Time-dependent decrease of presynaptic inotropic supersensitivity: physiological evidence of sympathetic reinnervation after heart transplantation.

Abstract

BACKGROUND: Sympathetic cardiac denervation of the transplanted human heart causes a loss of the presynaptic neuronal uptake1-mechanism with consecutive supersensitivity to uptake1-dependent catecholamines. A return of neuronal function (reinnervation) should result in a decrease of supersensitivity to catecholamines subjected to this uptake system and thus may alter the inotropic regulation. METHODS: Inotropic dose-response curves were compared in 12 patients who were studied 3 to 15 months after transplantation (early) and 17 patients who were studied 23 to 156 months after transplantation (late) with isoproterenol (uptake1-independent) and epinephrine (uptake1-dependent). The inotropic response to increasing doses of isoproterenol (5 to 20 ng/kg per min) and epinephrine (10 to 40 ng/kg per min) was assessed with echocardiography as increase of the systolic pressure/dimension ratio (delta P/D) and of the rate-corrected velocity of circumferential fiber shortening (delta Vcfc). RESULTS: Inotropic dose/response curves to isoproterenol were identical in the early and late recipients (during 20 ng/kg per min. isoproterenol: delta P/D 2.07 +/- 1.36 vs 2.18 +/- 1.42 mm Hg/mm; delta Vcfc 1.55 +/- 0.33 vs 1.40 +/- 0.38 square root of min-1 x %/ms), indicating an unchanged inotropic effect mediated by the postsynaptic beta-receptor/effector system. However, the inotropic response to epinephrine in early recipients was significantly attenuated in the late recipients (during 40 ng/kg per min. epinephrine: delta P/D 3.35 +/- 2.06 vs 1.51 +/- 0.68 mm Hg/mm, p < 0.01; delta Vcfc 1.80 +/- 0.42 vs 1.05 +/- 0.35 square root of min-1 x %/ms, p < 0.001). CONCLUSIONS: These findings provide evidence for an at least partial restoration of the neuronal catecholamine uptake and are consistent with a time-dependent sympathetic reinnervation after heart transplantation. Restoration of neuronal uptake seems to be of functional importance, because it profoundly alters the inotropic effect of circulating endogenous catecholamines in long-term survivors after heart transplantation.