Decoding POTS: A Patient Guide to Preload Failure and Recovery
- Graham Exelby
- Oct 17
- 13 min read
A Patient Guide to Understanding Mechanisms and Management
Condensed and adapted from “Reframing Postural Orthostatic Tachycardia Syndrome (POTS)- as a Disorder of Preload Failure: Integrating Neurovascular and Immune Pathways” by Dr Graham Exelby October 2025
What POTS Is and Why It Matters
Postural Orthostatic Tachycardia Syndrome (POTS) is a condition of orthostatic intolerance—the body struggles to maintain blood flow to the brain when upright. Heart rate rises excessively (≥ 30 bpm in adults) to compensate, but this tachycardia is not the disease itself; it is a response to poor blood return to the heart—known as preload failure.
Patients often describe dizziness, fatigue, “brain fog,” pressure in the head, or near-fainting when standing. For many years these symptoms were dismissed as anxiety or autonomic malfunction. Modern imaging, echocardiography, and molecular studies now show that POTS reflects a system-wide disturbance of circulation, oxygen use, and immune signalling.
Understanding the Individual Pathophysiology of POTS
Although POTS presents with a recognisable clinical pattern—rapid heart rate on standing, fatigue, cognitive fog, and a broad range of multisystem symptoms—the biological reasons why it develops vary markedly from person to person. The unifying feature is preload failure—an inability to sustain normal cardiac filling and cerebral perfusion when upright—but the drivers that cause this failure differ according to each patient’s genetic, structural, and immunometabolic background.
Genetic Blueprint: Why DNA Matters
Modern analysis shows that many people with POTS carry clusters of gene variants that influence inflammation, vascular stability, and energy metabolism. These polymorphisms do not cause disease on their own, but they lower the threshold for activation when stressors occur. Critically, these variants do not act in isolation; they form pathway-cluster redundancies—parallel defects that converge on the same neuroimmune and metabolic circuits.
This redundancy explains why distinct activators (e.g., viral infection vs. trauma) produce similar phenotypes and why recovery trajectories vary: even if one pathway fails, others compensate until cumulative stress tips the system into chronic dysregulation, leading to overlaps with conditions like ME/CFS, fibromyalgia, or Long COVID.
Common findings include:
Innate-immune variants (TLR4, CCL2, NLRP3, STAT3, RAGE): Heighten innate immune reactivity, sustaining NF-κB, inflammasome activation, and HIF-1α stabilisation for persistent neuroinflammation and fibrosis.
Metabolic and membrane variants (PEMT, MTHFR, COMT): Impair phosphatidylcholine synthesis, methylation, and catecholamine clearance, yielding endothelial leak, vascular instability, and heightened sympathetic tone—hallmarks of preload failure.
Mast-cell and connective-tissue genes (KIT, DAO, HNMT, COL5A1, TNXB): Potentiate mediator release (histamine, tryptase) and tissue laxity, linking immune activation to vascular permeability and fascial remodelling.
Oxidative-stress and glial-vascular susceptibility (MnSOD, GST, APOE4): Blunt antioxidant defence and reduce pericyte/astrocyte resilience, predisposing to microvascular leak, cognitive dysfunction, and glymphatic congestion.
Kynurenine-tryptophan pathway (IDO, TPH2): Disrupt excitatory-inhibitory balance (e.g., low GABA/high glutamate), amplifying neurodivergence traits like ADHD/ASD overlap (20–35% in cohorts).
Recognising these DNA signatures, via accessible genetic screening, can help clinicians anticipate which pathways dominate (e.g., immune-driven vs. metabolic) and personalise therapy, shifting from uniform symptomatic treatment to precision restoration.
Activators: The Sparks That Ignite the Syndrome
POTS seldom arises spontaneously. It is usually triggered by an activator—or series of activations—that disturbs vascular or immune homeostasis and exposes underlying vulnerabilities. Despite varied origins, they converge on shared pathological hubs:
hypoxia/HIF-1α stabilisation,
RAGE activation (often via Serum Amyloid A),
mast-cell degranulation,
PDH inhibition (lactate surge),
excitatory amino-acid imbalance (↓GABA/↑glutamate),
pericyte–astrocyte dysfunction (BBB breakdown, AQP4 loss, glymphatic failure)
This convergence explains phenotypic uniformity: Activators tip redundant pathways (e.g., DAO/COMT for histamine/catecholamine excess) into chronicity, with 2025 metabolomics confirming a uniform quinolinic-acid signature across cohorts.
Drivers: What Sustains the Illness
Once initiated, POTS persists because of self-reinforcing loops—notably the RAGE/HIF/NLRP3 feed-forward cycle that couples inflammation, oxidative stress, and glycolytic energy trapping. Hypoxia accelerates non-enzymatic glycation, forming advanced glycation end-products (AGEs) that stiffen vessels (via collagen cross-linking) and bind RAGE, bridging metabolic stress to vascular rigidity and neuroinflammation.
Typical drivers include:
Chronic tissue hypoxia from venous obstruction or poor preload, stabilising HIF-1α and perpetuating the loop.
Mast-cell and microglial activation maintaining vascular leak and neuroinflammation.
Mitochondrial rigidity and PDH inhibition, locking cells into anaerobic metabolism (pseudo-Warburg state) with lactate/ROS buildup.
Fibrosis and ECM stiffening, impairing lymphatic/venous drainage—e.g., post-COVID emergence of Median Arcuate Ligament Syndrome (MALS) or Nutcracker Syndrome via hypoxia-driven pericyte failure and myofibroblast activation.
These are magnified by the gastro-cranial hydraulic continuum: a bidirectional axis of anatomical chokepoints linking cranial venous outflow (e.g., styloid-C1 compression, loss of cervical lordosis) to abdominal/pelvic congestion (e.g., thoracic outlet, SMA/Nutcracker, pelvic reflux). Upright posture unmasks these, dropping preload by 20–40% (per echocardiography) and reinforcing brainstem hypoxia.
Therapy aims to interrupt the dominant loop—mechanical decompression, immune modulation, metabolic repair, or combinations.
Liver Involvement and Fatty Change (Functional NAFLD)In many patients with long-standing POTS, especially those with abdominal venous congestion or connective-tissue laxity, the liver becomes a “pressure target.” When blood returning through the inferior vena cava or hepatic veins is slowed, oxygen delivery to liver cells falls, activating the same RAGE–HIF-1α–STAT3 pathways that operate elsewhere. Over time, this can produce a potentially reversible functional form of non-alcoholic fatty liver disease (NAFLD) driven not by obesity or diet, but by venous congestion, low-grade hypoxia, and inflammation. Because the liver lies downstream of the systemic venous return, hepatic congestion mirrors the same preload failure seen in the heart and brain. This makes functional NAFLD a sentinel marker of systemic vascular stress rather than primary liver disease.
Comorbidities: The Amplifiers
Comorbid conditions both reveal and reinforce mechanisms, emerging from dominant genetic clusters. Prevalence varies by subtype (e.g., POTS weights preload/mast-cell; Long COVID hits all).
Recognising these patterns views POTS as part of a neuro-immune-vascular continuum. Addressing comorbidities (e.g., pelvic PT for congestion) stabilises the system and accelerates recovery.
Toward Personalised Care
Integrating DNA analysis, activator identification, driver mapping, and comorbidities reconstructs causation per patient. This precision shifts management from suppression to restoration—improving preload, correcting hypoxia, rebalancing metabolism, and calming immunity.
The Core Mechanism: Preload Failure and Regional Hypoxia
When standing, blood pools excessively in POTS due to connective-tissue laxity, endothelial stiffness, vein/lymphatic compressions. Supine-to-standing echocardiography shows a 20–40% drop in left-ventricular end-diastolic volume (with preserved ejection fraction >55%), reducing stroke volume and cerebral perfusion—triggering compensatory tachycardia.
This creates regional hypoxia (tissue-level oxygen deficit), not just shortage but a cellular alarm:
HIF-1α senses low oxygen, reprogramming to glycolysis (lactate/fatigue generation).
RAGE detects damaged molecules (e.g., AGEs from glycation) and amplifies inflammation via NF-κB/CCL2/STAT3.
NLRP3 Inflammasome releases cytokines (IL-1β/IL-18) from mitochondrial distress/ROS.
Simplified RAGE–HIF–NLRP3 Loop Flowchart:
Step 1: Activator → Tissue stress/DAMPs → Hypoxia.
Step 2: Hypoxia → HIF-1α stabilisation + AGE formation → RAGE activation.
Step 3: RAGE/NLRP3 → Inflammation/fibrosis → Vascular constriction + metabolic trap (glycolysis/ROS).
Feedback: Worsened hypoxia → Loop sustains (mast-cell/lymphatic amplifiers).
