Preload Dysfunction in POTS and ME/CFS: The Azygous System, Autonomic Plexii, and Inflammatory Pathways

Dr Graham Exelby May 2025

Abstract

This paper investigates the pivotal but underrecognized role of the azygous venous system in preload dysfunction among patients with Postural Orthostatic Tachycardia Syndrome (POTS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). These syndromes are frequently characterized by orthostatic intolerance, cerebral hypoperfusion, and impaired venous return. We explore how structural and functional abnormalities in the azygous system may exacerbate or even initiate preload failure, baroreceptor dysregulation, and systemic venous hypertension, mediated through autonomic plexus dysfunction in the coeliac and cardiac plexii.  Integrating clinical observations, imaging findings, and vascular compression syndromes, this paper posits a novel framework wherein compromised azygous venous dynamics—interlinked with lymphatic obstruction and autonomic feedback loops—contribute to the pathophysiology of POTS.

This paper investigates a unified neurovascular model of preload dysfunction in Postural Orthostatic Tachycardia Syndrome (POTS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), focusing on the integration of the azygous venous system, the cardiac and coeliac autonomic plexii, and inflammatory influences on splanchnic vasomotor tone.

Preload failure—defined as insufficient ventricular filling despite adequate blood volume—is increasingly understood as a product of regional venous maldistribution, altered baroreflex dynamics, and lymphatic dysfunction. This framework includes anatomical variants (e.g., vascular compression syndromes), autonomic misfiring (via the Bainbridge reflex and brainstem hypoperfusion), and neuroimmune disruption. In particular, we examine the emerging role of mast cell infiltration and neurogenic inflammation in splanchnic vascular beds as modulators of effective venous return. Distinguishing this model from oversimplified attributions to mast cell activation syndrome (MCAS), the paper also addresses the overlooked relevance of DAMP/NF-κB/RAGE/CCL2 signaling cascades in mediating immune-metabolic dysfunction. Clinical and imaging findings are synthesized to support a reconceptualization of preload failure as a hydraulically and immunologically dynamic state.

Introduction

Postural Orthostatic Tachycardia Syndrome (POTS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are complex, multisystem disorders marked by a shared constellation of symptoms, including orthostatic intolerance, exercise-induced fatigue, cognitive dysfunction, and systemic autonomic instability. Central to both conditions is a persistent unexplained shortness of breath from preload dysfunction—defined by insufficient ventricular filling and reduced stroke volume—often in the absence of overt hypovolemia. Emerging evidence suggests that this phenomenon may not solely be due to total blood volume deficits, but rather involve regional maldistribution and impaired venous return, frequently linked to structural abnormalities such as May-Thurner and Nutcracker syndromes.  This paper integrates the critical roles of the cardiac and coeliac plexii—autonomic relay centres governing cardiac performance and splanchnic capacitance.

The cardiac plexus, located near the aortic arch and tracheal bifurcation, modulates heart rate, atrial compliance, and baroreflex sensitivity via sympathetic and vagal innervation. The coeliac plexus, surrounding the coeliac trunk, controls splanchnic blood volume distribution—a critical determinant of venous return. Aberrant input from these plexii, whether due to anatomical compression (e.g., MALS, SMA syndrome) or neuroimmune activation (e.g., mast cell-mediated or post-viral vagalopathy), leads to dysregulated venous capacitance, splanchnic pooling, and maladaptive tachycardia.

A critical but underappreciated player in this vascular dynamic is the azygous venous system. As a conduit between the superior and inferior vena cava, the azygous system provides collateral drainage under conditions of caval obstruction or elevated intrathoracic pressures. In POTS and ME/CFS patients, where venous congestion, autonomic dysregulation, and lymphatic stasis are frequent findings, dysfunction of this system may act as both a compensatory adaptation and a pathogenic driver.

When combined with azygous system dysfunction—either compensatory or pathological—the resulting triad of venous congestion, autonomic misfiring, and impaired baroreflexes provides a compelling explanatory framework for preload dysfunction in POTS and ME/CFS. This paper integrates structural, autonomic, and hemodynamic data to better define this phenotype and propose mechanistic targets for investigation and therapy.

Fluge et al 2021(1) described similar dilemmas in CFS of differentiation of common fatigue from CFS where main symptoms are  post exertional malaise (PEM), fatigue, orthostatic intolerance, cognitive disturbances, sleep problems with inadequate restitution after rest, sensory hypersensitivity with pain, and symptoms related to autonomic and immune dysfunction that exists in POTS, convincingly making these variations of the same problem.   They described similar immune dysregulation, vascular dysregulation with endothelial dysfunction and impaired venous tone and venous return but with maladaptive compensatory adaptations in the autonomic responses and metabolic dysregulation. (1)(2)

The persistent and often unexplained shortness of breath experienced by patients with POTS and Chronic Fatigue Syndrome (CFS) can usually be attributed to a fundamental haemodynamic disturbance known as preload dysfunction (failure). At the core of this mechanism lies impaired venous return—particularly from the great veins, including the superior and inferior vena cava—which compromises the filling of the right atrium and ventricle during diastole.

