Beyond the Symptoms: Targeting Underlying Mechanisms in POTS

Dr Graham Exelby April 2025

Table of Contents

1.     Introduction: A Shift Toward Root-Cause POTS Management

2.     Hypoxia as the Common Denominator

3.     COVID-Associated Pathology: A Distinct Driver Within the Same Framework

4.     Feedforward Loops: RAGE, NF-κB, and Central Sensitization

5.     Amino Acid Dysfunction: Aspartate, GABA, and Glutamate Imbalance

6.     Fatigue and PEM: A Metabolic-Autonomic Failure

7.     Preload Failure: The Cornerstone of Orthostatic Intolerance

8.     Mechanical and Hydraulic Dysregulation: The Hidden Structural Burden

9.     The Cardiac and Coeliac Plexuses: Overlapping Neural Control of Vascular and Visceral Tone

10.  Diagnostic and Therapeutic Strategies: Targeting Upstream Drivers

11.  Conclusion: Reframing POTS as a Systems Failure Syndrome

1. Introduction: A Shift Toward Root-Cause POTS Management

Postural Orthostatic Tachycardia Syndrome (POTS) has traditionally been treated within a symptomatic paradigm—primarily managing heart rate, hydration, and autonomic instability. However, this approach frequently neglects the multilayered pathophysiology underlying the condition. Clinical insights from over 700 patients, advanced imaging modalities, and molecular assays now suggest that POTS is a manifestation of a deeper interplay between hypoxia, immune activation, metabolic dysfunction, and mechanical impediments to venous return. This article aims to reframe the discussion of POTS by integrating these emerging data into a coherent, systems-based understanding of the disease.

Rather than categorizing patients based on symptom clusters, a pathophysiological approach enables targeted interventions—whether they be immunological, structural, metabolic, or neurological. The goal is to move beyond beta-blockers and compression garments and toward precise diagnostics and corrective strategies that identify the upstream drivers of preload failure, fatigue, post-exertional malaise (PEM), and orthostatic intolerance.

Recent work has shown how regional hypoxia, especially in the brainstem and peripheral tissues, drives RAGE (Receptor for Advanced Glycation End Products) activation, leading to chronic neuroinflammation and glial sensitization. In parallel, amino acid dysfunction—most notably the glutamate-aspartate-GABA axis—has emerged as a biochemical correlate of central sensitization and PEM. In this series, we will explore how each major symptom cluster in POTS arises from a convergence of vascular, metabolic, and immune pathology.

Of particular innovation is the application of supine Spectral CT venography (which offers excellent arteriographic and venographic contrast with significantly reduced radiation and contrast dye exposure, though it lacks postural resolution) and dynamic upright ultrasound imaging to identify postural obstruction of venous return, revealing a critical mechanical link that exacerbates hypoxic and inflammatory drivers, complementing brain SPECT scanning to assess brainstem hypoperfusion and cerebral hypo- and hyperperfusion, reflecting blood brain barrier dysfunction providing an entry for neuroexcitable neurotransmitters such as glutamate and other inflammatory products.

2. Hypoxia as the Common Denominator

Emerging insights suggest that brainstem hypoxia in POTS is not solely a consequence of vascular bottlenecks but is also driven by heightened sympathetic tone originating from the superior cervical sympathetic ganglion. This activation appears linked to biomechanical dysfunction in the upper cervical spine—particularly at the C0/C1/C2/C3 levels—commonly observed in Ehlers-Danlos Syndrome (EDS) and post-traumatic cases. Sympathetic-mediated vasoconstriction of vertebrobasilar and posterior cerebral circulation may underlie hypoperfusion, especially in patients with cranio-cervical instability or postural venous collapse.

Further compounding this, thoracic sympathetic contributions—particularly from the T1–T4 spinal segments—intersect with the anatomic zone of thoracic outlet syndrome (TOS). TOS-related compression may not only impair venous return but also aberrantly activate these upper thoracic ganglia, contributing to dysautonomia and splanchnic vascular dysregulation.

Although direct evidence is sparse, a plausible pathway involves convergence between the thoracic ganglia and both cardiac and coeliac plexuses, amplifying systemic sympathetic output and impairing cerebral autoregulation. These integrated biomechanical-autonomic influences have been historically overlooked, with past research narrowly focusing on cerebral vasospasm without exploring root triggers such as segmental spinal dysfunction or ganglionic sensitization.

