Evidence for functional sympathetic reinnervation of left ventricle and coronary arteries after orthotopic cardiac transplantation in humans

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±0.1xbasal, respectively; P=NS). In late reinnervated patients, CBFV fell significantly (CBFV=0.94±0.1xbasal; P<.05). In healthy patients, CBFV fell even more (CBFV=0.88±0.1xbasal; 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.