Artur Fedorowski

Background: Postural orthostatic tachycardia syndrome (POTS) and inappropriate sinus tachycardia (IST) are two main cardiovascular autonomic disorders in patients with post-COVID syndrome. According to epidemiological estimates, between 10,000-15,000 patients in Sweden may suffer from these two conditions with persistent symptoms 1-4 years after initial infection. The syndromes affect younger population, predominantly women 20-55-year-old, no longer able to work or take care of their families. The long-term prognosis of POTS/IST remains largely unexplored and therapy is still unsatisfactory. Symptoms persist over years and cardiovascular therapy does not address major non-cardiac symptoms such as cognitive impairment, deconditioning, and delayed post-exertional recovery. Aims: A) To explore the natural course of post-COVID POTS/IST 1-5 years after the index infection, and impact of treatment, reinfections, vaccination, and other factors on syndrome development over time. B) To explore new potential disease biomarkers such as circulating microclots and mast cell activation biomarkers in patients with persistent symptom non-responding to cardiovascular therapy, with a healthy control group as reference. C) To test novel therapeutic approach to POTS/IST by application of non-invasive vagus nerve stimulation (VNS) in a randomised sham-controlled manner. Work plan: As of today, more than 350 patients are treated at dysautonomia unit, Dept. of Cardiology for post-COVID POTS/IST with daily new referrals. Healthy controls will be recruited among age- and sex matched asymptomatic individuals. In the first phase (year 1), the eligible patients will be re-evaluated using cardiovascular autonomic tests and disease-specific symptom scores. Blood samples will be collected. In the second phase (year 1-2), blood samples collected from patients and controls will be analysed by group of prof. Pretorius (microclots) and collaborating labs at Karolinska. In the third phase (year 2-3), a randomized blinded sham-controlled study with vagus nerve stimulation will be performed (year 2-3). The sample based on power calculation is >50 patients in each arm (active stimulation vs sham). Significance: Hundreds of patients suffer from poorly defined post-COVID dysautonomia and treatment options are limited. Continuing previous studies, we aim to explore longitudinal impact of the disease, presence of microclots and potential for vagus nerve stimulation in symptom resolution.

Post-acute C OVID-19 syndrome (PACS) is a novel clinical syndrome affecting &gt

60 million patients world-wide with unknown biological mechanisms and no evidence-based treatments. We have recently discovered two cardiovascular phenotypes in PACS: Postural orthostatic tachycardia syndrome (POTS, prevalence 30%) and microvascular endothelial dysfunction (MVD, prevalence 30%). Acute COVID-19 triggers a profound autoimmune response and previous research in POTS and MVD suggest an autoimmune disease mechanism but this hypothesis has not been tested in PACS-associated POTS and MVD. Primary research aim is to test the hypothesis that autoimmunity contributes to PACS complicated by POTS and MVD. Serum and plasma from patients with PACS-associated POTS and MVD will be used in a comprehensive translational approach studying several aspects of autoimmunity: (i) Autoantibody (AAb) levels, (ii) AAb effect on receptor activation in reporter cells (iii) AAb effect on cultured human cardiomyocytes and endothelial cells and (iv) AAb effect in a mouse model in-vivo (heart rate, pain sensitivity, muscle strength) and ex-vivo (AAb binding sites in vasculature and vascular reactivity). Upon discovery of an autoimmune mechanism in PACS, we will conduct a proof-of-concept clinical trial with rituximab and a FnRc receptor blocker compared to placebo hypothesizing that these drugs, that reduce circulating autoantibody levels, improve quality of life in PACS patients with cardiovascular complications.