3. COVID-Associated Pathology: A Distinct Driver Within the Same Framework

COVID-19, and particularly Long COVID, has introduced a distinct cohort of patients with overlapping POTS phenotypes. SARS-CoV-2 initiates profound immune and endothelial disruption through ACE2 binding, TLR4 activation, and downstream NF-κB and RAGE pathway activation. Persistent elevation of D-dimer in Long COVID patients has been linked to fibrin-amyloid co-aggregation resistant to fibrinolysis, enhanced by oxidative stress and SAA-driven RAGE activation. This hypercoagulable state fuels hypoxia, endothelial injury, and further immune activation.

Spectral CT, while limited in positional diagnostics, offers high sensitivity for early neoplastic changes and may identify paraneoplastic or immune-reactive sequelae in COVID-affected patients.   A new development from this is “fast pass” breast Spectral scanning providing a high level of differentiation of breast pathology previously relegated to high level MRI.  This may enable differentiation of malignant from lesions such as fibroadenomas, which the “normal” Spectral CT was unable to provide accurately.  It can be provided for these and other “at risk” patients during the initial scanning for POTS.

Given COVID-19's documented suppression of NK cell activity and broader immune surveillance, this imaging modality may incidentally capture malignancy development in the post-viral immune landscape—highlighting the importance of integrating radiological and immunological perspectives in persistent post-COVID syndromes.

Importantly, post-COVID patients often exhibit impaired glymphatic clearance due to dysfunctional astrocytes whose end feet line the paravascular channels. This is particularly concerning given the reliance of glymphatic drainage on functional CSF-lymphatic coupling at the cribriform plate and cervical outflow routes—both vulnerable to fascial tension, venous congestion, and sympathetic hyperactivity.  Emerging evidence indicates that glymphatic dysfunction may perpetuate post-viral neuroinflammation, sleep dysregulation, and cognitive fog by trapping excitotoxic metabolites, cytokines, and RAGE ligands within the CNS interstitium.   The research into the areas involving glymphatic flow and amino acid dysregulation as we are seeing in Long COVID have provided insights into other neurodegenerative conditions especially Alzheimer’s and Parkinson’s Diseases.

Additionally, post-viral pyruvate dehydrogenase (PDH), inhibition, (critical in mitochondrial functioning), impaired nicotinamide metabolism, as well as impaired aspartate and lactate pathways,(critical in post exertional malaise) and low ethanolamine availability converge to produce a sustained hypometabolic and inflammatory phenotype.

These alterations parallel those seen in POTS but are often more refractory. Importantly, imaging in post-COVID patients has revealed similar venous and lymphatic flow disruptions—suggesting that mechanical elements remain core contributors. The COVID cohort thus exemplifies an immune-metabolic phenotype that converges mechanistically with classical POTS but often requires broader immune modulation strategies, including IVIG, phospholipid restoration, and potentially mitochondrial reactivation therapies targeting SIRT4.

4. Feedforward Loops: RAGE, NF-κB, and Central Sensitization

Once RAGE is activated by ligands such as HMGB1, S100 proteins, or AGE-modified fibrin, it initiates a cascade involving NF-κB activation, intracellular ROS generation, and cytokine release. In the CNS, this cascade primes microglia, recruits astrocytes, and sensitizes mast cells. The feedback loop between these glial elements sustains a state of heightened excitability and neuroinflammation.

Astrocytes lose their capacity to maintain glutamate homeostasis, resulting in synaptic excitotoxicity. Microglial activation shifts from neuroprotective surveillance to a pro-inflammatory, neuro-destructive state. Mast cell degranulation, particularly around the meninges and circumventricular organs, exacerbates blood-brain barrier permeability and contributes to afferent hypersensitivity.

Neuropeptides such as Substance P and CGRP further reinforce this state. Released by nociceptive fibres, they bind to endothelial, glial, and immune cell receptors, amplifying pain perception, vasodilation, and immune cell recruitment. The net result is a persistent state of central sensitization that clinically manifests as fatigue, PEM, allodynia, and visceral hypersensitivity.

