Postural orthostatic tachycardia syndrome (POTS) may be an autoimmune disease

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New research from The University of Toledo College of Medicine and Life Sciences strongly suggests postural orthostatic tachycardia syndrome, or POTS, is an autoimmune disorder and may help pave the way for a simple blood test that could help physicians diagnose the condition.

POTS is characterized by large increases in heart rate and sometimes decreases in blood pressure when standing up.

That can cause lightheadedness, heart palpitations and even loss of consciousness.

In addition to fainting, POTS patients also regularly suffer from a litany of additional symptoms, including fatigue, pain, gastrointestinal issues, bleeding disorders, anxiety and brain fog.

About 3 million Americans are believed to be affected, but because of its wide-ranging and seemingly unrelated symptoms, POTS is notoriously difficult to identify.

“The trouble with diagnosing POTS is that it’s currently principally a clinical diagnosis.

It’s based on history, the absence of other illness as well as the finding of increase in heart rate when standing.

There is no blood test right now to aid in the diagnosis.

It can be an incredibly frustrating process for patients,” said Dr. Blair Grubb, Distinguished University Professor of Medicine and Pediatrics in the UToledo College of Medicine and Life Sciences and director of electrophysiology services at The University of Toledo Medical Center.

In the largest study of POTS patients to date, published Sept. 9 in the Journal of the American Heart Association, Grubb and UToledo research collaborators found 89 percent of patients they examined had elevated levels of autoantibodies against the adrenergic alpha 1 receptor.

“People have suspected an autoimmune connection for years, and other small-scale studies have suggested it,” said Grubb, one of the world’s foremost experts in syncope and disorders of the autonomic nervous system.

“We did a much larger cross-section of patients than has ever been done before, and found that almost all of them tested positive for autoimmune antibodies.

That’s a significant finding.”

None of the 55 patients who participated in the study had another recognized autoimmune disorder. Fifty-two were female, with an average age of 30.

Researchers screened the patients’ blood for autoantibodies against nine receptors.

A handful of patients showed elevated levels against all nine.

But it was the prevalence of adrenergic A1 subtype receptor autoantibodies that make their findings so intriguing.

“I think that we have identified a biomarker. We now might have the ability to diagnosis this, or at least have an inkling.

Like other autoimmune diseases, we can take a blood sample and detect if there are increased levels of autoantibodies present.

According to our results, autoantibodies against this particular receptor should be present in about 90 percent of patients with POTS,” said Dr. William Gunning, a professor of pathology in the UToledo College of Medicine and Life Sciences, and the paper’s lead author.

However, this study adds significantly to the evidence that POTS is an autoimmune disorder.

Gunning and Grubb say much more research is needed. However, this study adds significantly to the evidence that POTS is an autoimmune disorder — and it shows it may be possible to give physicians unfamiliar with the condition an easy way to test for it.

“What this does is prove the concept,” Grubb said.

“Other studies had used very expensive research tests. What we used are the same kind of testing methods that would be used by regular hospitals. We wanted to do something that would potentially be a test applicable to the general population, not just a research test.”

While Gunning and Grubb caution they’re still investigating the precise methods by which POTS is established, their study does raise the possibility that existing immune modulating medications could be a viable therapeutic method for some patients.

Funding: The study was supported by funding from the Dysautonomia Advocacy Foundation, the Life as a Zebra Foundation, and the Virginia Lounsbury Foundation.


Orthostasis and fatigue with autonomic dysfunction frequently occur in autoimmune diseases.1 

Postural orthostatic tachycardia syndrome (POTS) is the most common form of orthostatic intolerance characterized by lightheadedness, presyncope and palpitations, and nonorthostatic symptoms, such as fatigue, abnormalities of sleep, myofascial pain, nausea, and migraine headache.2 

Gastrointestinal (GI) disturbances are common and prolonged in patients with POTS, and it remains unknown whether extravascular volume depletion and deconditioning contribute to POTS in patients with other autonomic symptoms.34 

The pathophysiology of POTS is heterogeneous and includes impaired sympathetically‐mediated vasoconstriction, excessive sympathetic drive, volume dysregulation, and deconditioning.2

An autoimmune basis has been suggested as a causal mechanism of POTS, and several autoreactive IgGs have been identified, including ganglionic acetylcholine receptor (gAChR), voltage‐gated potassium channel complex, cardiac lipid raft‐associated proteins, α1‐adrenergic receptor, as well as β1‐ and β2‐adrenergic receptors.567 

Moreover, Blitshteyn recently determined the high prevalence of positive ANA and other autoantibodies and the high prevalence of comorbid autoimmune disorders that exist in patients with POTS.89 Sandroni and Low demonstrated occasional positivity to gAChR antibodies in POTS patients.10 

Previously, we reported the relationship among the anti‐gAChR antibodies, autonomic dysfunction, and autoimmune rheumatic diseases.111213 We attempted to elucidate the autoimmune pathophysiology of POTS in this study as a part of our comprehensive approach.

