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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) 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.

SUBMITTER: Zhao N

PROVIDER: S-EPMC7402519 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Heart failure-induced atrial remodelling promotes electrical and conduction alternans.

Zhao Na N Li Qince Q Zhang Kevin K Wang Kuanquan K He Runnan R Yuan Yongfeng Y Zhang Henggui H

PLoS computational biology 20200713 7

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 o ...[more]

PMID: 32658888

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Project description:Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.

Project description:AimsLeft atrial (LA) remodelling is an important predictor of cardiovascular events of heart failure (HF) and atrial fibrillation. Data regarding diagnostic value of LA remodelling on diastolic dysfunction (DD) and preclinical HF remain largely unexplored.Methods and resultsWe assessed LA dimension (LAD) in 8368 consecutive asymptomatic Asians (mean age: 49.7, 38.9% women) and related such measure to updated American Society of Echocardiography (ASE) DD criteria and newly revised N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off (≥125 pg/mL) and HF with preserved ejection fraction criteria incorporating NT-proBNP and echocardiography parameters by the European Society of Cardiology (ESC). LAD and indexed LAD (LADi) were both inversely correlated with myocardial relaxation e' and positively associated with indexed LA volume, left ventricular E/e', and tricuspid regurgitation velocity (all P < 0.001) and showed significantly graded increase across ASE-defined 'normal', 'inconclusive', and 'DD' categories (30.9, 34.4, and 36.5 mm; 16.7, 19.1, and 20.6 mm/m2 , for LAD/LADi, both P for trend: <0.001, respectively). Substantial differences of LAD/LADi (31.3 vs. 33.6 mm/16.7 vs. 19.2 mm/m2 , both P < 0.001) between ESC low and high HF probability using NT-proBNP cut-off were also observed. Multivariate linear and logistic models demonstrated that LAD set at 34 mm was independently associated with ASE-defined diastolic indices, DD existence, and elevated NT-proBNP (all P < 0.05). The use of LAD further yielded high diagnostic accuracy in DD (area under receiving operative characteristic curve: 0.77, 95% confidence interval [0.73, 0.80]; negative predictive value: 97.9%) and in ESC-recommended HF with preserved ejection fraction criteria (area under receiving operative characteristic curve: 0.70, 95% confidence interval [0.65, 0.75]; negative predictive value: 98.7%) with high predictive value in LA remodelling (>34 mL/m2 ; positive predictive value: 96%) and well-discriminated ESC-recommended NT-proBNP (≥125 pg/mL, LAD: 37 mm) for HF.ConclusionsSingle utilization of atrial remodelling is highly useful for ruling out presence of DD and provides practical threshold for identifying preclinical HF based on most updated guidelines.

Dataset Information

Heart failure-induced atrial remodelling promotes electrical and conduction alternans.

Publications

Heart failure-induced atrial remodelling promotes electrical and conduction alternans.

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