Abstract Body (Do not enter title and authors here): Background: Fibroblast activation protein (FAP) is abundantly expressed in cancer associated fibroblasts and contributes to extracellular matrix (ECM) remodeling. More recently, using imaging techniques, increased left ventricular (LV) FAP levels have been identified in patients at risk for developing heart failure. However, the role of FAP in terms regulating LV myocardial structure and underlying signaling pathways remains unclear. This project tested the hypothesis that genetic ablation of FAP would modify LV structure and function and would be pronounced with aging.

Methods and Results: Mice with FAP gene deletion (FAPKO, C57BL/6 background, 13 and 20 weeks of age, with equal sex distribution) and age matched wild type (WT, equal sex distribution) underwent LV echocardiography. Sample sizes and results are shown in Table. While LV ejection fraction and end-diastolic volume were within normal limits, LV mass to body weight ratio increased as did left atrial area. LV myocyte cross sectional area (CSA) increased in the FAPKO mice as did fibrillar collagen content. Transforming growth factor beta (TGF) and TGF intracellular signaling elements Smad-1 and -2 mRNA levels increased in the young FAPKO mice, as did evidence of fibroblast transdifferentiation (smooth muscle actin, SMA). Interestingly, natriuretic peptide B (NPPB) expression increased in both young and mature mice. In silico mapping and proteolytic assays identified NPPB as an FAP substrate.

Conclusion: FAP gene deletion in mice caused LV hypertrophy and fibrosis with transcriptional shifts in biological signaling pathways. These findings demonstrated for the first time that FAP, most commonly associated with cancer associated fibroblasts, and emerging evidence in HF patients, plays a role in maintaining a normal LV myocardial phenotype.