Cardiac Plexus in POTS- a Central Node in POTS Pathophysiology

Dr Graham Exelby May 2025

with physiotherapy input from Stuart Stevenson

Abstract

This hypothesis paper presents the cardiac plexus—a dense autonomic relay interfacing both sympathetic and parasympathetic circuits— as a central node in the pathophysiology of Postural Orthostatic Tachycardia Syndrome (POTS). Its dysregulation, shaped by thoracic outlet syndrome, vertebral dyskinesia, and azygous venous congestion, amplifies autonomic instability via impaired baroreflex integration and maladaptive chronotropic responses. This review, based on collected clinical data, synthesizes anatomical, electrophysiological, and neuroimmune data implicating cardiac plexus dysfunction in hallmark features of POTS, including preload failure, and dysrhythmia.

Postural changes in PR and QT intervals offer electrophysiological insight into subtype differentiation within POTS—pointing to vagal-hyperreflexive and sympathetically driven profiles mediated by the cardiac and coeliac plexuses. These observations reinforce a model of mechano-neuro-vascular convergence: where postural compression, neuroimmune inflammation (e.g., RAGE/CCL2/NF-κB), and metabolic dysfunction (e.g., GABA/aspartate depletion) intersect to sustain dysautonomia. This framework supports a targeted, multidimensional therapeutic approach.

Contents:

1.     Introduction

2.     Brainstem Hypoxia as a Central Driver of Dysautonomia

3.     Functional Continuum with Cardiac and Coeliac Plexuses

4.     Anatomy and Function of the Cardiac Plexus

5.     Physiology Concepts

6.     Cardiac Plexus Dysfunction in POTS

7.     Preload Regulation and Central Venous Return-Integrated Model

8.     TOS, Stellate Ganglion, and Cardiac Autonomic Imbalance

9.     Mechanical and Postural Stressors

10.  Short PR Interval, QTc Prolongation and Dysrhythmias

11.  Summary Table: Anatomical vs Molecular Disruption in Cardiac Plexus Dysfunction in POTS

12.  Conclusion

Introduction

The brainstem, particularly the medulla and rostral ventrolateral medulla (RVLM), plays a crucial role in autonomic regulation.  Brainstem hypoperfusion and consequent hypoxia can be viewed as a central initiator of dysautonomia in syndromes such as POTS, ME/CFS, Long COVID, and fibromyalgia. This hypoperfusion triggers maladaptive autonomic responses—including baroreflex failure, sympathetic overactivation, and parasympathetic withdrawal—which cascade through interconnected anatomical networks.

The cardiac and coeliac plexii, anatomically linked via descending thoracic sympathetic pathways and sharing vagal innervation from central nuclei, serve as key peripheral mediators.   The activation and dysfunction of the coeliac and cardiac plexii in POTS—and particularly in patients with overlapping syndromes such as MALS, Long COVID, and trauma-induced dysautonomia are emerging as critical but under-recognized features in the complex pathophysiology of POTS.    

Activated (sensitised) T4 and T8 are extremely common in POTS, but the downstream effects of these are seldom considered.  The complex nature of the Thoracic Outlet Syndrome, with  neurological, arterial and venous dysfunction, as well as the scalene pull on C3 affecting a dysfunctional upper cervical spine with potential impact on all the major mechanical and hydraulic “drivers” can be very difficult to elucidate.  T4 activation provides a further complicating factor, as well as likely effects on the cardiac plexus.   The complex pathophysiology of the various TOS “drivers” appears to find a place in dysfunction in the cardiac plexus.  

The cardiac plexus serves as a critical autonomic integrator at the intersection of sympathetic and parasympathetic signalling, mediating reflex control of heart rate, contractility, and vascular tone. It integrates afferent input from baroreceptors and mechanoreceptors with efferent control of the sinoatrial and atrioventricular nodes, coronary vasculature, and myocardial tissue.

In POTS, dysautonomia frequently arises from aberrant signalling within this plexus. Overactivation of the stellate ganglion, reduced vagal tone, and impaired baroreflex gain are central features of hyperadrenergic POTS, but their anatomical substrate is rarely scrutinized.

