Skip to content
Inciteful Med

The Biology of POTS: Subtypes and Related Conditions

Last updated:

Postural Orthostatic Tachycardia Syndrome (POTS) is a complex condition driven by different biological mechanisms. Its three primary subtypes—neuropathic, hyperadrenergic, and hypovolemic—often overlap and frequently co-occur with hEDS and MCAS in a cluster known as the POTS Trifecta.

Key Takeaways

  • • POTS is a heterogeneous condition, meaning it has different biological causes and symptoms from one person to the next.
  • • The three primary subtypes of POTS are neuropathic, hyperadrenergic, and hypovolemic, which frequently overlap in patients.
  • • Secondary POTS is caused by an underlying condition like diabetes, Sjögren’s syndrome, or amyloidosis, which must be treated directly.
  • • The 'Trifecta' is a common clinical cluster consisting of POTS, hypermobile Ehlers-Danlos Syndrome (hEDS), and Mast Cell Activation Syndrome (MCAS).

POTS is not a single disease with one cause. Instead, it is a heterogeneous condition—meaning it can look different and have different biological drivers from one person to the next [1][2]. To understand why your body reacts the way it does when you stand, it helps to look at the specific physiological “glitches” that can occur.

What Happens When You Stand?

In a healthy person, standing up causes gravity to pull about 500–1000mL of blood toward the lower body [3]. The body immediately compensates: nerves tell the blood vessels to tighten (vasoconstriction) and the heart to beat slightly faster to keep blood flowing to the brain [3][4].

In a patient with POTS, this system fails. The heart beats excessively fast (an increase of 30+ beats per minute) to try and compensate for the fact that blood isn’t reaching the brain effectively [5][6]. This leads to symptoms like dizziness, “brain fog,” and palpitations.

The Three Primary Subtypes

Most patients do not fit into just one category; many have an overlap of these three biological drivers [1][2].

1. Neuropathic POTS

This subtype is driven by Small Fiber Neuropathy (SFN)—damage to the tiny nerve fibers that control the “tightening” of blood vessels [7][1]. Because these nerves aren’t working, blood pools in the legs and abdomen when you stand, making it hard for the heart to pump blood back up to the head [7][8].

2. Hyperadrenergic POTS

In this subtype, the body produces too much norepinephrine (a stress hormone/neurotransmitter) upon standing [9][10]. Patients often have high blood pressure when they stand and may feel “wired,” shaky, or anxious because their sympathetic nervous system (the “fight or flight” system) is in overdrive [11][10].

3. Hypovolemic POTS

Many POTS patients have a low total volume of blood [2][12]. Interestingly, they often have a “low renin” paradox: their body fails to produce enough renin (an enzyme that helps the kidneys retain salt and water), so they struggle to stay hydrated even if they drink plenty of fluids [13][14].

Primary vs. Secondary POTS

  • Primary POTS: The condition occurs on its own, often following a viral infection (like COVID-19 or mono) or a period of high stress [15][16].
  • Secondary POTS: The POTS symptoms are caused by another underlying disease, such as diabetes, Sjögren’s syndrome (an autoimmune condition), or amyloidosis [15][17]. In these cases, treating the underlying disease is the priority.

The “Trifecta”: POTS, hEDS, and MCAS

Clinicians often see a “cluster” of three conditions occurring together, sometimes called the Trifecta [18][19]:

  1. POTS: Dysautonomia.
  2. hEDS (hypermobile Ehlers-Danlos Syndrome): A connective tissue disorder where the “glue” of the body is too stretchy. This stretchiness can affect blood vessels, making them more likely to expand and allow blood to pool [20][21].
  3. MCAS (Mast Cell Activation Syndrome): A condition where immune cells (mast cells) release too many inflammatory chemicals, like histamine [22][23]. Histamine is a powerful vasodilator (it opens up blood vessels), which can worsen POTS symptoms and lead to flushing, hives, and digestive issues [22][24].

When these three occur together, they can create a cycle of inflammation, stretchy blood vessels, and autonomic “glitches” that require a specialized approach to manage.

