Gastroparesis in POTS and Long COVID: A Simplified Version

Simplified from “Gastroparesis in POTS and Long COVID: A Unified Hydraulic–Neuroimmune Model” by Dr Graham Exelby November 2025

Abstract

Gastroparesis—delayed gastric emptying in the absence of obstruction—is common among patients with Postural Orthostatic Tachycardia Syndrome (POTS) and Long COVID. Mounting evidence shows it to be a systemic, potentially reversible disorder driven by impaired venous return, lymphatic congestion, and neuro-immune-metabolic imbalance.

In upright posture, preload failure limits cerebral and brainstem perfusion, particularly within the locus coeruleus (LC) and nucleus tractus solitarius (NTS). Hypoxia in these regions destabilizes autonomic coordination of gastric tone and nitric-oxide–mediated relaxation. The ensuing cycle—RAGE–NF-κB–STAT3 activation, mitochondrial redox collapse, and low-grade inflammation—extends through the gut, vasculature, and fascia.

Hydraulic amplifiers such as Median Arcuate Ligament Syndrome, Nutcracker Syndrome, and Pelvic Congestion Syndrome restrict splanchnic and lymphatic flow, while connective-tissue fragility in Ehlers-Danlos Syndrome (EDS) magnifies venous pooling and lymphatic inertia. These mechanical and biochemical derangements converge on a single continuum—the gastro-cranial hydraulic axis—linking orthostatic intolerance, gastrointestinal dysmotility, and cognitive fatigue.

Encouragingly, multimodal management targeting this continuum—mechanical decompression, lymphatic therapy, immune stabilization (H₁/H₂ blockers, LDN, potentially telmisartan), and metabolic re-oxygenation (nicotinamide riboside, α-lipoic acid, vitamin K₂, tirzepatide)—can restore function. Understanding gastroparesis within this framework moves clinical practice from symptom suppression to systems repair.

List of Abbreviations

Abbreviation	Full Meaning
ANA	Antinuclear Antibody
ALA	Alpha-Lipoic Acid
ARB	Angiotensin II Receptor Blocker
ATP	Adenosine Triphosphate
CCL2	Chemokine (C–C motif) Ligand 2 (Monocyte Chemoattractant Protein-1)
CoQ₁₀	Coenzyme Q₁₀ (Ubiquinone)
CRP	C-Reactive Protein
CT	Computed Tomography
CTV	Computed Tomography Venography
DAMPs	Damage-Associated Molecular Patterns
ECM	Extracellular Matrix
EDS	Ehlers-Danlos Syndrome
ENS	Enteric Nervous System
Fe	Iron
GABA	Gamma-Aminobutyric Acid
GI	Gastrointestinal
GLP-1	Glucagon-Like Peptide 1
GIP	Glucose-Dependent Insulinotropic Polypeptide
HIF-1α	Hypoxia-Inducible Factor 1-Alpha
H₁ / H₂	Histamine 1 and 2 Receptor Blockers
ICC	Interstitial Cells of Cajal
ICG	Indocyanine Green
IJV	Internal Jugular Vein
IL-6	Interleukin 6
IMT	Inspiratory Muscle Training
IV	Intravenous
IVIG	Intravenous Immunoglobulin
K₂ (MK-7)	Menaquinone-7 (Vitamin K₂ form)
LC	Locus Coeruleus
LDH	Lactate Dehydrogenase
LDN	Low-Dose Naltrexone
LVEDV	Left-Ventricular End-Diastolic Volume
MALS	Median Arcuate Ligament Syndrome
MAS	Malate–Aspartate Shuttle
MCAS	Mast-Cell Activation Syndrome
Mg	Magnesium
MK-7	Menaquinone-7 (Vitamin K₂)
MRI	Magnetic Resonance Imaging
MRA	Magnetic Resonance Angiography
MMP	Matrix Metalloproteinase
NAD⁺ / NADH	Nicotinamide Adenine Dinucleotide (oxidized/reduced forms)
NAM	Nicotinamide (Vitamin B₃ amide form)
NF-κB	Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells
NLRP3	NOD-Like Receptor Pyrin Domain-Containing 3 Inflammasome
NMN	Nicotinamide Mononucleotide
NTS	Nucleus Tractus Solitarius
PAI-1	Plasminogen Activator Inhibitor 1
PDH	Pyruvate Dehydrogenase
PDH-MAS	Pyruvate Dehydrogenase–Malate Aspartate Shuttle Axis
PEM	Post-Exertional Malaise
PEMT	Phosphatidylethanolamine N-Methyltransferase
POTS	Postural Orthostatic Tachycardia Syndrome
PPARG (PPARγ)	Peroxisome Proliferator-Activated Receptor Gamma
PRP	Platelet-Rich Plasma
PVN	Paraventricular Nucleus (of the Hypothalamus)
RAGE	Receptor for Advanced Glycation End Products
RAAS	Renin–Angiotensin–Aldosterone System
RNA	Ribonucleic Acid
ROS	Reactive Oxygen Species
SAA	Serum Amyloid A
SIRT	Sirtuin (NAD⁺-dependent deacetylase family)
SPECT	Single-Photon Emission Computed Tomography
STAT3	Signal Transducer and Activator of Transcription 3
TGF-β	Transforming Growth Factor Beta
TLR4	Toll-Like Receptor 4
TNF-α	Tumour Necrosis Factor Alpha
TOS	Thoracic Outlet Syndrome
VTI	Velocity–Time Integral
VEGF	Vascular Endothelial Growth Factor
VDR	Vitamin D Receptor
Zn	Zinc

