Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders
Abstract
Postural tachycardia syndrome (POTS) is a disabling condition that commonly affects otherwise normal young females. Because these patients can present with a flushing disorder, we hypothesized that mast cell activation (MCA) can contribute to its pathogenesis. Here we describe POTS patients with MCA (MCA+POTS), diagnosed by episodes of flushing and abnormal increases in urine methylhistamine, and compared them to POTS patients with episodic flushing but normal urine methylhistamine and to normal healthy age-matched female controls. MCA+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse. In addition, patients were disabled by orthostatic intolerance and a characteristic hyperadrenergic response to posture, with orthostatic tachycardia (from 79±4 to 114±6 bpm), increased systolic blood pressure on standing (from 117±5 to 126±7 mm Hg versus no change in POTS controls), increased systolic blood pressure at the end of phase II of the Valsalva maneuver (157±12 versus 117±9 in normal controls and 119±7 mm Hg in POTS; P =0.048), and an exaggerated phase IV blood pressure overshoot (50±10 versus 17±3 mm Hg in normal controls; P <0.05). In conclusion, MCA should be considered in patients with POTS presenting with flushing. These patients often present with a typical hyperadrenergic response, but β-blockers should be used with great caution, if at all, and treatment directed against mast cell mediators may be required.
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Common comorbid conditions seen with POTS include hypermobile Ehlers-Danlos syndrome, mast cell activation syndrome, migraine and ME/CFS.
“Common comorbid conditions seen with POTS4,21 include hypermobile Ehlers–Danlos syndrome, mast cell activation syndrome,22 migraine and ME/CFS (Table 1).18”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [22]
Hyperadrenergic features can include tremulousness, anxiety, migraine and angina-like chest pain.
“Hyperadrenergic features can include tremulousness, anxiety, migraine and angina-like chest pain.22”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [22]
These hyperadrenergic episodes resemble those seen in patients with mast cell activation disorders (MCAD).
“These episodes resemble those seen in patients with mast cell activation disorders (MCAD). Indeed, we have previously reported the association of MCAD and POTS in patients with a hyperadrenergic clinical phenotype responsive to central sympatholytics.12”
From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [12]
Patients with hyperadrenergic POTS tend to have exaggerated pressor responses to the Valsalva maneuver.
“We and others have observed that these patients tend to have exaggerated pressor responses to the Valsalva maneuver (VM),12”
From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [12]
Clinically indistinguishable hyperadrenergic episodes were seen in POTS patients without MCAD and are also seen in patients with pseudopheochromocytoma.
“Clinically indistinguishable hyperadrenergic episodes were seen in POTS patients without MCAD12 and are also seen in patients with pseudopheochromocytoma.34,35”
From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [12]
We previously used methyldopa in the treatment of POTS associated with mast cell activation disorders that have a similar hyperadrenergic phenotype.
“We previously used methyldopa in the treatment of POTS associated with mast cell activation disorders that have a similar hyperadrenergic phenotype.12”
From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [12]
Spontaneous hyperadrenergic episodes with flushing, hypertension, and tachycardia are associated with MCAD in patients with POTS.
“We have previously reported that spontaneous hyperadrenergic episodes with flushing, hypertension, and tachycardia are associated with MCAD in patients with POTS.12”
From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [12]
Treatments that improve symptoms of POTS might decrease the occurrence of syncope.
“Treatments that improve symptoms of POTS might decrease the occurrence of syncope, although this is unknown (24,514–523).”
From 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope (2017) · cites this paper as [515]
An exaggerated sympathetic vasoconstrictor response during the Valsalva maneuver or the presence of orthostatic hypertension may suggest hyperadrenergic POTS.
“An exaggerated sympathetic vasoconstrictor response during the Valsalva maneuver or the presence of orthostatic hypertension may suggest hyperadrenergic POTS (46).”
From Postural Orthostatic Tachycardia Syndrome (2019) · cites this paper as [46]
Patients with MCAD may also demonstrate hyperadrenergic POTS features with testing, such as an exaggerated BP overshoot during recovery after the Valsalva maneuver.
“Patients with MCAD may also demonstrate hyperadrenergic POTS features with testing, such as an exaggerated BP overshoot during recovery after the Valsalva maneuver (46).”
From Postural Orthostatic Tachycardia Syndrome (2019) · cites this paper as [46]
Some patients with MCAD and associated POTS anecdotally responded to H1 and H2 histamine receptor blockers, the sympatholytic alphamethyldopa, or both.
