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Background: Atrial fibrillation (AF) is the most common arrhythmia and is associated with considerable morbidity and mortality. Ischaemic heart failure (IHF) remains one of the most common causes of AF in clinical practice. However, ischaemia‐mediated mechanisms leading to AF are still incompletely understood, and thus, current treatment approaches are limited. To improve our understanding of the pathophysiology, we studied a porcine IHF model. Methods: In pigs, IHF was induced by balloon occlusion of the left anterior descending artery for 90 min. After 30 days of reperfusion, invasive haemodynamic measurements and electrophysiological studies were performed. Masson trichrome and immunofluorescence staining were conducted to assess interstitial fibrosis and myofibroblast activation in different heart regions. Results: After 30 days of reperfusion, heart failure with significantly reduced ejection fraction (left anterior obique 30°, 34.78 ± 3.29% [IHF] vs. 62.03 ± 2.36% [control], p <.001; anterior–posterior 0°, 29.16 ± 3.61% vs. 59.54 ± 1.09%, p <.01) was observed. These pigs showed a significantly higher susceptibility to AF (33.90% [IHF] vs. 12.98% [control], p <.05). Histological assessment revealed aggravated fibrosis in atrial appendages but not in atrial free walls in IHF pigs (11.13 ± 1.44% vs. 5.99 ±.86%, p <.01 [LAA], 8.28 ±.56% vs. 6.01 ±.35%, p <.01 [RAA]), which was paralleled by enhanced myofibroblast activation (12.09 ±.65% vs. 9.00 ±.94%, p <.05 [LAA], 14.37 ±.60% vs. 10.30 ± 1.41%, p <.05 [RAA]). Correlation analysis indicated that not fibrosis per se but its cross‐regional heterogeneous distribution across the left atrium was associated with AF susceptibility (r =.6344, p <.01). Conclusion: Our results suggest that left atrial cross‐regional fibrosis difference rather than overall fibrosis level is associated with IHF‐related AF susceptibility, presumably by establishing local conduction disturbances and heterogeneity. [ABSTRACT FROM AUTHOR]