Introduction: The time-course of Pitx2 down-regulation and the associated molecular pro-arrhythmic changes in the left atria (LA) of atrial fibrillation (AF) patients remain unknown. We aimed to assess atrial transcriptomic profile associated with atrial arrhythmogenicity in a rat model of spontaneous AF and to evaluate the temporal relationship between Pitx2 changes and the onset of arrhythmias in these rats. Methods: LA sampling was performed in 3 groups of young, adult, and aging spontaneously hypertensive rats (SHR; n = 4 each), and 3 groups of age-matched Wistar-Kyoto (WKY) rats. LA mRNA expressions of Pitx2 and other 89 pro-arrhythmogenic genes were studied using RT-PCR and TaqMan Low-Density Array analyses and assessed in relationship with the presence of AF at radiotelemetry ECG monitoring. Results: ECG monitoring demonstrated the presence and the age-dependency of AF in hypertensive rats. No difference was found between LA Pitx2 expression in young or adult SHRs compared to age-matched WKY rats (P > 0.05), while aging SHRs presented signifi cantly lower LA Pitx2 expression compared to agematched WKY rats (P = 0.02). Among SHRs, Pitx2 expression showed an age-dependent decrease (34.9 ± 6.7 in young, 17.1 ± 3.6 in adult, and 10.7 ± 1.7 in aging SHRs, P = 0.04) and was significantly negatively correlated with age (r = -0.86, P < 0.01). Of the 89 studied genes, 6 were diff erentially expressed between aging SHRs and WKY rats, showing decreased ICa, L, connexin-43, and desmocollin 2 densities, and increased type VI collagen. Conclusions: Similarly to what has been found in AF patients, hypertensive rats with spontaneous AF presen ted decreased LA expression of Pitx2, ICa, L, desmo collin 2, and connexin-43, and increased type VI collagen. Th is study demonstrates a temporal relationship between Pitx2 down-regulation and AF onset in hypertensive rats, suggesting that Pitx2 might be involved in long-standing arterial hypertension-induced AF. Th e age-dependency of Pitx2 changes suggests that a timely appropriate therapy in hypertensive patients may prevent AF onset in this population.