Theranostics 2018; 8(15):4155-4169. doi:10.7150/thno.26055 This issue

Research Paper

Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production

Weijie Du1,2*, Arnold Piek1*, E. Marloes Schouten1, Cees W.A. van de Kolk1, Christian Mueller3, Alexandre Mebazaa4,5, Adriaan A. Voors1, Rudolf A. de Boer1✉, Herman H.W. Silljé1✉

1. Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands
2. Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
3. Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
4. Research Medical Unit, INSERM, U-942, 'BIOmarkers in CArdioNeuroVAScular diseases', Paris, France.
5. Université Paris VII-Denis Diderot, Assistance Publique-Hôpitaux de Paris, Paris, France.Department of Anesthesiology and Critical Care Medicine, AP-HP, Saint Louis Lariboisière University Hospitals, Paris, France.
*Equal contribution

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Du W, Piek A, Schouten EM, van de Kolk CWA, Mueller C, Mebazaa A, Voors AA, de Boer RA, Silljé HHW. Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production. Theranostics 2018; 8(15):4155-4169. doi:10.7150/thno.26055. Available from

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Graphic abstract

Plasma heart failure (HF) biomarkers, like natriuretic peptides, are important in diagnosis, prognosis and HF treatment. Several novel HF biomarkers have been identified, including Gal-3, GDF-15 and TIMP-1, but their clinical potential remains vague. Here we investigated plasma biomarker levels in relation to tissue expression and structural and functional cardiac changes.

Methods: Cardiac remodeling, cardiac function, and plasma and tissue biomarker levels were investigated in mice after myocardial infarction induced by temporal and permanent LAD ligation (tLAD and pLAD). In addition, a pressure overload model induced by transverse aortic constriction (TAC) and an obese/hypertensive HFpEF-like mouse model were investigated.

Results: Plasma levels of ANP and its cardiac expression were strictly associated with cardiac remodeling and function. Gal-3, GDF-15 and TIMP-1 cardiac expressions were also related to cardiac remodeling and function, but not their plasma levels. Only directly after myocardial infarction could elevated plasma levels of Gal-3 and TIMP-1 be detected. Eight weeks after infarction, plasma levels were not elevated despite enhanced cardiac expression and low EF (18.3±3.3%, pLAD). Plasma levels of TIMP-1 and GDF-15 were elevated after TAC, but this also correlated with increased lung expression and congestion. In obese-hypertensive mice, elevated plasma levels of Gal-3, GDF-15 and TIMP1 were associated with increased adipose tissue expression and not with cardiac function.

Conclusions: The Gal-3, GDF-15 and TIMP-1 plasma pool levels are hardly influenced by dynamic changes in cardiac expression. These biomarkers are not specific for indices of cardiac remodeling, but predominantly reflect stress in other affected tissues and hence provide health information beyond the heart.

Keywords: heart failure, cardiac remodeling, biomarker, Galectin-3, GDF-15, TIMP-1