Amino Acids

, Volume 50, Issue 12, pp 1739–1748 | Cite as

Simplified plasma essential amino acid-based profiling provides metabolic information and prognostic value additive to traditional risk factors in heart failure

  • Chao-Hung WangEmail author
  • Mei-Ling Cheng
  • Min-Hui Liu
Original Article


In heart failure (HF), metabolic disturbances represent functional perturbations in peripheral tissues and also predict patient outcomes. This study developed a simplified essential amino acid-based profile and tested whether it could improve prognostication. Plasma essential amino acids and lipidomics were measured on 1084 participants. The initial cohort included 94 normal controls and 599 patients hospitalized due to acute/decompensated HF. The validation cohort included 391 HF patients. Patients were followed for composite events (death/HF related re-hospitalization) and were categorized into three groups: high risk type 1 (leucine ≥145 μM and phenylalanine ≥ 88.9 μM), high risk type 2 (leucine < 81.2 μM), and low risk (other). Types 1 and 2 were associated with higher event rates [hazard ratio (95% confidence intervals) = 1.88 (1.27–2.79) and 7.71 (4.97–11.9), respectively, p < 0.001]. Compared to the low-risk group, both types of high-risk patients were older and had lower blood pressure and estimated glomerular filtration rates, but higher B-type natriuretic peptides (BNP). In addition, type 1 was associated with more incompletely metabolized lipids in the blood; type 2 patients had lower body mass indexes, rates of using guideline-based medications, and levels of cholesterol, hemoglobin, and albumin. The prognostic value of types 1 and 2 remained significant after adjusting for age, BNP and other risk factors. The value of using high-risk types for prognosis was confirmed in the validation cohort. In conclusion, simplified essential amino acid-based profiling identified two high-risk populations and provided metabolic information and prognostic value additive to traditional risk factors.


Heart failure Metabolomics Amino acid Prognosis B-type natriuretic peptide 



B-type natriuretic peptide


Confidence interval


Estimated glomerular filtration rate


Hazard ratio


Heart failure




Left ventricular ejection fraction




Receiver operating characteristic curve


Ultra-performance liquid chromatography



The authors thank Cardiology Section, Department of Internal Medicine, Chang Gung Memorial Hospital, Keeling, Taiwan for providing samples from patients and normal controls. We also 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.


This study was supported in part by the Ministry of Science and Technology of Taiwan (MOST105-2314-B-182-046-MY2, 107-2314-B-182-071-MY2); Chang Gung Memorial Hospital (CMRPG2C0313, G2E0351, G2G0601, G2G0581); and the Ministry of Education of Taiwan (EMRPD1G0251, EMRPD1H0401).

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

726_2018_2649_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1077 kb)


