Abstract
Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate-dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate-adaptation of ionic current remodeling seen with PeAF. Ionic remodeling in PeAF was simulated by reducing L-type Ca2+ channel current (ICaL), increasing inward rectifier K+ current (IK1) and modulating five other ionic currents. Parameter sensitivity analysis, which quantified how each ionic current influenced APD in control and PeAF conditions, identified interesting results, including a negative effect of Na+/Ca2+ exchange on APD only in the PeAF condition. At high pacing rate (2 Hz), electrical remodeling in IK1 alone accounts for the APD reduction of PeAF, but at slow pacing rate (0.5 Hz) both electrical remodeling in ICaL alone (-70%) and IK1 alone (+100%) contribute equally to the APD reduction. Furthermore, AP rate-adaptation was affected by IKur in control and by INaCa in the PeAF condition. In a 2D tissue model, a large reduction (-70%) of ICaL becomes a dominant factor leading to a stable spiral wave in PeAF. Our study provides a quantitative and unifying understanding of the roles of ionic current remodeling in determining rate-dependent APD changes at the cellular level and spatial reentry patterns in tissue.
Highlights
Atrial fibrillation (AF) is a common atrial arrhythmia, especially prevalent among people older than 70 years old, and is the major cause of cardioembolic stroke [1, 2]
Sensitivity analysis showed that model parameters with the most influence on action potential duration (APD) ranked in the order: GK1 > INaK(max) > GCaL > GKr (Fig 1C)
Na+/Ca2+ exchange current (INaCa), for instance, has a parameter sensitivity near zero in control, but a relatively large, negative parameter sensitivity in Persistent atrial fibrillation (PeAF). This implies that blocking INaCa would have little effect in healthy atrial cells but produces action potential (AP) prolongation in remodeled atrial cells. Another interesting difference is that in PeAF, INaK(max) is more influential than GK1 in determining APD, whereas the opposite is true in healthy atrial myocytes
Summary
Atrial fibrillation (AF) is a common atrial arrhythmia, especially prevalent among people older than 70 years old, and is the major cause of cardioembolic stroke [1, 2]. When AF occurs in a young person with a structurally normal heart, it tends to appear only intermittently and to PLOS ONE | DOI:10.1371/journal.pone.0150779. Ionic Currents on Rate-Dependent APD in AF and analysis, decision to publish, or preparation of the manuscript When AF occurs in a young person with a structurally normal heart, it tends to appear only intermittently and to PLOS ONE | DOI:10.1371/journal.pone.0150779 March 10, 2016
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