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Background Vasovagal syncope (VVS) is the result of an autonomic reflex that has a final effect of reducing sympathetic drive and increasing vagal activity. However, whether syncopal symptoms are associated with pathological cardiac autonomic modulation is not fully known. We tested the hypothesis that cardiac autonomic function is impaired in patients with VVS. Methods Eighty-four consecutive patients (59 males; 48.8 ± 20.9 years) with recurrent unexplained syncope were enrolled. The head-up tilt test (HUTT) was positive in 38 patients and negative in 46 patients. Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability, plasma concentrations of norepinephrine, and 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Results BRS indices were significantly lower in the HUTT-positive group than in the HUTT-negative group (6.1 ± 5.5 mm Hg/s vs 9.8 ± 7.6 mm Hg/s, P = 0.02). With regard to cardiac 123I-MIBG scintigraphy, the mean heart-to-mediastinum ratio at the delayed phase tended to be lower in HUTT-positive than in HUTT-negative individuals, but this difference was not significant (2.75 ± 0.55 vs 3.02 ± 0.49, P = 0.08).The percent washout rate of 123I-MIBG was significantly higher in the positive group compared with the negative group (40.7 ± 13.1% vs 31.5 ± 13.3%, P = 0.02). Multivariate logistic analysis revealed that the appearance of HUTT-induced VVS was predicted independently by a high percent washout rate of 123I-MIBG (odds ratio, 0.954; 95% confidence interval, 0.903-0.998; P = 0.048). Conclusions Our results suggest that pathological autonomic cardiac modulation may play a role in the appearance of syncope in VVS patients. [ABSTRACT FROM AUTHOR]