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 β-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 uptake1 carriers ([3H]mazindol binding) as a marker of presynaptic function as well as β-receptor density ([3H]CGP 12177 binding) and βARK-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 uptake1 was related to local hydroxyephedrine (HED) retention (as determined by pre-operative PET, r=0.65), whereas it was inversely correlated to regional βARK-1 levels (r=−0.61, P=0.04). In contrast, β-adrenergic receptor density was not significantly correlated either to uptake1 density or to local HED retention (r=0.15 and r=0.21). Conclusions: Regional βARK-1 levels rather than β-adrenergic receptor density were correlated with presynaptic alterations in cardiomyopathic human left ventricles. It can be assumed that in the cardiomyopathic human heart, regional β-adrenergic desensitization might be determined by differences in local βARK levels rather than by changes in β-receptor density.