5. Amino Acid Dysfunction: Aspartate, GABA, and Glutamate Imbalance

In POTS and allied conditions, a striking metabolic feature is low GABA, low aspartate, and elevated glutamate. This profile reflects a disrupted balance in excitatory and inhibitory neurotransmission and energy metabolism. Aspartate is essential for the malate-aspartate shuttle, which facilitates the transfer of NADH from the cytosol into mitochondria for oxidative phosphorylation. Its deficiency thus limits ATP production and impairs PDH activity, deepening metabolic stress.

GABA, derived from glutamate via glutamate decarboxylase (GAD), is reduced under oxidative stress and when cofactor availability (e.g., vitamin B6, NAD+) is impaired. Low GABA heightens CNS excitability and predisposes to anxiety, insomnia, and sensory overload—hallmark features of central sensitization and PEM.

Glutamate excess, without sufficient GABA or astrocytic buffering, becomes neurotoxic and fuels a cycle of excitotoxicity and neuroinflammation. These amino acid patterns are reproducible on urinary organic acid profiles and may guide targeted therapy using mitochondrial cofactors, liposomal NAD+ precursors, and SIRT4 activators such as nicotinamide riboside.

6. Fatigue and PEM: A Metabolic-Autonomic Failure

Post-exertional malaise (PEM) in POTS reflects a failure of both metabolic upregulation and autonomic resilience. It is characterized by delayed recovery, neurocognitive dysfunction, and physical collapse following exertion. Biochemically, PEM correlates with lactic acidosis, incomplete glucose oxidation, and redox imbalance—suggesting a PDH blockade.

With reduced PDH activity, pyruvate is shunted into lactate instead of acetyl-CoA, impairing ATP generation. This is compounded by a failure in the malate-aspartate shuttle when aspartate is low. The resulting mitochondrial backlog leads to ROS accumulation and loss of redox flexibility.

Autonomically, impaired baroreceptor sensitivity, low vagal tone, and catecholamine overdrive exacerbate the problem. Patients remain in a sympathetic-locked state, unable to shift into recovery mode. The brain interprets this as a metabolic danger signal, triggering enforced downregulation of activity—a neuroimmune brake on exertion.

In upcoming sections, we will discuss preload failure and mechanical contributors to orthostatic intolerance, as well as the anatomic and functional integration of the cardiac and coeliac plexuses in POTS pathogenesis.

7. Preload Failure: The Cornerstone of Orthostatic Intolerance

Preload failure—the inability to provide the necessary increased cardiac output during postural change, is a defining pathophysiological event in POTS. Rather than originating in deconditioning, this failure often stems from anatomical and hydraulic impairments affecting venous return, complicated by dysfunctional autonomic regulation especially from the Cardiac and Coeliac Plexii (and Coeliac ganglion).  That deconditioning is not the cause has been clearly demonstrated in post-COVID POTS patients.

Dynamic upright imaging and Doppler ultrasound frequently reveal collapsible internal jugular veins, obstructed iliac and renal veins, and diversion into the vertebral venous system. The renal vein obstruction of Nutcracker Syndrome in particular may not be seen in supine CT venography, requiring dynamic ultrasounds for confirmation. 

May-Thurner syndrome, Nutcracker syndrome, and pelvic venous congestion often co-occur, impeding return flow from the lower extremities and splanchnic regions. The resulting reduction in right atrial filling pressures leads to compensatory tachycardia, which paradoxically reduces diastolic filling time and further impairs preload.   The increased flow through the Azygous system from Subclavian Vein obstruction in venous Thoracic Outlet Syndrome (vTOS) is thought to provide an “overfill” of the right atrium, although no studies have been conducted into this.  It’s importance in POTS has been seen in case studies where the azygous has been ligated in cardiac surgery tipping the patients into POTS.

Autonomic baroreflexes, particularly those involving the Bainbridge reflex and low-pressure mechanoreceptors, become maladaptive under these conditions. Reflexive sympathetic overdrive and parasympathetic withdrawal exacerbate peripheral vasoconstriction and reduce cardiac compliance.

8. Mechanical and Hydraulic Dysregulation: The Hidden Structural Burden

The venous system lacks intrinsic contractility and depends entirely on respiratory, fascial, and postural mechanics for propulsion. Any structural impingement—such as vertebral rotation, fascial tethering, large breast weight, or military backpacks—can disrupt this system. In patients with connective tissue disorders like EDS, these effects are magnified.

