Antiadrenergic autoimmunity in postural tachycardia syndrome (Fedorowski et al., 2016)

mango

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Antiadrenergic autoimmunity in postural tachycardia syndrome

Artur Fedorowski1,2,*,†, Hongliang Li3, Xichun Yu3, Kristi A. Koelsch3,4, Valerie M. Harris3,4, Campbell Liles3, Taylor A. Murphy3, Syed M.S. Quadri3,4, Robert Hal Scofield3,4, Richard Sutton5, Olle Melander1 and David C. Kem3,†

1 Department of Clinical Sciences, Lund University, Lund, Sweden
2 Department of Cardiology, Skåne University Hospital, Inga Marie Nilssons gata 46, Malmö 20502, Sweden
3 Department of Medicine, University of Oklahoma Health Sciences Center and VA Medical Center, Oklahoma City, OK, USA
4 Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
5 National Heart & Lung Institute, Imperial College, London, UK

Europace (2016) doi: 10.1093/europace/euw154 First published online: October 4, 2016

Abstract
Aims

Postural tachycardia syndrome (POTS), a common and debilitating cardiovascular disorder, is characterized by an exaggerated heart rate increase during orthostasis and a wide spectrum of adrenergic-related symptoms. To determine the aetiology of POTS, we examined a possible pathophysiological role for autoantibodies against α1-adrenergic (α1AR) and β1/2-adrenergic receptors (β1/2AR).

Methods and results
Immunoglobulin G (IgG) derived from 17 POTS patients, 7 with recurrent vasovagal syncope (VVS), and 11 normal controls was analysed for its ability to modulate activity and ligand responsiveness of α1AR and β1/2AR in transfected cells and to alter contractility of isolated rat cremaster arterioles in vitro. Immunoglobulin G activation of α1AR and β1/2AR was significantly higher in POTS compared with VVS and controls in cell-based assays.

Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of α1AR and β1/2AR. Eight of 17 POTS IgG decreased the α1AR responsiveness to phenylephrine and 13 of 17 POTS IgG increased the β1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. Postural tachycardia syndrome IgG contracted rat cremaster arterioles, which was reversed by α1AR blockade. The upright heart rate correlated with IgG-mediated β1AR and α1AR activity but not with β2AR activity.

Conclusion
These data confirm a strong relationship between adrenergic autoantibodies and POTS. They support the concept that allosteric-mediated shifts in the α1AR and β1AR responsiveness are important in the pathophysiology of postural tachycardia.

Key words
Autoimmunity, Postural tachycardia syndrome, Vasovagal syncope, Adrenergic receptors, Allosteric activation

http://europace.oxfordjournals.org/content/early/2016/10/04/europace.euw154.abstract
 

OverTheHills

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OK science brains, how important is this?

Its a small study, and rat receptors may not work the same as human receptors.

How many other researchers have tested POTS patients adrenergic receptors (since they conclude they are confirming others results).

My specialist really wants me to do POTS training exercises and I'm very dubious. He winced when I mentioned Rituximab research.
 

Kati

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OK science brains, how important is this?

Its a small study, and rat receptors may not work the same as human receptors.

How many other researchers have tested POTS patients adrenergic receptors (since they conclude they are confirming others results).

My specialist really wants me to do POTS training exercises and I'm very dubious. He winced when I mentioned Rituximab research.
POTS training exercises? Like what? :bang-head::ill::mad:
 

OverTheHills

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POTS training exercises? Like what? :bang-head::ill::mad:
I'll see if I can find the link to the research - which he has swallowed hook line and sinker - it is POTS not ME/CFS research from one of the big names in the States and if I recall managed to get some POTsers just under the threshold for POTs. So of course they were completely cured then.Not. And all POTSies have ME. Not.

A lot of people call themselves specialists even though they may be dangerously misinformed about the subject.
Yes. I put much more reliance on what I learn here than on his views. Dr Vallings has I think influenced him to finally understand that conventional exercise is bad for ME patients.

PS I managed a multiquote! First time!!!:woot:
 

J.G

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I'll take a stab at it.

From what I can see, this study offers further evidence for a subtype of orthostatic intolerance rooted in autoimmunity. It rhymes with an earlier 2014 study that reported on α1, β1, and β2-receptor autoantibodies in POTS. β2 autoantibodies have been also found elevated in patients with orthostatic hypotension (OH). And there's also a recent Rituximab-related publication pointing to these antibodies.

Loebel et al 2016, comparing pre- and post-Rituximab antibody activity, observed a sharp drop-off in autoantibodies against adrenergic and cholinergic-muscarinic receptors among responders to the drug. A total 29.5% of ME patients included in the trial had pre-treatment elevated levels of β2, M3, M4-receptor antibodies, and from what I understand, normalisation coincided with remission.

Collectively, these findings have me wondering what ailment Rituximab is actually targeting, OI or ME, but they could be good news for those whose ME symptoms stem primarily from OI, i.e. the ME/OI cohort.
 
