What Is the Role of &bgr;-Adrenergic Signaling in Heart Failure?

Abstract— This review addresses open questions about the role of &bgr;-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three &bgr;-adrenergic receptor subtypes—&bgr;1, &bgr;2, and, at least in some species, &bgr;3. The &bgr;1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The &bgr;2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the &bgr;1 subtype. In heart failure, the sympathetic system is activated, cardiac &bgr;-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, &bgr;-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the &bgr;-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.