Abstract
Atrial fibrillation (AF) is the most frequently encountered clinical arrhythmia and is associated with increased morbidity and mortality. Ectopic activity and reentry are considered major arrhythmogenic mechanisms contributing to the initiation and maintenance of AF. In addition, AF is self-reinforcing through progressive electrical and structural remodeling which stabilize the arrhythmia and make it more difficult to treat. Recent research has suggested an important role for Ca2+-dysregulation in AF. Ca2+-handling abnormalities may promote ectopic activity, conduction abnormalities facilitating reentry, and AF-related remodeling. In this review article, we summarize the Ca2+-handling derangements occurring in AF and discuss their impact on fundamental arrhythmogenic mechanisms. We focus in particular on the role of the multifunctional Ca2+/calmodulin-dependent protein kinase type-II (CaMKII), which acts as a major link between Ca2+-dysregulation and arrhythmogenesis. CaMKII expression and activity are increased in AF and promote arrhythmogenesis through phosphorylation of various targets involved in cardiac electrophysiology and excitation-contraction coupling. We discuss the implications for potential novel therapeutic strategies for AF based on CaMKII and Ca2+-handling abnormalities.
Highlights
Atrial fibrillation (AF) is the most prevalent heart-rhythm disorder, estimated to affect more than 33 million people worldwide (Chugh et al, 2013)
We review recent studies detailing the proarrhythmic role of AFrelated Ca2+-handling abnormalities, with particular focus on the contributions of the Ca2+/calmodulin-dependent protein kinase type-II (CaMKII)
MECHANISMS PROMOTING CaMKII DYSREGULATION IN AF CaMKIIδ protein expression and activity are increased in dogs with pacing-induced atrial tachycardia remodeling (Wakili et al, 2010), goats with long-standing AF (Greiser et al, 2009), and patients with chronic AF; (Tessier et al, 1999; Neef et al, 2010; Voigt et al, 2012), suggesting that increased CaMKII function can be a consequence of AF
Summary
Atrial fibrillation (AF) is the most prevalent heart-rhythm disorder, estimated to affect more than 33 million people worldwide (Chugh et al, 2013). Current pharmacological treatments for rhythmcontrol of AF mainly include class-I and class-III antiarrhythmic drugs, which have modest efficacy, providing sinus-rhythm maintenance in only 30–70% of patients after >1 year of follow-up (Camm, 2012). These drugs are associated with substantial adverse side-effects including ventricular proarrhythmia and extra-cardiac toxicity (Zimetbaum, 2012; Heijman et al, 2013a). Accumulating evidence has highlighted a central role for abnormal Ca2+handling in AF-pathophysiology (Dobrev and Nattel, 2008; Heijman et al, 2012; Nattel and Dobrev, 2012). We review recent studies detailing the proarrhythmic role of AFrelated Ca2+-handling abnormalities, with particular focus on the contributions of the Ca2+/calmodulin-dependent protein kinase type-II (CaMKII)
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