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Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation

Nature Medicine volume 16, pages 470–474 (2010)Cite this article

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Abstract

Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation1. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.

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Figure 1: Mpo−/− mice show less atrial fibrosis, reduced matrix metalloproteinase activity and lower chlorotyrosine bioavailability after AngII treatment.
Figure 2: Analysis of atrial fibrillation inducibility in Mpo−/− and WT mice in vivo.
Figure 3: Epicardial mapping of Langendorff-perfused hearts of AngII- or saline (vehicle)-treated WT or Mpo−/− mice.
Figure 4: Atrial MPO amounts and protein-bound 3-chlorotyrosine in individuals with or without atrial fibrillation.

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Acknowledgements

We wish to thank H. Wieboldt for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (BA 1870/3-2 and BA 1870/7-1 to S.B., Ru 1472/1-1 to T.K.R. and SFB-TR19 to K.K.), the US National Institutes of Health (P01 HL076491-055328 and P01 HL087018-02001 to S.H.), the Deutsche Herzstiftung (to V.R. and R.P.A.) and the Werner Otto Stiftung (to S.B.).

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  1. Volker Rudolph and René P Andrié: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of General and Interventional Cardiology and Cardiovascular Research Center, University Heart Center, Hamburg, Germany

    Volker Rudolph, Tanja K Rudolph, Kai Friedrichs, Anna Klinke, Denise Lau, Karsten Sydow, Eike-Christin von Leitner, Katalin Szoecs, Thomas Meinertz, Stephan Willems & Stephan Baldus

  2. Department of Medicine–Cardiology, University of Bonn, Bonn, Germany

    René P Andrié, Jan W Schrickel, Thorsten Lewalter & Georg Nickenig

  3. Department of Physiology, University Hospital Eppendorf, Hamburg, Germany

    Birgit Hirsch-Hoffmann, Alexander P Schwoerer, Anika Seniuk & Heimo Ehmke

  4. Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio, USA

    XiaoMing Fu & Stanley L Hazen

  5. Department of Molecular Pathology, Institute for Pathology, University Hospital Tübingen, Tübingen, Germany

    Karin Klingel

  6. Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Eppendorf, Hamburg, Germany

    Michael Didié, Wolfram-Hubertus Zimmermann, Rainer H Böger & Thomas Eschenhagen

  7. Department of Pharmacology, Georg-August University Göttingen, Göttingen, Germany

    Michael Didié & Wolfram-Hubertus Zimmermann

  8. Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany

    Hendrik Treede & Hermann Reichenspurner

  9. Department of Medicine, Division of Nephrology, University Hospital Eppendorf, Hamburg, Germany

    Ulrich Wenzel

  10. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Bruce A Freeman

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  1. Volker Rudolph
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Contributions

V.R. designed the project, performed experiments, performed statistical analysis and wrote the manuscript. T.K.R. performed experiments and prepared the manuscript. K.F., A.K., K. Sydow, D.L., E.-C.v.L. and K. Szoecs performed experiments. R.P.A., J.W.S., T.L. and G.N. were responsible for the design and the performance of the electrophysiological studies in mice. B.H.-H., A.P.S., A.S. and H.E. were responsible for the radiotelemetric measurements in mice and cellular electrophysiology. X.F. and S.L.H. were responsible for mass spectrometry analysis. M.D. performed the echocardiography in mice. H.T. provided human atrial tissue. K.K. was responsible for the fibrosis analysis. U.W., W.-H.Z., R.H.B., H.R., T.M., T.E., H.E., S.L.H., B.A.F. and S.W. provided suggestions on the project and revised the manuscript. S.B. supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Stephan Baldus.

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The authors declare no competing financial interests.

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Rudolph, V., Andrié, R., Rudolph, T. et al. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 16, 470–474 (2010). https://doi.org/10.1038/nm.2124

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