{"doi":"10.1101/2025.04.28.25326587","title":"Deep Phenotyping Long-COVID Postural Tachycardia Syndrome","abstract":"Abstract Background & Objectives Long COVID postural tachycardia syndrome (LC-POTS) is increasingly recognized as a manifestation of post-viral autonomic dysfunction following SARS-CoV-2 infection, however its pathogenic mechanisms remain incompletely understood. We aimed to evaluate patterns of autonomic dysfunction in a cohort of carefully phenotyped, previously healthy participants with LC-POTS using autonomic, cerebrovascular, respiratory, blood, and tissue analyses. Comparison groups included participants with non-COVID POTS (NC-POTS) and controls with a history of SARS-CoV-2 infection without lasting sequaelae. Methods Participants 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 CO 2 (ETCO 2 ), 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 The final cohort included 43 participants with LC-POTS, 17 with NC-POTS, and 27 controls. Both LC-POTS and NC-POTS had higher ΔHRs on HUT compared to controls (42 ± 18.6, 46 ± 15.9, 25 ± 12.9, p<0.01). 42.5% of LC-POTS had hyperadrenergic responses on HUT, however mean norepinephrine values were similar to NC-POTS and controls. LC-POTS participants had the lowest mean ETCO values of all groups at end-tilt (22.1 ± 7.5, 25.3 ± 5.8, 29.7 ± 7.3, p<0.01). While LC-POTS exhibited abnormalities across sudomotor (39%), sympathetic adrenergic (11.3%) and cardiovagal (9.3%) domains, we well as reduced IENFD (12.2%), there was no difference when compared to NC-POTS and controls. Measures of cerebral perfusion and oxygen extraction (vCBF, NIRS), were also similar. Dermal P-Syn deposition was identified in 5% of LC-POTS participants and absent in NC-POTS and controls. Conclusions Orthostatic tachycardia, sympathetic adrenergic hyperactivity, hypocapnia and other autonomic abnormalties were relatively common in our LC-POTS cohort, although many of these findings overlapped with NC-POTS and controls. Measures of cerebrovascular changes during orthostatic challenge were also similar and failed to correlate with symptoms of orthostatic intolerance.","journal":"medRxiv","year":2025,"id":565044,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1468613,"name":"Jannika Machnik","orcid":null,"position":1,"is_corresponding":false},{"id":714575,"name":"Jordan Seliger","orcid":null,"position":2,"is_corresponding":false},{"id":1468614,"name":"Ruba Shaik","orcid":null,"position":3,"is_corresponding":false},{"id":252223,"name":"Maarten G. Lansberg","orcid":"0000-0002-3545-6927","position":5,"is_corresponding":false},{"id":270877,"name":"Srikanth Muppidi","orcid":"0000-0002-2773-2506","position":6,"is_corresponding":false},{"id":701207,"name":"Safwan Jaradeh","orcid":null,"position":7,"is_corresponding":false},{"id":292132,"name":"Christopher H. Gibbons","orcid":"0000-0003-0087-5336","position":8,"is_corresponding":false},{"id":22091,"name":"Paul J. Utz","orcid":"0000-0003-1181-1565","position":9,"is_corresponding":false},{"id":619242,"name":"Mitchell G. Miglis","orcid":"0000-0001-8488-0313","position":10,"is_corresponding":false},{"id":1468200,"name":"Nicholas Larsen","orcid":"0000-0001-9966-1471","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}