TIME-DEPENDENT DECREASE OF PRESYNAPTIC INOTROPIC SUPERSENSITIVITY - PHYSIOLOGICAL EVIDENCE OF SYMPATHETIC REINNERVATION AFTER HEART-TRANSPLANTATION

Background: Sympathetic cardiac denervation of the transplanted human heart causes a loss of the presynaptic neuronal uptake(1)-mechanism wi th consecutive supersensitivity to uptake(1)-dependent catecholamines. A return of neuronal function (reinnervation) should result in a decr ease of supersensitivity to catecholamines subjected to this uptake sy stem and thus may alter the inotropic regulation. Methods: Inotropic d ose-response curves were compared in 12 patients who were studied 3 to 15 months after transplantation (early) and 17 patients who were stud ied 23 to 156 months after transplantation (late) with isoproterenol ( uptake(1)-independent) and epinephrine (uptake(1)-dependent). The inot ropic 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 echoc ardiography as increase of the systolic pressure/dimension ratio (Delt a P/D) and of the rate-corrected velocity of circumferential fiber sho rtening (Delta V-cfc). Results: Inotropic dose/reponse curves to isopr oterenol 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 m m Hg/mm; Delta V-cfc 1.55 +/- 0.33 vs 1.40 +/- 0.38 root min(-1) x %/m s), indicating an unchanged inotropic effect mediated by the postsynap tic beta-receptor/effector system. However, the inotropic response to epinephrine in early recipients was significantly attenuated in the la te 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 V-cfc 1.80 +/- 0.42 vs 1.05 +/- 0.35 root min(-1) x %/ms, p < 0.001). Conclusions: These f indings provide evidence for an at least partial restoration of the ne uronal catecholamine uptake and are consistent with a time-dependent s ympathetic reinnervation after heart transplantation. Restoration of n euronal uptake seems to be of functional importance, because it profou ndly alters the inotropic effect of circulating endogenous catecholami nes in long-term survivors after heart transplantation.