Because of its restricted expression pattern and key role in SAN function, blockade of Hcn channels would be predicted to cause pure heart rate reduction without other cardiovascular effects. Moreover, because If regulates the SAN firing rate under resting conditions as well as in response to autonomic inputs, Hcn channels are attractive targets for the treatment of IST, a condition in which both autonomic and intrinsic cardiac mechanisms may be involved. Ivabradine, a specific blocker of Hcn channels, functions as a pure negative chronotrope (19) and was first used clinically for patients with symptomatic stable coronary disease to reduce myocardial oxygen demand (20). Subsequent trials have tested or sought to test ivabradine in acute coronary syndromes (21), in chronic angina with left ventricular dysfunction (22), and in heart failure (23). Although a few case reports and nonrandomized studies have suggested that ivabradine may have efficacy for patients with IST ((24),(25),26), defining the role of ivabradine in the routine treatment of this disease using rigorous methods has not been undertaken until the elegant study, a double-blind, randomized, placebo-controlled trial with a crossover design, of Cappato et al. (27) in this issue of the Journal. Patients were included if they had typical symptoms of IST with average daytime heart rate >95 beats/min and/or exaggerated heart rate response to exercise or orthostatic challenge. The patients were randomized to receive either ivabradine (using a stepwise dosing algorithm) or placebo for 6 weeks, with subsequent crossover after a brief washout period, permitting within-subject comparisons. Symptoms and heart rate parameters were determined for each patient on and off therapy. The results were striking: 75% of IST-related symptoms were eliminated, with nearly 50% of patients experiencing prompt and complete resolution of all symptoms on the drug. Ivabradine consistently lowered daytime, nighttime, and maximum ambulatory heart rates. In addition, exercise capacity improved with ivabradine in association with a marked decrease in maximum heart rate on a treadmill test, alleviating one of the hallmarks of the disease. Adverse events were infrequent, with only 1 patient stopping the drug because of visual changes, a known and reversible side effect of the drug. Taken together, the results suggest great promise for ivabradine with an excellent side effect profile for many, if not most, patients with IST.