Artur Fedorowski

Background: Almost one third of those affected by post-acute COVID sequelae (PACS) or Long Covid demonstrate clinical signs of postural orthostatic tachycardia syndrome (POTS). The demographics of post-COVID POTS poses a huge burden as the syndrome impacts mainly younger and middle-aged women who are no longer able to work and take care of their families. The cause of POTS remains a mystery and therapy is largely unsatisfactory. Aims: The following hypotheses will be tested: A) Post-COVID POTS is a condition with an autoimmune aetiology directed against major types of cardiovascular(CV) G-protein coupled receptors. B) Post-COVID POTS is a chronic inflammatory condition with significant changes in inflammatory proteins and immunological markers. C) Post-COVID POTS is a condition associated with microvascular dysfunction. D) Post-COVID POTS may share different additional phenotypes such as inappropriate sinus tachycardia and low-blood pressure phenotype, which should be detected and treated appropriately. E) A subset of patients with post-COVID POTS share the same pathophysiological mechanisms as mast cell activation disorders. Work plan: The patients will be recruited 2022-2023 through referrals from a dedicated post-COVID clinic at Karolinska and directly from specialists and primary care plus from external referrals from other administrative regions. As of today, more than 350 patients have been identified and will be included. Patients will be examined by CV autonomic tests, long-term hemodynamic monitoring, cardiac MRI,, endothelial function tests, and immunological (for GPCR-autoantibodies), neuroendocrine (for endothelial dysfunction), less discriminative proteomics (through mass spectrometry) and mast cell activation tests. Based on autonomic, cardiac, endothelial and biochemical tests, the most promising therapeutic targets will be selected for the second stage of project (interventional). This part will be launched first 2023-2024. Significance:Our understanding, diagnostics, and therapy of long-term post-COVID cardiovascular dysautonomia such as POTS, are largely unsatisfactory. It is estimated that one third of Long COVID patients will develop this chronic condition. This project is aimed to answer the questions whether post-COVID POTS and dysautonomia are chronic autoimmune and inflammatory conditions, what are the main mechanisms behind syndrome s debilitating consequences, how to best diagnose it and how to treat it more effectively.

We have recently discovered three cardiovascular phenotypes in post covid: Postural orthostatic tachycardia syndrome (POTS), unspecific sinus tachycardia and cardiac microvascular dysfunction. The pathophysiology and optimal treatment strategies for these remain unknown. The overall aim is to characterize several biological aspects of the cardiovascular phenotypes to identify pathophysiological mechanisms (identifying novel therapeutic targets) and to conduct a series proof-of-concept randomized, placebo-controlled, double-blind, clinical trials (RCTs) using available interventions targeting putative mechanisms.Patients will be included from the post covid clinic at Karolinska University Hospital and the study will run 2022-2025. In collaboration with several experts at Karolinska University Hospital and nationally, stress-perfusion cardiac magnetic resonance imaging (microvascular dysfunction), endothelial function studies and advanced assessment of dysautonomias (e.g. POTS) will be performed. Protein- and lipid biomarkers (proteomics and lipidomics

mass spectrometry) will be analyzed. In parallel, proof-of-concept RCT using drugs with documented effect in similar diseases will be conducted. These RCTs will then serve as a foundation for future clinical studies targeting discovered mechanisms. The result from this study may lead to rapid implementation of evidence-based treatment and discoveries of novel therapeutic targets in a large and underserved patient population.