Progressive ventricular dilatation is a major complication of myocardial infarction (MI), resulting in heart failure. In a comparison of infarct healing in mice of different genetic backgrounds, we have established a correlation between myofibroblast numbers in the infarct area and preservation of left ventricular geometry. Myofibroblasts not only can produce extracellular matrix proteins, but also possess contractile properties similar to smooth muscle cells. These characteristics allow them to limit infarct expansion. However, our knowledge of the molecular control of myofibroblast differentiation is not complete. Myofibroblasts in the infarct area express Frizzled-1 and -2 (Fzd-1 and -2), receptors for Wnt proteins. We hypothesized that Fzd-1 and -2 can modulate the characteristics of these myofibroblasts. To test this, we blocked Fzd-1 and -2 with UM206 (6 microgram/kg.hr), a potent Fzd antagonist. UM206 administration significantly increased myofibroblast numbers, reduced adverse remodeling and completely prevented heart failure development. Subsequently we compared different treatment regimens for UM206 in mice subjected to MI and followed for 5 weeks: treatment for the first 2 weeks (wk1–2), the last three weeks (wk3–5) or the full 5 weeks (wk1–5). All regimens had a beneficial effect on EF (saline: 18±1%, wk1–2: 24±0,5%, wk3–5: 31±2%, wk1–5: 37±0,5%; P<0.05). The improvement of the EF was associated the myofibroblast numbers in the infarct area (saline: 4±0,2%, wk1–2: 6±0,4%, wk3–5: 11±0,9%, wk1–5: 13±1,4%; P<0.05). We conclude that blocking of Fzd-1 and -2 receptors with UM206 improves cardiac function after MI by increasing myofibroblast numbers in the infarct area, thereby reducing infarct expansion. Continuous UM206 therapy was found to be superior over late or early therapy, but any UM206 treatment regimen was better than saline. The results show that pharmacotherapy specifically aimed at the myofibroblast can be a successful approach to prevent heart failure after MI.