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Prognostic value of leucine/phenylalanine ratio as an amino acid profile of heart failure

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Abstract

Heart failure (HF) causes a hypercatabolic state that enhances the catabolic activity of branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in the heart and skeletal muscles and reduces protein synthesis in the liver. Consequently, free plasma aromatic amino acids (AAA, tyrosine and phenylalanine) are increased. To date, we have reported the prognostic value of the BCAA/AAA ratio (Fischer’s ratio) in patients with HF. However, the leucine/phenylalanine ratio, which is a simpler index than the Fischer’s ratio, has not been examined. Therefore, the prognostic value of the leucine/phenylalanine ratio in patients with HF was investigated. Overall 157 consecutive patients hospitalized for worsening HF (81 men, median age 78 years) were enrolled in the study. Plasma amino acid levels were measured when the patients were stabilized at discharge. Cardiac events were defined as a composite of cardiac death and hospitalization for worsening HF. A total of 46 cardiac events occurred during the median follow-up period of 238 (interquartile range 93–365) days. The median leucine/phenylalanine ratio was significantly lower in patients with cardiac events than in those without cardiac events (1.4 vs. 1.8, P < 0.001). The best cutoff value of the leucine/phenylalanine ratio was determined as 1.7 in the receiver operating characteristic (ROC) curve for cardiac events. Following a Kaplan–Meier survival analysis, the low group (leucine/phenylalanine ratio < 1.7, n = 72) had more cardiac events than the high group (leucine/phenylalanine ratio ≥ 1.7, n = 85) (log-rank, P < 0.001). Multivariate Cox proportional hazards regression analysis showed that the leucine/phenylalanine ratio was an independent predictor of cardiac events. Furthermore, on comparing the prognostic values for cardiac events based on ROC curves of leucine levels, BCAA levels, Fischer’s ratio, and leucine/phenylalanine ratio, the leucine/phenylalanine ratio was the most accurate in predicting future cardiac events (area under the curve 0.763,; sensitivity 0.783,; specificity 0.676,; P < 0.001). The leucine/phenylalanine ratio could be a useful predictor of future cardiac events in patients with HF, reflecting an imbalance in amino acid metabolism.

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Acknowledgments

H.H., T.O., T. Kondo, and T. Kato conceived and designed this study. S. Kazama, T.I., E.I., M.S., S. Kondo, S.A., Yasunori Kanzaki, D.T., H.S., and Y.A. collected and analyzed data. H.H., T.O., T. Kondo, T. Kato, Yuki Kimura, S.Y., and T.M. interpreted the results. H.H., T.O., and T.M. drafted the manuscript.

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Authors and Affiliations

  1. Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan

    Hiroaki Hiraiwa, Takahiro Okumura, Toru Kondo, Shingo Kazama, Yuki Kimura, Toshikazu Ishihara, Etsuo Iwata, Masafumi Shimojo & Toyoaki Murohara

  2. Department of Cardiology, Nagoya Ekisaikai Hospital, Nagoya, Japan

    Hiroaki Hiraiwa, Toshiaki Kato, Sayano Kondo, Soichiro Aoki, Yasunori Kanzaki, Daisuke Tanimura, Hiroaki Sano & Yoshifumi Awaji

  3. Department of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Sumio Yamada

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  1. Hiroaki Hiraiwa
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Correspondence to Takahiro Okumura.

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Conflict of interest

T.O. received research grants from Ono Pharmaceutical Co., Ltd., Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Pharma Inc., and Amgen Astellas BioPharma K.K. outside the submitted work. T.O. received honorariums from Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Medtronic Japan Co., Ltd. T.M. received lecture fees from Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Pfizer Japan Inc., Sanofi-Aventis K. K., and Takeda Pharmaceutical Co., Ltd. T.M. received an unrestricted research grant from the Department of Cardiology, Nagoya University Graduate School of Medicine from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Otsuka Pharma Ltd., Pfizer Japan Inc., Sanofi-Aventis K. K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. The remaining authors declare that there are no conflicts of interest.

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Hiraiwa, H., Okumura, T., Kondo, T. et al. Prognostic value of leucine/phenylalanine ratio as an amino acid profile of heart failure. Heart Vessels 36, 965–977 (2021). https://doi.org/10.1007/s00380-020-01765-z

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