Introduction

From Local Neuropathy to Systems Failure

Patients with POTS and Long COVID often present with nausea, early satiety, bloating, and post-prandial fatigue. Traditionally these are ascribed to idiopathic “autonomic neuropathy” or “functional GI disorder,” yet dynamic imaging tells another story: a 20–40 % reduction in left-ventricular end-diastolic volume (LVEDV) and diminished stroke volume on standing confirm orthostatic preload failure. This under-fills the cerebral circulation, inducing brainstem hypoxia and disrupted vagal–sympathetic coordination.

The Hydraulic–Neuroimmune Loop

Hypoxia triggers stabilization of HIF-1α and activation of RAGE, NF-κB, and STAT3, producing cytokines that impair mitochondrial redox balance and energy-dependent gastric relaxation. The same process occurs in enteric neurons and smooth muscle, uniting gastric dysmotility with central autonomic failure. Lymphatic stagnation, fascial tension, and venous congestion feed this cycle—creating a self-reinforcing “hydraulic feedback loop” between abdomen and brainstem.

Ehlers-Danlos Syndrome: The Structural Amplifier

Connective-tissue fragility in EDS amplifies the problem. Lax venous walls and impaired fascial recoil reduce mechanical return of blood and lymph, while collagen cross-linking defects promote tissue hypoxia and chronic mast-cell activation. The result is exaggerated venous pooling, pelvic congestion, and visceral ptosis—mechanical triggers for nausea and presyncope. On a molecular level, oxidative stress inhibits proline- and lysyl-hydroxylases, weakening collagen synthesis and reinforcing the redox imbalance already present in POTS and Long COVID.

Toward Reversibility

When preload and lymphatic flow are restored—whether by postural therapy, fascial release, or metabolic re-oxygenation—patients frequently report parallel recovery of gastric function, cognition, and energy. These observations position gastroparesis as part of a reversible, multisystem disorder rather than an isolated motility defect. The remainder of this paper explores the pathophysiology, diagnostic strategies, and multimodal treatments that can be employed in clinical practice.

