Abstract
Elevated phenylalanine has been observed in patients with advanced heart failure (HF) and in community cohorts at risk of HF, and has been shown to have prognostic value. This study aimed to explore the factors associated with elevated phenylalanine in HF patients. Mass spectrometry was performed on blood from 669 participants, including 75 normal controls and 594 HF patients (stages A, B, and C). We measured phenylalanine and associated degradation products on the catecholamine pathway, C-reactive protein, valerylcarnitine, methionine sulfoxide, estimated glomerular filtration rate (eGFR), and B-type natriuretic peptide. Longitudinal analysis was conducted on 61 stage C HF patients who had recovered systolic function after 1 year. Phenylalanine and tyrosine levels increased from normal through stages A, B and C. Cross-sectional analysis in patients at stage C showed that phenylalanine levels were related to total bilirubin, eGFR, valerylcarnitine, methionine sulfoxide, C-reactive protein, and male gender. Longitudinal analysis in the patients at stage C with recovered systolic function after 1 year revealed that phenylalanine, tyrosine, methionine sulfoxide, total bilirubin, and C-reactive protein levels significantly decreased from baseline to 12 months. Based on a generalized estimating equations analysis model with time interaction considered, the only significant factor associated with changes in phenylalanine was changes in C-reactive protein concentrations from baseline to 12 months [B (coefficient) = 0.81, P < 0.001] after adjusting for methionine sulfoxide and total bilirubin levels. In conclusion, phenylalanine levels respond sensitively to HF improvement. Our findings suggest that inflammation plays a pivotal role in the elevation of phenylalanine levels in patients with HF.
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Abbreviations
- BH4:
-
Tetrahydrobiopterin
- BNP:
-
B-type natriuretic peptide
- C5:
-
Valerylcarnitine
- CI:
-
Confidence interval
- CRP:
-
C-reactive protein
- eGFR:
-
Estimated glomerular filtration rate
- FIA:
-
Flow injection analysis
- HF:
-
Heart failure
- LC/MS:
-
Liquid chromatography/mass spectrometry
- LVEF:
-
Left ventricular ejection fraction
- Met-SO:
-
Methionine sulfoxide
- Phe:
-
Phenylalanine
- Tyr:
-
Tyrosine
- UPLC:
-
Ultra-performance liquid chromatography
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Acknowledgements
We thank Healthy Aging Research Center, Chang Gung University from the Featured Areas Research Center Program within the Framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan.
Funding
This study was supported in part by the Ministry of Science and Technology of Taiwan (MOST107-2314-B-182-071-MY2); Chang Gung Memorial Hospital (CMRPG2G0601, 2G0611, 2G0641, CORPG2J0021, CORPG2J0012); and the Ministry of Education of Taiwan (EMRPD1G0251, EMRPD1H0401).
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H-YT and M-LC contributed the methodology clarification and analysis details, and provided new information and interpretation about the precision and accuracy of all metabolites. They approved the version to be published, and agree to be accountable for the accuracy or integrity of the work appropriately investigated and resolved.
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This study was designed and carried out in accordance with the principles of the 1964 Declaration of Helsinki and with approval from the Ethics Review Board of Chang Gung Memorial Hospital. This article does not contain any studies with animals performed by any of the authors.
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Cheng, CW., Liu, MH., Tang, HY. et al. Factors associated with elevated plasma phenylalanine in patients with heart failure. Amino Acids 53, 149–157 (2021). https://doi.org/10.1007/s00726-020-02933-1
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DOI: https://doi.org/10.1007/s00726-020-02933-1