Supine–Standing Echocardiography Reveals Preload Failure as the Primary Driver of POTS and Long COVID Orthostatic Intolerance

Christoper Thomas, Graham Exelby November 2025

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Abstract

Background:Orthostatic intolerance in Postural Orthostatic Tachycardia Syndrome (POTS) and Long COVID has been framed primarily as an autonomic disorder, despite weak correlations between symptoms, heart rate, and autonomic testing.(Zhang, Zhou & Yu. Zhong Nan Da Xue Xue Bao Yi Xue Ban.2009)   Tilt-table testing does not assess venous return, ventricular filling, or thoracic inlet dynamics. We investigated whether supine–standing echocardiography could identify reproducible haemodynamic signatures that more accurately explain orthostatic symptoms.

Methods:Consecutive patients with POTS or Long COVID underwent standardised supine and standing echocardiography assessing LVOT/AV VTI, early diastolic tissue velocities (E′), E/E′, inferior vena cava behaviour, and superior vena cava (SVC) velocity/phasicity. Echocardiographic changes were correlated with clinical features and used to define mechanistic preload-failure phenotypes.

Results:All patients demonstrated impaired upright preload, with reduced VTI, loss of early diastolic suction, and abnormal SVC behaviour. Rather than separating into discrete phenotypes, findings aligned with a single integrated preload-failure physiology expressed through variable contributions from five interacting domains:

• Mechanical–Venous Preload Failure (MVPF): (thoracic inlet impedance, vertebral–azygos diversion, abdominal/pelvic congestion)

• Neurovascular–Brainstem (CBPF) (cervical venous outflow resistance impairing brainstem autonomic integration, increased intracranial venous pressure, glymphatic stagnation)

• Endothelial–RAAS (CPPF-R) (blunted  renin–aldosterone dysfunction, impaired vasoconstriction, pericyte injury, NO uncoupling and microvascular instability)

• Immune–Inflammatory (mast-cell/glial activation, RAGE–TLR4–STAT3–CCL2 signalling, microclot burden, oxidative stress)

• Metabolic–Mitochondrial (PDH inhibition, altered amino-acid energetics, reduced diastolic energy reserve)

Each patient expressed a different combination of these factors, but the haemodynamic outcome was the same: inadequate upright diastolic filling.   Across all domain patterns, tachycardia consistently occurred after mechanical underfilling, functioning as an appropriate compensatory response rather than a primary driver of symptoms.

These findings sit within a broader Neuro-Immune–Hydraulic Integrative Phenotype Axis (NIH-IPA) that spans POTS, Long COVID, endometriosis, venous compression syndromes, ECM disorders, and other complex multi-system conditions (Exelby & Vittone, MCMC-Research 2025).

Conclusions:

Supine–standing echocardiography consistently reveals preload failure as the primary haemodynamic mechanism in POTS and Long COVID, reframing tachycardia as secondary compensation. The five-domain preload-failure model integrates mechanical, vascular, neuroimmune, endocrine, and metabolic contributors and provides a physiologically coherent basis for diagnosis and treatment. Supine–standing echocardiography should be adopted as a first-line diagnostic tool in orthostatic intolerance.

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