POTS 2026: Preload Failure, Pericyte Loss, and a New Path to Recovery

Dr Graham Exelby December 2025

By late 2025 a clearer picture is emerging. 

A simple change in diagnostic technique—standing (or active-stand) echocardiography instead of passive tilt-table testing—has revealed a pattern that appears in the majority of patients with postural tachycardia syndrome (POTS): a pronounced drop in stroke volume and cardiac filling on assuming upright posture, despite a structurally normal heart. This has been variously labelled “preload dependence,” “low-flow POTS,” or “impaired venous return,” but the net result is the same: reduced delivery of blood to the right heart and, in many cases, reduced cerebral perfusion.

The older tripartite classification (hypovolaemic, neuropathic, hyperadrenergic) remains clinically useful, yet an increasing number of patients appear to share a final common pathway: microvascular instability leading to impaired venous return and upright cerebral hypoperfusion. Formal papers integrating the clinical, physiological, and molecular evidence will appear in 2026.

Figure 1: Simplified Immune Pathways

Why standing is so hard: a microvascular hypothesis

The dizziness, air hunger, head pressure, and compensatory tachycardia do not primarily originate in the heart or the autonomic nerves. Increasing evidence points to dysfunction at the level of the microcirculation—particularly the pericytes that regulate capillary diameter, endothelial integrity, and regional oxygen delivery.

A wide range of triggers—post-viral illness (including SARS-CoV-2), pregnancy, physical trauma (whiplash, concussion), chronic mould exposure, severe stress, PTSD, surgery, or connective-tissue disorders—can initiate pericyte injury or detachment. Once this occurs, standing produces:

• reduced venous return and stroke volume

• decreased cerebral blood flow (repeatedly documented on upright transcranial Doppler)

• a noradrenergic compensatory response that is often misinterpreted as the primary problem

In susceptible individuals this process can become self-sustaining through hypoxia-driven inflammatory loops (HIF-1α/HIF-2α → RAGE → STAT3/CCL2 → NLRP3), shown in Figure 1, preventing pericyte re-attachment and leading to progressive microvascular rarefaction.  Genomic “hits” (TLR4, RAGE, STAT3, PEMT, COMT, APOE4 and others, Exelby & Vittone 2025) determine whether the switch resets or becomes chronic.

Mechanical amplifiers commonly seen in this population. 

A number of structural and biomechanical factors appear to magnify the degree of upright hypoperfusion:

• craniocervical junction crowding or subtle instability

• internal jugular vein compression or stenosis

• low-lying cerebellar tonsils / Chiari 0

• thoracic outlet syndrome

• Ehlers-Danlos syndrome / hypermobility

• pelvic compression syndromes (May-Thurner, nutcracker)

• median arcuate ligament or superior mesenteric artery syndrome

• impaired thoracic duct or cervical lymphatic drainage

These are not random associations; they all increase resistance to venous and lymphatic outflow from the cranium when upright, worsening cerebral hypoxia and symptom severity.

Pericytes: The Central Switch

The universal switch that converts a reversible preload drop into a chronic, self-sustaining illness is pericyte dysregulation.   In POTS — as in Long COVID, ME/CFS, and post-infectious dysautonomias — pericyte injury appears to occur early, long before overt autonomic symptoms are recognised.

Pericytes are now recognised as key regulators of:

• capillary tone and blood-brain barrier integrity

• cerebral blood flow autoregulation

• glymphatic clearance

• neurovascular unit metabolic coupling

What actually starts the sequence

Across all major POTS activators (viral, traumatic, inflammatory, biomechanical), the initiating step is:

Spike protein, viral RNA, inflammatory mediators, ROS, or biomechanical venous congestion → TLR4/RAGE activation → early pericyte injury & detachment from capillary walls

This precedes hypoxia — it does not follow it.

Once pericytes detach:

• capillaries lose fine-tuned control of diameter

• endothelial junctions loosen (BBB and peripheral leak)

• oxygen extraction becomes inefficient

• perfusion becomes patchy and unstable

• standing produces exaggerated drops in venous return

This is the root cause of the microvascular instability seen in preload failure POTS.

