Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome
Open accessAbstract
Background— Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance notable for an excessive increase in heart rate that occurs on standing. Many current therapeutic strategies focus on sympatholysis, but the alternative strategy of enhancing cardiovagal tone has not been studied. The objective of this study was to test the hypothesis that acetylcholinesterase inhibitors will attenuate the tachycardia and improve symptom burden in patients with POTS. Methods and Results— Seventeen patients with POTS underwent acute drug trials of pyridostigmine 30 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressures, heart rate, and symptoms were assessed while patients were seated and after they had been standing for up to 10 minutes both before the study drug was given and at 2 and 4 hours after study drug. The heart rate was significantly lower at 2 hours after pyridostigmine than after placebo (100±16 versus 111±14 bpm, P =0.001). Pyridostigmine significantly decreased the standing heart rate from baseline (119±16 bpm) at 2 hours (104±16 bpm, P <0.001) and 4 hours (100±16 bpm, P <0.001) after administration. There was no significant change in blood pressure. The decrease in symptom burden within 4 hours after study drug was significantly greater with pyridostigmine than placebo (−10.4±14.0 AU versus 0.6±7.5 AU, P <0.025). Conclusions— Acute acetylcholinesterase inhibition significantly attenuated tachycardia in POTS. There was also an improvement in symptom burden with this promising therapy.
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Pyridostigmine blunts orthostatic tachycardia and can improve chronic symptoms, but it is limited by adverse effects including diarrhea, abdominal pain or cramps, nausea, and increased urinary urgency and frequency.
“The drug blunts orthostatic tachycardia and can improve chronic symptoms but is limited by adverse effects such as diarrhea, abdominal pain and cramps, nausea, and increased urinary urgency and frequency.45,46”
From 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope (2015) · cites this paper as [45]
The Pyridostigmine Hemodynamics and Symptoms sections report reduced standing heart rate and improved symptom burden over four hours. Study Limitations says long-term efficacy and tolerability are unknown and identifies only increased gastrointestinal motility as a possible limiting side effect; it does not document sustained symptom improvement or the listed adverse effects. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPyridostigmine (30-60 mg orally 3 times daily) can acutely decrease upright heart rate in patients with POTS.
“A 2005 study found that pyridostigmine (30–60 mg, given orally 3 times daily) can acutely decrease upright heart rate in patients with POTS;48”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [48]
The Drug Trials section reports a single oral 30 mg dose of pyridostigmine, and the Pyridostigmine Hemodynamics section reports a significant decrease in standing heart rate at 2 hours compared with placebo. The study does not establish the claimed 30–60 mg three-times-daily regimen or test the acute effect of a 60 mg dose. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThree experimental proof-of-concept trials of Desmopressin, Pyridostigmine, and Propranolol (low dose more than high dose and high dose more than placebo) were effective in reducing symptom burden compared to placebo or high dose controls after 4 h tilt test.
“Three of these experimental proof-of-concept trials, of Desmopressin, Pyridostigmine, and Propranolol (low dose more than high dose and high dose more than placebo) were effective in reducing symptom burden compared to placebo or high dose controls after 4 h tilt test.”
From Self-reported symptom burden in postural orthostatic tachycardia syndrome (POTS): A narrative review of observational and interventional studies (2023) · cites this paper as Raj et al., 2005
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe Vanderbilt POTS Symptom Score had been used before by the authors' center, and its items were selected because they reflect common POTS complaints.
“This symptom score has been previously used by our center 6 and the symptoms were chosen as they reflect common complaints of patients with POTS.”
From Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More (2009) · cites this paper as [6]
Many POTS patients have increased sympathetic nervous system tone, measured by direct nerve recordings or elevated standing plasma norepinephrine.
“Many patients with POTS have increased sympathetic nervous system tone measured with direct nerve recordings 5 or biochemically with an elevated plasma norepinephrine on standing 6–8.”
From Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More (2009) · cites this paper as [6]
Pyridostigmine can increase parasympathetic autonomic tone and has a lower risk of hypertension compared with other medications.
“Pyridostigmine (a cholinergic agonist that works by inhibiting acetylcholinesterase) 30 to 60 mg 3 times a day can increase parasympathetic autonomic tone (107,108) and has a lower risk of hypertension compared with other medications.”