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Sidereal

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I'll see if I can find the link to the research - which he has swallowed hook line and sinker - it is POTS not ME/CFS research from one of the big names in the States and if I recall managed to get some POTsers just under the threshold for POTs. So of course they were completely cured then.Not. And all POTSies have ME. Not.
Levine protocol? It was thrown at me a few years ago by a supposed POTS expert too, after I had just described spending months practically bedridden and being unable to do my ADLs. Even getting to her office was an ordeal which sent my heart rate to 100, while supine, on a beta blocker! Merely standing up I was well above my anaerobic threshold. "Join the gym and follow the protocol" was the answer. Needless to say I never went back to that "specialist".
 

Sushi

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Levine protocol? It was thrown at me a few years ago by a supposed POTS expert too, after I had just described spending months practically bedridden and being unable to do my ADLs.
If it is Levine, from what I remember the protocol was developed for astronauts who had developed autonomic problems. I've never heard of it being helpful for us lot.
 

J.G

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To elaborate on what I said earlier: to my understanding adrenergic autoimmunity is not specific to POTS. β1 autoantibodies are for instance also found in Graves' Disease even though thyroid autoimmunity defines the illness. I don't know why they should co-occur, but they do.

So up until now, adrenergic autoantibodies have been non-specific, i.e. of themselves not biomarkers of a defined autoimmune disease. I suppose it's for this reason that no hospitals routinely test for them. They are however useful as general indicators that some autoimmune process is present.

However, now that multiple POTS studies are turning up the same autoantibody findings, it's starting to look like the combination of α1, β1 and β2 could be definitive of autoimmune POTS.

Of course many PWME have co-morbid rather than primary POTS. For them, the Graves' Disease autoimmune logic I sketched above might apply, with α1, β1 and β2 defaulting back to evidence for an underlying, yet unidentified autoimmune process (i.e. the process that is ME/CFS).

P.S. I was surprised to find evidence of autoimmunity in ME/CFS dating back to this 2003 article, which looks to me like it should have made waves but somehow didn't.
 
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FMMM1

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I found this thread via the Follow ME in Denmark website (extract below from that site).

I think it would be interesting to have Jonathan Edwards take on this publication.

At the Invest in ME Conference 2016 Dr Jo Cambridge highlighted (from memory) that the known cases in which Rituximab works are autoimmune conditions. I think recently there have been other theories re how Rituximab works in ME CFS.

As stated above by J.G "Collectively, these findings have me wondering what ailment Rituximab is actually targeting, OI or ME, but they could be good news for those whose ME symptoms stem primarily from OI, i.e. the ME/OI cohort".

PS - I didn't figure out how to do quotes.


Extract from Follow ME in Denmark website:

"Find an autoantibody - and read in Wikipedia![/paste:font]

ME / CFS, POTS and MCS are diseases with a high symptom overlap, and perhaps even different pages of the same disease.

ME / CFS is especially characterized by exercise intolerance. POTS is a form of orthostatic intolerance. MCS's reaction to scents during each toxicological threshold.

Has been demonstrated autoantibodies to the adrenergic receptor alfa1AR in POTS patients. It disturbs the functioning of the receptor. (1)

Wikipedia informs that alfa1AR:

  • affects the muscles during exercise.
  • affected by some medicines, then triggered orthostatic hypotension.
  • enhances inhibition of odors system.
Interestingly context!

It is also interesting that ME / CFS patients have genetic variations (SNP 's ) in the genes for alfa1AR, muscarinM3 and TRPC4 receptor. All receptors are both involved in the regulation of blood vessel contraction / expansion and regulation of the inhibition of the olfactory system (2 and 3).

references:
  1. Fedorowski et al: Antiadrenergic aytoimmunity in POTS. doi: 10.1093 / euro pace / EUW 154
  2. Griffith University https://www.griffith.edu.au/health/national-centre-neuroimmunology-emerging-diseases
  3. Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology www.springer.com/series/164 volumen1,222 Editors: Bernd Nilius, Veit Flockerzi."
 

actup

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It is also interesting that ME / CFS patients have genetic variations (SNP 's ) in the genes for alfa1AR, muscarinM3 and TRPC4 receptor. All receptors are both involved in the regulation of blood vessel contraction / expansion and regulation of the inhibition of the olfactory system (2 and 3).
Fascinating information. Fwiw I have OI and olfactory hallucinations.My sister with me/cfs has the same issues( though she has lost her sense of smell after many years of olfactory hallucinations post me/cfs diagnosis). So far treatment with midodrine has decreased the severity of both disorders for me but is short acting and tricky to use.

I continue to have serious PEM after overexertion but less severe episodes than pre- midodrine. Maybe targeted therapies for the above receptors might effect something closer to a cure if we are indeed a subgoup of me/cfs. I can always hope.
 

FMMM1

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I'm glad this was of interest.

I find the lack of a diagnostic test frustrating e.g. if some cases are autoimmune (confirmed by diagnostic test i.e. to a specific auto-antibody) then presumably these would be treated with immuno suppressants.

Angela Vincent's laboratory (Cambridge University) has a track record in autoimmune encephalitis but I'm not sure if they ever got the funding to look at autoimmune antibodies in ME/CFS.

Re Follow ME in Denmark website; I've found some of the articles interesting.
 

Belbyr

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Sorry if I am bumping this up from several months. My recent appointment with another major POTS specialists stated to me that he is seeing this in his studies as well. He thinks we will see some major changes in how we approach POTS and CFS in a year or two... (which he thinks they are the same thing, just presents slightly different in the same way that one lupus patient will present a little different from another lupus patient)