Structural contributors—such as thoracic outlet syndrome (TOS), vertebral dysfunction, and venous obstruction (particularly involving the azygous system)—may compress or irritate the neural fibres converging on the cardiac plexus. These mechanical stressors propagate autonomic dysregulation, exacerbating chronotropic intolerance, preload failure, and in some cases, atrial and ventricular dysrhythmias.

Emerging data suggest electrophysiological patterns—particularly posture-dependent alterations in PR and QT intervals—can stratify subtypes of autonomic dysfunction within POTS. These changes reflect underlying reflex arc dysregulation across the cardiac and coeliac plexuses and may serve as real-time biomarkers of vagal hyperreflexia, sympathetic overdrive, or ion channel vulnerability. Understanding these dynamic electrical shifts within the broader context of mechanical, neuroimmune, and metabolic stressors offers a refined approach to diagnosis, phenotyping, and treatment in complex dysautonomic syndromes.

Brainstem Hypoxia as a Central Driver of Dysautonomia

Persistent hypoxia is increasingly recognized as a central mechanism in the chronic neuroimmune dysfunction seen in Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). At the molecular level, hypoxia triggers a cascade of inflammatory and metabolic stress signals, most notably through activation of the Receptor for Advanced Glycation End Products (RAGE). This receptor integrates signals from tissue injury, oxidative stress, and immune activation.

In parallel, neuropeptides such as Substance P, CGRP, and VIP—released from sensory and autonomic neurons—exacerbate inflammation by activating mast cells, glial cells, and endothelial cells. Together, these pathways promote blood-brain barrier breakdown, neuroinflammation, and autonomic instability.

A key feature of this model is the persistence of inflammation in brain regions critical to autonomic control (e.g., the brainstem), even after systemic recovery.  Hypoxia and its downstream immune and neurovascular effects form a self-sustaining loop—one that may explain the chronicity of symptoms across multiple systems.

Functional Continuum with Cardiac and Coeliac Plexuses

The medulla oblongata and rostral ventrolateral medulla (RVLM) in the brainstem coordinate cardiovascular, respiratory, and autonomic function. Chronic or dynamic hypoperfusion compromises neuronal viability and reflex integration.- discussed in Brainstem Hypoperfusion in POTS, CFS, Fibromyalgia, Long COVID and GWS-a Key Role (8).

The downstream consequences of brainstem hypoxia extend beyond central autonomic nuclei and permeate peripheral autonomic relay systems. Given the longitudinal continuity of the sympathetic chain and shared parasympathetic pathways, disturbances originating in the rostral medulla and nucleus tractus solitarius (NTS) can propagate functionally through spinal intermediolateral columns, ultimately manifesting as aberrant signalling in downstream plexuses.

A critical but often overlooked concept is the gastrocranial hydraulic continuum, which links abdominal venous and lymphatic congestion to central neurovascular dysfunction. In this model, mechanical or vascular compression syndromes such as Nutcracker Syndrome (NCS) or Superior Mesenteric Artery Syndrome (SMA) disrupt venous outflow from the splanchnic circulation and left renal vein.

 Given the valveless architecture of the vertebral and paravertebral venous systems, this venous congestion may propagate cranially, contributing to cerebrospinal fluid impedance, intracranial hypertension (ICH), and impaired glymphatic clearance. The coeliac plexus, anatomically and functionally proximal to these vascular bottlenecks, becomes a critical relay in this continuum—subjected to mechanical stress, neuroinflammation, and sympathetic overdrive.

This gastrocranial pathway provides a plausible mechanistic link between abdominal autonomic dysfunction, impaired venous return, and brainstem hypoperfusion observed in POTS, ME/CFS, and Long COVID. Recognition of this continuum underscores the need for integrated imaging approaches and orthostatic haemodynamic assessments when evaluating these patients

The cardiac and coeliac plexuses serve as principal nodal points within this distributed autonomic hierarchy. They relay centrally-derived signals into somatovisceral outputs—regulating cardiac contractility, vascular tone, splanchnic perfusion, adrenal output, and gastrointestinal motility.

Importantly, the structural and functional integrity of these plexuses is susceptible to both central influences (e.g., hypoperfusion-induced parasympathetic withdrawal) and regional mechanical perturbations (e.g., MALS, SMA compression, thoracic vertebral dysfunction). In syndromes like POTS and ME/CFS, the combined effect of descending sympathetic hyperactivation and vagal suppression precipitates a multilevel dysautonomia, where both cardiac and coeliac plexus dysfunction converge to shape the systemic phenotype—characterized by preload failure, postprandial hypotension, and central-peripheral mismatched autonomic tone.

