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

Abstract

In congestive heart failure, down-regulation of myocardial beta-adrenoceptors (beta-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 beta-adrenoceptor density and distribution of the beta 1-/beta 2-AR subtypes. In 49 cases, the coupling of the beta-AR to the adenylate cyclase (AC) was examined. In a further study of 19 myocardial samples, AC was selectively stimulated with beta 1- or beta 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 beta-AR densities. (2) In most of the cases, the beta-AR down regulation is beta 1-subtype selective, but in critically ill newborns with congenital aortic valve stenosis or transposition of the great arteries, there is additional significant beta 2-AR down-regulation. In Fallot patients treated with the beta-antagonist propranolol, a significant increased beta-AR number compared with untreated Fallot patients was found. (3) beta-Adrenoceptor reduction in CHD is correlated with elevated noradrenaline plasma levels, thus proving a sympathetic dysregulation. (4) In CHD with moderate hemodynamic load, beta 2-AR coupling to AC was markedly more efficient than beta 1-AR coupling. The small number of myocardial beta 2-AR produced most of the cyclic adenosine monophosphate. (5) In severe acyanotic and cyanotic CHD, a partial decoupling of the beta 2-AR to the AC occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress response and mode of ventilation in preterm infants

“…There is evidence that a persistent stress response may be detrimental. A reduction in cardiac beta adrenoceptor density has been demonstrated in infants and children with persistently elevated catecholamine concentrations due to cardiac failure secondary to congenital heart disease 20. This resulted in a failure to respond to catecholamine treatment and would compromise the effectiveness of further increases in endogenous catecholamines in response to external stressors.…”

Pharmacological support for children with myocardial dysfunction

“…The reason for this upregulation of β‐adrenoreceptors and sensitization of the signalling pathway in symptomatic children is unknown, though it does explain why β‐adrenoreceptor antagonists are of benefit in these patients. In patients treated with propanolol, β‐adrenoreceptor density is significantly higher than that in untreated patients (55). Experimental studies have also shown that chronic hypoxia can produce a decrease in the density of α 1A ‐adrenoreceptors and myocyte concentration of α 1C ‐adrenoreceptor mRNA (67).…”

“…Children in heart failure also have a reduced density of β‐adrenoreceptors compared to their matched controls (53,54). Most of the reduction in β‐adrenoreceptor density is due to a reduction in numbers of β 1 ‐adrenoreceptors, but a significant decrease in β 2 ‐adrenoreceptor density may also occur (55). The decrease in β 1 ‐adrenoreceptor density in the failing human ventricle is accompanied by a similar reduction in β 1 ‐adrenoreceptor mRNA levels, though β 2 ‐adrenoreceptor mRNA concentrations usually remain normal (56).…”

New Inotropic Pharmacologic Strategies Targeting the Failing Myocardiumin the Newborn and Infant

“…It was shown that in different congenital heart diseases, up-or down regulation of beta-adrenoreceptor subtypes occurs. Furthermore, the coupling of the betaadrenoreceptor subtypes to downstream signaling cascades also varies in different diseases [86][87][88]. This leads to a reduced reponse of the neonatal heart to catecholamines.…”