Why pericyte loss converts POTS from temporary to chronic

When pericytes detach, perfusion becomes heterogeneous, endothelial leakage increases, and oxygen extraction falls — creating regional hypoxia even when macro-level cerebral blood flow appears adequate.

Acute hypoxia stabilises HIF-1α, while sustained hypoxia stabilises HIF-2α, driving chronic inflammation, endothelial stress, and vascular remodelling.  

When pericyte coverage is lost, standing triggers regional hypoxia even when bulk blood flow looks “normal” on routine imaging.   Hypoxia then stabilises the two key transcription factors:

• HIF-1α (acute, rapidly re-triggered by exertion, heat, infection, or stress)

• HIF-2α (chronic, maintains long-term hypoxic reprogramming)

Both pathways reinforce the same inflammatory cascade ( HIF-1α/HIF-2α → RAGE → STAT3 → CCL2 → NLRP3 → continued pericyte dropout ) that prevents pericyte reattachment — locking POTS into a chronic state unless the loop is interrupted.

Clinical consequences

This feed-forward loop explains why POTS becomes persistent once pericyte injury has occurred:

• upright tachycardia (compensation)

• reduced stroke volume

• brainstem hypoperfusion

• unstable cerebral blood flow autoregulation

• impaired glymphatic clearance

• sensory hypersensitivity

• susceptibility to “crashes” (acute HIF-1α firing on top of chronic HIF-2α tone)

It also explains why so many comorbidities cluster: migraine, MCAS, neuropathy, gastroparesis, fibromyalgia-like pain, sleep fragmentation, mood disturbances — all reflect regional microvascular compromise.

Figure 2 The Neurovascular Unit

Pericyte injury appears to be one of the earliest and most critical events in Long COVID and in many cases of post-infectious ME/CFS and POTS.

Source: Thomas Daubon, Audrey Hemadou, Irati Romero Garmendia, and Maya Saleh, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons

Why the original POTS categories now look incomplete

The traditional hypovolaemic / neuropathic / hyperadrenergic labels describe phenotypes, not root causes.

Pericyte dysfunction can produce each of them:

• Low-flow/hypovolaemic features: reduced capillary tone + impaired oxygen extraction → reduced venous return

• Neuropathic features: microglial activation + small-fibre vulnerability from regional hypoxia

• Hyperadrenergic features: appropriate noradrenergic compensation to maintain perfusion

Seen through the microvascular lens, these categories become manifestations of the same underlying physiological problem.

Why POTS often begins after a single event — but persists indefinitely

A defining feature in our cohort is that POTS often starts after a single trigger (viral illness, pregnancy, trauma, mould, surgery), but persists because:

Initial trigger → pericyte injury → microvascular instability → preload failure → brainstem hypoxia → HIF loop → chronic autonomic dysfunction

This model unifies the mechanical, metabolic, immune, and vascular findings from our supine-standing echo cohorts and matches the genomic vulnerability clusters Dr Vittone and I have identified (TLR4, RAGE, STAT3, PEMT, COMT, ApoE4, CCL2)

Where this is heading

The 2026 publications will present:

• detailed standing-echocardiography signatures across large POTS cohorts

• patterns of renin–aldosterone suppression and cerebral perfusion

• genetic risk clusters that appear to determine progression from reversible to chronic states

• early therapeutic approaches targeting pericyte stabilisation and microvascular repair

For the first time, a single testable framework appears able to integrate the mechanical, vascular, metabolic, neuroimmune, and genomic drivers of POTS. Perhaps most importantly, if pericyte injury and the downstream inflammatory loop prove to be the dominant mechanism in a majority of patients, many cases may be far more reversible than previously thought.

The heart rate rise is real, but in most patients it is a compensation, not the disease. The problem starts much smaller in many — perhaps most — patients, on the walls of the smallest vessels.