Fractalkine promotes platelet activation and vascular dysfunction in congestive heart failure

Steven K. Hildemann; Christian Schulz; Daniela Fraccarollo; Corinna Schöpp; Ulrike Flierl; Kerstin Wissel; Jaroslav Pelisek; Steffen Massberg; Johann Bauersachs; Andreas Schäfer

doi:10.1160/TH13-08-0640

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(04): 725-735
DOI: 10.1160/TH13-08-0640

Platelets and Blood Cells

Schattauer GmbH

Fractalkine promotes platelet activation and vascular dysfunction in congestive heart failure

Steven K. Hildemann

¹Heart Center Freiburg University, Department of Cardiology and Angiology I, Freiburg-Bad Krotzingen, Germany

,

Christian Schulz

²Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, UK

³CMCBI, Division of Immunology, Infection and Inflammatory Diseases, Guy’s Campus, King’s College London, UK

,

Daniela Fraccarollo

⁵Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany

,

Corinna Schöpp

⁵Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany

,

Ulrike Flierl

⁴Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany

,

Kerstin Wissel

⁵Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany

,

Jaroslav Pelisek

⁶Klinik für Gefäßchirurgie, Klinikum rechts der Isar, Technische Universität München, Germany

,

Steffen Massberg

⁷Medizinische Klinik und Poliklinik I, Klinikum der Universität, Ludwig-Maximilians-Universität, Munich, Germany

⁸DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

,

Johann Bauersachs

⁴Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany

,

Andreas Schäfer

⁴Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany

› Author Affiliations

Abstract

Summary

Endothelial dysfunction and enhanced platelet reactivity in congestive heart failure (CHF) contribute to poor prognosis. CHF patients display an impaired responsiveness to clopidogrel. Fractalkine activates platelets and elevated plasma levels of this chemokine are a feature of CHF. We here addressed the interrelation of fractalkine, platelet reactivity and clopidogrel efficacy in humans and rats with CHF. Fractalkine serum levels determined by ELISA were increased in CHF patients (CHF: 1548 ± 650 pg/ml; Control: 968 ± 575 pg/ml, p<0.01) and following CHF induction in rats (CHF: 1509 ± 753 pg/ ml; Sham: 1181 ± 275 pg/ml, p<0.05). Expression of fractalkine and its receptor CX₃CR1 was enhanced in aortas of CHF rats as determined by immunofluorescence microscopy and molecular analysis. Fractalkine significantly aggravated endothelial dysfunction and augmented P-selectin expression on platelets from CHF rats. Platelet surface expression of CX₃CR1 was increased in CHF rats, who displayed an impaired response to clopidogrel (platelet reactivity to ADP: CHF 30 ± 22%; Sham: 8 ± 5%, p<0.05). Similarly in humans with CHF, elevated fractalkine levels were accompanied by reduced clopidogrel responsiveness. Patients with high on-clopidogrel treatment platelet P2Y₁₂ reactivity displayed higher fractalkine levels (1525 ± 487 pg/ml) than those with sufficient clopidogrel response (684 ± 315 pg/ml, p<0.01). In conclusion, in CHF fractalkine was increased on the endothelium and in blood serum, and platelet surface- expression of CX₃CR1 was enhanced. Fractalkine diminished endothelial function beyond the impairment already observed in CHF and was associated with a reduced responsiveness to the platelet inhibitor clopidogrel. These findings may indicate a novel pathophysiological mechanism contributing to impaired clopidogrel responsiveness in CHF.

Keywords

Fractalkine - chemokines - heart failure - platelets - endothelial dysfunction - clopidogrel

Full Text

References

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