Calcium signalling silencing in atrial fibrillation

摘要

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.