There is descending sympathetic continuity along the thoracic sympathetic chain from T1–T12, with inter-ganglionic communication. The cardiac plexus governs chronotropy, inotropy, and coronary vascular tone.  It receives sympathetic innervation from T1–T4 via cervical and stellate ganglia.  Parasympathetic fibres arise from the vagus, converging near the base of the heart.

The coeliac plexus receives preganglionic sympathetic fibres from T5–T12 via greater, lesser, and least splanchnic nerves, Integrates vagal efferents and phrenic input, and modulates mesenteric, renal, and adrenal perfusion and gut motility.

Overactivity or dysfunction in the upper thoracic ganglia (affecting cardiac plexus) can propagate signals caudally, influencing the splanchnic sympathetic outflow.  This becomes highly relevant in central autonomic syndromes such as POTS, where a spinal or brainstem signal may be amplified and relayed across both cardiac and coeliac levels.

The sympathetic chain continuity permits vertical signal propagation from upper thoracic segments to abdominal plexuses.  The loss of vagal tone (from brainstem hypoperfusion) concurrently depresses parasympathetic output to both plexuses.

Anatomy and Function of the Cardiac Plexus

The cardiac plexus consists of superficial and deep components spanning the anterior and posterior mediastinum, within the anterior and posterior regions of the aortic arch, extending from the root of the neck (T1–T4 level) down into the superior mediastinum.  

It integrates inputs from cervical and thoracic sympathetic ganglia and the vagus nerve. These fibres converge to innervate the sinoatrial (SA) and atrioventricular (AV) nodes, as well as myocardial and coronary vasculature. Key components include:

• Superficial cardiac plexus: Below the aortic arch, near the ligamentum arteriosum; receives fibres primarily from left vagus and left sympathetic trunk.

• Deep cardiac plexus: It bifurcates into a deep cardiac plexus (posterior to the aortic arch, adjacent to the tracheal bifurcation). It is heavily integrated with cervical and thoracic sympathetic ganglia, vagal branches, and possibly afferents from the pericardium and oesophageal plexus.

Nerves incorporated in the Cardiac Plexus

• Sympathetic fibres from the cervical (superior, middle, inferior) and upper thoracic ganglia. Sympathetic fibres from stellate ganglion (C7-T1) and upper thoracic ganglia (T2–T5), modulate chronotropy, inotropy, and coronary vasoconstriction.

• Parasympathetic fibres primarily from the vagus nerve (via the recurrent laryngeal branches and direct cardiac branches). Parasympathetic fibres via the vagal cardiac branches, mediating bradycardia and vasodilation.

• The plexus also integrates afferent baroreceptor inputs from the aortic arch and great veins, relaying to central nuclei for cardiovascular reflexes.

Physiology Concepts

This section is extracted from “Cardiovascular Physiology Concepts” by Klabunde 2022 (1):

The heart is innervated by vagal and sympathetic fibres.   The right vagus primarily innervates the sinoatrial (SA) node, while the left vagus innervates the atrioventricular (AV) node.  There can be a significant overlap in anatomical distribution.    Atrial muscle is also innervated by vagal efferent nerves, whereas the ventricular myocardium is only sparsely innervated by vagal efferent nerves.  

Sympathetic efferent nerves are present throughout the atria, especially in the SA node, as well as the ventricles.     Sympathetic activation of the heart increases heart rate (positive chronotopy), contractility (inotropy)and conduction velocity, while parasympathetic stimulation has the opposite effect.  Sympathetic and parasympathetic effects on heart function are mediated by b-adrenoceptors and muscarine receptors respectively.

Sympathetic adrenergic nerves travel in the adventitia of arteries, lymphatics and nerves.  Varicosities along the nerve fibres are the source of neurotransmitter (noradrenalin) release.  Activation of the vascular sympathetic nerves causes vascular smooth muscle contraction of arteries and veins mediated by a-adrenoreceptors.

