During exercise, as heart rate (HR) increases, the QT interval of the electrocardiogram shortens. The mechanism(s) involved in this QT shortening has not been clearly defined. To distinguish the influence of increased circulating catecholamines from myocardial efferent stimulation, the relationship between HR and QT interval was investigated during exercise and cardiovascular reflex stimulation in cardiac transplant patients and normal control subjects. Because of cardiac denervation, increases in HR in these patients are solely due to circulating catecholamines and thus allow isolation of their effect on the QT interval. Twenty-one cardiac transplant patients were studied and compared with 16 normal control subjects. The QT-HR relationship was determined according to an exponential model during treadmill exercise in both groups [QT = 0.12 + 0.492e(-0.008.HR) and QT = 0.12 + 0.459e(-0.007.HR) in normal subjects and transplant patients, respectively] and was statistically similar between groups, suggesting similar QT interval shortening in both groups. During cold pressor and Valsalva maneuvers, HR increased significantly in normal subjects only, whereas QT interval changed minimally in both groups. These results suggest that during exercise the QT interval is influenced predominantly by increases in circulating catecholamines rather than by neurally mediated reflex autonomic changes.