The heart operates not as an isolated pump but as a hydraulically integrated component within a dynamic thoracic volume reservoir. This concept frames preload as a function of thoracic venous capacitance, compliance, and pressure gradients across the inferior and superior vena cavae.

The azygous system, along with vertebral venous plexuses and thoracic lymphatics, serves as a dynamic buffer, accommodating shifts in venous return during posture change, respiratory modulation, or Valsalva manoeuvres.   In POTS, mechanical distortion of this hydraulic reservoir—whether through vascular compression, hypercompliant splanchnic vessels, or lymphatic stasis—results in inadequate atrial filling despite preserved total blood volume, thereby precipitating preload failure. This altered thoracic compliance may be a key determinant of why upright intolerance occurs in the absence of measurable hypovolemia.

Since the heart functions as a demand-sensitive hydraulic pump, inadequate ventricular filling due to compromised venous inflow results in a reduced stroke volume. This diminished forward output, especially during orthostatic stress or exertion, fails to meet peripheral oxygen demands and activates compensatory tachypnoea or dyspnoea. Importantly, this occurs in the absence of primary pulmonary pathology, underscoring the central role of circulatory underfilling in the pathogenesis of breathlessness in these syndromes.

The azygos venous system plays a crucial role in systemic venous return, particularly in the context of vascular compression syndromes and thoracic circulatory dynamics. In patients with POTS, where preload dysfunction, venous pooling, and autonomic dysregulation are well-documented, the azygos vein may serve as an adaptive or maladaptive compensatory pathway.

The azygous  help regulate pressure in the venous system, especially with changes in intrathoracic or intra-abdominal pressures, which is likely to be highly relevant when there is venous pooling.   The azygos system's ability to redistribute blood flow during postural changes helps mitigate venous congestion and maintain hemodynamic stability

The exact role of the azygos vein in POTS may vary depending on the individual patient's vascular anatomy and the specific underlying mechanisms contributing to their condition. The complex interplay between various vascular structures, including the azygos system, carotid and aortic baroreceptors, and intracranial pressure dynamics, likely contributes to the diverse presentation and pathophysiology of POTS.

From our clinic studies, POTS patients exhibit distinct fluid regulation phenotypes, which we propose can be associated with a dysfunctional or overwhelmed azygous system.  Fudim et al 2021(3) provided evidence for preload dysfunction association with fatty liver disease as we further hypothesize the close association with this and the amino acid dysfunction seen in CFS and POTS where ethanolamine function is impaired.

Azygous Connections

The azygous venous system provides an important connection between the superior vena cava (SVC)and the inferior vena cava.(IVC) In cases where there is subclavian vein obstruction the azygous may become an important alternative route for venous drainage, helping maintain venous return despite obstruction of other major veins. 

The azygos vein can become engorged or enlarged in response to increased venous pressure, such as in conditions like portal hypertension or right atrial pressure elevation.   Changes in azygos vein size have been correlated with right atrial pressure, suggesting its role as a buffer for systemic venous pressure changes.(Bosch et al 1985. (4))(Piciucchi et al 2014 (5))

Postural changes can influence venous return via the azygos system.  Head elevation improves intracranial pressure (ICP) control by facilitating venous outflow through pathways like the azygos system, though it may reduce cerebral perfusion pressure (CPP) if autoregulation is impaired. (Mithun  et al. 2022 (6))

The azygous system has connections to the vertebral venous plexus, which in turn connects to intracranial veins.  Clinic radiology using Spectral CT venography has confirmed dilated paravertebral veins, sometimes with varices in many patients with left renal vein compression (Nutcracker) and Pelvic Congestion.   Scholback (7) confirmed the potential for increased intracranial pressure in this valveless system from the venous congestion syndromes in the abdomen. 

In POTS patients with these vascular compression syndromes, the azygous may play a role in providing alternative drainage routes for cerebral blood flow, and in anatomical variants, the azygous capacity to control these alternative route is impaired.   In patients with longstanding head and neck venous obstruction, collaterals are often seen providing the alternative drainage pathways.

Case studies have shown activation of POTS after ligation of the azygous veins in the chest during cardiac surgery.    Clinic radiology has demonstrated venous flow into the azygous system with subclavian vein obstruction in VTOS.  Anatomical variations of the azygous anatomy may lend itself to the overall dysfunctional picture.   Imaging this system remains very difficult, as it can usually only be seen on CT venography when enlarged.

Preload Dysfunction and Proposed Alternative Pathway

Preload dysfunction is a characteristic finding explaining the shortness of breath in postural change in most POTS.  There are numerous variations in azygous system anatomy which may play a critical role in this.   The azygous vein plays a crucial role in returning blood from the chest and abdomen to the heart.  In POTS patients, changes in azygous flow could contribute to preload dysfunction, which is a key factor in their symptoms.  

Baker et al 2024 (8) challenged current hypotheses in POTS where postural hyperventilation was implicated, by revealing that exaggerated peripheral chemoreceptor activity is not the primary driver of postural hyperventilation, but demonstrated significant contributions from reduced stroke volume and compromised brain perfusion during orthostatic stress. 

