Mollenhauer, Martin, Friedrichs, Kai, Lange, Max, Gesenberg, Jan ORCID: 0000-0003-1279-8104, Remane, Lisa, Kerkenpass, Christina, Krause, Jenny, Schneider, Johanna, Ravekes, Thorben, Maass, Martina, Halbach, Marcel, Peinkofer, Gabriel, Saric, Tomo, Mehrkens, Dennis ORCID: 0000-0002-8578-0290, Adam, Matti ORCID: 0000-0002-6990-8135, Deuschl, Florian G., Lau, Denise, Geertz, Birgit, Manchanda, Kashish, Eschenhagen, Thomas, Kubala, Lukas ORCID: 0000-0002-7729-7338, Rudolph, Tanja K., Wu, Yuping, Tang, W. H. Wilson, Hazen, Stanley L., Baldus, Stephan, Klinke, Anna and Rudolph, Volker (2017). Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. Circ.Res., 121 (1). S. 56 - 97. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4571

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Abstract

Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b(-/-)) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo(-/-)) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wildtype mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo(-/-) mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2 incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo(-/-) mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation. Conclusions: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mollenhauer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedrichs, KaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lange, MaxUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gesenberg, JanUNSPECIFIEDorcid.org/0000-0003-1279-8104UNSPECIFIED
Remane, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerkenpass, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ravekes, ThorbenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maass, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halbach, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peinkofer, GabrielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saric, TomoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehrkens, DennisUNSPECIFIEDorcid.org/0000-0002-8578-0290UNSPECIFIED
Adam, MattiUNSPECIFIEDorcid.org/0000-0002-6990-8135UNSPECIFIED
Deuschl, Florian G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lau, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geertz, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manchanda, KashishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eschenhagen, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubala, LukasUNSPECIFIEDorcid.org/0000-0002-7729-7338UNSPECIFIED
Rudolph, Tanja K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, YupingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, W. H. WilsonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hazen, Stanley L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-227463
DOI: 10.1161/CIRCRESAHA.117.310870
Journal or Publication Title: Circ.Res.
Volume: 121
Number: 1
Page Range: S. 56 - 97
Date: 2017
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1524-4571
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MYOCARDIAL-INFARCTION; ISCHEMIA; CONDUCTION; NEUTROPHIL; ACTIVATION; MECHANISM; CELLS; TACHYARRHYTHMIAS; ASSOCIATION; ARRHYTHMIASMultiple languages
Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular DiseaseMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22746

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