Atrial remodeling, fibrosis, and atrial fibrillation

Abstract

Fundamental mechanisms governing the perpetuation of atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, are poorly understood, which explains in part why AF prevention and treatment remain suboptimal. Although some clinical parameters have been identified as predicting a transition from paroxysmal to persistent AF in some patients, the molecular, electrophysiological and structural changes leading to such a progression have not been described in detail. Oxidative stress, atrial dilatation, calcium overload, inflammation, microRNAs and myofibroblast activation are all thought to be involved in AF-induced atrial remodeling. However, it is unknown to what extent and at which time points such alterations influence the remodeling process that perpetuates AF. Here we postulate a comprehensive model that might open new pathways for future investigation into mechanisms of AF perpetuation. We start from the premise that the progression to AF perpetuation is the result of an interplay among manifold signaling pathways with differing kinetics. Some such pathways have relatively fast kinetics (e.g., oxidative stress mediated shortening of refractory period); others likely depend on molecular processes with slower kinetics (e.g., transcriptional changes in myocyte ion channel protein expression mediated through inflammation and fibroblast activation). We stress the need to fully understand the relationships among such pathways should one hope to identify novel, truly effective targets for AF therapy and prevention.

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

“…27 Elevated systemic levels of reactive oxygen species (ROS) are seen with increasing age, heart failure, and coronary heart disease which are known risk factors for AF. 28 Here, flow cytometry was used to quantify the level of oxidative stress in atrial fibroblasts (Figs.…”

“…Excessive oxidative stress has been associated with AF leading to atrial structural remodeling including atrial myocyte hypertrophy and fibrosis. 27,28 Experimental animal models and clinical studies have implicated multifactorial processes including atrial dilatation, cellular hypertrophy, apoptosis, ER stress, fibrosis, and oxidative stress as contributing to structural remodeling. 27,30 Increased fibrosis initiated by pro-fibrotic cytokines such as TGF-β1 has been observed in AF patients.…”

Rosuvastatin reduces the recurrence rate following catheter ablation for atrial fibrillation in patients with heart failure

“…With the extension of time of AF, the left atrium gradually expanded. Enlargement of the left atrium causes myocardial cell deformation, leading to changes in the mechanisms of ion-channel electrophysiology, and therefore the excitability and self-regulation of the myocardium may increase (31). These factors would explain why LAD and the duration of AF are of value in predicting the recurrence of AF in patients with HF.…”

Advances in cardiac cellular electrophysiology – Relevance for clinical translation

“…Although cellular Ca 2+ overload is accepted to contribute to some of the electrophysiological alterations [15], a more comprehensive view has been given recently, where the major players, i. e. oxidative stress, inflammation and fibrosis, as well as cardiomyocytefibroblast interaction and microRNAs have been integrated [16]. Here, the complex functions of fibroblasts and their indirect (via secreted factors) and direct communication with cardiomyocytes (via gap junctions) are outlined in the context of fibrosis, effects on conduction and contribution to electrophysiological remodelling [17].…”