Although anatomic reinnervation of the donor heart is unlikely after transplantation, individual subjects have been noted to show near physiologic heart rate (HR) responses to exercise. To assess development of this phenomenon, we studied HR changes in response to orthostasis and treadmill exercise in 52 orthotopic cardiac transplant recipients grouped according to time after transplantation. In group 1 (2.0 +/- 0.9 months), no significant increase in HR was seen up to 100 cardiac cycles after standing. A maximal acceleration of 4.0 +/- 3.8 beats was seen within 100 cardiac cycles after standing in group 2 (15.8 +/- 5.6 months). Patients in group 3 (42.4 +/- 12.4 months) showed significant cardioacceleration by 5 cardiac cycles after standing to a maximum of 10.7 +/- 5.8 beats/min within the first 100 cardiac cycles. During exercise, HR increased more rapidly during the first minute in group 3 compared with group 1 (p less than 0.01). After exercise, HR continued to increase in group 1 but decreased rapidly in the other groups, most notably group 3 (-26.5 +/- 16.5 by 2 minutes, p less than 0.0001 vs groups 1 and 2). These data indicate development of functional reinnervation after orthotopic heart transplantation. The phenomenon of early acceleration of the HR after orthostasis and rapid deceleration after exercise in transplant recipients implies a local cardiac mechanism rather than response to circulating catecholamines.