AIMS: The least understood aspect of re-entrant cardiac arrhythmias is how they start spontaneously. The known mechanisms for re-entry induction involve the application of premature electrical stimuli or rapid pacing, whereas in a clinical setting, re-entry often occurs at normal heart rates. Here, we propose a physiological mechanism of re-entry onset at normal and slow heart rates, which is based on structurally determined heterogeneities. METHODS AND RESULTS: Using a two-dimensional tissue model with Luo-Rudy II kinetics, we study electrical propagation in the presence of macroscopic coupling heterogeneities. We find that spiral wave re-entry occurs if steep and smooth coupling gradients are situated side by side, with the critical steepness depending on the frequency of stimulation. We demonstrate how bradycardia can unmask a slow endogenous pacemaker in a poorly coupled region, subsequently leading to spiral wave re-entry. CONCLUSION: In the presence of coupling heterogeneities, a single excitation coming from the less coupled region may induce spiral wave re-entry.