POTS Activators – Clinical Overview with Mechanistic Insights

Dr Graham Exelby May 2025

Abstract

Background:

Postural Orthostatic Tachycardia Syndrome (POTS) is a heterogenous dysautonomic condition that emerges following diverse physiological insults but converges on a remarkably conserved clinical phenotype—preload failure, central sensitization, neurovascular instability, and profound fatigue. Although viral, traumatic, immune, and environmental activators vary in nature, they appear to converge on common immunometabolic and neurovascular dysfunctions.

An under-recognized but pivotal role is played by mast cell activation, which modulates connective tissue dynamics, neurovascular sensitivity, and immune-amplifying responses—especially in fascia-rich regions such as the head, neck, and thoracic outlet.

Objective:

This paper proposes a unifying molecular framework in which POTS activators converge on key pathological hubs: autonomic dysregulation from brainstem hypoxia, cardiac and coeliac plexus dysfunction and the functional continuum uniting these and spinal and other mechanical factors, metabolic dysregulation from pyruvate dehydrogenase (PDH) inhibition, immune dysfunction from RAGE/TLR4/NF-κB pathway activation in people with predisposed genetic mutations, excitatory amino acid imbalance (low GABA/aspartate, high glutamate), and sustained mitochondrial and endothelial dysfunction.

Methods:

Drawing from clinical analysis of over 700 POTS cases, DNA studies and biochemical profiles, we integrate clinical observations with established immunometabolic mechanisms from Long COVID, post-infectious syndromes, and trauma literature. This synthesis is applied to categorize both overt activators and underlying vulnerabilities in a structured pathophysiological continuum.

Results:

Despite etiological diversity, activators exhibit shared molecular signatures: PDH suppression via PDK, sustained RAGE/inflammasome signalling, hypoxia-induced HIF-1α activation, collagen dysfunction and glutamate-driven excitotoxicity. These promote mitochondrial rigidity, autonomic imbalance, and neuroimmune sensitization.

Introduction

Postural Orthostatic Tachycardia Syndrome (POTS) is a multifaceted disorder of the autonomic nervous system, classically defined by exaggerated heart rate response to orthostatic stress but increasingly understood as a systemic neuroimmune and metabolic disease. Clinical symptoms—fatigue, orthostatic intolerance, cognitive dysfunction, gastrointestinal dysmotility, and sensory hypersensitivity—are underpinned by complex dysfunction in energy metabolism, neurovascular regulation, and immune signalling.

Historically, POTS has been attributed to dysautonomia of unknown cause. However, emerging evidence from post-viral syndromes (particularly SARS-CoV-2), immune-mediated disorders, and trauma-associated cases has shifted the paradigm toward a model of convergent pathophysiology.

Patients often report a precipitating event—an infection, trauma, surgery, vaccination, or toxic exposure—preceding onset. Notably, these external insults reveal a set of internal predispositions, ranging from mitochondrial fragility to immune dysregulation, connective tissue laxity, and impaired cerebral venous drainage.

POTS, Long COVID, Chronic Fatigue Syndrome and Gulf War Syndrome are unified through brainstem hypoxia, similar patterns of underlying DNA mutations, similar symptoms, similar patterns of amino acid and neurotransmitter dysfunction and similar “drivers.”

RAGE Activation as a Central Amplifier

We hypothesize that diverse POTS activators exert their pathogenic influence via a set of shared immunometabolic pathways, including:

• TLR4 and RAGE activation in response to PAMPs and DAMPs (e.g., HMGB1, viral RNA, advanced glycation end-products)

• Inflammasome-mediated IL-1β and IL-18 signalling perpetuating chronic low-grade inflammation

• PDH inhibition via PDK overactivation, impairing aerobic respiration and shifting metabolism toward glycolysis

• HIF-1α signalling, reflective of tissue-level hypoxia and venous congestion, particularly in patients with jugular vein reflux or impaired cerebral autoregulation and posture-related cerebral perfusion defects.