Parasympathetic fibres are found associated with blood vessels in salivary, gastrointestinal glands and genital erectile tissue.  Parasympathetic nerves release acetylcholine that binds to muscarinic Ach receptors.   This causes vasodilatation through formation of nitric oxide and subsequent guanylyl cyclase activation. Ach release can stimulate kallikrein release from glandular tissue that acts on kininogen to form kinins eg bradykinin that causes increased capillary permeability and venous constriction and arterial vasodilatation in specific organs.

Cardiac Plexus Dysfunction in POTS

The cardiac plexus provides autonomic innervation to the sinoatrial (SA) node, atrioventricular (AV) node, myocardial tissue, and it communicates bidirectionally with both pulmonary and coronary vasculature and the sinoatrial (SA) node.  This innervation controls vasoconstriction and vasodilation of these vessels through sympathetic activation, (1) playing a central role in heart rate modulation, contractility, and coronary blood flow- chronotropy, inotropy, and venous return modulation.  The right vagus nerve primarily innervates the SA node, while sympathetic efferent nerves are especially present in the SA node region.  Postganglionic fibres from both components of the cardiac plexus are most densely distributed to the sinoatrial node. 

This  bidirectional communication enables:

• Sympathetic stimulation to increase heart rate (positive chronotropic effect (Klabunde 2022 (1)(Gordan et al 2015 (2))

• Parasympathetic (vagal) stimulation to decrease heart rate (1)

• Afferent fibres to carry sensory information back to the central nervous system.

This regulates coronary vascular tone, integrates baroreceptor input from both high-pressure (aortic arch, carotid sinus) and low-pressure (atrial, venous) sensors and modulates heart rate and contractility via SA and AV node innervation. 

Importantly, the cardiac plexus also integrates afferent baroreceptor input from:

• Low-pressure receptors in the atria and great veins (volume sensing)

• High-pressure baroreceptors in the aortic arch and carotid sinus

The cardiac plexus integrates afferent vagal fibres from baroreceptors; dysfunction may impair feedback control of venous capacitance vessels in the splanchnic and lower limb beds.  Disruption of cardiac plexus function impairs autonomic balance and reflex control which may cause:

• Reflexive venous tone regulation, thus reducing venoconstriction and preload, with inadequate venoconstriction upon orthostasis, and blunted Bainbridge reflex, impairing heart rate response to low cardiac preload.

• Excessive sympathetic tone in the cardiac plexus may decrease ventricular compliance, promoting diastolic dysfunction.

• Inappropriate vagal modulation may cause blunted atrial natriuretic peptide release, exacerbating fluid maldistribution.

• Potential neurogenic inflammation around the aortic arch (including post-viral vagal neuropathy or post-vaccine autoimmunity) may compromise plexus function.

Sympathetic dysregulation of the cardiac plexus may manifest as:

• Palpitations, arrhythmias.

• Vasovagal-like episodes (when vagal input is simultaneously involved).

• Thoracic or retrosternal chest pain not of coronary origin.

Stretch- or Pressure-Induced Sympathetic Reflexes

• Atrial stretch (e.g., via preload failure, left atrial dilation) can induce abnormal autonomic feedback:

  • Bezold–Jarisch reflex (via mechanosensitive C-fibers) with a loss of sympathetic tone (hypotension) followed by an intense vagal discharge causing bradycardia.

  • Bainbridge reflex, increasing HR in response to venous return—but potentially dysregulated if vagal counterbalance is impaired.

The cardiac plexus location makes it vulnerable to dysfunction from:

• Upper thoracic musculoskeletal derangement

• Sympathetic hyperactivity or entrapment from structures like scalene muscles or costoclavicular space (as in TOS)

Autonomic dysregulation may result from structural impingement (TOS), neuroinflammation (e.g., post-viral vagal neuropathy), or sympathetic overactivity at the stellate ganglion.

Preload Regulation and Central Venous Return-Integrated Model

In POTS, resting vagal tone is often diminished, disrupting cardiac baroreflex gain and venous tone reflex loops.   Preload regulation is particularly sensitive to disruptions in these convergent neurovascular and mechanical inputs, many of which converge through the following mechanisms, which could manifest as:

• Reflex Arc Integration: The cardiac plexus processes afferent signals from baroreceptors (aortic arch, carotid sinus) and low-pressure mechanoreceptors in the great veins, pulmonary arteries, and right atrium. This system modulates sympathetic and parasympathetic output to regulate venous capacitance, vascular compliance, and myocardial filling.- blunted Bainbridge and Bezold–Jarisch reflexes

• Sympathetic Overdrive and Small Cavity Dysfunction in POTS: In hyperadrenergic states, notably POTS, sympathetic hyperactivity leads to tachycardia, reduced diastolic filling time, and ventricular stiffening, particularly in patients with a morphologically small LV cavity. This sympathetic tone also impairs venous return by promoting vasoconstriction in capacitance vessels, reducing preload.