Clinical Takeaways

Pathophysiologic Axis	Key Clinical / Imaging Clues	Targeted Interventions
Preload failure → brainstem hypoxia	Orthostatic tachycardia, cognitive fog, fatigue; ↓ LVEDV/VTI on dynamic echo; SPECT brainstem hypoperfusion	Volume expansion, compression garments, telmisartan (-experimental RAGE block + PPARγ activation), nicotinamide riboside, ALA, vit K₂
Coeliac/splanchnic compression (MALS)	Post-prandial pain & nausea; duplex/MRA showing coeliac narrowing	Surgical or fascial decompression, tirzepatide for ECM elasticity, immune support
Pelvic congestion / vagal paradox	Pelvic heaviness, urinary urgency, presyncope after defaecation; CTV showing ovarian or iliac varices	Pelvic vein embolisation ± lymphatic therapy, LDN, telmisartan (experimental)
EDS connective-tissue fragility	Joint hypermobility, venous pooling, mast-cell reactivity, pelvic congestion	Structural rehabilitation, Vit C/proline/lysine support, NR, ALA, K₂,
Lymphatic stasis / fascial restriction	Head pressure, neck fullness, fatigue relieved by manual therapy	Vodder MLD, Watson method, osteopathy, posture re-education
Viral persistence in ENS / vagus	GI dysmotility post-COVID, anosmia, mild ANA positivity	H₁/H₂ blockers, LDN, plasmapheresis in select cases, mitochondrial restoration
Mitochondrial redox collapse	Low aspartate/GABA, high glutamate, PEM & fatigue	NR/NMN, ALA, vit K₂, CoQ₁₀, Mg, gentle aerobic re-conditioning

2 Pathophysiological Integration — From Brainstem Hypoxia to Lymphatic Dysfunction

2.1 Brainstem Hypoxia and Autonomic Dysregulation

At the top of the cascade lies brainstem hypoperfusion — a hallmark of orthostatic preload failure in both POTS and Long COVID. Dynamic echocardiography shows a 20–40 % drop in left-ventricular end-diastolic volume and stroke volume when standing, reducing oxygen delivery to the locus coeruleus (LC), nucleus tractus solitarius (NTS), and paraventricular nucleus (PVN).These nuclei orchestrate the sympathetic–parasympathetic balance controlling heart rate, blood pressure, and gastric motility.

When oxygen tension falls, HIF-1α becomes stabilised and triggers RAGE–NF-κB–STAT3 signalling in astrocytes, microglia, and endothelial cells. The ensuing cytokine storm—TNF-α, IL-6, CCL2—locks the LC into a “tonic” stress mode, suppressing adaptive vagal outflow and impairing the stomach’s nitrergic relaxation. Clinically this appears as nausea, early satiety, and post-prandial fatigue.

Within the gastric wall, hypoxia injures pericytes and interstitial cells of Cajal (ICC), disrupting smooth-muscle rhythmicity and propagation of gastric waves. Mitochondrial inhibition—notably of pyruvate dehydrogenase (PDH) and the malate–aspartate shuttle—further limits ATP generation, deepening the cycle of sluggish motility and oxidative stress.

2.2 Mechanical and Hydraulic Amplifiers

Structural compression syndromes intensify this loop.

• Median Arcuate Ligament Syndrome (MALS) restricts coeliac inflow and irritates the coeliac plexus, directly coupling vascular compromise to autonomic reflexes.

• Nutcracker and Pelvic Congestion Syndromes obstruct venous return, producing a cranio-caudal pressure gradient that extends through the valveless vertebral venous system.

  
  

These “hydraulic amplifiers” explain why many patients worsen in upright posture or after meals—periods of maximal splanchnic engorgement. evidence of post-infectious fibrosis in these ligaments and veins suggests that hypoxia-driven RAGE activation converts what were once benign anatomic variants into symptomatic flow obstructions.

Restoring preload or relieving these compressions often improves both orthostatic tolerance and gastric symptoms.

2.3 Ehlers-Danlos Syndrome as a Structural Amplifier

In Ehlers-Danlos Syndrome (EDS), collagen types I, III and V are weakened, reducing venous tone and fascial recoil. This promotes venous pooling, pelvic congestion, and lymphatic inertia.Up to 40 % of EDS patients meet criteria for orthostatic intolerance, and a substantial subset develop gastroparesis. Lax connective tissue fails to stabilise vascular structures, allowing dynamic compression of the coeliac axis (MALS), renal veins (Nutcracker), or pelvic veins.

Beyond mechanics, chronic mast-cell activation and oxidative stress in EDS degrade extracellular-matrix integrity via matrix metalloproteinases and collagenase release. Redox imbalance suppresses prolyl- and lysyl-hydroxylases, impairing collagen maturation and perpetuating tissue fragility. These molecular weaknesses magnify the same RAGE-driven inflammatory and hypoxic mechanisms seen in Long COVID and POTS.

Clinically, EDS acts as a terrain modifier—a genetic substrate that lowers hydraulic and structural resilience, predisposing to both preload failure and neuroimmune sensitization.

