HYPERTROPHIC CARDIOMYOPATHY - A DESENSITIZED CARDIAC BETA-ADRENERGIC SYSTEM IN THE PRESENCE OF NORMAL PLASMA-CATECHOLAMINE CONCENTRATIONS

Only few data are available concerning the biochemical and functional state of the beta-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial beta-adrenergic s ignal transduction system in hypertrophic obstructive cardiomyopathy ( HOCM). Thin myocardial strips were prepared from surgically excised, s eptal myocardium from 7 patients with HOCM and their force of contract ion was measured in vitro. The positive inotropic effects of calcium a nd dihydro-ouabain, both acting independently of beta-adrenoceptors an d cAMP, were similar in these preparations to those, previously publis hed, seen with nonfailing myocardium. In contrast, the beta-adrenocept or agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl -1-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC(50)-values were about 10 fold higher than the respective EC(50)-va lues published for nonfailing myocardium. The positive inotropic poten cies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whethe r the functional alterations are related to changes in the beta-adreno ceptors, beta-adrenoceptor density and beta(1):beta(2)-adrenoceptor su btype distribution were determined in the same myocardium using I-125- Iodocyanopindolol saturation binding. Myocardial beta-adrenoceptor den sity was reduced to 68% in HOCM and to 56% in MR compared to nonfailin g myocardium controls (NF: 64.8 +/- 6.5 fmol/mg protein). In HOCM, thi s reduction was due to a selective down regulation of beta(1)-adrenoce ptors (24.9 +/- 3.7 fmol/mg protein vs NF: 46.4 +/- 6.8 fmol/mg protei n, P < 0.05), whereas beta(2)-adrenoceptor density was unchanged (19.0 +/- 1.9 fmol/mg protein vs NF: 18.4 +/- 3.3 fmol/mg protein, n.s.). I n MR both beta-adrenoceptor subtypes were reduced (beta(1): 26.9 +/- 1 .4 fmol/mg protein, beta(2): 9.6 +/- 1.7 fmol/mg protein; both P < 0.0 5 vs NF). Electrochemically determined plasma catecholamine levels wer e elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM. In summary, myocardial beta-adrenocepto rs are downregulated and their function is impaired in HOCM. This dese nsitization is not caused by a negative feedback regulation due to inc reased plasma catecholamines. The present results show that the desens itizations of the beta-adrenergic system associated with HOCM has char acteristics that indicate a major deviation in its development from th at of the beta-adrenergic desensitization previously described to occu r in congestive heart failure.