Distribution of Myocardial β‐Adrenoceptor Subtypes and Coupling to the Adenylate Cyclase in Children With Congenital Heart Disease and Implications for Treatment

In congestive heart failure, down‐regulation of myocardial β‐adrenoceptors (β‐AR) due to an elevated sympathetic tone is well known. In infancy and childhood, heart failure is usually related to congenital heart disease (CHD). Therefore, 71 samples of right atrial tissue of infants and children with CHD undergoing cardiac surgery were studied for β‐adrenoceptor density and distribution of the β 1 ‐/β 2 ‐AR subtypes. In 49 cases, the coupling of the β‐AR to the adenylate cyclase (AC) was examined. In a further study of 19 myocardial samples, AC was selectively stimulated with β 1 ‐ or β 2 ‐AR whereas the other subtype was blocked by an antagonist. The following results were obtained: (1) Infants and children with severe acyanotic or cyanotic CHD had severely reduced β‐AR densities. (2) In most of the cases, the β‐AR down regulation is β 1 ‐subtype selective, but in critically ill newborns with congenital aortic valve stenosis or transposition of the great arteries, there is additional significant β 2 ‐AR down‐regulation. In Fallot patients treated with the β‐antagonist propranolol, a significant increased β‐AR number compared with untreated Fallot patients was found. (3) β‐Adrenoceptor reduction in CHD is correlated with elevated noradrenaline plasma levels, thus proving a sympathetic dysregulation. (4) In CHD with moderate hemodynamic load, β 2 ‐AR coupling to AC was markedly more efficient than β 1 ‐AR coupling. The small number of myocardial β 2 ‐AR produced most of the cyclic adenosine monophosphate. (5) In severe acyanotic and cyanotic CHD, a partial decoupling of the β 2 ‐AR to the AC occurred. This may be a first step before β 2 ‐AR are reduced in number in severe cardiac failure. These results explain why catecholamine therapy in in/ants and children with CHD sometime fails. Because the contractile force can be increased by β 2 ‐AR, partial β 2 ‐agonists may improve cardiac performance in acute heart failure. The most appropriate drugs are those that modulate or bypass the neurohumoral pathomechanisms in chronic heart failure like angiotensin‐converting enzyme‐inhibitors, β‐AR antagonists, dopamine 2 ‐agonists, and phosphodiesterase‐inhibitors. Further studies are needed to validate the actions of these therapeutics in infants and children with CHD.