• Parasympathetic Withdrawal: Impaired vagal modulation reduces compensatory venous vasodilation, disrupts baroreflex sensitivity, and compromises cardiac-vascular coupling, particularly in the right atrium and vena cava, where low-pressure baroreceptors are functionally downregulated.   impaired baroreflex gain, inadequate venous vasodilation, reduced atrial natriuretic peptide release.

In this integrated model, TOS and azygous obstruction act as upstream contributors to preload dysfunction, creating a feedback loop where mechanical outflow resistance, venous pooling, and autonomic imbalance converge. These distort the reflex control of cardiac function and systemic haemodynamics, particularly under orthostatic stress, and may underlie a significant proportion of the cardiac symptoms in dysautonomia and POTS, including presyncope, exertional intolerance, and inappropriate sinus tachycardia.

TOS, Stellate Ganglion, and Cardiac Autonomic Imbalance

In POTS, preload failure is exacerbated by:

• Azygous vein obstruction → impaired venous return, intracranial hypertension.

• TOS → subclavian vein compression, collateral overload via azygous system.

• Sympathetic irritation of the stellate ganglion → further biasing toward adrenergic dominance.

Azygous Vein Obstruction: The azygous system, a critical conduit for thoracic and abdominal venous return, becomes pathologically relevant when mechanically compressed or haemodynamically congested, particularly in upright posture. Azygous congestion impairs return from the intercostal and spinal venous plexuses, contributing to venous hypertension, preload failure, and possibly intracranial hypertension via vertebral venous reflux. The resulting stagnation may further amplify afferent input to the cardiac plexus, perpetuating sympathetic overactivation. Two case studies have confirmed ligation of the Azygous Veins in the thorax during cardiac surgery can activate POTS.  In the cases involved, both had significant venous TOS.

Thoracic Outlet Syndrome (TOS): TOS, particularly in its venous and neurogenic forms, may compromise subclavian vein outflow and brachial plexus integrity, generating a dual impact, with mechanisms which may include:

• Mechanical impingement by scalene hypertrophy or cervical ribs

• Subclavian artery/vein compression altering cerebral perfusion and venous return

• Vascular diameter reduction via tensioned vascular/venous structures ie in downward rotated scapula position in the absence of hypertrophied scalenes should be an additional consideration. This can happen with many shoulder related pain events that cause dyskinesia. 

Mechanically, impaired drainage from the upper extremities leads to collateral flow recruitment via the azygous-hemiazygous system, exacerbating central venous congestion.

Neuroanatomically, irritation of sympathetic fibres at the stellate ganglion and upper thoracic chain (T2–T6) can aberrantly activate the cardiac plexus, biasing towards sympathetic dominance and further destabilizing preload regulation.

However, no direct mapping studies or high-resolution autonomic neuroimaging confirm direct cardiac plexus dysfunction from TOS.

Stellate Ganglion irritation: TOS-induced compression near the brachial plexus can directly irritate the stellate ganglion (C7-T1), a key relay for cardiac sympathetic innervation. (Larsen 2018 (3)) (Goldberger et al 2019 (4))  This may trigger:

• Excessive noradrenaline release- Linked to ventricular arrhythmias and prolonged QT intervals. (Goldberger et al 2019 (4))  (Borovac et al 2020 (5))

• Reduced cerebral perfusion- Subclavian/vertebral artery compression alters blood flow to brainstem autonomic centres (e.g., nucleus tractus solitarius), impairing baroreflex function (Larsen 2018 (4)) (Goldberger et al 2019 (5))

Stellate-Driven Adrenergic Effect on the Cardiac Plexus: The right stellate ganglion preferentially modulates SA node activity, and closely integrated with the cardiac plexus, disproportionately influences the SA node and may underlie the hyperadrenergic subtype of POTS.  Its overactivation may:

• Elevate standing noradrenaline levels (hyperadrenergic POTS)

• Shorten ventricular action potential duration, increasing arrhythmia risk

• Inhibit vagally-mediated bradycardic reflexes, especially in patients with underlying vagus nerve dysfunction (iatrogenic or viral)

• Reflex propagation through the paraventricular nucleus (PVN), nucleus ambiguus, and nucleus tractus solitarius (NTS)

These interactions destabilize preload regulation, alter baroreflex function, and predispose to arrhythmogenesis.

