Recent advances in the molecular pathophysiology of atrial fibrillation

Abstract

Atrial fibrillation (AF) is an extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality. The mechanisms underlying AF are complex, involving both increased spontaneous ectopic firing of atrial cells and impulse reentry through atrial tissue. Over the past ten years, there has been enormous progress in understanding the underlying molecular pathobiology. This article reviews the basic mechanisms and molecular processes causing AF. We discuss the ways in which cardiac disease states, extracardiac factors, and abnormal genetic control lead to the arrhythmia. We conclude with a discussion of the potential therapeutic implications that might arise from an improved mechanistic understanding.Authorship note: Reza Wakili and Niels Voigt contributed equally to this work.

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

“…Adaptation to this new situation results in profound changes in the ion channels controlling Ca 2+ reuptake and release by the sarcoplasmic reticulum 13,21 . These changes persist for some time after the restoration of a normal sinus rhythm (for example, after cardioversion), rendering the recurrence of AF more likely 58 .…”

“…These changes not only contribute to a shortening of atrial refractoriness, favouring re-entry, but also to prolongation of the atrial action potential and the triggered electrical activity 13,21 . In addition to these adaptive changes in ion-channel regulation, the local milieu within atrial myocytes -influenced for example by shear stress 16 , metabolic factors, atrial work load, or cellular age -also alters the expression and function of ion channels, possibly contributing to changes in refractoriness or in ectopic activity occurrence 61 .…”

“…Unfortunately, most of these current approaches are disconnected from our understanding of the major mechanisms that cause AF 1,13,14 1,2,7,19,20 Abstract | Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications.…”

Is altered atrial microRNA-ome a critical contributor to the pathophysiology of atrial fibrillation?

“…The generally poor outcome with current antiarrhythmic drugs likely reflects the fact that most of the used agents were developed in the absence of precise understanding of pro-and anti-arrhythmic drug actions and the arrhythmogenic disease-specific cardiac substrate. Conceptually, AF induction requires a vulnerable substrate and a trigger that acts on the substrate to initiate the arrhythmia [25,35]. Once AF is initiated, the rapid-atrial rate creates progressive AF-related changes in atrial electrical and structural properties (atrial remodeling).…”

“…signaling, whereas increased atrial fibrosis and heterogeneous conduction slowing are typical characteristics of structural remodeling. Atrial remodeling can promote ectopic (triggered) activity and facilitate reentry, thereby contributing to AF perpetuation and the progression from short-lasting (paroxysmal) to long-standing persistent AF [7,10,25,26,35], which makes AF more resistant to both pharmacological and nonpharmacological therapeutic approaches. Therefore, it is assumed that a better understanding of the molecular mechanisms underlying AF maintenance will help to design novel drugs with improved efficacy and safety profiles [8].…”