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Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome, 2018, Yu et. al.

voner

Senior Member
Messages
592
Abstract
BACKGROUND:
Both the adrenergic and renin-angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome (POTS). Activating autoantibodies to the α1-adrenergic and β1/2-adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor (AT1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT1R autoantibodies in POTS.

METHODS AND RESULTS:
Serum immunoglobulin G from 17 patients with POTS, 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT1R and alter AT1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT1R antibody activity in immunoglobulin G purified from their serum. No significant AT1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT1R activation by POTS immunoglobulin G was specifically blocked by the AT1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT1R and α1-adrenergic receptor.

CONCLUSIONS:
Most patients with POTS harbor AT1R antibody activity. This supports the concept that AT1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS.

https://www.ncbi.nlm.nih.gov/pubmed/29618472

other authors include Dr. Satish Raj and Dr. Kem. Seems like a significant finding.
 

Gingergrrl

Senior Member
Messages
16,171
@voner Thanks for sending me this and for posting it here. Are there labs (outside of research studies) that test POTS patients for this angiotensin II autoantibody (AT1R)? I assume if someone had it, this would also be classified as "Autoimmune POTS" (like me who has the alpha & beta adrenergic autoantibodies, etc).

It seems very significant and I know Dr. Kem is trying to solve the mystery behind POTS. I tried to contact him once but got no reply. Would the treatment be autoimmune like high dose IVIG, etc?
 

voner

Senior Member
Messages
592
@Gingergrrl,

I don’t know the answers to those questions. I doubt there’s any commercial lab that contest for these antibodies yet. Consider forwarding that paper onto your docs and see how they respond. Satish Raj used to be at Vanderbilt – who has a well published dysautonomia faculty. I hope someone else will comment.
 

Malea

Senior Member
Messages
260
This study was shared some days ago in a german group on facebook, so I already had a look which lab would test these antibodies. I have found one here in Germany, its called "Labor Berlin".

Unfortunately you can't just send your blood there but you will need a (I suspect german) doctor who will do that for you.

So thats maybe just an option for german folks with cooperating doctors.

Celltrend is testing Angiotensin autoantibodies, too. But its the wrong type.
 
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Gingergrrl

Senior Member
Messages
16,171
I don’t know the answers to those questions. I doubt there’s any commercial lab that contest for these antibodies yet.

Thank you @voner and I just replied to your PM.

This study was shared some days ago in a german group on facebook, so I already had a look which lab would test these antibodies. I have found one here in Germany, its called "Labor Berlin". Unfortunately you can't just send your blood there but you will need a (I suspect german) doctor who will do that for you.

I suspect it is just a German lab and from my research the labs in Germany are much more advanced than other countries re: testing for autoantibodies and in some other medical procedures.

Celltrend is testing Angiotensin autoantibodies, too. But its the wrong type.

Is that a new test that Cell Trend recently added? When I did the Cell Trend testing, they offered nine different autoantibody tests and I did all nine. Do you know if the angiotensin autoantibodies is something new? Also, when you said it is the "wrong type" does that mean it is not the one from @voner's article that potentially correlates with POTS?
 

Gingergrrl

Senior Member
Messages
16,171
And, if one had these antibodies, what would the treatment be?

I wondered that too @Learner1 (and we are posting in all of the same threads today :hug:). Someone mentioned that it might be "losartan" but I have not had a chance to Google this yet and see what it is. Since I do not know if I have this autoantibody, I would not try it but was curious, like you, what the proposed treatment might be. It sounds like this is all at the experimental stage though.

I would assume all of the meds to stop tachycardia are for symptom relief vs. something like IVIG can get to the root cause (if you have Autoimmune POTS vs. another kind of POTS). I would love to speed up the research on all of this but I know it is a slow and arduous process.
 

voner

Senior Member
Messages
592
well.... take a look at this case (n=1) study paper...

