What Actually Causes POTS? A Mechanistic Reading of Postural Orthostatic Tachycardia Syndrome — When pathways combine

Most cases I see have features of more than one pathway. The most common combination is Pathway 1 (post-viral) plus Pathway 4 (deconditioning), because the post-viral fatigue that produces the initial POTS often leads to extended low-activity periods that produce secondary deconditioning. Treatment then addresses both: the upstream NAD+ and viral-sequelae work for Pathway 1, the structured reconditioning for Pathway 4, sequenced appropriately so that reconditioning does not exceed the bioenergetic capacity restored by the upstream work. Pathway 2 (gut-driven) often combines with Pathway 1 in post-viral cases where the gut barrier was also affected. The CD38-NAD+-SIRT3 cascade is expressed in colonocytes and in autonomic ganglia simultaneously. Both gut and autonomic symptoms emerge. Pathway 3 (connective tissue) often appears alone in early hEDS-POTS but acquires features of Pathway 2 as gut inflammation develops, and Pattern B MCAS often co-emerges, producing the full triad. The clinical task is to identify the dominant pathway, name any contributing pathways, and sequence the interventions in the order that produces the best response. Symptomatic management runs in parallel throughout because it produces relief while the upstream work proceeds.