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Cited by 225Cardiovascular Syncope and Autonomic DisordersHeart Rate Variability and Autonomic ControlLong-Term Effects of COVID-19

Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More

Open access
Raj, Satish R., Black, Bonnie K., Biaggioni, Italo, Paranjape, Sachin Y., Ramirez, Maricelle, Dupont, William D., Robertson, David·2009·Circulation
DOI 10.1161/circulationaha.108.846501PMC PMC2758650
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Abstract

Background— Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate on standing. β-Blockade is an appealing treatment approach, but conflicting preliminary reports are conflicting. We tested the hypothesis that propranolol will attenuate the tachycardia and improve symptom burden in patients with POTS. In protocol 1, a low dose (20 mg) was compared with placebo, and the dose response was assessed in protocol 2. Methods and Results— In protocol 1, patients with POTS (n=54) underwent acute drug trials of propranolol 20 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, heart rate, and symptoms were assessed while the patients were seated and after standing for up to 10 minutes before and hourly after the study drug. Supine ( P <0.001) and standing ( P <0.001) heart rates were significantly lower after propranolol compared with placebo. The symptom burden improvement from baseline to 2 hours was greater with propranolol than placebo (median, −4.5 versus 0 arbitrary units; P =0.044). In protocol 2, 18 patients with POTS underwent similar trials of high-dose (80 mg) versus low-dose (20 mg) propranolol. Although the high dose elicited a greater decrease than the low dose in standing heart rate ( P <0.001) and orthostatic tachycardia ( P <0.001), the improvement in symptoms at 2 hours was greater with low-dose propranolol (−6 versus −2 arbitrary units; P =0.041). Conclusions— Low-dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS. Higher-dose propranolol did not further improve, and may worsen, symptoms.

Integrity signals

Registry

Crossref · 10.1161/circulationaha.108.846501

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 17 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Animal or experimental models of orthostatic intolerance showed no improvement in orthostatic tolerance with propranolol or esmolol.

    “Unfortunately, in experimental models of orthostatic intolerance, neither propranolol 15, 16 nor esmolol 17 were found to improve orthostatic tolerance.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [15]
    • cites [16] source
    • cites [17] source
  • Findingown data

    In Protocol #1, the primary endpoint, delta heart rate at 2 hours, was lower with propranolol 20 mg than placebo.

    “Delta HR decreased in both groups, but significantly more at 1 hour following propranolol 20mg (16±11 min−1) than placebo (26±17 min−1; P=0.004), and remained significantly lower with propranolol at each hour during follow-up (the primary study endpoint was delta HR at 2 hours following study drug [P=0.033]).”
    Quote in the paperSubstantial claim
  • Findingown data

    In Protocol #2, high-dose propranolol (80 mg) reduced standing heart rate more than low-dose (20 mg) from 1 hour through 4 hours.

    “Standing HR at 1-hour was lower with high dose (84±12 min−1) than low dose propranolol (93±15 min−1; P<0.001), and this significant difference persisted through the 4 hour follow-up.”
    Quote in the paperSubstantial claim
  • Findingown data

    In Protocol #1, propranolol 20 mg lowered seated systolic blood pressure compared with placebo.

    “By 2 hours post study drug, propranolol 20mg had significantly lowered seated SBP compared with placebo (98±11 mmHg vs. 107±15 mmHg; P=0.001; Fig 1e), and it remained significantly lower up to 4 hours post study drug.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In Protocol #2, high-dose propranolol lowered standing systolic blood pressure more than low dose.

    “Although standing SBP following propranolol decreased for both low dose and high dose, this was significantly greater for the high dose (P<0.001).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 16

  • Classified as probably not a substantial claim.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [5] source
    • cites [6] source
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8] source

      The Results report elevated standing plasma norepinephrine in the proband, and the Discussion says central sympathetic tone seems increased in many patients with orthostatic intolerance. But the paper does not establish elevated standing norepinephrine as a measure of increased sympathetic outflow in many POTS patients; its clearance analysis shows that reduced norepinephrine removal contributed to the proband’s elevated level. The direct-nerve-recording portion is attached to a different citation in the citing sentence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The 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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Findingown data

    In both protocols, standing produced a large rise in heart rate and norepinephrine relative to supine values.

