Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome (2018) Yu et al

[Milo]

Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

Authors:Xichun Yu, Hongliang Li, Taylor A. Murphy, Zachary Nuss, Jonathan Liles, Campbell Liles, Christopher E. Aston, Satish R. Raj, Artur Fedorowski, David C. Kem
(from Oklahoma, Sweden and Calgary)

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

Clinical Perspective
What Is New?

-Activating autoantibodies to the posture‐related angiotensin II type 1 receptor were present in a cohort with postural orthostatic tachycardia syndrome.

-Angiotensin II type 1 receptor–activating autoantibodies had a negative allosteric effect on angiotensin II action.

• What Are the Clinical Implications?
  • These data support previous reports for an impaired responsiveness to angiotensin II in postural orthostatic tachycardia syndrome and a rationale for the beneficial impact of salt loading on blood pressure and pulse responsiveness in postural orthostatic tachycardia syndrome.
    
    
  • Pharmacological or physiological suppression of relevant autoantibodies may have a therapeutic benefit in postural orthostatic tachycardia syndrome

Link to paper (open access) : http://jaha.ahajournals.org/content/7/8/e008351

 

[Milo]

As an aside note, I wasn’t sure where to put this paper. While this is not ME research, POTS is a very significant comorbidity which in my opinion deserves being posted alongside with ME related research. This is an important paper.

 

[adreno]

Where do these shitty antibodies come from? And why?

 

[Milo]

Where do these shitty antibodies come from? And why?

Auto-immunity is still a scientific mystery, but psychiatrists and psychologizers would say ‘child abuse’.
In this case with this paper, we have a potential to better treatments for POTS, however this is a small sample size. I wonder if a commercial test will follow.

 

[Milo]

Here is an interesting bit:

Although the identified AT1R‐AAbs have demonstrated in vitro activity, it will be important to establish their relevance in vivo in animal models and eventually in human subjects who harbor these suspect antibodies. Ultimately, successful removal or inactivation of the antibodies and concurrent improvement of their signs and symptoms will be needed to conclusively document their role in POTS. The marked presence of either or both AT1R‐AAbs and α1AR‐AAbs in concordance with β1/2AR‐AAbs provides a rational framework to support an autoimmune pathophysiological condition in POTS. This concept, if validated, will provide the basis for development of novel therapeutic approaches against POTS based on immunotherapy.

These data support an autoimmune relationship to the cardiovascular components of POTS. This relationship may also relate to other manifestations of this otherwise perplexing disease. Because POTS has several presentations that are similar to those observed in chronic fatigue syndrome, in several other autonomic dyscrasias, and even with some people with otherwise unexplained protean diseases, it is important that the clinician who cares for these patients be aware of possible relationships that may exist and provide important clues in our future understanding of their pathophysiological characteristics.

These data are of interest because they demonstrate that activating autoantibodies may present with differing and opposing effects on a given receptor complex. They, therefore, provide an enigma requiring the observer to determine which or whether both effects are operative. The absence of applicable animal models is also a roadblock to such studies. It appears likely that final resolution of the autoantibodies’ relative importance to the pathophysiological characteristics will depend on our ability to remove the antibodies from limited animal models and, eventually, patients with POTS and to determine whether they will permit a return to normal homeostasis

(Bolding mine)

 

[adreno]

In this case with this paper, we have a potential to better treatments for POTS

Immunoglobulin?

 

[adreno]

@Gingergrrl you have some experience with POTS, antobodies and immunoglobulin?

 

[Milo]

Immunoglobulin?

No, they mentioned Losartan. Angiotensin 1receptor blockers.

 

[Gingergrrl]

@Gingergrrl you have some experience with POTS, antobodies and immunoglobulin?

I think you meant "autoantibodies" (autoimmunity) and if so, then yes, I have experience with POTS, many different autoantibodies, high dose IVIG, and also Rituximab. I have a very long thread about it all on the other board (it's close to 40 pages now but goes off topic several times... and then back on track)!

I am happy to answer any questions re: my personal experience if it would be helpful. I am very interested in testing for the autoantibody in this study (Angiotensin II Type 1 Receptor) through Cell Trend in Germany but I have not done it yet. My doctor is open to me trying Losartan regardless (if I wanted to) but since Atenolol works well for me for POTS, I would not want to make any changes right now unless I had confirmation of the AT1R auto-antibody first. I'll be discussing it with my doctor further in my next phone consult in a couple weeks.

 

[Gingergrrl]

I wonder if a commercial test will follow.

There is now a commercial test for this autoantibody through Cell Trend in Germany. To my knowledge you cannot test for this autoantibody in the United States.

Immunoglobulin?

IVIG is now being used by many doctors for POTS in cases like mine in which they suspect the patient has Autoimmune POTS vs. another sub-type.

No, they mentioned Losartan. Angiotensin 1receptor blockers.

The treatment that is being mentioned for this new AT1R autoantibody is Losartan. If I have this autoantibody, I am open to trying it as I mentioned above but would not try it at present without this confirmation.