Defective mobilization of Ca2+ by cardiomyocytes predisposes to cardiac insufficiency, but the causative mechanisms leading to congestive heart failure (HF) remain unclear. Here, we perform exhaustive global proteomic surveys of cardiac ventricle isolated from a mouse model of cardiomyopathy overexpressing a phospholamban mutant, R9C (PLN R9C) and exhibiting impaired Ca2+ handling and death at 24 weeks and compare them with normal control littermates. The relative expression patterns of 6190 high-confidence proteins were monitored by shotgun tandem mass spectrometry at 8, 16 and 24 weeks of disease progression. Significant differential abundance of 593 proteins was detected. These proteins mapped to select biological pathways such as ER-stress response, cytoskeletal remodeling and apoptosis, and included known biomarkers of HF (e.g. BNP/ANF, ACE) and other indicators of pre-symptomatic functional impairment. These altered proteomic profiles were concordant with cognate mRNA patterns recorded in parallel using high-density mRNA microarrays, and top candidates were validated by RT-PCR and Western-blotting. Mapping of our highest ranked proteins against a human diseased explant and to available datasets indicate that many of these proteins could serve as markers of disease. Indeed, we show that several of these proteins are detectable in mouse and human plasma, and display differential abundance in the plasma of diseased mice and affected patients. These results offer a systems-wide perspective of the dynamic mal-adaptions associated with impaired Ca2+ homeostasis that perturb myocyte function and ultimately converge to cause HF.