    “On standing, there was a marked increase in HR (Protocol#1: 122±26 min−1, P<0.001; Protocol #2: 130±29 min−1, P<0.001) and norepinephrine (Protocol#1: 4.94±3.35 nmol/l, P<0.001; Protocol#2: 3.93±2.21 nmol/l, P=0.015) compared with respective supine values.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Protocol #2, lightheadedness, mental clouding, and shortness of breath improved significantly only with low-dose propranolol, not high-dose.

    “Interestingly, 3 symptoms (lightheadedness, mental clouding and shortness of breath) improved significantly only with low dose (20mg) propranolol, but not with high dose (80mg) propranolol.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Repeated symptom ratings from the same patient use a relatively stable frame of reference.
    • Rests on an assumption: The nine symptoms in the Vanderbilt POTS Symptom Score reflect common complaints of POTS patients.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Protocol #1 had 54 POTS patients with complete paired data for analysis, and Protocol #2 had 18.

    “In protocol #1 (propranolol vs. placebo), 54 subjects with POTS had complete paired datasets suitable for analyses, as did 18 subjects in protocol #2 (propranolol 80 mg vs. propranolol 20 mg).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    POTS is characterized by an excessive increase in heart rate on standing without hypotension.

    “A most striking feature of this disorder is the excessive increase in heart rate (HR) that occurs upon standing in the absence of hypotension 4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Case reports and open-label studies have described symptom improvement with beta-blockers, which can also lower plasma norepinephrine in hyperadrenergic states.

    “Beta-blockers have been reported to improve symptoms in case-reports 10, 11 and open-label studies 12, 13 and can decrease plasma norepinephrine levels in a hyperadrenergic state 14.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [10] source
    • cites [11] source
    • cites [12] source
    • cites [13] source
    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    POTS is linked to diminished quality of life and major functional impairment, with few effective treatments.

    “POTS is associated with a very poor quality of life and significant functional disability 9; there are a paucity of effective therapies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Protocol #2 compared propranolol 80 mg with 20 mg in a randomized single-blind crossover design on separate days.

    “In protocol #2, a high dose (80 mg) was compared to a low dose (20 mg) of propranolol (Mylam Pharmaceuticals, Morgantown VW) in a randomized single-blind, cross-over fashion on separate days, with study endpoints as in protocol #1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study was registered with ClinicalTrials.gov under NCT00262470.

    “The data reported are a part of “The Treatment of Orthostatic Intolerance” study, which is registered with www.ClinicalTrials.gov (NCT00262470).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A low stroke volume in POTS may mean that a higher heart rate is necessary to sustain cardiac output.

    “One reason for the limited effectiveness of beta-blockade might be that patients with POTS have a low stroke volume and might require an elevated HR in order to maintain their cardiac output 18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Protocol #1 compared oral propranolol 20 mg with placebo in a randomized single-blind crossover design on separate mornings.

    “In protocol #1, the patients with POTS were given a tablet of propranolol 20 mg (Mylam Pharmaceuticals, Morgantown VW) or placebo in a randomized single-blind, cross-over fashion on separate days.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Low-dose propranolol benefits POTS, whereas higher doses may be counter-productive.

    “These data suggest that while low doses of propranolol are of benefit in POTS, that higher doses might be counter-productive.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Protocol #2 had a relatively small sample, though comparable to other POTS trials.

    “Another limitation of this study is the relatively small sample of patients in protocol #2, although it is comparable to other reported POTS trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The study was single-blind rather than double-blind because the research nurse was not blinded to treatment.

    “Our studies were conducted with the patient and the principal investigator blind to study drug order until after an individual’s study completion, but the research center nurse was not blind to the intervention. The study was thus single-blind, and not double-blind.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Low-dose oral propranolol reduced tachycardia and improved symptoms in POTS.

    “Low dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS.”
    • Also stated in: § Conclusion · boosted
      “We have found that low dose propranolol is a highly effective agent in acutely decreasing the orthostatic tachycardia and improving symptoms in patients with POTS.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Repeated symptom ratings from the same patient use a relatively stable frame of reference.
    • Rests on an assumption: The nine symptoms in the Vanderbilt POTS Symptom Score reflect common complaints of POTS patients.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The symptom score lacks an objective anchor, so ratings can differ greatly between individuals.