From Postural Orthostatic Tachycardia Syndrome (2019) · cites this paper as [107]
Pyridostigmine can reduce heart rate in POTS.
“Increasing parasympathetic tone with pyridostigmine can also curtail HR in POTS [65] (HRS Class IIb) [8].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [65]
In the same study, supine and upright blood pressures were no different between the pyridostigmine group and the placebo group.
“Supine and upright blood pressures were no different between the group that received pyridostigmine and the placebo group.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [80]
In a study of 17 POTS patients, symptoms and standing heart rate were significantly reduced after pyridostigmine administration versus placebo in the acute setting.
“In a study of 17 POTS patients, symptoms and standing heart rate were significantly reduced after pyridostigmine administration versus placebo in the acute setting (80).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [80]
Pyridostigmine is an acetylcholinesterase inhibitor.
“Acetylcholinesterase inhibitor.”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [99]
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Autonomic Dysfunction in Cardiology: Pathophysiology, Investigation, and Management
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Pyridostigmine in the Treatment of Orthostatic Intolerance
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Confounders of Vasovagal Syncope
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Clinical challenges in the diagnosis and management of postural tachycardia syndrome
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Self-citationDiagnosis and management of postural orthostatic tachycardia syndrome: A brief review
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The Value of Acetylcholine Receptor Antibody in Children with Postural Tachycardia Syndrome
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Self-citationEvaluating and managing postural tachycardia syndrome
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Self-citationConfounders of Vasovagal Syncope
Nwazue, V. C., & Raj, S. R. (2013) · Cardiology Clinics · doi:10.1016/j.ccl.2012.09.004 · Cited by 23 · see citing works
Self-citationPostural orthostatic tachycardia syndrome and migraine: A narrative review
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Moving from the present to the future of Postural Tachycardia Syndrome – What we need
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Self-citation2020 Clinical practice guidelines for Supraventricular tachycardia in adults
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Autonomic Manifestations of Long-COVID Syndrome
Hira, R., Karalasingham, K., Baker, J. R., & Raj, S. R. (2023) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-023-01320-z · Cited by 22 · see citing works
Self-citationManagement of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia and Vasovagal Syncope
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“, 2014), increasing parasympathetic nervous system activity (and therefore decreasing HR) and enhancing cardiovagal tone (Pyridostigmine) (Raj et al., 2005; Moon et al., 2018), increasing blood volume/pressure Table 5c Orthostatic Baseline scores.”
InfluentialPostural Orthostatic Tachycardia Syndrome: A State-of-the-Art Review
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Evaluation and Management of Autonomic Nervous System Disorders
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Glucose Reduces the Effect of Water to Promote Orthostatic Tolerance
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Postural Orthostatic Tachycardia Syndrome (POTS)
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Postural orthostatic tachycardia syndrome: an underrecognized disorder
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Postural orthostatic tachycardia syndrome: Diagnosis and treatment
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Isolated Sympathetic Failure With Autoimmune Autonomic Ganglionopathy
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Enhanced Cholinergic Activity Improves Cerebral Blood Flow during Orthostatic Stress
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Recognizing postural orthostatic tachycardia syndrome
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- Authors
- Raj, S. R., Black, B. K., Biaggioni, I., Harris, P. A., & Robertson, D.
- Affiliations
- Vanderbilt University (US)
- Venue
- Circulation
- Published
- 2005-05-31
- Volume
- 111
- Issue
- 21
- Pages
- 2734-2740
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2119590578
- Semantic Scholar
- ea9f143f5988a05a320e77ea7e1b2ae553870d10
- Cited by
- 171
- References
- 25
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 6 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 11 · 2013: 13 · 2012: 10
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University (M01 RR00095)
- Deutsches Krebsforschungszentrum
- National Institutes of Health
- National Heart, Lung, and Blood Institute (2P01-HL-56693, P01HL056693)
- National Center for Research Resources (M01RR000095, M01-RR-00095, K23RR020783)
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- postural orthostatic tachycardia syndrome, acetylcholinesterase inhibitors, pyridostigmine, orthostatic intolerance, heart rate, symptom burden, drug trials
- MeSH terms
- Adult, Blood Pressure, Cholinesterase Inhibitors, Female, Heart Rate, Humans, Male, Middle Aged, Posture, Pyridostigmine Bromide, Tachycardia, Cross-Over Studies
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