Sympathetic reinnervation of sinus node and left ventricle after heart transplantation in humans:: Regional differences assessed by heart rate variability and positron emission tomography

Background: Orthotopic heart transplantation (HTx) results in complete cardiac denervation. Reestablished partial sympathetic nerve function has been found in patients some years after HTx. However, the atrial and ventricular regional patterns of reinnervation have not been established. Methods: Two parallel methods were used to evaluate the regional restoration of sympathetic nerves in the myocardium. Patients were investigated with respect to ventricular reinnervation (VI) using positron emission tomography (PET) and the norepinephrine analogue C-ll-hydroxyephedrine (HED). Tracer uptake was quantified using dynamic imaging protocols, yielding regional HED retention fraction. A regional value above 7%/minute (+/- 2.5 SD above the mean value of denervated hearts) was considered evidence of sympathetic reinnervation. Spectral analysis of heart rate variability (HRV) served as a quantitative marker for reinnervation at the sinus node (SI). Spectra of HRV during positive head-up tilt were calculated. The low frequency (LF) power spectral density (0.05 to 0.18 Hz) was evaluated. Results: after HTx (4.6 +/- 3.9 years; range, 0.2 to 13.6 years), 38 patients (aged 50.9 +/- 7.6 years; range, 37 to 65 years) were investigated by PET imaging and HRV. Twenty-two patients with a mean HED retention of 10.7 +/- 2.6%/minute were classified as left ventricular reinnervated. Sixteen patients with a mean HED retention of 4.8 +/- 0.8%/minute did not reach the threshold. The time difference after HTx was significant for these 2 groups, 5.3 +/- 3.0 years vs 3.8 +/- 4.7 years (p < 0.05). The LF power spectral density of the ventricular reinnervated patients was 5.9 +/- 8.6 ms(2), and 1.8 +/- 4.4 ms(2) (p <0.005) for those not reinnervated. Low frequency showed small values and narrow distribution for the patients not reinnervated, assuming sinus node denervation, and showed extended distribution for the reinnervated, suggesting a heterogeneous reinnervation pattern. Conclusion: Two non-invasive parallel methods were used to investigate regional reestablishment of cardiac nerves in the myocardium in HTx patients. Left VI assessed by PET imaging and SI by HRV was congruent in 60% of HTx patients. Lack of SI paralleled absence of VI. Our results suggest that partial VI occurs prior to SI.