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Unlabelled: The transplanted heart is initially denervated but undergoes subsequent sympathetic reinnervation. It thus provides a unique model for studying regeneration as a specific component of autonomic nerve biology. The aim of this study was to determine the effect of diabetes mellitus on the regenerational capacity of sympathetic neurons using molecule-targeted PET., Methods: Twenty-two nonrejecting, otherwise healthy cardiac transplant recipients underwent PET with the (11)C-labeled physiologic neurotransmitter epinephrine at 4.0 +/- 3.3 y after surgery. Sympathetic reinnervation was defined as regional restoration of epinephrine retention to values within normal limits., Results: Reinnervation was observed in 8 of 12 patients with no evidence of diabetes and in 6 of 10 patients with a long-term history of diabetes mellitus. The regional extent of reinnervation (4.7% +/- 5.3% of left ventricle vs. 19.1% +/- 20.6% for nondiabetic recipients, P = 0.04) and the regeneration rate (0.8% +/- 1.0% of left ventricle per year vs. 8.0% +/- 10.1% for nondiabetic recipients, P = 0.04) were significantly reduced in diabetic subjects. In a multivariate model, diabetes mellitus was an independent determinant of allograft reinnervation. Finally, the reappearance of innervation was found to correlate with an improved chronotropic and inotropic response to stress in a standardized, symptom-limited exercise test including radionuclide angiography., Conclusion: The regenerational capacity of the sympathetic nervous system of the heart is reduced, but not abolished, by diabetes mellitus. This study on cardiac transplant recipients further supports a general link between impaired glucose handling and cardiac autonomic nerve function.

Aims: To evaluate effects of beta-adrenergic receptor blockade on allograft performance, and to correlate these effects with sympathetic reinnervation., Methods and Results: Myocardial catecholamine storage capacity was determined in 12 non-rejecting transplant recipients using PET and C-11 adrenaline (epinephrine). Haemodynamics and left ventricular function were measured using radionuclide angiography at rest and during symptom-limited exercise before and after non-selective beta-blockade (propranolol iv). Exercise time and stress-induced increases of heart rate and LVEF before beta-blockade were significantly higher in reinnervated compared to denervated recipients. While resting LVEF remained unchanged, heart rate and blood pressure were generally reduced by beta-blockade, which was well tolerated by all patients. Exercise time and increases of heart rate and LVEF were more attenuated in reinnervated recipients. Differences of chronotropic and inotropic response to exercise between groups were no longer present following beta-blockade. Correlations between myocardial adrenaline retention, peak heart rate and increase of global, as well as regional ejection fraction during exercise were observed before, but not during beta-blockade., Conclusion: Acute, non-selective beta-blockade is well tolerated by transplant recipients, but significantly attenuates beneficial functional effects of sympathetic reinnervation on exercise performance. The data suggest that reappearance of sympathetic nerve terminals is associated with reestablishment of intact pre-/postsynaptic interaction.

Background: It has been demonstrated that ventricular sympathetic reinnervation after cardiac transplantation improves exercise performance. The extent of reinnervation increases with time but is variable. Little is known about other influencing factors., Methods and Results: Seventy-seven nonrejecting transplant recipients were cross-sectionally studied by PET with the catecholamine analogue C-11 hydroxyephedrine at 4.8+/-3.5 years after transplantation. Results were compared with history-derived parameters related to recipient's clinical course before, during, and after surgery; donor characteristics; and immunogenetics. Partial reinnervation was observed in 52 patients (extent, 21+/-16% of left ventricle). Complete denervation was found in 25 patients at various times after transplantation. Reinnervation extent correlated with time after surgery (r=0.387; P<0.001) but also inversely with donor age (r=-0.309, P=0.006) and recipient age (r=-0.243, P=0.032). Maximal hydroxyephedrine retention correlated inversely with frequency of rejection episodes (r=-0.267, P=0.019), was reduced when aortic complications occurred perioperatively (9 patients), and correlated inversely with aortic cross-clamp time (r=-0.331, P=0.006). Other parameters were not associated with reinnervation. Patients were surveyed for clinical complications over >12 months after PET (until 7.3+/-4.2 years after transplantation), but significant effects of reinnervation on outcome were not observed., Conclusions: The present data suggest that sympathetic reinnervation after cardiac transplantation is not simply a function of time. Reinnervation is more likely with young age, fast and uncomplicated surgery, and low rejection frequency. Despite few effects on prognosis in otherwise healthy recipients, improved understanding of clinical determinants may contribute to enhance allograft reinnervation and thereby augment exercise capacity in the future.

Background: Late after cardiac transplantation, limited reinnervation of the transplanted heart may occur, but little is known about the effect of reinnervation on cardiac function and exercise performance., Methods: We quantified the extent of myocardial reinnervation noninvasively in 29 cardiac-transplant recipients, using positron-emission tomography and the catecholamine analogue [11C]hydroxyephedrine. Global and regional ventricular function at rest and during standardized exercise testing were measured with the use of radionuclide angiography, and the results were compared with those in 10 healthy controls., Results: Sympathetic reinnervation, mainly in the anteroseptal wall, was present in 16 of the 29 transplant recipients. At rest, hemodynamic differences were not observed between the patients with reinnervation and those with denervation. However, the latter group had a shorter mean (+/-SD) exercise time (6.1+/-1.5, minutes vs. 8.2+/-1.2 in the group with reinnervation; P<0.01) and a lower peak heart rate (121+/-13 vs. 143+/-15 beats per minute, P<0.01). The contractile response to exercise was significantly enchanced in transplant recipients with reinnervation and similar to that of normal controls. In a multivariate analysis, hydroxyephedrine retention was the only independent determinant of the exercise-induced increase in the ejection fraction., Conclusions: In heart-transplant recipients, the restoration of sympathetic innervation is associated with improved responses of the heart rate and contractile function to exercise. These results support the functional importance of reinnervation in transplanted hearts.

Background: Little is known about the progressiveness of sympathetic reinnervation late after cardiac transplantation (HTX). The aim of the present study was to describe individual growth of sympathetic terminals after HTX by a longitudinal quantitative assessment., Methods and Results: In 20 patients after HTX, dynamic PET with C-11 hydroxyephedrine (HED) was performed twice within 3.0+/-0.5 years. According to the time interval between HTX and first PET, subgroups of patients early (group A, <1.5 years; n=7), intermediate (group B, 1.5 to 7 years; n=7) and late (group C, >7 years; n=6) after HTX were defined. At the time of first HED PET, 10 patients were completely denervated (7 in group A, 2 in group B, and 1 in group C). Only 3 remained denervated at second PET. A significant increase of reinnervated myocardium between first and second PET was found in all 3 groups (0% to 9+/-9% of left ventricle for group A, P<0.05; 13+/-12% to 23+/-17% for group B, P<0.05; 21+/-21% to 37+/-23% for group C, P<0.05). The magnitude of increase was similar between groups. Reinnervation was first surveyed in the basal anterior region, then toward apex, septal, and lateral wall. Inferior wall remained denervated. The largest reinnervated area surveyed in an individuum was 66% of the left ventricle., Conclusions: The present data confirm the low likelihood of sympathetic reinnervation within 18 months after HTX. Once the reinnervation process is initiated, a continuous growth is observed even late after HTX, suggesting a progressive nature of reinnervation. Reinnervation, however, remained regionally heterogeneous, and a complete restoration was not found until 15 years after HTX.