• Excitatory amino acid imbalance, with implications for autonomic dysregulation, neurotransmission, and immune modulation

• Mitochondrial oxidative stress and redox collapse, compounding energy failure under orthostatic and cognitive load

  
  

A unifying mechanism emerging across POTS activators is the chronic activation of the Receptor for Advanced Glycation End Products (RAGE), particularly in response to hypoxia and DAMP accumulation. RAGE is a pattern recognition receptor expressed on microglia, astrocytes, endothelium, and neurons, and becomes hyperactivated by ligands such as HMGB1, S100A8/9, oxidized phospholipids, and Serum Amyloid A (SAA). When triggered, RAGE initiates a self-perpetuating inflammatory loop involving NF-κB, MAPK, and IL-6/STAT3 signalling. This amplifies microglial priming, endothelial dysfunction, and neurovascular sensitization.

SAA appears to be the most potent and persistent RAGE ligand, induced under hypoxic conditions, and contributes to amyloidogenic coagulopathy, as seen in persistently elevated D-dimers. Critically, RAGE–SAA–IL-6 signalling intersects with PDH inhibition and mitochondrial dysfunction, placing RAGE as a central amplifier of both immune and metabolic failure in POTS. This axis also enhances mast cell–fibroblast crosstalk in fascia-dense regions, linking environmental triggers with fascial stiffening and neuroimmune hypersensitivity. Full mechanisms are detailed in our accompanying paper, RAGE Activation: A Central Amplifier in POTS (Exelby, 2025).

Integral to these mechanisms is mast cell activation, which serves as a first responder to environmental and endogenous stressors. Mast cells interface directly with peripheral nerves, endothelial linings, and fascial structures, releasing vasoactive amines (histamine, tryptase), cytokines (IL-6, TNF), and growth factors (TGF-β, VEGF) that drive vasodilation, neurogenic inflammation, and fibrosis. Clinically, this is evident in regional fascial stiffness, cervical tension, and sensitization patterns involving the trapezius, splenius capitis, and suboccipital regions. Dysregulated mast cell activity, whether driven by mycotoxins, stress, or trauma, contributes to both the initiation and perpetuation of neuroimmune dysregulation in POTS.

This paper classifies common POTS activators observed in clinical practice and links each to its predominant pathophysiological mechanism. By mapping these triggers to downstream dysfunctions, we aim to provide a clinical guide and mechanistic model to support individualized treatment strategies.

This section provides a structured clinical overview of common POTS activators seen in practice, annotated with molecular and physiological mechanisms through which they precipitate autonomic dysfunction. Each will be expanded in subsequent focused papers.

POTS Activators and Underlying Dysfunctions seen commonly in clinic

COVID

• SARS-CoV-2 spike protein activates TLR4 and RAGE, inducing NF-κB–driven cytokine production (IL-1β, IL-6, TNF).

• PDH inhibition via PDK activation results in impaired aerobic metabolism, increased lactate, and fatigue.

• Amino acid dysregulation: low GABA/aspartate and elevated glutamate contribute to excitotoxicity and central sensitization.

• Persistent endothelial dysfunction, microthrombosis, and amyloid-fibrin persistence elevate neurovascular resistance.

• Hypoxia-driven HIF-1α signaling observed in jugular and vertebral venous congestion, and intracranial hypertension worsens cerebral autoregulation.

• Mitochondrial injury reduces metabolic flexibility, particularly under orthostatic and exertional stress.

• Reactivation of latent viruses (e.g., EBV) and persistent DAMP/PAMP signaling maintains immune overactivation.

Post-Vaccination Syndromes

• COVID mRNA and other adjuvanted vaccines in suspectable people may hyperactivate TLR4 and RAGE in genetically predisposed individuals.

• Potential RAGE-mediated autoantibody formation, especially given data showing autoantibodies in some vaccine-associated POTS patients. This reflects possible antigen–antibody complex formation and immune amplification

• This immune amplification can mimic post-infectious POTS via PDH suppression, IL-1β/IL-6 elevation, and endothelial inflammation.

• Microglial priming and excitatory amino acid imbalance may sustain central sensitization post-vaccination.

• Increased CCL2-driven monocyte recruitment may sustain neuroinflammation and autonomic instability.

• In some cases, mast cell degranulation may contribute to the initial cascade, through cross-linking of IgE or TLR4 priming in predisposed individuals, contributing to rapid-onset dysautonomia and fascial hypersensitivity.

Physical Trauma or Surgery

• Trauma induces mechanical venous outflow impairment, which can lead to microvascular ischaemia and DAMP release, triggering RAGE activation and TLR4-mediated inflammation in the cervical and vertebral region

• Physical trauma especially to neck or orthopaedic instability can disrupt spinal autonomic afferents.

