Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a cardiovascular dysautonomic condition affecting predominantly young women. POTS is defined as the presence of chronic symptoms of orthostatic intolerance associated with an increased heart rate ≥30 bpm, or heart rate exceeding 120 bpm, within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension. The etiology is still unknown though autoimmunity has been hypothesized to play an important role. Purpose: To investigate whether an inflammatory biomarker signature is associated with POTS. Methods: We performed a cross-sectional study enrolling 475 patients aged between 15 and 55 years with unexplained syncope or symptoms of orthostatic intolerance. Of these 118 have been diagnosed with POTS and 357 controls demonstrated normal hemodynamic response during passive phase of HUT i.e. no orthostatic hypotension or POTS. A total of 318 patients provided supine blood plasma samples that were analyzed through the antibody-based Proximity Extension Assay technique, simultaneously measuring 53 inflammatory and cancer-related human protein biomarkers. After excluding 5 biomarkers with low call rate <65% (VEstatin, LITAF, MYD88, MICA, CEA) and 9 patients with missing data, the final study sample consisted of 309 patients (POTS, n=78; no POTS n=231). The discovery algorithm was a sequential two-step process of biomarker signature identification by multivariate principal component analysis (PCA), and verification by univariate ANOVA with Bonferroni correction. Results: POTS patients were younger (28 vs. 35 years; p<0.001) compared with controls. PCA and Bonferroni-adjusted ANOVA identified furin and FADD as the most robust targeted biomarker signature for POTS. The plasma concentration of furin was significantly lower (6.39 (0.5) vs 6.64 (0.4), p<0.001), whereas FADD levels were significantly higher (2.37 (0.72) vs 2.14 (0.69), p=0.01) in POTS patients compared with controls. In multivariable regression analysis, adjusting for age and sex, the results remained significant. Conclusion: Targeted protein profiling in POTS revealed a biomarker signature associated with immunoregulatory functions. Circulating levels of furin were downregulated, whereas circulating levels of FADD were elevated in POTS, suggesting the presence of a characteristic inflammatory signature in this unexplained condition.
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