something like this is vitally needed and there must be a way.

    • Issie

      April 30, 2018 at 3:48 am - Reply

      I have a lot of years of dealing with POTS, MCAS, FMS and other complicated DXs. I have found that slowly getting new material to a doc is better then handing them a book. (Although, I’ve done that too.) If there are a few pieces of the puzzle I want addressed or tested – I write a bullet paper listing why with reference and then supply reference material. I usually start out with acknowledgment that they are busy and maybe had not seen this new study – I had been researching and would like to either rule in or out and have a list of what and how to test. You may have to leave it with them for review and come back to get labs or test scheduled. But that approach has been very effective. As for new ideas and questions that possibly others have not yet written about or testing hasn’t been connected to something….yet. I present why I think it applies and give science backing as to why. Ask if that could be a piece and can we rule this hypothesis in or out. I’ve gotten many, many of my puzzle pieces this way. But ultimately WE are responsible for our own health and what is done for it. It pays to be diligent and even a little respectfully insistant if we feel it could improve our quality of life. We invite a doctor into “our world”, we trust that he/she intends to become significant in our journey. If that doc isn’t of the same mindset and willing to explore what hasn’t been explored……find another doctor.

      Issie

  • Lorraine

    April 30, 2018 at 5:02 am - Reply

    As always, thanks for your hard work Cort.

    I’m so frustrated by the lack of attention I get when I “complain” of my POTS like symptoms. I have 4 autoimmune disorders already and they are checking me for a 5th.
    I often have to either sit back down after standing or hold onto something so I don’t fall. I also get very fatigued when standing. If I’m standing with a group of people I’m always thinking “I wish I could sit down”.
    I’ve asked to be tested and the doctor took my blood pressure before and after standing and told me that I did not have POTS. No table tilt test, that was it.
    My doctor was a strong supporter, but recently she’s grown weary of me. She has taken to blaming everything on anxiety/depression, my personal favorite.
    Anyway, thanks for this post. That there may be an anti-body component makes me hopeful that when a test for the anti-body profile is available I may finally get my answer.
    I once asked my doctor why she thought I had so many auto-immune diseases. She replied that it wasn’t unusual, that once an immune system becomes “disordered” it continues to create “all kinds of anti-bodies”. Yet I’ve not met a single person who has as many as I do. Anyone out there? Is this common?

    • Issie

      April 30, 2018 at 1:30 pm - Reply

      Well, not sure how common……but we are in the boat together…..so you’re not alone.

      Issie

    • Cort Johnson

      April 30, 2018 at 6:33 pm - Reply

      Very frustrating Lorraine,

      Have you checked out Dysautonomia International’s list of Dysautonomia doctors? I wonder if there’s anyone in your area?

  • Leave a Reply