A POSTRECEPTOR DEFECT OF ADENYLYL-CYCLASE IN SEVERELY FAILING MYOCARDIUM FROM CHILDREN WITH CONGENITAL HEART-DISEASE

The aim of this study was to determine whether a defect at the post-re ceptor level of adenylyl cyclase may also contribute to the decreased effectiveness of cAMP-increasing agents in severely failing patients w ith congenital heart disease. The severity of congestive heart failure in 31 patients with congenital heart disease was graded by a scoring system which included a description of historical and clinical variabl es. Patients were divided into a group with no or mild heart failure ( score less than or equal to 6) and a group with severe heart failure ( score > 6), beta-Adrenoceptor-stimulated adenylyl cyclase activity was significantly decreased by 65% in patients with severe heart failure in comparison to the group of patients with no or mild heart failure. In addition, receptor-independent adenylyl cyclase stimulation by fors kolin was reduced by 52% in patients with score > 6 compared to patien ts with score less than or equal to 6. This post-receptor defect of ad enylyl cyclase was apparently due to a decrease in the activity of cat alytic subunit of adenylyl cyclase as adenylyl cyclase stimulation by forskolin in the presence of Mn2+ which uncouples catalytic subunit fr om the G proteins, G(s) and G(i), was also significantly diminished in the patients with severe heart failure. In contrast, the level of inh ibitory G protein alpha-subunits was apparently not different in the t wo groups. In summary, the data indicate that a defect at the catalyti c subunit of adenylyl cyclase apparently contributes to the decreased effectiveness of cAMP-increasing agents in severely failing patients w ith congenital heart disease. (C) 1997 Elsevier Science B.V.