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Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling.

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 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.

SUBMITTER: Mollenhauer M

PROVIDER: S-EPMC5482785 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling.

Mollenhauer Martin M Friedrichs Kai K Lange Max M Gesenberg Jan J Remane Lisa L Kerkenpaß Christina C Krause Jenny J Schneider Johanna J Ravekes Thorben T Maass Martina M Halbach Marcel M Peinkofer Gabriel G Saric Tomo T Mehrkens Dennis D Adam Matti M Deuschl Florian G FG Lau Denise D Geertz Birgit B Manchanda Kashish K Eschenhagen Thomas T Kubala Lukas L Rudolph Tanja K TK Wu Yuping Y Tang W H Wilson WHW Hazen Stanley L SL Baldus Stephan S Klinke Anna A Rudolph Volker V

Circulation research 20170412 1

<h4>Rationale</h4>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.<h4>Objective</h4>To reveal the role of myeloperoxidase for the development of ventricular arrhythmias.<h4>Methods and results</h4>In different murine models of myocardial ischemia, myeloperoxidase deficiency ...[more]

PMID: 28404615

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Project description:RationaleMitochondrial Ca2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+ overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The MCU (mitochondrial Ca2+ uniporter) mediates mitochondrial Ca2+ influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit.ObjectiveHere, we sought to examine the function of the MCUb subunit of the MCU-complex in regulating mitochondria Ca2+ influx dynamics, acute cardiac injury, and long-term adaptation after ischemic injury.Methods and resultsCardiomyocyte-specific MCUb overexpressing transgenic mice and Mcub gene-deleted (Mcub-/-) mice were generated to dissect the molecular function of this protein in the heart. We observed that MCUb protein is undetectable in the adult mouse heart at baseline, but mRNA and protein are induced after ischemia-reperfusion injury. MCUb overexpressing mice demonstrated inhibited mitochondrial Ca2+ uptake in cardiomyocytes and partial protection from ischemia-reperfusion injury by reducing mitochondrial permeability transition pore opening. Antithetically, deletion of the Mcub gene exacerbated pathological cardiac remodeling and infarct expansion after ischemic injury in association with greater mitochondrial Ca2+ uptake. Furthermore, hindlimb remote ischemic preconditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca2+ uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub-/- mice were more sensitive to Ca2+ overload.ConclusionsOur studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.

Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. Although structural abnormalities of the right ventricle predominate, it is well recognized that left ventricular involvement is common, particularly in advanced disease, and that left-dominant forms occur. The pathological characteristic of ARVC is myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982, significant advances have been made in understanding this disease. Once the diagnosis of ARVC is established, the single most important clinical decision is whether a particular patient's sudden cardiac death risk is sufficient to justify placement of an implantable cardioverter-defibrillator. The importance of this decision reflects the fact that ARVC is a common cause of sudden death in young people and that sudden death may be the first manifestation of the disease. This decision is particularly important because these are often young patients who are expected to live for many years. Although an implantable cardioverter-defibrillator can save lives in individuals with this disease, it is also well recognized that implantable cardioverter-defibrillator therapy is associated with both short- and long-term complications. Decisions about the placement of an implantable cardioverter-defibrillator are based on an estimate of a patient's risk of sudden cardiac death, as well as their preferences and values. The primary purpose of this article is to provide a review of the literature that concerns risk stratification in patients with ARVC and to place this literature in the framework of the 3 authors' considerable lifetime experiences in caring for patients with ARVC. The most important parameters to consider when determining arrhythmic risk include electric instability, including the frequency of premature ventricular contractions and sustained ventricular arrhythmia; proband status; extent of structural disease; cardiac syncope; male sex; the presence of multiple mutations or a mutation in TMEM43; and the patient's willingness to restrict exercise and to eliminate participation in competitive or endurance exercise.

Dataset Information

Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling.

Publications

Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling.

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