Haemodynamic Consequences:

Subclavian artery compression in TOS redistributes blood flow, causing paradoxical cerebral hyperperfusion (headaches) or hypoperfusion (dizziness). (Larsen 2018 (3))  Impaired venous return from subclavian vein compression exacerbates POTS-like tachycardia. (Larsen 2018 (3))

Mechanical and Postural Stressors

Complicating the Thoracic Outlet Syndrome (TOS), sternal distortion/postural syndromes may affect the sympathetic chain or stellate ganglion, leading to abnormal input into the cardiac plexus.

• Forward head posture and T1–T4 dyskinesia can place mechanical strain on the cervicothoracic junction, potentially irritating cardiac sympathetic pathways and facilitating autonomic imbalance.   This potentially compresses the T1-T4 nerve roots that contribute to cardiac innervation. (Physiopedia (6))  Reduced thoracic mobility increases mechanical stress on sympathetic ganglia, amplifying catecholamine release. (Physiopedia (6))  This has led to the hypothetical “T4 Syndrome.”

• Recurrent diaphragmatic traction, especially in abdominal preload failure, can distort or irritate cardiac plexus fibres.

• Post-surgical scarring, mediastinal fibrosis, or vertebral instability (e.g., T1–T4 dyskinesia) may disrupt cardiac autonomic coordination.

Short PR Interval, QTc Prolongation and Dysrhythmias

Atrial and ventricular dysrhythmias in patients with preload dysfunction, TOS, and azygous flow impairment reflect a deep interconnection between mechanical compression, autonomic dysregulation, regional hypoxia, and ion channel maladaptation. This demands a multimodal therapeutic approach: decompression (where appropriate), autonomic modulation (e.g., via vagal nerve stimulation, mast cell stabilization, or SIRT activators), and careful electrolyte and repolarization management.

The mechanistic convergence of cardiac plexus dysfunction, preload failure (including azygous obstruction), thoracic outlet syndrome (TOS), and autonomic imbalance, with molecular, anatomical, and electrophysiological integration.

This pathophysiological milieu promotes ventricular electrical instability, manifesting as shortened PR interval, QTc prolongation, dysrhythmias, and in susceptible individuals, syncope or ventricular tachyarrhythmia (especial concern for torsades de pointes). This highlights the need for careful ECG surveillance, especially looking at postural change, electrolyte correction, and autonomic stabilization in these syndromes.

Common cardiac electrical abnormalities seen when comparing supine to lying ECGs, involves PR and QT intervals.  This may also be accompanied by various arrythmias, that may increase with increasing QT intervals.  This can be of extreme importance in POTS and medication employed to “control” POTS symptoms may increases these electrical abnormalities.   Many of these can be traced back to dysfunction in the cardiac and coeliac plexuses. 

The PR interval measures the time it takes for electrical impulses to travel from the atria to the ventricles of the heart- atrioventricular (AV) nodal conduction time.   Potential causes associated with finding in clinic observation may include:

• Parasympathetic withdrawal or excessive sympathetic input from the cardiac plexus, particularly involving T1–T5 efferents

• Plexus-level dysautonomia (e.g., hypothalamic-brainstem–cardiac plexus axis hyperresponsivity) could manifest as PR interval variability based on baroreflex unloading in the supine state.