    “Since there is no objective anchor to these symptoms, one individual’s rating may vary greatly from that of another individual (e.g. one person’s rating of 4 may reflect more severe symptoms than another person’s rating of 6).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    All symptom analyses used within-person paired comparisons.

    “This is one reason that all of our symptom-based analyses were done using paired comparisons within an individual.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The dose-symptom relationship is complex: some symptoms improved with high-dose propranolol, while others did not.

    “In fact, the relationship between propranolol dose and symptoms is more complicated. Some individual symptoms did improve with high dose propranolol (such as palpitation and tremulousness; see Table 4), while other symptoms did not improve (lightheadedness, mental clouding, and shortness of breath).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Repeated symptom ratings from the same patient use a relatively stable frame of reference.
    • Rests on an assumption: The nine symptoms in the Vanderbilt POTS Symptom Score reflect common complaints of POTS patients.

  • May combine two claims.

    Interpretationown data

    Higher-dose propranolol did not further improve symptoms and might worsen them in POTS.

    “Higher dose propranolol did not further improve, and may worsen, symptoms.”
    • Also stated in: § Conclusion · hedged
      “Symptoms did not further improve with higher doses of propranolol, suggesting that caution should be used by clinicians in titrating up the propranolol dose.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Repeated symptom ratings from the same patient use a relatively stable frame of reference.
    • Rests on an assumption: The nine symptoms in the Vanderbilt POTS Symptom Score reflect common complaints of POTS patients.

  • May combine two claims.

    Interpretationown data

    Higher-dose propranolol further restrained orthostatic tachycardia but did not further improve symptoms.

    “The higher dose of propranolol did further restrain orthostatic tachycardia in the patients with POTS, but there was no further improvement in symptoms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The research nurse did not collect the reported data directly; hemodynamics came from an automated cuff and symptoms were self-reported by the blinded patient.

    “It is noteworthy, however, that the research center nurse did not directly collect the data presented in this report. The hemodynamic data were collected by an automated oscillometric BP cuff that was connected to a personal computer for digital data collection, and the symptoms were all self-reported by the blinded patient.”
    Quote in the paperNot a substantial claim
22 of 22

  • The paper relies on this without support.

    The study is the first placebo-controlled trial of a beta-blocker in POTS.

    “This paper is the first placebo controlled trial of a beta-blocker in patients with POTS.”
    “These are the first blinded data comparing oral beta-blocker therapy to placebo in POTS.”

  • The paper relies on this without support.

    Repeated symptom ratings from the same patient use a relatively stable frame of reference.

    “Like serial chest pain rating scales, however, we expect serial intrapatient reports to use a more constant frame of reference.”

  • The paper relies on this without support.

    Standing from a seated position gives a clinically relevant and reproducible orthostatic stress.

    “While conducting the study while seated might decrease the magnitude of the orthostatic tachycardia, it does provide a clinically relevant and reproducible scenario.”

  • The paper relies on this without support.

    The nine symptoms in the Vanderbilt POTS Symptom Score reflect common complaints of POTS patients.

    “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.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Low-dose oral propranolol (10-20 mg) acutely lowers standing heart rate and improves POTS symptoms, while higher doses are less well tolerated.

    “low-dose propranolol (10–20 mg PO) acutely lowers standing heart rate and improves symptoms in patients with POTS, while higher doses of propranolol are less well tolerated.42”

    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 [42]

    The Abstract’s Methods and Results report that oral propranolol 20 mg acutely lowered standing heart rate and improved symptoms in patients with POTS; symptom improvement was smaller with 80 mg. The Discussion’s Clinical Significance section says patients commonly receive and generally tolerate 10–20 mg, but the acute trial tested 20 mg, not 10 mg. The paper suggests higher doses may worsen symptoms rather than establishing that they are generally less well tolerated. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Propranolol may have off-target side effects due to the broad distribution of beta-adrenergic receptors throughout the body.