Frequently Asked Questions

What are the three main subtypes of POTS?
The three primary subtypes are neuropathic POTS (driven by nerve damage), hyperadrenergic POTS (caused by excess stress hormones upon standing), and hypovolemic POTS (associated with low blood volume). Many patients do not fit into just one category and experience an overlap of these drivers.
What is the POTS 'Trifecta'?
The 'Trifecta' refers to a common clinical cluster of three conditions: POTS, hypermobile Ehlers-Danlos Syndrome (hEDS), and Mast Cell Activation Syndrome (MCAS). Together, they can create a complex cycle of inflammation, overly stretchy blood vessels, and autonomic nervous system dysfunction.
Why does my heart race when I stand up if I have POTS?
In a healthy body, blood vessels tighten when you stand to push blood up to your brain. In POTS, this tightening process fails, causing blood to pool in your lower body, so your heart beats excessively fast to compensate and keep blood flowing to your head.
What is the difference between primary and secondary POTS?
Primary POTS occurs on its own, often developing after a viral infection like COVID-19 or a period of high stress. Secondary POTS is directly caused by another underlying disease, such as diabetes, Sjögren’s syndrome, or small fiber neuropathy.
What happens in hyperadrenergic POTS?
In this subtype, the body produces too much norepinephrine—a stress hormone—upon standing. This puts the sympathetic nervous system into overdrive, often causing patients to experience high blood pressure, anxiety, and shakiness.

Questions for Your Doctor

  • • Based on my symptoms, do you think I have a specific subtype of POTS, or a mix of several?
  • • Should we test my standing norepinephrine levels to see if I have the hyperadrenergic subtype?
  • • Could my symptoms be 'secondary' to another condition like an autoimmune disorder or small fiber neuropathy?
  • • Can we screen me for hEDS (hypermobile Ehlers-Danlos Syndrome) or MCAS (Mast Cell Activation Syndrome) given how often they occur with POTS?
  • • How does my 'low renin' profile affect the way we should approach my salt and fluid intake?

Questions for You

  • • Do you notice specific triggers like heat, high-histamine foods, or stress that make your heart rate spike more than usual?
  • • Have you always been 'double-jointed' or had very stretchy skin, which might point toward a connective tissue disorder like hEDS?
  • • Do you experience frequent flushing, hives, or unexplained allergic-like reactions alongside your POTS symptoms?
  • • When you stand up, do you feel like blood is 'pooling' in your legs, making them feel heavy or look purple?

Want personalized information?

Type your question below to get evidence-based answers tailored to your situation.

References

  1. 1

    Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies.

    Mar PL, Raj SR

    Annual review of medicine 2020; (71()):235-248 doi:10.1146/annurev-med-041818-011630.

    PMID: 31412221
  2. 2

    Use of Ivabradine in the Treatment of Patients with Postural Orthostatic Tachycardia Syndrome (POTS): A Systematic Review.

    Melo APG, Moretti MA, Chagas ACP

    Arquivos brasileiros de cardiologia 2025; (122(11)):e20250347 doi:10.36660/abc.20250347.

    PMID: 41538594
  3. 3

    [Postural orthostatic tachycardia syndrome].

    Brinth L, Pors K, Mehlsen J

    Ugeskrift for laeger 2015; (177(18)):853-6.

    PMID: 26539574
  4. 4

    Orthostatic intolerance and postural tachycardia syndrome: new insights into pathophysiology and treatment.

    Ruzieh M, Grubb BP

    Herzschrittmachertherapie & Elektrophysiologie 2018; (29(2)):183-186 doi:10.1007/s00399-018-0563-1.

    PMID: 29696346
  5. 5

    Postural Orthostatic Tachycardia Syndrome (POTS)--A novel member of the autoimmune family.

    Dahan S, Tomljenovic L, Shoenfeld Y

    Lupus 2016; (25(4)):339-42 doi:10.1177/0961203316629558.

    PMID: 26846691
  6. 6

    Monitoring of cerebral oximetry in patients with postural orthostatic tachycardia syndrome.

    Kharraziha I, Holm H, Bachus E, et al.

    Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2019; (21(10)):1575-1583 doi:10.1093/europace/euz204.

    PMID: 31384930
  7. 7

    Management of Post-Viral Postural Orthostatic Tachycardia Syndrome With Craniosacral Therapy.

    Tafler L, Chaudry A, Cho H, Garcia A

    Cureus 2023; (15(2)):e35009 doi:10.7759/cureus.35009.

    PMID: 36938206
  8. 8

    Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

    Joseph P, Arevalo C, Oliveira RKF, et al.

    Chest 2021; (160(2)):642-651 doi:10.1016/j.chest.2021.01.082.

    PMID: 33577778
  9. 9

    Carbidopa: beyond Parkinson's disease.

    Lenka A, Vernino S

    Clinical autonomic research : official journal of the Clinical Autonomic Research Society 2025; (35(3)):347-352 doi:10.1007/s10286-025-01122-y.

    PMID: 40056295
  10. 10

    Pathophysiology and management of postural orthostatic tachycardia syndrome (POTS): A literature review.

    Ghazal M, Akkawi AR, Fancher A, et al.

