Funding source: This work was supported by the Chang Gung Memorial Hospital Medical Research Program [CMRPG36136], Taiwan to C.C. Chou.
Effects of SEA0400 on Arrhythmogenicity in a Langendorff-Perfused 1-Month Myocardial Infarction Rabbit Model
Article first published online: 4 FEB 2013
©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.
Pacing and Clinical Electrophysiology
Volume 36, Issue 5, pages 596–606, May 2013
How to Cite
CHOU, C.-C., CHANG, P.-C., WEN, M.-S., LEE, H.-L., CHU, Y., BABA, A., MATSUDA, T., YEH, S.-J. and WU, D. (2013), Effects of SEA0400 on Arrhythmogenicity in a Langendorff-Perfused 1-Month Myocardial Infarction Rabbit Model. Pacing and Clinical Electrophysiology, 36: 596–606. doi: 10.1111/pace.12091
Conflict of Interest: The authors have no conflicts of interest to disclose.
- Issue published online: 24 APR 2013
- Article first published online: 4 FEB 2013
- Manuscript Accepted: 28 NOV 2012
- Manuscript Revised: 29 OCT 2012
- Manuscript Received: 27 MAY 2012
- Chang Gung Memorial Hospital Medical Research Program. Grant Number: [CMRPG36136]
- animal studies;
- electrophysiology – basic;
The effects of SEA0400, a Na+/Ca2+ exchanger (NCX) blocker, on dynamic factors and arrhythmogenic alternans in 1-month myocardial infarction (MI) hearts remain unknown.
Simultaneous voltage and intracellular Ca2+ (Cai) optical mapping was performed in 12 rabbit hearts with MI for 1 month and six normal rabbit hearts as control. Western-blot studies were performed in both groups in an additional six hearts for each. Action potential duration (APD) restitution was constructed and arrhythmogenic alternans was induced by dynamic pacing. SEA0400 (0.03, 3 μM) was administered after baseline studies.
SEA0400 suppressed pacing-induced ventricular premature beats in a concentration-dependent manner. SEA0400 at 0.03 μM steepened APD restitution slopes and enhanced spatially discordant alternans (SDA), which became insignificant at 3 μM. The VF inducibility was seven of nine at baseline, nine of nine at 0.03 μM SEA0400, and five of nine at 3 μM SEA0400 (P = NS). Significant upregulation of NCX in the remote but not periinfarct zone and less degree downregulation of DHP1α in the remote versus periinfarct zone may play a role in enhancing SDA induction by SEA0400 in 1-month MI hearts.
In 1-month MI hearts, SEA0400 suppresses pacing-induced ventricular premature beats, but also is proarrhythmic by steepening APD restitution and enhancing SDA via NCX inhibition. Heterogeneous upregulation of NCX and downregulation of DHP1α may contribute to SDA augmentation by SEA0400 in this model. The insignificant effect of SEA0400 on VF inducibility suggests that suppression of both reentry and triggered activity is required to suppress VF induction in this model.