We recently developed a mouse model with a single functional allele of Serca2 (Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco (endo) plasmic reticulum Ca 2+-ATPase (SERCA) 2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/–mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that∼ 64% of coarcted Serca2+/–mice were in heart failure compared with 0% of coarcted wild-type mice (P< 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/–mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/–mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/–mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice (P< 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (> 50%) in coarcted Serca2+/–mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.