Circulation, Vol 88, 2501-2509, Copyright © 1993 by American Heart Association
SL Beau, TK Tolley and JE Saffitz
BACKGROUND. Downregulation of myocardial beta-adrenergic receptor density
does not occur in a spatially uniform distribution in patients with
congestive heart failure. Rather, it results primarily from loss of
receptors in the subendocardium. In patients with dilated cardiomyopathy,
beta 1-receptors have been found to be downregulated selectively. These
observations suggest that considerable transmural heterogeneity in the
distribution of beta-adrenergic receptor subtypes exists in the failing
human heart. The present study was designed to test this hypothesis.
METHODS AND RESULTS. We used quantitative autoradiography of radioligand
binding sites to measure the distribution of beta-adrenergic receptor
subtypes in transmural sections of left ventricular myocardium obtained
from cardiac transplant patients with ischemic (n = 13) and idiopathic
dilated (n = 12) cardiomyopathy and from 4 subjects with no history of
cognitive heart failure. Analysis of radioligand binding isotherms revealed
a significant reduction in total beta-adrenergic receptor density in hearts
of patients with ischemic and idiopathic cardiomyopathy (20.3 +/- 1.9 and
18.2 +/- 2.0 fmol/mg protein, respectively, versus 40.0 +/- 11.4 in control
subjects; P < .01 for both). Loss of the beta 1-subtype accounted for
86% of the total reduction in beta-receptor density in failing hearts.
Despite the significant decreases in overall tissue receptor content, the
densities of total beta-receptors and beta- receptor subtypes in
subepicardial myocytes were equivalent in failing and control hearts.
However, in contrast to control hearts, in which the transmural
distribution of total and beta 1-receptors was uniform (endocardial:
epicardial receptor density ratios, 0.97 +/- 0.14 and 1.0 +/- 0.2,
respectively), hearts of patients with ischemic and idiopathic dilated
cardiomyopathy had significantly lower total beta-receptor and beta
1-receptor densities in the subendocardium (ratios, 0.66 +/- 0.06 and 0.46
+/- 0.09 for total and beta 1-receptors, respectively, in ischemic
cardiomyopathy and 0.60 +/- 0.08 and 0.52 +/- 0.11 in dilated
cardiomyopathy; P < .001 for all values compared with a ratio of 1).
Thus, beta 1: beta 2 receptor density ratios were markedly decreased in the
subendocardium of ischemic and idiopathic dilated left ventricles compared
with control hearts. CONCLUSIONS. A significant transmural gradient in the
density of myocardial beta 1-adrenergic receptors exists in the hearts of
patients with ischemic and dilated cardiomyopathy, resulting in a markedly
altered beta 1: beta 2 receptor density ratio in the subendocardium.
ARTICLES
Heterogeneous transmural distribution of beta-adrenergic receptor subtypes in failing human hearts
Department of Pathology, Washington University School of Medicine, St Louis, Mo 63110.
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