Calcium signalling silencing in atrial fibrillation.

Abstract

Subcellular calcium signalling silencing is a novel and distinct cellular and molecular adaptive response to rapid cardiac activation. Calcium signalling silencing develops during short-term sustained rapid atrial activation as seen clinically during paroxysmal atrial fibrillation (AF). It is the first 'anti-arrhythmic' adaptive response in the setting of AF and appears to counteract the maladaptive changes that lead to intracellular Ca2+ signalling instability and Ca2+ -based arrhythmogenicity. Calcium signalling silencing results in a failed propagation of the [Ca2+ ]i signal to the myocyte centre both in patients with AF and in a rabbit model. This adaptive mechanism leads to a substantial reduction in the expression levels of calcium release channels (ryanodine receptors, RyR2) in the sarcoplasmic reticulum, and the frequency of Ca2+ sparks and arrhythmogenic Ca2+ waves remains low. Less Ca2+ release per [Ca2+ ]i transient, increased fast Ca2+ buffering strength, shortened action potentials and reduced L-type Ca2+ current contribute to a substantial reduction of intracellular [Na+ ]. These features of Ca2+ signalling silencing are distinct and in contrast to the changes attributed to Ca2+ -based arrhythmogenicity. Some features of Ca2+ signalling silencing prevail in human AF suggesting that the Ca2+ signalling 'phenotype' in AF is a sum of Ca2+ stabilizing (Ca2+ signalling silencing) and Ca2+ destabilizing (arrhythmogenic unstable Ca2+ signalling) factors. Calcium signalling silencing is a part of the mechanisms that contribute to the natural progression of AF and may limit the role of Ca2+ -based arrhythmogenicity after the onset of AF.