LMI1195 PET imaging in evaluation of regional cardiac sympathetic denervation and its potential role in antiarrhythmic drug treatment

Abstract

Purpose: Regional cardiac sympathetic denervation (RCSD) associated with reduced noradrenaline transporter (NAT) function has been linked to cardiac arrhythmia. This study examined the association of LMI1195, an (18)F-labeled NAT substrate developed for positron emission tomography (PET) imaging, with NAT in vitro, and its imaging to detect RCSD and guide antiarrhythmic drug treatment in vivo.

Methods: LMI1195 association with NAT was assessed in comparison with other substrates, noradrenaline (NA) and (123)I-metaiodobenzylguanidine (MIBG), in NAT-expressing cells. LMI1195 cardiac imaging was performed for evaluation of RCSD in a rabbit model surgically developed by regional phenol application on the left ventricular (LV) wall. The normal LV areas in images were quantified as regions with radioactivity ≥50 % maximum. Potential impact of RCSD on dofetilide, an antiarrhythmic drug, induced ECG changes was assessed.

Results: NAT blockade with desipramine reduced LMI1195 cell uptake by 90 ± 3 %, similar to NA and MIBG. NA, MIBG, or self inhibited LMI1195 cell uptake concentration-dependently with comparable IC(50) values (1.09, 0.21, and 0.90 μM). LMI1195 cardiac imaging differentiated innervated and denervated areas in RCSD rabbits. The surgery resulted in a large denervated LV area at 2 weeks which was partially recovered at 12 weeks. Myocardial perfusion imaging with flurpiridaz F 18 showed normal perfusion in RCSD areas. Dofetilide induced more prominent QTc prolongation in RCSD than control animals. However, changes in heart rate were comparable.

Conclusion: LMI1195 exhibits high association with NAT and can be used for imaging RCSD. The detected RCSD increases cardiac risks to the antiarrhythmic drug, dofetilide, by inducing more QTc prolongation.