Once engaged, it persists post-trigger, explaining chronicity.
Why Some People Develop POTS and Others Do Not
Susceptibility depends on genetic and anatomical context—how the body handles inflammation, oxidative stress, and vascular tone.
Immune-regulatory variants such as TLR4, CCL2 heighten innate immune reactivity.
Metabolic and membrane genes like PEMT and COMT influence phospholipid integrity and catecholamine breakdown.
Oxidative-stress and methylation genes (MTHFR, MnSOD, GST) reduce antioxidant capacity.
Glial-vascular genes like APOE4 impair repair of micro-vessels and glymphatic clearance.
Structural genes (COL5A1, TNXB) underlie connective-tissue laxity seen in Ehlers-Danlos spectrum disorders.
These create pathway redundancy: even if one defence pathway fails, others attempt to compensate—until cumulative stress tips the system into chronic dysregulation.
The Neurovascular Unit (NVU):
The smallest brain vessels are lined by endothelial cells, wrapped by pericytes, and supported by astrocytes. Together they form the neurovascular unit, which regulates blood–brain exchange and waste clearance through the glymphatic system. The NVU (endothelial cells + pericytes + astrocytes + microglia) regulates brain perfusion/glymphatic clearance. During sustained hypoxia:
Pericytes detach, narrowing capillaries and allowing micro-leaks
The blood–brain barrier becomes porous, letting inflammatory molecules enter sensitive brainstem nuclei.
Astrocytes lose their aquaporin-4 (AQP4) polarity, halting glymphatic drainage.
Microglial priming → cytokine release/central sensitisation.
This NVU collapse translates hypoxia to symptoms: orthostatic issues from brainstem nuclei (NTS/LC/PVN hypoperfusion 20–30% on SPECT), fog from glymphatic failure. This explains why POTS symptoms are neurological yet systemic: orthostatic tachycardia, brain fog, fatigue, and pain all stem from regional hypoxia and glial inflammation.
Figure 1: The Neurovascular Unit showing the Pericytes lining blood vessels and the close relationship with the Astrocytes
Source: Sato, Y.; Falcone-Juengert, J.; Tominaga, T.; Su, H.; Liu, J. Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage. Cells 2022, 11, 2823. https://doi.org/10.3390/cells11182823
Figure 2:The Glymphatic System
Source: Mogensen FL, Delle C, Nedergaard M. The Glymphatic System (En)during Inflammation. Int J Mol Sci. 2021 Jul 13;22(14):7491. doi: 10.3390/ijms22147491. PMID: 34299111; PMCID: PMC8305763.
Symptoms and Their Physiological Meaning
Symptoms are signals of regional stress rather than isolated complaints.
Each symptom cluster corresponds to specific anatomical or metabolic dysfunctions:
These patterns reflect regional hypoxia and its molecular signature. For example,
Each cluster identifies a region where perfusion and immune balance are disturbed.Mapping these patterns helps clinicians determine whether the dominant driver is hydraulic, immune, or metabolic, guiding targeted therapy.
How the Loop Is Reinforced
Three chronic amplifiers keep the system active:
Mast-cell activation → releases histamine, cytokines, and enzymes that loosen vessel walls
Lymphatic stagnation → prevents clearance of inflammatory molecules, increasing local pressure.
Mitochondrial fatigue → reduced oxidative phosphorylation feeds further hypoxia and ROS generation.
Together they create a self-sustaining triad of vascular leak, inflammation, and energy deficit.
Clinical Management Principles
Validate experiences; avoid psychogenic framing, educate on pacing/fluid monitoring.
A. Foundation Therapies (Hydraulic Stabilisation)
Fluids and salt: 2.5–3 L water + 8–10 g sodium/day if tolerated
Compression: waist-to-ankle garments to limit pooling.
Recumbent exercise: start with rowing or cycling, tilt increase gradually.
Sleep with head elevated 10–15 cm to condition baroreflexes.
Avoid triggers: heat, alcohol, dehydration, prolonged standing, high- histamine foods.
B. Current Pharmacological Options
Heart-rate modulation: propranolol 10–20 mg QID, ivabradine 2.5–5 mg BID.
Volume expansion: fludrocortisone 0.1 mg daily, desmopressin 0.1 mg PRN.
Vasoconstrictors: midodrine 2.5–10 mg TDS.
Sympatholytics: methyldopa 125 mg TDS, clonidine 100 µg BD.
Adjuncts: modafinil 50–200 mg daily, duloxetine 30–60 mg daily.
