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Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation

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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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.

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Correspondence to Stephan Baldus.

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The authors declare no competing financial interests.

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Supplementary Figs. 1–5 and Supplementary Tables 1–3 (PDF 3532 kb)

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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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