Autonomic Complications of PASC

Introduction: Long COVID POTS (LC-POTS) is being described with increasing frequency, and autonomic dysfunction is being increasingly recognized as a core feature of chronic post-viral syndromes including Long COVID. Despite these associations and the fact that POTS is a relatively common and disabling condition, the pathogenic mechanisms of POTS have remained incompletely understood for decades.

Objective: To evaluate potential mechanisms of autonomic dysfunction in a cohort of carefully phenotyped, previously healthy patients with Long COVID postural tachycardia syndrome LC-POTS using a detailed protocol of autonomic, cerebrovascular, respiratory, blood, and tissue analyses.

Methods: Participants 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-SARS-CoV-2 infection with no lasting sequelae and participants with POTS not triggered by COVID-19 (NC-POTS).

Results: LC-POTS (n=44, 40.25±18.18, p=0.001) and NC-POTS (n=17, 47.00±15.81, p<0.001) participants both exhibited a greater increase in maximum heart rate on HUT than did HC (n=27, 25.07±12.91), but heart rate increase did not differ between LC-POTS and NC-POTS (p=0.28). The increase in norepinephrine levels from supine to upright posture was greater in both LC-POTS (270.5±255.4) and NC-POTS (420.9±344.9) compared to HC (47.2±254.3), but the difference was only significant for the NC-POTS group (p=0.009). CBFv and NIRS did not significantly differ between LC-POTS, NC-POTS and HC. Thirty-eight percent of LC-POTS, 46% of NC-POTS and 22% of HC had abnormal QSART responses. Abnormal IENFD was seen in 12% of LC-POTS, 7% of NC-POTS and 17% of HC. Dermal P-Syn aggregation on skin biopsy was seen in low numbers of LC-POTS (2.4%) and HC (4.2%).

Conclusion/Discussion: LC-POTS is associated with widespread autonomic dysfunction, including orthostatic tachycardia, sympathetic adrenergic hyperactivity, and small fiber neuropathy. No notable differences were seen between LC-POTS and NC-POTS suggesting similar pathophysiological mechanisms.

Key Topics:

• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Clinical assessment and pathogenesis of clinical manifestations
• Comparative studies of Long COVID with other post-viral and post-infectious syndromes
• Long COVID and other chronic conditions,Long COVID in special populations
• Studies of vascular injury, thrombosis, and other potential mechanisms of Long COVID