Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.

Each gating mechanism controlling permeability in a membrane may be influenced by only a few charge binding sites on the membrane surface, so that fluctuations in the occupancy of these sites are important. Tow extreme cases arise. (a) The time scale of these fluctuations is much shorter than the gating time constant. Then the gating mechanisms are subject to a rapidly varying electric field. If the gating in the absence of these fluctuations obeys exponential kinetics, so does the gating in the presence of the fluctuations. Changes in surface charge do not simply shift the gating variable curves on the voltage axis, but also change their shape. Such effects are seen experimentally and cannot be explained in terms of conventional surface charge theory. If the activation curve in the absence of any surface charge binding is symmetric about the half-activation point, when some of the surface charge sites are occupied the activation curve is in general asymmetric. (b) The fluctuations occur much more slowly than the gating reaction. There are several pools of channels present with different time constant and activation curves. Again the activation curve is asymmetric about the half-activation point, and its shape is changed by alterations in the surface charge. The kinetics of gating of the whole population of channels are multiexponential.