These remain valuable for stabilisation but rarely address the root cause.
C.Targeting the Core Molecular Axis
Understanding that POTS is sustained by a self-reinforcing cycle of inflammation, metabolic stress, and vascular dysfunction — centred on the RAGE–HIF-1α–NLRP3 axis — allows treatment to move beyond symptom control toward actual recovery. In this model, traditional medications such as β-blockers, midodrine, SSRIs, or fludrocortisone play a valuable stabilising role: they reduce heart rate surges, help retain blood volume, and ease immediate discomfort. However, long-term improvement requires addressing why the body remains stuck in the inflammatory-hypoxic state that drives the illness.
Newer, mechanism-based therapies focus on calming the RAGE–HIF–NLRP3 inflammatory cycle, improving energy metabolism, and restoring vascular and glial health. Clinical experience and emerging data suggest that combining agents which target these molecular and metabolic pathways offers the best results.
Reprograming the RAGE–HIF–NLRP3 loop via:
Mast-cell stabilisation: H1/H2 antihistamines, cromolyn, low-dose naltrexone (LDN)— helps protect the fragile interface between blood vessels and the nervous system. This reduces vascular leak, inflammation, and neuro-sensitisation often seen after infection, trauma, or pregnancy.
Telmisartan: targets hypoxia (PPAR-γ ) supports vascular integrity by calming RAGE-driven inflammation and improving oxygen delivery to tissues. Clinically, patients note clearer cognition, reduced head pressure, and improved energy once telmisartan is established as a core therapy.
Tirzepatide: Dual GIP/GLP-1 agonist; assists in metabolic and extracellular-matrix (ECM) repair, helping tissues recover from the fibrotic and hypoxic changes that occur in chronic illness. By improving glucose handling and mitochondrial efficiency, it reduces the metabolic “stuckness” that fuels fatigue and post-exertional malaise.
Metabolic support: including NAD⁺ precursors (nicotinamide riboside or nicotinamide), CoQ10, and alpha-lipoic acid (ALA) — strengthens mitochondrial energy production and antioxidant defences. These agents assist in breaking the glycolytic trap created by hypoxia and restore cellular resilience.
Vitamin K₂ (particularly MK-7 or MK-4) complements this metabolic group by directing calcium away from vessels and into bone, thereby improving vascular elasticity and endothelial resilience. It also supports mitochondrial redox cycling and works synergistically with NAD⁺ and ALA to reduce oxidative stress.
Optimal vitamin C and iron stores are essential cofactors in this pathway—vitamin C enhances iron absorption and maintains iron in its reduced (Fe²⁺) form for mitochondrial and collagen synthesis, while adequate iron supports oxygen transport and HIF-1α regulation. Together they ensure K₂-dependent enzymes function efficiently, stabilising vascular and metabolic recovery once perfusion has been restored.
Telmisartan—Guidance and Cautions Telmisartan is not just a blood-pressure medicine; it also calms RAGE-driven inflammation and improves oxygen delivery by stabilising the vascular lining. Yet its effects differ across POTS subtypes.
In people with low blood pressure or dehydration, starting too early or at high doses can worsen dizziness—begin slowly, usually at night, after fluids and salt are optimised.
In hyperadrenergic POTS, some patients feel temporarily more fatigued or light-headed in the first week as the body readjusts sympathetic tone—these effects usually pass with gradual titration.
In renal or hepatic congestion, telmisartan may initially raise kidney or liver markers as flow patterns normalise; medical monitoring is advised during the first fortnight.
Because it acts on the angiotensin system, telmisartan should not be used in pregnancy or breastfeeding.
Always discuss with a clinician familiar with autonomic disorders, and never stop other stabilising medicines abruptly when beginning telmisartan
Tirzepatide — Guidance and Cautions Tirzepatide (Mounjaro) is a dual GLP-1/GIP agonist originally designed for diabetes and metabolic syndrome, but in POTS and Long COVID it can help restore metabolic flexibility, improve vascular stiffness, and reduce fibrotic changes in fascia and liver. By stabilising insulin–glucose signalling and reducing inflammation in the extracellular matrix, it supports energy recovery and lowers oxidative stress.
However, it must be used with careful supervision:
Dose titration: Start at low doses and increase gradually. Rapid escalation may trigger nausea, dizziness, or worsening orthostatic symptoms as blood flow redistributes.
