Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation

Abstract

Antibodies specific for the beta(1)-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these antibodies actually contribute to the pathogenesis of chronic heart failure. This commentary discusses mechanisms by which these antibodies may engender cardiomyopathy.

Figure 1

Schema for β₁-AR–mediated cardiomyocyte stimulation and β₁-AR desensitization. The seven-membrane-spanning β₁-AR is stimulated by the physiologic agonist norepinephrine or by IgG specific for the receptor’s second extracellular loop (ECII) (in CHF subjects). The stimulated β₁-AR then activates the heterotrimeric G_s, which dissociates into its Gα_s* and Gβγ substituents. The Gα_s* activates both adenylyl cyclase (AC), which catalyzes cAMP formation, and the L-type calcium channel (L), which then permits Ca²⁺ to enter the cardiomyocyte. This Ca²⁺ can both augment contractility and, on a slower time scale, promote cardiomyocyte apoptosis by activating Ca²⁺/calmodulin kinase II (CaMK II). The cAMP produced by adenylyl cyclase activates PKA, which subsequently phosphorylates (P) numerous substrates important to sarcoplasmic [Ca²⁺] regulation: the L-type Ca²⁺ channel, the ryanodine receptor (RyR), and phospholamban (PLB). The net effect of this activity in the short term is to augment sarcoplasmic [Ca²⁺] and contractility. (In the long term, this activity engenders cardiomyocyte toxicity.) The activated β₁-AR is desensitized when it is phosphorylated by PKA (not shown) and by GRK2, the cellular expression of which increases with chronic β₁-AR stimulation. Translocation of GRK2 from the sarcoplasm to the sarcolemma requires Gβγ subunits, and this translocation is inhibited when GRK2ct is expressed heterologously in cardiomyocytes. Asterisks denote activated proteins.