Heart failure-induced atrial remodelling promotes electrical and conduction alternans

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) Ca 2+ content and Ca 2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) Ca 2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K + current ( I to ). The underlying mechanism has been suggested that the increased SR Ca 2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca 2+ release and AP in the next beat. These produced Ca 2+ transient alternans and AP alternans, and further caused AP alternans and Ca 2+ transient alternans through Ca 2+ →AP coupling and AP→Ca 2+ 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.

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“…Furthermore, we detected the key proteins that affect electrical remodeling, including SERCA2α, PLB, CAMK II, and Kv1.5. SERCA2α and PLB influence cardiomyocyte repolarization and depolarization by regulating diastolic calcium channels, while CAMK II and Kv1.5 activate K + currents and affect cell membrane excitability 33–36 . Our data confirmed that intramyocardial Tx inhibited sarcoplasmic reticulum calcium leakage by lowering PLB and CAMK II expression and increasing SERCA2α expression to prevent arrhythmia, and the stimulating effect of intramyocardial Tx based on Kv1.5 may be a potential physiological advantage for regulating myocardial excitability.…”

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“…An uncharacteristic discordant alternans can be observed under the action of ATO ( Supplementary Figure S2 ). The tissue alternans in this study were not as obvious as those in heart failure-associated atrial alternans research ( Zhao et al, 2020 ) because except for single cell characters, the decreased CV in atrial tissue was also an essential factor in inducing tissue alternans. There is no evidence that ATO reduced the CV in ventricular tissue, so the alternans did not easily occur in this present simulation.…”

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“…Their results indicated that AF remodeling enhanced spontaneous single-cell Ca 2+ release, prolonged the refractory period of the Ca 2+ transient, increased the slope of the Ca 2+ transient restitution curve, and eventually predisposed hearts to Ca 2+ transient alternans [ 23 ]. Furthermore, in a recent simulation study, Zhao et al [ 24 ] revealed that HF-induced atrial electrical remodeling increased Ca 2+ transient amplitude and SR Ca 2+ concentration. They demonstrated that the enhanced SR Ca 2+ reuptake was the primary reason that HF-induced atrial electrical remodeling increased susceptibility to atrial alternans [ 24 ].…”

“…Furthermore, in a recent simulation study, Zhao et al [ 24 ] revealed that HF-induced atrial electrical remodeling increased Ca 2+ transient amplitude and SR Ca 2+ concentration. They demonstrated that the enhanced SR Ca 2+ reuptake was the primary reason that HF-induced atrial electrical remodeling increased susceptibility to atrial alternans [ 24 ].…”