2.4 Lymphatic and Fascial Dynamics — The Hydraulic Off-Ramp

The lymphatic system forms the drainage arm of the vascular–interstitial continuum, clearing cytokines, metabolites, and oxidised lipids generated under hypoxia. In POTS and Long COVID, this system becomes both mechanically constrained (fascial tightness, venous congestion) and biologically compromised (viral injury, immune-mediated endothelial damage).

SARS-CoV-2 RNA and protein have been detected in lymph nodes and spleen, with loss of follicular architecture and CD169⁺ macrophage infiltration, demonstrating viral persistence at the lymphoid–lymphatic interface. These lesions impair immune-cell trafficking and fluid clearance, sustaining interstitial inflammation and fibrotic remodelling.

The thoracic inlet, diaphragm, and coeliac fascia act as mechanical bottlenecks for major lymphatic trunks. TGF-β–driven fibroblast activation and pericyte-to-myofibroblast transition stiffen these fascial planes, reducing lymph propulsion and indirectly tensioning the vagus nerve within the carotid sheath. This creates a vicious cycle: trapped cytokines activate RAGE–NF-κB–CCL2, further inflaming glia, mast cells, and endothelium while perpetuating redox stress.

Manual decompression (Vodder lymphatic therapy, Watson cervical release, or fascial osteopathy) demonstrably improves flow, reduces intracranial and splanchnic pressures, and re-oxygenates the vagal–brainstem axis. These therapies, supported by vascular-metabolic modulation (e.g., telmisartan (experimental), nicotinamide riboside, ALA, vitamin K₂, tirzepatide), provide a practical means to reopen this “hydraulic off-ramp.”

2.5 Integration: A Self-Reinforcing Loop

Hydraulic, neuroimmune, and metabolic stressors interlock to form a closed circuit:

1. Preload failure → brainstem hypoxia → reduced vagal control.

2. Hypoxia → RAGE–NF-κB activation → inflammation and mitochondrial inhibition.

3. Fibrosis + mechanical compression → venous/lymphatic stagnation → further hypoxia.

4. EDS fragility and viral persistence lower the threshold for each step.

This loop explains the variable presentation of gastroparesis across POTS, Long COVID, and hypermobility syndromes. By reopening lymphatic flow, restoring NAD⁺ redox tone, and dampening immune activation, clinicians can interrupt the cycle and often observe parallel recovery in gastric, cognitive, and orthostatic domains.

3 Diagnostic and Imaging Approach — Translating the Continuum into Clinical Practice

3.1 Bedside Clues: Recognising the Systemic Pattern

Evaluation begins with pattern recognition rather than isolated organ focus. Patients typically describe:

• Post-prandial worsening of nausea, bloating, or presyncope.

• Orthostatic intolerance with relief on lying flat.

• Facial or cervical fullness, often with symptom improvement after lymphatic or fascial release.

• Diffuse joint laxity or easy bruising, suggesting a connective-tissue amplifier such as EDS.

Simple tests can reveal early physiologic signatures:

• NASA Lean Test – safer alternative to tilt-table testing; demonstrates tachycardia and perfusion decline without provoking collapse.

• Capillary refill and dependent cyanosis – indicators of venous pooling.

• Inspiratory hold manoeuvre – transient improvement in head pressure or nausea implies preload-linked symptoms.

3.2 Dynamic Echocardiography — Quantifying Preload Failure

Conventional resting echocardiograms may appear normal. Diagnostic yield rises sharply when imaging is repeated in upright posture or after a meal.Key parameters:

• Left-ventricular end-diastolic volume (LVEDV) drop > 20 % from supine → standing confirms preload dysfunction.

• Velocity–time integral (VTI) decrease indicates reduced stroke volume.

• Right-atrial filling and IVC collapsibility provide further clues to venous return.

These findings correlate closely with symptom severity and brainstem hypoperfusion on SPECT. Restoration of LVEDV with compression or volume loading provides both diagnostic confirmation and therapeutic guidance.

3.3 SPECT/CT and MRI NeuroQuant — Visualising Brainstem Hypoperfusion

Cerebral perfusion imaging bridges subjective fatigue with measurable physiology.

