Heart failure (HF) and atrial fibrillation (AF) are the two of major epidemics of cardiovascular diseases behind increasing rate of morbidity and mortality. There is an increased prevalence of AF among HF patients. However, the impact of HF-induced electrophysiological changes in atrial properties on AF genesis has not been adequately studied. The aim of this study is to study the influence of HF-induced membrane ion channel and the intracellular Ca2+ handling on the membrane electrical action potentials, and vulnerability of AF initiation in a response to a premature stimulus at the left atrium and pulmonary veins junction (LA-PVs junction) in an 3D model of the sheep atria. Experimental data on HF-induced remodelling for different ion channels and Ca+2 handling on sheep atrial myocytes were collected from literatures, and then incorporated into the multiscale model of the sheep atria developed by Butters at all. (2013) at single cell and 3D organ levels. The 3D model of the sheep atria considered detailed anatomical structures and electrical heterogeneity and tissue anisotropy. In the 3D model, the S1 -S2 pacing protocol was applied at the LA/PVs junction, with two S1 stimuli being applied at a basic cycle length (BCL) of 350 ms, which were followed by four S2 stimuli applied at the same location with a shorter BCL. The vulnerability of the tissue for AF genesis was computed as the time window (VW) during which the S2-evoked excitation wave propagated only in one direction of the LA, leading to the formation of sustained re-entrant circuits. It was shown that the HF-induced electrical and Ca2+ handling remodelling abbreviated the action potential duration at 90% of repolarisation (APD90) of both the LA and PVs cells, which is consistent with experimental observations. However, it preserved though reduced the APD90 dispersion by 39 ms at the junction of the LA and PVs. Owing to the APD abbreviation and the preserved dispersion, the measured VW at the LA/PVs junction was greater in HF than that in control (CTL) condition, resulting in an increased tissue vulnerability for AF genesis at the LA/PVs junction by 46%. Further analysis showed that the Dominant frequency (DF) of the re-entry in the HF was greater in both the LA and PVs than those in CTL condition. In conclusion, this study demonstrated that the HF-induced remodelling on different ion channels and Ca2+ handling abbreviated atrial APD90, reduced but preserved the APD90 dispersion at the LA/PVs junction, increased tissue’s VW for the genesis of sustained re-entry in the sheep atria.