Fibrosis in Atrial Fibrillation – Role of Reactive Species and MPO

Kai Friedrichs,Anna Klinke,Stephan Baldus

doi:10.3389/fphys.2012.00214

Abstract

Atrial fibrosis with enhanced turnover and deposition of matrix proteins leads to inhomogeneous atrial electrical conduction and gives rise to electrical reentry circuits resulting in atrial fibrillation. The multifactorial pathogenesis of atrial fibrosis involves resident cardiac cells as well as infiltrating leukocytes, both generating and sequestering matrix metalloproteinases (MMPs), a key enzyme family involved in fibrosis. A growing body of evidence points toward an important role of reactive oxygen species (ROS) in the release and activation of pro-MMPs and the stimulation of pro-fibrotic cascades. Myeloperoxidase (MPO), a bactericidal enzyme released from activated polymorphonuclear neutrophils (PMN) is not only associated with a variety of cardiovascular diseases, but has also been shown to be mechanistically linked to atrial fibrosis and fibrillation. MPO catalyzes the generation of reactive species like hypochlorous acid, which affect intracellular signaling cascades in various cells and advance activation of pro-MMPs and deposition of atrial collagen resulting in atrial arrhythmias. Thus, inflammatory mechanisms effectively promote atrial structural remodeling and importantly contribute to the initiation and perpetuation of atrial fibrillation.

Highlights

Atrial fibrillation (AF) remains the most prevalent rhythm disorder affecting 1–1.5% of the population in western industrialized countries and its prevalence is supposed to double within the 50 years (Go et al, 2001; Savelieva and Camm, 2008)
AF may be triggered by spontaneous premature depolarizations of myocytes originating, e.g., from the pulmonary veins, alternatively by rapid electrical activity in the form of pulmonary vein tachycardia
Enhanced matrix turnover affects signaling cascades of cardiomyocytes, fibroblasts, endothelial cells, and leukocytes creating an inflammatory milieu, which results in increased fibrotic remodeling (Figure 1)

Summary

INTRODUCTION

Atrial fibrillation (AF) remains the most prevalent rhythm disorder affecting 1–1.5% of the population in western industrialized countries and its prevalence is supposed to double within the 50 years (Go et al, 2001; Savelieva and Camm, 2008). A significant number of patients with persistent or chronic AF remains refractory to this approach, pointing toward involvement of atrial tissue as a substrate in those types of AF (Allessie, 1998; Calkins et al, 2012). In particular cardiovascular diseases such as arterial hypertension, heart failure, coronary artery disease, valvular, or inflammatory disease are independent risk factors to AF. These disorders are believed to be mechanistically involved, since they participate in electrical, contractile, and structural remodeling of atrial tissue (Kannel et al, 1982). Accumulating evidence advocates for a critical mechanistic role of inflammatory processes in the pathogenesis of atrial fibrosis. This review intends to summarize the role of reactive species in the development of atrial fibrosis and to elucidate the impact of the leukocyte-derived enzyme myeloperoxidase (MPO)

FIBROSIS IN ATRIAL FIBRILLATION

IMPACT OF REACTIVE SPECIES ON MMPs AND CARDIAC CELLS

ROLE OF MYELOPEROXIDASE

Findings

MPO PROMOTES FIBROSIS