Abstract Heart failure (HF) continues to be a leading cause of death, disability and health care expenditures. Coronary artery disease culminating in a myocardial infarction (MI) remains a major cause for HF. HF secondary to MI is fundamentally due to changes in the structure and function of the left ventricle (LV) termed LV remodeling. In pathological remodeling such as cancer, the proliferation of an aggressive degradative cell type, the cancer associated fibroblast emerges. The cancer associated fibroblast alters normal tissue structure through degradation/remodeling of the extracellular matrix (ECM). In particular, a robust expression of a proteolytic enzyme, fibroblast activation protein (FAP). We have identified that the post-MI fibroblast contains a very similar proteolytic signature as the cancer associated fibroblast, in terms of ECM degradation and ultimately LV remodeling. Accordingly, we will test the guiding hypothesis that FAP induction/activation is essential for adverse post-MI remodeling and progression to HF and that specific localized targeting of FAP within the MI region is feasible and effective. The outcome from these translational studies will be to establish an entirely new therapeutic direction for myocardial recovery following MI and prevention of HF. We have established a transgenic line of FAP conditional knockout mice which will allow for FAP silencing following MI induction as well as following the development of HF. We have developed unique hydrogel formulations that allow for the release of small molecule therapeutics and protease inhibitors, which have been deployed in our pig model post-MI using a minimally invasive approach. The deliverables from this project will be to establish a novel therapeutic direction for the prevention as well as the treatment for HF secondary to MI through both temporal and localized control of FAP activation. These results will move the entire ECM field forward by establishing the role of the fibroblast in HF and open an entirely new direction through harnessing novel molecular tools and therapeutics to target specific cell phenotypes in this disease process.