Heart failure (HF) is a major health problem in Western countries. Despite significant progress in pharmacological and device-based treatment, the disease burden imposed continues to increase, particularly as the population ages. HF incidence approaches 10 per 1000 after age 65 years. 1 Congestive HF is the final consequence of diverse cardiovascular disorders, including atherosclerosis, cardiomyopathy, and hypertension. Described as a complex pathophysiological syndrome that involves interactions of the circulatory, neurohormonal, and renal systems, HF is first a disease of the myocardium, although it soon induces defects in other systems. Current treatments for HF, focused on blocking neurohormonal pathways, improve survival, but they do not halt the progression of HF. Late-stage HF has a poor prognosis, and therapeutic options are limited. Faced with these challenges, researchers are exploring novel therapeutic options. Chronic HF is associated with increased sympathetic outflow, which may be compensatory early on, but long-term neurohormonal activation induces significant damage to the heart; in addition, it results in multiple alterations in the ß-adrenergic receptor (ß-AR) signaling cascade, including receptor downregulation, upregulation of receptor kinases, and increased inhibitory G-protein function. 2 The amplitude and velocity of Ca2+ cycling are regulated by a dynamic balance of phosphorylation and dephosphorylation through kinases and phosphatases. Activation of ß-ARs stimulates cAMP production and results in protein kinase A (PKA) phosphorylation of key regulators of excitationcontraction coupling, such as L-type Ca2+ channels, phospholamban, troponin I, ryanodine receptors (RyR), myosinbinding protein C, and protein phosphatase inhibitor-1 (I-1; Figure), which leads to increased amplitude and velocity of Ca2+ cycling and increased contractility on a beat-to-beat basis. 3 Protein phosphatases PP1 and PP2A counterbalance phosphorylation of these proteins. There is clear evidence that alterations in sarcoplasmic reticulum (SR) Ca2+ cycling are a component of the impaired contractile performance of the failing heart. 4, 5 The abnormal intracellular Ca2+ handling includes SR Ca2+ leak through the RyR, 6 decreased SR Ca2+ uptake, 7 and decreased SR content. Impaired SR Ca2+ uptake results from lower expression of the SR Ca2+ pump, SERCA2a (Sarco/endoplasmic reticulum Ca2+ ATPase), 7–9 and from an increased inhibitory function of phospholamban. 10 Furthermore, Ca2+, via the activation of various kinases and phosphatases, acts on Ca2+-dependent transcription pathways.