Regional Pre- and Postsynaptic Sympathetic System in the Failing Human Heart — Regulation of βARK-1

OBJECTIVES: Regional presynaptic sympathetic innervation varies considerably in the cardiomyopathic human heart, as shown in previous studies in vivo and in vitro. The goal of the present study was to correlate markers of presynaptic sympathetic innervation with local measurement of the postsynaptic beta-adrenergic system in failing human hearts. METHODS AND RESULTS: In nine left ventricular regions of hearts explanted from patients suffering from dilated cardiomyopathy, we measured the density of uptake(1) carriers ([3H]mazindol binding) as a marker of presynaptic function as well as beta-receptor density ([3H]CGP 12177 binding) and beta ARK-1 levels as the pivotal compounds of postsynaptic adrenergic signal transduction. Additionally, a subgroup of the patients was examined in vivo by HED-PET prior to heart transplantation. The density of uptake(1) was related to local hydroxyephedrine (HED) retention (as determined by pre-operative PET, r=0.65), whereas it was inversely correlated to regional beta ARK-1 levels (r=-0.61, P=0.04). In contrast, beta-adrenergic receptor density was not significantly correlated either to uptake(1) density or to local HED retention (r=0.15 and r=0.21). CONCLUSIONS: Regional beta ARK-1 levels rather than beta-adrenergic receptor density were correlated with presynaptic alterations in cardiomyopathic human left ventricles. It can be assumed that in the cardiomyopathic human heart, regional beta-adrenergic desensitization might be determined by differences in local beta ARK levels rather than by changes in beta-receptor density.