Postural orthostatic tachycardia syndrome: a dermatologic perspective and successful treatment with losartan.
Landero J1.
Author information

Abstract
The postural orthostatic tachycardia syndrome is a disease characterized by excessively increased heart rate during orthostatic challenge associated with symptoms of orthostatic intolerance including dizziness, exercise intolerance, headache, fatigue, memory problems, nausea, blurred vision, pallor, and sweating, which improve with recumbence. Postural orthostatic tachycardia syndrome patients may present with a multitude of additional symptoms that are attributable to vascular vasoconstriction. Observed signs and symptoms in a patient with postural orthostatic tachycardia syndrome include tachycardia at rest, exaggerated heart rate increase with upright position and exercise, crushing chest pain, tremor, syncope, loss of vision, confusion, migraines, fatigue, heat intolerance, parasthesia, dysesthesia, allodynia, altered traditional senses, and thermoregulatory abnormalities. There are a number of possible dermatological manifestations of postural orthostatic tachycardia syndrome easily explained by its recently discovered pathophysiology. The author reports the case of a 22-year-old woman with moderate-to-severe postural orthostatic tachycardia syndrome with numerous dermatological manifestations attributable to the disease process. The cutaneous manifestations observed in this patient are diverse and most noticeable during postural orthostatic tachycardia syndrome flares. The most distinct are evanescent, hyperemic, sharply demarcated, irregular patches on the chest and neck area that resolve upon diascopy. This distinct "evanescent hyperemia" disappears spontaneously after seconds to minutes and reappears unexpectedly. Other observed dermatological manifestations of this systemic disease include Raynaud's phenomenon, koilonychia, onychodystrophy, madarosis, dysesthesia, allodynia, telogen effluvium, increased capillary refill time, and livedo reticularis. The treatment of this disease poses a great challenge. The author reports the unprecedented use of an oral angiotensin II type 1 receptor antagonist resulting in remarkable improvement.


full paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142820/pdf/jcad_7_8_41.pdf

pretty interesting. Losartan extended her exercise tolerance also.
 

voner

Senior Member
Messages
592
...and losartan significantly decreased her allodynia. That’s almost unheard of.
 

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Gingergrrl

Senior Member
Messages
16,171
@voner Wow, thanks for finding this stuff and I am definitely going to read the study and research Losartan. I Googled Losartan and POTS and a lot of stuff came up. I have some reading to do and don't know enough about this to even comment yet.

In 5+ years, I have been recommended just about every med on the planet for POTS by different docs but no one has ever even mentioned Losartan! Is this a new medication?
 

voner

Senior Member
Messages
592
and!!

Dr. Julian Stewart has completed a double-blind clinical trial study on young POTS patients using losartan, but I could not find any publication about the study. Perhaps he has not published yet?

https://clinicaltrials.gov/ct2/show/NCT01210430

Brief Summary:
The investigators study will determine how often blood flow regulation abnormalities and abnormalities of sympathetic regulation produced by nitric oxide, angiotensin-II, and oxidative stress occur in POTS and the mechanism(s) of POTS in individual patients. Specific causes for POTS may vary from patient to patient. Patients will be compared to healthy control subjects. There is a treatment arm with a medication (losartan) that reduces the binding of angiotensin and increases NO. If the investigators know the specific biochemical mechanism the investigators may be able to offer further specific treatments to specific patients.

Condition or disease Intervention/treatment Phase
Postural Tachycardia Syndrome Drug: LosartanDrug: Ascorbic Acid (Vitamin C)Drug: Normal Saline Early Phase 1

Detailed Description:
Chronic orthostatic intolerance due to the postural tachycardia syndrome (POTS) severely impairs daily life in over a million Americans, mostly young women. POTS is defined by symptoms of orthostatic intolerance associated with excessive upright heart rate. While there is general agreement that abnormalities in vascular regulation and autonomic activity account for the tachycardia and symptoms of POTS, its pathophysiology is heterogeneous and only partially characterized.

The key feature of POTS is symptoms which are most prominent when standing. However, in some, findings are present supine (lying down) but worsened standing. Symptoms of POTS include dizziness in all patients, exercise provoked symptoms and thus exercise intolerance, excessive fatigue, nausea and abdominal pain, headache, shortness of breath and deep breathing, weakness, shakiness and postural anxiety, pallor, and neurocognitive loss (difficulty thinking). These occur on a day-to-day basis. The symptoms overlap with the case definition of chronic fatigue syndrome (CFS) and POTS is often found in CFS in the young. Fainting is relatively uncommon during daily life.

