Reframing Postural Orthostatic Tachycardia Syndrome (POTS) as a Disorder of Preload Failure: Integrating Neurovascular and Immune Pathways

Dr Graham Exelby October 2025

Abstract

Background:

Postural Orthostatic Tachycardia Syndrome (POTS) is a multisystem disorder of orthostatic intolerance characterised by excessive heart-rate increments (≥ 30 bpm in adults) upon standing, accompanied by fatigue, cognitive dysfunction, and visceral dysregulation. (Vernino et al., 2021)

Emerging haemodynamic and metabolic evidence reframes POTS not as primary autonomic denervation but as a syndrome of dynamic preload failure—a posture-dependent reduction in ventricular filling (20–70 % fall in stroke volume via LVOT VTI) that triggers brainstem hypoxia, neurovascular instability, and self-sustaining inflammation.( (Thomas & Exelby 2025; Baker et al., 2024; Seeley et al., 2025).

Pathogenesis:

At the centre of POTS pathophysiology lies a feed-forward RAGE–HIF-1α–NLRP3 axis that integrates vascular, immune, and metabolic dysfunction into a self-perpetuating inflammatory circuit. (Xu et al., 2025; Zhao et al., 2024; Ye et al., 2024).

Venous congestion and regional hypoxia stabilise HIF-1α, which in turn activates RAGE and TLR4, amplifying NF-κB, CCL2, and STAT3 signalling. ( Exelby & Vittone, 2025; Exelby,2025) This cascade drives endothelial and glial inflammation, converting transient hypoperfusion into chronic neuroimmune activation. (Blitshteyn, 2025; Woźny-Rasała & Ogłodek, 2025).

Diverse initiating events—viral infection, trauma, chemical or metabolic stress—ignite this pathway by creating localised hypoxia or oxidative injury. (Dash et al., 2025; Jammoul et al., 2023)  Once engaged, RAGE signalling sustains itself through reciprocal reinforcement with HIF-1α and NLRP3, remaining active until the underlying hypoxic driver is resolved. This renders the inflammatory process self-amplifying and anatomically self-localising, explaining why different triggers converge on a common phenotype.

The neurovascular unit (NVU) becomes the principal casualty.  Pericytes detach from endothelial junctions, producing capillary constriction and blood–brain-barrier (BBB) leakage; astrocytes lose aquaporin-4 (AQP4) polarity, halting glymphatic exchange and permitting inflammatory metabolite accumulation.  (Exelby, 2025; Blitshteyn, 2025) This pericyte–astrocyte uncoupling marks the final common pathway of POTS and related post-viral dysautonomias, translating molecular injury into clinical expression—orthostatic intolerance, cognitive fog, fatigue, and central sensitisation.

Secondary amplifiers—mast-cell activation, impaired lymphatic drainage, and mitochondrial energy failure—further entrench this cycle.  (Hoel et al., 2021; Fluge et al., 2016) Together they sustain a system locked in a state of metabolic hypoxia, neuroinflammation, and vascular stiffness, the triad responsible for the enduring symptom complex of POTS.

Integrative Model:

This paper synthesises anatomical, genetic, and immune-metabolic findings into a unified framework—the “gastro-cranial hydraulic continuum”—where cranio-cervical venous bottlenecks interact with abdominal and pelvic congestion to impair venous return and perpetuate hypoxia. (Fakhri et al., 2025; Novak et al., 2024).

Genetic susceptibilities (TLR4, CCL2, STAT3, PEMT, COMT, APOE4, MTHFR) create pathway redundancy explaining phenotypic overlap across POTS, ME/CFS, Fibromyalgia, and Long COVID. (Qu et al., 2025; Exelby & Vittone, 2025).

Conclusion:

POTS should be redefined as a preload-failure-driven neuroimmune–metabolic disorder. Recognition of its hydraulic and molecular origins enables causal, precision-based interventions—combining decompression of venous bottlenecks with metabolic and immune modulation—to restore physiological coherence and break the chronic hypoxia–inflammation cycle.

Main body to follow