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The sensitivity of the passive head-up tilt test (HUT) in the evaluation of unexplained short-lasting syncope in young adults remains insufficient. The infusion of isoproterenol was proposed to improve the benefit. To evaluate the sensitivity-specificity relationship during isoproterenol dosing, we studied 76 young adults (aged 20.9 +/- 1.7 years) (group S) with recurrent (mean 3.8 +/- 1.6) losses of consciousness that remained unexplained after clinical and noninvasive assessment and 35 young healthy volunteers (aged 22.6 +/- 2.7 years) (group V). Subjects underwent either passive HUT (45 min, 60 degrees without drug dosing for 48 subjects in group S (S1) and 17 in group V (V1), or HUT with isoproterenol infusion at progressive doses (2 then 5 @mg/min) after 30 minutes of passive tilting for 28 patients in group S (S2) and 18 in group V (V2). During passive HUT, the test was positive (asystole, bradycardia, or fall in systolic blood pressure) in 2 of 17 (11.8%) patients in group V1 and in 7 of 48 (14.6%) in group S1 before 30 minutes, and in 3 of 17 (17.6%) in group V1 compared with 10 of 48 (20.8%) in group S1 at the end of the 45-minute infusion, with no difference in delay before the appearance of a positive result. During HUT with isoproterenol dosing, the test was positive in 2 of 18 (11.1%) patients in group V2 and in 18 of 28 (64.2%) in group S2 before 45 minutes (2 @mg/min; p < 0.01) in 7 of 18 (38.8%) in group V2 compared with 24 of 28 (85.7%) in group S2 before 60 min (5 @mg/min; p < 0.01). In both cases the mean delay in evoking a positive response was significantly shorter. No asystolic response was observed in the volunteers regardless of the protocol used. The most characteristic response to isoproterenol injection was the appearance of a junctional escape rate with a fall in systolic blood pressure (61.5% of subjects in group S2). The infusion of isoproterenol considerably improves the sensitivity of the HUT with satisfactory specificity if low doses are used (<3 @mg/min). These results support the use of HUT with isoproterenol in the evaluation of unexplained syncope in young adults. (Am Heart J 1997; 133:346-52.)