Therefore, we assessed the frequency of autonomic dysfunction in the patients with two highly prevalent orthostatic intolerances of POTS and neurally mediated syncope (NMS) using objective clinical indicators.

And, we examined potential immune‐mediation of POTS by evaluating autoantibodies against gAChR, which have been implicated in both POTS and POTS‐associated autonomic dysfunction.

Results

Frequencies of autoantibodies against gAChR in first analysis

Using the LIPS assay, we found that 29% (10 of 34) of patients with POTS were positive for autoantibodies. Specifically, anti‐gAChRα3 antibodies were detected in 8 samples (24%), and anti‐gAChRβ4 antibodies were detected in two samples (6%). Furthermore, no samples from the seropositive patients with POTS were positive for both antibodies. In contrast, we found that only one patient (5%) with NMS was positive for autoantibodies against gAChRα3. The frequencies of gAChRα3 antibodies in patients with POTS were statistically higher than those in patients with NMS (P = 0.041). However, no statistically significant difference was detected in between the POTS group and NMS group on the prevalence of anti‐gAChR antibodies (P = 0.479). In all 73 HC, anti‐gAChRα3 and anti‐gAChRβ4 antibodies were absent, and anti‐gAChRα3 antibodies were detected in the serum of one patient in the OND group, who had suspected amyloid neuropathy (Fig. ​(Fig.11B).

The mean A.I. value for anti‐gAChRα3 antibodies in the POTS group was 0.746, which was significantly greater than those obtained for the HC (0.305) or OND (0.336) groups (P < 0.001). The mean A.I. for anti‐gAChRβ4 antibodies in the POTS group was 0.536, which was also significantly greater than those obtained for the HC (0.367) or OND (0.302) groups (P = 0.007) (Fig. ​(Fig.1B).1B). However, the mean A.I. value for anti‐gAChRα3 antibodies in the NMS group was 0.638, and the mean A.I. for anti‐gAChRβ4 antibodies in the NMS group was 0.421. No statistically significant difference was seen in between the POTS group and NMS group on the mean A.I. for anti‐gAChRα3 and gAChRβ4 antibodies (P = 0.774 and 0.744, respectively).

Clinical assessment of autonomic function in patients with POTS and NMS in first analysis

Table 1 summarizes the clinical characteristics and autonomic symptoms of patients with POTS and NMS. Age and age at onset in the patients with POTS were significantly younger than those in the patients with NMS (P = 0.004 and 0.013, respectively). Antecedent infections were reported in 10 patients (29%) in POTS group, and there was a difference between POTS group and NMS group (P = 0.010). Female was more frequently suffered in POTS group (24 patients, 71%) than in NMS group (7 patients, 37%) (P = 0.018).

Table 1

Clinical features of patients with POTS and NMS

POTSNMSP value
Number of patients3419
Age (year)22.2 ± 10.840.9 ± 23.90.004a
Age at onset (year)19.8 ± 10.838.4 ± 22.90.013a
Sex, female (%)24 (71)7 (37)0.018a
Anti‐gAChRα3 abs (A.I.)0.746 ± 0.5490.638 ± 0.3720.774
Anti‐gAChRβ4 abs (A.I.)0.536 ± 0.6530.421 ± 0.1450.744
Seropostive for anti‐gAChRα3 abs (%)8 (24)1 (5)0.041a
Seropostive for anti‐gAChRβ4 abs (%)2 (6)0 (0)0.479
Onset (%)bAcute, subacute: 8 (24)
Gradual: 26 (76)
Acute, subacute: 5 (26)
Gradual: 14 (74)
0.832
Antecedent infections (%)10 (29)c0 (0)0.010a
Orthostatic intolerance (%)d33 (97)19 (100)0.479
Arrhythmia (%)6 (18)8 (42)0.901
Pupil abnormalities (%)2 (6)0 (0)0.299
Sicca complex (%)13 (38)5 (26)0.639
Coughing episodes (%)1 (3)0 (0)0.479
Heat intolerance and/or anhidrosis (%)14 (41)5 (26)0.289
Upper gastrointestinal tract symptoms (%)e13 (38)4 (21)0.145
Lower gastrointestinal tract symptoms (%)f14 (41)9 (47)0.674
Bladder dysfunction (%)4 (12)2 (11)0.906
Endocrine disorder complications (%)4 (12)g0 (0)0.129
Autoimmune disease complications (%)8 (24)h4 (21)i0.979

aP< 0.05

abs, antibodies.bSubacute onset was defined as the reaching of the peak of autonomic failure within 3 months, and chronic was defined as reaching of the peak after 3 months.c