• SPECT/CT commonly shows reduced uptake in the pons, medulla, and cerebellar peduncles, matching the locus-coeruleus and NTS territories.

• MRI NeuroQuant may reveal subtle brainstem or periaqueductal enlargement, consistent with glymphatic congestion as well as volume differences in specific regions of the brain

• Correlation of imaging change with orthostatic symptoms reinforces the hydraulic-neuroimmune model.

3.4 Duplex and Cross-Sectional Vascular Imaging — Identifying Hydraulic Amplifiers

Targeted vascular imaging often reveals overlooked compressive syndromes:

• Coeliac and superior mesenteric arteries for MALS.

• Left renal and gonadal veins for Nutcracker and Pelvic Congestion Syndromes.

• Cervical venous and internal jugular systems for outflow obstruction contributing to head pressure.

• Thoracic Outlet scanning including venous obstruction 

Interpretation should consider positional change; supine images may miss dynamic collapse that appears on upright Doppler. Correlating duplex flow velocities with symptoms adds mechanistic credibility and guides referral for decompression.

3.5 Lymphatic and Fascial Assessment

Functional lymphatic studies remain limited, yet indirect measures are revealing:

• Infra-red thermography or indocyanine green (ICG) lymphography may show delayed clearance in thoracic or abdominal quadrants.

• Physical therapy mapping of fascial restriction—especially diaphragm, thoracic inlet, and coeliac regions—identifies hydraulic choke points.

• Symptom rebound after manual therapy often predicts responsiveness to longer-term fascial or metabolic interventions.

3.6 Metabolic and Immunologic Profiling

Biochemical investigations help quantify the neuro-metabolic dimension:

• Amino-acid profiling: low GABA, low aspartate, high glutamate signal excitotoxic and mitochondrial stress.

• Inflammatory markers: modestly raised IL-6, ferritin, or C-reactive protein often coexist with normal routine tests.   CRP and complement C3 may be suppressed

• Autoantibodies and viral markers: low-titre ANA, and lingering anti-spike antibodies may suggest immune persistence.

Interpreting these within the hydraulic model shifts focus from “normal labs” to dysregulated networks.

3.7 Integrative Diagnostic Logic

No single test defines this disorder. Diagnosis emerges from the pattern where reduced preload + brainstem hypoxia + lymphatic congestion ± EDS fragility ± viral persistence → systemic dysautonomia with gastric dysmotility.

This pattern-based approach empowers clinicians to recognise reversible contributors and communicate a coherent explanation to patients who have often been dismissed as functional or anxious.

4 Therapeutic Framework — Restoring Flow, Tone, and Metabolic Balance

4.1 Principles of Management

The unifying aim is to re-establish hydraulic integrity, dampen neuro-immune activation, and restore redox equilibrium.Therapy proceeds in stages rather than silos. Addressing one domain (e.g. vascular compression) without correcting the others often yields only transient benefit.A practical order of operations is:

1. Mechanical and hydraulic restoration – unblock flow, stabilise posture, optimise preload.

2. Immune and inflammatory modulation – reduce RAGE–NF-κB–STAT3 activity and mast-cell amplification.

3. Metabolic and mitochondrial re-oxygenation – rebuild NAD⁺/NADH balance and PDH function.

4. Rehabilitation and autonomic recalibration – gradually retrain circulation, respiration, and vagal tone.

4.2 Mechanical and Hydraulic Restoration

Postural and fascial correction

• Begin with posture retraining and gentle cervical and diaphragmatic mobilisation.

• Physiotherapy (Watson) C2/3 desensitisation and osteopathic release sympathetic–vascular tension.

• Vodder-style manual lymphatic drainage re-establishes cranio-cervical and coeliac outflow; clinical improvement is often immediate.

Compression and preload support

• Graduated stockings (30–40 mmHg), abdominal binders, or head-up sleeping to maintain preload overnight.

• Oral rehydration with balanced electrolytes; IV saline reserved for acute decompensation.

Structural decompression

• In MALS, Nutcracker, or pelvic-congestion physiology, consider vascular-surgical or interventional radiology assessment.

• In EDS, use caution: connective-tissue fragility increases risk; combine surgical minimalism with fascia-stabilising rehabilitation.

Respiratory-diaphragmatic training

• Improves venous and lymphatic return via thoraco-abdominal pressure oscillation.

