Longitudinal Changes in Heart Rate Recovery After Maximal Exercise in Pediatric Heart Transplant Recipients: Evidence of Autonomic Re-innervation? Tajinder P. Singh, MD, MSc, Kimberlee Gauvreau, ScD, Jonathan Rhodes, MD, and Elizabeth D. Blume, MD Background: Cardiac autonomic innervation modulates heart rate (HR) response during and HR recovery after exercise in normal subjects. Heart transplantation results in surgical interruption of autonomic innervation. We assessed whether HR response during exercise and HR recovery after exercise in pediatric heart transplant recipients are consistent with autonomic denervation of the heart after transplant and whether they evolve over years in a manner consistent with autonomic re-innervation. Methods: We compared HR response during and HR recovery after a maximum treadmill exercise test in 35 children (median age 13.4 years) after a median follow-up of 1 year after heart transplant with two control groups: post-operative Fontan patients (n = 31) and normal children (n = 35). We then analyzed 153 treadmill exercise tests performed serially in 45 heart transplant recipients (median 3 tests/patient) for longitudinal changes in peak HR and HR recovery after exercise. Results: Transplant recipients had higher body mass index, higher resting HR and significantly attenuated 1- and 3-minute HR recovery after cessation of exercise compared with both control groups ( p  0.001). In transplant recipients with serial exercise tests, peak HR increased an average of 2.0 beats/min per year after transplant ( p  0.001), percent predicted peak HR increased by 1.3% per year (p  0.001), 1-minute HR recovery increased by 1.0 beats/min per year ( p  0.001), and 3-minute HR recovery by 2.6 beats/min per year ( p  0.001). Conclusions: HR response to exercise and HR recovery after exercise in pediatric heart transplant recipients are consistent with autonomic denervation after transplant and suggestive of late autonomic re- innervation of these hearts. J Heart Lung Transplant 2007;26:1306 –12. Copyright © 2007 by the International Society for Heart and Lung Transplantation. Peak heart rate (HR) during a maximal exercise test depends on sinus node function and cardiac sympa- thetic innervation. 1–3 On cessation of exercise, initial HR recovery is mediated by vagal re-activation and subsequent recovery by a combination of vagal tone and withdrawal of sympathetic drive. 4,5 Heart trans- plantation results in surgical interruption of autonomic innervation of the heart. Chronotropic impairment in transplant recipients has been explained by cardiac sympathetic denervation and lack of local release of norepinephrine; the increase in HR in these patients during exercise is a response to circulating cat- echolamines. 1 HR recovery on exercise cessation would thus depend solely upon the decline in circulat- ing catecholamines and is therefore also attenuated in adult heart transplant recipients. 6 Eventually, sympathetic re-innervation occurs in 50% to 60% of adult heart transplant recipients. It usually begins 18 months after transplant, is regionally heter- ogeneous when assessed with scintigraphic imaging, involves progressively more regions of the myocar- dium, and is associated with improvement in HR re- sponse to exercise. 7–9 The presence, extent and physi- ologic effects of autonomic re-innervation are unknown in pediatric heart transplant recipients. The purpose of this study was to assess whether HR response during exercise and HR recovery after exercise in pediatric heart transplant recipients are consistent with early autonomic denervation of the heart and evolve over time in a manner consistent with auto- nomic re-innervation. METHODS This was a retrospective study with two components. First, to characterize HR response approximately 1-year post-transplant, we analyzed exercise data from all chil- From the Department of Cardiology, Children’s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Submitted June 21, 2007; revised August 29, 2007; accepted August 29, 2007. Reprint requests: Tajinder P. Singh, MD, Department of Cardiology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Telephone: 617-355-0558. Fax: 617-734-9930. E-mail: tp.singh@cardio. chboston.org Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2007.08.013 1306 PEDIATRIC TRANSPLANTATION