Background-Myocardial infarction modifies the distribution of stress within the heart, increasing wall stress in ischemic and surrounding tissue, which often leads to adverse left ventricular remodeling. Electrical preexcitation pacing with appropriate timing of high-stress regions can reduce local strain and may attenuate global remodeling. Methods and Results-Myocardial infarction was induced in 24 swine to study the short-term (nϭ12) and long-term (nϭ12) effects of therapy. Sonomicrometry and hemodynamic measurements were used to show the mechanistic effects of preexcitation and to determine the optimal stimulation site and atrioventricular delay. Lagrangian strain was used to assess regional loading characteristics. Long-term study animals were randomized to 8 weeks of preexcitation (therapy) or no pacing (control). Echocardiograms were performed 2 days after myocardial infarction and repeated at 60 days, when tissue weights and apoptosis were assessed. Preexcitation reduced regional strain in the short term, with the best results achieved when the border region was paced at an atrioventricular delay of 50% of the intrinsic PR interval. In the long term, the changes in left ventricular internal diameter and left atrial size were decreased in therapy animals versus control animals (0.9Ϯ0.3 versus 1.5Ϯ0.5 cm, Pϭ0.03, and 1.06Ϯ0.78 versus 2.32Ϯ0.88 cm, PϽ0.04, respectively). Heart weight was significantly lower in the therapy animals than in the control animals (319.8Ϯ20.8 versus 359.6Ϯ29.3 g, Pϭ0.02). Although not significant, cardiomyocyte apoptosis trended lower in the therapy group. Conclusions-Preexcitation of the left ventricle after myocardial infarction reduced strain and stroke work in the infarct and border regions in the short term and attenuated adverse ventricular remodeling in the long term.