Failing Human Heart

Background. In chronic heart failure, the positive inotropic effects of -adrenergic receptor agonists are greatly reduced, in part as a result of two alterations of the cardiac -adrenergic receptors: loss of their function (receptor uncoupling) and reduction of their number (downregulation). In vitro studies have shown that a major mechanism leading to fadrenergic receptor uncoupling involves phosphorylation of the receptors by the specific f8-adrenergic receptor kinase (.BARK). Methods and Results. We have therefore investigated expression of BARK and 13-adrenergic receptors in samples from the left ventricles of patients with dilated cardiomyopathy or ischemic cardiomyopathy and from nonfailing control ventricles. Contractile responses to P-receptor stimulation were decreased in the failing hearts compared with control hearts, whereas those to forskolin and calcium remained unchanged. The messenger RNA (mRNA) levels of j3ARK, 1,and P2-receptors, and of glyceraldehyde phosphate dehydrogenase and P-actin as controls were measured by quantitative polymerase chain reactions. In addition, P3ARK enzyme activity assays were performed, and the levels of PIand 32-receptors were determined by radioligand binding. PARK mRNA levels were increased almost threefold in both forms of heart failure, and PARK activity was enhanced. f3-Receptor mRNA levels and f3-receptor numbers were decreased by -50% in both failing groups, whereas these levels were unaltered for j3-receptors. There were no differences between dilated and ischemic cardiomyopathy for any of these parameters. Conclusions. In addition to other alterations found in failing hearts, the diminished response to 1-receptor agonists appears to involve the combined effects of enhanced expression of P3ARK and reduced expression of .13-receptors. (Circulation 1993;87:454-463) KEY WoRDs * heart failure * receptors, fi-adrenergic * kinase, 3-adrenergic receptor * RNA,