Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans

Background. Cardiac transplantation (CT) causes total cardiac denervation. Methods and Results. To test directly for sympathetic reinnervation in humans, we measured the cardiac release of norepinephrine (NE) in response to tyramine (an agent that causes NE release from intact sympathetic nerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) in 12 patients less than 5 months after CT, in 50 patients 1 year or more after CT, and in eight patients without CT. Plasma [NE] was measured in the aorta ([NE]_Ao) and coronary sinus ([NE]_CS) at rest, after tyramine administration (55 μg/kg, i.v.), and during sustained handgrip exercise. Cardiac NE release was determined by subtracting [NE]_Ao from [NE] _CS ([NE]_CS-Ao). NE release was defined as [NE]_CS-Ao during the intervention - [NE]_CS-Ao at rest (Δ[NE]_CS-Ao). In patients studied within 5 months of CT, no significant NE release occurred after tyramine administration (Δ[NE]_CS-Ao, 33±18 pg/ml; range, -98 to 117 pg/ml) or handgrip exercise (Δ[NE]_CS-Ao, -34±10 pg/ml; range, -46 to 8 pg/ml; n=10). Conversely, in 39 of 50 patients studied 1 year or more after CT, tyramine administration caused a significant cardiac NE release (Δ[NE]_CS-Ao, 500±59 pg/ml; range, -11 to 1,918 pg/ml), and handgrip exercise caused a significant NE release in 17 of 41 patients (Δ[NE]_CS-Ao, 189±34 pg/ml; range, -211 to 949 pg/ml). In normally innervated patients, tyramine caused an even larger NE release (Δ[NE]_Ao-CS, 1,943±210 pg/ml; range, 1,152 to 2,977 pg/ml), and handgrip exercise caused a significant NE release in two of seven patients (Δ[NE]_CS-Ao, 143±51 pg/ml; range, -15 to 338 pg/ml). Conclusions. Early after CT, neither tyramine nor handgrip exercise caused a significant cardiac release of NE, suggesting sympathetic denervation. Late after CT, most patients had a significant, but subnormal, NE release in response to pharmacological or reflex stimuli, suggesting that limited sympathetic reinnervation occurs in most patients after orthotopic CT.