Effects of SEA0400 on Arrhythmogenicity in a Langendorff-Perfused 1-Month Myocardial Infarction Rabbit Model

Authors

  • CHUNG-CHUAN CHOU M.D.,

    Corresponding author
    1. Chang Gung University College of Medicine, Taoyuan, Taiwan
    • Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital, Linko, Taiwan
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  • PO-CHENG CHANG M.D.,

    1. Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital, Linko, Taiwan
    2. Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • MING-SHIEN WEN M.D.,

    1. Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital, Linko, Taiwan
    2. Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • HUI-LING LEE M.D.,

    1. Department of Anesthesia, Chang Gung Memorial Hospital, Taipei, Taiwan
    2. Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • YEN CHU D.V.M., D.S.C.,

    1. Division of Thoracic Surgery, Chang Gung Memorial Hospital, Linko, Taiwan
    2. Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • AKEMICHI BABA Ph.D.,

    1. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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  • TOSHIO MATSUDA Ph.D.,

    1. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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  • SAN-JOU YEH M.D.,

    1. Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital, Linko, Taiwan
    2. Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • DELON WU M.D.

    1. Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital, Linko, Taiwan
    2. Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Funding source: This work was supported by the Chang Gung Memorial Hospital Medical Research Program [CMRPG36136], Taiwan to C.C. Chou.

  • Conflict of Interest: The authors have no conflicts of interest to disclose.

Address for reprints: Chung-Chuan Chou, M.D., Second Section of Cardiology, Chang Gung Memorial Hospital, 199 Tung-Hwa North Road, Taipei 10591, Taiwan, ROC. Fax: 886-3-3289134; e-mail: 2867@adm.cgmh.org.tw

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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