• Vertebral or coccygeal compression may impair sacral and pelvic parasympathetic circuits.

• Prolonged backpack or occupational strain may provoke Thoracic Outlet Syndrome, sensitize critical regions in T4 and T8 region leading to venous and lymphatic congestion and coeliac plexus sensitization.

Pregnancy and Postpartum Period

• Marked hormonal shifts (estrogen, progesterone, relaxin) affect vascular tone, baroreflex function, and mast cell activation.

• Increased venous pressure and IVC compression during pregnancy can precipitate preload failure and cerebral venous congestion.

• Postpartum involution and immune reactivation may trigger autoimmune flares and post-infectious phenomena.

• Elevated relaxin and connective tissue laxity may unmask structural vulnerabilities such as Nutcracker or MALS.

Severe Psychological Stress

• Sustained activation of the HPA axis increases cortisol, which suppresses immune regulation and augments NF-κB signalling.

• Chronic sympathetic activation alters norepinephrine transporter (NET) function, leading to hyperadrenergic symptoms.

• Stress also depletes GABAergic tone and ethanolamine, contributing to excitotoxicity and central sensitization.

• Enhanced TLR4 responsiveness observed in stress-prone states increases vulnerability to immune triggers.

PTSD

• Characterized by persistent sympathetic overdrive, vagal withdrawal, and baroreceptor desensitization.

• Neuroimmune priming via RAGE and TLR4 pathways contributes to heightened inflammatory responsiveness.

• Associated with GABA-glutamate imbalance and hippocampal dysfunction exacerbating dysautonomia and fatigue.

Prolonged Mould or Chemical Exposure

• Mycotoxins (e.g., ochratoxin A, trichothecenes) directly activate TLR4, induce oxidative stress, and impair mitochondrial enzymes.

• Environmental aldehydes and volatile organic compounds activate the RAGE axis and provoke mast cell destabilization and blood-brain barrier dysfunction.

• Mast cells are particularly sensitive to environmental aldehydes, VOCs, and fungal antigens, serving as amplifiers of local inflammation and contributors to fascial changes.

• Hypoxia from sinus congestion or lungs may exacerbate RAGE-SAA signalling, not just direct chemical activation

• Sustained antigenic exposure fosters a feed-forward inflammatory loop and dysregulation of the coeliac and cardiac plexuses.

• Chronic exposure is also linked to lymphatic stasis, impaired detoxification, and ethanolamine depletion.

Blastocystis and Helicobacter Pylori

• Chronic gut infection disrupts epithelial barrier integrity and evokes persistent low-grade inflammation.

• Associated lymphatic congestion (due to venous angle compression) limits lacteal clearance and propagates immune stasis.

• Ethanolamine depletion (involved in membrane repair) hinders gut-barrier resolution and may impair microbial clearance.

• Feed-forward loop via antigenic stimulation sustains mucosal immune priming, amplifying central sensitization.

Lyme and similar disease

• Borrelia burgdorferi LPS and flagellin are potent TLR2/4 agonists, driving chronic neuroinflammation.

• Autoimmune mimicry and persistent immune stimulation contribute to post-infectious dysautonomia.

• Observed PDH suppression and metabolic shutdown similar to post-viral POTS.

• Elevated IL-6, CCL2, and mast cell activation contribute to vascular instability.

Underlying Dysfunctions Facilitating POTS Development

These systemic predispositions amplify vulnerability to external activators and contribute to chronic autonomic instability.

Immune Dysregulation

• Autoantibodies targeting adrenergic and muscarinic receptors alter autonomic tone and vascular responses.

• Elevated ANA, antiphospholipid antibodies, and thyroid autoantibodies suggest autoimmune overlap with POTS.

• Pro-inflammatory cytokine elevation (IL-1, IL-6, IL-21, TNF, IFN) drives sympathetic hyperactivity and endothelial dysfunction.

• Mast cell activation contributes not only to vascular instability and neuroinflammation but also promotes fibrosis and dysautonomia via interactions with fibroblasts, substance P, and CRH receptors, forming a neuro-immune-fascial axis.

Vascular Instability

• Connective tissue disorders (e.g., EDS) impair venous return and vessel compliance, promoting preload failure.

