Effect of diabetes mellitus on sympathetic neuronal regeneration studied in the model of transplant reinnervation

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 ¹¹C-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.