    “Propranolol is a nonselective beta-blocker that has been shown to mitigate tachycardia and symptoms in patients with POTS, but may have off-target side effects due to the broad distribution of beta-adrenergic receptors throughout the body.6, 7, 8”

    From A Randomized Crossover Trial of Ivabradine, Propranolol, and Placebo in Postural Orthostatic Tachycardia Syndrome (2026) · cites this paper as [6]

    The Discussion section, “Less is More: Benefits of Low Dose Propranolol” (page unavailable), identifies propranolol as a nonselective beta-blocker and raises the possibility of central adverse effects. It does not attribute potential off-target side effects to the broad distribution of beta-adrenergic receptors throughout the body. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Beta-blockers, specifically propranolol, have been shown, in low doses, to improve orthostatic tachycardia and reduce norepinephrine levels in these patients.

    “Beta-blockers, specifically propranolol, have been shown, in low doses, to improve orthostatic tachycardia and reduce norepinephrine levels in these patients.6”

    From A Randomized Crossover Trial of Ivabradine, Propranolol, and Placebo in Postural Orthostatic Tachycardia Syndrome (2026) · cites this paper as [6]

    The Discussion’s Clinical Significance section reports that low-dose (20 mg) propranolol reduced orthostatic tachycardia in patients with POTS. But the Less is More section says the authors cannot conclude whether propranolol lowers peripheral norepinephrine; it presents that mechanism as a possibility, not a demonstrated effect. Page numbers were not provided in our copy. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • Orthostatic tachycardia in POTS is due to sympathetic activation, as it is associated with elevated plasma norepinephrine and is blunted by low doses of beta-blockers.

    “This orthostatic tachycardia is due to sympathetic activation, given that it is associated with a significant elevation in plasma norepinephrine and is blunted by even low doses of beta-blockers.2”

    From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [2]

    The Results (Patient Characteristics) report a significant rise in plasma norepinephrine on standing, and the Discussion (Clinical Summary) reports that low-dose propranolol reduced orthostatic tachycardia. The Introduction says many patients have increased sympathetic tone, but the paper does not establish that sympathetic activation is the cause of orthostatic tachycardia in POTS generally; that causal wording is stronger than its evidence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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 [520]

    The Discussion (page unavailable) reports that low-dose propranolol improved symptoms in patients with POTS. But the Methods’ symptom score does not include syncope, and the paper does not assess whether symptom improvement decreases its occurrence. The proposed link to syncope remains unsupported by this source, even as a possibility. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abstract calls a post-treatment measurement supine despite seated trial procedures

    Minor

    The abstract reports a supine heart-rate comparison after treatment, but the drug-trial procedures say patients remained seated except when standing. The described post-treatment measurements therefore were seated and standing, not supine and standing.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 10.1161/hyp.38.6.1377 · DOI

Cited by

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Related

Authors
Raj, S. R., Black, B. K., Biaggioni, I., Paranjape, S. Y., Ramirez, M., Dupont, W. D., & Robertson, D.
Affiliations
Vanderbilt University (US)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2009-09
Volume
120
Issue
9
Pages
725-734
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.108.846501
PMC
PMC2758650
OpenAlex
W2145724863
Cited by
225
References
27
Citations by year
2026: 10 · 2025: 15 · 2024: 16 · 2023: 15 · 2022: 20 · 2021: 18 · 2020: 13 · 2019: 10 · 2018: 16 · 2017: 13 · 2016: 9 · 2015: 8 · 2014: 9 · 2013: 14 · 2012: 15
FWCI
13.16
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL071784, P01HL056693)
  • National Institute of Neurological Disorders and Stroke (R01NS055670)
  • National Center for Research Resources (M01RR000095, UL1RR024975, K23RR020783)
Topics
  • Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
Keywords
postural orthostatic tachycardia syndrome, propranolol, beta-blockers, orthostatic intolerance, heart rate, symptom burden, dose-response relationship
MeSH terms
Administration, Oral, Adrenergic beta-Antagonists, Adult, Blood Pressure, Dose-Response Relationship, Drug, Female, Heart Rate, Humans, Male, Placebos, Propranolol, Sympathetic Nervous System, Tachycardia, Treatment Outcome, Cross-Over Studies, Postural Orthostatic Tachycardia Syndrome, Young Adult

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