A major subset of POTS has increased peripheral resistance and low blood flow(LFP) related to increased angiotensin-II (Ang-II), and decreased nitric oxide (NO). NO deficits are reversed by Ang-II type-1 receptor (AT1R) blockade, ascorbic acid (AA) and tetrahydrobiopterin in skin suggesting the importance of oxidative stress. Preliminary data also suggest that the coupling of sympathetic nerve activity to blood vessel contraction is enhanced via ↑Ang-II and ↓NO. We hypothesize that this is due to activation of reactive oxygen species (ROS) including superoxide, which scavenges NO to generate peroxynitrite, and hydrogen peroxide. Combined measurements in the skin and the systemic circulation will be combined with local measurement of ROS production and sympathetic nerve activity will enable us to determine precisely how the autonomic nervous system is affected by the illness. Methods include cutaneous microdialysis to measure ROS, skin biopsy and blood tests to measure gene expression of nitric oxide synthase and Ang-II receptors, and peroneal microneurography to measure muscle sympathetic nerve activity (MSNA). Combined with ultrasonic femoral artery blood flow this will yield assessment of the interactions of nerves with the blood vessels that they control.

If we discover specific biochemical mechanisms of POTS in patients, then we may be able to specifically treat the defect.


can anybody find this study published or any other info about it?
 

voner

Senior Member
Messages
592
@voner Wow, thanks for finding this stuff and I am definitely going to read the study and research Losartan. I Googled Losartan and POTS and a lot of stuff came up. I have some reading to do and don't know enough about this to even comment yet.

In 5+ years, I have been recommended just about every med on the planet for POTS by different docs but no one has ever even mentioned Losartan! Is this a new medication?


Wikipedia says it’s a little over 20 years old and it’s inexpensive.
 

Gingergrrl

Senior Member
Messages
16,171
Wikipedia says it’s a little over 20 years old and it’s inexpensive.

Wow, that is so bizarre! I just printed out your study (from post #8) to read later. I don't know enough to comment yet but am fascinated b/c I thought I had heard of every POTS med & treatment that existed (beta blockers, CA+ Channel blockers, Midodrine, Droxidopa, Mestinon, IV saline, Salt tablets, etc).

The treatment that's finally helped me to move past my (limited) improvement with Atenolol & Midodrine is IVIG. But I can still trigger an episode if I do certain movements and can still only walk short distances. I don't want to get too excited yet b/c there may be a reason that I cannot tolerate this med or it is contra-indicated for me. Will read up first and be back later. Thx again!
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
So, after trying olmesartan and then telmisartan for over a year, I finally decided they were doing nothing to reduce my blood pressure which runs high, or POTS.

My POTS is doing better with a combo of pyridostigmine and propranolol, while the propranolol is helping my BP.
 

Malea

Senior Member
Messages
260
I suspect it is just a German lab and from my research the labs in Germany are much more advanced than other countries re: testing for autoantibodies and in some other medical procedures.



Is that a new test that Cell Trend recently added? When I did the Cell Trend testing, they offered nine different autoantibody tests and I did all nine. Do you know if the angiotensin autoantibodies is something new? Also, when you said it is the "wrong type" does that mean it is not the one from @voner's article that potentially correlates with POTS?

I don‘t want to get too excited yet... but I googled again for the Angiotensin-Autoantibodies at Celltrend and found they seem to not only test the wrong type (by which I meant the TYpe 2 not the Type 1 which was used in the study) but also the Angiotensin II Receptor 1 autoantibodies. Which should be the „right“ type.

It‘s in german, unfortunately:
http://www.celltrend.de/g-gekoppelte-rezeptor-auto-antikoerper-elisa.html
http://www.celltrend.de/tl_files/inhalte/dateien/Produktinfo dt/AT1-AA Produktinfo dt-2012-06.pdf

I have no idea if it is something new at celltrend, because I‘m very new to this whole autoantibody-topic. But the „product information“ (link number 2) says that this autoantibody test is used to find out if a transplant is accepted (that might the wrong word) by a body and also in testing for scleroderma. So maybe it is not totally new.


