Abstract Body: Approximately one third of the population in the US has metabolic syndrome (MetS), a condition associated with increased risk for coronary artery disease and myocardial infarction. But whether MetS alters properties of the myocardium before the occurrence of ischemic insults remains to be fully elucidated. For this purpose, MetS was induced in C57Bl/6 female mice with a dietary paradigm recapitulating Western-style alimentary habits in humans. Animals on regular chow were used as control (Ctrl). Cardiac function was assessed by echocardiography and myocytes were studied under field stimulation, following enzymatic dissociation. From 3-12 months on the diet, MetS mice had increased body weight, impaired glucose metabolism, augmented left ventricular (LV) mass, but preserved cardiac function, with respect to Ctrl mice. Using ECGs, heart rate variability was attenuated in MetS mice, suggesting that metabolic disorders alter cardiac sympathovagal balance. At the cellular level, LV myocytes from MetS mice had increased volume (+24%), enhanced fractional cell shortening (+42%), and faster kinetics of relaxation (-27%), with respect to Ctrl myocytes. Because cAMP and protein Kinase A (PKA) modulates myocardial contractility upon activation of G-protein coupled receptors, including beta-adrenergic receptors (B-AR), levels of these molecules were assessed by ELISA assay. Consistent with enhanced cell shortening and faster relaxation, levels of cAMP and PKA activity were, respectively, 1.8-fold and 1.9-fold larger in MetS myocytes, in comparison to Ctrl cells. Interestingly, inhibition of PKA with H-89 reduced cell shortening (-30%) and delayed kinetics of relaxation (+50%) in MetS myocytes but had no major effects on Ctrl cells. To establish the contribution of the cAMP/PKA signaling in the functional behavior of the heart with MetS, mice were treated with the B-AR blocker propranolol. Under this condition, MetS mice had reduced ejection fraction and impaired indices of diastolic function, with respect to Ctrl animals. Interestingly, myocytes obtained from Ctrl and MetS mice treated with the B-AR blocker had comparable cell shortening and kinetics of relaxation. Collectively, these results indicate that metabolic syndrome alters the functional properties of the myocytes and heart by affecting cAMP homeostasis. These properties may increase myocardial oxygen demand predisposing the heart to ischemic insults.