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AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs

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Abstract

Purpose

Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective.

Method

To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6 weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14 days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group).

Results

In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-β1 expression and increases in AKT phosphorylation.

Conclusions

IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.

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Acknowledgments

The authors thank Mrs. Yuki Hamada for their technical assistance. We also thank the collaborative work with Adsorptive Medicine Technology Center at KUREHA Corporation.

Sources of Funding

This work was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare, Japan; grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan; grants-in-aid from Japan Agency for Medical Research and Development, AMED; and grants from the Japan Heart Foundation and Grants from the Japan Cardiovascular Research Foundation for M. Kitakaze. This work is also supported by grants-in-aid of the collaborative research with Kureha Corporation and Mitsubishi Tanabe Pharma Corporation for M. Kitakaze.

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Authors and Affiliations

  1. Department of Internal Medicine, Meiji University of Integrative Medicine, Kyoto, Japan

    Hiroshi Asanuma

  2. Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan

    Hiroshi Asanuma & Masaru Sugimachi

  3. Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan

    Hyemoon Chung & Hiroko Takahama

  4. Division of Cardiology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Hyemoon Chung

  5. Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, 5-7-1, Fujishirodai, Osaka, Suita, 565-8565, Japan

    Shin Ito, Kyung-Duk Min, Madoka Ihara, Hiroko Takahama, Marina Funayama, Miki Imazu, Hiroki Fukuda, Akiko Ogai, Masanori Asakura & Masafumi Kitakaze

  6. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Yoshihiro Asano

  7. Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Takamatsu, Kagawa, Japan

    Tetsuo Minamino

  8. Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Osaka, Japan

    Seiji Takashima

  9. Department of Laboratory Medicine, Toho University Faculty of Medicine, Tokyo, Japan

    Toshisuke Morita

  10. Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Masanori Asakura

  11. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan

    Masafumi Kitakaze

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  1. Hiroshi Asanuma
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Corresponding author

Correspondence to Masafumi Kitakaze.

Ethics declarations

All procedures complied with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (the 8th Edition, NRC 2011) and were approved by the National Cerebral and Cardiovascular Center Committee for Laboratory Animal Use.

Conflict of Interest

T. Morita reports grants from LSI Medience, AMNOS Company, UNITIKA, and TED Pharmaceutical Co. M. Asakura reports grants from the government during the conduct of the study, personal fees and non-financial support from Pfizer, and personal fees from Boehringer-Ingerheim, Mitsubishi-Tanabe, Kowa, and Takeda. M. Kitakaze reports grants from the Japanese government;grants from Japan Heart Foundation; grants from Japan Cardiovascular Research Foundation; grants and personal fees from Takeda, Asteras, Sanofi, Pfizer, Novartis, Boehringer-Ingerheim, Mitsubishi-Tanabe, Kyowa-Hakko-Kirin, Abott, and Otsuka; personal fees from Daiichi-Sankyo, Ono, Bayer, from Kowa, Dainihon-Sumitomo, Sawai, MSD, Calpis, Shionogi, AstraZeneca, Asahikasei, Novo Nordisk, Fuji-film RI, and Japan Medical Data; and grants from Nihon Kohden.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Supplementary Figure 1.

Western Blot Analysis of Canine Hearts at 6 weeks. Top panels: representative Western blots for p-AKT, AKT, p-ERK, ERK, TGF-β1, GAPDH, Bcl-2, and Bax in control, sham, and AST-120 groups (n = 2). Bottom panels: Densitometric analysis of the individual immunoblots (n = 2). (PNG 894 kb)

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Asanuma, H., Chung, H., Ito, S. et al. AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs. Cardiovasc Drugs Ther 33, 277–286 (2019). https://doi.org/10.1007/s10557-019-06875-z

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