Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Abstract

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca 2+ -handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management.

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication

“…The final phenotypic product of the CHF-induced Ca 2+ -handling abnormalities is focal ectopic activity due to aberrant diastolic Ca 2+ -release events from the SR, similar to abnormalities seen with paroxysmal and long-standing persistent AF. 116 Congestive heart failure also causes atrial hypocontractility, despite increased cytosolic Ca 2+ transient, indicating reduced contractile sensitivity to intracellular Ca 2+ , possibly because of reduced expression of total and phosphorylated myosin-binding protein C. 115 This hypocontractility may be important in contributing to the increased likelihood of thromboembolic events in AF patients who also have CHF. Of the atrial changes that occur in CHF, many are also seen in the ventricle.…”

“…41,116 The high atrial rate causes cellular Ca 2+ loading. This induces a decrease in ICa,L due to down-regulation of the underlying Cav1.2 subunits, and an increase in constitutively active I 41,116,122,123 MiR-328 up-regulation with consequent repression of Cav1.2-translation and Ca 2+ dependent calpain activation, causing proteolytic breakdown of L-type Ca 2+ channels. 41,116 The rate-dependent up-regulation of IK1 results from a Ca 2+ /calcineurin/NFAT-mediated down-regulation of the inhibitory miR-26, removing translational -inhibition of Kir2.1.…”

“…41 Small-conductance Ca 2+ -activated K + (SK) currents (ISK) also play a role in AF. 41,116 Computational modelling shows that increased total inwar-drectifier K + current in chronic atrial fibrillation (cAF) is the major contributor to the stabilization of re-entrant circuits by shortening APD and hyperpolarizing the resting membrane potential. 41,116 Atrial tachycardia remodelling reduces Ca 2+ transient amplitude by a variety of mechanisms, contributing to atrial contractile dysfunction.…”

“…41,116 Computational modelling shows that increased total inwar-drectifier K + current in chronic atrial fibrillation (cAF) is the major contributor to the stabilization of re-entrant circuits by shortening APD and hyperpolarizing the resting membrane potential. 41,116 Atrial tachycardia remodelling reduces Ca 2+ transient amplitude by a variety of mechanisms, contributing to atrial contractile dysfunction. 41,116,124 Reduced atrial contractility causes atrial 'stunning' that may be involved in thromboembolic complications.…”

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

“…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 . Increases in spontaneous electrical activity have been suggested to have a major role in abnormal intracellular Ca 2+ handling in the genesis of AF 59 . Although this theory has been challenged by reports demonstrating improved Ca 2+ -handling stability, and even Ca 2+ silencing, after AF 56,60 , increases in the sympathetic activity in the atrial tissue might still underlie the increase in the rate of ectopic activity during AF.…”