Introduction

Postural Orthostatic Tachycardia Syndrome, or POTS, is a chronic condition that can be life-altering for those who live with it. It is characterised by an excessive increase in heart rate upon standing and is often accompanied by dizziness, weakness, fatigue, brain fog, heart palpitations, and fainting. It is one of several disorders that fall under the umbrella of dysautonomia, which refers to dysfunction of the autonomic nervous system. The autonomic nervous system controls involuntary bodily functions like heart rate, blood pressure, and digestion.¹

Research suggests POTS may arise from a mix of causes, including genetic predispositions, autoimmune responses, or as a secondary condition linked to other illnesses or diseases. Understanding what causes POTS is essential  not only for patients and families but also for healthcare providers trying to find the right treatment.¹ From understanding POTS, this article will explore the causes behind POTS, highlighting current research, and explaining its importance and relevance.

What is POTS, and who does it affect?

POTS primarily affects women aged 15 to 45, though it can affect anyone regardless of age or sex. The prevalence of POTS, how common it is in the general population, is estimated to be between 0.2% and 1%. On average, it takes years for patients to get a POTS diagnosis, primarily due to a lack of awareness and variability in symptoms.¹ Understanding and knowing these symptoms may save someone’s life. 

There are several subtypes of POTS:

• Neuropathic POTS: Characterised by damage or dysfunction in the small nerve fibres that regulate blood flow¹
• Hyperadrenergic POTS: Characterised by an overactivation of the sympathetic nervous system, which is part of the autonomic nervous system and is commonly known as the “fight or flight” response. This leads to high levels of norepinephrine, affecting heart rate, blood flow, and digestion, among other things¹
• Hypovolemic POTS is characterised by low blood volume, which can lead to poor circulation and a rapid heart rate when standing

POTS is a complex condition; these categories can overlap, and not all causes are fully understood, often making POTS a complex and sometimes confusing diagnosis. These subtypes of POTS can help you better understand and manage the disease. 

Genetic causes of POTS

Although POTS is not considered an inherited disorder, there is growing evidence that genetics plays a role in its development. Many patients report a family history of similar symptoms, with 14% of POTS patients having a family member with a POTS diagnosis, suggesting a hereditary component.²

Genetic studies are still in their early stages, but some researchers believe that genes regulating the autonomic nervous system, blood vessels, and fluid regulation could be involved. For example, a gene which regulates the level of norepinephrine, a chemical signal used by the nervous system, is altered in patients with POTS. Patients also exhibit changes in genes that regulate the immune system and autoimmunity, which may contribute to POTS development.

No single gene has been identified as the main cause of POTS. In fact, due to its complexity, the genetic predisposition behind POTS is likely attributable to several genes. It is also likely that POTS results from a complex interaction between genetic changes and environmental triggers. Further research into larger studies evaluating the genetic links to POTS needs to be conducted to better understand its causes.³

Autoimmune causes of POTS

Another promising area of research points to autoimmunity as the root cause. Autoimmune diseases occur when the body’s immune system mistakenly attacks its cells and tissues.¹

In POTS, some patients have been found to carry autoantibodies, which are proteins secreted by immune system cells that incorrectly target one’s own cells and can disrupt normal nervous system function. For instance, approximately 1 in 4 POTS patients have elevated levels of anti-nuclear antibodies (ANA), and a recent study showed 76% of POTS patients had high levels of antiphospholipid antibodies.^1,2 Antibodies attacking receptors for acetylcholine, a chemical signal used by the nervous system, have also been found in POTS patients.³

Autoimmune links are further supported by the fact that people with POTS are also more likely to have autoimmune diseases, with 15-20% of patients reporting an autoimmune disease history, including diseases such as:^1,2

• Lupus
• Sjögren’s syndrome
• Hashimoto’s thyroiditis
• Rheumatoid arthritis

Recent attention has also focused on post-viral POTS, developed after an infection, especially after COVID-19. Many people who developed long COVID, where symptoms persist for weeks or months after infection, met the diagnostic criteria for POTS. POTS has been linked to a variety of infections, but most commonly viral infections in the respiratory or gastrointestinal tracts. It is estimated that in about 20-50% of patients, a previous infection played a significant role in the development of POTS.²