We propose an alternative pathway, with a dysfunctional Azygous system in the chest and abdomen triggering low-pressure cardiopulmonary baroreceptors in the walls of the atria and large vessels in the thorax. 

The low-pressure receptors, also known as cardiopulmonary baroreceptors or veno-atrial stretch receptors, are crucial for detecting changes in circulating blood volume. These receptors are located in the atria of the heart and the great veins, including the venae cavae and pulmonary veins.  They play a significant role in regulating blood volume and blood pressure through various mechanisms.

Baroreceptors

Low pressure receptors in the atria/venae carvae may also contribute as blood in the vertebral system moves to the direction of least resistance, which may be back to the splanchnic circulation or azygous system.

• Hypoperfusion of the nucleus tractus solitarius (NTS) in the medulla from brainstem hypoperfusion affects the Paraventricular Nucleus (PVN) a major autonomic regulator in the hypothalamus, which impairs baroreflex integration

• Compression of the carotid sinus, which contains baroreceptors, could trigger the baroreceptor reflex, leading to changes in heart rate and blood pressure as the body attempts to maintain cerebral perfusion.

• From the observations by Geddes el al 2022 (9), it appears to account for one of the characteristic heart rate variability (HRV) patterns we have found in POTS demonstrating the marked autonomic dysregulation that may occur.

Function of low-pressure receptors

• Detection of blood volume changes -the receptors are sensitive to changes in blood volume and central venous pressure, able to detect changes as small as 5-10% of the total blood volume. When blood volume increases, the atrial walls stretch, activating these receptors. Conversely, a decrease in blood volume reduces the stretch, leading to decreased receptor activity.(10)

• Regulation of hormone secretion where stimulation of low-pressure receptors leads to the release of atrial natriuretic peptide (ANP).  ANP promotes sodium excretion by the kidneys, increasing urine production and reducing blood volume and pressure. (11)(12)

• Neurological signalling Signals from these receptors are transmitted to the brain, influencing sympathetic and parasympathetic nervous system activity. This can lead to changes in heart rate, cardiac output, and peripheral resistance. (11)(13)

  
  

Subtypes of Azygous Dysfunction- the “overfill” and “underfill” hypothesis- Linking Intra-abdominal Venous Compression with Preload Dysfunction

Compelling evidence from invasive cardiopulmonary exercise testing (iCPET) confirms that preload failure is a cardinal haemodynamic abnormality in POTS and ME/CFS. Joseph et al. 2021 (14) demonstrated that a significant subset of patients with orthostatic intolerance exhibit a marked decline in right atrial pressure and stroke volume, often exceeding 30%, upon upright tilt or exertion, despite normal ejection fraction. These findings are consistent with an underfilled heart phenotype, wherein the chronotropic response is compensatory rather than primary.

Importantly, this reduction in cardiac output correlates strongly with both fatigue severity and ventilatory inefficiency. The failure to recruit adequate preload under stress suggests that regional flow misdistribution, especially involving the splanchnic, azygous, and thoracic compartments, is central to symptom generation.

Underfill POTS, defined by low blood volume, reduced renin-angiotensin activity, and compensatory tachycardia due to ineffective cardiac preload, where there is  insufficient blood volume returning to the heart, impairing cardiac output and oxygen delivery during activity.(14)    May-Thurner Syndrome, (15) Pelvic Congestion and Nutcracker Syndromes, with symptoms similar to those seen in heart failure, such as shortness of breath during exercise, without the typical cardiac dysfunction associated with heart failure are a proposed major underlying cause.  

Overfill POTS can be characterized by increased renin-angiotensin activation, venous pooling, oedema, and excessive blood volume shifting to the splanchnic bed.   Research on cardiovascular dynamics in ME/CFS has primarily identified "underfill" mechanisms, but emerging evidence suggests some patients exhibit paradoxical hemodynamic patterns that could be interpreted as relative "overfill" in specific vascular compartments.   

A subset of ME/CFS patients (25-30%) shows elevated cardiac output  during exercise despite low right atrial pressures.  It is seen to coexist with chronic hypovolaemia and autonomic dysregulation. (14)(16).   Small fibre neuropathy is believed to drive this mismatch demonstrating paradoxical vasodilation during exercise despite systemic hypoperfusion. (16)  This apparent circulatory mismatch—systemic hypoperfusion coexisting with regional vascular engorgement—may explain symptoms like peripheral oedema in some patients despite overall hypovolemia. However, no studies directly describe classical right atrial overfill (e.g., volume overload) in ME/CFS. Current evidence points to maldistributed flow  rather than true fluid excess, with simultaneous deficits in critical vascular beds and shunting through alternative pathway. (14)(16)

The observational studies of excess subclavian flow being diverted into the azygous via thoracic outlet obstruction (TOS)—venous subtype—could result in azygous engorgement, increased intrathoracic venous pressures, and impaired cardiac compliance, especially right atrial filling.  It could also impact on intracranial pressure via impaired CSF resorption, particularly through vertebral venous plexuses and spinal veins that drain into the azygous.

