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Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice

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Abstract

Purpose

Cardiac rupture is a fatal complication following myocardial infarction (MI). An increase in heart rate (HR) is reportedly an independent risk factor for cardiac rupture during acute MI. However, the role of HR reduction in cardiac rupture after MI remains to be fully elucidated. We aimed to evaluate the therapeutic efficacy of HR reduction with ivabradine (IVA) on post-MI cardiac rupture in mice.

Methods

We induced MI in mice by ligating the left anterior descending coronary artery. Subsequently, we subcutaneously implanted osmotic pumps filled with IVA solution or vehicle (Veh) in the surviving MI mice at 24 h postoperatively. We biochemically analyzed the myocardium on day 5, additionally observed the mice for 10 days, and analyzed the rates of cardiac rupture and non-cardiac rupture death, and survival after MI.

Results

HR was significantly lower in the IVA-treated mice, whereas blood pressure was comparable between the two groups. Compared to the Veh-treated mice, apoptosis was significantly reduced in the MI border zone in the IVA-treated mice. Although there were no differences in the infarct size of the surviving MI mice between the two groups, HR reduction with IVA significantly reduced cardiac rupture (rupture rate 26 and 8% in the Veh-treated and IVA-treated groups, respectively) and improved survival after MI.

Conclusion

Our findings suggest that HR reduction with IVA prevents cardiac rupture after MI. This may be particularly effective in MI patients with a high HR who are either unable to adequately tolerate β-blockers or whose HR remains high despite receiving β-blockers.

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Fig. 1

Data Availability

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Acknowledgments

We thank Midori Sato and Akiko Hanada for their excellent experimental and technical assistance.

Funding

This work was supported by JSPS KAKENHI (grant number 16H07049 and 18K15892 to MI, 17K09582 and 20K08426 to TI), the Takeda Science Foundation, the Uehara Memorial Foundation, the Japan Foundation for Applied Enzymology (VBIC: Vascular Biology of Innovation), the YOKOYAMA Foundation for Clinical Pharmacology (grant number YRY-1911), the MSD Life Science Foundation, the Public Interest Incorporated Foundation (MI), and AMED (grant number 20ek0109339h0003) (HT).

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masataka Ikeda, Tomomi Ide, Shun Furusawa, Kosei Ishimaru, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Ko Abe, Shouji Matsushima & Hiroyuki Tsutsui

  2. Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masataka Ikeda, Tomomi Ide, Shun Furusawa, Kosei Ishimaru, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Ko Abe, Shouji Matsushima & Hiroyuki Tsutsui

Authors
  1. Masataka Ikeda
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  2. Tomomi Ide
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  3. Shun Furusawa
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  4. Kosei Ishimaru
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  5. Tomonori Tadokoro
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  6. Hiroko Deguchi Miyamoto
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  7. Soichiro Ikeda
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  9. Akihito Ishikita
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Contributions

MI, SF, KI, TT, HDM, SI, KO, AI, and KA performed the experiments. MI, TI, SM, and HT interpreted the data obtained from the experiments. MI and TI designed experimental protocols, wrote the manuscript, and prepared the figures. MI and TI conceived the project. HT approved and supervised the project.

Corresponding authors

Correspondence to Masataka Ikeda or Tomomi Ide.

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Conflict of Interest

Masataka Ikeda, Tomomi Ide, Shun Furusawa, Kosei Ishimaru, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Ko Abe, and Shouji Matsushima have nothing to declare. Hiroyuki Tsutsui received honoraria from Otsuka, Takeda Pharmaceutical, Mitsubishi-Tanabe Pharma, Daiichi Sankyo, Nippon Boehringer, Bayer Yakuhin, Pfizer, Novartis Pharma, Ono Pharmaceutical, MSD, Teijin Pharma, Bristol-Myers Squibb, and Astellas Pharma; manuscript fees from Medical View and Nippon Rinsho; and research funding from Nippon Boehringer, Mitsubishi-Tanabe Pharma, Japan Tobacco, Daiichi Sankyo, IQVIA Services Japan, Takeda Pharmaceutical, Bayer Yakuhin, Sanofi, Acterion Pharmaceuticals Japan, and MSD.

Ethics Approval

All procedures involving animals and animal care protocols were approved by the Committee on Ethics of Animal Experiments at the Faculty of Medical Sciences, Kyushu University (A20–021) and were performed in accordance with the Guidelines for Animal Experiments of Kyushu University and the Guideline for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (revised in 2011).

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Ikeda, M., Ide, T., Furusawa, S. et al. Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice. Cardiovasc Drugs Ther 36, 257–262 (2022). https://doi.org/10.1007/s10557-020-07123-5

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