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Cited by 398Cardiovascular Syncope and Autonomic DisordersHeart Rate Variability and Autonomic ControlPain Management and Treatment

The neuropathic postural tachycardia syndrome

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Jacob, Giris, Costa, Fernando, Shannon, John R., Robertson, Rose Marie, Wathen, Mark, Stein, Michael, Biaggioni, Italo, Ertl, Andy +2 more·2000·New England Journal of Medicine
DOI 10.1056/nejm200010053431404
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Abstract

BACKGROUND: The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. METHODS: We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. RESULTS: At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). CONCLUSIONS: The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.

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  • Impaired sympathetic tone reduces venoconstriction, causing venous pooling in the lower limbs and splanchnic beds.

    “It is believed that impaired sympathetic tone (as measured by norepinephrine spillover) reduces venoconstriction, leading to venous pooling in the lower limbs and splanchnic beds.24”

    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 [24]

    The discussion (section 2.0; page unavailable) links impaired norepinephrine spillover to noradrenergic dysfunction in the legs and discusses minimizing orthostatic blood pooling in the lower body. It does not establish reduced venoconstriction or pooling in splanchnic beds; instead, it suggests that sympathetic neurons in organs such as the mesentery remain intact. (LLM, conf=0.86)

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  • Features described in subgroups of POTS patients include increased sympathetic nervous system tone (hyperadrenergic POTS), partial peripheral sympathetic denervation leading to relative central hypovolemia (neuropathic POTS), and low blood volume (absolute hypovolemia), which may drive some other hemodynamic findings.

    “Features described in subgroups of patients include increased sympathetic nervous system tone (i.e., hyperadrenergic POTS),17 partial peripheral sympathetic denervation leading to relative central hypovolemia (i.e., neuropathic POTS)27 and low blood volume (i.e., absolute hypovolemia),28 which may drive some of the other hemodynamic findings.”

    From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [27]

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  • More commonly proposed causes of POTS include partial peripheral neuropathy, a deficit in blood volume, abnormalities in the renin-angiotensin-aldosterone system, physical deconditioning, autoantibodies targeting peripheral adrenergic receptors, and a hyperadrenergic state resulting from central activation of the sympathetic nervous system.

    “More commonly proposed causes include partial peripheral neuropathy (“neuropathic POTS”),19 a deficit in blood volume, abnormalities in the renin-angiotensin-aldosterone system (RAAS)20, physical deconditioning,10 autoantibodies targeting peripheral adrenergic receptors21 and a hyperadrenergic state resulting from central activation of the sympathetic nervous system (“HyperPOTS”).”

    From Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine (2024) · cites this paper as [19]

  • Neuropathic POTS was first described when sympathetic activation increased norepinephrine spillover in the lower limbs of some patients less than in healthy controls, despite similar arm responses.

    “Neuropathic POTS was first described when activation of the sympathetic nervous system increased norepinephrine spillover in the lower limbs of some patients to a lesser extent than in healthy controls, despite similar responses in the arms [42].”

    From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [42]

  • POTS patients have significantly impaired sympathetic nervous system activity in the lower extremities.

    “Jacob et al. (18) demonstrated significantly impaired sympathetic nervous system activity in the lower extremities of POTS patients.”

    From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [18]

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Research works printed but not linked: 3

  1. [4]4. Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypo- volemia. Ann Intern Med 1986;104:298-303.
  2. [30]30. Rea RF, Eckberg DL, Fritsch JM, Goldstein DS. Relation of plasma norepinephrine and sympathetic traffic during hypotension in humans. Am J Physiol 1990;258:R982-R986.
  3. [35]35. Grossman E, Chang PC, Hoffman A, Tamrat M, Kopin IJ, Goldstein DS. Tracer norepinephrine kinetics: dependence on regional blood flow and the site of infusion. Am J Physiol 1991;260:R946-R952.

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Authors
Jacob, G., Costa, F., Shannon, J. R., Robertson, R. M., Wathen, M., Stein, M., Biaggioni, I., Ertl, A., Black, B., & Robertson, D.
Affiliations
Vanderbilt University (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2000-10-05
Volume
343
Issue
14
Pages
1008-1014
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm200010053431404
OpenAlex
W2323218437
Semantic Scholar
407efaeed6a32a863bb8fc0e44db81b5b8d4944b
Cited by
398
References
40
Citations by year
2026: 9 · 2025: 16 · 2024: 12 · 2023: 14 · 2022: 16 · 2021: 13 · 2020: 19 · 2019: 9 · 2018: 14 · 2017: 14 · 2016: 10 · 2015: 11 · 2014: 21 · 2013: 16 · 2012: 16
FWCI
20.53
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Aeronautics and Space Administration
  • Vanderbilt University
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL56693, P01HL056693)
  • National Center for Research Resources (RR00095)
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 › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
postural orthostatic tachycardia syndrome, sympathetic denervation, norepinephrine spillover, plasma norepinephrine, orthostatic intolerance, cold pressor test, sodium nitroprusside, tyramine, sympathetic nervous system, autonomic dysfunction
MeSH terms
Adult, Arm, Autonomic Nervous System Diseases, Blood Pressure, Cold Temperature, Female, Femoral Vein, Heart Rate, Humans, Leg, Male, Nitroprusside, Norepinephrine, Posture, Reference Values, Sympathetic Nervous System, Tachycardia, Tyramine, Case-Control Studies

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