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PubMed This is a summary of 24 peer-reviewed journal articles Updated
Cardiology

The Biology of POTS: Subtypes and Related Conditions

At a Glance

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.

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.

Common questions in this guide

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 to Ask Your Doctor

Curated prompts to bring to your next appointment.

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

Questions For You

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References

References (24)
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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.

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