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CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study

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Abstract

Chemokines are involved in the remodeling of the heart; however, their significance as biomarkers in heart failure is unknown. We observed that circulating CXCR3 receptor chemokines CXCL9 and CXCL10 in a rat model of heart failure were increased 1 week after myocardial infarction. CXCL10 was also increased in both remote and infarcted regions of the heart and remained elevated at 16 weeks; CXCL9 was elevated in the remote area at 1 week. In humans, hierarchical clustering and principal component analysis revealed that circulating CXCL10, MIP-1α, and CD40 ligand were the best indicators for differentiating healthy and heart failure subjects. Serum CXCL10 levels were increased in patients with symptomatic heart failure as indexed by NYHA classification II through IV. The presence of CXCL10, MIP-1α, and CD40 ligand appears to be dominant in patients with advanced heart failure. These findings identify a distinct profile of inflammatory mediators in heart failure patients.

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Abbreviations

ACCF/AHA:

American College of Cardiology Foundation/American Heart Association

BNP:

B-type natriuretic peptide

CD40:

Cluster of differentiation 40

CXCL:

Chemokine (C-X-C motif) ligand

CXCR:

Chemokine (C-X-C motif) receptor

FLEMENGHO:

Flemish Study on Environment, Genes, and Health Outcomes

HF:

Heart failure

IFN-γ:

Interferon gamma

IL:

Interleukin

IP-10:

Interferon gamma-induced protein 10

LAD:

Left anterior descending artery

LV:

Left ventricle/ventricular

MCP1:

Monocyte chemoattractant protein 1

MI:

Myocardial infarction

MIF:

Macrophage migration inhibitory factor

MIP-1α:

Macrophage inflammatory protein-1 alpha

NYHA:

New York Heart Association

NT-proBNP:

N-terminal of the prohormone brain natriuretic peptide

PCA:

Principal component analysis

SDF1:

Stromal cell-derived factor 1

TIMP-1:

Tissue inhibitor of metalloproteinases-1

TNFα:

Tumor necrosis factor alpha

TRIUMPH:

TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure

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Acknowledgments

The authors would like to thank Dr. F.A. Zouein for the thoughtful discussion on this study. We are appreciative of the outstanding contribution of Dr. Joke Orsel in helping with the ELISA assay.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

    Raffaele Altara, Harry A. J. Struijker-Boudier & W. Matthijs Blankesteijn

  2. Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA

    Raffaele Altara & George W. Booz

  3. DG-DI, Medical Applications, CERN, Geneva, Switzerland

    Marco Manca

  4. Leiden University Medical Center, Leiden, The Netherlands

    Marleen H. Hessel

  5. Studies Coordinating Centre, Research Unit Hypertension, Leuven, Belgium

    Yumei Gu & Jan A. Staessen

  6. Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium

    Yumei Gu & Jan A. Staessen

  7. Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands

    Laura C. van Vark & K. Martijn Akkerhuis

Authors
  1. Raffaele Altara
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Corresponding author

Correspondence to Raffaele Altara.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Human Subjects/Informed Consent

The recruitment of subjects was performed according to the Medical Ethical Committees of Groningen and Maastricht University, The Netherlands, and in accordance with of the Declaration of Helsinki of 1975.

Animal Studies

All experimental and surgical procedures were approved by the Institutional Council on Animal Care and Use of the Maastricht University and complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Sources of Funding

This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project TRIUMPH grant 01C-103, and supported by the Dutch Heart Foundation.

Additional information

Associate Editor Enrique Lara-Pezzi oversaw the review of this article

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

Shown are the cytokines that were most increased in terms of fold-change for heart failure patients enrolled in the TRIUMPH cohort compared to healthy individuals. Serum levels of the cytokines were analyzed by multiplex membrane-based immunoassay. (PDF 80 kb)

Supplementary Figure 2

A scatter plot showing the correlation between the ELISA and membrane-based assay for CXCL10 determination in TRIUMPH patients. (PDF 36 kb)

Supplementary Figure 3a

No difference was observed between ischemic and non-ischemic heart failure patients enrolled in the TRIUMPH cohort in either (A) CXCL10 or (B) NT-proBNP levels. Data are shown as box and whiskers plots according to the Tukey method. (PDF 39 kb)

Supplementary Figure 3b

(PDF 41 kb)

Supplementary Table 1

Shown are the loading values for component 1 and 2 determined from the principal component analysis of the circulating inflammatory profile of heart failure patients from the TRIUMPH cohort compared to healthy subjects. (DOCX 23 kb)

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Altara, R., Manca, M., Hessel, M.H. et al. CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study. J. of Cardiovasc. Trans. Res. 9, 302–314 (2016). https://doi.org/10.1007/s12265-016-9703-3

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