“Some patients with MCAD and associated POTS anecdotally responded to H 1 and H 2 histamine receptor blockers, the sympatholytic alphamethyldopa, or both (46).”
From Postural Orthostatic Tachycardia Syndrome (2019) · cites this paper as [46]
In the same series, beta-blockers triggered episodes of worsening symptoms in several patients.
“Of note, in the same series, beta-blockers triggered episodes of worsening symptoms in several patients and should be used with caution if MCAD is suspected.”
From Postural Orthostatic Tachycardia Syndrome (2019) · cites this paper as [46]
Some POTS patients present with severe flushing in addition to tachycardia and have an associated mast cell activation disorder.
“Some POTS patients present with severe flushing in addition to their tachycardia and have an associated mast cell activation disorder.”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [56]
Many conditions such as mast cell activation disorders, Ehlers-Danlos syndrome, deconditioning, and genetic mutations of norepinephrine transporters coexist with POTS, and their downstream effects funnel into the three principal pathophysiologic mechanisms.
“While many conditions, such as mast cell activation disorders (9), Ehlers-Danlos syndrome (10, 11), deconditioning (12), and genetic mutations of norepinephrine transporters (13), coexist with POTS, their downstream effects also funnel into these three principal pathophysiologic mechanisms.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [9]
Mast cell activation disorders frequently coexist with POTS.
“Mast cell activation disorders are another condition that frequently coexists with POTS (9).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [9]
Some POTS patients may present with flushing and orthostatic intolerance in the absence of mast cell activation disorder.
“Some POTS patients may present with flushing and orthostatic intolerance in the absence of mast cell activation disorder”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Shibao et al., 2005
A subgroup of POTS patients has been reported to present with episodic flushing and comorbid mast cell activation disorder.
“a subgroup of POTS patients has been reported to present with episodic flushing and comorbid mast cell activation disorder”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Shibao et al., 2005
Abnormal sympathetic activation may be related in some POTS patients to abnormal mast cell activation.
“abnormal sympathetic activation may be related in some patients to the abnormal mast cell activation.”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [57]
This mast cell activation POTS subset is characterized by flushing, dyspnoea, headache, excessive diuresis, and gastrointestinal symptoms such as diarrhoea, nausea, and vomiting, with elevated urine methylhistamine.
“This specific subset of POTS is characterized by episodes of flushing, dyspnoea, headache, excessive diuresis and gastrointestinal symptoms such as diarrhoea, nausea and vomiting, accompanied by elevated urine methylhistamine [57].”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [57]
An alternative broader diagnostic scheme can lead to overdiagnosis of mast cell activation syndrome, as described in case reports of POTS and hypermobile Ehlers-Danlos syndrome.
“An alternative broader diagnostic scheme125 can lead to overdiagnosis of mast cell activation syndrome as has been described in case reports of POTS and hypermobile Ehlers-Danlos syndrome.”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [125]
Exercise is an HRS Class IIA indication for POTS but remains a target of study, and its value in IST is unknown.
“Exercise is an HRS Class IIA indication for POTS but remains a target of study49,50,125,170,173; its value in IST is unknown.49,50,125”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [125]
POTS is excessive sinus tachycardia triggered by minimal physical activity, especially movement to upright posture.
“POTS is excessive sinus tachycardia triggered by minimal physical activity, especially movement to upright posture.36,50,125,171”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [125]
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Self-citation
- Authors
- Shibao, C., Arzubiaga, C., Roberts, L. J., Raj, S., Black, B., Harris, P., & Biaggioni, I.
- Affiliations
- Vanderbilt University (US)
- Venue
- Hypertension
- Published
- 2005-03
- Volume
- 45
- Issue
- 3
- Pages
- 385-390
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2158298420
- Cited by
- 220
- References
- 24
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 15 · 2023: 9 · 2022: 18 · 2021: 13 · 2020: 23 · 2019: 9 · 2018: 21 · 2017: 20 · 2016: 10 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 7
- FWCI
- 5.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL67232, R01HL067232, HL56693, P01HL056693)
- National Center for Research Resources
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- postural orthostatic tachycardia syndrome, mast cell activation, flushing, orthostatic intolerance, Valsalva maneuver, beta-blocker therapy, mast cell mediators, pathogenesis
- MeSH terms
- Adrenergic beta-Antagonists, Adult, Autonomic Nervous System, Female, Histamine H1 Antagonists, Histamine H2 Antagonists, Humans, Hypotension, Orthostatic, Mast Cells, Methyldopa, Sympatholytics, Syndrome, Tachycardia, Case-Control Studies
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