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Review
. 2018 Oct 4:9:1380.
doi: 10.3389/fphys.2018.01380. eCollection 2018.

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

Nathan C Denham  1 , Charles M Pearman  1 , Jessica L Caldwell  1 , George W P Madders  1 , David A Eisner  1 , Andrew W Trafford  1 , Katharine M Dibb  1
Affiliations
Review

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

Nathan C Denham et al. Front Physiol. .

Abstract

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.

Keywords: atrial fibrillation; calcium; heart failure; pathophysiology; t-tubules.

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Figures

Figure 1
Figure 1
Calcium cycling and mechanisms of arrhythmia. (A) The role of the calcium cycling mechanism in calcium induced calcium release (B) Early afterdepolarizations arise through reactivation of ICa(L) and / or INa and are facilitated by INCX. (C) Delayed afterdepolarizations arise through spontaneous calcium release from the sarcoplasmic reticulum. (D) (i) Wavebreak occurs when a smooth depolarizing wave front encounters an area of inexcitable tissue (ii) which may progress to re-entry whereby the depolarizing wave continues to rotate around an inexcitable core. EAD, early afterdepolarization; DAD, delayed afterdepolarization; LTCC, L-type calcium channel; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; NCX, sodium/calcium exchanger; SERCA, sarco-endoplasmic reticulum calcium ATPase.
Figure 2
Figure 2
Alterations to atrial calcium handling (top left) in response to short-term rapid atrial stimulation, (top right) in paroxysmal atrial fibrillation, (bottom right) in persistent atrial fibrillation, (bottom left) and in heart failure. APD, action potential duration; DAD, delayed afterdepolarization; LTCC, L-type calcium channel; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; NCX, sodium/calcium exchanger; SERCA, sarco-endoplasmic reticulum calcium ATPase; SLN, sarcolipin; PLB, phospholamban.
Figure 3
Figure 3
The bidirectional relationship between atrial fibrillation and heart failure. Text highlighted in Blue indicates that perturbed calcium handling is implicated in this aspect of the pathophysiology.
See this image and copyright information in PMC

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