Myocardial dysfunction leading to heart failure is a major cause of death due to endotoxemia and sepsis. Mammalian adaptation to stressors is mediated primarily by Corticotropin Releasing Hormone or Factor (CRH/CRF) and the corresponding activation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, we demonstrate for the first time that mice genetically deficient in CRH (Crh-/-), exhibit defective responses following systemic exposure to lipopolysaccharide (LPS). Intriguingly, Crh-/- mice showed unexpected elevated levels of mortality (90-100% 16-28h post-LPS treatment), compared to no mortality observed among their wild-type (Crh + / + ) littermates. Crh-/- mice have significantly reduced EF and FS (60%) values, histological abnormalities, including perivascular fibrosis, increased vasculature, vascular thickness and hyperplastic intima, and rate of cardiomyocytes' apoptosis after LPS administration compared to Crh + / + mice. LPS treatment induces MMP-8 and MMP-13 expression in Crh-/- mice, suggestive of myofibrillar dysfunction. Corticosterone administration to correct the glucocorticoid insufficiency of Crh-/- mice did not rescue them from LPS-induced mortality or ameliorate the cardiac function indices. We found that CRH is expressed in both atria and ventricles. In further support of the impact of Crh deficiency in cardiac function, Crh-/- mice have lower FS and EF values in basal state. Crh + /- exhibit intermediate phenotype. Comparison of microarray results of Crh + / + and Crh-/- cardiac tissue revealed differences in genes involved in lipid metabolism, cell proliferation and extracellular matrix organization processes. Our preliminary real time PCR results show significantly lower levels of PPARα, PPARgamma, AMPKα, and Cpt1b in Crh-/- heart suggestive of their impaired metabolic activity. As known, the heart relies mostly on fatty acids for its energy demands, a process altered in states of increased stress such as ischemia and heart failure. Based on the above findings, our working hypothesis is that CRH may play a fundamental role in cardiac function and its adaptation to increased metabolic demands, which is unmasked in states of increased stress such as infections. On-going studies in mice and human cells aim to elucidate the exact role of CRH in normal cardiac development and function and its putative use in cardioprotection in states of altered metabolic demands.