The combination of azygous and lymphatic dysfunction provides a probable cause for many of the chest pains seen in POTS and CFS, although imaging at present is unable to confirm this.

These patients do poorly with volume loading, worsen with compression garments, and may improve with thoracic decompression (e.g., manual lymphatic drainage, thoracic mobility exercises).

While bodies of research reach for the azygous system dysfunction and the haemodynamic abnormalities in CFS and POTS, concrete evidence is as yet remains limited. It role though in:

• Regulating central venous pressure

• Compensating for caval obstruction

• Modulating intrathoracic blood flow

Which makes it a high probability contributor to the observed preload failure and circulatory mismatches. 

ECM Clearance, PEM Resolution, and Manual Lymphatic Therapy

Recent clinical observations indicate that manual lymphatic therapy (MLT), when performed with precision—particularly targeting the cervical, axillary, parasternal, and thoracoabdominal fascial and lymphatic sheaths—can reverse post-exertional malaise (PEM) in patients with POTS and ME/CFS. This suggests that hypoxic and inflammatory metabolites accumulate within the extracellular matrix (ECM) and that dysfunctional venous and glymphatic systems are insufficient to clear these waste products under pathological conditions.

PEM in this context may reflect not just metabolic strain but a failure of interstitial drainage, in which impaired thoracic duct clearance and azygous rerouting lead to ECM trapping of lactic acid, cytokines, oxidized lipids, and excitotoxic metabolites. The malate-aspartate shuttle, already suppressed in ME/CFS, becomes overburdened, further depleting aspartate and GABA.

MLT thus operates as a third-compartment decompressor, complementing pharmacologic strategies and intravascular techniques.  Unlike therapies targeting the intravascular or intracellular compartments, MLT directly mobilizes ECM-stored metabolic debris, reducing tissue toxicity, improving vagal tone, and enhancing thoracic compliance—especially in patients with concurrent lymphatic congestion and azygous system overload.

Bainbridge Reflex and Azygous-Induced Tachycardia

The Bainbridge reflex, a key regulator of heart rate in response to venous return, is intimately linked to low-pressure receptors in the atria and great veins. Under normal conditions:

• Increased venous return stretches the atrial walls, triggering afferent signals to the medulla (NTS).

• The NTS modulates the PVN (paraventricular nucleus of the hypothalamus), influencing sympathetic tone.

• This leads to increased heart rate and reduced vagal tone, facilitating circulatory adaptation.

The PVN is a key autonomic relay centre that modulates:

• Vasopressin release (fluid retention and osmotic regulation).

• Sympathetic and parasympathetic balance (cardiovascular homeostasis).

• Baroreceptor integration (Bainbridge and baroreflex interactions).

If brainstem hypoperfusion limits PVN function, this could result in persistent sympathetic dominance, compounding the exaggerated Bainbridge response seen in POTS. 

The Role of the Coeliac and Cardiac Plexii in Preload Dysfunction and Bainbridge Reflex Activation

Two underexplored autonomic structures—the cardiac and coeliac plexii—play pivotal roles in the regulation of preload and systemic vascular tone. These plexuses act as dynamic neurovascular hubs, integrating sympathetic and parasympathetic inputs to modulate heart rate, venous return, and splanchnic blood distribution. Their dysfunction in POTS contributes to impaired volume handling, paradoxical autonomic responses, and persistent orthostatic intolerance. The causes and impact of the cardiac and coeliac axis dysfunction is discussed in Cardiac and Coeliac Plexii in POTS

The cardiac plexus, situated near the aortic arch and tracheal bifurcation, mediates chronotropic responses, atrial compliance, and baroreflex sensitivity via projections from the cervical and upper thoracic sympathetic ganglia (T1–T4) and the vagus nerve. Dysfunction in this plexus, particularly under conditions of vagal insufficiency or sympathetic overdrive, may exaggerate the Bainbridge reflex—a volume-sensitive tachycardic response to increased atrial stretch.

In POTS, preload failure results in erratic atrial filling patterns; venous congestion in the thorax, especially through a dysfunctional azygous system, may paradoxically trigger Bainbridge-mediated tachycardia despite systemic hypovolemia. Compromised afferent input from atrial low-pressure receptors or altered processing within the NTS–PVN axis may further distort reflex output, sustaining a loop of inappropriate tachycardia and impaired preload recovery.

The coeliac plexus, located at the T12–L1 level and surrounding the coeliac trunk, governs splanchnic vasomotor tone and gastrointestinal autonomic reflexes via sympathetic fibres from the thoracic splanchnic nerves and parasympathetic input from the vagus. Normally, sympathetic activation of this plexus promotes splanchnic vasoconstriction, facilitating blood mobilization into the central circulation.

In POTS, this reflex is often blunted or paradoxically reversed, resulting in splanchnic pooling, orthostatic hypotension, and a downstream reduction in right atrial preload.

Mechanical compression syndromes such as Median Arcuate Ligament Syndrome (MALS) or SMA syndrome may further destabilize this balance, with coeliac plexus irritation promoting aberrant sympathetic discharge or dysautonomic vasodilation.

