Assessing the activity of cardiac sympathetic innervation with a novel PET tracer

Abstract

When he was awarded the Nobel Prize in 1970, Ulf vonEuler described cardiac adrenergic neurotransmission asfollows: “Section of the adrenergic nerves to the heart andsome other organs and subsequent degeneration caused thenoradrenaline content to fall to very low values, or to dis-appear, which also indicated that it was normally bound tothe nerves in the organs”…“With the aid of radioactivelylabelled noradrenaline it could be shown that uptake oftransmitter occurred in the particles concomitantly with therelease”. His seminal work in 1946 was the foundation forthe noninvasive study of cardiac sympathetic activity [1].Thesympatheticoutflowtotheheartistonicallyandphasi-cally modulated both in health and disease by the continuousinteraction between central neural integration and peripheralinhibitory and excitatory reflexes. The importance of themeasurement of neurotransmitter concentrations as an indica-tion of neural activity directed to the heart was highlighted in1982byHaskingetal.[2].Thetenetatthattime,derivedfromassays on atrial tissue or papillary muscle samples, was thatthefailingheartshowedaprofounddepletionofnoradrenalinestores. The finding that noradrenaline spillover was increasedby540%abovenormalvaluesrevealedtheoveractivityofthesympathetic outflow directed to the heart. A few years laterBohm et al. using tissue samples of the left ventricle provedthat there is a presynaptic defect leading to reduced uptake-1activity in the failing heart. This unpaired mechanism ispharmacologically mimicked by the effects of uptakeblocking agents in the normal heart [3]. The consequence isan increased synaptic concentration of noradrenaline predis-posingto adenylyl cyclase desensitization[3]. Dr. Esler in hisrecent Paton lecture pointed out that at that time he had “toprovide a spirited defence of the research ethics” to carry outinvasive noradrenaline spillover measurements in healthyvolunteers.In the last three decades two tracers have been used toassess the function of the reuptake-1 mechanism noninva-sively in humans: