The Unifying Hypotheses to understand the processes Driving POTS, how hypoxia, neuroimmune Dysregulation and Autonomic Dysfunction in POTS, Long COVID, and Fibromyalgia are Interconnected.
Dr Graham Exelby March 2025
Abstract:
This paper presents a unifying pathophysiological model for Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, and Fibromyalgia (FMS), integrating hypoxia-induced neuroimmune activation, mitochondrial dysfunction, autonomic instability, and central sensitization. The core hypothesis proposes that diverse triggers such as infection, trauma, or metabolic stress initiate a self-sustaining inflammatory cascade driven by the RAGE receptors which are self-promoting until the source of the hypoxia is removed. Multiple immune pathways are involved, and this cascade is amplified by mast cell activation, impaired venous and lymphatic drainage, and mitochondrial energy deficits, culminating in sustained neuroinflammation and autonomic dysregulation.
Central to this model is brainstem hypoperfusion, which disrupts baroreflex sensitivity, vagal tone, and neurovascular regulation. Metabolic profiling reveals glutamate excess, GABA depletion, and aspartate deficiency as consistent biochemical features, underpinning post-exertional malaise and energy failure. By delineating predisposing genetic vulnerabilities, initial immune-metabolic activators, and chronic drivers of disease, this framework proposes novel avenues for individualized diagnostics and targeted therapeutic strategies.
Introduction
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 is evident in “coat hanger” pain and brainstem hypoperfusion, but also part of the pathology of venous compression syndromes eg Nutcracker, Stylohyoid and May-Thurner Syndromes. We believe hypoxia provides the key to the 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.
Hypoxia-driven immune dysregulation in the RAGE/NFKB/CCL2, TLR4/NF-κB/RAGE/CCL2 axis activated by DAMPs (damage associated molecular patterns,) a byproduct of hypoxia, is emerging as a central driver of neuroinflammation, oxidative stress, and immune activation, linking these disorders through persistent immune dysregulation.
RAGE serves as a key interface between immune activation, oxidative stress, and chronic inflammation, and RAGE overactivation in hypoxic conditions fuels a self-sustaining inflammatory cycle through NF-κB and CCL2-mediated pathways, leading to persistent autonomic dysfunction, cognitive impairment, and neuroinflammatory sensitization.
Two primary pathways contribute to RAGE hyperactivation in hypoxic environments:
The persistence of hypoxia-driven RAGE activation leads to sustained microglial and astrocytic activation, which recovers more slowly than other RAGE-expressing tissues, perpetuating long-term autonomic and cognitive dysfunction. Genetic predispositions, particularly mutations affecting TLR4, CCL2, mast cells, STAT3, PEMT, COMT, oxidative stress, glycation and methylation pathways, further exacerbate immune dysfunction and metabolic failure, perpetuating chronic symptoms.
Glycation is the process where reducing sugars spontaneously (non-enzymatically) bind to proteins, lipids or nucleic acids and result in production of advanced glycation end-products (AGEs.) It is implicated in aging, diabetic complications, collagen and the skin changes, many degenerative diseases including Alzheimers Disease, chronic renal disease and arteriosclerosis.
RAGE, the receptor for advanced glycation end-products is a pattern recognition transmembrane receptor, and RAGE activation is both a consequence and driver of metabolic dysfunction, insulin resistance, and altered glucose metabolism. AGEs contribute to a vicious cycle of inflammation, oxidative stress, and tissue damage, central to diabetes, obesity, and cardiovascular disease, and form a large part of understanding the chronic inflammation in POTS, FMS, Long COVID and Gulf War Syndrome.
The self-sustaining inflammatory loop that is formed as a consequence of tissue hypoxia 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 DAMP/RAGE and 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.
Until “activated,” there may be few clues to underlying mechanical problems such as venous obstruction, although clinically in an overt POTS or Fibromyalgia they are usually clues to be found. Thus a patient who has POTS following glandular fever, or surgery or neck trauma is usually completely unprepared for the symptoms they are presented with, especially if their medical advisers concentrate only on controlling the symptoms such as tachycardia and stocking for the venous pooling.
Close examination of causes of sensitisation, autonomic instability (dysautonomia,) fatigue, post-exertional malaise (PEM), inflammation, and symptoms of intracranial pressure and venous flow change (usually labelled as migraine or stress etc) provides an insight into the complex nature of these conditions, and with this, provides tools for dealing with the causes of the tissue hypoxia and follow-on dysfunction.
Whatever the source of the “activation” in POTS, it is hypoxia with its secondary immune and metabolic dysregulation that we believe primarily continues the inflammatory process, complicated by the variety of stressors that results in the symptoms seen in POTS. Examination of symptoms and co-morbidities provides the clues for patients for the ongoing symptoms and for most, a way to control or remove them. With the feed forward looping from RAGE receptor activation symptoms may continue until the source of the hypoperfusion is dealt with.
Contents of this Part- The Unifying Hypotheses:
1. Hypoxia-Driven RAGE Activation: A Core Pathophysiology
2. The Neurometabolic Model of PEM and Central Sensitisation
3. Modified Geddes Hypothesis: Hydraulic and Vascular Dysregulation
4. The Azygous System and preload dysfunction in POTS patients
5. Brainstem Hypoxia in POTS, CFS, Long COVID, fibromyalgia, and GWS.
Mast Cell Activation as a Driver of Central Sensitization in POTS, Long COVID, and Fibromyalgia: Mechanistic Hypotheses and the Role of Collagenase
7. Glutamate/Aspartate Dysfunction
8. GABA/Glutamate Balance and Its Role in Dysautonomia and Mitochondrial Dysfunction
9. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction in POTS
10. Intracranial Hypertension, venous and lymphatic flow dysfunction.
11. Overall Conclusion
Full paper following
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