Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling

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Circulation Research


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 wild-type 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.


This work was supported by the Deutsche Forschungsgemeinschaft (KL 2516/1-1 to A. Klinke; BA 1870/7-1, BA 1870/9-1, and BA 1870/10–1 to S. Baldus; AD 492/1-1 to M. Adam; RU 1876/1-1 and RU 1876/3-1 to V. Rudolph); The Ministry of Education, Youth and Sports CR (the National Program of Sustainability II No. LQ1605 to L. Kubala); and the Center for Molecular Medicine Cologne funding (Baldus 2-GA and B-02). The GeneBank studies were supported by National Institutes of Health grants P01HL076491, R01HL126827, and the Cleveland Clinic Clinical Research Unit of the Case Western Reserve University CTSA (UL1TR 000439).

Original Citation

M. Mollenhauer et al., “Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular RemodelingNovelty and Significance,” Circulation Research, vol. 121, no. 1, pp. 56–70, Jun. 2017.