Oh and I really have to remind myself of that we have advanced labs here in Germany and that it is quite a lucky situation. I often feel dismissed as a patient when you just can‘t get things tested but need a doctor who agrees that you get stuff tested. But not all labs are doing it like that and I feel like things are getting a little more patient-friendlier.
 
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Gingergrrl

Senior Member
Messages
16,171
So, after trying olmesartan and then telmisartan for over a year, I finally decided they were doing nothing to reduce my blood pressure which runs high, or POTS

I never got a chance to read the Losartan study from Voner but printed it out to read hopefully over the weekend. I'm not expecting any miracle cure for Autoimmune POTS but am curious to see what it says.

I don‘t want to get too excited yet... but I googled again for the Angiotensin-Autoantibodies at Celltrend and found they seem to not only test the wrong type (by which I meant the TYpe 2 not the Type 1 which was used in the study) but also the Angiotensin II Receptor 1 autoantibodies. Which should be the „right“ type.

Thanks for explaining that @Malea and it sounds like Cell Trend does not test for the autoantibodies in the study (so for now I guess they are only tested within a research study and not a commercial lab which is what I'd suspected).

Oh and I really have to remind myself of that we have advanced labs here in Germany and that it is quite a lucky situation. I often feel dismissed as a patient when you just can‘t get things tested but need a doctor who agrees that you get stuff tested. But not all labs are doing it like that and I feel like things are getting a little more patient-friendlier.

You definitely have lab tests and procedures that are not yet available in the US. In 2014, my doctor had wondered if I had a prior viral infection of the heart (like myocarditis) but said the only definitive test is a heart biopsy and that they are only done in Germany and not the US. I was not going to do one anyway but thought it was interesting that Germany was so much more advanced and open-minded (medically) than we are here. The autoantibody research that most interests me is also from Germany. But I know access to care is a separate issue from lab tests and research, etc.
 

Malea

Senior Member
Messages
260
Sorry @Gingergrrl, I'm not good in explaining what I mean because of the language barrier.

I googled again after you've asked about Celltrend. And I think they are also testing the antibodies from the study.
 

Gingergrrl

Senior Member
Messages
16,171
Sorry @Gingergrrl, I'm not good in explaining what I mean because of the language barrier. I googled again after you've asked about Celltrend. And I think they are also testing the antibodies from the study.

Thanks and I think I misunderstood your prior post (and your English is excellent)! So, Cell Trend actually does test the autoantibody from that study? Now I am confusing myself, and still have not read the study, but I think the one we are talking about is the "Angiotensin II, Type 1 Receptor Autoantibody" or (AT1R)? I don't think this test was available when I did the nine Cell Trend autoantibody tests in 2016, but maybe it was and I just did not know it?
 

Malea

Senior Member
Messages
260
Yes, they're testing the AngiotensinII Recpt1-autoantibody. :) I don't know if its a new test.

The price is 27 Euro.

(If they still have my blood from the POTS-Panel last month, which they weren't sure about when I called, I will have the antibody tested.)
 

Sushi

Moderation Resource Albuquerque
Messages
19,935
Location
Albuquerque
Satish Raj used to be at Vanderbilt – who has a well published dysautonomia faculty.
As I remember, Vanderbilt tested for this but probably only on patients in their Autonomic clinic--might be worth checking though.
I thought I had heard of every POTS med & treatment that existed (beta blockers, CA+ Channel blockers, Midodrine, Droxidopa, Mestinon, IV saline, Salt tablets, etc).
A major subset of POTS has increased peripheral resistance and low blood flow(LFP) related to increased angiotensin-II (Ang-II), and decreased nitric oxide (NO). NO deficits are reversed by Ang-II type-1 receptor (AT1R) blockade, ascorbic acid (AA) and tetrahydrobiopterin in skin suggesting the importance of oxidative stress.
Here is an important point: there are a number of causes for POTS and while decreased NO is an important subset, it is probably not true for the majority. (increasing NO is Julian Stewart's usual treatment choice). If you increase NO, you increase vasodilation. The majority of POTS patients seem to respond better to vasoconstriction (hence Midodrine works). So it looks like testing is very important to determine treatment. For instance, testing showed that I was low in norepinephrine in the synapses. This is also a subset but not the majority. So I responded extremely well to Strattera, a norepinephrine reuptake inhibitor.