The β₁-adrenergic receptor/calcium connection. β₁-adrenergic receptor (β₁AR) stimulation is known to activate cardiac excitation-contraction (EC) coupling via PKA phosphorylation of the following: (I) the trigger for cardiac EC coupling, the voltage-gated calcium channel (VGCC); (II) the SR calcium release channel RyR2; and (III) the calcium uptake pathway (via PKA phosphorylation of phospholamban, which reduces inhibition of the calcium ATPase SERCA2a). Activation of these proteins by PKA phosphorylation increases systolic SR calcium release which causes both increased cardiac contraction and output. This system results in a maladaptive chronic hyperadrenergic state in heart failure because the damaged heart cannot respond adequately to the adrenergic stimulation and the sympathetic nervous system remains in a futile activated state. This results in PKA-hyperphosphorylated RyR2 channels that can cause a diastolic SR calcium leak (4), which, along with reduced SERCA2a-dependent SR calcium uptake, depletes SR calcium and contributes to contractile dysfunction. Zhou et al. (5) have now added an additional component to this model based on observations that chronic β₁AR stimulation can activate CaMKII (possibly via increased calcium influx through the VGCC) and cause apoptosis.