Dynamic remodeling of intracellular Ca²⁺ signaling during atrial fibrillation

During atrial fibrillation (AF) intracellular Ca(2+) signaling in atrial myocytes changes substantially. This 'remodeled' intracellular Ca(2+) homeostasis plays an important role in the development of the contractile dysfunction and the changes in atrial electrophysiology (contractile and electrical remodeling) that are characteristic of AF. Recent studies also show that unstable intracellular Ca(2+) signaling (i.e. increased Ca(2+) sparks and Ca(2+) waves) is present in atrial myocytes from AF patients and that it might contribute to cellular arrhythmogenic mechanisms that help maintain the arrhythmia. It is currently not well understood how and when unstable Ca(2+) signaling develops during the progression of AF, or if, in cases of structural heart disease, it even precedes the onset of AF. Current work therefore in particular aims to elucidate the molecular and sub-cellular mechanisms underlying the arrhythmogenic intracellular Ca(2+) signaling instability in AF. As treatment of AF remains difficult, the identification of novel targets for counteracting or preventing arrhythmogenic Ca(2+) signaling is an important part of AF research. It is therefore important to recognize which phase of AF is addressed in a specific research (and ultimately treatment) approach. Here we review and critique the distinct alterations in intracellular Ca(2+) signaling during the progression of AF from initial intracellular Ca(2+) overload to the remodeling process. We address Ca(2+) signaling after cardioversion of the arrhythmia and its potential role in the recurrence of AF. We propose that altered Ca(2+) signaling during AF progression consists of three phases 1.) Ca(2+) Overload, 2.) Remodeling, and 3.) Steady State. Similarly, after AF termination three distinct phases of 'recovery' of intracellular Ca(2+) handling occur. 4.) Calcium Unloading, 5.) Reverse Remodeling and 6.) Full Recovery. While there is evidence that unstable Ca(2+) signaling is part of phases 1, 3 and 4, phase 2 (remodeling) appears to have a more stabilizing function on Ca(2+) signaling ('Ca(2+) silencing'). This has important implications for the timing and type of pharmacological intervention, especially for new compounds aimed at intracellular 'Ca(2+) stabilization'.