Understanding POTS: A ConditionThat's More Complex Than It Looks
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Postural Orthostatic Tachycardia Syndrome (POTS) is one of those diagnoses that can feel maddeningly elusive. Patients often spend years collecting cardiology referrals before anyone steps back to ask a more fundamental question: why is the heart racing in the first place?
The answer, it turns out, rarely has much to do with the heart at all. As Dr. Kunkel put it: “The heart’s just responding to the environment. It’s not getting enough blood return, so it can’t do what it needs to do.”
Not One Disease
POTS is best understood not as a single condition but as a cluster of dysfunctional patterns that frequently overlap within the same patient. Lumping them together under one label can obscure what’s actually driving the problem, and what might actually help.
Neuropathic POTS involves faulty norepinephrine receptors in the blood vessels of the lower extremities, impairing the vascular system’s ability to constrict and push blood back upward. Dr. Gordon noted this form can develop with age and is associated with small fiber neuropathy and diabetic neuropathy. It can be confirmed through a minimally invasive skin biopsy assessing nerve density.
Hyperadrenergic POTS is characterized by an overactive sympathetic nervous system. Because the receptors aren’t responding well, the body compensates by flooding the system with norepinephrine, producing a cycle of elevated, dysregulated adrenergic signaling that often manifests as anxiety, racing heart, and sensory sensitivity.
Hypovolemic POTS centers on low blood volume and a disrupted renin-aldosterone axis. In a paradoxical twist, the kidneys may misread fluid pooled in the abdomen as a sign of over-hydration, causing the body to excrete sodium and water it can’t afford to lose, a phenomenon Dr. Kunkel referred to as the “Aldosterone Paradox.”
Structural or vascular POTS is strongly associated with hypermobile Ehlers-Danlos Syndrome, where lax connective tissue in the venous walls allows blood to pool under gravity. Mast cell activation frequently compounds this, as mast cell mediators promote vasodilation and further undermine vascular tone.
Running beneath nearly all of these subtypes is chronic, systemic inflammation. In Dr. Gordon’s words: “POTS is very rarely a single cause. It’s more likely a bunch of things that aren’t in balance because your body is inflamed and each organ is reacting differently to those inflammatory signals.”
What Testing Actually Looks Like
Dr. Kunkel described his diagnostic approach as deliberately comprehensive. “I cast a broad net and reel it in,” recognizing that what looks like a single diagnosis is often a convergence of multiple dysfunctional systems.
Orthostatic assessment is a starting point, though a formal tilt table test can be unnecessarily taxing for patients with chronic fatigue or post-exertional illness.
The NASA Lean Test is a more accessible alternative: the patient leans against a wall with shoulder blades touching (reducing leg muscle tension), and heart rate and blood pressure are measured every two minutes for ten minutes.
A rise of more than 30 beats per minute in adults suggests POTS, though Dr. Gordon noted that even a 20-beat increase can be clinically meaningful.
The NASA Lean Test has been validated by the Bateman Horne Center as a reliable point-of-care tool for identifying orthostatic intolerance, and research suggests a full ten minutes is needed to detect the condition in a meaningful proportion of patients.
Beyond that, key areas of testing include:
Seated and standing norepinephrine levels, to identify hyperadrenergic patterns; a 24-hour urine collection can add further detail
The CellTrend autoantibody panel, a specialized laboratory test evaluating adrenergic and muscarinic receptor antibodies, as well as antibodies to endothelial cells and ACE2 receptors, is increasingly relevant in post-viral and Long COVID presentations. Dr. Kunkel noted that while elevated antibodies don’t always confirm them as the cause, they serve as an important signal. Published research has identified elevated G-protein coupled adrenergic receptor autoantibodies in a significant proportion of POTS patients, supporting the hypothesis that autoimmunity plays a role in at least some cases, though findings across studies have been mixed.
Renin-to-aldosterone ratio, to assess how well the kidneys are managing blood volume, alongside standard metabolic panels for sodium, potassium, and chloride anomalies
Small fiber neuropathy biopsy, a quick, suture-free skin punch that can confirm neuropathic involvement and is one of the clearest indications for IVIG
Inflammatory cytokine panels, including IL-6, TNF-alpha, and IL-8, are particularly elevated in patients with Long COVID overlap. Elevated IL-6 in particular can directly perpetuate POTS-like states by promoting endothelial dysfunction
Immune-Targeted Treatments
As the immunological dimensions of POTS have become better understood, treatments that directly address immune dysregulation have begun to enter the picture for select patients.
IVIG (intravenous immunoglobulin) has shown benefit in patients with confirmed small fiber neuropathy or autoantibody-mediated autonomic dysfunction. It works by reducing systemic inflammation and modulating the autoantibody burden.
Dr. Kunkel was clear-eyed about its timeline: “It does take a long time for it to work, but it can.” At Gordon Medical, IVIG has shown meaningful benefit in their patient population, particularly those with confirmed autoimmune involvement, even as the broader research landscape continues to evolve.
While randomized controlled trials have produced mixed results and formal consensus guidelines have yet to catch up, the clinical experience at practices specializing in complex chronic illness suggests that careful patient selection is key. Those with confirmed small fiber neuropathy or a clear autoantibody burden appear to be the most likely candidates to respond.
Plasmapheresis, which physically removes antibodies from the bloodstream, is typically reserved for patients with very high autoantibody loads. It can provide meaningful symptom relief, but as Dr. Gordon emphasized, it’s important to understand what it does and doesn’t do: “It buys you time. It doesn’t fix the problem.” If the underlying trigger, a chronic infection, toxin exposure, or ongoing immune activation, isn’t addressed, the antibodies will simply replenish.
This is perhaps the most important framing for both treatments: they’re downstream interventions. Durable improvement depends on identifying and addressing whatever is keeping the immune system in a state of chronic alert, whether that’s Lyme disease, Bartonella, mold illness, or a post-viral process like Long COVID.
The Bottom Line
POTS is a systems-level problem. Meaningful progress typically requires identifying which subtype or combination of subtypes is present, what’s sustaining the underlying inflammation, and which interventions are most appropriate given that picture. It’s a more complex path than a single diagnosis and a single prescription, but for most patients, it’s also a more honest one.
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