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Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome
Abstract
Background— Patients with postural tachycardia syndrome (POTS) experience considerable disability, but in most, the pathophysiology remains obscure. Plasma volume disturbances have been implicated in some patients. We prospectively tested the hypothesis that patients with POTS are hypovolemic compared with healthy controls and explored the role of plasma renin activity and aldosterone in the regulation of plasma volume. Methods and Results— Patients with POTS (n=15) and healthy controls (n=14) underwent investigation. Heart rate (HR), blood pressure (BP), plasma renin activity, and aldosterone were measured with patients both supine and upright. Blood volumes were measured with 131 I-labeled albumin and hematocrit. Patients with POTS had a higher orthostatic increase in HR than controls (51±18 versus 16±10 bpm, P <0.001). Patients with POTS had a greater deficit in plasma volume (334±187 versus 10±250 mL, P <0.001), red blood cell volume (356±128 versus 218±140 mL, P =0.010), and total blood volume (689±270 versus 228±353 mL, P <0.001) than controls. Despite the lower plasma volume in patients with POTS, there was not a compensatory increase in plasma renin activity (0.79±0.58 versus 0.79±0.74 ng · mL −1 · h −1 , P =0.996). There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L; P =0.017). Conclusions— Patients with POTS have paradoxically unchanged plasma renin activity and low aldosterone given their marked reduction in plasma volume. These patients also have a significant red blood cell volume deficit, which is regulated by the renal hormone erythropoietin. These abnormalities suggest that the kidney may play a key role in the pathophysiology of POTS.
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“Circulating angiotensin II levels are approximately 2-fold higher in POTS, perhaps due to reduced levels or activity of its degrading enzyme ACE2”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Raj et al., 2005
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In the citing paper
“Despite their low blood volume, patients with POTS were found to have paradoxically low aldosterone levels and inappropriately low plasma renin activity, while having elevated concentrations of circulating angiotensin II [12,25].”
From Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome (2012) · cites this paper as [12]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Paradoxically, some of these patients have low plasma renin activity and aldosterone levels compared with healthy subjects.32”
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 [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The findings of a small 2005 case–control intervention study suggest that advising patients to drink 3 L of water per day and to maximize their dietary salt intake can promote sodium retention and blood volume expansion.28”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [28]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“We and others have found that many patients with POTS have low blood volume [12,24].”
From Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome (2012) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Some POTS patients with hypovolemia, however, have inappropriately low standing plasma renin activity and aldosterone compared with normovolemic controls [46;12].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [46]
The cited source says what the claim attributes to it.
In the citing paper
“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 [28]
The cited source says what the claim attributes to it.
In the citing paper
“These studies strongly implicate a perturbed RAAS axis leading to low blood volume as a potential mechanism that contributes to POTS pathophysiology.”
From Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome (2012) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“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 [20]
In the citing paper
“While circulating angiotensin II levels are high, POTS patients have impaired ability of the RAAS to expand blood volume (Li et al., 2015a; Mustafa et al., 2011; Raj et al., 2005; Stewart et al., 2006b).”
From Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1 (2021) · cites this paper as Raj et al., 2005
In the citing paper
“Absolute hypovolemia is commonly observed in POTS, with up to 70% of patients exhibiting deficits in plasma volume and red blood cell volume (Fu et al., 2010; Raj et al., 2005; Sheldon et al., 2015; Stewart et al., 2006a).”
From Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1 (2021) · cites this paper as Raj et al., 2005
In the citing paper
“Many POTS patients have a blood volume that is lower than expected for their size and sex, suggesting that hypovolemia may underlie some of the hemodynamic findings of POTS (Fu et al., 2010; Mar and Raj, 2014; Raj et al., 2005).”
From Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1 (2021) · cites this paper as Raj et al., 2005
In the citing paper
“One of the more consistent findings in patients with POTS is a deficit in total blood, plasma and red cell volume [45;13;46].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [46]
In the citing paper
“Additionally, the aldosterone:renin ratio was found to be lower in POTS patients than in healthy control subjects (34).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“Studies have shown that some POTS patients have 13-22% less plasma or blood volume than do healthy controls (33-35).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“A significant portion of POTS patients suffer from a state of persistent hypovolemia.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“Despite these low blood and plasma volumes, plasma renin activity and aldosterone levels are also inappropriately low in POTS patients.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“Supine levels of norepinephrine are similar between healthy controls and POTS patients (34).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“Hyperadrenergic POTS is an important endophenotype of POTS with the characteristic, neurohormonal hallmark of elevated upright plasma norepinephrine (34, 36).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“Levels of plasma epinephrine appear to be similar between POTS patients and healthy subjects (34, 36).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [34]
In the citing paper
“Low blood volume or hypovolemia is a common finding in POTS, with many patients reported to have deficits in red cell and plasma volume”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Raj et al., 2005
In the citing paper
“POTS patients appear to have a “renin-aldosterone paradox” in response to both hypovolemia and orthostatic challenge.”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Raj et al., 2005
In the citing paper
“In these patients, POTS phenotype might be caused by neuroendocrine and renal dysfunction leading to chronic intravascular fluid deficiency.”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [54]
In the citing paper
“Further, a subset of POTS patients demonstrate relative hypovolaemia and impaired renin-angiotensin-aldosterone regulation [54].”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [54]
In the citing paper
“Many POTS patients have a decreased plasma volume (6–8) and high standing plasma norepinephrine (9).”
From Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome (2021) · cites this paper as [6]
In the citing paper
“Although a plasma volume deficit should stimulate the renin–angiotensin–aldosterone system to promote sodium retention, this regulatory link might be defective in POTS (6).”
From Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome (2021) · cites this paper as [6]
In the citing paper
“Studies that reported a plasma volume deficit in POTS patients despite a normal- to high-sodium diet (≥150 mEq sodium/day) (6, 14, 15), suggest that patients may not effectively respond to dietary sodium with plasma volume expansion.”
From Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome (2021) · cites this paper as [6]
In the citing paper
“Plasma volume (PV) was determined by the indicator tracer-dilution technique, using the DAXOR BVA-100 Blood Volume Analyzer system (6) (DAXOR Corporation), on Day 7.”
From Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome (2021) · cites this paper as [6]
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Metadata
- Authors
- Raj, S. R., Biaggioni, I., Yamhure, P. C., Black, B. K., Paranjape, S. Y., Byrne, D. W., & Robertson, D.
- Affiliations
- Vanderbilt University (US)
- Venue
- Circulation
- Published
- 2005-04-05
- Volume
- 111
- Issue
- 13
- Pages
- 1574-1582
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2104389637
- Semantic Scholar
- e12b9205141272d6254be2fee9f95b225517fc05
- Cited by
- 286
- References
- 44
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 22 · 2023: 13 · 2022: 14 · 2021: 18 · 2020: 26 · 2019: 14 · 2018: 13 · 2017: 10 · 2016: 9 · 2015: 14 · 2014: 16 · 2013: 10 · 2012: 15
- FWCI
- 9.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University (M01 RR00095)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (2P01-HL-56693, P01HL056693)
- National Center for Research Resources (M01RR000095, M01-RR-00095)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- postural orthostatic tachycardia syndrome, plasma volume, hypovolemia, renin-aldosterone system, plasma renin activity, aldosterone, erythrocyte volume, erythropoietin, blood volume regulation, renal pathophysiology
- MeSH terms
- Adult, Aldosterone, Blood Volume, Erythropoietin, Female, Hemodynamics, Humans, Male, Middle Aged, Posture, Prospective Studies, Renin, Renin-Angiotensin System, Tachycardia, Case-Control Studies, Hypovolemia
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