Superior thoracic inlet crowding and C0-C3 vertebral instability compromise vertebral venous return and cervical lymphatic outflow. Meanwhile, abdominal compression syndromes such as MALS (median arcuate ligament syndrome) and SMA (superior mesenteric artery) syndrome contribute to mesenteric ischaemia and coeliac plexus irritation.

Pelvic congestion and iliac compression force blood into the vertebrovertebral and azygous systems, often producing a compensatory rise in intracranial pressure. This has been overlooked in traditional supine MRI studies but is frequently visualized via dynamic ultrasound, and when combined with Internal Jugular Vein (IJV) obstruction, appears to underpin the head pressure when erect, a very common finding in POTS.  The Azygous/hemiazygous system may be incomplete complicating the flow dysfunction, reducing the system’s ability to control the flow. 

This is complicated by EDS and Chiari malformations, where the cerebellum potentially drops into the foramen magnum obstructing both venous and lymphatic outflow from the brain when erect.  Another complicating factor with as yet no dynamic studies is the CSF Canalicular System which probably provides a larger CSF outflow when erect, as it’s flow is gravitational only but potentially obstructed at the critical C1 and base of neck in its passage adjacent the IJV to flow into the Subclavian Veins.

The interaction between venous and lymphatic flow becomes especially critical in the context of cervical vertebral rotation and thoracic inlet crowding. The cervical lymphatic vessels, which also course adjacent to the IJV and subclavian veins, are often seen clinically, and frequently with fascial changes, reflecting mechanical obstruction and reduced diaphragmatic excursion. When compounded by CSF outflow restriction at C1/C2, this impairs glymphatic drainage, particularly during sleep when interstitial clearance via the perivenous pathways is most active. This stagnation traps inflammatory ligands (e.g., HMGB1, SAA, and AGE-modified proteins), contributing to sustained RAGE activation and astrocytic dysfunction. The result is a neuroimmune environment primed for excitotoxicity, sleep fragmentation, and central sensitization.

9. The Cardiac and Coeliac Plexuses: Overlapping Neural Control of Vascular and Visceral Tone

The cardiac and coeliac plexuses represent major autonomic relay points coordinating baroreception, vascular tone, visceral pain, and immune reactivity. The cardiac plexus integrates inputs from vagal and sympathetic fibres across the T1–T5 segments and influences heart rate, myocardial contractility, and atrial baroreceptor signalling.

The coeliac plexus, which includes the coeliac ganglia—adjacent to the diaphragmatic crura and intimately related to the SMA and renal arteries—controls splanchnic blood flow, adrenal output, and visceral sensation. Mechanical compression from MALS or rotational dysfunction at T8 can induce sympathetic overactivity and postprandial splanchnic pooling, contributing to orthostatic symptoms.

Increasing evidence points to dysfunctional interplay between these plexuses as a modulator of preload, immune activation, and gastrointestinal dysmotility in POTS. While direct evidence remains sparse, the anatomical and clinical overlap is compelling, particularly when supported by imaging and symptom provocation studies.

In the next section, we will explore diagnostic imaging strategies and practical therapeutic approaches tailored to these upstream drivers.

10. Diagnostic and Therapeutic Strategies: Targeting Upstream Drivers

To address the multifactorial pathophysiology of POTS, diagnostic and therapeutic strategies must be aligned with the underlying immune, vascular, metabolic, and structural disturbances unique to each patient. Instead of a symptom-based model, a mechanistic and tiered diagnostic approach is advocated.

Diagnostic Imaging and Biomarkers

·       Dynamic ultrasound and Doppler studies: Assess IJV collapse, vertebral vein diversion, pelvic congestion, and coeliac axis compression in supine and upright posture, and cervical venous flow with added rotational studies.

·       Spectral CT venography and arteriography: Detect vascular anomalies with low radiation and contrast load, enabling screening of renal vein compression, SMA impingement, IJV obstruction at C1 and base of neck, pelvic congestion, paravertebral venous dilatation, vertebral artery status, coeliac axis compression, or neoplastic change (including "fast pass" breast Spectral imaging in post-COVID patients with immune dysregulation).

