The multidimensional role of calcium in atrial fibrillation pathophysiology: Mechanistic insights and therapeutic opportunities

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its prevalence is increasing with the ageing of the population. Presently available treatment options are far from optimal and new insights into underlying mechanisms are needed to improve therapy. A variety of recent lines of research are converging to reveal important and relatively underappreciated multidimensional roles of cellular Ca2 content, distribution, and handling in AF pathophysiology. The objective of the present paper is to review the participation of changes in cell Ca2 and related processes in the mechanisms that lead to AF initiation and maintenance, and to consider the relevance of new knowledge in this area to therapeutic innovation. We first review the involvement of Ca2-related functions in the principal arrhythmia mechanisms underlying AF: focal ectopic activity due to afterdepolarizations and re-entrant mechanisms. The detailed molecular pathophysiology of focal ectopic and re-entrant activity is then discussed in relationship to the participation of cell Ca2 changes and related Ca2-handling and Ca2-sensitive signalling systems. We then go on to consider the participation of Ca2-related functions in electrical and structural remodelling processes leading to the AF substrate. Finally, we consider the implications for development of new arrhythmia management approaches and future research and development. © The Author 2011.