Mycoplasma pneumonia; four patients of flu‐like symptom (fever, throat, and joint pain); three patients of upper respiratory tract (URT) infection; gastroenteritis; trauma.d

Orthostatic intolerance = orthostatic hypotension and/or palpitation and/or syncope.eUpper gastrointestinal tract symptoms = appetite loss and/or nausea and/or vomiting and/or early satiety and/or postprandial abdominal pain.f

Lower gastrointestinal tract symptoms = constipation and/or diarrhea and/or ileus.g

Four patients of Amenorrhea.h

Three patients of antinuclear antibody positive; two patients of Graves’ disease; Sjögren’s syndrome; allergic bronchitis; rheumatoid arthritis and fibromyalgia.iUlcerative colitis; type I diabetes; Hashimoto’s disease; IgG4‐related disorder.

Clinical assessment of autonomic function in patients with seropositive POTS in second analysis

Table 2 summarizes the clinical characteristics and autonomic symptoms of patients with POTS, according to seroreactivity to anti‐gAChR antibodies. The age in seropositive POTS group was significantly higher than those in seronegative POTS group (P = 0.012). As for the age at onset, similar trend was observed, but we found no statistical significance (P = 0.052).

Antecedent infections were reported in five patients (50%) with seropositive POTS, but there were no differences between seropositive and seronegative patients. For autonomic symptoms, pupil abnormality and lower gastrointestinal tract symptoms were most frequently observed (P = 0.029 and 0.032, respectively). Other autoimmune diseases were more common in anti‐gAChR antibody‐positive patients than in those who were antibody‐negative (P < 0.001).

Three of 10 patients in the group of seropositive POTS were treated with intravenous methylprednisolone (IVMP) and resulted in clinical improvements. In the group of seronegative POTS, four of 24 patients were treated with IVMP. Three patients maintained improvements in OI, however, we found no clinical improvement in one patient.

Table 2

Clinical characteristics of patients with POTS

Patients with POTS Anti‐gAChR Abs positivePatients with POTS Anti‐gAChR Abs negativeP value
Number of patients1024
Age (year)28.5 ± 12.019.5 ± 9.30.012a
Age at onset (year)25.6 ± 12.717.4 ± 9.20.052
Sex, female (%)8 (80)16 (68)0.458
Onset (%)Acute, subacute: 3 (30)
Gradual: 7 (40)
Acute, subacute: 5 (21)
Gradual: 19 (79)
0.589
Antecedent infections (%)5 (50)b5 (21)c0.099
Orthostatic intolerance (%)10 (100)23 (96)0.561
ΔHeart rate (/min)39.8 ± 10.446.8 ± 13.80.084
Arrhythmia (%)1 (10)2 (8)0.917
Pupil abnormalities (%)2 (20)0 (0)0.029a
Sicca complex (%)5 (50)8 (33)0.381
Coughing episodes (%)1 (10)0 (0)0.138
Heat intolerance and/or anhidrosis (%)2 (20)12 (50)0.116
Upper gastrointestinal tract symptoms (%)6 (60)7 (29)0.101
Lower gastrointestinal tract symptoms (%)7 (70)7 (29)0.032a
Bladder dysfunction (%)1 (10)3 (13)0.866
Endocrine disorder complications (%)2 (20)d2 (8)e0.361
Autoimmune disease complications (%)6 (60)f2 (8)g0.001a

aP< 0.05bMycoplasma pneumonia; Three patients of flu‐like symptom (fever, throat, and joint pain); URT infection.cTrauma; gastroenteritis; flu‐like symptom (fever, throat, and joint pain); Two patients of URT infection.dAmenorrhea.eAmenorrhea.fThree patients of antinuclear antibody positive; Graves’ disease; Sjögren’s syndrome; rheumatoid arthritis; and fibromyalgia.gGraves’ disease; allergic bronchitis.


Source:
University of Toledo
Media Contacts:
Tyrel Linkhorn – University of Toledo
Image Source:
The image is in the public domain.

Original Research: Open access
“Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G‐Protein Coupled Receptor Autoantibodies”. William T. GunningIII, Heather Kvale, Paula M. Kramer, Beverly L. Karabin, and Blair P. Grubb.
JAHA: Journal of the American Heart Association doi:10.1161/JAHA.119.013602

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