BACKGROUND: A change in activation sequence electrically remodels ventricular myocardium, causing persistent changes in repolarizing currents (T-wave memory). However, the underlying mechanism for triggering activation sequence-dependent remodeling is unknown. METHODS & RESULTS: Optical action potentials were mapped with high resolution from the epicardial surface of the arterially-perfused canine wedge preparation (n=23) during 30 min of baseline endocardial stimulation, followed by 40 min of epicardial stimulation, and finally, restoration of endocardial stimulation. Immediately after the change from endocardial to epicardial stimulation, phase 1 notch amplitude of epicardial cells was attenuated by 74 ± 8% (p<0.001) compared to baseline, and continued to diminish during the period of epicardial pacing, suggesting progressive remodeling of the transient outward current, I_to. When endocardial pacing was restored, notch amplitude did not immediately recover, but remained attenuated by 23 ± 10% (p<0.001), also consistent with a remodeling effect. Peak I_to current measured from isolated epicardial myocytes changed by 12 ± 4% (p<0.025), providing direct evidence for I_to remodeling occurring on a surprisingly short time scale. The mechanism for triggering remodeling of I_to was a significant reduction (by 14 ± 4%, p<0.001) of upstroke amplitude in epicardial cells during epicardial stimulation. Reduction in upstroke amplitude during epicardial pacing was explained by electrotonic load on epicardial cells by fully repolarized downstream endocardial cells. CONCLUSIONS: These data suggest a novel mechanism for triggering electrical remodeling in ventricle. Electrotonic load imposed by a change in activation sequence reduces upstroke amplitude, which, in turn, attenuates I_to according to its known voltage-dependent properties, triggering down-regulation of current.