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Ibutilide Reduces Ventricular Defibrillation Threshold and Organizes Ventricular Fibrillation Activation in Canine Heart Failure Model

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Abstract

Purpose

To compare the effects of class III antiarrhythmic agents (amiodarone vs. ibutilide) on ventricular fibrillation (VF) and hemodynamic status in a canine heart failure (HF) model.

Methods

A total of 12 beagles were used to establish the HF model by rapid pacing for 4 consecutive weeks. These canines were randomly divided into two groups based on the administration of ibutilide and amiodarone. A 12 × 12 unipolar electrode plaque was used for ventricular epicardial mapping, and a 6-electrode plunge needle was inserted for ventricular transmural mapping. The restitution curve was estimated from activation recovery intervals (ARIs) by pacing from the plaque electrodes before and after drug administration. The defibrillation threshold (DFT) and VF activation patterns, including the activation rate, cycle length (VF-CL) and the transmural dispersion of the activation rate, were evaluated and the hemodynamic parameters were mearsured and compared before and after drug administration.

Results

Compared to HF baseline, ibutilide administration has markedly decreased the DFT by 28% (18 ± 2 J vs. 13 ± 2.7 J, P < 0.01) without affecting the canine’s hemodynamics (mean arterial pressure 91 ± 15 mmHg vs. 92 ± 17 mmHg, P > 0.05). Furthermore, VF activation pattern became more organized, and spontaneous termination was observed only after ibutilide administration. Conversely, amiodarone has significantly compromised the hemodynamic status (mean arterial pressure 92 ± 6.1 mmHg vs. 52 ± 11.6 mmHg, P < 0.05), but did not alter the DFT (17 ± 2.3 J vs. 16 ± 2.0 J, P > 0.05). Compared to pre-medication, both ibutilide and amiodarone have significantly prolonged the VERP (178 ± 9.6 ms vs. 208 ± 8.9 ms, P < 0.05; 185 ± 10.5 ms vs. 202 ± 7.5 ms, P < 0.05, respectively) and reduced the dispersion of refractoriness, the maximal slope of restitution curve, and the epicardial dispersion during pacing. Additionally, both drugs have significantly increased the VF-CL and reduced the transmural dispersion of the VF activation rate.

Conclusions

Ibutilide had potential antifibrillatory properties, which was shown by decreasing the DFT and organizing the VF activation in HF, and with no apparent impact on the hemodynamic status. In contrast, intravenous amiodarone administration demonstrated prominent negative effects on the hemodynamic status possibly by affecting the myocardial contractility before and after defibrillation but did not alter the DFT.

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Funding

This study was funded by grants from the National Natural Science Foundation of China (No. 81600270) and the Shanghai Science and Technology Committee (No. 16140904602).

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Author notes

  1. Ning Zhang, Qingzhi Luo and Qi Jin the first three authors contributed equally to this work

Authors and Affiliations

  1. Department of Cardiology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China

    Ning Zhang, Qingzhi Luo, Qi Jin, Yanxin Han, Shangwei Huang, Yue Wei, Changjian Lin, Kang Chen, Weifeng Shen & Liqun Wu

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  1. Ning Zhang
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Correspondence to Weifeng Shen or Liqun Wu.

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The authors declare that they have no conflict of interests.

Ethical Approval

All animals were acquired from the Shanghai Jiao Tong University Agriculture College (China) and raised under controlled conditions at the Department of Animals for Scientific Research, Shanghai Jiao Tong University School of Medicine. All the study procedures were approved by the Shanghai Jiao Tong University School of Medicine Animal Care and Use Committee in accordance with the recommendations from the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (eighth edition, 2011).

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Zhang, N., Luo, Q., Jin, Q. et al. Ibutilide Reduces Ventricular Defibrillation Threshold and Organizes Ventricular Fibrillation Activation in Canine Heart Failure Model. Cardiovasc Drugs Ther 34, 323–334 (2020). https://doi.org/10.1007/s10557-020-06958-2

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