• Low-load inspiratory-muscle training (IMT) restores rhythmic preload modulation.

4.3 Immune and Inflammatory Modulation

Persistent RAGE activation sustains the cytokine field driving vascular and gastric dysfunction.Therapeutic anchors include:

Agent/Class	Mechanistic Rationale	Clinical Note
H₁/H₂ antihistamines ± cromolyn	Mast-cell stabilisation; reduced vascular leak & nitric-oxide scavenging	Foundation therapy; trial for ≥ 6 weeks
Low-dose naltrexone (1–4.5 mg nocte)	Microglial & astrocytic NF-κB dampening	Improves fatigue, pain, cognitive clarity
Telmisartan (20–40 mg daily)-experimental	ARB + PPARγ agonist → suppresses RAGE–IL-6–STAT3; improves endothelial tone	Favoured ARB; caution with hypotension
Omega-3 & vit D₃	NF-κB modulation; endothelial repair	Supportive adjuncts
IVIG or plasmapheresis	Antibody or cytokine clearance in severe immune persistence	Reserved for refractory Long COVID or vaccine injury

In EDS, the same agents reduce matrix degradation by limiting collagenase and MMP activation.

4.4 Metabolic and Mitochondrial Re-Oxygenation

Hypoxia and PDH inhibition drive the energy deficit underlying gastric atony and fatigue.Therapeutic re-balancing aims to restore NAD⁺ flux, antioxidant capacity, and nitric-oxide-dependent relaxation.

Intervention	Mechanism	Notes / Evidence
Nicotinamide riboside (NR) or nicotinamide (NAM)	Replenishes NAD⁺ → activates SIRT1/4 → restores PDH & redox tone	Improves GABA and ethanolamine levels; well tolerated
Alpha-lipoic acid (ALA)	Recycles glutathione; PDH cofactor	Aids neuropathic pain & mitochondrial coupling
Vitamin K₂ (MK-7)	γ-carboxylates matrix proteins; reduces vascular calcification	Synergises with telmisartan
CoQ₁₀ + magnesium aspartate	Electron-transport & malate–aspartate shuttle support	Particularly in PDH-MAS dysfunction
Tirzepatide (GLP-1/GIP agonist)	Enhances mitochondrial biogenesis, ECM elasticity, glycaemic stability	Emerging data for Long COVID & EDS fascia
Balanced amino-acid repletion	Restores aspartate, GABA, and glutamate equilibrium	Tailored via urinary or plasma amino-acid profiling

Adjunctive B-vitamin and trace-element repletion (vit C, Zn, Cu, Fe) supports collagen hydroxylases and PDH enzymes. Caution with B6.

4.5 Rehabilitation and Autonomic Re-Calibration

• Graded upright conditioning (recumbent cycling → tilt walking) retrains baroreflex and venous tone.

• Slow nasal breathing and vagal toning exercises (chanting, humming, gentle cold exposure) strengthen parasympathetic pathways.

• Sleep-state normalisation—by light hygiene, magnesium glycinate, and circadian anchoring—restores glymphatic clearance.

• Psychophysiologic reframing is essential: educating patients that their symptoms arise from reversible neuro-vascular loops, not anxiety or malingering, often reduces sympathetic drive and improves compliance.

4.6 Integrated Therapeutic Ladder

Phase	Primary Goal	Representative Interventions
I. Stabilise flow	Restore preload & drainage	Compression, hydration, manual lymphatic therapy
II. Quench inflammation	Suppress RAGE/NF-κB signalling	H₁/H₂ blockers, LDN, telmisartan (experimental)
III. Re-energise cells	Rebuild mitochondrial redox capacity	NR/NAM, ALA, vit K₂, CoQ₁₀
IV. Rehabilitate autonomic loops	Retrain LC–NTS–vagal axis	Graded exercise, vagal stimulation, sleep restoration

Progress through these phases is nonlinear; improvements in one domain often facilitate gains in others. Importantly, reversibility remains the guiding principle—each therapy seeks to reopen a blocked circuit rather than suppress a symptom.