Finding this in supine ECGs that correct when standing might suggest there’s withdrawal of vagal input and augmentation of sympathetic tone, which normally shortens PR.   However, in POTS, excessive noradrenaline spillover and baroreflex hypersensitivity can normalize or slightly prolong AV conduction time due to altered autonomic gating at the nodal level, likely involving:

• Impaired presynaptic NE reuptake (NET mutation in some patients)

• Desensitization of β-adrenergic receptors from chronic NE excess

• Enhanced afferent traffic from coeliac or splanchnic autonomic plexuses, particularly when gut congestion or MALS is present

The QT interval is a measurement on an electrocardiogram (ECG) that represents the duration of ventricular depolarization and repolarization. It is measured from the start of the QRS complex (which represents ventricular depolarization) to the end of the T wave (which represents ventricular repolarization).    The sympathetic nervous system is responsible for regulating heart rate, blood pressure, and cardiac contractility.  Increased sympathetic tone, as seen in sympathetic overactivity, can lead to an increase in heart rate and contractility, which in turn can prolong the QT interval. 

QT prolongation in POTS is frequently seen in clinic assessments, often normal when supine, then abnormal when erect when supine and standing ECGs are employed.   This has critical importance in pathogenesis of POTS and also in management as many medications may impact adversely on QT intervals, which may cause dysrhythmias.    

This might reflect:

• Subclinical hypokalaemia or hypomagnesemia from renal wasting (especially if aldosterone is dysregulated or due to chronic hyperventilation).

• Sympathetic overdrive impairing cardiac repolarization reserve, especially in patients with subclinical ion channel mutations (e.g., KCNH2, KCNQ1) or SCN5A variants, which are increasingly being linked to autonomic disorders.

• Mitochondrial dysfunction and low GABA/aspartate leading to repolarization failure. This is more pronounced during orthostatic challenge, when metabolic demand increases but is not matched by adequate ATP-dependent ion channel function.

• Coeliac plexus overactivation during standing (due to MALS, splanchnic pooling, or mechanical plexus compression) may trigger reflex vagal hypertonia and splanchnic vasodilation, leading to ischaemic-repolarization mismatch in the inferior wall or septum (also seen in Bezold–Jarisch reflex contexts).

These changes reflect converging pathophysiological processes:

• Mechanical stressors (TOS, vertebral compression)

  • Mechanical compression → venous pooling, impaired cerebral perfusion.

  • Stellate ganglion irritation → elevated noradrenaline, QT prolongation, arrhythmias.

  • Vertebral/postural strain → T1–T4 dyskinesia, stretching cardiac sympathetic pathways.

• Haemodynamic strain (preload failure, venous congestion)

• Autonomic imbalance (sympathetic excess, vagal failure)

• Metabolic dysregulation (hypoxia, ion channel dysfunction)

Medication, low magnesium, potassium and calcium are potential causes, and especially when blocking mast cells with H2 blockade, needs to be carefully watched for.  Magnesium is commonly required to effectively manage the metabolic dysfunction found in POTS, and this aligns with the metabolic dysfunction found in POTS, CFS and Long COVID patients in clinic amino acid testing.   Medications that prolong the QT Interval are discussed in QT Interval. (7)

Section summary.

When looking at these 2 findings that reflect opposite poles of autonomic dysregulation:

• Cardiac Plexus (T1–T5, stellate influence)

  • Overactivation → short PR, ectopy, or atrial fibrillation.(Chen et al 2014 (9))

  • Plexus compression or irritation (e.g., from thoracic outlet syndrome, pectus, cervical sympathetic chain irritation) → erratic AV nodal behaviour.

• Coeliac Plexus (T6–T12, splanchnic feedback)

  • Dysautonomia of this plexus alters splanchnic capacitance, triggering maladaptive baroreceptor responses and reflex cardioinhibitory/vagal arcs.

  • This may explain QT prolongation during orthostasis, as vagal activation paradoxically slows ventricular repolarization in some patients due to poor sympathetic-vagal balance.

One pattern seen in parasympathetic-dominance POTS subtypes is short PR interval supine, prolonged QT interval standing.  This may represent a "vagal-hyper-reflexive coeliac plexus subtype", potentially driven by:

• Gut and splanchnic mechanosensory overload (i.e., MALS, SMA compression, pelvic congestion)

• Neuroimmune inputs via vagal afferents, possibly engaging the dorsal motor nucleus of the vagus (DMNV)

• Repolarization vulnerability during sympathetic shift with orthostasis due to coexisting mitochondrial stress, common in POTS-Long COVID

This may explain why patients worsen upright, despite “normalized” PR: the sympathetic masking uncovers an unstable repolarization substrate, which can be proarrhythmic.