• Increased vascular capacitance and impaired vasoconstriction exacerbate orthostatic intolerance.

Gut-Brain Axis Disruption

• Chronic gut infections (e.g., Blastocystis, H. pylori) provoke systemic immune activation via mucosal inflammation.

• Lymphatic congestion (e.g., at venous angles) impairs gut detoxification and perpetuates parasitic resistance.

• Ethanolamine and phosphatidylcholine depletion impairs membrane repair and increases barrier permeability.

Mitochondrial Dysfunction

• Defects in oxidative phosphorylation and pyruvate entry (via PDH inhibition) limit ATP production under stress.

• Mitochondrial redox imbalance contributes to central fatigue, PEM, and poor orthostatic tolerance.

Postural Dysfunction with Brainstem Hypoperfusion

• Poor posture or vertebral misalignment impairs vertebrobasilar flow and brainstem perfusion.

• Brainstem hypoxia impairs nucleus tractus solitarius (NTS) and locus coeruleus (LC), disrupting autonomic integration.

  
  

Metabolic Impairment

• Aspartate depletion in PEM reflects disrupted urea cycle and malate-aspartate shuttle dysfunction.

• Chronic aspartate-GABA-glutamate imbalance reflects a collapsed metabolic buffer system under load.

  
  

Genetic Predispositions

• Variants in NET, PEMT, CCL2, TLR4, and connective tissue genes predispose to POTS via autonomic and immune vulnerability.

• NET polymorphisms impair noradrenaline clearance, promoting sympathetic overdrive and anxiety.

TLR4/RAGE/NF-κB/CCL2 Dysregulation

• Feed-forward inflammation loops involving DAMP/PAMP sensing pathways perpetuate neuroimmune sensitization.

• RAGE activation by AGEs, HMGB1, and mitochondrial debris sustains microglial priming and autonomic dysfunction.

Prolonged Immobility or Deconditioning

• Cardiovascular deconditioning reduces stroke volume, venous return, and baroreceptor sensitivity.   Deconditioning is NOT the cause in Long COVID

• Muscle atrophy impairs skeletal muscle pump function, worsening orthostatic intolerance.

Catabolic Metabolism

• Coat hanger pain describes the hypoxia-driven muscle depolarization with weakness, pain and move towards catabolic metabolism

Cerebrovascular Contributions

• Intracranial hypertension due to venous sinus anomalies or lymphatic congestion impairs cerebral autoregulation.

• Brainstem compression from structural anomalies disrupts cardiorespiratory centers.

Hormonal Dysregulation

• Puberty and menopause alter oestrogen-progesterone ratios affecting autonomic balance and vascular tone.

• Thyroid dysfunction and cortisol imbalances modulate baroreflex and adrenergic sensitivity.

Conclusion

Postural Orthostatic Tachycardia Syndrome is not a singular disease but a final common pathway for a wide array of immunometabolic and neurovascular insults. Whether triggered by viral pathogens like SARS-CoV-2, environmental toxins such as mycotoxins, structural compression syndromes, or psychological trauma, the progression to overt POTS reflects the convergence of dysregulated innate immunity, compromised mitochondrial metabolism, and impaired neurovascular feedback.

This review proposes that the sustained activation of the TLR4–RAGE–NF-κB axis, coupled with mitochondrial PDH suppression and excitotoxic neurotransmission, drives a self-reinforcing loop of metabolic and autonomic collapse. These shared mechanisms offer targets for intervention—ranging from PDK inhibitors and phospholipid or amino acid repletion, to vagal tone restoration and endothelial repair.

Integral to this loop is mast cell activation, which serves not only as a sentinel of immune stress but also as a transducer of mechanical, neurovascular, and environmental signals. Mast cell mediators (histamine, tryptase, TGF-β, VEGF) promote neurogenic inflammation, fibrosis, and fascial stiffening—particularly in the cervical spine, thoracic inlet, and coeliac plexus. Their dysregulation amplifies vascular instability, pain, and autonomic chaos, forming a key link between environmental sensitivity, connective tissue dysfunction, and chronic dysautonomia.

By dissecting each activator and mapping it onto this common pathophysiological framework, we advocate for a paradigm shift toward mechanism-based phenotyping in POTS care. Future work should refine stratified treatment pathways—including mast cell modulation—and validate targeted therapies across clinical subtypes and molecular signatures.