Abstract
Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that HF-induced remodelling of atrial cellular and tissue properties promotes the genesis of atrial action potential (AP) alternans and conduction alternans that perpetuate AF. However, the mechanism underlying the increased susceptibility to atrial alternans in HF remains incompletely elucidated. In this study, we investigated the effects of how HF-induced atrial cellular electrophysiological (with prolonged AP duration) and tissue structural (reduced cell-to-cell coupling caused by atrial fibrosis) remodelling can have an effect on the generation of atrial AP alternans and their conduction at the cellular and one-dimensional (1D) tissue levels. Simulation results showed that HF-induced atrial electrical remodelling prolonged AP duration, which was accompanied by an increased sarcoplasmic reticulum (SR) Ca2+ content and Ca2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K+ current (Ito). The underlying mechanism has been suggested that the increased SR Ca2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca2+ release and AP in the next beat. These produced Ca2+ transient alternans and AP alternans, and further caused AP alternans and Ca2+ transient alternans through Ca2+→AP coupling and AP→Ca2+ coupling, respectively. Simulation of a 1D tissue model showed that the combined action of HF-induced ion channel remodelling and a decrease in cell-to-cell coupling due to fibrosis increased the heart tissue’s susceptibility to the formation of spatially discordant alternans, resulting in an increased functional AP propagation dispersion, which is pro-arrhythmic. These findings provide insights into how HF promotes atrial arrhythmia in association with atrial alternans.
Highlights
Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases that frequently coexist with each other, resulting in higher mortality than AF or HF alone [1]
HF-induced atrial remodelling varies during various stages and complications of HF, but possible mechanisms underlying their pro-susceptibility to alternans have not been completely elucidated
We investigated the effects of HF-induced atrial remodelling with prolonged action potential duration (APD) and decreased cell-to-cell coupling on susceptibility to atrial alternans
Summary
Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases that frequently coexist with each other, resulting in higher mortality than AF or HF alone [1]. Over one-third of patients with AF in the Framingham Heart Study had HF, and more than half of patients with HF had AF [2]. This is because HF shares many similar risk factors (e.g. advanced age, coronary disease, hypertension, diabetes mellitus, sleep apnoea, etc.) and pathophysiology to AF such that HF and AF can induce and facilitate each other [3,4,5,6]. HF-induced atrial fibrosis, electrical remodelling, stretch and dilatation, and oxidative stress promote AF [3,7]. Other studies have reported prolonged APD [18,19,20,21] and increased atrial ERP [22] in HF
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