·       Brain SPECT and Neuroquant MRI (or MRI venography): SPECT (or newly developed MRI Neuroquant) to quantify brainstem hypoperfusion and areas of cerebral damage.  This or MRI venography which is frequently overlooked, to evaluate cerebral dural sinus status (critical in pulsatile tinnitus and thunderclap headache especially after COVID where transverse sinuses may be thrombosed,) and state of the arachnoid granulations.

·       Urinary amino acids and organic acid profiles: Identify glutamate/GABA imbalance, low aspartate, and dysfunctional energy metabolism.

Therapeutic Framework

·       Mitochondrial and redox support: Use SIRT4 activators (e.g., nicotinamide riboside), B vitamins, l-carnitine, and thiamine to restore PDH function and reduce lactate buildup.

·       Anti-inflammatory modulation: Consider IVIG in select post-viral cases, especially with small fibre neuropathy, TLR4 activation. Evaluate alternative RAGE/NF-κB modulators when IVIG is not feasible.

·       Structural decompression and postural retraining: Conservative myofascial therapies targeting vertebral rotation, thoracic inlet crowding, and pelvic tilt.

·       Pharmacologic autonomic modulation: Low-dose beta blockers may help in hyperadrenergic states, but are less effective where preload is compromised. Midodrine, fludrocortisone, or ivabradine may offer symptomatic benefit depending on volume status and cardiac autonomic tone.

·       Nutritional immunometabolic therapies: Ethanolamine precursors, PEMT cofactors, omega-3 fatty acids, and tailored anti-inflammatory and low glutamate as appropriate diets address phospholipid repair and mast cell stabilization without resorting to mast cell–focused monotherapy.  Important to avoid any food the body registers as a threat, provoking increased cytokine responses, overloading an already compromised immune system.

·       Regaining functionality: Avoiding boom-bust” cycles, becoming aware of what increases symptoms and work towards a gradual reintroduction of daily activities. 

This strategy promotes individualized care based on definable upstream dysfunctions rather than reactive symptom management. Importantly, lymphatic dysfunction must also be considered a core contributor, as impaired cervical and thoracic lymphatic drainage—often secondary to fascial tension, vertebral rotation, or venous congestion—can hinder immune clearance, exacerbate intracranial pressure, and sustain a pro-inflammatory milieu. Dynamic ultrasound and lymphoscintigraphy are emerging tools for evaluating lymphatic flow disturbances. Interventions that improve fascial mobility, diaphragmatic mechanics, and glymphatic clearance may be essential adjuncts in addressing both neuroinflammation and systemic congestion.

11. Conclusion: Reframing POTS as a Systems Failure Syndrome

Postural Orthostatic Tachycardia Syndrome is frequently misrepresented as a disorder of cardiovascular adaptation. The evidence now overwhelmingly suggests it is a convergent clinical endpoint of upstream dysfunctions across vascular drainage, immune signalling, metabolic efficiency, and neural integration. What presents as tachycardia and fatigue is often a visible downstream effect of invisible upstream failures in venous and lymphatic return, mitochondrial throughput, redox balance, and autonomic feedback control.

By shifting the clinical lens from symptom suppression to upstream driver identification, we empower a new era of precision medicine for POTS. Structural decompression, metabolic recalibration, immune modulation, and autonomic rehabilitation must all be viewed as complementary strategies—not siloed interventions. Tools such as dynamic ultrasound, spectral CT, brain SPECT, MRI venography or Neuroquant, and amino acid profiling allow this upstream mapping to occur.

Crucially, the inclusion of lymphatic dysfunction, RAGE-related immune looping, mast cell mischaracterization, and coeliac/cardiac plexus instability reframes POTS as a syndrome of systems collapse. It is not the body failing to adapt to standing; it is the system failing to maintain equilibrium under biological, immunological, and mechanical stressors.  This includes the underrecognized convergence of glymphatic stagnation, cervical lymphatic impedance, and venous outflow collapse—constituting a failure of CNS clearance that sustains neuroinflammatory looping.

This integrated perspective restores the complexity of the syndrome and provides the granularity needed to engineer recovery. Moving forward, individualized assessment, layered diagnostics, and upstream therapeutic correction offer the best promise for resolution—not just management—of this debilitating condition.