The β-adrenergic receptor/adenylyl cyclase/protein kinase A (PKA) axis is the central signaling pathway that serves to stimulate cardiac function. It is classically perceived as a linear signaling cascade (Figure), and cAMP is thought to be the second messenger responsible for the positive inotropic, chronotropic, and lusitropic effects of catecholamines. New data gained from a series of transgenic animals overexpressing various elements of this axis show that this system has a far more complex makeup than previously thought. Transgenic models of the cardiac β-adrenergic receptor/PKA system. The signaling cascade is represented as a simple linear chain. Proteins that are detrimental when overexpressed are shown in black; those causing beneficial effects upon overexpression are depicted in white. PLB indicates phospholamban. It has been known for about two decades that the β-adrenergic receptor system is dysfunctional in heart failure.1 The loss of receptor responsiveness has been attributed to a reduced β-receptor number, particularly of the β1-subtype, plus a functional desensitization of the remaining receptors—presumably mediated via increased activity of G protein–coupled receptor kinases.2 The extent of the receptor downregulation and the functional loss correlate with the severity of the disease.3,4 This phenomenon has long been regarded as detrimental to the compromised function of the failing heart, and it has been proposed that restoration of β-adrenergic receptor responsiveness might be a strategy to improve cardiac function. However, recent clinical studies and observations on a panel of transgenic animals suggest that the opposite is the case. Sustained stimulation or overexpression of cardiac β1-adrenergic receptors leads to hypertrophy, fibrosis, and heart failure,5–7 and blockade of β-adrenergic receptors with several antagonists—bisoprolol, carvedilol, and metoprolol—improves survival in heart failure patients.8 Thus, the loss of β-adrenergic receptor responsiveness in heart failure is more likely to represent a protective mechanism than …