However, proving that changes in the immune system directly cause POTS is difficult. The immune system is incredibly complex, and not all patients with POTS have identifiable autoantibodies. Medical professionals also argue that autoimmunity is not likely to be the only cause of POTS. Still, research is ongoing and may lead to new treatments in the future, such as immune-modulating therapies, which regulate how the immune system works, for certain subgroups of patients.³

Secondary causes: POTS as a symptom of other conditions

POTS can also develop secondary to another medical condition. This means the syndrome arises as a complication or symptom of something else. Often, the primary condition affects blood vessels, nerve cells, blood flow, or the immune system.³ There may be other secondary conditions that complicate the original diagnosis of POTS

Some conditions associated with POTS include:

• Ehlers-Danlos Syndrome (EDS): This condition can cause stretchy skin, joint hypermobility, and fragile blood vessels. When blood vessels are too stretchy or weak, the body struggles to maintain blood pressure during position changes, especially when standing, contributing to POTS-like symptoms. EDS patients often show a gradual onset of POTS, with symptoms developing over years. POTS symptoms occur in about 20-40% of EDS patients^1,2
• Diabetes and Neuropathy: Long-term diabetes can damage small nerve fibres, a condition called small fibre neuropathy, which impairs the autonomic nervous system and affects heart rate and blood pressure control³
• Chronic Fatigue Syndrome (ME/CFS): There’s a significant overlap between POTS and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Both conditions involve fatigue, exercise intolerance, and autonomic dysfunction. Approximately 10-15% of people with ME/CFS may also meet the criteria for POTS¹
• Mast Cell Activation Syndrome (MCAS): MCAS is a disorder where mast cells, cells of the immune system, release too many inflammatory chemicals. This can cause flushing, hives, stomach issues, and cardiovascular symptoms. Some patients with POTS have overlapping MCAS symptoms and are more likely to suffer from gastrointestinal symptoms compared to other POTS patients²
• Physical Triggers: Illness, Injury, and Deconditioning: Sometimes, POTS can begin after a physical stressor like a severe illness, surgery, or even prolonged bed rest. When the body is inactive for long periods, blood vessels and muscles weaken, leading to poor blood flow upon standing. This is often referred to as "deconditioning" and can both trigger and worsen POTS symptoms¹
• Hormonal and Nutritional Imbalances: Low blood volume, or hypovolemia, iron deficiency, and even thyroid disorders can influence autonomic function. In some cases, correcting these imbalances can improve or resolve POTS symptoms, especially when caught early^1,2

Putting it all together: a complex puzzle

The causes of POTS are diverse and often overlapping. One person might develop POTS due to genetic vulnerability, while another develops it after a viral infection. For some, multiple factors combine, such as an underlying autoimmune disease, hormonal changes, and a physical trigger like illness or injury.³

That’s why POTS is often described as a syndrome rather than a disease; it is a cluster of symptoms that can arise from different root causes. This makes treatment complicated, but it also means there are many paths to potential relief. For example:

• People with hypovolemia may benefit from increased salt and fluid intake¹
• Those with autoimmune involvement might respond to medications that regulate the immune system¹
• Patients with deconditioning may improve with carefully monitored physical therapy¹
• In some cases, medications that regulate blood pressure and heart rate can be effective³

Conclusion

While much about POTS remains unknown, recent research has significantly advanced our understanding. Knowing the causes behind POTS can help patients and doctors approach diagnosis and treatment in a more personalised way. Organisations such as Dysautonomia International and POTS UK provide resources, research updates, and community support. Spreading awareness of POTS can help facilitate faster diagnosis and increase research funding to explore the causes behind it, as well as support the development of new treatments.

Summary

• POTS (Postural Orthostatic Tachycardia Syndrome) causes a dramatic increase in heart rate when standing, and symptoms like dizziness, fatigue, and brain fog
• It mainly affects young women and has several subtypes, including neuropathic, hyperadrenergic, and hypovolemic POTS
• Genetic factors may predispose individuals to POTS, and individuals often have a family history
• Autoimmune causes involve antibodies that disrupt nervous system function and may be triggered by infections, in particular, viral infections, such as COVID-19
• Secondary causes include EDS, diabetes, chronic fatigue syndrome, mast cell disorders, deconditioning, and hormonal imbalances
• POTS often has multiple contributing factors, with various causes affecting the development of the disease