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.

Keywords: atrial fibrillation; atrial myocyte; calcium dynamics; calcium imaging.

Figure 1. Schematic depiction of changes in function, expression and phosphorylation levels of key Ca²⁺ handling proteins in Ca²⁺ signalling silencing

Arrows denote direction of change; see text for details. CaM, calmodulin; CaMKII, Ca²⁺/calmodulin‐dependent kinase II; I _CaL, L‐type Ca²⁺ current; MyBP‐C, myosin‐binding protein C; NCX, Na⁺/Ca²⁺ exchanger; NKA, Na⁺/K⁺‐ATPase; P, phosphate group; PKA, protein kinase A; PLB, phospholamban; PLM, phospholemman; PMCA, plasma membrane Ca²⁺‐ATPase; RyR2, ryanodine receptor type 2; Ser, serine residue; Serca2a, SR Ca²⁺‐ATPase type 2a; SR, sarcoplasmic reticulum; Thr, threonine residue; TnI, troponin I; TnC, troponin C.

Figure 2. Schematic diagram for the proposed role of Ca²⁺ signalling silencing in Ca²⁺‐based arrhythmogenesis during the natural progression of different types of AF

See text for details.