EVIDENCE FOR FUNCTIONAL SYMPATHETIC REINNERVATION OF LEFT-VENTRICLE AND CORONARY-ARTERIES AFTER ORTHOTOPIC CARDIAC TRANSPLANTATION IN HUMANS

Background Structural sympathetic reinnervation of the transplanted hu man heart is believed to occur >1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefine d. Methods and Results To test directly for functional sympathetic rei nnervation, we measured left ventricular or coronary hemodynamics in 1 1 patients less than or equal to 4 months after transplantation, in 45 patients greater than or equal to 1 year after transplantation, and i n 13 untransplanted, normally innervated patients. Sympathetic neurons were stimulated with left coronary injection of tyramine (10; mu g/kg ), which causes norepinephrine release from intact sympathetic nerve t erminals. Reinnervation was defined as a measure of cardiac norepineph rine 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 b lood flow velocity (CBFV) was measured with a 3F Doppler catheter (Num ed), and coronary artery cross-sectional area was calculated using qua ntitative coronary angiography. In both early patients and patients st udied greater than or equal to 4 months after transplantation without reinnervation (late denervated), there was no change in left ventricul ar function in response to tyramine (Delta dP/dt=31+/-61 and 49+/-54 m m Hg/s, respectively; P=NS). In transplant recipients with reinnervati on (late reinnervated), left ventricular dP/dt rose significantly (Del ta dP/dt=210+/-97 mm Hg/s; P<.05) but less than in healthy patients (D elta dP/ dt=577+/-66 mm Hg/s; P<.05). In both early and late denervate d 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 reinnerva ted 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 t yramine in transplant recipients causes a significant but subnormal in crease in dP/dt and a transient decrease in CBFV, suggesting that rein nervating sympathetic neurons can produce physiologically meaningful c hanges in left ventricular function and coronary artery tone.