Abstract
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting more than 33 million people worldwide. Despite important advances in therapy, AF's incidence remains high, and treatment often results in recurrence of the arrhythmia. A better understanding of the cellular and molecular changes that (1) trigger AF and (2) occur after the onset of AF will help to identify novel therapeutic targets. Over the past 20 years, a large body of research has shown that intracellular Ca(2+) handling is dramatically altered in AF. While some of these changes are arrhythmogenic, other changes counteract cellular arrhythmogenic mechanisms (Calcium Signaling Silencing). The intracellular Na(+) concentration ([Na(+)])(i) is a key regulator of intracellular Ca(2+) handling in cardiac myocytes. Despite its importance in the regulation of intracellular Ca(2+) handling, little is known about [Na(+)](i), its regulation, and how it might be changed in AF. Previous work suggests that there might be increases in the late component of the atrial Na(+) current (I(Na,L)) in AF, suggesting that [Na(+)](i) levels might be high in AF. Indeed, a pharmacological blockade of I(Na,L) has been suggested as a treatment for AF. Here, we review calcium signaling silencing and changes in intracellular Na(+) homeostasis during AF. We summarize the proposed arrhythmogenic mechanisms associated with increases in I(Na,L) during AF and discuss the evidence from clinical trials that have tested the pharmacological I(Na,L) blocker ranolazine in the treatment of AF.