These changes when seen point to functional electrophysiological stratification within POTS subtypes, suggesting that the PR/QT interval dynamics, especially in postural context, may act as non-invasive biomarkers of deeper autonomic and metabolic signatures.

Summary Table: Anatomical vs Molecular Disruption in Cardiac Plexus Dysfunction in POTS

Category	Mechanism of Disruption	Downstream Effects
Anatomical	Thoracic Outlet Syndrome (TOS)	Mechanical compression of plexus, subclavian vein, and stellate ganglion
	Vertebral dyskinesia (T1–T4)	Irritation of sympathetic chain, distortion of autonomic afferents
	Azygous venous congestion	Impaired venous return, preload failure, vagal reflex suppression
	Diaphragmatic traction / Mediastinal fibrosis	Stretch-induced plexus irritation
Molecular	RAGE activation	NF-κB/CCL2 induction, neuroinflammation, baroreflex suppression
	CCL2–CCR2 axis	Monocyte/glia recruitment, sympathetic neuron hyperexcitability
	NF-κB/IL-6/IL-1β	Cytokine-driven ion channel modulation, increased sympathetic firing
	TLR4 signalling	Viral/DAMP-induced sympathetic overactivity and vagal afferent distortion
	Ethanolamine/PEMT dysfunction	Membrane instability, vagal transmission failure, impaired acetylcholine release
	Hypoxia/HIF-1α activation	Local vascular remodelling, chronic sympathetic sensitization

Conclusion

This hypothesis paper presents cardiac plexus dysfunction as a key mechanistic node in the pathophysiology of POTS, linking neuroanatomical disruption with autonomic dysregulation, mechanical compression, vascular flow disturbance, and now well-defined molecular inflammatory circuits. Through impaired baroreflex integration, altered vagal-sympathetic tone, reflex arc distortion, and chronic neuroinflammatory activation (via RAGE, TLR4, CCL2, and NF-κB), this autonomic hub contributes to hallmark features of POTS—including inappropriate sinus tachycardia, QT prolongation, and exertional intolerance.

Mechanistically, the convergence of thoracic outlet compression, azygous obstruction, stellate ganglion overactivity, and ethanolamine-phospholipid dysfunction defines a multifaceted model of preload failure and electrophysiological instability. These dysfunctions are further amplified by post-viral autonomic neuropathy, immune-mediated neuroinflammation, and biomechanical strain at the cervicothoracic junction.

A mechanistic appreciation of cardiac plexus involvement—including both anatomical and molecular layers—allows for precision-oriented interventions: decompressive therapies (e.g., addressing TOS and azygous impedance), autonomic recalibration (e.g., vagal nerve stimulation, SIRT activation), immune modulation, and vigilant cardiac monitoring. Recognizing the interplay between structural, neuroimmune, and electrophysiological contributors reframes POTS as a systemic disorder of reflex failure and hydraulic-immune imbalance, anchored in autonomic circuitry.

Cardiac plexus dysfunction represents a key mechanistic node in the pathophysiology of POTS, linking neuroanatomical disruption with autonomic dysregulation, mechanical compression, and vascular flow disturbance. Through impaired baroreflex integration, altered vagal-sympathetic tone, and reflex arc distortion, this autonomic hub contributes to hallmark features of POTS—including inappropriate sinus tachycardia, QT prolongation, and exertional intolerance.

Mechanistically, the convergence of thoracic outlet compression, azygous obstruction, and stellate ganglion overactivity defines a multifaceted model of preload failure and electrophysiological instability. These dysfunctions are further amplified by post-viral autonomic neuropathy, immune-mediated neuroinflammation, and biomechanical strain at the cervicothoracic junction.

A mechanistic appreciation of cardiac plexus involvement allows for precision-oriented interventions: decompressive therapies (e.g., addressing TOS and azygous impedance), autonomic recalibration (e.g., vagal nerve stimulation, SIRT activation), and vigilant cardiac monitoring. Recognizing the interplay between structural, neuroimmune, and electrophysiological contributors reframes POTS as a systemic disorder of reflex failure and hydraulic imbalance, anchored in autonomic circuitry.

References:

1.     Klabunde,R. Autonomic Innervation of the Heart and Vasculature. Cardiovascular Physiology Concepts. 2022. https://cvphysiology.com/blood-pressure/bp008

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