Background-We hypothesize that a therapy that improves left ventricular (LV) pump function early after infarction should decrease the need for compensation through sympathetic activation and dilation, thereby reducing the risk of developing heart failure. The mechanical properties of healing myocardial infarcts are an important determinant of LV function, yet improving function by altering infarct properties has proven unexpectedly difficult. Using a computational model, we recently predicted that stiffening a large anterior infarct anisotropically (in only one direction) would improve LV function, whereas isotropic stiffening, the focus of previous studies and therapies, would not. The goal of this study was to test the novel strategy of anisotropic infarct reinforcement. Methods and Results-We tested the effects of anisotropic infarct reinforcement in 10 open-chest dogs with large anteroapical infarcts that depressed LV pump function. We measured regional mechanics, LV volumes, and cardiac output at a range of preloads at baseline, 45 minutes after coronary ligation (ischemia), and 30 minutes later, after surgical reinforcement in the longitudinal direction (anisotropic). Ischemia shifted the end-systolic pressure-volume relationship and cardiac output curves rightward, decreasing cardiac output at matched end-diastolic pressure by 44%. Anisotropic reinforcement significantly improved systolic function without impairing diastolic function, recovering half the deficit in overall LV function. Conclusions-We conclude that anisotropic reinforcement is a promising new approach to improving LV function after a large myocardial infarction. © 2012 American Heart Association, Inc.