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.
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.
Authors: H Kawai; A Mohan; J Hagen; E Dong; J Armstrong; S Y Stevens; C S Liang Journal: Am J Physiol Heart Circ Physiol Date: 2000-05 Impact factor: 4.733
Authors: I Matsunari; T Yoneyama; S Kanayama; M Matsudaira; K Nakajima; J Taki; S G Nekolla; N Tonami; K Hisada Journal: J Nucl Med Date: 2001-10 Impact factor: 10.057
Authors: Jamshid Maddahi; Johannes Czernin; Joel Lazewatsky; Sung-Cheng Huang; Magnus Dahlbom; Heinrich Schelbert; Richard Sparks; Alexander Ehlgen; Paul Crane; Qi Zhu; Marybeth Devine; Michael Phelps Journal: J Nucl Med Date: 2011-08-17 Impact factor: 10.057
Authors: M J Stevens; D M Raffel; K C Allman; F Dayanikli; E Ficaro; T Sandford; D M Wieland; M A Pfeifer; M Schwaiger Journal: Circulation Date: 1998-09-08 Impact factor: 29.690
Authors: Arthur J H A Scholte; Joanne D Schuijf; Victoria Delgado; Jurriaan A Kok; Mieke T J Bus; Arie C Maan; Marcel P Stokkel; Antje V Kharagitsingh; Petra Dibbets-Schneider; Ernst E van der Wall; Jeroen J Bax Journal: Eur J Nucl Med Mol Imaging Date: 2010-04-22 Impact factor: 9.236
Authors: Tetsuo Sasano; M Roselle Abraham; Kuan-Cheng Chang; Hiroshi Ashikaga; Kevin J Mills; Daniel P Holt; John Hilton; Stephan G Nekolla; Jun Dong; Albert C Lardo; Henry Halperin; Robert F Dannals; Eduardo Marbán; Frank M Bengel Journal: J Am Coll Cardiol Date: 2008-06-10 Impact factor: 24.094
Authors: Xinyu Chen; Rudolf A Werner; Mehrbod S Javadi; Yoshifumi Maya; Michael Decker; Constantin Lapa; Ken Herrmann; Takahiro Higuchi Journal: Theranostics Date: 2015-02-15 Impact factor: 11.556
Authors: Xinyu Chen; Rudolf A Werner; Constantin Lapa; Naoko Nose; Mitsuru Hirano; Mehrbod S Javadi; Simon Robinson; Takahiro Higuchi Journal: EJNMMI Res Date: 2018-02-06 Impact factor: 3.138
Authors: Rudolf A Werner; Xinyu Chen; Mitsuru Hirano; Steven P Rowe; Constantin Lapa; Mehrbod S Javadi; Takahiro Higuchi Journal: Clin Transl Imaging Date: 2018-07-03