Low BMI or poor intake: In underweight or nutritionally depleted patients, tirzepatide can suppress appetite too strongly and worsen fatigue — nutritional monitoring is essential.
Gallbladder and pancreatic caution: Patients with a history of gallstones, pancreatitis, or significant hepatic disease should be reviewed before starting; rare cases of gallbladder irritation have been reported.
Hypoglycaemia risk: When combined with other glucose-lowering or fasting protocols, it can cause low blood sugar, especially in patients with adrenal dysregulation.
Fluid balance: Tirzepatide shifts glucose and water between tissues — adequate hydration and salt support are critical in preload-sensitive POTS phenotypes.
Pregnancy and thyroid disease: It is contraindicated in pregnancy, and thyroid function should be reviewed during long-term therapy.
Used correctly, tirzepatide complements telmisartan and NAD⁺-supportive nutrients to reverse the metabolic-fibrotic loop that sustains chronic POTS, but dosing must always be individualised and closely monitored. As both agents modulate vascular tone and glucose handling, coordination and slow titration are vital—introducing both together can transiently destabilise blood pressure or energy balance.
Integrating and Sequencing Therapies
Effective recovery from POTS and related syndromes depends on how and when each therapy is introduced. These interventions work synergistically only when aligned with the individual’s dominant phenotype, whether primarily immune, vascular, metabolic, or mechanical.
DNA profiling can clarify the underlying drivers by identifying variants in genes such as TLR4, CCL2, PEMT, COMT, or APOE4, which influence inflammatory tone, vascular reactivity, and metabolic flexibility. This allows clinicians to target the most active pathways, calming inflammation before stimulating metabolism, and restoring preload before increasing activity.
These approaches recognise that POTS is not a fixed diagnosis but a dynamic state within a functional continuum—restoration depends on rebalancing circulation, immunity, and metabolism in synchrony.
Sequencing is critical.
Stabilising immune and vascular tone with telmisartan or LDN should precede metabolic acceleration with tirzepatide or NAD⁺ precursors. Simultaneously, mechanical strategies such as manual lymphatic therapy, diaphragmatic breathing, and fascial release help normalise venous and lymphatic return, supporting vagal activation and glymphatic clearance.
Ultimately, this approach moves beyond symptom control toward retraining the RAGE–HIF–NLRP3 axis itself—reducing inflammation, restoring mitochondrial efficiency, and re-establishing vascular homeostasis. When applied with clinical pacing and adequate nutritional support, this sequencing allows patients to move from reactive instability toward gradual and sustained physiological recovery.
Putting It Together: A System Out of Balance
POTS represents the body caught between competing survival systems- Hydraulic perfusion needs vs. immune hypoxia response vs. metabolic energy struggle—each compensation (tachycardia/inflammation) feeds the next. Recovery interrupts loops via three domains: hydraulic restoration + immune stabilisation + metabolic repair.
the hydraulic need to maintain brain perfusion,
the immune response to hypoxia, and
the metabolic struggle to generate energy efficiently.
Once locked in this configuration, each attempt at compensation—tachycardia, vasoconstriction, inflammation—feeds the next. Recovery begins only when one or more loops are interrupted.
Looking Forward
Research now focuses on integrated interventions that address why preload fails and how hypoxia persists. Dynamic imaging combined with genomic and metabolomic profiling can personalise therapy. Future trials should test combination strategies—telmisartan + tirzepatide + NAD⁺ support, alongside physical and lymphatic therapies—to restore vascular compliance and metabolic resilience.
Take-Home Summary
POTS = preload failure + regional hypoxia → inflammatory loop.
The key molecular players are RAGE, HIF-1α, and NLRP3.
Symptoms reflect where the hypoxia occurs—brainstem, fascia, gut, or pelvis.
Genetics and structure determine susceptibility and chronicity.
True recovery requires a three-domain approach:
Hydraulic restoration + Immune stabilisation + Metabolic repair.
Final Perspective
POTS is not a minor curiosity or an anxiety disorder—it is a complex neuroimmune-metabolic condition centred on preload failure and hypoxia-driven inflammation.
Understanding this mechanism allows physicians and patients to work collaboratively: to identify mechanical obstructions, modulate inflammatory drivers, restore mitochondrial energy, and ultimately re-establish physiological balance.
By recognising preload failure and hypoxia as the unifying threads, POTS can be reframed as a reversible systems disorder—where restoring circulation and cellular energy, rather than merely suppressing symptoms, becomes the pathway to lasting recovery.