When dysfunction in these plexii converges with impaired azygous venous return—a common finding in POTS patients with thoracic outlet or venous compression syndromes—the result is a triple-hit model of preload failure. The system is marked by:

• Inadequate venous mobilization from the abdomen via the coeliac plexus,

• Inappropriate tachycardia from cardiac plexus-Bainbridge reflex dysregulation,

• And inefficient thoracic drainage via the azygous system, culminating in circulatory mismatch and neurovascular stress.

This integrative framework situates the Bainbridge reflex not merely as an epiphenomenon, but as a perpetuator of sympathetic overdrive in the context of distorted volume sensing and impaired baroreceptor integration. Understanding and targeting the upstream contributors—whether mechanical, inflammatory, or neurodegenerative—offers a pathway to restoring autonomic equilibrium and improving preload regulation in POTS.

Gastrointestinal Manifestations of Coeliac Plexus and Brainstem Dysfunction

Gastrointestinal symptoms in POTS—including early satiety, bloating, constipation, nausea, and faecal retention—are not incidental findings, but core expressions of both central autonomic dysregulation and regional neurovascular dysfunction. One critical upstream driver is hypoperfusion of the brainstem, particularly the dorsal vagal complex, which encompasses the nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV). These nuclei integrate afferent input from visceral organs and modulate parasympathetic vagal outflow to the gastrointestinal tract. When chronically under-perfused, these nuclei may fail to coordinate peristalsis, gastric accommodation, and enteric motility, resulting in functional gastric stasis and intestinal pseudo-obstruction phenotypes observed clinically.

In parallel, regional dysfunction of the coeliac plexus—whether due to mechanical compression (e.g., MALS, SMA syndrome), neuroinflammation, or mast cell infiltration—contributes to abnormal splanchnic vasomotor tone.  Instead of appropriately constricting to mobilize venous blood, the splanchnic bed may vasodilate paradoxically, leading to blood pooling, increased intestinal wall tension, and bowel distension.

These effects are compounded by lymphatic obstruction at the thoracic duct or mesenteric root, further impairing local perfusion and immune surveillance. The combined result is a neurovascular–hydraulic mismatch, wherein the gut experiences both functional ischaemia and motor incoordination, closely tied to both preload failure and autonomic chaos. This offers a mechanistic rationale for the gastrointestinal symptoms being particularly prominent in the “preload failure subtype” of POTS.

Mast Cells as Regional Vasomotor Modulators in the Splanchnic Bed

The coeliac plexus and its splanchnic vascular targets are richly innervated by sympathetic nerves and are also populated by perivascular mast cells, particularly within the mesenteric and periarterial adventitia. In chronic inflammatory states—including post-viral syndromes, dysautonomia, or connective tissue disorders—these mast cells may become hyperresponsive or infiltrative, a pattern increasingly recognized in mast cell activation syndrome (MCAS).

Literature confirms the relationship between POTS, MCAS, and post-viral conditions, providing strong scientific support for the mechanisms  regarding how mast cells in the splanchnic circulation contribute to preload failure in POTS through vasodilation, endothelial disruption, neural crosstalk alterations, and neurogenic inflammation.  (Adler et al 2024 (22)) (Kohno et al 2021 (25))

Mechanisms by Which Mast Cells Affect Splanchnic Vascular Tone:

1. Histamine and Nitric Oxide Release → Vasodilation

Activated mast cells release large quantities of histamine, prostaglandin D2, and tryptase, which act directly on vascular smooth muscle and endothelial nitric oxide synthase (eNOS) to induce splanchnic vasodilation.  Histamine has a more potent vasodilating effect on veins than arteries due to higher histamine receptor density in veins and their thinner smooth muscle layer, making them more responsive to histamine-induced relaxation.(Wirth & Löhn 2023.(20))

This heightened venous sensitivity is particularly significant since veins are the primary capacitance vessels involved in orthostatic regulation.( Wirth & Löhn 2023.(20))

This effect can be patchy and disproportionate, leading to maldistributed blood flow and ineffective volume mobilization during orthostasis.

• Histamine H1 receptor activation → increased vascular permeability

• H2 receptor stimulation → direct smooth muscle relaxation

• Prostaglandins (e.g., PGD2) → further vasodilation via G-protein coupled pathways

2. Endothelial Barrier Disruption → Capillary Leak

Chronic mast cell degranulation impairs endothelial integrity, causing microvascular leakage and contributing to interstitial oedema within the gut wall. This not only exacerbates preload failure (by effectively removing intravascular volume) but also triggers low-grade ischaemia that stimulates further mast cell activation in a vicious loop. ( Wirth & Löhn 2023.(20))(Tran et al 2019 (21))

3. Sensory–Sympathetic Crosstalk Disruption

Mast  cells are located adjacent to nociceptors/neurons and act as intermediaries between the immune system and nervous system.  Mast cell mediators sensitize visceral afferents (e.g., via TRPV1 and PAR2 receptors), altering the reflex sympathetic control of splanchnic vessels.

