Dr Graham Exelby March 2025
Part of major review of POTS based on causes, drivers demonstrating the linking between inflammation, immune dysregulation, metabolic dysfunction, DNA mutations and mechanical drivers. The full folio is expected to be loaded in the next month
Abstract
Postural Orthostatic Tachycardia Syndrome (POTS) is a complex, multifactorial disorder characterized by autonomic dysfunction, central sensitization, and metabolic disturbances. While traditionally classified as a disorder of orthostatic intolerance, emerging evidence suggests that POTS shares pathophysiological mechanisms with chronic fatigue syndrome (CFS/ME), fibromyalgia (FMS), Gulf War Syndrome (GWS), and Long COVID. These conditions appear to converge through mitochondrial dysfunction, brainstem hypoxia, baroreceptor dysregulation, venous and lymphatic congestion, and chronic inflammatory feedforward loops.
Tissue hypoxia, evident in “coat hanger” pain and brainstem hypoperfusion, we believe provides the primary unifying pathology behind POTS, Chronic Fatigue Syndrome, Fibromyalgia and Long COVID. This is associated with immune system, mitochondrial and metabolic dysfunction that in turn leads to autonomic dysfunction and the chronic inflammatory feedforward loops that typify these conditions.
Immune dysregulation in the TLR4/NF-κB/RAGE/CCL2 axis is emerging as a central driver of neuroinflammation, oxidative stress, and immune activation, linking these disorders through persistent immune dysregulation. Genetic predispositions, particularly mutations affecting TLR4, CCL2, mast cells, STAT3, PEMT, COMT, oxidative stress, and methylation pathways, further exacerbate immune dysfunction and metabolic failure, perpetuating chronic symptoms.
The self-sustaining inflammatory loop that is formed until underlying causes driving the immune dysregulation are controlled or removed, disrupts nervous system homeostasis and vascular function, offering a unifying model to explain the overlapping symptomatology across these conditions. This TLR4/NF-κB/RAGE/CCL2 axis and immune dysregulation can be identified in all “activators” and “drivers” in POTS, as well as comorbidities.
The mechanistic underpinnings of POTS appear multifactorial, involving metabolic dysfunction, preload failure, intracranial hypertension (ICH), and progressive brainstem hypoperfusion, all of which converge to impair autonomic regulation.
Brainstem dysfunction, in particular, is emerging as a central unifying factor in POTS, given its role in coordinating baroreflex function, cerebral autoregulation, and immune signalling.
Additionally, hydraulic dysfunctions, including internal jugular vein (IJV) obstruction, thoracic outlet syndrome (TOS), Nutcracker syndrome, May-Thurner syndrome, and impairments in the glymphatic, lymphatic, and cerebrospinal fluid (CSF) Canalicular System, contribute to preload failure, intracranial hypertension, and cerebrovascular instability in POTS and its comorbid conditions. Mechanical factors such as neck trauma, Ehlers-Danlos Syndrome (EDS), and Chiari malformations further exacerbate these dysfunctions, influencing cerebrovascular dynamics and exacerbating migraine and other neurological symptoms.
This folio synthesizes key pathophysiological insights, emphasizing the intricate interplay between immune dysregulation, metabolic dysfunction, and vascular instability in POTS and related syndromes. It highlights the urgent need for a comprehensive, multidisciplinary treatment approach that integrates structural, metabolic, and neuroimmune interventions, moving beyond conventional compression therapy and pharmacologic symptom management.
Full paper to follow
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