Postural orthostatic tachycardia syndrome

POTS is typically triggered by an event involving immunological stress.[1] A viral infection (often upper respiratory or gastrointestinal) is the most common precipitant and is reported in 20% to 50% of patients.[1][11][12][13][14][15] Pathogens commonly linked to POTS include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Epstein Barr virus.[16] Other precipitants include physical trauma (such as concussion), menarche, pregnancy, and surgery.[1][11][13][17] Hormonal changes during pregnancy affect peripheral vascular resistance and blood volume, which may trigger orthostatic intolerance, particularly early in pregnancy (i.e., the first trimester).[18]

Patients may also have a genetic disposition for POTS.[1][11] There is increased prevalence (up to 14%) of POTS in family members of affected people compared with the general population.[1][11] Although there is no evidence for a single causative gene, polymorphisms in many genes have been identified in several case series.[1][19][20]

Several different pathophysiological mechanisms for POTS have been proposed, although these are poorly understood.[1][4] These mechanisms overlap and a patient may often have features of more than one mechanism.[1][4]

Immune dysfunction

Immune dysfunction may play a role in POTS.[1] Many patients with POTS report an infectious prodrome before the onset of orthostatic symptoms.[1][11][13] In addition, patients with POTS and their close relatives have a higher prevalence of autoimmune disorders such as coeliac disease, Hashimoto’s thyroiditis, Sjogren syndrome, and systemic lupus erythematosus than the general population.[21][22][23][24]

A few studies have reported that some patients with POTS have elevated levels of autoantibodies, which act as partial agonists to alpha- and beta-adrenergic receptors.[25][26][27] This may cause the typical postural and cardiovascular features seen in POTS.[28] Despite these findings, a definite link between autoantibodies and POTS has not been established.[1]

Abnormal cardiovascular physiology

Some 70% of patients with POTS have absolute hypovolaemia, with low plasma and red blood cell volume.[1][2][4][5][6] Hypovolaemia in POTS is due to impaired regulation of plasma volume, which occurs as a result of reduced ability of the renin-angiotensin-aldosterone system to expand the blood volume.[1][2][6][29][30][31] Hypovolaemia causes reduced systemic venous return and reduced cardiac output, with subsequent reflex tachycardia and orthostatic intolerance.[6][7]

Many patients with POTS also have reduced left ventricular mass, low stroke volume, and impaired cardiac filling due to cardiovascular deconditioning, which can further contribute to hypovolaemia and symptoms of POTS.[1][2] However, it is unclear whether cardiovascular deconditioning is a primary cause of POTS, or caused by avoidance of exercise due to orthostatic symptoms.[2]

Excessive sympathetic activation

Patients with hyperadrenergic POTS may have abnormally increased sympathetic activity and circulating catecholamine excess.[1][2]

Peripheral autonomic dysfunction

Many patients with POTS have peripheral autonomic denervation, which leads to venous pooling, relative central hypovolaemia, and low blood volume (absolute hypovolaemia).[1][2][4] This is particularly seen with neuropathic POTS.

Types of POTS

Hypovolaemic

Up to 70% of patients with POTS have absolute hypovolaemia, with low plasma and red blood cell volume.[1][2][5][6] Hypovolaemia causes reduced systemic venous return and reduced cardiac output, with subsequent reflex tachycardia and orthostatic intolerance.[6][7]

Hyperadrenergic

Hyperadrenergic POTS is associated with increased sympathetic response and excess circulating catecholamine.[1][2] Patients will have orthostatic hypertension (increase in systolic blood pressure ≥10 mmHg after standing for 10 minutes).[2]

Neuropathic

Neuropathic POTS is associated with peripheral venous pooling and reduced effective intravascular volume, which is caused by peripheral sympathetic denervation.[1][2]

POTS and related syndromes

A position statement by the Canadian Cardiovascular Society has proposed a different framework to current US guidelines for classifying POTS and its related syndromes, on the basis of limitations of the current nomenclature and overdiagnosis of POTS.[4]

POTS

The patient must meet the diagnostic criteria - see Criteria.[4]
The patient should have significant orthostatic symptoms, which should be dominant in the clinical presentation and get better with a supine position. There are no specific cardinal symptoms, and no minimum number of symptoms required for diagnosis.[4]

POTS plus

The patient must meet all the criteria for POTS - see 'POTS' above.[4]
In addition, the patient should have one or more debilitating non-cardiovascular symptom(s).[4]
The patient may also have additional associated comorbidities, such as migraine headaches or Ehlers-Danlos syndrome. These comorbidities and the POTS symptoms may or may not have a common underlying cause.[4]

Postural symptoms without tachycardia (PSWT)

The patient has symptoms of orthostatic intolerance, but does not meet the criteria for POTS - see 'POTS' above. There may be lots of underlying causes for the patient’s symptoms.[4]

PSWT plus

The patient has symptoms of orthostatic intolerance, but does not meet the criteria for POTS - see 'POTS' above. There may be lots of underlying causes for the patient’s symptoms.[4]
In addition, the patient should have one or more debilitating non-cardiovascular symptom(s).[4]
The patient may also have additional associated comorbidities, such as migraine headaches or Ehlers-Danlos syndrome. These comorbidities and the POTS symptoms may or may not have a common underlying cause.[4]

Postural tachycardia of other cause

The patient meets the criteria for POTS (see 'POTS' above) with the exception that there is a clear, secondary underlying cause for their symptoms.[4]

Asymptomatic orthostatic tachycardia

The patient meets the criteria for POTS (see 'POTS' above) but with the exception that they are asymptomatic or minimally symptomatic.[4]

Inappropriate sinus tachycardia

Defined as sinus heart rate >100 bpm at rest (with a mean 24-hour heart rate >90 bpm), that is not due to a primary underlying cause, and is associated with distressing symptoms of palpitations.[4]

[Figure caption and citation for the preceding image starts]: Proposed framework for postural orthostatic tachycardia syndrome (POTS) and related disordersRaj SR et al. Can J Cardiol. 2020 Mar;36(3):357-72; used with permission [Citation ends]. com.bmj.content.model.Caption@4a3cf98a

Pathophysiology

Classification

Types of POTS

POTS and related syndromes