  1. Ahmad T, Kelly JP et al (2016) Prognostic implications of long-chain acylcarnitines in heart failure and reversibility with mechanical circulatory support. J Am Coll Cardiol 67(3):291–299CrossRefGoogle Scholar
  2. Aquilani R, La Rovere MT et al (2012) Preserved muscle protein metabolism in obese patients with chronic heart failure. Int J Cardiol 160(2):102–108CrossRefGoogle Scholar
  3. Cheng ML, Wang CH et al (2015) Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics. J Am Coll Cardiol 65(15):1509–1520CrossRefGoogle Scholar
  4. Chioncel O, Collins SP et al (2016) Natriuretic peptide-guided management in heart failure. J Cardiovasc Med 17(8):556–568CrossRefGoogle Scholar
  5. Frank MP, Powers RW (2007) Simple and rapid quantitative high-performance liquid chromatographic analysis of plasma amino acids. J Chromatogr B Analyt Technol Biomed Life Sci 852(1–2):646–649CrossRefGoogle Scholar
  6. Griffin JL, Atherton H et al (2011) Metabolomics as a tool for cardiac research. Nat Rev Cardiol 8(11):630–643CrossRefGoogle Scholar
  7. Hakuno D, Hamba Y et al (2015) Plasma amino acid profiling identifies specific amino acid associations with cardiovascular function in patients with systolic heart failure. PLoS One 10(2):e0117325CrossRefGoogle Scholar
  8. Hunter WG, Kelly JP et al (2016) Metabolic dysfunction in heart failure: diagnostic, prognostic, and pathophysiologic insights from metabolomic profiling. Curr Heart Fail Rep 13(3):119–131CrossRefGoogle Scholar
  9. Lavie CJ, Berra K et al (2013) Formal cardiac rehabilitation and exercise training programs in heart failure: evidence for substantial clinical benefits. J Cardiopulm Rehabil Prev 33(4):209–211CrossRefGoogle Scholar
  10. Liu Z, Barrett EJ (2002) Human protein metabolism: its measurement and regulation. Am J Physiol Endocrinol Metab 283(6):E1105–E1112CrossRefGoogle Scholar
  11. Maisel AS, Clopton P et al (2004) Impact of age, race, and sex on the ability of B-type natriuretic peptide to aid in the emergency diagnosis of heart failure: results from the breathing not properly (BNP) multinational study. Am Heart J 147(6):1078–1084CrossRefGoogle Scholar
  12. Nagabhushan VS, Narasinga Rao BS (1978) Studies on 3-methylhistidine metabolism in children with protein-energy malnutrition. Am J Clin Nutr 31(8):1322–1327CrossRefGoogle Scholar
  13. Nishijima Y, Sridhar A et al (2011) Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology. Cardiovasc Res 91(1):71–79CrossRefGoogle Scholar
  14. Pappa-Louisi A, Nikitas P et al (2007) Optimization of separation and detection of 6-aminoquinolyl derivatives of amino acids by using reversed-phase liquid chromatography with on line UV, fluorescence and electrochemical detection. Anal Chim Acta 593(1):92–97CrossRefGoogle Scholar
  15. Rajadurai J, Tse HF et al (2017) Understanding the epidemiology of heart failure to improve management practices: An Asia-Pacific Perspective. J Card Fail 23(4):327–339CrossRefGoogle Scholar
  16. Rehman SU, Mueller T et al (2008) Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 52(18):1458–1465CrossRefGoogle Scholar
  17. Reid C (2006) Frequency of under- and overfeeding in mechanically ventilated ICU patients: cause and possible consequences. J Hum Nutr Diet 19(1):13–22CrossRefGoogle Scholar
  18. Savarese G, Lund LH (2017) Global public health burden of heart failure. Card Fail Rev 3(1):7–11CrossRefGoogle Scholar
  19. Schooneman MG, Vaz FM et al (2013) Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62(1):1–8CrossRefGoogle Scholar
  20. Sperry BW, Ruiz G et al (2015) Hospital readmission in heart failure, a novel analysis of a longstanding problem. Heart Fail Rev 20(3):251–258CrossRefGoogle Scholar
  21. Wang CH, Yang NI et al (2016) Estimating systemic fibrosis by combining galectin-3 and ST2 provides powerful risk stratification value for patients after acute decompensated heart failure. Cardiol J 23(5):563–572PubMedGoogle Scholar
  22. Wang CH, Cheng ML et al (2017) Metabolic profile provides prognostic value better than galectin-3 in patients with heart failure. J Cardiol 70(1):92–98CrossRefGoogle Scholar
  23. Ziolo MT, Maier LS et al (2004) Myocyte nitric oxide synthase 2 contributes to blunted beta-adrenergic response in failing human hearts by decreasing Ca2+ transients. Circulation 109(15):1886–1891CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Heart Failure Research Center, Division of Cardiology, Department of Internal MedicineChang Gung Memorial HospitalKeelungTaiwan
  2. 2.Chang Gung University College of MedicineTaoyuanTaiwan
  3. 3.Metabolomics Core Laboratory, Healthy Aging Research CenterChang Gung UniversityTaoyuanTaiwan
  4. 4.Department and Graduate Institute of Biomedical Sciences, College of MedicineChang Gung UniversityTaoyuanTaiwan
  5. 5.Clinical Metabolomics Core LaboratoryLinkou Chang Gung Memorial HospitalTaoyuanTaiwan
  6. 6.Department of NursingNational Yang-Ming UniversityTaipeiTaiwan

Personalised recommendations