Here, we examined the influence of Epac1 on the phosphorylation of myofilament-associated proteins, and its effects on the contractility of cardiac myofilaments, Ca2+ sensitivity of force and ATPase activity in skinned myocardium, and its role in the pathogenesis of heart failure by means of a series of studies in transgenic mice with cardiac-specific overexpression of Epac1 (Epac1TG) as well as in wild-type (WT) control mice by activating endogenous Epac1 with 8-(4-chlorophenylthio)-2’-O-Me-cAMP-AM (8CPT-AM), an Epac-specific cAMP activator. Here, RAPGEF3 is linked to heart failure.