Serial assessment using two [¹¹C]-mHED PET scans within 3–4 years demonstrated a continuous increase of extent and intensity of reinnervation with time after transplantation (Bengel et al. 1999). Sympathetic nerve terminals first reappeared in the basal parts of the myocardium and then extended further into distal parts, while the apex was occasionally involved late after transplantation. This finding is consistent with growth of sympathetic fibers along arterial structures. If reinnervation occurs, basal parts are reached first. In addition to a gradient from base to apex, anterior and septal walls were reinnervated earlier, while the lateral wall was involved later. These results suggest that sympathetic nerves are first restored in the territory of the left anterior descending artery, while later the left circumflex territory is involved additionally. Complete restoration of sympathetic innervation, however, was not observed until 15 years after transplantation, because inferior myocardium consistently remained denervated (Bengel et al. 1999; Uberfuhr et al. 2000b).

Using regionally heterogeneous reinnervation as a model, several studies have validated the results of catecholamine imaging by comparison with alternative tests of sympathetic innervation. [¹¹C]-mHED PET-derived evidence of ventricular reinnervation, e.g., correlated with invasive measurements of tyramine-induced coronary arteriovenous norepinephrine spillover (Odaka et al. 2001) and with electrophysiologic indexes of reinnervation derived from heart rate variability measurements (Ziegler et al. 1996; Uberfuhr et al. 2000a).

While time after surgery is considered a major determinant of presence and extent of reinnervation, observations of interindividual heterogeneity and the regionally incomplete pattern suggest that additional determinants are involved. This has been studied in a comparably large sample of 77 transplant recipients by a multivariate analysis. In this analysis using [¹¹C]-mHED PET, some patients remained denervated until late after transplantation, and other factors such as donor and recipient age, duration and complexity of transplant surgery, and frequency of allograft rejection were identified as independent determinants of sympathetic reinnervation (Bengel et al. 2002) (Table 17.1). Aging has been suggested to be associated with reduced availability of target-derived neurotrophic factors, which may explain reduced sympathetic reinnervation with increasing age. Reduced availability and synthesizing capacity of neurotrophins in the myocardium may also explain the lower degree of reinnervation in case of more frequent rejection episodes. Also, because surgical dissection results in axonal degeneration, sympathetic nerve fibers need to regrow along arterial structures to reach the allograft as their target organ. Extensive areas of scar tissue or other morphologic alterations along the path of regrowth may thus impair reappearance of nerve terminals in the myocardium. This is confirmed by less extensive reinnervation in patients with aortic complications at transplant surgery and by a significant inverse correlation with aortic cross-clamp time (Bengel et al. 2002). Hence, the surgical procedure appears to be another factor which may influence reinnervation. The observation of more intense reinnervation in patients transplanted for dilated compared to ischemic cardiomyopathy (Bengel et al. 2002) may also be explained in this context, as regrowth along sclerotic aorta and other vessels may be more difficult.

Finally, diabetes mellitus has also been shown to influence sympathetic reinnervation of the transplanted heart (Bengel et al. 2006). The regional extent of reinnervation and the regeneration rate were significantly reduced in diabetic transplant recipients compared to a matched transplant recipient group without diabetes (Fig. 17.2). The regenerative capacity of the sympathetic nervous system of the heart was reduced, but not abolished, by diabetes mellitus.