What Actually Causes POTS? A Mechanistic Reading of Postural Orthostatic Tachycardia Syndrome — The four mechanistic pathways of POTS

In the cases I have worked through, four pathways appear repeatedly. Most cases are dominated by one pathway. Some cases have two pathways operating simultaneously. A few cases shift between pathways as the underlying state changes. The framework below is a working stratification. It has held up across case work and it points to different interventions for different pathways, which is what a useful stratification needs to do. Pathway 1: Post-viral autonomic ganglion dysfunction In Pathway 1, the proximate driver is damage to the autonomic ganglia produced by a viral infection or its inflammatory sequelae. SARS-CoV-2 is the dominant current example, but the same pathway operates after EBV, Coxsackie virus, parvovirus B19, and other neurotropic viral infections. The ganglia that integrate cardiovascular reflexes are damaged either directly by viral cytopathy or indirectly by the inflammatory response that the infection produced. The damage is functional rather than structural. The ganglia still exist. They are not signaling properly. The mechanism at the cellular level is increasingly characterized in the long-COVID literature. Type I interferons induced during the acute infection upregulate CD38 expression. CD38 consumes NAD+ at rates that outpace salvage synthesis. The NAD+ pool collapses. SIRT3 activity falls in proportion. Mitochondrial proteome regulation fails. The autonomi