5 Discussion and Conclusion — Reframing Gastroparesis as a Reversible Systems Disorder

5.1 The Hydraulic–Neuroimmune Continuum

Gastroparesis, POTS, and Long COVID represent not separate conditions but differing expressions of one hydraulic–neuroimmune disorder. Each manifests when cerebral and visceral circulation can no longer maintain homeostatic flow under gravitational stress. The result is regional hypoxia, triggering RAGE-mediated inflammation, mitochondrial suppression, and impaired autonomic sequencing.

Where traditional models isolate the stomach or the autonomic nerves, this framework shows that the true pathology lies in the integration failure between vascular mechanics and immune-metabolic signalling. The same pathways—HIF-1α, RAGE, NF-κB, STAT3, and CCL2—link vascular obstruction, viral persistence, and redox collapse across multiple organ systems. The stomach thus becomes the “barometer” of a broader circulatory and metabolic imbalance.

5.2 Ehlers-Danlos Syndrome and Structural Susceptibility

Ehlers-Danlos Syndrome (EDS) illustrates how structural vulnerability can lower the threshold for hydraulic failure. Lax connective tissue reduces venous and lymphatic recoil, amplifying orthostatic pooling and compressive syndromes such as MALS or Nutcracker. At a molecular level, impaired collagen cross-linking and mast-cell activation perpetuate oxidative stress, fuelling the same RAGE–STAT3 axis that drives Long COVID pathology.

The clinical overlap between EDS, POTS, and post-viral dysautonomia is therefore not coincidental—it reflects shared terrain: fragile matrix, impaired preload, and chronic neuroimmune activation. This insight reframes EDS from a benign genetic curiosity to a key structural amplifier within the dysautonomia spectrum.

5.3 Mechanistic Convergence and Clinical Implications

The integration of hydraulic, immune, and metabolic perspectives clarifies several longstanding paradoxes:

• Why symptoms worsen upright yet improve supine.

• Why fatigue, nausea, and “brain fog” co-vary despite affecting distant organs.

• Why therapies restoring circulation or mitochondrial redox tone relieve both gastric and cognitive dysfunction.

Clinicians who recognise these patterns can shift from symptom-based suppression (anti-emetics, β-blockers) toward network repair—addressing preload, flow, and immune tone concurrently. This multi-axis correction underpins the reproducible improvements seen with telmisartan (experimental), LDN, NAD⁺ restoration, manual lymphatic therapy, and targeted decompression.

5.4 Translational Outlook

Emerging research supports this unified model:

• Neuroimaging demonstrates brainstem hypoperfusion proportional to orthostatic intolerance severity.

• Proteomic and amino-acid assays reveal low aspartate, GABA, and ethanolamine—biochemical signatures of mitochondrial inhibition and excitotoxic stress.

• Connective-tissue studies highlight altered collagen fibrillogenesis in both EDS and post-viral syndromes.

• Therapeutic pilots using telmisartan, tirzepatide, and NAD⁺ precursors show parallel improvement in vascular elasticity and symptom burden.

Together these findings validate a systems-level paradigm: POTS, Long COVID, and related dysautonomias represent varying entry points into a shared failure of perfusion, drainage, and metabolic adaptation.

5.5 The Message for Clinicians and Patients

For physicians:

• Replace the reductionist search for a single lesion with a dynamic view of flow physiology.

• Consider preload and lymphatic dynamics whenever faced with unexplained fatigue, nausea, or cognitive dysfunction.

• Integrate vascular imaging, metabolic testing, and connective-tissue assessment into diagnostic routines.

For patients:

• Recognise that these conditions are not psychological but physiologically measurable and often reversible.

• Improvement depends on restoring circulation and metabolic tone, not merely suppressing symptoms.

• Recovery is typically incremental but cumulative—each layer of flow restoration enables the next.

5.6 Conclusion

Gastroparesis in POTS and Long COVID exemplifies a potentially reversible failure of the gastro-cranial hydraulic axis, sustained by neuroimmune activation and mitochondrial suppression. The disorder’s anatomy is mechanical, its chemistry inflammatory, and its physiology metabolic—yet each domain is modifiable.

By treating the system rather than the symptom, clinicians can restore function in patients once considered untreatable. The broader implication is a shift in medicine itself: from organ-based fragmentation toward integrative flow biology, where preload, lymphatic propulsion, and redox balance are viewed as central determinants of health