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Heart rupture and heart failure are deleterious complications of myocardial infarction. The ShcA gene encodes for three protein isoforms, p46-, p52- and p66ShcA. p66ShcA induces oxidative stress. We studied the role of p66ShcA post-infarction. Expression of p66ShcA was analyzed in myocardium of patients with stable angina (n = 11), in explanted hearts with end-stage ischemic heart failure (n = 9) and compared to non-failing hearts not suitable for donation (n = 7). p66ShcA was increased in the patients with stable angina, but not in the patients with end-stage heart failure. Mice (n = 105) were subjected to coronary artery ligation. p66ShcA expression and phosphorylation were evaluated over a 6-week period. p66ShcA expression increased transiently during the first weeks post-infarction. p66ShcA knockout mice (KO) were compared to wild type (n = 82 in total). KO had improved survival and reduced occurrence of heart rupture post-infarction. Expression of cardiac matrix metalloproteinase 2 (MMP-2) was reduced; fibroblast activation and collagen accumulation were facilitated, while oxidative stress was attenuated in KO early post-infarction. 6 weeks post-infarction, reactive fibrosis and left ventricular dilatation were diminished in KO. p66ShcA regulation of MMP-2 was demonstrated in cultured fibroblasts: lack or overexpression of p66ShcA in vitro altered expression of MMP-2. Myocardial infarction induced cardiac p66ShcA. Deletion of p66ShcA improved early survival, myocardial healing and reduced cardiac fibrosis. Upon myocardial infarction p66ShcA regulates MMP-2 activation. The role of p66ShcA in human cardiac disease deserves further study as a potential target for reducing adverse cardiac remodeling post-infarction.