Simmaron Research blog post, by Cort Johnson, 28 April 2018: POTS Rising! Research & Advocacy Producing Breakthroughs in Neglected Disease

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.

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.

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

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.

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 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.

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.

Check out Lauren’s remarkable story  – From Chronic Fatigue Syndrome to Fibromyalgia To POTS To Success: One Woman’s Journey Through the Medical Profession

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.