This can contribute to neuroinflammation and alter neural signalling which can affect sympathetic control of vascular tone, potentially explaining the vasoplegic (or paradoxical pooling) response seen in  the splanchnic circulation of POTS patients.(Adler et al 2024 (22))

4. Neurogenic Inflammation at the Coeliac Plexus

Mast cells are densely concentrated near the coeliac ganglion, where they interact with sympathetic neurons and glia. Tryptase and histamine released locally may impair ganglionic transmission, skewing the balance between vasoconstrictor and vasodilator signals.

In POTS patients with mast cell activation, there is evidence of a hyperadrenergic response with orthostatic tachycardia and increased blood pressure on standing which  suggests an imbalance between vasoconstrictor and vasodilator signals.  This neurogenic inflammation may underpin the “frozen” or vasoplegic splanchnic phenotype seen in some preload failure cases.(Shibao et al 2005 (23)) (Raj 2006 (24)

Clinical Correlation to POTS and Preload Failure

In this setting, mast cell activation becomes not only a driver of gut dysmotility, nausea, and bloating, but also a peripheral contributor to central hypovolaemia, through:

• Maladaptive vascular tone

• Plasma extravasation

• Reflex autonomic disruption

This reinforces the maldistributed volume hypothesis in POTS and ME/CFS, where the effective circulating volume is low, not from true hypovolemia, but from volume sequestration in low-resistance, inflamed vascular beds—particularly the mesenteric and pelvic circulation.

Linking MCAS to Immune Dysregulation and reservations on overdiagnosis of MCAS

While mast cell activation undoubtedly contributes to immune dysregulation in subsets of POTS and Long COVID patients, there is growing evidence that the broader and more persistent immune-metabolic dysregulation is better explained by DAMP-driven RAGE activation and its downstream signaling through NF-κB and CCL2.

Persistent RAGE stimulation—triggered by hypoxia, HMGB1, S100 proteins, and advanced glycation end-products—amplifies oxidative stress and primes inflammasome activity in macrophages, endothelial cells, and microglia, establishing a self-sustaining proinflammatory loop independent of mast cells. NF-κB activation downstream of RAGE leads to chronic induction of CCL2 (MCP-1), which not only recruits monocytes but also reinforces vascular inflammation and metabolic stress in tissues such as the brainstem, splanchnic vasculature, and myocardium.

This pathway is now well-described in COVID-19-related endotheliitis, venous thrombosis, and persistent neuroinflammation. (MacCann et al 2023 (26))(Paul et al 2021 (27))   Moreover, as clinically observed, the low GABA, high glutamate, and aspartate dysfunction profile (Molnar et al 2024 (28))  commonly present in these patients is not readily explained by mast cell–histamine dynamics, but is consistent with RAGE-induced excitotoxicity and mitochondrial uncoupling, especially when compounded by PEMT and CCL2 polymorphisms.

The fixation on MCAS as a primary aetiology risks overlooking these deeper, systemic redox and immune pathomechanisms, which may operate with or without mast cell involvement.  Diagnostic guidelines emphasize that MCAD diagnosis should only be considered after excluding relevant differential diagnoses that could better explain symptoms. (Molderings et al 2011 (29))  A shift in focus to DAMP/RAGE-driven inflammatory persistence may better capture the complexity and chronicity of the syndromic presentation.

Linking Lymphatic obstruction and Thoracic Duct with Azygous Dysfunction

The thoracic duct, the body's principal lymphatic vessel, typically drains into the venous system at the junction of the left subclavian and internal jugular veins, known as the left venous angle. A bicuspid valve at this junction prevents venous blood from refluxing into the lymphatic system . Obstruction or dysfunction at this critical juncture can impede lymphatic drainage, potentially leading to lymphatic congestion and rerouting through alternative pathways.  Obstruction at the venous angle can impede thoracic duct drainage, potentially causing lymphatic fluid to reroute through collateral pathways, including the azygous system, thereby mimicking volume overload with impaired drainage.

Collateral pathways mimicking “overfill”.  When obstructed, lymph may divert through”

• Azygous/hemiazygous veins via lymphatico-venous shunts (5)(18)

• Accessory thoracic lymphatics (19)

• Vertebral venous plexus- linked to cerebral hypoperfusion in ME/CFS, intracranial pressure changes (18)

While direct evidence confirming lymphatic obstruction at the venous angles leading to thoracic duct dysfunction and subsequent diversion through the azygous system is scarce except in clinical observation, the anatomical and clinical data suggest that such a mechanism is probable. Obstruction at the venous angle can impede thoracic duct drainage, potentially causing lymphatic fluid to reroute through collateral pathways, including the azygous system, thereby mimicking volume overload with impaired drainage, and have widespread ramifications in symptoms from lymphatic obstruction in the abdomen, pelvis and below, as described by Raymond Perrin,(3) and including lipoedema.

Lipoedema involves dilated lymphatic vessels  and impaired interstitial drainage, with fluid accumulation linked to venous leakage and reduced lymphatic reserve. Chronic inflammation increases fibrosis, further reducing lymphatic compliance and promoting collateralization. (109)(110) 

Lipoedema’s progression aligns with chronic lymphatic obstruction, though causal relationships remain unproven.

