Author + information
- Received August 2, 2017
- Revision received August 20, 2017
- Accepted August 20, 2017
- Published online December 25, 2017.
- Masanobu Ishii, MDa,
- Koichi Kaikita, MD, PhDa,∗ (, )
- Koji Sato, MD, PhDa,
- Daisuke Sueta, MD, PhDa,
- Koichiro Fujisue, MD, PhDa,
- Yuichiro Arima, MD, PhDa,
- Yu Oimatsu, MDa,
- Tatsuro Mitsuse, MDa,
- Yoshiro Onoue, MD, PhDa,
- Satoshi Araki, MD, PhDa,
- Megumi Yamamuro, MD, PhDa,
- Taishi Nakamura, MD, PhDa,
- Yasuhiro Izumiya, MD, PhDa,
- Eiichiro Yamamoto, MD, PhDa,
- Sunao Kojima, MD, PhDa,
- Shokei Kim-Mitsuyama, MD, PhDb,
- Hisao Ogawa, MD, PhDc and
- Kenichi Tsujita, MD, PhDa
- aDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- bDepartment of Pharmacology and Molecular Therapeutics, Kumamoto University, Kumamoto, Japan
- cDepartment of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
- ↵∗Address for correspondence:
Dr. Koichi Kaikita, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
• Although the long-term effects of LCZ696 (sacubitril/valsartan) on cardiac dysfunction have been previously elucidated, the short-term effects on acute phase after acute MI is unknown.
• Wild-type mice subjected to ligation of left anterior descending artery were randomly allocated to the vehicle, enalapril, or LCZ696 group 1 day after MI, resulting in the belief that LCZ696 could prevent cardiac rupture compared to the vehicle, whereas there was no significant difference in rate of cardiac rupture-free survival in the enalapril compared to the vehicle.
• At 3 days after MI, the expression of interleukin-1β, interleukin-6, matrix MMP-9 mRNA and MMP-9 activity in the infarcted myocardium were significantly lower, plasma aldosterone levels were significantly lower, and cGMP levels were significantly higher, in the LCZ696 than the other groups.
• In vitro assay using peritoneal macrophages found that the combination of valsartan plus LBQ657 (active form of sacubitril) reduced the LPS-induced gelatinolytic activity and MMP-9 mRNA expression of macrophages.
• LCZ696 could suppress pro-inflammatory cytokines and extracellular matrix degradation in macrophages, and provides protection against post-MI cardiac rupture in mice.
LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.
Supported in part by Novartis Pharma AG. Dr. Kaikita has received grants from Bayer Yakuhin, Ltd., Daiichi-Sankyo Co., Ltd., Novartis Pharma AG., and SBI Pharma K.K.; and honoraria from Bayer Yakuhin, Ltd., and Daiichi-Sankyo Co., Ltd. Dr. Ogawa has received grants from Astellas BioPharma K.K., Dainippon Sumitimo Pharma Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Genzyme Japan K.K., Kissei Pharmaceutical Co., Ltd., Abbott Vascular Japan, Boston Scientific Japan K.K., Fukuda Denshi Co., Ltd., Johnson & Johnson, Medtronic Japan Co., Ltd., Nihon Kohden, and Terumo; personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan, Kowa Co., Ltd., and Kyowa Hakko Kirin Co., Ltd.; grants and personal fees from Bayer Yakuhin, Ltd., Bristol-Myers Squibb Co., Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma, MSD K.K., Pfizer Japan Inc., Sanofi K.K., Shionogi Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Co., Ltd. Dr. Tsujita has received honoraria from Amgen, Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Daiichi-Sankyo Co., Ltd., MSD K.K., and Sanofi K.K.; and has received grants from AstraZeneca K.K., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Boston Scientific Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Kowa Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma, MSD K.K., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., and Takeda Pharmaceutical Co., Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 2, 2017.
- Revision received August 20, 2017.
- Accepted August 20, 2017.
- 2017 The Authors