How does postural orthostatic tachycardia syndrome cause fatigue?

How POTS Causes Fatigue

POTS causes fatigue through multiple interconnected mechanisms: cerebral hypoperfusion from inadequate blood flow to the brain during upright posture, excessive sympathetic nervous system activation that depletes energy reserves, hypovolemia (low blood volume) that reduces oxygen delivery, and physical deconditioning that perpetuates exercise intolerance. 1, 2, 3

Primary Pathophysiologic Mechanisms

Cerebral Hypoperfusion

• The fundamental problem in POTS is impaired blood flow to the brain when standing, leading to symptoms of cerebral hypoperfusion including extreme fatigue, lightheadedness, and mental clouding ("brain fog"). 2, 3
• Despite the compensatory tachycardia (heart rate increase ≥30 bpm), blood pressure regulation fails to maintain adequate cerebral perfusion in the upright position, forcing the body into a chronic state of physiologic stress. 1, 4
• This inadequate oxygen delivery to the brain manifests as profound fatigue, cognitive difficulties, and exercise intolerance that worsens throughout the day. 1, 3

Excessive Sympathetic Activation

• POTS patients demonstrate excessive sympathoexcitation with high levels of upright plasma norepinephrine, reflecting chronic sympathetic nervous system overdrive that is metabolically exhausting. 2, 3
• The hyperadrenergic state—characterized by pallor, sweating, tremor, and palpitations—represents a continuous "fight-or-flight" response that depletes energy reserves and contributes to overwhelming fatigue. 4, 2
• This sympathetic overactivity occurs because of either impaired sympathetically mediated vasoconstriction (requiring more compensatory effort) or excessive sympathetic drive itself. 2

Hypovolemia and Volume Dysregulation

• Many POTS patients have low blood volume (hypovolemia), which reduces oxygen-carrying capacity and forces the cardiovascular system to work harder to maintain perfusion, directly contributing to fatigue. 2, 3, 5
• The hypovolemic phenotype is particularly associated with dehydration and physical deconditioning, creating a vicious cycle where fatigue leads to inactivity, which worsens blood volume regulation. 5

Physical Deconditioning

• Deconditioning is both a cause and consequence of POTS—initial symptoms lead to reduced activity, which further impairs cardiovascular fitness and autonomic regulation, perpetuating severe fatigue and exercise intolerance. 1, 2
• The inability to maintain normal activity levels after illness or injury (common in adolescent POTS) creates a downward spiral where fatigue begets more deconditioning. 6

Secondary Contributing Factors

Multisystem Symptom Burden

• POTS patients frequently experience additional symptoms beyond orthostatic intolerance—including functional gastrointestinal disorders, chronic headache, fibromyalgia, and sleep disturbances—all of which compound fatigue. 2
• The constellation of symptoms (headache, nausea, abdominal discomfort, chest pain) creates a cumulative burden that significantly impairs quality of life and energy levels. 1, 4, 6

Postexertional Malaise

• Patients with POTS often report postexertional malaise similar to chronic fatigue syndrome, where even minimal physical or cognitive exertion triggers disproportionate and prolonged fatigue. 1, 4
• This overlap with chronic fatigue syndrome/ME/CFS suggests shared pathophysiologic mechanisms involving autonomic dysfunction and impaired energy metabolism. 1

Temporal Pattern and Exacerbating Factors

• Fatigue in POTS characteristically worsens in the morning, with heat exposure, after meals, and with exertion—reflecting the dynamic nature of autonomic dysfunction throughout the day. 4
• Symptoms develop upon standing and are relieved by sitting or lying down, demonstrating the direct relationship between postural stress and fatigue severity. 1, 4

Clinical Implications

Phenotype-Specific Mechanisms

• The three primary POTS phenotypes (hyperadrenergic, neuropathic, and hypovolemic) each contribute to fatigue through distinct but overlapping mechanisms, requiring tailored assessment. 5
• Hyperadrenergic POTS causes fatigue through excessive norepinephrine production; neuropathic POTS through impaired vasoconstriction requiring compensatory effort; hypovolemic POTS through reduced circulating volume. 5

Common Pitfall

• Do not dismiss fatigue in POTS as purely psychological—while cognitive and behavioral factors may contribute to symptom chronicity, the fatigue has clear physiologic underpinnings in autonomic dysfunction and cerebral hypoperfusion. 2
• However, recognize that somatic hypervigilance associated with anxiety and depression can amplify symptom perception and disability. 2