Dr Graham Exelby March 2025
Abstract
Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a heterogenous dysautonomic condition that can emerge following a diverse array of physiological stressors, yet culminates in a strikingly convergent phenotype of preload failure, central sensitization, fatigue, and neurovascular instability. Despite varied triggers—ranging from viral infections such as SARS-CoV-2, environmental exposures, trauma, and immune stressors—emerging evidence suggests that these activators intersect via common molecular and immunometabolic dysfunctions.
Objective: This paper presents a unifying molecular framework in which diverse POTS activators converge on key bioenergetic and inflammatory nodes, notably pyruvate dehydrogenase (PDH) inhibition, RAGE/TLR4 activation, excitotoxic amino acid imbalance (low GABA/aspartate, high glutamate), and mitochondrial and endothelial dysfunction.
Methods: Through clinical observation of >700 POTS patients and biochemical analyses of plasma and urine amino acids, alongside existing mechanistic data from post-COVID and neuroimmune literature, we delineate a shared pathophysiological cascade initiated by diverse insults. These include trauma-induced HMGB1 and DAMP signalling, pathogen-associated molecular pattern (PAMP) activation via viral RNA or parasitic antigens, environmental TLR4 agonists (e.g., mycotoxins), and HIF-1α-driven hypoxia signalling in chronic congestion states.
Results: Across activator categories, we observe convergence on (i) PDH inhibition via NF-κB–PDK axis; (ii) sustained RAGE/inflammasome activation; (iii) glutamate-aspartate-GABA axis imbalance; and (iv) mitochondrial oxidative stress. These pathways perpetuate impaired metabolic flexibility, endothelial dysfunction, and autonomic instability.
Conclusion: We propose that POTS represents a syndrome of convergent metabolic injury across varied inciting stimuli, leading to a bioenergetic-autonomic-inflammatory loop. This model provides an integrative framework to guide targeted therapeutic interventions such as PDK inhibition, amino acid modulation, and immune-metabolic reprogramming.
Introduction
Postural Orthostatic Tachycardia Syndrome (POTS) is a complex and often debilitating disorder of the autonomic nervous system, characterized by orthostatic intolerance, tachycardia, and a constellation of symptoms including fatigue, cognitive impairment, gastrointestinal dysmotility, and exercise intolerance. While initially classified by haemodynamic criteria, POTS is increasingly recognized as a neuroimmune and metabolic disorder arising from a wide spectrum of inciting events.
Over the past decade, a growing body of clinical and mechanistic evidence has identified a range of POTS triggers including viral infections (e.g., Epstein-Barr virus, SARS-CoV-2), parasitic infections, environmental toxicants (e.g., mould/mycotoxins), severe physiological stress (e.g., trauma, surgery, pregnancy), and psychological stressors (e.g., PTSD). Despite this etiologic heterogeneity, the downstream phenotype is remarkably conserved—suggesting a final common pathway of pathophysiological convergence.
Recent research has highlighted the central role of pyruvate dehydrogenase (PDH) inhibition and mitochondrial dysfunction in POTS, particularly in post-viral and post-traumatic subtypes. In parallel, elevated glutamate with suppressed GABA and aspartate levels point to excitotoxicity, impaired GABAergic tone, and dysfunction of the malate-aspartate shuttle—critical for mitochondrial redox balance. These biochemical abnormalities align with clinical findings of central sensitization, post-exertional malaise, and cognitive fog.
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
Excitatory amino acid imbalance, with implications for autonomic dysregulation, neurotransmission, and immune modulation
This paper aims to delineate how such distinct initiating insults—ranging from pathogens to toxins and trauma—may converge upon these central molecular derangements, forming the pathophysiological substrate of POTS. In doing so, we propose a unified framework for understanding the condition and exploring individualized interventions that restore immunometabolic balance.
Full paper to follow
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