Autoimmune Basis for Postural Tachycardia Syndrome

Abstract

BackgroundPatients with postural tachycardia syndrome (POTS) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS. We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors (AR).Methods and ResultsFourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P<0.001) when coexisting β2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased β1AR activation (130±3% of baseline, P<0.01) and a subset had increased β2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells.ConclusionsPOTS patients have elevated α1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1AR for vasoconstriction and concurrent βAR‐mediated tachycardia. Coexisting β1AR and β2AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.

Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

“…AT1R‐AAb produced in a rabbit model attenuated the Ang II–induced vasoconstriction10 and may lead to an impaired vascular response, similar to that induced by α1AR‐AAb 6, 7. In the present study, the minimal BP during passive orthostatic challenge was significantly lower in AT1R‐AAb–positive patients with POTS compared with AT1R‐AAb–negative patients with POTS.…”

“…In the pilot study, remaining sera from 6 subjects with POTS previously submitted from Vanderbilt University6 were tested for α1AR and AT1R autoantibody‐mediated contractile activity using an isolated rat cremaster arteriole assay. After the α1AR blocker prazosin was added, residual contractility in 4 subjects was suppressed by addition of the AT1R blocker losartan.…”

“…Sera from 6 subjects with POTS in our original article6 from Vanderbilt University (Nashville, TN) were screened for the presence of AT1R‐AAbs. These studies had been approved by the Vanderbilt University Institutional Review Board.…”

“…The syndrome affects predominantly young women (70–80%), but its cause has not been established 3, 4, 5. In 2014, our laboratory demonstrated that a marked relationship of activating autoantibodies (AAbs) to the α1‐adrenergic (α1AR) and β1/2‐adrenergic (β1/2AR) receptors existed in 14 of 14 such patients 6. A second confirmatory report demonstrated a similar AAb pattern in most of 17 additional patients with POTS; data were collected independently in Sweden and assayed in blinded manner in the same laboratory as before but using modified assay techniques for the α1AR‐AAb 7.…”

“…A second confirmatory report demonstrated a similar AAb pattern in most of 17 additional patients with POTS; data were collected independently in Sweden and assayed in blinded manner in the same laboratory as before but using modified assay techniques for the α1AR‐AAb 7. We previously demonstrated that α1AR‐AAbs possess the orthosteric ability to directly activate the target receptor; however, they also produce an allosteric inhibition of α1AR, resulting in a net inhibitory effect on receptor responsiveness to its orthosteric ligand phenylephrine in rat resistance cremaster arteries 6. In contrast, there was an AAb‐mediated allosteric facilitation of β1/2AR responsiveness to the βAR agonist isoproterenol in transfected cells.…”