Lack of fibronectin-EDA promotes survival and prevents adverse remodeling and heart function deterioration after myocardial infarction.

RATIONALE The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin-EDA (EIIIA; EDA) is upregulated after tissue injury and may act as a "danger signal" for leukocytes to cause adverse cardiac remodeling after infarction. OBJECTIVE In the present study, we evaluated the role of EDA in regulation of postinfarct inflammation and repair after myocardial infarction. METHODS AND RESULTS Wild-type and EDA(-/-) mice underwent permanent ligation of the left anterior coronary artery. Despite equal infarct size between groups (38.2±4.6% versus 38.2±2.9% of left ventricle; P=0.985), EDA(-/-) mice exhibited less left ventricular dilatation and enhanced systolic performance compared with wild-type mice as assessed by serial cardiac MRI measurements. In addition, EDA(-/-) mice exhibited reduced fibrosis of the remote area without affecting collagen production, cross-linking, and deposition in the infarct area. Subsequently, ventricular contractility and relaxation was preserved in EDA(-/-). At tissue level, EDA(-/-) mice showed reduced inflammation, metalloproteinase 2 and 9 activity, and myofibroblast transdifferentiation. Bone marrow transplantation experiments revealed that myocardium-induced EDA and not EDA from circulating cells regulates postinfarct remodeling. Finally, the absence of EDA reduced monocyte recruitment as well as monocytic Toll-like receptor 2 and CD49d expression after infarction. CONCLUSIONS Our study demonstrated that parenchymal fn-EDA plays a critical role in adverse cardiac remodeling after infarction. Absence of fn-EDA enhances survival and cardiac performance by modulating matrix turnover and inflammation via leukocytes and fibroblasts after infarction.