Journal
FRONTIERS IN PHARMACOLOGY
Volume 5, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2014.00030
Keywords
atrial fibrillation; calcium; CaMKII; ectopic activity; reentry
Categories
Funding
- European North American Atrial Fibrillation Research Alliance [07CVD03]
- Alliance for Calmodulin Kinase Signaling in Heart Disease [08CVD01]
- Fondation Leducq
- European Network for Translational Research in Atrial Fibrillation (EUTRAF) [261057]
- German Federal Ministry of Education and Research through the DZHK (German Center for Cardiovascular Research)
- American Heart Association [13EIA14560061]
- Muscular Dystrophy Association [186530]
- National Institutes of Health [HL089598, HL091947, HL117641]
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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.
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