The potential of chronic nicotine exposure for atrial fibrillation (AF) and atrial flutter (AFL) in hearts with and without chronic myocardial infarction (MI) remains poorly explored. MI was created in dogs by permanent occlusion of the left anterior descending coronary artery and administered nicotine (2.5-5mg/kg/day, subcutaneously) for one month using osmotic minipumps. High-resolution epicardial (1,792 bipolar electrodes) and endocardial Halo catheter were used to map activation during induced atrial rhythms. Nicotine promoted inducible sustained AFL at mean cycle length of 134±10 ms in all MI dogs (N=6) requiring pacing and electrical shocks for termination. No AFL could be induced in MI dogs (N=6) and control (non-MI) dogs (N=3) not exposed to nicotine and in dogs with no MI and exposed to nicotine (N=3). Activation maps during AFL showed a single, reentrant wavefront in the right atrium that rotated either clockwise (60%) or counterclockwise (40%) around the crista terminalis and through the isthmus. Ablation of the isthmus prevented the induction of AFL. Nicotine caused significant (P<0.01) but highly heterogeneous increase in atrial interstitial fibrosis (2-10 fold increase in left and right atria respectively) in the MI group but only 2 fold increase in the right atrium in the non-MI group. Nicotine also flattened (P<0.05) the slope of the epicardial monophasic action potential duration (electrical restitution) curve of both atria in the MI but not in non-MI dogs. Two-dimensional simulation in an excitable matrix containing an isthmus and nicotine restitutional parameters and reduced gap junctional conductances (fibrosis) replicated the experiments. Chronic nicotine in hearts with MI promotes AFL that closely resembles typical human AFL. Increased atrial interstitial fibrosis and flattened electrical restitution are important substrates for the AFL.