In this cross-sectional study, participants with LC POTS (n=24) completed a battery of autonomic function tests including sudomotor, heart rate variability with deep breathing (HRDB), Valsalva, and head-up tilt (HUT) along with bilateral transcranial Doppler measures of cerebral blood flow (CBF), end-tidal CO₂ (ETCO₂), cerebral and skeletal muscle near-infrared spectroscopy (NIRS) measures of oxygen extraction, and norepinephrine (NE) measurements. 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 ≥ 3 months post-COVID infection with no lasting sequelae (n=10).

Compared to controls, LC-POTS participants exhibited a greater increase in heart rate on HUT (31.1±20.3, p=0.01). Forty-one percent of LC-POTS participants exhibited elevated upright NE levels consistent with a hyperadrenergic response. CBF during HUT was abnormal in 70.6% of  LC-POTS and 50% of healthy controls but did not significantly differ between groups (combined MCA CBFv -12.9 ±9.3 vs -11.2±8.8, p=0.63). EtCO₂ and NIRS did not differ between groups, though hypocapnea was common in both. Reduced intrepidermal nerve fiber density was seen in both LC-POTS and controls (37% vs. 35, p.>0.99). P-syn was present in 41% of PC-POTS and none of the controls.

LC-POTS was associated with widespread autonomic dysfunction, including orthostatic tachycardia, sympathetic hyperactivity, abnormal cerebral blood flow, reduced intraepidermal nerve fiber density and skin deposition of P-Syn. COVID recovered controls also demonstrated abnormal measures of cerebral blood flow and hyocapnea on tilt.