Abstract Body: BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) commonly affects young females and is characterized by orthostatic intolerance and fatigue. Its etiology is unclear, and no specific therapies are available. Circulating T cell/monocyte complexes (doublets) occur in conditions such as active tuberculosis and dengue fever. Ongoing immune activation can promote autonomic dysfunction and mimic many aspects of POTS. We have also shown that isolevuglandin (IsoLG)-adducted proteins accumulate in several cardiovascular conditions and can serve as antigens presented by myeloid cells to T cells, thereby engaging the adaptive immune response.
HYPOTHESIS: IsoLG-adducts accumulate in POTS and are presented to T cells, leading to increased circulating doublets and ongoing immune activation.
METHODS AND RESULTS: POTS (N=8) and LCPOTS (N=23) patients exhibited a greater increase in heart rate (HR) during a 10-minute upright tilt compared to controls (N=10) (47.75 ± 7, 50.23 ± 4.6 vs. 20.33 ± 3.17 bpm, p<0.01, Figure). Circulating doublets, analyzed by flow cytometry, were detected in POTS and LCPOTS with high TCR/HLA FRET (p<0.005), but were very low in control subjects. Doublets exhibited higher levels of IL-17A and IFN-γ compared to non-complexed T cells, along with a significant increase in intracellular IsoLG-adducts compared to non-complexed monocytes. Notably, the percentage of IFN-γ+ and IL-17A+ T cells in the doublets of POTS and LCPOTS subjects positively correlated with clinical parameters (ΔHR) in the tilt table test (Figure). POTS and LCPOTS exhibited a significantly increased proportion of intermediate (CD14highCD16high) and non-classical monocytes (CD14LowCD16high) compared to healthy controls.
In contrast to these flow cytometric properties, traditional markers of inflammation were less discriminatory. 87.5% of patients were in the low to normal range of CRP, and 62.5% had D-dimer levels below 0.27 ng/mL. WBC counts were also normal among patients.
CONCLUSION: POTS and LCPOTS patients exhibit altered immune profiles, characterized by elevated circulating T cell-monocyte doublets and a distinct monocyte subtype profile. The increased levels of IsoLG-adducts in these immune complexes suggest that ongoing intracellular oxidation of arachidonic acid is a likely pathogenic mechanism and provides a previously unrecognized therapeutic avenue.