Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling
Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase (MPO), 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 MPO for the development of ventricular arrhythmias.
Methods and Results: In different murine models of myocardial ischemia MPO deficiency profoundly decreased vulnerability for ventricular tachycardia (VT) upon programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry following isoproterenol injection. Experiments employing CD11b/CD18-integrin-deficient (CD11b -/-) mice and intravenous MPO infusion revealed that neutrophil infiltration is a prerequisite for myocardial MPO accumulation. Ventricles from MPO-deficient (Mpo-/-) mice showed less pronounced slowing and decreased heterogeneity of electrical conduction in the periinfarct zone than WT mice. Expression of the redox sensitive gap-junctional protein connexin43 (Cx43) was reduced in the periinfarct area of WT compared to Mpo-/- mice. In isolated WT cardiomyocytes, Cx43 protein content decreased upon MPO/H2O2-incubation. Mapping of induced pluripotent stem-cell-derived cardiac myocyte (iPSCM) networks and in vivo investigations linked Cx43 breakdown to MPO-dependent activation of matrix-metalloproteinase 7. Moreover, Mpo-/- mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, MPO was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases (MAPK) resulting in upregulated collagen generation. In support of our experimental findings, baseline MPO 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 above 35% undergoing elective diagnostic cardiac evaluation.
Conclusions: MPO emerges as a crucial mediator of post-ischemic myocardial remodeling, and may evolve as a novel pharmacological target for secondary disease prevention following myocardial ischemia.
- Received February 21, 2017.
- Revision received March 20, 2017.
- Accepted April 11, 2017.