BackgroundHead-upright tilt (HUT) testing is valuable in evaluating syncope. Isoproterenol is used to increase sensitivity. However, isoproterenol is contraindicated or dangerous in undiagnosed heart disease and produces false-positives. We introduced esmolol withdrawal during esmolol HUT, hypothesizing that (1) acute withdrawal of the ultrashort-acting β-blocker induces (-adrenergic effects by unmasking endogenous catecholamines and may provoke syncope with fewer risks, and (2) response to esmolol/esmolol withdrawal may predict effective therapy.Methods and ResultsThirty-six patients with unexplained recurrent syncope/presyncope (7 to 35 years old, known heart disease or arrhythmia in 14) underwent 2 to 4 HUT tests (600, 49 minutes): (1) baseline, (2) esmolol (500 μg/kg plus 50 ug kg−1· min−1), (3) esmolol withdrawal (HUT continued after esmolol stopped), and (4) isoproterenol if tests 1 through 3 were negative and isoproterenol was not contraindicated. A positive test reproduced symptoms with hypotension or bradycardia, requiring recumbency for recovery. Twenty-five had positive tests, and 11 had negative tests. In 5, only the baseline test was positive; in 15, esmolol/esmolol withdrawal tests were also positive, with 3 in whom esmolol withdrawal was positive although negative at baseline. Two isoproterenol tilts were positive. Esmolol withdrawal and isoproterenol tilts had the highest initial heart rate and similar maximal heart rate increment. Only isoproterenol caused hypertension. One isoproterenol test was false-positive, with hypertension-induced arterial baroreflex. Treatment was p-blockers (8), Na/fludrocortisone (9), both (6), and DDD pacemakers (2). Esmolol/ esmolol withdrawal accurately predicted therapeutic response in 15; isoproterenol predicted therapeutic response in none.ConclusionsEsmolol withdrawal tilt testing is preferable to isoproterenol for provocative testing of syncope in the young, and it appears to be safer. Esmolol withdrawal testing has clinical utility before invasive testing as a first-line investigation for syncope in patients with or without heart disease.