Background
Vasovagal reflex is the most common form of syncope, but the pathophysiological mechanisms that initiate the reflex are not well understood. We aimed to study supine and early orthostatic levels of the neurohormones involved in control of circulatory homeostasis in relation to the onset of tilt‐induced vasovagal syncope (VVS).

Methods and Results
A total of 827 patients who were investigated for unexplained syncope with head‐up tilt test (HUT) and optional nitroglycerin provocation (Italian protocol) had blood samples collected while supine and after 3‐minutes of HUT. Of these, 173 (20.9%) patients developed VVS during drug‐free HUT, 161 of whom (males 44.7%; age 45±21 years) had complete data. We analyzed levels of epinephrine, norepinephrine, C‐terminal pro–arginine vasopressin, C‐terminal endothelin‐1, and midregional fragments of pro–atrial natriuretic peptide and pro‐adrenomedullin in relation to time from tilt‐up to onset of VVS. We applied a linear regression model adjusted for age and sex. The mean time to syncope was 11±7 minutes. Older age (β=0.13; SE=0.03, P<0.001), higher supine systolic blood pressure (β=0.06; SE=0.03, P=0.02), and higher supine midregional fragment of pro‐adrenomedullin predicted longer time to syncope (β=2.31; SE=0.77, P=0.003), whereas supine levels of other neurohormones were not associated with time to syncope. Among 151 patients who developed VVS later than 3 minutes of HUT, increase in epinephrine (β=−3.24; SE=0.78, P<0.001) and C‐terminal pro–arginine vasopressin (β=−2.07; SE=0.61, P=0.001) at 3 minutes of HUT were related to shorter time to syncope.

Conclusions
Older age, higher blood pressure, and higher level of pro‐adrenomedullin are associated with later onset of VVS during tilt testing, whereas greater increase of tilt‐induced epinephrine and vasopressin release correlate with shorter time to syncope.