Conclusion

 This analysis presents a reconceptualized model of preload failure in POTS and ME/CFS, identifying a complex interplay between the azygous venous system, autonomic plexii, and immune-inflammatory pathways.

This analysis highlights the azygous system, cardiac plexus, and coeliac plexus as interdependent regulators of preload and autonomic stability in POTS and ME/CFS. The azygous system, often viewed as a passive conduit, emerges here as a critical modulator of thoracic venous dynamics, particularly in the context of vascular compression syndromes and thoracic outlet dysfunction.

Superimposed upon this are maladaptive responses from the cardiac plexus, affecting chronotropic competence and baroreflex engagement, and from the coeliac plexus, driving paradoxical splanchnic vasodilation and impaired venous mobilization.

The centrality of the azygous venous system in the pathophysiological landscape of POTS and ME/CFS suggests that far from being a passive collateral route, the azygous vein may serve as a dynamic regulator of preload, intrathoracic pressure, and autonomic equilibrium. Dysfunction within this system—whether structural, flow-mediated, or as a result of venous or lymphatic obstruction—appears to underlie a subset of patients with profound preload failure, refractory orthostatic intolerance, and complex symptomatology including dyspnoea, cognitive dysfunction, and gastrointestinal disturbance.

The azygous system’s unique anatomical connections to the vertebral venous plexus, thoracic duct, and intracranial venous sinuses further implicate it in neurovascular and neuroimmune dysregulation. Importantly, its interplay with low-pressure baroreceptor systems and pathological Bainbridge reflex activation suggests a plausible mechanism for the sympathetic overdrive seen in POTS.

Together, this neurovascular triad helps explain the mismatch between circulating volume and perceived hypovolemia, the paradox of coexisting underfill and overfill states, and the failure of compensatory autonomic responses.

By reconceptualizing preload failure as a product of complex interactions between autonomic plexii and venous return pathways, this work underscores the need for refined diagnostics, targeted autonomic imaging, and novel interventions addressing both the anatomical and neuroimmune contributors to preload dysregulation.

Layered upon this is a compelling role for regional mast cell infiltration, which may distort local vascular tone and autonomic signalling through histamine-driven vasodilation, endothelial permeability, and neurogenic inflammation.

However, this paper urges caution in over-diagnosing MCAS as a primary cause, noting that many immunopathological patterns observed in POTS and ME/CFS—particularly those involving CCL2 upregulation and RAGE/NF-κB feedback loops—are insufficiently explained by classical mast cell paradigms. Instead, these data point toward a broader, dysregulated immune-metabolic milieu underpinning vascular instability.Together, these findings support a hydraulic-neuroimmune model of preload failure, emphasizing structural venous obstruction, autonomic misprocessing, and immune interference as converging drivers. This triadic dysfunction may help explain the clinical paradox of coexisting underfill and overfill states, as well as resistance to conventional therapies. Future research should prioritize mechanistic stratification using autonomic imaging, lymphatic flow analysis, and targeted modulation of neuroimmune pathways to refine phenotyping and treatment.

References:

1.     Fluge Ø, Tronstad KJ, Mella O. Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Clin Invest. 2021;131(14):e150377. doi:10.1172/JCI150377

2.     Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chest. 2021 Aug;160(2):642-651. doi: 10.1016/j.chest.2021.01.082. Epub 2021 Feb 10. PMID: 33577778; PMCID: PMC8727854.

3.     Fudim M, Sobotka PA, Dunlap ME. Extracardiac Abnormalities of Preload Reserve: Mechanisms Underlying Exercise Limitation in Heart Failure with Preserved Ejection Fraction, Autonomic Dysfunction, and Liver Disease. Circ Heart Fail. 2021 Jan;14(1):e007308. doi: 10.1161/CIRCHEARTFAILURE.120.007308. Epub 2021 Jan 19. PMID: 33464948.

4.     Bosch J, Mastai R, Kravetz D, Bruix J, Rigau J, Rodés J. Measurement of azygos venous blood flow in the evaluation of portal hypertension in patients with cirrhosis. Clinical and haemodynamic correlations in 100 patients. J Hepatol. 1985;1(2):125-39. doi: 10.1016/s0168-8278(85)80761-3. PMID: 3877113.

5.     Piciucchi S, Barone D, Sanna S, et al. The azygos vein pathway: an overview from anatomical variations to pathological changes. Insights Imaging. 2014;5(5):619-628. doi:10.1007/s13244-014-0351-3

6.     Mithun, G et al. Head Elevation, Cerebral Venous System, and Intracranial Pressure: Review and Hypothesis. AHA/ASA Journals. 2022. https://doi.org/10.1161/SVIN.122.000522

7.     Scholbach, T.: Diagnosis and treatment of vascular compression syndromes of the abdomen based on the anatomical features of man and gender-specific characteristics after puberty. https://scholbach.de/wp-content/uploads/2017/09/20170917-vascular-compression-syndromes-website.pdf

8.     Baker JR, Incognito AV, Ranada SI, Sheldon RS, Sharkey KA, Phillips AA, Wilson RJA, Raj SR. Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome. JACC Basic Transl Sci. 2024 Jun 26;9(8):939-953. doi: 10.1016/j.jacbts.2024.04.011. PMID: 39297140; PMCID: PMC11405806.

