Evidence for Functional Sympathetic Reinnervation of Left Ventricle and Coronary Arteries After Orthotopic Cardiac Transplantation in Humans

Abstract

Background Structural sympathetic reinnervation of the transplanted human heart is believed to occur >1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefined. Methods and Results To test directly for functional sympathetic reinnervation, we measured left ventricular or coronary hemodynamics in 11 patients ≤4 months after transplantation, in 45 patients ≥1 year after transplantation, and in 13 untransplanted, normally innervated patients. Sympathetic neurons were stimulated with left coronary injection of tyramine (10 μg/kg), which causes norepinephrine release from intact sympathetic nerve terminals. Reinnervation was defined as a measure of cardiac norepinephrine release after intracoronary tyramine injection. Left ventricular pressure was measured before and at 1-minute intervals after tyramine with a micromanometer-tipped catheter (Millar Instruments). Coronary blood flow velocity (CBFV) was measured with a 3F Doppler catheter (Numed), and coronary artery cross-sectional area was calculated using quantitative coronary angiography. In both early patients and patients studied ≥4 months after transplantation without reinnervation (late denervated), there was no change in left ventricular function in response to tyramine (ΔdP/dt=31±61 and 49±54 mm Hg/s, respectively; P =NS). In transplant recipients with reinnervation (late reinnervated), left ventricular dP/dt rose significantly (ΔdP/dt=210±97 mm Hg/s; P <.05) but less than in healthy patients (ΔdP/dt=577±66 mm Hg/s; P <.05). In both early and late denervated patients, there was no change in CBFV in response to tyramine (CBFV=1.02±0.1 and 1.0±0.1×basal, respectively; P =NS). In late reinnervated patients, CBFV fell significantly (CBFV=0.94±0.1×basal; P <.05). In healthy patients, CBFV fell even more (CBFV=0.88±0.1×basal; P <.05). Conclusions Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.