Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G-Protein Coupled Receptor Autoantibodies

Abstract

Background The etiology of postural orthostatic tachycardia syndrome (POTS) is yet to be established. The disorder is often misdiagnosed as chronic anxiety or a panic disorder because the autonomic failure in these patients is not severe. A growing body of evidence suggests that POTS may be an autoimmune disorder. Antinuclear antibodies and elevations of ganglionic, adrenergic, and muscarinic acetylcholine receptor antibodies have all been reported. Methods and Results We collected detailed clinical symptoms of 55 patients diagnosed with POTS. We also evaluated serum levels of autoantibodies against 4 subtypes of G-protein coupled adrenergic receptors and 5 subtypes of G-protein coupled muscarinic acetylcholine receptors by ELISA. Our patients had a multitude of comorbidities, were predominantly young females, and reported viral-like symptoms preceding episodes of syncope. We detected a significant number of patients with elevated levels of autoantibodies against the adrenergic alpha 1 receptor (89%) and against the muscarinic acetylcholine M₄ receptor (53%). Surprisingly, elevations of muscarinic receptor autoantibodies appeared to be dependent upon elevation of autoantibodies against the A₁ adrenergic receptor! Four patients had elevations of G-protein coupled autoantibodies against all 9 receptor subtypes measured in our study. Five POTS patients had no elevation of any autoantibody; similarly, controls were also negative for autoantibody elevations. There was a weak correlation of clinical symptom severity with G-protein coupled autoantibodies. Conclusions Our observations provide further evidence that, in most cases, POTS patients have at least 1 elevated G-protein coupled adrenergic autoantibody and, in some instances, both adrenergic and muscarinic autoantibodies, supporting the hypothesis that POTS may be an autoimmune disorder.

Keywords: adrenergic receptor; antibody; autoimmune; hypotension; muscarinic receptor; postural orthostatic tachycardia syndrome; syncope.

Figure 1

Clinical symptoms reported vs concentration of autoantibodies against adrenergic Alpha1. Receptors weak correlations for both adrenergic and muscarinic receptor autoantibodies detected in POTS patients sera was found with the number of clinical symptoms reported. This graph of adrenergic A1 autoantibody concentration vs symptom number serves as an example. AdrR indicates adrenergic receptor; POTS, postural orthostatic tachycardia syndrome.

Figure 2

Elevated autoantibodies against adrenergic receptors in patients diagnosed with postural orthostatic tachycardia syndrome. Autoantibodies against the adrenergic alpha 1 receptor was the most common elevation of detected. Adr‐R indicates adrenergic receptor.

Figure 3

Concentration of autoantibodies against adrenergic receptors in patients diagnosed with postural orthostatic tachycardia syndrome. Adrenergic alpha 1 receptor antibodies had the highest mean concentration in serum for the study group with a mean of 15.5±10.3 units/mL. Some patients had antibodies against all 4 receptor subtypes and some had elevations exceeding the assay maximum concentration cutoff. Five patients had AdrR A₁ antibody values that exceed the chart, and 1 patient each had antibodies >40 units/mL for AdrR A₂ and B₁; no one had antibodies >40 units/mL for B₂; these patient values are graphed in Figure 4.

Figure 4

Patients with extremely elevated autoantibodies. Patients were found to have extreme elevations of multiple autoantibodies detected, some of whom with antibodies against all 9 receptor subtypes. AdrR indicates adrenergic receptor; mAChR, muscarinic acetylcholine receptor.

Figure 5

Elevated autoantibodies against muscarinic cholinergic receptors in patients with postural orthostatic tachycardia syndrome. The most common muscarinic acetylcholine receptor autoantibody was against the M4 subtype.

Figure 6

Concentration of autoantibodies against muscarinic cholinergic receptors in patients with postural orthostatic tachycardia syndrome. The mean concentration of muscarinic acetylcholine receptor autoantibodies was lower than the cut‐off value, except for the M4 subtype with a mean of 11.0±9.3 units/mL. Some patients had autoantibodies against all 5 receptor subtypes that exceeded the maximum cut‐off value. Three patients had mAChR M1 antibody values that exceed the chart, 5 patients had antibodies >40 units/mL for mAChR M2, and 4 patients each had antibodies against mAChR M3, M4, and M5 >40 units/mL; these patient values are graphed in Figure 4.