    Current problems in cardiology 2025; (50(3)):102977 doi:10.1016/j.cpcardiol.2024.102977.

    PMID: 39706392
  11. 11

    Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome.

    Taub PR, Zadourian A, Lo HC, et al.

    Journal of the American College of Cardiology 2021; (77(7)):861-871 doi:10.1016/j.jacc.2020.12.029.

    PMID: 33602468
  12. 12

    Pathophysiological mechanisms of Postural Orthostatic Tachycardia Syndrome analyzed by means of hemodynamics.

    Wei L, Cheng H, Chen S, et al.

    PloS one 2025; (20(7)):e0327236 doi:10.1371/journal.pone.0327236.

    PMID: 40601666
  13. 13

    Evidence for Impaired Renin Activity in Postural Orthostatic Tachycardia Syndrome.

    Spahic JM, Mattisson IY, Hamrefors V, et al.

    Journal of clinical medicine 2023; (12(14)) doi:10.3390/jcm12144660.

    PMID: 37510775
  14. 14

    Recent advances in the understanding of the mechanisms underlying postural tachycardia syndrome in children: practical implications for treatment.

    Zheng X, Chen Y, Du J

    Cardiology in the young 2017; (27(3)):413-417 doi:10.1017/S1047951116002559.

    PMID: 27938459
  15. 15

    Postural Orthostatic Tachycardia Syndrome: JACC Focus Seminar.

    Bryarly M, Phillips LT, Fu Q, et al.

    Journal of the American College of Cardiology 2019; (73(10)):1207-1228 doi:10.1016/j.jacc.2018.11.059.

    PMID: 30871704
  16. 16

    Autonomic neuropathy as post-acute sequela of SARS-CoV-2 infection: a case report.

    Agnihotri SP, Luis CVS, Kazamel M

    Journal of neurovirology 2022; (28(1)):158-161 doi:10.1007/s13365-022-01056-5.

    PMID: 35181863
  17. 17

    Autoimmunity in Syndromes of Orthostatic Intolerance: An Updated Review.

    Pena C, Moustafa A, Mohamed AR, Grubb B

    Journal of personalized medicine 2024; (14(4)) doi:10.3390/jpm14040435.

    PMID: 38673062
  18. 18

    The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS).

    Kucharik AH, Chang C

    Clinical reviews in allergy & immunology 2020; (58(3)):273-297 doi:10.1007/s12016-019-08755-8.

    PMID: 31267471
  19. 19

    The Suggested Relationships Between Common GI Symptoms and Joint Hypermobility, POTS, and MCAS.

    Quigley EMM, Noble O, Ansari U

    Gastroenterology & hepatology 2024; (20(8)):479-489.

    PMID: 39205953
  20. 20

    A new insight on postural tachycardia syndrome in 102 adults with hypermobile Ehlers-Danlos Syndrome/hypermobility spectrum disorder.

    Celletti C, Borsellino B, Castori M, et al.

    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace 2020; (90(2)) doi:10.4081/monaldi.2020.1286.

    PMID: 32434316
  21. 21

    Cardiovascular Symptoms, Dysautonomia, and Quality of Life in Adult and Pediatric Patients with Hypermobile Ehlers-Danlos Syndrome: A Brief Review.

    Hertel A, Black WR, Malloy Walton L, et al.

    Current cardiology reviews 2024; doi:10.2174/011573403X271096231203164216.

    PMID: 38275067
  22. 22

    Some cases of hypermobile Ehlers-Danlos syndrome may be rooted in mast cell activation syndrome.

    Afrin LB

    American journal of medical genetics. Part C, Seminars in medical genetics 2021; (187(4)):466-472 doi:10.1002/ajmg.c.31944.

    PMID: 34719842
  23. 23

    Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series.

    Weinstock LB, Nelson RM, Blitshteyn S

    Journal of personalized medicine 2023; (13(11)) doi:10.3390/jpm13111562.

    PMID: 38003876
  24. 24

    Can H2 -receptor upregulation and raised histamine explain an anaphylactoid reaction on cessation of ranitidine in a 19-year-old female? A case report.

    Allen SJ, Chazot PL, Dixon CJ

    British journal of clinical pharmacology 2018; (84(7)):1611-1616 doi:10.1111/bcp.13578.

    PMID: 29667234

This page explains the biology and subtypes of POTS for educational purposes only. It is not a substitute for professional medical advice or a formal diagnosis by your healthcare team.

Stay up to date

Get notified when new research about Postural Orthostatic Tachycardia Syndrome (POTS) is published.

No spam. Unsubscribe anytime.