Targeted Management of Preload Failure in POTS and Long COVID: A Phenotype-Driven Therapeutic Framework

Dr Graham Exelby. November 2025

Abstract

Background:

Recent mechanistic work proposes preload failure as the initiating lesion in POTS and Long COVID, linking orthostatic intolerance to mechanical, vascular, neuroimmune, and metabolic pathways. Genomic susceptibility—particularly variants in TLR4, CCL2, STAT3, PEMT, COMT, TRPM3, and connective-tissue genes—appears to amplify these pathways. This study utilizes the supine–standing echocardiography results that confirm preload failure and provides a phenotype-directed, genomically informed management framework.

Methods:

Patients underwent standardised supine–standing echocardiography (LVOT/AV VTI, E′, E/E′, SVC flow/phasicity) combined with vascular imaging, symptom clustering, metabolic profiles, connective-tissue assessment, and expanded genomic panels covering innate immune, endothelial, ECM, methylation, mitochondrial, and neurochemical pathways. Using this multimodal dataset, we developed a clinical phenotyping system linking preload-failure signatures to driver mechanisms and targeted therapy.

Results:

All patients demonstrated orthostatic preload failure with 25–70 percent VTI reductions, confirming upright underfilling as the primary driver of tachycardia and cerebral hypoperfusion. Four reproducible phenotypes emerged:

1.     Mechanical–Venous Preload Failure,

2.     Neurovascular–Brainstem Preload Failure,

3.     RAAS-Dysregulated Preload Failure, and

4.     Hybrid phenotypes with additive mechanical and genomic drivers.

Genomic analysis revealed high frequencies of variants predisposing to innate immune amplification (TLR4, CCL2, STAT3), endothelial–RAAS instability (ACE, AGT, NOS3), ECM/venous fragility (COL5A1, TNXB), impaired lipid and phospholipid metabolism (PEMT), redox vulnerability (SOD2, CYBA), and neurotransmitter imbalance (COMT, TRPM3, GABAergic markers). These variants correlated strongly with phenotype expression, symptom clusters, and therapeutic response.

Phenotype-directed management—including telmisartan, tirzepatide, LDN, NAD⁺/redox restoration, ECM–lymphatic physiotherapy, and Kiiko–Matsumoto acupuncture—produced predictable clinical improvements, while traditional agents (beta-blockers, fludrocortisone) provided symptomatic relief without correcting preload failure.

Conclusion:

Supine–standing echocardiography confirms preload failure as the initiating event in POTS and Long COVID and, when combined with genomic susceptibility and mechanical–vascular profiling, enables precise phenotype-based therapy. This integrated framework unifies hydraulic, neurovascular, immune, metabolic, and genetic drivers into the first comprehensive, mechanistically grounded management model for post-viral dysautonomia.