9.     Geddes JR, Ottesen JT, Mehlsen J, Olufsen MS. Postural orthostatic tachycardia syndrome explained using a baroreflex response model. J R Soc Interface. 2022 Aug;19(193):20220220. doi: 10.1098/rsif.2022.0220. Epub 2022 Aug 24. PMID: 36000360; PMCID: PMC9399868

10.  Baroreceptor. Wikipedia. https://en.wikipedia.org/wiki/Baroreceptor

11.  Low pressure receptors. Wikipedia. https://en.wikipedia.org/wiki/Low_pressure_receptors

12.  Atrial volume receptors. Wikipedia. https://en.wikipedia.org/wiki/Atrial_volume_receptors

13.  Pelletier CL, Shepherd JT. Circulatory reflexes from mechanoreceptors in the cardio-aortic area. Circ Res. 1973 Aug;33(2):131-8. doi: 10.1161/01.res.33.2.131. PMID: 4580350.

14.  Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chest. 2021 Aug;160(2):642-651. doi: 10.1016/j.chest.2021.01.082. Epub 2021 Feb 10. PMID: 33577778; PMCID: PMC8727854

15.  Morris RI, Sobotka PA, Balmforth PK, et al. Iliocaval Venous Obstruction, Cardiac Preload Reserve and Exercise Limitation. J Cardiovasc Transl Res. 2020;13(4):531-539. doi:10.1007/s12265-020-09963-w

16.  Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024 Jun 3;15:1386607. doi: 10.3389/fimmu.2024.1386607. PMID: 38887284; PMCID: PMC11180809.

17.  Janssen SL, Scholbach T, Jeno S, Laurie H, Meyer M, Combs C. Interprofessional Management of Median Arcuate Ligament Syndrome (Dunbar Syndrome) Related to Lumbar Lordosis and Hip Dysplasia: A Patient's Perspective. Eur J Case Rep Intern Med. 2020;7(7):001605. Published 2020 Apr 16. doi:10.12890/2020_001605

18.  Bell, D Azygous Venous System. Radiopedia. 2024. https://radiopaedia.org/articles/azygos-venous-system

19.  Vach M, Wagenpfeil J, Henkel A, et al. MR-lymphangiography identifies lymphatic pathologies in patients with idiopathic recurrent cervical swelling. Laryngoscope Investig Otolaryngol. 2022;7(5):1456-1464. Published 2022 Sep 19. doi:10.1002/lio2.919

20.  Wirth KJ, Löhn M. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?. Medicina (Kaunas). 2023;59(5):978. Published 2023 May 18. doi:10.3390/medicina59050978

21.  Tran H, Mittal A, Sagi V, et al. Mast Cells Induce Blood Brain Barrier Damage in SCD by Causing Endoplasmic Reticulum Stress in the Endothelium. Front Cell Neurosci. 2019;13:56. Published 2019 Feb 19. doi:10.3389/fncel.2019.00056

22.  Adler BL, Chung T, Rowe PC, Aucott J. Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome?. Front Neurol. 2024;15:1344862. Published 2024 Feb 8. doi:10.3389/fneur.2024.1344862

23.  Shibao C, Arzubiaga C, Roberts LJ 2nd, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005 Mar;45(3):385-90. doi: 10.1161/01.HYP.0000158259.68614.40. Epub 2005 Feb 14. PMID: 15710782.

24.  Raj SR. The Postural Tachycardia Syndrome (POTS): pathophysiology, diagnosis & management. Indian Pacing Electrophysiol J. 2006;6(2):84-99. Published 2006 Apr 1.

25.  Kohno R, Cannom DS, Olshansky B, et al. Mast Cell Activation Disorder and Postural Orthostatic Tachycardia Syndrome: A Clinical Association. J Am Heart Assoc. 2021;10(17):e021002. doi:10.1161/JAHA.121.021002

26.  MacCann R, Leon AAG, Gonzalez G, Carr MJ, Feeney ER, Yousif O, Cotter AG, de Barra E, Sadlier C, Doran P, Mallon PW. Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity. Front Immunol. 2023 May 16;14:1166574. doi: 10.3389/fimmu.2023.1166574. PMID: 37261339; PMCID: PMC10229044.

27.  Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2021 Aug 24;118(34):e2024358118. doi: 10.1073/pnas.2024358118. PMID: 34400495; PMCID: PMC8403932.

28.  Molnar T, Lehoczki A, Fekete M, Varnai R, Zavori L, Erdo-Bonyar S, Simon D, Berki T, Csecsei P, Ezer E. Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches. Geroscience. 2024 Oct;46(5):5267-5286. doi: 10.1007/s11357-024-01165-5. Epub 2024 Apr 26. PMID: 38668888; PMCID: PMC11336094.

29.  Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011;4:10. Published 2011 Mar 22. doi:10.1186/1756-8722-4-10