Long-COVID Postural Tachycardia Syndrome: A deep phenotyping study

BackgroundPostural tachycardia syndrome (POTS) has emerged as one of the most common autonomic complications of Long-COVID (LC), however disease mechanisms remain incompletely understood. ObjectivesTo evaluate the frequency and severity of autonomic dysfunction in a subset of carefully phenotyped, previously healthy patients with LC-POTS using a detailed protocol of autonomic, cerebrovascular, respiratory, blood, and tissue analyses. MethodsParticipants in this study completed a battery of autonomic function tests including measures of sudomotor, cardiovagal, and sympathetic adrenergic function, and head-up tilt (HUT) with transcranial Doppler measures of cerebral blood flow velocity (CBFv), end-tidal CO2 (ETCO2), cerebral and skeletal muscle near-infrared spectroscopy (NIRS) and plasma catecholamines. Skin biopsy was performed at proximal and distal sites and analyzed for intraepidermal nerve fiber density (IENFD) and phosphorylated alpha-synuclein (P-Syn). Results were compared to healthy controls (HC) [≥] 3 months post-COVID infection with no lasting sequelae. ResultsLC-POTS participants (n=24) exhibited a greater increase in heart rate on HUT (31.1{+/-}20.3, p=0.01), and 38% exhibited elevated upright norepinephrine levels consistent with a hyperadrenergic response. CBFv did not significantly differ between LC-POTS and HC (n=10). EtCO2 and NIRS were also similar between groups. Twenty-two percent of LC-POTS and 38% of HC had decreased IENFD on skin biopsy, while 8.7% LC-POTS had dermal P-Syn aggregation on skin biopsy, compared to none of HC. ConclusionsLC-POTS was associated with widespread autonomic dysfunction, including orthostatic tachycardia, sympathetic adrenergic hyperactivity, small fiber neuropathy, and dermal P-Syn deposition. Our findings support the concept of multiple patholophysiological mechanisms in most patients with POTS triggered by SARS-CoV-2. Condensed AbstractPOTS is a common autonomic complication of LC, however mechanisms remain incompletely understood. LC-POTS participants completed autonomic function testing with orthostatic cerebral blood flow velocity (CBFv), end-tidal CO2 (ETCO2), near-infrared spectroscopy (NIRS), plasma catecholamines and skin biopsy. Results were compared to controls with no lasting sequale of COVID. LC-POTS (n=24) exhibited a greater increase in heart rate on HUT, and 38% exhibited a hyperadrenergic response. CBFv, EtCo2,and NIRS were no different between groups.. 8.7% LC-POTS had dermal synucleln aggregation on skin biopsy. LC-POTS was associated with widespread autonomic dysfunction, including sympathetic hyperactivity, small fiber neuropathy, and dermal synuclelin deposition.