Preprint Long-COVID Postural Tachycardia Syndrome: A deep phenotyping study, 2025, Larsen et al.

Long-COVID Postural Tachycardia Syndrome: A deep phenotyping study
Nicholas W Larsen; Jannika V Machnik; Jordan Seliger; Ruba Shaik; Christopher H Gibbons; Paul J Utz; Maarten G Lansberg; Srikanth Muppidi; Safwan Jaradeh; Mitchell G Miglis

BACKGROUND
Postural tachycardia syndrome (POTS) has emerged as one of the most common autonomic complications of Long-COVID (LC). However, disease mechanisms remain incompletely understood.

OBJECTIVES
To 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.

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 α-synuclein (P-Syn). Results were compared to healthy controls (HC) ≥ 3 months post-COVID infection with no lasting sequelae.

RESULTS
LC-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.

CONCLUSIONS
LC-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 pathophysiological mechanisms in most patients with POTS triggered by SARS-CoV-2.

Link | PDF (Preprint: MedRxiv) [Open Access]

 

This claiming of useful finding when it's not even supported in a separate paragraph of the abstract is not going to help people with POTS. To spell it out, a bigger percentage of healthy controls had decreased intraepidermal nerve fibre density than the POTS patients. And the healthy controls don't have symptoms.

No change in cerebral blood flow velocity is disappointing.

The authors are saying that the people selected for the study because they have a bigger heart rate increase than normal when standing showed a bigger heart rate increase in the head-up tilt. And that's not at all surprising. Even then, the change is only 31 beats per minute, which I would have thought was pretty marginal for a tilt test, which is typically thought of as more extreme than a standing test.

The skeletal and cerebral near infra-red spectroscopy didn't find anything different. That's disappointing and a bit surprising. It's probably worth a look to see what they investigated.

That looks to be the most interesting result. They say that the LC-POTS group had 24 people. 8.7% of 24 is 2.088 people, which is a strange amount of people to have something where you either have it or you don't. It's not many people, but it's worth looking into more.