What are the causes of Postural Orthostatic Tachycardia Syndrome (POTS)?

Causes of Postural Orthostatic Tachycardia Syndrome (POTS)

Postural Orthostatic Tachycardia Syndrome (POTS) has multiple etiologies including post-viral infections (particularly COVID-19), autoimmune disorders, genetic predisposition, and hypermobile Ehlers-Danlos syndrome, with up to 40% of cases following a viral illness. 1, 2

Primary Pathophysiological Mechanisms

POTS is characterized by autonomic nervous system dysfunction resulting in excessive heart rate increases upon standing. The main pathophysiological mechanisms include:

1. Neuropathic POTS

   • Peripheral autonomic denervation affecting sympathetic nervous system
   • Impaired vasoconstriction in lower extremities
   • Results in venous pooling and compensatory tachycardia 1, 2

2. Hyperadrenergic POTS

   • Excessive sympathetic nervous system activation
   • Elevated plasma norepinephrine levels
   • May involve increased activity of norepinephrine transporter protein 1

3. Hypovolemic POTS

   • Reduced blood volume
   • Impaired renin-angiotensin-aldosterone system
   • Decreased red blood cell volume 2

4. Autoimmune POTS

   • Presence of autoantibodies against adrenergic receptors (particularly α1 receptors - 89% of patients)
   • Autoantibodies against muscarinic acetylcholine receptors (M4 receptor - 53% of patients)
   • Other autoantibodies including antinuclear antibody, Sjogren's antibodies 1, 3

Secondary Causes and Associated Conditions

Post-Infectious

• Up to 40% of POTS cases report preceding viral respiratory or GI infection 1
• Post-COVID-19 POTS (2-14% of COVID-19 survivors develop POTS) 2
• Part of post-acute COVID-19 syndrome (PASC) 2

Connective Tissue Disorders

• Hypermobile Ehlers-Danlos syndrome (hEDS)
• Hypermobility spectrum disorders (HSDs)
• Altered connective tissue microstructure leading to vascular laxity 1

Mast Cell Activation Syndrome (MCAS)

• Often coexists with POTS
• Abnormal mast cell degranulation causing multisystemic symptoms
• In one study, 25.2% of MCAS patients had POTS 1

Other Associated Conditions

• Chronic fatigue syndrome 2
• Autoimmune disorders (increased prevalence in POTS patients and family members) 1
• Deconditioning following prolonged bed rest or illness 4
• Endocrine disorders (thyroid dysfunction) 2

Demographic and Temporal Patterns

• Predominantly affects females of childbearing age 5
• Often begins during adolescence, particularly 1-3 years after growth spurt 4
• May follow a period of inactivity from illness or injury 4
• Symptoms typically present for at least 6 months 1

Genetic Factors

• Family history of orthostatic intolerance or autonomic dysfunction
• Possible genetic predisposition affecting autonomic regulation
• May involve genetic variants affecting norepinephrine transporter function 6

Idiopathic POTS

• In some cases (approximately 10%), no clear etiology is identified 5, 3
• May represent complex interaction of multiple subtle pathophysiological factors

Clinical Implications

Understanding the specific cause of POTS in individual patients is crucial for targeted management. The pathophysiological heterogeneity explains why treatment responses vary significantly between patients. For example:

• Neuropathic POTS may respond better to volume expansion and vasoconstricting agents
• Hyperadrenergic POTS may benefit from beta-blockers
• Autoimmune POTS might warrant consideration of immunomodulatory approaches
• Post-infectious POTS typically improves gradually over time with supportive management

The high prevalence of autoimmune markers and post-infectious onset suggests immune dysregulation plays a significant role in many POTS cases, supporting emerging research into targeted immunological therapies 1, 3.